EP3592427A1 - Prävention der risikos im zusammenhang mit arzneimittelinduzierter qt-intervallverlängerung durch verwendung eines spezifischen inhibitors der produktion von ros mitochondrialen ursprungs - Google Patents

Prävention der risikos im zusammenhang mit arzneimittelinduzierter qt-intervallverlängerung durch verwendung eines spezifischen inhibitors der produktion von ros mitochondrialen ursprungs

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Publication number
EP3592427A1
EP3592427A1 EP18712965.5A EP18712965A EP3592427A1 EP 3592427 A1 EP3592427 A1 EP 3592427A1 EP 18712965 A EP18712965 A EP 18712965A EP 3592427 A1 EP3592427 A1 EP 3592427A1
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EP
European Patent Office
Prior art keywords
drug
ros
atx
att
pharmaceutical composition
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP18712965.5A
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English (en)
French (fr)
Inventor
Olivier Petitjean
Guillaume Petitjean
Elodie PETITJEAN
Grégoire PETITJEAN
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Childs Marc
Original Assignee
Childs Marc
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Priority claimed from FR1751839A external-priority patent/FR3063643A1/fr
Priority claimed from FR1751836A external-priority patent/FR3063640B1/fr
Application filed by Childs Marc filed Critical Childs Marc
Publication of EP3592427A1 publication Critical patent/EP3592427A1/de
Withdrawn legal-status Critical Current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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/385—Heterocyclic compounds having sulfur as a ring hetero atom having two or more sulfur atoms in the same ring
    • 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
    • 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
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • A61K31/435—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
    • A61K31/4468—Non condensed piperidines, e.g. piperocaine having a nitrogen directly attached in position 4, e.g. clebopride, fentanyl
    • 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
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • 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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5383—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with heterocyclic ring systems
    • 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
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/5415—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
    • 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
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/55—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/06—Antiarrhythmics

