WO2000010546A2 - Nouveau traitement de maladies neurodegeneratives - Google Patents

Nouveau traitement de maladies neurodegeneratives Download PDF

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WO2000010546A2
WO2000010546A2 PCT/EP1999/006241 EP9906241W WO0010546A2 WO 2000010546 A2 WO2000010546 A2 WO 2000010546A2 EP 9906241 W EP9906241 W EP 9906241W WO 0010546 A2 WO0010546 A2 WO 0010546A2
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arginine
analog
arg
dex
cell
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PCT/EP1999/006241
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WO2000010546A3 (fr
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Maria Griselda Canteros
Osborne F. X. Almeida
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MAX-PLANCK-Gesellschaft zur Förderung der Wissenschaften e.V.
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Priority to AU58547/99A priority Critical patent/AU5854799A/en
Publication of WO2000010546A2 publication Critical patent/WO2000010546A2/fr
Publication of WO2000010546A3 publication Critical patent/WO2000010546A3/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
    • A61K31/185—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]
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates generally to the modulation of apoptotic cell death.
  • the present invention provides pharmaceutical compositions comprising D-arginine or an analog thereof which are particularly useful for treating, preventing and/or delaying neuronal cell death.
  • the present invention also relates to a method for treating, preventing and/or delaying neuronal cell death in a subject comprising administering to a subject D-arginine or an analog thereof.
  • the present invention further involves the use of D-arginine or an analog thereof for the preparation of pharmaceutical compositions for the treatment of neurodegenerative diseases.
  • the present invention relates to food, feed and supplements therefor comprising D-arginine or an analog thereof.
  • the present invention relates to methods for identifying and obtaining neuroprotective drugs.
  • Apoptosis is an active, genetically controlled process that removes unwanted or damaged cells and plays a pivotal role of many diseases (Thatte, Drugs 54 (1997), 511-532). Much effort has been spent in order to investigate various factors that are responsible for and/or capable of inducing apoptosis which in turn leads to the manifestation of different kinds of disorders and diseases. For example, apoptosis is associated with a number of brain diseases (for general reviews, see: Hajimohamadreza & Treherne, Prog. Drug Res.
  • AIDS and neurodegenerative disorder like Alzheimer's or Parkinson's disease represent the most widely studied group of disorders where an excess of apoptosis has been implicated.
  • Amyotrophic lateral sclerosis, retinitis pigmentosa, epilepsy and alcoholic brain damage are other neurological disorders in which apoptosis has been implicated.
  • glucocorticoids are known to induce apoptosis.
  • the hippocampus is a major brain target of glucocorticoids (GC).
  • Hippocampal CR contribute to the maintenance of homeostasis within the hypothalamo-pituitary- adrenal axis (HPA axis), in addition to mediating GC effects on behaviour and cognition in health and disease 1 , 2
  • Two types of CR, mineralocorticoid (MR; Type I) and glucocorticoid (GR; type II) receptors mediate GC actions. Acting in apparently opposing modes, both, MR and GR are involved in the maintenance of the structural integrity of the dentate gy s (DG), a subfield of the hippocampus.
  • DG dentate gy s
  • Glucocorticoid (GC) actions in the brain range from effects on cognition, mood and behavior to the regulation of immunity and the endocrine response to stress.
  • excessive GC concentrations have been shown to lead to hippocampal cell death, a phenomenon which may have negative consequences for mental health and physiological homeostasis (Lupien and McEwen, Brain Res. Brain Res. Rev. 24 (1997), 1 ; Herbert, Br. Med. J. 315 (1997), 530; Turnbull, Physiol. Rev. 79 (1999), 1 ).
  • the classical mechanism of GC action involves gene transcription, but there is now convincing evidence that some GC actions may be mediated by fast- signaling pathways.
  • GC can cause rapid membrane depolarization by stimulating Ca 2+ influx in neurons.
  • This latter effect has been proposed to contribute significantly to GC-mediated neuronal death (Joels and Vreugdenhil, Mol. Neurobiol. 17 (1998), 87; Nair, Werkman, Craig, Finnell, Joels et al., Neurosci. 18, 2685; Porter and Landfield, Nature Neurosci. 1 (1998), 3; Turner, Prog. Brain Res. 116 (1998), 3).
  • increases in intracellular Ca 2+ are also known to activate several enzyme systems implicated in cell death.
  • nitric oxide synthase neuronal and endothelial nitric oxide synthase
  • ROS reactive oxygen species
  • the technical problem of the present invention is to provide compositions and methods useful for protecting the human or animal body from neuronal cell damaging effects such as apoptosis, in particular from neurodegenerative processes that follow endogenous or exogenous insults to the brain.
  • the solution to this technical problem is achieved by providing the embodiments characterized in the claims.
  • the present invention is based on the observation that the D-isomer of arginine is capable of protecting neuronal cells from apoptotic cell death.
  • the apoptosis and 5HT IA receptor down-regulation which occurs in the hippocampus of rats treated with glucocorticoids (GC) involves activation of neuronal nitric oxide synthase (nNOS) and production of damaging free radicals.
  • GC act by altering nNOS substrate (L-arginine) availability by altering the expression of cationic amino acid transporter 1 and 2 proteins (CAT1 and CAT2).
  • the invention provides a pharmaceutical composition comprising D-arginine or an analog thereof and optionally a pharmaceutically acceptable carrier.
  • the invention provides methods and uses for treating, preventing and/or delaying neuronal cell death in a subject comprising administering to the subject an effective amount of D-arginine or an analog thereof.
  • the invention provides a method for screening neuroprotective drugs.
  • compositions, methods and uses of the invention are useful for the treatment of apoptotic cell death, especially those involved in neurodegenerative diseases and disorders.
  • Glucocorticoids have many deleterious actions on the brain, notably, stimulation of apoptosis and down-regulation of serotonergic (5HT-IA) receptors in the dentate gyms of the hippocampus, in addition to disruption of hypothalamic- pituitary-adrenal (HPA) axis regulation.
  • 5HT-IA serotonergic
  • HPA hypothalamic- pituitary-adrenal
  • the biological actions of GC are attenuated following inhibition of neuronal nitric oxide synthase (nNOS), indicating a role for nitric oxide (NO) and the associated production of damaging free radicals.
  • nNOS neuronal nitric oxide synthase
  • D-arginine which has until now been considered to be biologically inactive, can counteract the observed GC actions.
  • GC treatment stimulates the expression of cationic amino transporter (CAT) genes and increases transport of L- Arg from glial to neuronal cells; this, together with a rise in nNOS synthesis and activity, and therefore, an overproduction of damaging ROS.
