WO2008034202A2 - Traitement de la sclérose latérale amyotrophique - Google Patents

Traitement de la sclérose latérale amyotrophique Download PDF

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WO2008034202A2
WO2008034202A2 PCT/BE2007/000107 BE2007000107W WO2008034202A2 WO 2008034202 A2 WO2008034202 A2 WO 2008034202A2 BE 2007000107 W BE2007000107 W BE 2007000107W WO 2008034202 A2 WO2008034202 A2 WO 2008034202A2
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ivermectin
analogue
motor neuron
treatment
formula
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PCT/BE2007/000107
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WO2008034202A3 (fr
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Maria Andries
Wim Robberecht
Ludo Van Den Bosch
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Katholieke Universiteit Leuven
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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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system

Definitions

  • the present invention relates generally to the use of certain compounds for treatment, prevention or retardation of a Motor Neuron Disease (MND) and more particularly of amyotrophic lateral sclerosis (ALS). It in particularly relates to such use of an ivermectin or an analogue of ivermectin from the class of the macrocyclic lactones.
  • the invention also involves an Ivermectin or analogues of ivermectin from the class of the macrocyclic lactones for the preparation of a medicament to treat amyotrophic lateral sclerosis.
  • ALS Amyotrophic lateral sclerosis
  • SODl superoxide dismutase 1
  • the selective toxicity of the mutant SODl for motor neurons is not fully understood and most likely involves multiple pathways including formation of protein aggregates, proteasome dysfunction, axonal strangulation, oxidative damage, mitochondrial defects, caspase activation, changes in levels of Bcl-2 family members, changes in Ca 2+ homeostasis and AMPA receptor-mediated excitotoxicity.
  • proinflammatory molecules released from activated microglia could contribute to the propagation of the neurodegenerative process (for reviews see Bruijn, L.I., Miller, T.M., Cleveland, D.W. 2004. Annu. Rev. Neurosci. 27, 723- 749.; Cleveland, D.W., Rothstein, J.D. 2001. Nature Reviews 2, 806-819; Jullien, J.-P.
  • NBQX an AMPA-receptor antagonist
  • ALS is one of the most common neuromuscular diseases worldwide. Worlwide about 400 000 people are affected by this disease and people of all races and ethnic backgrounds are affected. In 90 to 95 percent of all ALS cases, the disease occurs apparently at random with no clearly associated risk factors. Patients do not have a family history of the disease, and their family members are not considered to be at increased risk for developing ALS. ALS most commonly strikes people between 40 and 60 years of age, but younger and older people also can develop the disease. Men are affected more often than women.
  • a medicament comprising an ivermectin or a functional derivative thereof that can be used to decrease discomfort caused by a motor neuron disease (MND) such as amyotrophic lateral sclerosis (ALS) and moreover can be used to prevent, retard and ameliorate a motor neuron disease (MND) such as amyotrophic lateral sclerosis (ALS).
  • MND motor neuron disease
  • MND amyotrophic lateral sclerosis
  • ALS amyotrophic lateral sclerosis
  • an ivermectin can extend the lifespan of a subject who is affected by ALS.
  • the invention is broadly drawn to a novel medicament for medical treatment of Motor Neuron Disease (MND) such as Progressive Bulbar Palsy (PBP) or such as amyotrophic lateral sclerosis (ALS), a fatal neurological disorder, characterised by progressive degeneration of the motor cells in the spinal cord and the brain.
  • MND Motor Neuron Disease
  • PBP Progressive Bulbar Palsy
  • ALS amyotrophic lateral sclerosis
  • Motor Neuron Disease is a disease affecting the motor neurons in the brain and spinal cord.
  • Motor neurons are the nerve cells along which the brain sends instructions, in the form of electrical impulses, to the muscles.
  • Degeneration of the motor neurons leads to weakness and wasting of muscles. This generally occurs in arms or legs initially, some groups of muscles being affected more than others. Some people may develop weakness and wasting in the muscles supplying the face and throat, causing problems with speech and difficulty chewing and swallowing.
  • MND does generally not affect touch, taste, sight, smell or hearing, nor directly bladder, bowel, or sexual function. In the vast majority of cases, the intellect remains unaffected. MND is generally a steadily progressive disease, but the rate of progression varies greatly from one person to another, hi most cases of MND, degeneration of both the upper and lower motor neurons occurs. This condition is called amyotrophic lateral sclerosis (ALS), characterised by muscle weakness, stiffness and fasciculations (muscle twitching) or, when the muscles involved in speech and swallowing are solely affected, Progressive Bulbar Palsy (PBP).
  • ALS amyotrophic lateral sclerosis
  • PBP Progressive Bulbar Palsy
  • ALS patients manifest symptoms associated with the loss of motor neurons, and/or the nerve cells in the spinal cord, brainstem, and motor cortex, which are normally in good control of the body's voluntary muscles.