Definitions

  • the present invention relates to the prevention and / or treatment of diseases in which are involved the reactive oxygen species (or ROS) of mitochondrial origin. It relates more particularly to the use of an inhibitor of the production of mitochondrial ROS, in particular anethole trithione, to prevent the risks associated with prolongation of OT when taking drugs known to induce such a side effect. .
  • Mitochondria participate in the pathogenesis of almost all diseases associated with aging, including cardiovascular diseases, neurodegenerative diseases (Parkinson's disease, Alzheimer's disease, etc.), diabetes, as well as ischemic tissue dysfunction. . It is widely accepted that it plays a central role in the "theory of free radicals of aging”. This theory asserts that the accumulation of damage by reactive oxygen species (ROS) affects many cellular functions, particularly mitochondrial functions, which are essential for energy supply and proper functioning. cellular. Mitochondria thus appear to be the primary targets of ROS because optimal cell function is crucial in providing the energy a cell needs to repair itself.
  • ROS reactive oxygen species
  • mitochondria are the main source of ROS, they are also particularly sensitive to the damage caused by these ROS. Therefore, mitochondria themselves generate the ROS causing oxidative damage they undergo and contribute to their dysfunction later and cell death.
  • Drugs that can lead to prolongation of QT include fluoroquinolones (FQ), some anti-TB drugs used in cocktails for the treatment of multidrug-resistant TB - particularly the now-traditional combination of moxifloxacin, bedaquillin and clofazimine - macrolides and, above all, erythromycin for IV administration, imidazole antifungals, such as ketoconazole, or Trisenox ® indicated for the treatment of promyelocytic leukemias and antiarrhythmics such as Sotalol ® or Cordarone ® .
  • FQ fluoroquinolones
  • some anti-TB drugs used in cocktails for the treatment of multidrug-resistant TB - particularly the now-traditional combination of moxifloxacin, bedaquillin and clofazimine - macrolides and, above all, erythromycin for IV administration
  • imidazole antifungals such as ketoconazole
  • Trisenox ® indicated for the treatment of promy
  • antipseudomonas such as ciprofloxacin or moxifloxacin may regain activity with respect to Pseudomons spp. or Acinetobacter spp., for example.
  • the inventors propose to reduce the production of ROS at the mitochondrial level to reduce the risk of toxicity that can lead to the prolongation of QT, by avoiding the deleterious side effects of non-selective antioxidants.
  • the inventors have established the interest of administering a specific inhibitor of the production of ROS of mitochondrial origin, in particular anethole trithione (ATT), to prevent the risks of prolongation of drug-induced QT.
  • ATT anethole trithione
  • the ATT already has marketing authorization under the trade name Sulfarlem ® to increase the secretion of bile and saliva. It is used to treat difficult digestion and dryness of the mouth. Since 70 years that this product is marketed in France, no side effect has been reported to date relative to a long-term use of this molecule.
  • ⁇ unlike conventional antioxidants, acts directly and selectively on the production of mitochondrial ROS, mainly at complex I (or complex III) of the mitochondrial respiratory chain, sites which are at the same time the principal sites of production of ROS and the principal sites of the mitochondrial dysfunctions (Tebourbi O., 2012, idem above).
  • the ATT is the first FDA- and EMA-authorized human-use drug that prevents mitochondria from producing ROS at complex I or III of the respiratory chain.
  • the present invention has a triple advantage:
  • ATT has the necessary qualities to address the technical problem of preventing the risk of QT prolongation of drug origin, for several reasons.
  • ATT is a potent free radical and antioxidant scavenger with multiple mechanisms of action as has been shown on a human T cell model (Khanna et al., Biochem Pharmacol 1998, 56: 61-69). This property allows protection of the tenotoxicity caused by FQ. (ciprofloxacin, ofloxacin and pefloxacin) in a model of tendon cell culture; pre-incubation of the tenocytes with ATT at the concentration of ⁇ for 3 hours significantly reduces the cellular production of ROS and thus protects against oxidative stress induced by FQ.
  • the ATT is, unlike the majority of other antioxidants, a liposoluble molecule which gives it an excellent tissue penetration as a cell (the Vd of ADT is, in the rat, of the order 2L / kg, nearly 10 times the volume of extracellular liquids [Yu HZ et al J Pharm Sci, 2011, 100: 5048-5058]), explaining its access to the mitochondria.
  • the ATT acts at concentrations of the order of one micromolar, 10 ⁇ in the work of Pouzaud et al. (2004), a concentration that can easily be reached at the doses usually used; and this molecule seems to have persistent effects over time, certainly several hours which should facilitate the mode of administration of the product.
  • the ATT undergoes a rapid demethylation forming a very likely active derivative, 4-OH-anetholtrithione (or ATX), carrying an alcohol function on the aromatic cycle; this function is esterifiable and can thus give access to water-soluble esters even though the ATT and its ATX metabolite are insoluble in water.
  • ATX 4-OH-anetholtrithione
  • the present invention proposes, quite surprisingly and innovatively, to use this medicament in a new therapeutic indication, namely to prevent the risks of prolongation of drug-induced QT.
