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WO2020136221A1 - Utilisation de sécoiridoïdes pour le traitement de la névrite optique - Google Patents

Utilisation de sécoiridoïdes pour le traitement de la névrite optique Download PDF

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Publication number
WO2020136221A1
WO2020136221A1 PCT/EP2019/087044 EP2019087044W WO2020136221A1 WO 2020136221 A1 WO2020136221 A1 WO 2020136221A1 EP 2019087044 W EP2019087044 W EP 2019087044W WO 2020136221 A1 WO2020136221 A1 WO 2020136221A1
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Prior art keywords
ole
mice
eon
compound
treatment
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Inventor
Beatriz GUTIERREZ MIRANDA
Mª Luisa NIETO CALLEJO
Prokopios Magiatis
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Consejo Superior de Investigaciones Cientificas CSIC
National and Kapodistrian University of Athens
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Consejo Superior de Investigaciones Cientificas CSIC
National and Kapodistrian University of Athens
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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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/222—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin with compounds having aromatic groups, e.g. dipivefrine, ibopamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/63—Oleaceae (Olive family), e.g. jasmine, lilac or ash tree
    • 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
    • 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
    • A61K9/0043—Nose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • 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
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration

Definitions

  • the present invention relates to the use of the secoiridoids, such as oleacein and oleocanthal, to prevent or treat neuropathies that conduct to optic nerve injury, such as optic neuritis (hereafter ON).
  • the present invention also relates to pharmaceutical or nutraceutical compositions that contain said secoiridoids. Therefore, the present invention belongs to the technical field of medicine as well as to the food industry.
  • Optic neuritis is demyelinating inflammation that damages the optic nerve, a bundle of nerve fibers that transmits visual information from your eye to your brain. Pathologic changes involving various retinal structures may precede this occurrence. ON is a common neuro-ophthalmologic inflammatory disease that results in persistent vision impairment and usually affects one eye. Symptoms might include: pain, vision loss in one eye, visual field loss, loss of color vision, flashing lights (Wu GF et al, Curr Immunol Rev. 2015;11 :85-92; Beck RW et al, Am J Ophthalmol. 2004;137:77-83)
  • Ocular inflammation usually has an infectious or autoimmune etiology.
  • ON with unilateral involvement is most commonly associated with multiple sclerosis (MS).
  • MS multiple sclerosis
  • Atypical ON may, however, be associated with neuromyelitis optica spectrum disorders (with presence of anti-aquaporin-4 or anti-myelin oligodendrocyte glycoprotein, MOG, antibodies), acute disseminated encephalomyopathy and other autoimmune conditions such as sarcoidosis, systemic lupus erythematosus, Sjogren’s syndrome or Behget’s disease.
  • MOG has been shown to be present abundantly inside the optic nerve, and inflammatory cells presumably react to the MOG antigen of the optic nerve to cause tissue damage.
  • MOG antigen has a high possibility of causing optic neuritis.
  • Methylprednisolone pulse therapy has been the mainstay of treatment for the acute phase of ON. Corticosteroids accelerate the recovery of vision; however, they do not improve the visual prognosis. Numerous undesirable side effects are associated with corticosteroids. One study even indicates that methylprednisolone accelerates neuron apoptosis in the central nervous system. With the serious side effects of corticosteroids and their lack of neuroprotective effect, patients with ON urgently need a novel medication with anti-inflammatory properties, immune regulation, and neuroprotective effects.
  • the present invention relates to the search for new treatments for MS-related alterations, in particular, preferably optic neuritis and describes a new pharmacological application of the oleacein and oleocanthal as agents that markedly reduced the clinical and the immune/oxidative hallmarks of the experimental optic neuritis (EON).
  • EAE experimental autoimmune encephalomyelitis
  • Electroretinogram and visual-evoked potential studies have demonstrated that visual function is impaired in MS patients and in animals with experimental autoimmune encephalomyelitis (EAE), the animal model which mimicks many of the features of MS.
  • EAE autoimmune encephalomyelitis
  • mice with EAE often develop ON.
  • secoiridoids such as oleacein and oleocanthal
  • BBB blood-brain barrier
  • Secoiridoids are monoterpenoids, derived from iridoids in plants, based on the 7,8- seco-cyclopenta[c]-pyranoid skeleton. Most of secoiridoids and iridoids have been isolated from plants and approximately 600 different structures are known. Almost all the secoiridoids are glycosides. This group of phytochemicals occur wide-spread in nature, and exhibit a wide range of biological and pharmacological activities, including antibacterial, anticancer, anticoagulant, antifungal, antioxidative, antiprotozoal and hepatoprotective activities (Dinda B. et al. , Chem Pharm Bull (Tokyo). 2009 Aug; 57(8): 765-96)