  • motor neurons die, muscles weaken and shrink, and the body manifests the early-stage symptoms of ALS.
  • symptoms include, for example, unusual fatigue, clumsiness, muscle weakness, slurred speech, muscle atrophy, spasticity, spinal function disorders, and convulsions.
  • Psychiatric manifestations e. g., depression
  • depression may also result.
  • ALS cognitive impairment
  • some data suggest that as many as 15% of all ALS patients may experience some memory loss, behavioural changes, and problems with both judgment and simultaneously performing multiple tasks.
  • the usual cause of death from ALS is failure of the diaphragm muscles that control breathing.
  • ALS patients can prolong their lives by using a ventilator, especially since bladder and bowel function, sexual function, and all five senses are unaffected. But living on a ventilator is neither desirable nor free of complications such as pneumonia (resulting from pooling of secretions or aspiration).
  • a medicament comprising an ivermectin or a functional derivative thereof in particular of the microcyclic lactones can be used to decrease discomfort caused by a motor neuron disease (MND) such as amyotrophic lateral sclerosis (ALS) and moreover can be used to prevent, retard and ameliorate a motor neuron disease (MND) such as amyotrophic lateral sclerosis (ALS).
  • MND motor neuron disease
  • MND amyotrophic lateral sclerosis
  • ALS amyotrophic lateral sclerosis
  • the active compounds employed in the formulations according to the invention are known.
  • Ivermectin (MECTIZAN; 22,23 dihydroavermectin BIa) is a semisynthetic analog of avermectin BIa (abamectin), an insecticide developed for crop management.
  • Avermectins were isolated from the microorganism Streptomyces avermitilis as microbial metabolites (U.S. Pat. No. 4,310,519) and can occur essentially as a mixture consisting of the eight components A Ia, Alb, A2a, A2b, BIa, BIb, B2a, and B2b (I. Putter et al., Experentia 37 (1981) p.
  • the treatment of amyotrophic lateral sclerosis comprisese administering to an individual an effective amount of the group consisting of Ivermectin, Abamectin, Doramectin, Eprinomectin, Milbemycin oxime, Moxidectin and Selamectin.
  • Ivermectin Ivermectin
  • Abamectin Abamectin
  • Doramectin Eprinomectin
  • Milbemycin oxime Milbemycin oxime
  • Moxidectin Moxidectin
  • Selamectin Selamectin
  • the time allowed between doses and the length of time to take the medicine depend on several factors related to the condition of the patient and/or the medical problem for which he/she is taking ivermectin.
  • These compounds may be administered in a dosage of 20 to 500 microgram per kilogram (kg) of body weight, preferably in a dosage of 50 to 250 microgram per kilogram (kg) of body weight and most preferably in a dosage of 80 to 150 microgram per kilogram (kg) of body weight.
  • IGF-I or Myotrophin® Insulin- like growth factor 1
  • CNTF ciliary neurotrophic factor
  • VEGF vascular epithelial growth factor
  • IGF-I growth factor therapy
  • BBB blood brain barrier
  • Another avenue of therapy is in the regulation of brain glutamate levels, based on abnormally high glutamate concentrations found in cerebrospinal fluid of some ALS patients.
  • An abundance of the glutamate transporters in astrocytes (cells surrounding the neurons) known as EAAT2 involved in the removal of excess glutamate, is decreased in the cortex and spinal cord of patients with ALS and in mouse models.
  • EAAT2 an abundance of the glutamate transporters in astrocytes (cells surrounding the neurons) known as EAAT2
  • a high glutamate level leads to "excitotoxicity" (which is neuronal death due to the overactivation of glutamate receptors), a flooding of neurons with calcium, and a host of damaging downstream events.
  • SODl superoxide dismutase
  • ivermectin can increase the life span in a relevant transgenic mouse model affected by ALS.
  • Ivermectin was presented as a broad-spectrum anti-parasitic medicinal product for veterinary use (W. C. CAMPBELL, et al., (1983).
  • Ivermectin a potent new anti-parasitic agent, Science, 221, 823-828). It is effective against most common intestinal worms (except tapeworms), most acarids and some lice.
  • Ivermectin is a macrocyclic lacton that is efficient as a veterinary antiparasitic drug and as a successful medicine against river blindness in humans (Fisher, M.H., Mrozik, H. 1992. Annu. Rev. Pharmacol. Toxicol. 32, 537-553).
  • Ivermectin is generally a mixture of two compounds belonging to the avermectin class, 5-O- demethyl-22,23-dihydroavermectin Ala and 5-O-demethyl-22,23-dihydroavermectin Alb. They are also known as 22,23-dihydroavermectin BIa and 22-23 -dihydroavermectin B Ib. Ivermectin contains at least 80% of 22,23- dihydroavermectin B Ia and less than 20% of 22,23- dihydroavermectin BIb.