  • D-arginine (D-Arg) hitherto thought to be biologically inactive, can significantly attenuate the detrimental effects of GC on hippocampal cell loss and 5-HTiA-R concentrations. It would be shown that D-Arg abrogates GC- and L- Arg-stimulated increases in CAT gene expression, thus effectively blocking their stimulation of nNOS activity and ROS generation.
  • the present invention provides a novel way to exploit the benefits of GC and other drug therapy while bypassing their detrimental effects. Accordingly, the invention relates to a pharmaceutical composition comprising D- arginine or an analog thereof, and optionally a pharmaceutically acceptable carrier.
  • D-arginine administration antagonizes and/or neutralizes the effects of harmful free radicals such as those produced in the nitric oxide signaling pathway and blocks the neurodegenerative actions of glucocorticoids, without compromising the desired therapeutic actions of glucocorticoids in the periphery.
  • Apparent differences in the ability of the brain vs. peripheral tissues to respond to D-arginine indicates that D- arginine supplementation or administration as an adjunct therapy will lead to neuroprotection without reducing the peripheral efficacy of drugs with the potential to generate free radicals.
  • D-Arg can interfere with increased neuronal availability of L-Arg after GC treatment, thereby reducing the harmful effects of GC in the brain.
  • neurodection is not restricted to only morphologically-evident degeneration of neural tissue but includes maintenance and enhancement of the neurochemical substrates which underlie proper functioning of the nervous system.
  • the present invention is based on the novel and unexpected finding that D-arginine can reverse GC-stimulated neuronal apoptosis and GC inhibition of 5-HT 1A receptor binding and therefore, can functionally antagonize the deleterious actions of GC in the brain.
  • NO a mediator of GC effects in the hippocampus was shown by the ability of DEX to stimulate nNOS activity. This GC effect was reversed by 7-NI, a specific inhibitor of the neuronal isoform of NOS; see Example 1.
  • 7-NI a specific inhibitor of the neuronal isoform of NOS
  • Two other brain actions of GC, namely, the stimulation of apoptosis among dentate granule cells and the reduction of 5-HT-IA receptor binding in the hippocampus were also attenuated by 7-NI.
  • the involvement of NO mechanisms in GC actions has two important aspects. Although most GC actions are manifest rather slowly since they depend upon nuclear receptor activation, rapid actions, involving changes in membrane potential, have also been described.
  • NO can serve as a diffusible, fast-acting neurotransmitter by altering ion channel opening
  • the results presented here suggest that the electrophysiological actions of GC may, but not necessarily exclusively, occur secondarily to NO production.
  • NO is a free radical which has been implicated in the cascade leading to apoptosis. It is nevertheless important to note that the formation of other cell- damaging free radicals can occur through NOS 8, 9 ; thus, since DEX can stimulate nNOS activity, its apoptotic actions are not necessarily mediated by NO exclusively.
  • D-arginine and analogs thereof can be used in order to counteract the GC mediated cytotoxic effects of free radicals such as nitric oxide and superoxides and therefore is useful for the treatment of, e.g., Hypoxia-ischemia and neural injuries and in general for the treatment of apoptosis; see, e.g., Hall, J. Emergency Medicine 11 (1993), 31-36; Xia, Proc. Natl. Acad. Sci. USA 93 (1996), 7670-7674; Juurlink, Neuroscience and Biobehavioral Reviews 21 (1997), 151-166. Further applications are described in, for example, Beckman, Physiological Reviews 78 (1998), 548-581 and Thatte, supra.
  • D-arginine is capable of obviating severe side-effects of hormone treatment, such as glucocorticoids
  • hormone treatment such as glucocorticoids
  • D-arginine and analogs thereof can be used as an adjunct therapy, i.e. in combination with therapeutic agents so as to reduce the potentially health damaging effects of therapeutic agents in the brain or other neuronal tissues while retaining their desired therapeutic action.
  • Various therapeutic agents can be used in combination with D-arginine and analogs thereof.
  • the potential of therapeutic agents to generate cytotoxic free radicals is known to the person skilled in the art, e.g., (i) levodopa for treatment of Parkinson's disease - Ogawa, Eur. Neurol. 34 Suppl.
  • analog of D-arginine means molecules the chemical structure of which is based on that of D-arginine and which are capable of inducing neuroprotective effects as described above.
  • the neuroprotective effects of the D-arginine-derived compounds may even be enhanced as compared to those of D-arginine.
  • the action of the D- arginine analogs employed in accordance with the present invention may not be limited to the above-described property but they may also be active, for example, in endothelial cells. Methods for the preparation of such analogs are well known to those skilled in the art and are described in, for example, Beilstein, Handbook of Organic Chemistry, Springer edition New York Inc., 175 Fifth Avenue, New York, N.Y.
  • said analog is capable of reducing CAT1 and/or CAT2 expression or activity which can be tested in accordance with Example 5.
  • Such analogs also include the D-isomers of L- arginine analogs such as described, e.g., in Feelisch & Stamler, supra, at page 190, Table 1. If any of the L-arginine analogs prove to exhibit the neuroprotective effect of D-arginine, they are regarded for the purpose of the invention as being analogs of D-arginine and, therefore, are also included within the scope of the present invention.
  • D-arginine is preferably used in the pharmaceutical compositions, uses and methods of the invention. However, some analogs of D-arginine may also prove more potent.
  • any of the aforementioned D-arginine analogs as well as those described below can be tested for the capability of inducing neuroprotective effects according to methods known in the art such as described in Feelisch & Stamler, supra, or in the appended examples.
  • any D-arginine analog as defined above namely which is capable of exerting neuroprotective effects such as abrogating apoptosis can be used for the purpose of the present invention.
  • the analog of D-arginine is an N ⁇ - and/or N G - subustituted D-arginine such as N ⁇ -methy, -dimethyl, -ethyl, -nitro, -hydroxy or - amino D-arginine or N G -hydroxy-D-arginine.
  • N ⁇ - derivatives may be biologically more potent than N G -derivatives.
  • D-arginine and analogs thereof to be employed in the pharmaceutical compositions, methods and uses of the present invention may be obtained from various commercial sources or produced as described in the prior art.
  • analogs of D-arginine include compounds that have been obtained by mimetics and molecules that comprise D- arginine or an analog thereof, e.g., peptides, preferably dipeptides that may be modified by, e.g., chemical means but essentially retain neuroprotective function. The same may hold true for oligopeptides or polypeptides containing D-arginine or an analog thereof.
  • Appropriate mimetics of D-arginine and other neuroprotective agents can also be identified by the synthesis of arginine based mimetic combinatorial libraries through, e.g., successive alkylation and testing the resulting compounds, e.g., according to the methods described herein and in the appended examples.