  • a first aspect of the present invention relates to a compound of formula (I):
  • Ri is -OH or H
  • pharmaceutically acceptable salts or solvates thereof relates to salts or solvates which, on being administered to the recipient, are capable of providing a compound such as that described herein.
  • the preparation of salts and derivatives can be carried out by methods known in the state of the art.
  • pharmaceutically acceptable relates to molecular entities and compositions that are physiologically tolerable and do not typically produce an allergic reaction or a similar unfavourable reaction, such as gastric upset, dizziness and similar side effects, when administered to a human.
  • pharmaceutically acceptable means approved by a regulatory agency of a federal or state government or collected in the US Pharmacopoeia or other generally recognised pharmacopeia for use in animals and, more particularly, in humans.
  • the compounds used in the invention may be in crystalline form, either as free compounds or as solvates (e.g.: hydrates), and it is understood that both forms fall within the scope of the present invention.
  • Solvation methods are generally known in the state of the art. Suitable solvates are pharmaceutically acceptable solvates. In a particular embodiment, the solvate is a hydrate.
  • “Tautomers” are understood to be the two isomers that differ only in the position of a functional group because between the two forms there is a chemical balance in which a migration of a group or atom occurs.
  • the compounds used in the invention are intended to include compounds that differ only in the presence of one or more isotopically enriched atoms.
  • compounds having the present structures except for the substitution of a hydrogen atom for a deuterium atom or a tritium atom, or the substitution of a carbon atom for a carbon atom enriched in 13 C or 14 C or a nitrogen atom enriched in 15 N fall within the scope of this invention.
  • the compound of formula (I) is oleacein:
  • the compound of formula (I) is oleocanthal:
  • the administered dose of the compound of formula (I) its pharmaceutically acceptable salts, tautomers and/or solvates thereof varies between 5 mg/d ay and 20 mg/day, more particularly 10 mg per kg per day.
  • the compounds of the present invention can be administered by any suitable administration route, for example: oral, parenteral (subcutaneous, intraperitoneal, intravenous, intramuscular, etc.), intranasal inhaled etc.
  • the invention also relates to a composition comprising the compounds of the present invention for use in the treatment and/or prevention of optic neuritis.
  • the composition could be a pharmaceutical composition or a nutraceutical composition.
  • nutraceutical composition as used herein include food product, foodstuff, dietary supplement, nutritional supplement or a supplement composition for a food product or a foodstuff.
  • the composition is a pharmaceutical composition which comprises pharmaceutically acceptable excipients, adjuvants and/or vehicles.
  • excipients, adjuvants and/or carriers relates to molecular entities or substances through which the active ingredient is administered.
  • Such pharmaceutical excipients, adjuvants or carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and similar oils, excipients, disintegrating agents, humectants or dilutes. Suitable pharmaceutical excipients and carriers are described in "Remington's Pharmaceutical Sciences” by E.W. Martin.
  • compositions can be administered by any suitable administration route, for example: oral, parenteral (subcutaneous, intraperitoneal, intravenous, intramuscular, etc.), etc.
  • said pharmaceutical compositions may be in a pharmaceutical form of oral administration, either solid or liquid.
  • pharmaceutical forms of oral administration include tablets, capsules, granules, solutions, suspensions, etc., and may contain conventional excipients such as binders, dilutes, disintegrating agents, lubricants, humectants, etc., and may be prepared by conventional methods.
  • the pharmaceutical compositions may also be adapted for parenteral administration, in the form of, for example, solutions, suspensions or lyophilised, sterile products in the suitable dosage form; in this case, said pharmaceutical compositions will include suitable excipients, such as buffers, surfactants, etc. In any case, the excipients are chosen according to the pharmaceutical form of administration selected.
  • the compounds of the present invention may be used together with other additional drugs to provide a combined therapy.
  • Said additional drugs may form part of the same pharmaceutical composition or, alternatively, may be provided as a separate composition for simultaneous administration or not with the pharmaceutical composition comprising the compounds of the present invention.
  • the compounds of the present invention are in a pharmaceutically acceptable form or are substantially pure, that is, that it has a pharmaceutically acceptable level of purity excluding the normal pharmaceutical additives, such as diluents and carriers, and is free from any materials considered toxic at normal dosage levels.
