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WO2007012154A1 - Préparation pharmaceutique contenant un inhibiteur de l’acétylcholinestérase et un antidépresseur ayant des propriétés bloquant la 5-ht et l’alpha-2-adrénocepteur. - Google Patents

Préparation pharmaceutique contenant un inhibiteur de l’acétylcholinestérase et un antidépresseur ayant des propriétés bloquant la 5-ht et l’alpha-2-adrénocepteur. Download PDF

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Publication number
WO2007012154A1
WO2007012154A1 PCT/BR2005/000140 BR2005000140W WO2007012154A1 WO 2007012154 A1 WO2007012154 A1 WO 2007012154A1 BR 2005000140 W BR2005000140 W BR 2005000140W WO 2007012154 A1 WO2007012154 A1 WO 2007012154A1
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antidepressant
mianserin
mirtazapine
treatment
dementia
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PCT/BR2005/000140
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Carlos Henrique Horta Lima
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Priority to PCT/BR2005/000140 priority patent/WO2007012154A1/fr
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Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/27—Esters, e.g. nitroglycerine, selenocyanates of carbamic or thiocarbamic acids, meprobamate, carbachol, neostigmine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0031—Rectum, anus
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0034—Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms

Definitions

  • composition containing an acetylcholinesterase inhibitor and an antidepressant with 5-HT and alpha-2-adrenoceptor blocking properties.
  • IASP International Association for the Study of Pain
  • pain is an "Unpleasant sensorial and emotional experience associated with a current or potential tissue injury or described in terms of such an injury" .
  • the most usual classifications for pain are based in its inferred neurophysiological mechanisms, its length, etiology or affected region.
  • pain may be nociceptive or non-nociceptive; and nociceptive pain may be somatic or visceral; and non-nociceptive pain may be neuropathic or psychogenic.
  • Nociceptive pain results from the activation of nociceptors by stimuli that can be mechanic, thermal or chemical. Here, the nervous system is intact and properly detects the painful stimuli.
  • Neuropathic pain results from an injury or irritation of the nerve. This classification according to the physiopathology is inferred, since there are no definite evidences that a certain mechanism is contributing, within the clinical context, to keep a chronic painful syndrome.
  • the physiopathologic classification is based on the pain as described by the patient during the physical exam and complementary exams. Patients commonly show more than one pain generation mechanism. This classification became widely accepted by clinicians due to its usefulness when definition the type of required evaluation, required therapy and the prognosis.
  • neuropathic pain when patients use terms to characterize their compatible pains with dysesthesia, that is, an abnormal painful complaint that may be described as burning, electric shock or pulsation.
  • Neuropathic pain is usually different from any previous painful complaint.
  • the physical exam may show allodynia, that is, pain to a slight touch, hypoesthesia or hyperesthesia (decrease or increase in the perception of a non-painful stimulus) .
  • Supplementary exams such as electromyography and nervous conduction studies, may be useful to confirm the neurological injury.
  • the neuropathic pain is an important clinical condition due to its high incidence, no response to conventional or opiate analgesics, thus generating an extensive search for new drugs for its treatment .
  • the present invention is intended for the treatment of several chronic painful syndromes, that is, for more than three months in length, such as, the neuropathic pain, migraine, fibromyalgia, myofascial pain, painful syndromes in cancer patients, and others.
  • cholinergic agonists caused potent antinociception after the systemic or intracerebroventricular administration, by the action on muscarinic and nicotinic cholinergic receptors 1,2,3,4,5,6 _ Acetylcholine may cause analgesia through the direct action on muscarinic cholinergic spinal receptors Ml and M3 , nicotinic receptors and by the release of the second nitric oxide messenger .
  • anticholinesterase drugs promote their therapeutic effects optimizing the cholinergic function. It occurs by increasing the concentration of acetylcholine through the inhibition of the acetylcholinesterase hydrolysis, an enzyme responsible for acetylcholine metabolism.
  • the anticholinesterase drug donepezil primarily used in the treatment of the Alzheimer's disease, also showed analgesic efficacy in animal models of pain 8 (United States Patent 6,608,088 Nicolodi et al . August 19, 2003). In humans, donepezil was more effective in the prophylactic treatment of migraine than propranolol in a clinical trial involving 147 patients; it also showed benefits in the extension of this clinical trial with 346 patients 8 .
  • the anticholinesterase drug and the cholinergic agonist neostigmine by intrathecal route in combination with intrathecal morphine or with transdermal nitroglycerine, was effective in gynecological postoperative analgesia 7 ' 9 .
  • Galantamine and rivastigmine are anticholinesterase drugs primarily used in the treatment of the Alzheimer's disease.
  • Galantamine is a cholinergic agent with double mechanism of action, acetylcholinesterase (AchE) inhibition and allosteric modulation of nicotinic cholinergic receptors (nAchR) .
  • the nicotinic modulation potentiates the acetylcholine effects in nicotinic receptors .
  • Galantamine also modulates the release of glutamate, dopamine and gamma-aminobutyric acid (GABA) , neurotransmitters also involved in the neuronal transmission of pain 10 .