  • D-arginine a three-dimensional and/or (x-ray) crystallographic structure of D- arginine can be used for the design of mimetic agents (Rose, Biochemistry 35 (1996), 12933-12944; Rutenber, Bioorg. Med. Chem. 4 (1996), 1545-1558).
  • analogs of D-arginine which are arginine unrelated xenobiotics can be identified according to the screening method of the invention described herein below.
  • the invention relates to a method for treating, preventing and/or delaying neuronal cell death in a subject comprising administering to a subject an effective amount of D-arginine or an analog thereof.
  • This method also includes, e.g., contacting cerebral organs, tissue or cells with D-arginine or an analog thereof.
  • the respective organ may be kept alive in the presence of the above described compounds. This is because of the possibility that D-arginine or an analog thereof will act against free radical- induced tissue damage, both after transplant surgery but also during the recovery, storage and transportation of donor cells/tissue.
  • D-arginine analogs supplements may be useful in cell preparative and growing media for the same reason, e.g., it is known that cell survival upon removal from the organism is compromised due to tissue damage-associated release of excitatory amino acids (e.g. glutamate).
  • excitatory amino acids e.g. glutamate
  • neuroneuronal cell death denotes a disorder of the body, in particular the central nervous system and includes both open or penetrating head trauma, such as by surgery, or a closed head trauma injury, such as by an injury to the head region and in particular effects of harmful free radicals such as those produced in the nitric oxide signaling pathway. Also included within this definition is ischemic stroke, particularly to the brain area.
  • ischemic stroke may be defined as a focal neurologic disorder that results from insufficient blood supply to a particular brain area, usually as a consequence of an embolus, thrombi, or local atheromatous closure of the blood vessel.
  • embolus a focal neurologic disorder that results from insufficient blood supply to a particular brain area
  • thrombi a focal neurologic disorder that results from insufficient blood supply to a particular brain area
  • local atheromatous closure of the blood vessel usually as a consequence of an embolus, thrombi, or local atheromatous closure of the blood vessel.
  • the role of inflammatory cytokines in this have been emerging and the present invention provides a means for the potential treatment of these injuries. Relatively little treatment, for an acute injury such as these has been available.
  • the invention relates to the use of D-arginine or an analog thereof for the preparation of a pharmaceutical composition for preventing, treating and/or delaying neuronal cell death.
  • Said pharmaceutical compositions can be used, for example, in the brain with compounds which utilize, e.g., GC mediated (damaging) free radical-generating mechanisms for exerting their desired actions.
  • D-arginine or an analog thereof, pharmaceutically acceptable salts thereof and pharmaceutical compositions incorporating such may conveniently be administered by any of the routes conventionally used for drug administration, for instance, orally, topically, parenterally or by inhalation.
  • Acceptable salts comprise acetate, methylester, HCI, sulfate, chloride and the like.
  • D-arginine or an analog thereof may be administered in conventional dosage forms prepared by combining D-arginine or an analog thereof with standard pharmaceutical carriers according to conventional procedures.
  • D-arginine or an analog thereof may also be administered in conventional dosages in combination with a known, second therapeutically active compound.
  • Such therapeutically active compounds comprise, for example, those mentioned above.
  • the pharmaceutical 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 pharmaceutical carrier employed may be, for example, either a solid or liquid. Examplary of solid carriers are lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and the like.
  • liquid carriers are phosphate buffered saline solution, syrup, oil such as peanut oil and olive oil, water, emulsions, various types of wetting agents, sterile solutions and the like.
  • the carrier or diluent may include time delay material well known to the art, such as glyceryl mono-stearate or glyceryl distearate alone or with a wax.
  • time delay material well known to the art, such as glyceryl mono-stearate or glyceryl distearate alone or with a wax.
  • a wide variety of pharmaceutical forms can be employed.
  • the preparation can be tableted, placed in a hard gelatin capsule in powder or pellet form or in the form of a troche or lozenge.
  • the amount of solid carrier will vary widely but preferably will be from about 25 mg to about 1 g.
  • the preparation When a liquid carrier is used, the preparation will be in the form of a syrup, emulsion, soft gelatin capsule, sterile injectable liquid such as an ampule or nonaqueaous liquid suspension.
  • D-arginine or an analog thereof may be administered topically, that is by non- systemic administration. This includes the application of D-arginine or an analog thereof externally to the epidermis or the buccal cavity and the instillation of such a compound into the ear, eye and nose, such that compound does not significantly enter the blood stream.
  • systemic administration refers to oral, intravenous, intrape toneal and intramuscular administration.
  • Formulations suitable for topical administration include liquid or semi-liquid preparations suitable for penetration through the skin to the site of inflammation such as liniments, lotions, creams, ointments or pastes, and drops suitable for administration to the eye, ear or nose.
  • the active ingredient may comprise, for topical administration, from 0.001% to 10% w/w, for instance from 1% to 2% by weight of the formulation. It may however comprise as much as 10% w/w but preferably will comprise less than 5% w/w, more preferably from 0.1% to 1% w/w of the formulation.
  • Lotions according to the present invention include those suitable for application to the skin or eye which are suitable, for example, for use in UV protection.
  • An eye lotion may comprise a sterile aqueous solution optionally containing a bactericide and may be prepared by methods similar to those for the preparation of drops.
  • Lotions or liniments for application to the skin may also include an agent to hasten drying and to cool the skin, such as an alcohol or acetone, and/or a moisturizer such as glycerol or an oil such as castor oil or arachis oil.
  • Creams, ointments or pastes according to the present invention are semi-solid formulations of the active ingredient for external application. They may be made by mixing the active ingredient in finely-divided or powdered form, alone or in solution or suspension in an aqueous or non-aqueous fluid, with the aid of suitable machinery, with a greasy or non-greasy base.
  • the base may comprise hydrocarbons such as hard, soft or liquid paraffin, glycerol, beeswax, a metallic soap; a mucilage; an oil of natural origin such as almond, corn, arachis, castor or olive oil; wool fat or its derivatives or a fatty acid such as steric or oleic acid together with an alcohol such as propylene glycol or a macrogel.
  • the formulation may incorporate any suitable surface active agent such as an anionic, cationic or non- ionic surfactant such as a sorbitan ester or a polyoxyethylene derivative thereof.
  • Suspending agents such as natural gums, cellulose derivatives or inorganic materials such as silicaceous silicas, and other ingredients such as lanolin, may also be included.
  • Drops according to the present invention may comprise sterile aqueous or oily solutions or suspensions and may be prepared by dissolving the active ingredient in a suitable aqueous solution of a bactericidal and/or fungicidal agent and/or any other suitable preservative, and preferably including a surface active agent.