  • the purity levels for the active substance are particularly above 50%, more particularly above 70%, and still more particularly above 90%.
  • the levels of the compound with formula (I), or its salts or solvates are above 95%.
  • the invention relates to a compound of formula (I), its pharmaceutically acceptable salts, tautomers and/or solvates thereof or compositions for the treatment and/or prevention of optic neuritis.
  • the invention relates to method to treat and/or prevent optic neuritis comprising administering a compound or a composition of the invention to a subject in need thereof.
  • the invention relates to the use of a compound or a composition of the invention for the preparation of a medicament for the prevention and/or treatment of optic neuritis.
  • T reatment is understood widely, referring to reducing the potential for a certain disease, reducing the occurrence of a certain disease, and/or a reduction in the severity of a certain disease particularly, to an extent that the subject no longer suffers discomfort and/or altered function due to it.“T reatment” refers to provide a therapeutic benefit or desired clinical result, which it is not necessarily a cure for a particular disease or disorder, but rather encompasses a result which most typically includes alleviation of the disease, elimination of the disease, reduction or alleviation of a symptom associated with the disease, prevention of a secondary disease resulting from the occurrence of a primary disease, diminishment of extent of disease, stabilized (i.e. , not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable of the disease.
  • Prevention intends to avoid the appearance of said disease.
  • the prevention can be complete (e.g. the total absence of a disease).
  • the prevention can also be partial, such that for example the occurrence of a disease in a subject is less than that which would have occurred without the administration of the compounds of the present invention.
  • Prevention also refers to reduced susceptibility to a clinical condition.
  • Oleacein (OLE) treatment diminishes specific auto-antibody production in EAE mice. Titers of MOG-specific lgG1 in serum samples at 1/60 dilution.
  • C healthy mice.
  • C+OLE healthy mice treated with OLE.
  • Experimental optic neuritis hereafter, EON
  • EON+OLE induced mice.
  • Bar graphs represent the mean ⁇ SD of 5-8 animals. ⁇ p ⁇ 0.001 vs control and *p ⁇ 0.001 vs EAE.
  • Oleacein (OLE) treatment reduces inflammation in the optic nerve during EON.
  • OLE hematoxylin & eosin
  • Oleacein (OLE) treatment reduces inflammation in EON.
  • Expression in serum of inflammatory-related parameters were used as measures of protective responses: levels of tumor necrosis factor-a.TNFa (A), granulocyte-macrophage colony-stimulating factor, GM-CSF (B), galectin-3, Gal-3 (C) and interleukin-1 b, IL-1 b (D) in serum were used as measures of protective responses.
  • C healthy mice.
  • C+OLE healthy mice treated with OLE.
  • EON induced mice.
  • EON+OLE induced-mice treated with OLE. Bar graphs represent the mean ⁇ SD of 5-8 animals. ⁇ p ⁇ 0.001 and ⁇ p ⁇ 0.01 vs control and **p ⁇ 0.01 and ***p ⁇ 0.05 vs EAE.
  • Oleacein (OLE) treatment reduces demyelination in the optic nerve during EON.
  • OLE treatment prevents demyelination, optic nerves were isolated from mice 21-23 days postimmunization and were stained with LFB. Histological analysis of optic nerve from control mice, C; control mice treated with OLE, C+OLE; induced mice, EON; and induced-mice treated with OLE, EON+OLE, showed demyelination. Oleacein treatment ameliorated all these parameters.
  • Oleacein (OLE) treatment reduces oxidative stress in the optic nerve during EON.
  • optic nerves were isolated from mice 21-23 days postimmunization and were stained with the oxidative fluorescent dye, dihydroethidium, DHE.
  • A Representative images of DHE staining
  • B bar graph showing red fluorescence quantitation of sections of optic nerve from control mice, C; control mice treated with OLE, C+OLE; induced mice, EON; and induced-mice treated with OLE, EON+OLE, showed anion superoxide buildup. Oleacein treatment ameliorated all these parameters.
  • Oleacein (OLE) treatment increases neuroprotection in EON.
  • MDA malondialdehyde
  • AOPP advanced oxidation protein products
  • C ferric reducing/antioxidant power
  • FRAP ferric reducing/antioxidant power
  • D ROS scavenger sestrin-3
  • Oleacein (OLE) treatment protects blood-brain barrier disruption and diminishes molecular extravasation in EON mice. Endogenous extravasation of IgG was used as a measurement of blood-brain barrier disruption and plasma proteins extravasation in brain.
  • C healthy mice. C+OLE, healthy mice treated with OLE.
  • EON induced mice.
  • EON+OLE induced-mice treated with OLE. Bar graphs represent the mean ⁇ SD of 5 animals. ⁇ p ⁇ 0.001 vs control and ***p ⁇ 0.05 vs EAE.
  • Oleacein inhibits responses of activated microglia, including production of reactive oxygen species, ROS (A); induction of inflammatory regulators (B); and synthesis and release of inflammatory cytokines (C).
  • BV-2 microglial cells were pretreated for 30 min with the indicated doses of OLE:
  • Oleocanthal inhibits responses of activated microglia, including induction of inflammatory regulators (A); and synthesis and release of inflammatory cytokines (B).