  • GABA gamma-aminobutyric acid
  • Rivastigmine is a pseudo-irreversible inhibitor of acetylcholinesterase, mainly in its Gl form, having selective action on the central nervous system. Rivastigmine also inhibits butyrylcholinesterase l ⁇ ' 12 .
  • Donepezil is a reversible inhibitor of acetylcholinesterase, having selective action on the central nervous system 13 - 14 .
  • 15 galantamine are nausea, vomiting, diarrhea, anorexia, weight loss and sleeping disorders 20 .
  • rivastigmine is associated with significant GI effects, including nausea, vomiting, anorexia and weight loss. Other frequent adverse reactions include fatigue, 0 asthenia, dizziness, headache, diarrhea, dyspepsia, insomnia and confusion 21 . Predominant adverse effects of donepezil are nausea, vomiting, diarrhea, muscular cramps, insomnia, fatigue and anorexia 22 .
  • the antidepressants mirtazapine and mianserin Antidepressants are usually used in the treatment of chronic pain. Antidepressants have analgesic effects both on neuropathic and nociceptive pain and such effects are not dependent on their antidepressive effects 23 .
  • the analgesic action of the antidepressants is attributed to the neurotransmission optimization in serotoninergic and noradrenergic pain inhibitory descending pathways 24 ⁇ 2S .
  • Mianserin is a tetracyclic antidepressant.
  • Mirtazapine is an analog tetracyclic piperazinoazepine of mianserin. Both act by blocking the serotoninergic (5HT-2 and 5HT- 3) and adrenergic (alpha-2) receptors 26 ' 27 ' 28 . Mianserin is a more potent 5HT-2 blocker than mirtazapine 29 . Both have low or absent anticholinergic activity 30 ' 31 , and antihistamine action 29 ' 30 . The antidepressive action of these agents is associated with the affinity for 5HT-2 and ⁇ -2 adrenergic receptors. Mirtazapine is metabolized by the cytochrome CYP
  • cytochrome CYP 450 isoenzymes 2D6, 1A2 and 3A; it binds 85% to plasmatic proteins, is predominantly excreted by the kidneys, does not inhibit nor induces cytochrome CYP 450; its half-life ranges from 20 to 40 hours 32>33 ' 34 .
  • Mianserin is metabolized by cytochrome CYP 450, isoenzyme 2D6; it binds 90% to plasmatic proteins and has a half-life from 10 to 40.8 hours; it is excreted in 14 to 28% in the feces, 4 to 7% by the kidneys 3S ' 36 . in animal models of pain, mianserin increased the antinociceptive effects of indomethacin and metamizole 3?
  • Mianserin when administered with opiates, potentiated analgesia in mu, kappa 1 and kappa 2 receptors 3a ; and decreased morphine tolerability 39 .
  • Mianserin was effective in the treatment of pain in a study involving 16 patients with chronic idiopathic pain at a dose from 30 to 60 mg a day 40 . It also showed benefits in a randomized double-blind study on chronic tension-type headache 41 .
  • mianserin was also effective in reducing abdominal pain, abdominal discomfort symptoms, functional capacity in patients with irritable bowel syndrome or non-ulcerous dyspepsia 42 .
  • mirtazapine showed antinociceptive effects through noradrenergic, serotoninergic and opiate (kappa 3) receptors.
  • Mirtazapine showed efficacy in a randomized comparative clinical study using amitriptyline in 60 patients for the treatment of chronic tension-type headache 44 .
  • Mirtazapine was beneficial in an open-label trial involving patients with cancer and pain 45 .
  • Mirtazapine showed to be effective in a chronic pain report referring to a 47-year-old male patient with backache resulting from a neck and back injury after a fall, treated with amitriptyline 50 mg for several years.
  • Previously started associated depressive symptoms did not respond to fluoxetine and bupropion.
  • mirtazapine (15 mg a day) , pain decrease from ten to three points in a ten-point scale 4S .
  • mirtazapine significantly improved appetite and decreased weight loss, in addition to improve the quality of life 45 .
  • the antiemetic effects of mianserin and mirtazapine may be related to the 5HT-3 receptor blockage.
  • Ondasentron a drug having beneficial effects on emesis from different etiologies, acts by blocking the 5HT-3 receptor 47 .
  • the invention the pharmaceutical preparation A pharmaceutical combination consisting of an acetylcholinesterase inhibitor drug (rivastigmine, donepezil or galantamine, or another acetylcholinesterase inhibitor) and an antidepressant that blocks serotoninergic (5-HT-2 and 5HT-3) receptors and alpha-2 adrenergic receptors (mirtazapine or mianserin, or another antidepressant with these properties) .
  • Said combination has synergic analgesic effects and has antagonistic effects on the production of adverse events, promoting better tolerability than the treatment with one of the drugs alone.
  • the analgesic effects occur through the 5HT-2, alpha-2 adrenergic receptors, and muscarinic cholinergic Ml and M3 receptors (and nicotinic receptors, in case of galantamine) . Additionally, the 5HT-2 receptors may be also involved in the release of acetylcholine in generating analgesia
  • the combination has antagonistic effects on the production of the most common adverse events of both drug classes .
  • Nausea and vomiting caused by anticholinesterase drugs are treated with mianserin or mirtazapine through the 5HT-3 receptors.
  • Weight loss and anorexia caused by anticholinesterase drugs are treated with mianserin or mirtazapine through the histamine receptors
  • Electroencephalograph ⁇ measurements in animals showed that, contrary to other antidepressants with relevant anticholinergic activity, mianserin did not interfere with the electroencephalograph ⁇ activation promoted by galantamine 49 .
  • Synergism in the analgesic action and antagonism in the generation of adverse reactions allow a more efficient treatment .