  • the resulting solution may then be clarified by filtration, transferred to a suitable container which is then sealed and sterilized by autoclaving or maintaining at 98- 100°C for half an hour.
  • the solution may be sterilized by filtration and transferred to the container by an aseptic technique.
  • bactericidal and fungicidal agents suitable for inclusion in the drops are phenylmercuric nitrate or acetate (0.002%), benzalkonium chloride (0.01%) and chlorhexidine acetate (0.01 %).
  • Suitable solvents for the preparation of an oily solution include glycerol, diluted alcohol and propylene glycol.
  • D-arginine or an analog thereof may be administered parenterally, that is by intravenous, intramuscular, subcutaneous intranasal, intrarectal, intravaginal or intraperitoneal administration.
  • the subcutaneous and intramuscular forms of parenteral administration are generally preferred.
  • Appropriate dosage forms for such administration may be prepared by conventional techniques.
  • D-arginine or an analog thereof may also be administered by inhalation, that is by intranasal and oral inhalation administration.
  • Appropriate dosage forms for such administration such as an aerosol formulation or a metered dose inhaler, may be prepared by conventional techniques.
  • the daily oral dosage regimen will preferably be from about 0.1 to about 80 mg/kg of total body weight, preferably from about 0.2 to 30 mg/kg, more preferably from about 0.5 mg to 15 mg.
  • the daily parenteral dosage regimen about 0.1 to about 80 mg/kg of total body weight, preferably from about 0.2 to about 30 mg/kg, and more preferably from about 0.5 mg to 15 mg/kg.
  • the daily topical dosage regimen will preferably be from 0.1 mg to 150 mg, administered one to four, preferably two to three times daily.
  • the daily inhalation dosage regimen will preferably be from about 0.01 mg/kg to about 1 mg/kg per day.
  • the optimal quantity and spacing of individual dosages of D-arginine or an analog thereof or a pharmaceutically acceptable salt thereof will be determined by the nature and extent of the condition being treated, the form, route and site of administration, and the particular patient being treated, and that such optimums can be determined by conventional techniques. It will also be appreciated by one of skill in the art that the optimal course of treatment, i.e., the number of doses of D- arginine or an analog thereof or a pharmaceutically acceptable salt thereof given per day for a defined number of days, can be ascertained by those skilled in the art using conventional course of treatment determinations tests. The dosage regimen will be determined by the attending physician and other clinical factors.
  • dosages for any one patient depends upon many factors, including the patient's size, body surface area, age, the particular compound to be administered, sex, time and route of administration, general health, and other drugs being administered concurrently. Progress can be monitored by periodic assessment.
  • the pharmaceutical compositions, methods and uses of the invention may be employed for diseases wherein said cell death is caused by free radical-associated diseases such as any of the above mentioned diseases or disorders or by the following conditions: (i) aging (when free radicals appear to increase; also blood levels of arginine rise dramatically after stress in aged animals - Milakofsky, Phyiol. Behav. 54 (1993), 725-728; although basal arginine levels appear to decrease and to be associated with NO depletion - Sonaka, J. Gerontol. 49 (1994), B157-161 ; Reckelhoff, Life Sci. 55 (1994), 1895-1902; also see: Beckmann & Ames, Physiol. Rev.
  • hypercortisolaemic conditions e.g. Cushing's disease; depression-associated hypercortisolism
  • glucocorticoids - Sapolsky Science 273 (1996), 749-750
  • glucocorticoid therapy e.g. in rheumatic, allergic and other autoimmune diseases; organ transplantation to prevent tissue rejection; stroke therapy, neurosurgery etc.
  • any brain diseases involving free radicals e.g.
  • compositions, methods and uses of the invention are for the treatment of subjects before, during or after exposure to an agent or radiation or surgical treatment, wherein said exposure causes neuronal cell death.
  • the pharmaceutical composition, method and use of the invention can be employed in adjuncture with any therapeutically agent with the potential for generating damaging free radicals.
  • therapeutically agent include, for example, cytostatics, nitroprusside, nitroglycerine etc; see also supra.
  • the method of the invention further comprises administering to the subject a hormone, a cytostatic, a nitro-group containing drug or any other drug capable of elevating free radical levels such as one of those mentioned above.
  • a hormone, a cytostatic, a nitro-group containing drug or any other drug capable of elevating free radical levels such as one of those mentioned above.
  • the pharmaceutical composition or the use of the invention is administered to the subject a hormone, a cytostatic, a nitro-group containing drug or any other drug capable of elevating free radical levels such as one of those mentioned above.
  • (a) further comprises a hormone, a cytostatic, a nitro-group containing drug or any other drug capable of elevating free radical levels;
  • (b) is designed for administration in conjunction with any one of the agents of (a).
  • said agent is a hormone.
  • D-arginine is capable of antagonizing the cytotoxic effects of hormones such as glucocorticoid and agonists thereof.
  • hormones such as glucocorticoid and agonists thereof.
  • the hormone is a glucocorticoid.
  • glucocorticoids exert many undesirable effects on the brain, many of which have been causally implicated in a host of neuropsychiatric disorders, including major depression and cognitive impairment, they are important for the homeostatic and self-defense (immune) mechanisms of the organism. 1"3 Their immunosuppressive properties rank them among the most-commonly used therapeutic agents; they are also frequently applied in constraining brain damage resulting from stroke and neurotrauma. 29 The contrasting attributes of GC poses an obvious dilemma for the clinical practitioner.
  • the apparently innocuous D-isomer of arginine can obviate the detrimental actions of GC in the brain (increased apoptosis, reduction in 5-HT-IA binding) while preserving their beneficial actions on pituitary-adrenal (ACTH and corticosterone secretion) and immune (thymus weight) function and thus provides a novel, adjunct therapeutic approach to safely exploit the benefits of GC treatment.
  • the invention relates further to the use of D-arginine or an analog thereof for the preparation of a pharmaceutical composition for the treatment or prevention of aging, memory dysfunction, hypercortisolaemic conditions, autoimmune diseases, ischemia, destruction of nerve cells, for the prevention of the production of damaging free radicals, for the treatment or the prevention of radiation induced DNA damage, cardivascular, urogenital, neurodegenerative or gastrointestinal diseases or for use in obstetrics.
  • D-arginine and analogs thereof can be used in the manufacture of a medicament for the prophylactic or therapeutic treatment of any disease state in or disorders of a human, or other mammal, which is exacerbated or caused by a neurodegenerative event, such as those caused by free radicals, e.g., NO and NO " production.
  • a neurodegenerative event such as those caused by free radicals, e.g., NO and NO " production.
