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Nuevas drogas y drogas‘reutilizadas’ contra tuberculosis
Juan Carlos Palomino PhDGhent University - Belgium
December 2013
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Situacion Global TB
Año 2012
8.6 millones de casos de TB
1.3 millones de muertes por TB
320.000 muertes en HIV+
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Situacion Global TB
• Tasa de nuevos casos disminuyendo (2%)
• Mortalidad reducida en 45% desde 1990
• Regiones OMS: Americas y WPR
• 7/22 HBCs lograron objetivos 2015 MDGs
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Tendencias globales estimadas
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Situacion Global TB
• Disminucion prevalencia global 37%
• Europa y Africa: mortalidad y prevalencia
• 11/22 HBCs retrasados en objetivos MDG
• Objetivos MDR-TB lejos de conseguirse
• Menos de 25% MDR-TB detectado
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Multidrogo-resistencia
• MDR-TB: resistentes a INH y RIF
• 3.6% en nuevos casos y 20.2% en casosen tratamiento
• Europa del Este y Asia Central 20 y 50%
• 450.000 MDR-TB estimados en 2012 (India, China, Rusia)
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XDR-TB
• 9.6% de MDR-TB estimado XDR-TB
• MDR-TB + quinolona + inyectable 2° línea(CAP, KAN, AMK)
• Reportado en 92 paises
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XDR-TB
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Drogas anti-tuberculosis
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Bedaquiline
R207910 => TMC207 => Bedaquiline => Sirturo
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Bedaquiline actividad in vivo
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Bedaquiline: modo de acción
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Bedaquiline: ensayos clínicos
Palomino & Martin Future Microbiology 8(9), 2013
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Bedaquiline: críticas
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Delamanid
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Delamanid
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Delamanid
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Matsumoto et al. PLoS Med. 2006
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Diacon et al. IJTLD 2011
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Delamanid
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Sildenafil Minoxidil Thalidomide
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Therapeutic effect of a new antibacterial substance ofloxacin (DL8280) on pulmonary tuberculosis.
Tsukamura M, Nakamura E, Yoshii S, Amano H.Am Rev Respir Dis. 1985 Mar;131(3):352-6.
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Definición• Reutilización (repurposing/repositioning)
– Investigar nuevos usos de drogasexistentes ya ’aprobadas’
DuraciDuracióónn: 10: 10--17 17 aaññosos. . CostoCosto: 800: 800--1000 1000 millonesmillones USDUSD
Pre-clinical
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(Fluoro)quinolonas
• Acido nalidíxico (1962), acido oxolínico• Norfloxacin 1980s• Ciprofloxacin, Ofloxacin, Levofloxacin• Gatifloxacin, Moxifloxacin• Tratamiento de MDR-TB• Ensayos clínicos fase III en marcha (Tx de
DS-TB)
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Linezolid
Cicloserina
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Mecanismo de acción
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Linezolid (ZyvoxTM)
• Oxazolidinona aprobada por FDA (2000)• Bacteria Gram positivas• Neumonía nosocomial, infecciones de
tejido blando• MRSA, VRE• ‘Off-label’ contra MDR-TB• Effectos secundarios: anemia, polineuritis
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Oxazolidinones, a new class of synthetic antituberculosis agent. In vitro and in vivo activities of DuP-721 against Mycobacterium tuberculosis
Ashtekar DR, Costa-Periera R, Shrinivasan T, Iyyer R, Vishvanathan N, Rittel WDiagn Microbiol Infect Dis. 1991 Nov-Dec;14(6):465-71
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Sutezolid
ZyvoxTM
Linezolid
PNU-100480
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Co-trimoxazole
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• Paciente inmunodeficiente de 81años
• Sospecha de nocardiosis
• TMP-SMX por 2 ½ semanas => no síntomas clinicos
• Dx de TB pero no Nocardia
• DST del aislado M. tuberculosis => susceptible a TMP-SMX
• 43/44 aislados susceptibles a < 1/19 µg/ml TMP-SMX
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Arch Intern Med. 2003;163(4):402-410. doi:10.1001/archinte.163.4.402
VVííaa metabmetabóólicalica ssííntesisntesis de de folatofolato y y sitiositio de de acciaccióónn de TMP y SMX.de TMP y SMX.
DfrA
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Estudios adicionales
• TMP-SMX: mayores estudios con aisladosclínical (different regiones)
• TMP, SMX, la combinación
• Resistencia cruzada con PAS, INH, Eth
• Investigar mutaciones en dfrA, thyA
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Clofazimine (1957)
• OMS Tratamiento multidroga para lepra
• OMS lista drogas de segunda-línea grupo 5 paraMDR-TB
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Modo de acción
Cholo et al. J Antimicrob Chemother 2012
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β-lactámicos y TB• Dogma: ineficaz contra M. tuberculosis
McLean et al. Arch Biochem Biophys 2007
Fonzé et al. Acta Cryst. 1995
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Meropenem + clavulanate
• Inhibición de XDR M. tuberculosis (n=13)
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Reutilizando lo reutilizado…
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In-house light box
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Foto con celular
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(Un)usual suspects
• Mefloquina (Lariam)– Malaria cloroquine-resistente
• Phenothiazinas– Thioridazina: anti-psicótico
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TMC207 Bedaquiline
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Desventajas
• Efectos neurosiquiátricos reportados• Riesgo de aborto
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Phenothiazinas
• Thioridazina: acción en membrana celular
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Desventajas
• Posible prolongación de intervalo QT
• Estigma?
• Disponibilidad
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Perspectivas
• Poca inversión en R & D de antibióticos(aprobados vs inversión)
• Estrategia de desarrollo de nuevas drogas(orientado a un blanco)
• No investigar efectos adicionales• Reutilización puede ser buena alternativa
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Agradecimientos
• Gent Universiteit – Belgium• Damien Foundation• European Commission