  • a first object of the present invention relates to the use of a specific inhibitor of the production of mitochondrial ROS to prevent the risks of prolongation of the QT interval of drug origin.
  • telomeres a compound capable of specifically inhibiting the production of ROS at the mitochondrial respiratory chain level, without affecting the production of cellular ROS at the level of the cytosol; this specificity is essential because it prevents side effects associated with a defect of ROS at the level of the cytosol, as can be observed in case of excessive inhibition of the production of ROS by a non-selective antioxidant.
  • this inhibitor is capable of inducing specific inhibition of ROS production at complex I (or III) of the mitochondrial respiratory chain.
  • inhibitors are, by way of example, ATT, ⁇ or NC-POBS, but any other compound having the same specificity of inhibition is suitable.
  • an inhibitor means the use of at least one specific inhibitor of mitochondrial ROS production; it can therefore be an inhibitor or a combination of several inhibitors, as described below.
  • the ATT for anethole trithione is 5- (4-methoxyphenyl) -3H-1,2-dithiole-3-thione. It is also known as ADT. His formula is as follows:
  • ATX is the phenolic form of ⁇ as metabolized by the liver in both humans and animals. This 4-OH-anethole trithione form has been previously described (Li et al., J Pharm Biomed Anal, 2008, 47: 612-617). The structure of ATT is preserved during this metabolization, there is every reason to believe that the antiROS activity carried by ATT is found in ATX, especially since after oral administration which is currently the marketed form, the most of the circulating product found is ⁇ (Yu, 2011). In addition, ⁇ carries a para phenol group which allows the formation of esters.
  • ⁇ is used in its esterified form, for example in the form of ester of: phosphate, ethylidene phosphate, sulphate, hemisuccinate, acetate, propionate, isobutyrate, hexanoate, pivalate, ethoxycarbonate, nicotinate, or amino acid ester such as glycine, diethylglycine or valine ester, and the list is not limiting.
  • NC-POBS corresponds to the N-cyclohexyl-4- (4-nitrophenoxy) benzenesulfonamide, single molecule described in the literature so far as a specific inhibitor of mitochondrial ROS production site the Q of the respiratory chain ( Orr et al., Free Radie, Biol Med, 2013, 65: 1047-1059).
  • the specific inhibitor is selected from ⁇ , ⁇ and an ATX ester.
  • the prevention of Q.T elongation is achieved through the association of at least two of ⁇ , ⁇ molecules and an ATX ester.
  • prolongation of QT of drug origin is meant a pathological situation characterized by the fact that the QT interval is lengthened following the taking of a drug.
  • the QT interval is one of the electrical data of the electrocardiogram, it corresponds to the electrical duration of the cardiac contraction (systole).
  • the duration of this interval varies with the heart rate and with the activity of the autonomic nervous system.
  • the threshold from which QT prolongation is likely to degenerate to arrhythmia is not well established.
  • the upper limit is between 420 and 500 ms, depending on age and gender.
  • torsades de pointe that can progress to life-threatening ventricular fibrillation.
  • prevention means inhibiting the production of mitochondrial ROS before they cause QT elongation. Prevention is also about reducing the risk of QT prolongation associated with taking certain medications known to prolong QT space and decrease related damage. this medication at the heart function.
  • the subject to be treated is preferably a human being.
  • the inventors propose associating the administration of an inhibitor of the production of ROS of mitochondrial origin with the taking of a known medicament to promote the elongation of Q.T.
  • the inhibitor of mitochondrial ROS production may be administered before or concurrently with the drug taking associated with a risk of OT elongation.
  • Drugs known to promote the lengthening of OT include antiarrhythmics, antihistamines, antibiotics, anti-tuberculosis, antimalarials, anti-cancer and psychotropic drugs.
  • the ROS inhibitor of mitochondrial origin is associated with an antibiotic of the family of fluoroquinolones (FO).
  • ATX or one of these derivatives may be administered with the moxifloxacin-bedaquillin-clofazimine combination or at least one of these antibiotics to prevent OT elongation in the treatment of multidrug tuberculosis. resistant. It can also be combined with ciprofloxacin, levofloxacin, moxifloxacin or any other antibacterial FO, so as to be able to increase the dosage and thus make it possible to "recover" resistant strains present at low level.
  • the inhibitor of ROS production of mitochondrial origin is associated with arsenic trioxide (Trisenox ® ) to prevent OT elongation in the treatment of promyelocytic leukemia.
  • Trisenox ® arsenic trioxide
  • the inhibitor of ROS production of mitochondrial origin is associated with antiarrhythmics such as sotalol hydrochloride (Sotalol ® ) or amiodarone (Cordarone ® ) to prevent OT elongation in the prevention of recurrence of certain tachycardias.
  • antiarrhythmics such as sotalol hydrochloride (Sotalol ® ) or amiodarone (Cordarone ® ) to prevent OT elongation in the prevention of recurrence of certain tachycardias.
  • the inhibitor of ROS production of mitochondrial origin is associated with a drug known to extend the OT interval selected from the following list: Alfuzosin, Amantadine, Amiodarone, Amisulpride, Amitriptyline, Amphotericin B , Anagrelide, Apomorphine, Aripiprazole, Asenapine, Astemizole, Atazanavir, Atomoxetine, Azithromycin, Bedaquiline, Bendamustine, Bendroflumethiazide, Bendrofluazide, Benperidol, Bepridil, Betrixaban, Bortezomib, Bosutinib, Buprenorphine, Cabozantinib, Capecitabine, Ceritinib, Chloral Hydrate, Chloroquine, Chlorpromazine , Cilostazol, Ciprofloxacin, Cisapride, Citalopram, Clarithromycin, Clofazimine