  • the prevalence of Major Depression in patients with chronic lumbar pain may be 3 to 4 times higher than in the general population so , thus making the use of a drug with antidepressive and analgesic effects especially appropriate in chronic pain patients .
  • Dementia A general description of dementia, according to the Classification of Mental and Behavior Disorders of ICD-10 (international classification of diseases - 10 th revision) , is as follows :
  • Dementia is a syndrome resulting from a cerebral disease, usually of chronic or progressive nature, in which there is a disorder of multiple upper cortical functions, including memory, thinking, orientation, comprehension, calculation, learning capacity, language and judgment. There is no conscience disturbance. Dementia causes significant reduction of the intellectual functioning and may interfere with routine personal activities, such as cleaning, dressing, feeding and personal care, physiologic and restroom activities. The manifestation of such decrease widely depends on the social and cultural environment the patient lives in. The primary diagnosis requirement, as per the ICD-IO classification, is the evidence of a memory and thinking reduction, being sufficient to impair routine personal activities as described above. Memory impairment typically affects recording, storage and retrieving of new information, however family and previously learned materials may also be lost, particularly in later phases . Thinking and reasoning capacity are also impaired and the flow of ideas is also reduced. Since processing of received information is impaired, the individual progressively has more difficulties in responding to more than one stimulus each time, for example, joining a conversation with several persons and change the attention focus from one topic to another.
  • Dementia syndrome occurs in Alzheimer's disease, Lewy body dementia, cerebrovascular disease, mixed dementia (Alzheimer and vascular) and in a number of other conditions that, primarily or secondarily, affect the brain.
  • the Alzheimer's disease is the most common form of dementia, consisting in almost 60% of the cases of dementia; its prevalence in persons over 65 years old is approximately 5%. It is estimated that the Alzheimer's disease affects 15 million people worldwide 51 .
  • Lewy body dementia was recognized in the last decade as a common form of dementia, representing 15 to 25 % of all cases of dementia 52 .
  • Alzheimer- type dementia and Lewy body dementia the cholinergic neuronal pathways involved in cognitive processes, such as memory, attention, learning, and others, are impaired.
  • anticholinesterase drugs the precise mechanism of action of anticholinesterase drugs on such dementias is unknown, it is believed that they perform their therapeutic effects by optimizing the cholinergic function. It occurs by increasing the acetylcholine concentration through the inhibition of acetylcholinesterase hydrolysis, an enzyme responsible for metabolizing acetylcholine.
  • Depression is a psychiatric co-morbidity more frequently observed in Alzheimer's disease, affecting up to 50% of the cases S3 . Depression in elderly is many times sub-syndromic 54 (26) and has a complex diagnosis when associated with Alzheimer 5S .
  • the pharmaceutical preparation in dementia A pharmaceutical combination consisting in an acetylcholinesterase inhibitor drug (rivastigmine, donepezil or galantamine, or another acetylcholinesterase inhibitor) and an antidepressant that blocks serotoninergic receptors (5-HT-2 and 5HT-3) and alpha-2 adrenergic receptors (mirtazapine or mianserin, or another antidepressant with these properties) , improves cognitive symptoms and has antagonistic effects on the generation of adverse events, promoting improved tolerability than the treatment with one of the drugs alone; this is a very relevant aspect, for example, in the treatment of Alzheimer's disease where the dose of anticholinesterase drug usually recommended is the highest tolerated dose in the drug's therapeutic range.
  • the pharmaceutical combination has antagonistic effects on the generation of the most common adverse events of both drug classes.
  • Nausea and vomiting caused by anticholinesterase drugs are treated with mianserin or mirtazapine through 5HT-3 receptors; and weight loss and anorexia are treated through Hl receptors .
  • Sedation caused by mianserin or mirtazapine is treated by the action of anticholinesterase drugs.
  • Electroencephalograph ⁇ measurements in animals showed that, contrary to other antidepressants with relevant anticholinergic activity, mianserin did not interfere with the electroencephalograph ⁇ activation promoted by galantamine 49 .
  • Mirtazapine shows an even lower tendency to anticholinergic effects 5S
  • Antagonism in the generation of adverse reactions allows a more efficient treatment.
  • the patient with Alzheimer's disease associated with depression or sub-syndromic depressive symptoms may also have a better treatment with this combination.
  • Radio B Daly JW, Epibatidine, a potent analgesic and nicotinic agonist, MoI. Pharmacol. 45 (1994) 563- 569.
  • Rogers DT Iwamoto ET. Multiple spinal mediators in parenteral nicotine-induced antinociception. J. Pharmacol. Exp. Ther. 267 (1993) 341-349.
  • Jahansson IM & Nordberg A Pharmacokinetic studies of cholinesterase inhibitors. Acta Neurol Scand 1993; Suppl 149:22-25. 18. Polinsky RJ: Clinical pharmacology of rivastigmine: a new-generatian acetylcholinesterase inhibitor for the treatment of Alzheimer's disease Clin Ther; 20 (4) : 634-47, 1998 JuI-Aug
  • De Boer TH The pharmacologic profile of mirtazapine. J Clin Psychiatry 1996: 57(suppl 4):19-25.
  • Schmoll HJ The role of ondansetron in the treatment of emesis induced by non-cisplatin-containing chemotherapy regimens. Eur J Cancer Clin Oncol 1989; 25 (suppl 1) :S35-S39. 48. Obata H, Saito S, Sasaki M, Goto F.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Emergency Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