  • EON Experimental optic neuritis
  • mice were immunized by subcutaneous injection of this emulsion on day 0.
  • day 0 and 2 were administered intraperitoneally 300 ng/200 pi of Bordetella pertussis toxin.
  • OLE oleacein
  • the inventors also determine the circulating levels of the inflammatory proteins tumor necrosis factor-a (TNFa), galectin-3 (Gal-3) and granulocyte-macrophage colony- stimulating factor (GM-CSF) in serum samples.
  • TNFa tumor necrosis factor-a
  • Gal-3 galectin-3
  • GM-CSF granulocyte-macrophage colony- stimulating factor
  • Optic nerve demyelination begins after onset of inflammation and can be detected by luxol fast blue (LFB) staining of myelin.
  • LFB luxol fast blue
  • Untreated EAE mice showed a notably increase in demyelination compared to control mice. Unstained regions indicating destruction of the myelin sheath was observed in optic nerve from EON mice. (Fig. 4).
  • Optic nerves of OLE-treated EON mice showed increased LFB staining compared with optic nerves of untreated EAE mice, thus meaning a suppression in the demyelination in optic nerves.
  • optic nerve from EON mice showed an increased red fluorescence intensity throughout all tissue.
  • OLE treatment inhibited EON-induced ROS production: ethidium red fluorescence was extensively attenuated, being similar to the observed in tissues from healthy-control mice.
  • the inventors assessed the serum levels of advanced oxidation protein products (AOPP) and malondialdehyde (MDA), as the end products of lipid peroxidation (Fig. 6A and B).
  • the EON group showed significantly increased serum levels of MDA and AOPP in comparison with the control group. Meanwhile, OLE treatment effectively prevented these increases.
  • the serum anti-oxidant capacity evaluated by a ferric reducing/antioxidant power (FRAP) assay, as a marker of non-enzymatic antioxidant status, and Sestrin-3 levels, as a ROS disruptor, was significantly reduced in EON mice in comparison with that of control group (Fig. 6C and D). T reatment with OLE showed a significant attenuation of this decrease compared to untreated EAE mice.
  • FRAP ferric reducing/antioxidant power
  • the optic nerve is considered a part of the CNS.
  • BBB blood- brain-barrier
  • BBB brain-retinal-barrier
  • BBB brain-retinal-barrier
  • the inventors characterized the EON-induced BBB damage in OLE treated and untreated mice by analysis of endogenous serum IgG leakage into brain using immunohistochemistry. The intensity of fluorescence signals was quantified using Image J software (NIH, Bethesda, MD, USA). As shown in Fig. 7, brain from untreated EON-mice revealed a marked increase in IgG extravasation (c,g) compared to healthy-control animals (a,b). However, this enhanced permeability was prevented by the administration of OLE. The treatment with OLE did not modify BBB integrity in control animals.
  • the inventors evaluate whether the protective effects found in vivo in OLE-treated EON mice involve direct actions on relevant CNS inflammatory cells, the inventors studied the effects of OLE on activated BV-2 microglia cells - to mimic responses observed on neuroinflammatory disorders (Fig. 8). Given that ROS production may shape specific inflammatory programs the inventors investigated intracellular ROS accumulation. Flow cytometry analysis showed that intracellular ROS build up, which was significantly increased in LPS- treated BV-2 cells, was suppressed drastically in cells pretreated with different doses of OLE (Fig 8A).
  • BV-2 cells were pretreated with 1 , 10 and 20 mM of OLE for 30 min and then stimulated with LPS (0.1 pg/ml) for 4 and 24 h.
  • LPS 0.1 pg/ml
  • FIG. 8B western blot analysis of LPS-activated BV2 cells, showed an increase expression of iNOS and COX-2 after 4 and 24 h in comparison to control unstimulated cells.
  • cell pretreatment with OLE led to a dose-dependent inhibition of LPS-induced iNOs and COX-2 production, whereas OLE per se did not affect their basal expression.
  • This invention also relates to methods of using the natural compounds, oleacein and oleocanthal, to inhibit responses of activated microglia.
  • oleocanthal on relevant CNS inflammatory cells.
  • the inventors studied the effects of oleocanthal on activated BV-2 microglia cells - to mimic responses observed on neuroinflammatory disorders (Fig. 9).
  • Oleocanthal was isolated from an olive oil extract prepared using the extraction method described by Karkoula E. (Karkoula E. et al. , J Agric Food Chem. 2012;60:11696-11703) as described before.
  • BV-2 cells were pretreated with 1 , 10 and 20 mM of oleocanthal for 30 min and then stimulated with LPS (0.1 pg/ml) for 4 and 24 h.
  • LPS 0.1 pg/ml
  • FIG. 9A western blot analysis of LPS-activated BV2 cells, showed an increase expression of iNOS and COX-2 after 4 and 24 h in comparison to control unstimulated cells.
  • cell pretreatment with oleocanthal led to a dose-dependent inhibition of LPS-induced iNOS and COX-2 production, whereas oleocanthal per se did not affect their basal expression.
  • oleocanthal also reduced the ability of LPS to induce TNFa and mature I L-1 b secretion in a dose-dependent manner (Fig. 9B).
  • the activation of the signaling mediators/mechanisms that influence these inflammatory responses such as phosphorylation of P65-NFKB and overexpression of NLRP3 were also reduced (Fig. 9A).