  • the specific inhibitor of ROS production of mitochondrial origin described in the applications mentioned above is the anethole trithione (ATT) used in monotherapy.
  • ATT anethole trithione
  • the daily dose of anethole trithione for use in decreasing the risk of QT prolongation associated with taking a drug known to lengthen the QT gap is between 40 and 400. mg.
  • this daily dose is between 80 and 240 mg.
  • the daily dose of anethole trithione is separated into two doses of between 20 and 200 mg each, even more preferably in two doses of between 40 and 120 mg each.
  • each dose may comprise 40, 50, 60, 70, 80, 90, 100, 110, 120, 150 or 200 mg of ATT.
  • the dose of anethole trithione is 80 mg per dose, or 160 mg per day.
  • anethole trithione is used as monotherapy in the prevention of the risk of QT prolongation associated with taking a drug known to lengthen the QT gap in a pediatric population.
  • the daily dose of ATT is between 40 and 120 mg.
  • the daily dose of anethole trithione for a pediatric population is divided into two doses of 20 to 60 mg each depending on the age and weight of the child or adolescent.
  • each child dose may comprise 20, 30, 40, 50, 60, 70, 80, 90, 100, 110 or 120 mg of ATT.
  • the present invention also relates to a method of preventing drug-induced QT prolongation by administering a therapeutically effective dose of a specific inhibitor of mitochondrial ROS production to a patient who needs it.
  • Another embodiment of the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising ⁇ and / or ATX and / or an ATX ester and excipients suitable for preventing the elongation of drug-induced QT.
  • the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising (i) ⁇ and / or ATX and / or an ATX ester and (ii) a drug known to prolong the QT interval, as well as appropriate excipients.
  • the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising ⁇ and / or ATX and / or an ATX ester and (ii) a drug known to extend the QT interval selected from following list: Alfuzosin, Amantadine, Amiodarone, Amisulpride, Amitriptyline, Amphotericin B, Anagrelide, Apomorphine, Aripiprazole, Asenapine, Astemizole, Atazanavir, Atomoxetine, Azithromycin, Bedaquiline, Bendamustine, Bendroflumethiazide, Bendrofluazide, Benperidol, Bepridil, Betrixaban, Bortezomib, Bosutinib, Buprenorphine, Cabozantinib, Capecitabine, Ceritinib, Chloral hydrate, Chloroquine, Chlorpromazine, Cilostazol, Ciprofloxacin, Cis
  • the composition comprises (i) ⁇ and (ii) a drug known to extend the QT interval, as well as suitable excipients.
  • the invention relates to a pharmaceutical composition comprising (i) ATTA and (ii) moxifloxacin, as well as suitable excipients.
  • the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising (i) ATK and / or ATX and / or an ATX ester and (ii) a drug known to prolong the QT interval. having been withdrawn from the market due to an adverse benefit-risk ratio, as well as the appropriate excipients.
  • the invention relates to an ester-like chimera formed between ⁇ and a QT-prolonging drug (according to the foregoing list) having a carboxylic acid function.
  • chimera means the conjugation between 4-OH-Anetholetrithione and the carboxylic acid function of a drug causing an extension of the QT interval, allowing the formation of an ATX ester comprising said medicine.
  • the purpose of this chimera is to graft ⁇ on the drug causing a prolongation of the QT interval, in order to confer the preventive effect of ⁇ on the prolongation of the QT interval.
  • the invention relates to a chimera formed between ⁇ and a drug belonging to the class of fluoroquinolones.
  • the invention relates to a chimera formed between ⁇ and a fluoroquinolone selected from moxifloxacin, ciprofloxacin, levofloxacin or gepeploxacin.
  • the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a chimera formed between ⁇ and a QT-prolonging drug (according to the foregoing list) having a carboxylic acid function, and suitable excipients.
  • the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a chimera formed between ⁇ and a fluoroquinolone, as well as suitable excipients.
  • Such a preferred pharmaceutical composition comprises a chimera formed between ⁇ and a fluoroquinolone selected from moxifloxacin, ciprofloxacin, levofloxacin or gepeploxacin.
  • each dog is equipped with an implantable teletransmitter of the type "DSI radio-telemetry transmitter" allowing continuous ECG recording over 24h in 10 min sequences, recording including the measurement of the spaces PQ., QRS, QT and QTc (correction according to Van de Water's formula), heart rate as well as systolic and diastolic pA and mean pA.
  • ECG analysis is performed using ECG51a software from Notocord Systems ® and pA with APR30a software, also from Notocord Systems ® .
  • Expected results A significant prolongation of the QT and QTc intervals under moxifloxacin is expected and a maintenance of these intervals in the normality zone in case of pretreatment by ATT.
  • the volunteers, 16 men aged 18 to 40, are selected according to the following criteria: medical history, physical examination (including a BMI between 18 and 26 kg / m2), vital signs, clinical examinations, biological assessment and ECG, 12 leads .
  • the selected volunteers are equipped with an ECG Holter for 24h recording.
  • ⁇ 4th sequence each volunteer receives an oral dose of 400 mg moxifloxacin, 60 min after an oral dose of 75 mg ATT (3 tablets of Sulfarlem ® 25).