La présente invention concerne une combinaison pharmaceutique qui consiste en un médicament inhibiteur de l'acétylcholinestérase (rivastigmine, donépézil ou galantamine) et un antidépresseur bloqueur des récepteurs sérotoninergiques (5-HT) et alpha-2-adrénergique (mirtazapine ou miansérine). La préparation est utile pour le traitement de syndromes douloureux avec une meilleure efficacité et une meilleure tolérabilité que les médicaments seuls. Elle est utile pour le traitement de la démence avec une meilleure tolérabilité que les médicaments anticholinestérase seuls et pour le traitement de la démence associée à la dépression ou à des symptômes dépressifs.
PCT/BR2005/000140 2005-07-27 2005-07-27 Préparation pharmaceutique contenant un inhibiteur de l’acétylcholinestérase et un antidépresseur ayant des propriétés bloquant la 5-ht et l’alpha-2-adrénocepteur. Ceased WO2007012154A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
CA002616858A CA2616858A1 (fr) 2005-07-27 2005-07-27 Preparation pharmaceutique contenant un inhibiteur de l'acetylcholinesterase et un antidepresseur ayant des proprietes bloquant la 5-ht et l'alpha-2-adrenocepteur.
PCT/BR2005/000140 WO2007012154A1 (fr) 2005-07-27 2005-07-27 Préparation pharmaceutique contenant un inhibiteur de l’acétylcholinestérase et un antidépresseur ayant des propriétés bloquant la 5-ht et l’alpha-2-adrénocepteur.