  • This active agent is part of the avermectin class, a group of macrocyclic lactones produced by the bacterium Streptomyces avermitilis (Reynolds J E F (Ed) (1993) Martindale). The extra pharmacopoeia, 29 th Edition, Pharmaceutical Press, London). They consist of two sub groups, the avermectins and the milbemycins. Their basic chemical structure consists of a cyclic lactone and a spiroketal addition constructed of two 6- membered rings. The avermectins also include a sugar (disaccharide oxy) linked at position 13.
  • ligand- gated ion channels are activated and/or modulated by IVM. These include a crayfish multiagonist-gated chloride-selective channel (Zufall, F., C. Franke, and H. Hatt. 1989.
  • the insecticide avermectin BIa activates a chloride channel in crayfish muscle membrane. J. Exp.
  • GABA A receptor (Krusek, J., Zemkova, H. 1994. Eur. J. Pharmacol. 259, 121-128.), the ⁇ 7 nicotinic acetylcholine receptor (Krause, R.M., Buisson, B., Bertrand, S., Corringer, P.-J.,
  • the findings of present invention has now been developed into a compositions and methods of treating, preventing or retarding amyotrophic lateral sclerosis.
  • the invention concerns a pharmaceutical compositions and methods of use thereof for the acute, chronic and prophylactic treatment of amyotrophic lateral sclerosis, and prophylaxis of amyotrophic lateral sclerosis.
  • the pharmacological arsenal to fight, prevent, and/or decrease its symptoms and progress is surprisingly limited.
  • MND Motor Neuron Disease
  • ALS amyotrophic lateral sclerosis
  • ALS Amyotrophic lateral sclerosis
  • MNDs motor neuron diseases
  • SBMA spinal-bulbar muscular atrophy
  • ALS is the most common form of motor neuron disease. Loss of both lower and upper motor neurons occurs in ALS. Symptoms include progressive skeletal muscle wasting, weakness, fasciculations, and cramping. Some cases have predominant involvement of brainstem motor neurons (progressive bulbar palsy). Unfortunately, treatment of motor neuron and related diseases is largely supportive at this time. ALS afflicts 1.5 times more men than women.
  • ALS amyotrophic Lateral Sclerosis: Its Natural History," Neurologic Clinics, Vol. 5, No. 1, February 1987, pp. 1-8.
  • ALS afflicts 5 to 10 people out of every 100,000 people. The progression of the disease is rapid. Most patients die within 5 years of onset. About 5-10% of ALS cases, known as familial ALS (FALS), are inherited. Although FALS is clinically indistinguishable from the "sporadic" form of ALS, there is no predominance of FALS in men as with sporadic ALS.
  • FALS familial ALS
  • ALS amyotrophic lateral sclerosis
  • ALS amyotrophic lateral sclerosis
  • treatment of treating, preventing or retarding amyotrophic lateral sclerosis is carried out by administration of ivermectins, or their derivatives thereof of the Avermectins class or which are microcyclic lactones may administered orally in a regime of 5 to 1000 mg/patient/day, more preferably 20 to 500 mg/patient/day, and yet more preferably 50 to 300 mg/patient/day, and most preferably 80 to 150 mg/patient/day.
  • a possible daily dose can for instance be 7 to 10 mg/kg body weight.
  • the active compound may be delivered as a solid medicine in pill or tablet form and alternatively as liquid, semi-solid.
  • the parenteral administration form may be an isotonic injection solution.
  • the daily dose could be 3 to 6 mg/kg body weight
  • Administration of these ivermectins may be carried out orally, parenterally, subcutaneously, intravenously, intramuscularly, intraperitoneally, by intranasal instillation, by implantation, by intracavitary or intravesical instillation, intraocularly, intraarterially, intralesionally, transdermally, or by application to mucous membranes.
  • Oral dosage forms are preferred for those therapeutic agents that are orally active, and include tablets, capsules, caplets, solutions, suspensions and/or syrups, and may also comprise a plurality of granules, beads, powders or pellets that may or may not be encapsulated.
  • Such dosage forms are prepared using conventional methods known to those in the field of pharmaceutical formulation and described in the pertinent texts, e.g., in Remington: The
  • Tablets and capsules represent the most convenient oral dosage forms, in which case solid pharmaceutical carriers are employed.
  • Tablets may be manufactured using standard tablet processing procedures and equipment.
  • One method for forming tablets is by direct compression of a powdered, crystalline or granular composition containing the active agent(s), alone or in combination with one or more carriers, additives, or the like.
  • tablets can be prepared using wet-granulation or dry-granulation processes. Tablets may also be moulded rather than compressed, starting with a moist or otherwise tractable material; however, compression and granulation techniques are preferred.
  • tablets prepared for oral administration using the method of the invention will generally contain other materials such as binders, diluents, lubricants, disintegrants, fillers, stabilisers, surfactants, colouring agents, and the like. Binders are used to impart cohesive qualities to a tablet, and thus ensure that the tablet remains intact after compression.