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EP18712965.5A 2017-03-07 2018-03-07 Prävention der risikos im zusammenhang mit arzneimittelinduzierter qt-intervallverlängerung durch verwendung eines spezifischen inhibitors der produktion von ros mitochondrialen ursprungs Withdrawn EP3592427A1 (de)

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FR1751839A FR3063643A1 (fr) 2017-03-07 2017-03-07 Prevention des risques associes a un allongement de l'intervalle qt d'origine medicamenteuse a l'aide d'un inhibiteur specifique de la production de ros d'origine mitochondriale
FR1751836A FR3063640B1 (fr) 2017-03-07 2017-03-07 Traitement de la fibrose pulmonaire a l'aide d'un inhibiteur selectif de la production d'especes reactives de l'oxygene d'origine mitochondriale
PCT/FR2018/050521 WO2018162845A1 (fr) 2017-03-07 2018-03-07 Prevention des risques associes à un allongement de l'intervalle qt d'origine medicamenteuse à l'aide d'un inhibiteur specifique de la production de ros d'origine mitochondriale

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PT3562486T (pt) 2016-12-31 2024-06-12 Bioxcel Therapeutics Inc Uso de dexmedetomidina sublingual para o tratamento da agitação
EP3813802A4 (de) 2018-06-27 2022-06-08 Bioxcel Therapeutics, Inc. Filmformulierungen mit dexmedetomidin und verfahren zur herstellung davon
WO2021016112A2 (en) 2019-07-19 2021-01-28 Bioxcel Therapeutics, Inc. Non-sedating dexmedetomidine treatment regimens
FR3112220B1 (fr) 2020-07-02 2022-07-08 Lencify Procede de recherche assistee dans une base de donnees et systeme de recherche associe
US11806334B1 (en) 2023-01-12 2023-11-07 Bioxcel Therapeutics, Inc. Non-sedating dexmedetomidine treatment regimens
US11903944B1 (en) 2023-05-30 2024-02-20 King Faisal University Experimental model using pazopanib-induced cardiotoxicity

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AU6462500A (en) * 1999-07-29 2001-02-19 Patrick T. Prendergast Dithiolthione compounds for the treatment of neurological disorders and for memory enhancement
FR2807944B1 (fr) * 2000-04-25 2003-06-13 Solvay Pharma Utilisation de l'anethole-dithiolethione dans la prevention et le traitement de la tenotoxicite induite par un medicament
EP1886681A3 (de) * 2004-10-07 2008-11-19 Sulfidris S.r.l. 5-(p-Hydroxyphenyl)-3H-1,2-Dithiol-3-Thion-Valproatester
CN1732926B (zh) * 2005-09-02 2010-08-18 姚俊华 一种含药软胶囊
US9074254B2 (en) * 2007-03-29 2015-07-07 Vanda Pharmaceuticals, Inc. Method of predicting a predisposition to QT prolongation
ITMI20080382A1 (it) * 2008-03-07 2009-09-08 Ctg Pharma S R L Composizioni farmaceutiche oculari
SG184387A1 (en) * 2010-04-01 2012-11-29 Theravida Inc Methods of improving quality of sleep
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AU2016319184B2 (en) * 2015-09-08 2022-03-31 Centre Hospitalier Universitaire De Bordeaux Compounds for the treatment of diseases linked to mitochondrial reactive oxygen species (ROS) production

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US11554106B2 (en) 2023-01-17
US20210052549A1 (en) 2021-02-25
WO2018162845A1 (fr) 2018-09-13
JP2020510675A (ja) 2020-04-09

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