Applications Claiming Priority (1)

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PCT/BR2005/000140 WO2007012154A1 (fr) 2005-07-27 2005-07-27 Préparation pharmaceutique contenant un inhibiteur de l’acétylcholinestérase et un antidépresseur ayant des propriétés bloquant la 5-ht et l’alpha-2-adrénocepteur.

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008019431A1 (fr) * 2006-08-14 2008-02-21 Brc Operations Pty Limited Procédé et compositions pour réguler simultanément la mémoire et l'humeur
WO2010091234A2 (fr) 2009-02-06 2010-08-12 The General Hospital Corporation Procédés de traitement de lésions vasculaires
WO2015140265A1 (fr) * 2014-03-20 2015-09-24 Centre Hospitalier Universitaire De Clermont Ferrand Inhibiteurs de l'acétylcholinestérase d'action centrale pour la prévention et/ou le traitement des neuropathies chimio-induites et leurs symptômes, compositions, utilisations, méthodes et trousse correspondantes
RU2607946C2 (ru) * 2009-07-17 2017-01-11 Аллерган, Инк. Композиции, включающие ингибитор холинэстеразы, для лечения когнитивных расстройств
CN108451917A (zh) * 2018-03-22 2018-08-28 仁和堂药业有限公司 高稳定性米安色林制剂的制备方法
US10603272B2 (en) 2015-02-27 2020-03-31 Kindred Biosciences, Inc. Stimulation of appetite and treatment of anorexia in dogs and cats

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004034963A2 (fr) * 2002-05-17 2004-04-29 Eisai Co., Ltd. Methodes et compositions utilisant des inhibiteurs de la cholinesterase
US20050143350A1 (en) * 2003-11-19 2005-06-30 Seed John C. Combination drug therapy to treat obesity
WO2005065645A2 (fr) * 2003-12-31 2005-07-21 Actavis Group Hf Formulations de donepezil

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004034963A2 (fr) * 2002-05-17 2004-04-29 Eisai Co., Ltd. Methodes et compositions utilisant des inhibiteurs de la cholinesterase
US20050143350A1 (en) * 2003-11-19 2005-06-30 Seed John C. Combination drug therapy to treat obesity
WO2005065645A2 (fr) * 2003-12-31 2005-07-21 Actavis Group Hf Formulations de donepezil

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008019431A1 (fr) * 2006-08-14 2008-02-21 Brc Operations Pty Limited Procédé et compositions pour réguler simultanément la mémoire et l'humeur
WO2010091234A2 (fr) 2009-02-06 2010-08-12 The General Hospital Corporation Procédés de traitement de lésions vasculaires
RU2607946C2 (ru) * 2009-07-17 2017-01-11 Аллерган, Инк. Композиции, включающие ингибитор холинэстеразы, для лечения когнитивных расстройств
WO2015140265A1 (fr) * 2014-03-20 2015-09-24 Centre Hospitalier Universitaire De Clermont Ferrand Inhibiteurs de l'acétylcholinestérase d'action centrale pour la prévention et/ou le traitement des neuropathies chimio-induites et leurs symptômes, compositions, utilisations, méthodes et trousse correspondantes
FR3018689A1 (fr) * 2014-03-20 2015-09-25 Ct Hospitalier Universitaire De Clermont Ferrand Inhibiteurs de l'acetylcholinesterase d'action centrale pour la prevention et/ou le traitement des neuropathies chimio-induites et leurs symptomes, compositions, utilisations, methodes et trousse correspondantes.
US10603272B2 (en) 2015-02-27 2020-03-31 Kindred Biosciences, Inc. Stimulation of appetite and treatment of anorexia in dogs and cats
CN108451917A (zh) * 2018-03-22 2018-08-28 仁和堂药业有限公司 高稳定性米安色林制剂的制备方法

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