  • Suitable binder materials include, but are not limited to, starch (including corn starch and pregelatinised starch), gelatine, sugars (including sucrose, glucose, dextrose and lactose), polyethylene glycol, waxes, and natural and synthetic gums, e.g., acacia sodium alginate, polyvinylpyrrolidone, cellulosic polymers (including hydroxypropyl cellulose, hydroxypropyl methylcellulose, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, and the like), and Veegum. Diluents are typically necessary to increase bulk so that a practical size tablet is ultimately provided.
  • Suitable diluents include lactose, cellulose, kaolin, mannitol, sodium chloride, dry starch and powdered sugar.
  • Lubricants are used to facilitate tablet manufacture; examples of suitable lubricants include, for example, magnesium stearate and stearic acid. Stearates, if present, preferably represent at no more than approximately 2 wt. % of the drug-containing core.
  • Disintegrants are used to facilitate disintegration of the tablet, and are generally starches, clays, celluloses, algins, gums or crosslinked polymers.
  • Fillers include, for example, materials such as silicon dioxide, titanium dioxide, alumina, talc, kaolin, powdered cellulose and microcrystalline cellulose, as well as soluble materials such as mannitol, urea, sucrose, lactose, dextrose, sodium chloride and sorbitol.
  • Stabilisers are used to inhibit or retard drug decomposition reactions that include, by way of example, oxidative reactions.
  • Surfactants may be anionic, cationic, amphoteric or non-ionic surface active agents.
  • the dosage form may also be a capsule, in which case the active agent-containing composition may be encapsulated in the form of a liquid or solid (including particulates such as granules, beads, powders or pellets).
  • Suitable capsules may be either hard or soft, and are generally made of gelatine, starch, or a cellulosic material, with gelatin capsules preferred.
  • Two-piece hard gelatine capsules are preferably sealed, such as with gelatine bands or the like. See, for example, Remington: The Science and Practice of Pharmacy, which describes materials and methods for preparing encapsulated pharmaceuticals.
  • a liquid carrier is necessary to dissolve the active agent(s).
  • the carrier must be compatible with the capsule material and all components of the pharmaceutical composition, and must be suitable for ingestion.
  • Solid dosage forms may, if desired, be coated so as to provide for delayed release.
  • Dosage forms with delayed release coatings may be manufactured using standard coating procedures and equipment. Such procedures are known to those skilled in the art and described in the pertinent texts, e.g., in Remington, supra.
  • a delayed release coating composition is applied using a coating pan, an airless spray technique, fluidised bed coating equipment, or the like.
  • Delayed release coating compositions comprise a polymeric material, e.g., cellulose butyrate phthalate, cellulose hydrogen phthalate, cellulose- proprionate phthalate, polyvinyl acetate phthalate, cellulose acetate phthalate, cellulose acetate trimellitate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate, dioxypropyl methylcellulose succinate, carboxymethyl ethylcellulose, hydroxypropyl methylcellulose acetate succinate, polymers and copolymers formed from acrylic acid, methacrylic acid, and/or esters thereof.
  • a polymeric material e.g., cellulose butyrate phthalate, cellulose hydrogen phthalate, cellulose- proprionate phthalate, polyvinyl acetate phthalate, cellulose acetate phthalate, cellulose acetate trimellitate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate, dioxyprop
  • sustained release dosage forms provide for drug release over an extended time period, and may or may not be delayed release.
  • sustained release dosage forms are formulated by dispersing a drug within a matrix of a gradually bioerodible (hydrolysable) material such as an, insoluble plastic, a hydrophilic polymer, or a fatty compound, or by coating a solid, drug containing dosage form with such a material.
  • a gradually bioerodible (hydrolysable) material such as an, insoluble plastic, a hydrophilic polymer, or a fatty compound
  • Insoluble plastic matrices may be comprised of, for example, polyvinyl chloride or polyethylene.
  • Hydrophilic polymers useful for providing a sustained release coating or matrix cellulosic polymers include, without limitation: cell ⁇ losic polymers such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, ethyl cellulose, cellulose acetate, cellulose acetate phthalate, cellulose acetate trimellitate, hydroxypropylmethyl cellulose phthalate, hydroxypropylcellulose phthalate, cellulose hexahydrophthalate, cellulose acetate hexahydrophthalate, and carboxymethylcellulose sodium; acrylic acid polymers and copolymers, preferably formed from acrylic acid, methacrylic acid, acrylic acid alkyl esters, methacrylic acid alkyl esters, and the like, e.g.
  • Fatty compounds for use as a sustained release matrix material include, but are not limited to, waxes generally (e.g., camauba wax) and glyceryl tristearate.
  • transepidermal effective amounts of Ivermectins, their derivatives thereof may be administered topically on the respective areas of motor neuron loss.