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Abstract

La présente invention concerne l'utilisation des sécoiridoïdes, tels que l'oléaceine et l'oléocanthal, pour prévenir ou traiter des neuropathies qui conduisent à une lésion du nerf optique telle qu'une névrite optique. La présente invention concerne également une composition pharmaceutique ou une composition nutraceutique comprenant lesdits sécoiridoïdes.
PCT/EP2019/087044 2018-12-28 2019-12-26 Utilisation de sécoiridoïdes pour le traitement de la névrite optique Ceased WO2020136221A1 (fr)

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ESP201831296 2018-12-28
ES201831296A ES2769902B2 (es) 2018-12-28 2018-12-28 Uso de secoiridoides para el tratamiento de la neuritis óptica.

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CA2192209A1 (fr) * 1994-06-23 1996-01-04 Evan Benjamin Dreyer Traitement de la nevrite optique
WO2004028521A2 (fr) * 2002-09-24 2004-04-08 Novartis Ag Composes organiques
WO2006122128A2 (fr) * 2005-05-09 2006-11-16 The Trustees Of The University Of Pennsylvania Utilisation d'oleocanthal principal d'irrigation dans l'huile d'olive et composants structuralement et fonctionnellement semblables
WO2008001240A2 (fr) * 2006-06-29 2008-01-03 Kimberly-Clark Worldwide, Inc. Administration transdermique d'oléocanthal pour le soulagement de l'inflammation
US20090082738A1 (en) * 2007-09-24 2009-03-26 Vad Vijay B Natural Anti-Inflammatory Agents for Reducing Pain
WO2018114557A1 (fr) * 2016-12-22 2018-06-28 Novaliq Gmbh Compositions comprenant du tacrolimus pour le traitement de maladies oculaires inflammatoires intraoculaires
WO2018162769A2 (fr) * 2017-03-10 2018-09-13 Universidad De Sevilla Utilisation du dmso pour la synthèse d'oléacéine et d'oléocanthal

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