  • Such disorder also comprise those caused by, for example, oxidative stress which is known to occur by, e.g., sportsmen and managers.
  • free radicals are generated during physical exercise (recreational and occupational) including exercise at high-altitude (e.g. Germano, J. Neurosurg. 88 (1998), 1075-1081 ; McBride, Med. Sci. Sports Exerc.
  • nitric oxide and other free radicals are involved in neurodegenerative diseases such as Alzheimer's disease (Rebeck, Neurosci. Lett. 152 (1993), 165-168; Frohlich, Drug, Res. 45 (1995), 443- 447), Parkinson's disease (Ebadi, Progress in Neurobiology 48 (1996), 1-19), depression and schizophrenia (Bernstein, Neuroscience, 83 (1998), 867-875); for review see also Nicotera, Advances in Neuroimmunology 5 (1995), 411-420, Beckman, Physiological Reviews 78 (1998), 548-581 and Moncada, Pharmacological Reviews 49 (1997), 137-142.
  • compositions of the invention are immediately evident to the person skilled in the art including, for example, multiple sclerosis, AIDS-associated dementia, viral uveitis, pulmonary tuberculosis, asthma, lung cancer, pulmonary sarcoidosis, bacterial pneumonia. Crohn's disease, ulcerative colitis, rheumatoid arthritis, impotence, osteoarthritis, renal allografts, aortic aneurysms, and psoriasis, in blood monocytes from patients with malaria, rheumatoid arthritis and alcoholic hepatitis; and in neutrophils from infected urine; see, e.g., Nathan, J. Clin. Invest. 100 (1997), 2417-2423 and Christopherson, J. Clin. Invest. 100 (1997), 2424-2429 and references cited therein.
  • said neurodegenerative disease is any one of the diseases involving (or potentially involving) destruction of nerve cells such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, depression and schizophrenia, AIDS-associated dementia and those mentioned herein before.
  • the invention relates to food, feed or supplements therefor comprising D- arginine or an analog thereof.
  • Such compositions are useful, for example, for subjects which are in need of a diet because of an elevated level of GC that exhibits detrimental central effects in the brain. Such elevated levels can be due to, for example, an inherited disorder or to the application of medicaments that contain GC or agents which give rise to elevate levels of GC.
  • the addition of such supplements to feed or food are useful in case that feed or food contains large amounts of L-arginine or stimuli which may increase L-arginine entry into neurons (and therefore nNOS-related products).
  • the above-described food, feed and supplements therefore are useful for patients that suffer from anyone of the above-described disorders or diseases.
  • D-arginine or an analog thereof may either be added as supplement like glutamate or after cooking or frying or the like.
  • Amino acids in general, are rather thermo-stable, allowing them to be cooked.
  • D-arginine or an analog thereof can be used as an additive during food preparation, or perhaps may be added thereafter (like 'salt') in case there is racemization during cooking (not known for D-arginine, but see Man, Ann. Rev. Nutr. 7 (1987), 209-225).
  • D-arginine and analogs thereof can be used for a nutritional supplementation; see also, e.g., Beckman, supra.
  • the present invention relates to a method of identifying a neuroprotective drug comprising the steps of
  • responsive change refers to a change in a phenotypic characteristic of said cell other than the level of said component in said cell per se and includes graded cellular responses, preferably observable with the eye such as cultural or morphological responses as well as changes in signal transduction pathways such as receptor activity that can be measured by, e.g., in vitro binding and/or activity assays.
  • the responsive change is apoptotic cell death, 5-HTIA receptor binding, and/or CAT1 or CAT2 expression or activity.
  • the principles of determining the responsive change are well known to the person skilled in the art and are described, for example, in EP-A1 0403 506.
  • the term " compound" in the method of the invention includes a single substance or a plurality of substances which may or may not be identical.
  • Said compound(s) may be comprised in, for example, samples, e.g., cell extracts from, e.g., plants, animals or microorganisms.
  • said compounds may be known in the art but hitherto not known to be capable of neuroprotection or not known to be useful as a drug, respectively.
  • the plurality of compounds may be, e.g., added to the culture medium or injected into a cell or organ of a non-human animal such as rat; see also the appended examples.
  • a sample containing (a) compound(s) is identified in the method of the invention, then it is either possible to isolate the compound from the original sample identified as containing the compound, in question or one can further subdivide the original sample, for example, if it consists of a plurality of different compounds, so as to reduce the number of different substances per sample and repeat the method with the subdivisions of the original sample. It can then be determined whether said sample or compound displays the desired properties, for example, by the methods described herein, the appended examples or in the literature, cited herein. Depending on the complexity of the samples, the steps described above can be performed several times, preferably until the sample identified according to the method of the invention only comprises a limited number of or only one substance(s).
  • said sample comprises substances of similar chemical and/or physical properties, and most preferably said substances are identical.
  • the method of the present invention can be easily performed and designed by the person skilled in the art, for example in accordance with other cell based assays described in the prior art or by using and modifying the methods as described in the appended examples.
  • the person skilled in the art will readily recognize which further compounds and/or enzymes may be used in order to perform the method of the invention, for example, enzymes, if necessary, that convert a certain compound into the precursor which in turn represents a putative substrate for a given enzyme or receptor.
  • Such adaptation of the method of the invention is well within the skill of the person skilled in the art and can be performed without undue experimentation.
  • the component capable of inducing the responsive change is an agent as defined above, e.g., glucocorticoids or agonists thereof such as DEX.
  • agent e.g., glucocorticoids or agonists thereof such as DEX.
  • any one of the methods described in Example 5 can be adapted to the above described method.
  • Compounds which can be used in accordance with the present invention include peptides, proteins, nucleic acids, antibodies, small organic compounds, ligands, peptidomimetics, PNAs and the like.
  • said compounds are functional derivatives or analogs of arginine including D-arginine, ornithine, lysine, canavanine citmlline.
  • Methods for the preparation of chemical derivatives and analogs are well known to those skilled in the art and are described in, for example, Beilstein, supra.
  • the compounds identified according to the method of the invention in particular D- arginine analogs are expected to be very beneficial since neuroprotective agents that have been used so far are only of limited use due to their inefficient metabolism and/or unwanted side effects in the subject.
  • the compounds identified or obtained according to the method of the present invention are thus expected to be very useful in diagnostic and in particular for therapeutic applications such as those discussed above.
  • the invention relates to a method for the production of a pharmaceutical composition comprising the steps of the above described method and synthesizing and formulating the compound identified in step (c) or a derivative or homologue thereof in a therapeutically effective and pharmaceutically acceptable form.
  • the therapeutically useful compounds identified according to the method of the invention may be formulated and administered to a patient as discussed above. For uses and therapeutic doses determined to be appropriate by one skilled in the art see supra.