  • the transdermal administration of Ivermectins or derivatives thereof can be transdermal electromotive administration, the transdermal absorption being accelerated by use of an electrode-drug receptacle attached to the patients.
  • the pharmaceutical product can be used as liquid, semi-solid or solid medicine.
  • Liquid medicines are solutions, suspensions, emulsions or dispersions of the above-cited active ingredients or combinations of active ingredients as drops, tinctures and sprays.
  • semi-solid medicines for example, gels, ointments, creams and foams are used while, for example, powders, toilet powders, granulates, pellets and microcapsules are used as solid medicines.
  • the pharmaceutical product containing as active ingredient Ivermectins or their derivatives thereof is used as a liquid, it is recommended to use as far as possible irritation-free diluting agents, as for example water, monovalent alcohols, especially ethanol, polyvalent alcohols, especially glycerine and/or propanediol, polyglycols, especially polyethylene glycols and/or miglyols, glycerine formal, dimethylisosorbide, natural and synthetic oils and/or esters.
  • monovalent alcohols especially ethanol
  • polyvalent alcohols especially glycerine and/or propanediol
  • polyglycols especially polyethylene glycols and/or miglyols
  • glycerine formal, dimethylisosorbide natural and synthetic oils and/or esters.
  • the ivermectin may be in the form of a physico-chemical complex with a phospholipid selected from the group consisting of lecithin, cephalin, phosphatidylserine, phosphoinositide, and phosphatidic acid, or mixtures thereof in the form of a cream, an ointment, a pomade, a gel, or an emulsion to the area to be treated.
  • a phospholipid selected from the group consisting of lecithin, cephalin, phosphatidylserine, phosphoinositide, and phosphatidic acid, or mixtures thereof in the form of a cream, an ointment, a pomade, a gel, or an emulsion to the area to be treated.
  • the process of manufacture of such complexes has been described by Bertini Curri in US5,280,020.
  • polymers of vinylalcohol and vinylpyrrolidone alginates, pectines, polyacrylates, solid and/or liquid polyethylenglycols, paraffins, fatty alcohols, vaseline and/or waxes, fatty acids and/or fatty acid esters are used.
  • active ingredients without filler for the production of solid products, as for example powders, toilet powder, granulates, pellets and microcapsules.
  • the pharmaceutical product described here is especially suited for the attention of such of the above-described diseases which are in a very progressed stage so that at first an increased concentration of active ingredients is necessary.
  • solid pharmaceutical product which contain fillers, as for example Colloidal silicic acid, powdered soapstone, milk sugar, starch powder, sugar, cellulose derivatives, gelatin, metal oxides and/or metal salts, wherein the concentration of the active ingredient or of the combination of active ingredients varies between 0.001% by weight and 50% by weight.
  • fillers as for example Colloidal silicic acid, powdered soapstone, milk sugar, starch powder, sugar, cellulose derivatives, gelatin, metal oxides and/or metal salts, wherein the concentration of the active ingredient or of the combination of active ingredients varies between 0.001% by weight and 50% by weight.
  • a suitable kind of pharmaceutical form may be a topical deliver form of the above-described active ingredient, which is made by the application of the solid, liquid or semi-solid pharmaceutical product onto a gauze strip, a compress or a plaster so that such a gauze strip, such a compress or such a plaster then is only locally applied onto the spot which is to be treated.
  • the pharmaceutical product can be filled into the known receptacles, as for example bottles, tubes, toilet powder boxes and baby powder boxes as well as seal edge bags, which are possibly provided with metering means, as for example droplet forming means, metering valves or metering chambers.
  • Ivermectin (CAS-7-288-86-7) is synonym of a mixture of 5-0-demethyl-22,23- dihydroavermectin Ala and 5-0-demethyl-22,23-dihydroavermectin Alb or a mixture of 22,23 -dihydroavermectin BIa and 22,23 -dihydroavermectin BIb.
  • the ivermectin a mixture of at least 80% of 22,23-dihydroavermectin BIa and less than 20% of 22,23- dihydroavermectin BIb.
  • Avermectins and their derivatives which may be particularly emphasized are those of the general formula (above) in which the radicals R 1 to R 4 have the meaning indicated in Table 2 which follows and X can be a single or double bond between the C 22 - and C 23 - positions ( ⁇ C 22 Ri -X-C 23 R 2 -).
  • Avermectin Bib -CH CH- iso-Pr -H
  • the avermectins and 22,23 -dihydroavermectins Bi are employed as mixtures.
  • the product abamectin which essentially contains the avermectins Bi, and their hydrogenation products, the 22,23- dihydroavermectins Bi (ivermectin).
  • the mixture of both substances consisting of > 80% sec- butyl derivative (B la ) and ⁇ 20% iso-propyl derivative (B Ib), is isolated, and can be used according to the invention.
  • the substituents in the C 13 - and C 23 -positions can be arranged on the ring system both in the ⁇ - and ⁇ -positions, i. e. are located above or below the plane of the molecule. In each case, all stereoisomers are taken into account according to the invention.
