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1. WO2013149250 - METHODS OF TREATMENT, DIAGNOSIS AND MONITORING FOR METHAMPHETAMINE TOXICITY WHICH TARGET CERAMIDE METABOLIC PATHWAYS AND CELLULAR SENESCENCE

Publication Number WO/2013/149250
Publication Date 03.10.2013
International Application No. PCT/US2013/034834
International Filing Date 01.04.2013
IPC
A61K 31/138 2006.01
AHUMAN NECESSITIES
61MEDICAL OR VETERINARY SCIENCE; HYGIENE
KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
31Medicinal preparations containing organic active ingredients
13Amines, e.g. amantadine
135having aromatic rings, e.g. methadone
138Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
CPC
A61K 31/095
AHUMAN NECESSITIES
61MEDICAL OR VETERINARY SCIENCE; HYGIENE
KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
31Medicinal preparations containing organic active ingredients
095Sulfur, selenium, or tellurium compounds, e.g. thiols
A61K 31/137
AHUMAN NECESSITIES
61MEDICAL OR VETERINARY SCIENCE; HYGIENE
KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
31Medicinal preparations containing organic active ingredients
13Amines
135having aromatic rings ; , e.g. ketamine, nortriptyline
137Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine ; or methadone
A61K 31/195
AHUMAN NECESSITIES
61MEDICAL OR VETERINARY SCIENCE; HYGIENE
KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
31Medicinal preparations containing organic active ingredients
185Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic, hydroximic acids
19Carboxylic acids, e.g. valproic acid
195having an amino group
A61K 31/201
AHUMAN NECESSITIES
61MEDICAL OR VETERINARY SCIENCE; HYGIENE
KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
31Medicinal preparations containing organic active ingredients
185Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic, hydroximic acids
19Carboxylic acids, e.g. valproic acid
20having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
201having one or two double bonds, e.g. oleic, linoleic acids
A61K 31/4152
AHUMAN NECESSITIES
61MEDICAL OR VETERINARY SCIENCE; HYGIENE
KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
31Medicinal preparations containing organic active ingredients
33Heterocyclic compounds
395having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
41having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
4151,2-Diazoles
4152having oxo groups directly attached to the heterocyclic ring, e.g. antipyrine, phenylbutazone, sulfinpyrazone
A61K 31/42
AHUMAN NECESSITIES
61MEDICAL OR VETERINARY SCIENCE; HYGIENE
KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
31Medicinal preparations containing organic active ingredients
33Heterocyclic compounds
395having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
41having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
42Oxazoles
Applicants
  • THE REGENTS OF THE UNIVERSITY OF CALIFORNIA [US]/[US]
  • FONDAZIONE ISTITUTO ITALIANO DI TECNOLOGIA [IT]/[IT]
Inventors
  • PIOMELLI, Daniele
  • ASTARITA, Giuseppe
  • AVANESIAN, Agnesa
  • CAVALLI, Andrea
Agents
  • MYCROFT, Frank, J.
Priority Data
61/618,36130.03.2012US
61/806,33528.03.2013US
Publication Language English (EN)
Filing Language English (EN)
Designated States
Title
(EN) METHODS OF TREATMENT, DIAGNOSIS AND MONITORING FOR METHAMPHETAMINE TOXICITY WHICH TARGET CERAMIDE METABOLIC PATHWAYS AND CELLULAR SENESCENCE
(FR) PROCÉDÉS DE TRAITEMENT, DE DIAGNOSTIC ET DE SURVEILLANCE DE LA TOXICITÉ DE LA MÉTHAMPHÉTAMINE QUI CIBLENT DES VOIES MÉTABOLIQUES DES CÉRAMIDES ET LA SÉNESCENCE CELLULAIRE
Abstract
(EN)
Methamphetamine is a highly addictive psychostimulant that causes profound damage to the brain and other body organs. Post mortem studies of human tissues have linked the use of this drug to diseases associated with aging, such as coronary atherosclerosis, but the molecular mechanism underlying these findings remains unknown. We report now that methamphetamine accelerates cellular senescence in vitro and activates transcription of genes involved in cell-cycle control and inflammation in vivo by stimulating production of the sphingolipid messenger ceramide. This pathogenic cascade is triggered by reactive oxygen species, generated through methamphetamine metabolism via cytochrome Pas0-2D6, which recruit nuclear factor (NF)-KB to induce expression of enzymes in the de novo pathway of ceramide biosynthesis. Inhibitors of ceramide formation prevent methamphetamine-induced senescence and attenuate systemic inflammation and health deterioration in rats self- administering the drug. The results support therapeutic approaches to reduce the adverse consequences of methamphetamine abuse and improve effectiveness of treatments.
(FR)
La méthamphétamine est un psychostimulant hautement addictif qui entraîne des lésions profondes du cerveau et d'autres organes corporels. Des études post-mortem de tissus humains ont relié l'utilisation de cette drogue à des maladies liées au vieillissement, telles que l'athérosclérose coronaire, mais le mécanisme moléculaire qui est à la base de ces résultats reste inconnu. Il est rapporté aujourd'hui que la méthamphétamine accélère la sénescence cellulaire in vitro et active la transcription de gènes impliqués dans le contrôle du cycle cellulaire et l'inflammation in vivo par stimulation de la production du céramide messager sphingolipidique. Cette cascade pathogène est déclenchée par des espèces réactives de l'oxygène, générées par un métabolisme de méthamphétamine par l'intermédiaire du cytochrome P 450-2D6, qui recrutent le facteur nucléaire (NF)-KB pour induire une expression d'enzymes dans la voie de novo de biosynthèse de céramides. Des inhibiteurs de la formation de céramides empêchent la sénescence induite par la méthamphétamine et atténuent l'inflammation systémique et la détérioration de la santé chez des rats s'auto-administrant la drogue. Les résultats supportent des approches thérapeutiques pour réduire les conséquences néfastes d'abus de méthamphétamine et pour améliorer l'efficacité des traitements.
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