  • Example 5 The findings of the present invention are summarized in Example 5. As is described there, GC act by altering nNOS substrate (L-arginine) availability by altering the expression of cationic amino acid transporter 1 and 2 proteins (CAT1 and CAT2). Treatment with D-arginine attenuates GC actions, apparently by competing with L- arginine for transport into neurons and by reducing CAT1 expression. Due to the findings of the present invention, it is now possible to specifically employ agents such as D-arginine that are capable of competing with L-arginine for transport into neurons, reducing CAT1 expression and/or reducing CAT2 expression for counteracting the detrimental central effects of GC without compromising their usefulness in the periphery.
  • agents such as D-arginine that are capable of competing with L-arginine for transport into neurons, reducing CAT1 expression and/or reducing CAT2 expression for counteracting the detrimental central effects of GC without compromising their usefulness in the periphery.
  • the present invention also relates to the use of compounds which are capable of competing with L-arginine for transport into neurons, reducing CAT1 expression and/or CAT2 expression or the activity of the proteins for the preparation of the pharmaceutical composition for the treatment of any one of the above described diseases or disorders.
  • Such compounds can be, for example, any one of those described hereinbefore.
  • such compounds can be identified in accordance with the methods described in Example 5, in particular those which assay CAT1 and 2 expression or activity. Accordingly, the methods described in Example 5 that can be used for the identification of agents that can be used for specifically directing GC therapies to the periphery, e.g., without compromising brain function are also subject of the present invention.
  • Such agents comprise, for example, antibodies or binding fragments thereof, antisense RNA constructs and the like.
  • such agents are analogs of D-arginine including those described above.
  • the method described in Example 5 can be easily adapted to screening method such as those described above.
  • Further literature concerning any one of the methods, uses and compounds to be employed in accordance with the present invention may be retrieved from public libraries, using for example electronic devices.
  • the public database "Medline” may be utilized which is available on Internet, e.g. under http://www.ncbi.nlm.nih.gov/PubMed/medline.html.
  • compositions, uses, methods of the invention can be used for the treatment of all kinds of diseases hitherto unknown as being related to or dependent on unwanted GC actions such as release of cytotoxic free radicals.
  • the pharmaceutical compositions, methods and uses of the present invention may be desirably employed in humans, although animal treatment is also encompassed by the methods and uses described herein.
  • FIG. 2 Treatment of rats with dexamethasone (DEX), L-arginine and L-arginine + DEX results in stimulation of (a) apoptosis.
  • DEX dexamethasone
  • L-arginine alone does not alter the incidence of apoptosis
  • its co-administration with DEX results in an attenuation of the effects of the glucocorticoid.
  • DEX dexamethasone
  • nNOS neuronal nitric oxide synthase
  • FIG. 5 Glucocorticoid (GC) actions in the hippocampus are mediated by reactive oxygen species (ROS) generated in the nitric oxide (NO) signaling pathway.
  • ROS reactive oxygen species
  • A. Administration of the ROS scavenger methylene blue (MB) or the inhibitors of nitric oxide synthase 7-nitroindazole (7-NI) and L- arginine methyl ester (L-NAME), significantly diminish the in vivo apoptotic effects of the GC dexamethasone (DEX); none of these compounds produced any significant effects on their own.
  • D-Arg has no intrinsic activity on its own but potently antagonizes the effects of DEX and L-Arg.
  • Co-administration of D-Arg with DEX or L-Arg in vivo significantly attenuates the effects of the latter two compounds on apoptosis (A) and nNOS synthesis (B).
  • A apoptosis
  • B nNOS synthesis
  • C * vs. control (P ⁇ 0.05); ** vs.
  • FIG. 8 Model to illustrate proposed novel mechanism of action of glucocortioid action in the hippocampus.
  • Glucocorticoids stimulate L-arginine entry into neurons from the extracellular space and glial cell depots by increasing the synthesis of catioinic transporter protein 1 (CAT-1 ).
  • L-arginine fluxes into glial cells occur through the CAT-2 protein, the synthesis of which is also stimulated by glucocorticoids.
  • CAT-1 catioinic transporter protein 1
  • D-arginine inhibits the synthesis of CAT-1 and, to a lesser extent, CAT-2, thereby reducing the availability of l-arginine, the substrate for nitric oxide synthase (nNOS) which catalyzes the production of nitric oxide (NO) and other reactive oxygen species (ROS).
  • nNOS nitric oxide synthase
  • ROS reactive oxygen species
  • FIG. 9 D-Arg counteracts GC effects in the hippocampus but not in the periphery.
  • Co-treatment with D-Arg and either DEX or L-Arg reverses the behaviorally-detrimental effects of the latter two compounds (reductions in [ 3 H]8-hydroxy-2-(di-n-propylamino)tetralin - [ 3 H]8-OH-DPAT) binding to serotonin 1 A receptors) (A), but does not interfere with GC-induced suppression of adrenocorticotropin and corticosterone secretion (B) and involution of the thymus gland (C).
  • Significant differences (P ⁇ 0.05) from corresponding controls are indicated by *; significant differences (P ⁇ 0.05) from DEX-treated animals are indicated by +.
  • ANIMAL SYSTEM Male Wistar rats (220-250g) from Charles River (Sulzfeld, Germany) were used in these studies. All rats were group-housed under standard laboratory conditions, and had free acces to laboratory chow and water. Animals were sacrificed 13:00 and 14:00 h for collection of tissues. All procedures on living animals were in compliance with local regulations on animal welfare.
  • ASSESSMENT OF APOPTOSIS IN THE DG A previously-described modification 4 of Gavrieli & Ben-Sasson. 30 TUNEL stain was used to identify apoptotic cells. Briefly, cryofixed brains were sectioned (10 ⁇ m) at the level of the dorsal hippocampus, corresponding to bregma (between -3.3 and -4.3; see ref 31 ). Sections, which were placed on coded slides, were subsequently fixed in 4% p-formaldehyde, permeablized with 0.5% Triton X-100, and treated with 3% H 2 0 2 . Sections were then incubated (60 min.
  • 5-HT-t ⁇ RECEPTOR BINDING ASSAY A microassay, based on that published by Peroutka & Snyder 34 and DeVry et al. 14 was used to measure 5-HT 1A receptor binding in hippocampal homogenates. Briefly, membrane preparations were incubated (30 min. at 37 C) with 3 nM 3 H-8-OH-DPAT (8-hydroxy-2-(di-t?- propylamino)-tetralin; specific activity: 127 Ci/mmol; Dupont-NEN, Bad Homburg, Germany) in a final volume of 0.2 ml Tris-HCI (50 mM; including 4 mM CaCI2, 10 ⁇ M pargyline and 0.1% ascorbic acid; pH 7.4).