  • the Ivermectins which are particularly suitable for the purpose of present invention are compound with the formula
  • the milbemycins may be mentioned particularly.
  • the active compounds which may be very particularly emphasized are avermectin Bi 3 /B ⁇ (Abamectin), 22,23-dihydroavermectin B ⁇ a (ivermectin), doramectin, moxidectin.
  • the active compounds are present in the formulations according to the invention in concentrations from 0.1 to 10% by weight, preferably from 0.5 to 5% by weight, particularly preferably 1-2% by weight.
  • Ivermectin can also have the following formula:
  • R is an alkyl group and in particular wherein R is CH3 or C2H5.
  • Compounds that are particularly suitable for present invention may be a compounds of the group consisting of
  • Ivermectin is generally known as a mixture of 5-0-demethyl-22,23- dihydroavermectin Ala and 5-0-demethyl-22,23-dihydroavermectin Alb or a mixture of 22,23-dihydroavermectin BIa and 22,23 -dihydroavermectin BIb.
  • the ivermectin is a mixture of at least 80% of 22,23-dihydroavermectin BIa and less than 20% of 22,23- dihydroavermectin BIb.
  • the present invention thus involves a method for the treatment of amyotrophic lateral sclerosis (a fatal neurological disorder, characterised by progressive degeneration of the motor cells in the spinal cord and the brain), or a related motor neuron disease (MMD) said method comprising administering to an individual an effective amount of ivermectin, or an effective amount of 5 -0-demethyl-22,23 -dihydroavermectin Ala or of 5-0- demethyl-22,23-dihydroavermectin Alb or a mixture thereof, or an effective amount of 22,23- dihydroavermectin BIa, or 22,23 -dihydroavermectin BIb or a mixture thereof.
  • a mixture of at least 80% of 22,23-dihydroavermectin BIa and less than 20% of 22,23- dihydroavermectin BIb is suitable for the present invention.
  • Ivermectin derivatives suitable for the treatment of medicament of present invention are preferably Ivermectin derivatives of pentacyclic sixteen-membered lactones or pharmacologically acceptable salts and/or functional derivatives thereof. Some are methoxylated at the carbon atom in position five (A series) or compounds having an underivatized hydroxyl-group at this position (B group). Some of these compounds may have an olefinic bond between the two carbon atoms C22 and C23 (1 -subset) or this double bond can be hydrated (2-subset) resulting in a hydroxyl group at position 23.
  • the medicament to prevent, retard and ameliorate CNS degenerative disease and the associated loss of neurons can furthermore comprise magnesium (Mg), its pharmacologically acceptable salt or its derivatives, such as magnesium oxide, magnesium aspartate, magnesium sulphate, magnesium citrate chelated magnesium, magnesium EAP in a amount sufficient to treat, to prevent, to retard, to ameliorate or to cure amyotrophic lateral sclerosis (ALS).
  • Mg magnesium
  • its pharmacologically acceptable salt or its derivatives such as magnesium oxide, magnesium aspartate, magnesium sulphate, magnesium citrate chelated magnesium
  • magnesium EAP in a amount sufficient to treat, to prevent, to retard, to ameliorate or to cure amyotrophic lateral sclerosis (ALS).
  • ALS amyotrophic lateral sclerosis
  • Suitable compounds are the ivermectin like derivatives of the pentacyclic sixteen- membered lactones for instance the avermectins.
  • a and B Within the family of the avermectins, there exist two series, A and B, within which are two structural subsets, designated 1 and 2, consisting of two homologs a and b.
  • A-series Two series, A and B, within which are two structural subsets, designated 1 and 2, consisting of two homologs a and b.
  • MND motor neuron disease
  • ALS amyotrophic lateral sclerosis
  • 5- 0-demethyl-22,23-dihydroavermectin Ala or of 5-0-demethyl-22,23-dihydroavermectin Alb can be used.
  • the pharmaceutical products which can be used for the treatment of a motor neuron disease such as ALS or the associated motor neuron loss can also contain derivatives, preferably pharmacologically active metabolic products (metabolites), such as the compounds selected from the group consisting of avermectin, avermectin derivatives, milbemycin, milbemycin derivatives, ivermectin, ivermectin derivatives, milbemycin oxime, milbemycin oxime derivatives, moxidectin, and moxidectin derivatives
  • the active ingredient of present invention may preferably be orally or parenterally administered.
  • compositions according to the invention can be periodically administered to a mammalian patient (e.g., a human patient), in need of such treatment, to promote neuron regeneration and functional recovery and thereby to treat damage to the neurons caused by a motor neuron disease (MND) such as amyotrophic lateral sclerosis (ALS).
  • MND motor neuron disease
  • ALS amyotrophic lateral sclerosis
  • the compounds of present invention are thus useful to enhance regeneration of the motor neurons.
  • the present invention thus involves a method of promoting motor neuron regeneration in a mammal having a motor neuron disease (MND) such as amyotrophic lateral sclerosis (ALS), the method comprising: administering to the mammal a pharmaceutical composition comprising a motor neuron regeneration stimulating amount of the compounds of present invention.
  • the compounds of present invention can also be used to enhance motor recovery following a motor neuron damage by a motor neuron disease (MND) such as amyotrophic lateral sclerosis (ALS).
  • MND motor
  • the compounds of present invention may be combined with known neurotrophic factors, which have been shown to play an essential trophic role in the development, maintenance and regulation of neuronal function such as for instance ciliary neurotrophic factor (CNTF), glial growth factors (glial mitogenic factors), Schwann cell mitogenic factors, the nerve growth factors (NGF) and other members of the NGF family, brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3) or platelet- derived growth factor (PDGF).
  • CNTF ciliary neurotrophic factor
  • glial growth factors glial mitogenic factors
  • Schwann cell mitogenic factors the nerve growth factors (NGF) and other members of the NGF family
  • BDNF brain-derived neurotrophic factor
  • NT-3 neurotrophin-3
  • PDGF platelet- derived growth factor
  • Progressive CNS degeneration or degeneration of the motor cells in the spinal cord and the brain can be treated or retarded by combining compounds selected from the group consisting of the ivermectins of present invention with Idebenone or with CDP choline (known as cytidine 5-diphosphocholine).
  • the compounds of present invention may also be combined with known neurotrophic factors, which have been shown to play an essential trophic role in the development, maintenance and regulation of neuronal function such as for instance ciliary neurotrophic factor (CNTF), glial growth factors (glial mitogenic factors), Schwann cell mitogenic factors, the nerve growth factors (NGF) and other members of the NGF family, brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3) or platelet-derived growth factor (PDGF).
  • CNTF ciliary neurotrophic factor
  • glial growth factors glial mitogenic factors
  • Schwann cell mitogenic factors the nerve growth factors (NGF) and other members of the NGF family
  • BDNF brain-derived neurotrophic factor
  • NT-3 neurotrophin-3
  • PDGF platelet-derived growth factor
  • Progressive CNS degeneration or degeneration of the motor cells in the spinal cord and the brain can be treated or retarded by combining compounds selected from the group consisting of Ivermectins of present invention with compounds selected from the group consisting of Free radical scavenger, alpha-phenyl-tert- butyl nitrone (PBN), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), platelet-derived growth factor (PDGF), non-competitive antagonists of glutamate such as for instance l-(l-(2-thienyl)cyclohexyl)piperidine (TCP), superoxide dismutases, adenosine agonists such as cyclohexyladenosine (CHA), Gamma-amino butyric acid (GABA) and GABA-mimetic drugs, non-NMDA receptor antagonist such as 2,3-dihydroxy-6-nitro-7- sulfamoyl-benzo(F)quinoxaline (NBQX),
  • the compounds of present invention may be combined with known neuroprotective compounds such as the compounds of the group consisting of free radical scavenger, alpha-phenyl-tert-butyl nitrone (PBN); non-competitive antagonists of glutamate such as for instance l-(l-(2-thienyl)cyclohexyl)piperidine (TCP) or topiramate, peroxide dismutases, adenosine agonists such as cyclohexyladenosine (CHA), Gamma-amino butyric acid (GABA) and GABA-mimetic drugs, non-NMDA receptor antagonist such as 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaline (NBQX), the green tea polyphenol (-)-epigallocatechin-3-gallate, NAALADase inhibitors such 2- (phosphonomethyl)-pentanedioic acid (2-
  • PBN alpha-phenyl
  • MND motor neuron disease
  • ALS amyotrophic lateral sclerosis
  • ivermectins or functional analogues of present may in particular be combined with VEGF homologous , which have been shown to play a role in mediated survival signals to motor neurons or motor neuron protection.
  • the compounds of present invention may for instance be combined with for instance VEGFA, VEGFB, PLGF or compounds selected from the group consisting of 4-(pyrrolidinyl)-l (2,4,6-trimethoxyphenyl) -1-butanone, 2', 4', 6'-trimethoxy-4-(r-pyrrolidinyl) butyrophenone; (2,4,6-trimethoxyphenyl) (3-pyrrolidinopropyl) ketone, (2,4,6-Trimethoxyphenyl) (3-piperidinopropyl) ketone, (2,4,6- triethoxyphenyl) (3-diethylaminopropyl) ketone, (2,4,6-trimethoxyphenyl) [4- ⁇ -hydroxyethyl- piperazino) methyl] ketone dihydrochloride and (2,4,6-triethoxyphenyl) (3-pyrrolidinopropyl) ketone.