  • 3 nM 3 H-8-OH-DPAT 8-hydroxy-2-(di-t?- propylamino)-tetralin; specific activity: 127 Ci/mmol; Dupont-NEN, Bad Homburg, Germany
  • NEUROENDOCRINE ASSAYS Blood plasma, collected at the time of sacrifice, was assayed for ACTH and corticosterone using radioimmunoassay kits supplied by ICN Bioscience, (Costa Mesa, CA). Thymuses were collected at autopsy, and tissue weights were expressed relative to body weight.
  • the synthetic GC dexamethasone (DEX) was previously shown to lead to apoptosis of rat hippocampal granule neurons (Hassan, von Rosenstiel, Patchev, Holsboer and Almeida. Exp. Neurol. 140 (1996), 43).
  • DEX synthetic GC dexamethasone
  • MB methylene blue
  • NOS inhibitors L- ⁇ / ⁇ -nitro-L-arginine methyl ester
  • 7-NI 7-nitroindazole
  • the MB and L-NAME were solubilized in 0.9% saline and given at doses of 5 mg/kg and 20 mg/kg, respectively.
  • the 7-NI was prepared in oil and injected subcutaneously (s.c.) at 20 mg/kg.
  • L-Arg (Sigma) was dissolved in 0.9% saline and injected at 200 mg/kg.
  • Apoptotic cells in the dentate gyms were identified on cryosections at the level of the dorsal hippocampus (between bregma -3.3 and - 4.3) using a modification of the TUNEL stain described by Gavrieli and Sasson (J. Cell Biol. 119, 493, 1992); see also supra.
  • Nitric oxide synthase (NOS) activity was assessed in freshly-frozen hippocampi using a standard assay (Bredt, Proc. Natl. Acad. Sci., 86 (1989), 9030) with the modifications described by Canteros et al, (Proc. Natl. Acad. Sci. 93 (1996), 4246).
  • nNOS neuronal nitric oxide
  • RT-PCR reverse-transcriptase polymerase chain reaction
  • Oligonucleotide primers for ⁇ -actin were used to provide standardization ( ⁇ -actin mRNA levels).
  • CAT-1 , CAT-2 and CAT-3 Three CAT proteins (CAT-1 , CAT-2 and CAT-3) have been described; in the brain, CAT-1 and CAT-3 are localized primarily in neurons, whereas CAT-2 is found mainly in glial cells (Stevens et al., J. Biol. Chem. 271 (1996), 24017; Stevens and Vo, J: Neurochem. 71 , 564).
  • Fig. 7 chronic treatment of animals with DEX or L-arg, resulted in significant elevations in CAT-1 mRNA levels (The mRNA encoding the cationic amino acid transporter proteins CAT-1 and CAT-2 were measured using RT-PCR; results were standardized against ⁇ -actin mRNA levels in the same samples.
  • the primers used to detect CAT-1 were those described by Racke et al., (J. Physiol. 511 (1998), 813;); the following primers were designed for CAT-2 (NCBI accession number: RNU53927): sense (nucleotides 199-222) 5'- ATGCCTTTGTGGGCTTTGACTGCA-3 ' (SEQ ID N0.3), antisense (nucleotides 697-720) 5 ' -AACACAAGCCAGGTTGGTACCTGA-3 ' (SEQ ID NO:4)), indicating that the GC can indeed increase L-arg influx in neurons, thereby leading to increased ROS production.
  • CAT-2 is associated with glial cells. These cells in fact serve as reservoirs for L-Arg (Aoki, E, Semba, Mikoshiba, Kashiwamata, Brain Res. 547 (1991 ), 190; Grima, Cuenod, Pfieffer, Mayer, DO, J. Neurochem. 71 , 2139; Pow. Neurosci. Lett. 181 (1994), 141 ).
  • L-Arg L-Arg
  • neurons and glia express two different types of NOS, nNOS and inducible (i)NOS, respectively; whereas nNOS activation is Ca 2+ - dependent, that of iNOS is not (Bredt, Hwang, Snyder, Nature, 347 (1990), 768; Bredt et al., Neuron, 7 (1991 ), 615; Murphy et al., Trends Neurosci. 16 (1993), 323).
  • This information therefore suggests that glia-to-neuron L-Arg transport occurs secondary to Ca 2+ -mediated increases in nNOS activity and L-Arg utilization.
  • Nonspecific binding was determined by incubating matched tissue homogenates with an excess (10 ⁇ M) of unlabelled 5-HT. All determinations were performed in triplicate, and corrected for non-specific binding. Similar changes in 5-HT-IA receptor binding were observed in the dentate gyrus when studies were carried out using in situ receptor autoradiography); a similar decrease was obtained in animals treated with L-Arg (Fig. 9A). Hippocampal 5-HT1 A .R number was not changed after treatment with the D-isomer of arginine, but when co-administered with either DEX or L-Arg, D-Arg reversed the inhibitory effects of DEX and L-Arg on 5-HT1 A binding.
  • D-Arg does not interfere with DEX-mediated immunosuppression (Fig. 9C).

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Abstract

L'invention concerne d'une manière générale la modulation de la mort cellulaire apoptotique. Elle concerne plus particulièrement des compositions pharmaceutiques comprenant de la D-arginine ou un analogue de celle-ci, particulièrement utiles pour le traitement, la prévention et/ou le retardement de la mort des cellules neuronales. Elle se rapporte encore à une méthode de traitement, de prévention et/ou de retardement de la mort de cellules neuronales chez un sujet, méthode qui consiste à administrer à un sujet de la D-arginine ou un analogue de celle-ci, et à l'utilisation de la D-arginine ou d'un analogue de celle-ci pour la préparation de compositions pharmaceutiques pour le traitement de maladies neurodégénérative. Par ailleurs, des aliments pour l'homme et pour les animaux ainsi que des compléments alimentaires associés, comprenant de la D-arginine ou un analogue de celle-ci, sont décrits, ainsi que des méthodes d'identification et de production de médicaments neuroprotecteurs.