  • the ivermectins or function derivatives of present invention may also be combined with a compound selected of the group consisting of minocycline, Neurontin (gabapentin), Neurodex (dextromethorphan hydrobromide + quinidine sulfate), tamoxifen, Topamax (opiramate), CoQlO, PC-Ol, Celebrex (celecoxib), Indinavir, buspirone, oxandrolone, creatine, NAALADase, neotrophin and Rilutek (riluzole).
  • MND motor neuron disease
  • ALS amyotrophic lateral sclerosis
  • Transgenic mice with overexpression of the human mutant SOD1(G93A) gene were obtained from Jackson Laboratories (Bar Habor, Maine). They were crossbred for more than 5 generations in the C57/B16 background before the experiment was started. Treatment was started at the age of 50 days and continued untill time of death. There was a random distribution of littermates and sexes between the control group and the treatment groups. The treatment groups were given 3, 6 or 15 ml of Oramec ® /! of drinking water (Oramec ® is a trademark of Merial SAS, Lyon, France), which corresponds to a concentration of the active substance ivermectin of 2.4, 4.8 and 12 mg/1, respectively. The control group received the same amount of solvent in their drinking water without the active substance.
  • mice When mice could no longer roll over within 10 sec when pushed on their side, they were killed and this age was considered as the time of death. At all times the animals were kept in a strictly controlled environment and were free of parasites. The ethical committee of the University of Leuven approved all experiments.
  • mice of the control group and of the 12 mg/1 ivermectin group were anesthetized with i.p. Nembutal and a transcardiac perfusion with PBS and with 4 % paraformaldehyde was performed. After dissection, the lumbar part of the spinal cords was fixed in 4 % paraformaldehyde and embedded in parafin. Sections of 7 ⁇ m were deparafinated and stained with hematoxylin and eosin. Lumbar ventral roots were dissected, fixed in 2.5 % glutaraldehyde and embedded in epoxy resin. Ultra thin sections were stained with toluidine blue.
  • NCSS log-rank test
  • mice of the control and 12 mg/1 ivermectin group were sacrificed for histological examination of the lumbar spinal cord and lumbar ventral roots.
  • the number of large neurons (> 200 ⁇ m 2 ) in the ventral horn of the lumbar spinal cord was significantly higher (Students' t-test; p ⁇ 0.005) in the ivermectin group (18.0 ⁇ 0.4 large motor neurons/section) compared to the control group (10.9 ⁇ 0.6 large motor neurons /section).
  • ventral roots Fig. 6D-F
  • the area occupied by axons was 14.6 ⁇ 1.3 % in the control group and 23.3 ⁇ 1.5 % in the ivermectin group (p ⁇ 0.005).
  • Table 1 Effect of ivermectin on the survival of SODl(G93A)-mice.
  • mice 32 21 11 mean ⁇ s.e.m. 140.6 ⁇ 1.6 days 139.0 ⁇ 4.1 days 149.3 ⁇ 2.8 days 153.4 ⁇ 2.8 days
  • Treatment was started at 50 days of age and continued till time of death.
  • the control group received solvent in their drinking water.
  • FIG 1 shows a Kaplan-Meier plots of the cumulative probability of survival of SOD1(G93A)- mice.
  • FIG 1 are graphs and histological pictures that demonstrate the effect of ivermectin on neuronal loss in the lumbar spinal cord and on the axon loss in the ventral roots of 120-days- old SODl(G93A)-mice.
  • the inside area of axons is measured and expressed as percentage of total area of the ventral root section (F). Numbers are the mean ⁇ S.E.M. of 4 different ventral roots per treatment. For each root 2 sections were analyzed.

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Abstract

La présente invention concerne un nouveau médicament pour le traitement médical d'une maladie du neurone moteur (MND) telle que la sclérose latérale amyotrophique. Plus particulièrement, la présente invention concerne l'utilisation de l'ivermectine et d'analogues, pour prévenir, retarder et améliorer une maladie du neurone moteur (MND) telle que la sclérose latérale amyotrophique (ALS) et la dégénérescence associée des neurones moteurs.
PCT/BE2007/000107 2006-09-19 2007-09-19 Traitement de la sclérose latérale amyotrophique WO2008034202A2 (fr)

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WO2012150543A1 (fr) * 2011-05-02 2012-11-08 Universite De Geneve Lactones macrocycliques et leur utilisation
WO2014059797A1 (fr) * 2012-10-19 2014-04-24 厦门大学 Utilisation d'ivermectine et de ses dérivés

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012150543A1 (fr) * 2011-05-02 2012-11-08 Universite De Geneve Lactones macrocycliques et leur utilisation
US9351988B2 (en) 2011-05-02 2016-05-31 Universite De Geneve Macrocyclic lactones and use thereof
WO2014059797A1 (fr) * 2012-10-19 2014-04-24 厦门大学 Utilisation d'ivermectine et de ses dérivés
US10052340B2 (en) 2012-10-19 2018-08-21 Xiamen University Use of ivermectin and derivatives thereof

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