PCT/EP1999/006241 1998-08-25 1999-08-25 Nouveau traitement de maladies neurodegeneratives WO2000010546A2 (fr)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002057790A2 (fr) * 2001-01-19 2002-07-25 Mindsense Biosystems Ltd. Methodes et compositions permettant d'effectuer un diagnostic et de traiter un sujet souffrant de depression
WO2006126199A2 (fr) * 2005-05-24 2006-11-30 Fund For Medical Research Development Of Infrastructure & Health Services Rambam Medical Center Methodes et compositions pour traiter la schizophrenie
EP1848438A2 (fr) * 2005-02-18 2007-10-31 Children's Hospital & Research Center at Oakland Compositions de diaminophenothiazine et utilisations associees
JP2019129758A (ja) * 2018-01-31 2019-08-08 株式会社明治 Ｄ−アルギニンを含む組成物およびその製造方法。

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4789681A (en) * 1985-12-23 1988-12-06 Italfarmaco S.P.A. Cytoprotective guanidine derivatives useful in ischemic diseases
DE4311806A1 (de) * 1993-04-03 1994-10-06 Schering Ag Verwendung von Argininderivaten als Quisqualatantagonisten
EP0630649A1 (fr) * 1993-06-14 1994-12-28 Zeneca Limited Combinaison d'un inhibiteur de la synthase inductible de l'oxyde nitrique avec un agent antiinflammatoire, p.ex. un corticosteroide

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4789681A (en) * 1985-12-23 1988-12-06 Italfarmaco S.P.A. Cytoprotective guanidine derivatives useful in ischemic diseases
DE4311806A1 (de) * 1993-04-03 1994-10-06 Schering Ag Verwendung von Argininderivaten als Quisqualatantagonisten
EP0630649A1 (fr) * 1993-06-14 1994-12-28 Zeneca Limited Combinaison d'un inhibiteur de la synthase inductible de l'oxyde nitrique avec un agent antiinflammatoire, p.ex. un corticosteroide

Non-Patent Citations (12)

* Cited by examiner, † Cited by third party
Title
CANTEROS, M.G. ET AL: "Nitric oxide mediates dexamethasone-induced apoptosis in the dentate gyrus: The protective actions of D-arginine" SOCIETY FOR NEUROSCIENCE ABSTRACTS, vol. 24, no. 1-2, 1998, page 1047 XP000905168 *
CORASANTI, M.T. ET AL: "Death of cultured human neuroblastoma cells induced by HIV-1 gp120 is prevented by NMDA receptor antagonists and inhibitors of nitric oxide and cyclooxygenase" NEURODEGENERATION, vol. 4, no. 3, 1995, pages 315-321, XP000905597 *
DATABASE BIOSIS [Online] BIOSCIENCES INFORMATION SERVICE, PHILADELPHIA, PA, US; AN: 06892765, XP002137131 & ENDO, R. ET AL: "Cerebrospinal fluid vasopressin levels and the effect of 1-desamino-8-D-arginine vasopressin DDAVP in dementia" JOURNAL OF TOKYO WOMENS COLLEGE, vol. 59, no. 6, 1989, pages 615-619, *
FL]GGE, G.: "Dynamics of central nervous 5-HT1A-receptors under psychosocial stress" THE JOURNAL OF NEUROSCIENCE, vol. 15, no. 11, 1995, pages 7132-7140, XP000905495 cited in the application *
FORRAY, M. I. ET AL: "Transport of nitric oxide synthase inhibitors through cationic amino acid carriers in human erythrocytes" BIOCHEMICAL PHARMACOLOGY, vol. 50, no. 12, 1995, pages 1963-1968, XP000905497 *
HASSAN, A.H.S. ET AL: "Exacerbation of apoptosis in the dentate gyrus of the aged rat by dexamethasone and the protective role of corticosterone" EXPERIMENTAL NEUROLOGY, vol. 140, no. 1, July 1996 (1996-07), pages 43-52, XP000905487 cited in the application *
KOHNO, K. ET AL: "Intraventricular administration of nitric oxide synthase inhibitors prevents delayed neuronal cell death in gerbil hippocampal CA1 neurons" NEUROSCIENCE LETTERS, vol. 199, no. 1, 1995, pages 65-68, XP000905496 *
MASON, R.P. ET AL: "Inhibition of excessive neuronal apoptosis by the calcium antagonist amlodipine and antioxidants in cerebellar granule cells" THE JOURNAL OF NEUROCHEMISTRY, vol. 72, no. 4, April 1999 (1999-04), pages 1448-1456, XP000905185 *
MATTHEWS, R.T. ET AL: "S-methylthiocitrulline, a neuronal nitric oxide synthase inhibitor, protects against malonate and MPTP neurotoxicity" EXPERIMENTAL NEUROLOGY, vol. 143, no. 2, February 1997 (1997-02), pages 282-286, XP000905617 *
POW, D.V. ET AL: "Immunocytochemical analysis of the transport of arginine into nitrergic neurons and other cells in the retina and pituitary" CELL TISSUE RESEARCH, vol. 290, no. 3, December 1997 (1997-12), pages 501-514, XP000905482 cited in the application *
SHIBATA, S. ET AL: "NG-nitro-L-arginine protects against hypoxia/hypoglycemia-induced decrease in CA1 presynaptic spikes in rat hippocampal slices" EUROPEAN JOURNAL OF PHARMACOLOGY, vol. 273, no. 6, 2 June 1995 (1995-06-02), pages 223-228, XP000905608 *
WANG, JI-FENG ET AL: "Decreased production of reactive oxygen intermediates is an early event during in vitro apoptosis of rat thymocytes" FREE RADICAL BIOLOGY AND MEDICINE, vol. 20, no. 4, 1996, pages 533-542, XP000905498 *

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002057790A2 (fr) * 2001-01-19 2002-07-25 Mindsense Biosystems Ltd. Methodes et compositions permettant d'effectuer un diagnostic et de traiter un sujet souffrant de depression
WO2002057790A3 (fr) * 2001-01-19 2002-11-28 Mindsense Biosystems Ltd Methodes et compositions permettant d'effectuer un diagnostic et de traiter un sujet souffrant de depression
EP1848438A2 (fr) * 2005-02-18 2007-10-31 Children's Hospital & Research Center at Oakland Compositions de diaminophenothiazine et utilisations associees
EP1848438A4 (fr) * 2005-02-18 2010-09-01 Childrens Hosp & Res Ct Oak Compositions de diaminophenothiazine et utilisations associees
WO2006126199A2 (fr) * 2005-05-24 2006-11-30 Fund For Medical Research Development Of Infrastructure & Health Services Rambam Medical Center Methodes et compositions pour traiter la schizophrenie
WO2006126199A3 (fr) * 2005-05-24 2007-02-15 Fund For Medical Res Dev Of In Methodes et compositions pour traiter la schizophrenie
JP2019129758A (ja) * 2018-01-31 2019-08-08 株式会社明治 Ｄ−アルギニンを含む組成物およびその製造方法。
JP7078410B2 (ja) 2018-01-31 2022-05-31 株式会社明治 Ｄ－アルギニンを含む組成物およびその製造方法。

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