INMUNOMODULADORES IGerardo E Pea Barrera Pediatra Residente I de Inmunologa Clnica

TEMAS A TRATAR.CloroquinaColchicinaAzatioprinaMetotrexateHidroxicloroquina

Mecanismo de accinEstructura bsicaFarmacologa:Farmacocintica FarmacodinamiaEliminacinEfecto biolgico

INMUNOMODULADORES I CLOROQUINA E HIDROXICLOROQUINA4-aminoquinolonas

MECANISMO DE ACCIN

Incrementa la el pH intracelular (de 4 a 6) de las Vacuolas celulares alterando:

Inhibicin de las hidrolasas acidas en el lisosoma. Disminuye protelisis Disminuye formacin de macromolculas en los endosomas.La modificacin posttranscripcional de protenas en el aparato de Golgi.COOPER & MAGWERE: CHLOROQUINE & ITS USAGE. Indian J Med Res 127, April 2008, pp 305-316Fox RI. Mechanism of action of hydroxychloroquine as an antirheumatic drug. Semin Arthritis Rheum.1993 Oct;23(2 Suppl 1):82-91.

MECANISMO DE ACCIN

Interrumpe la capacidad ltica del lisosoma. Interrumpe la unin de protena antignicas en cadenas y del HCM IIEvita de formacin de complejo Pectido+HCM necerario para la expresin de HCMII y estimular LTCD4+ COOPER & MAGWERE: CHLOROQUINE & ITS USAGE. Indian J Med Res 127, April 2008, pp 305-316Fox RI. Mechanism of action of hydroxychloroquine as an antirheumatic drug. Semin Arthritis Rheum.1993 Oct;23(2 Suppl 1):82-91.

MECANISMO DE ACCIN

Evita la presentacin antignica de CPA al macrfago Estabilizacion de membrana citoplasmtica, disminucin de expresin de autoantgenos intracelulares. Ya que no se unen a HCM II (baja afinidad)Down-regulation en la respuesta a pptidos autoantigenicos.

COOPER & MAGWERE: CHLOROQUINE & ITS USAGE. Indian J Med Res 127, April 2008, pp 305-316Fox RI. Mechanism of action of hydroxychloroquine as an antirheumatic drug. Semin Arthritis Rheum.1993 Oct;23(2 Suppl 1):82-91.

MECANISMO DE ACCIN

Asociacin de la hidroxicloroquina con inhibicin de TLR-9.

Takeda, K.; Kaisho, T.; Akira, S. (2003). "Toll-Likereceptors".Annual Review of Immunology21: 335376.doi:10.1146/annurev.immunol.21.120601.141126.PMID12524386.

MECANISMO DE ACCINEfecto LisosomotropicoDisminuye:Produccin de citoquinas proinflamatorias IFN-, TNF- e Il6 fagocitos mononucleares.

Aumenta +Expresin de TNF-, Il1, IL-1 and Il-6 en monocitos y Microglias.+Produccin de citoquinas proinflamatorias en celulas astrogliales a traves de la activacin de transcripcin de factor NF-kB.

Efecto dosisdependienteCOOPER & MAGWERE: CHLOROQUINE & ITS USAGE. Indian J Med Res 127, April 2008, pp 305-316Fox RI. Mechanism of action of hydroxychloroquine as an antirheumatic drug. Semin Arthritis Rheum.1993 Oct;23(2 Suppl 1):82-91.

MECANISMO DE ACCIN

Efecto no Lisosomotropico.

Inhibe la liberacin de TNF- en macrfagos mediante la inhibicin de ARNm especifico. Sin modificar la liberacin posttranscripcional de citoquinas por los macrfagos

Interfiere con la funcin de macrfagos al bloquear la maduracin proteica asociada a TNF-, reduciendo los niveles de ARNm para IL-1 and Il-6 al modificar la estabilidad a traves de cambios en el pH. COOPER & MAGWERE: CHLOROQUINE & ITS USAGE. Indian J Med Res 127, April 2008, pp 305-316Fox RI. Mechanism of action of hydroxychloroquine as an antirheumatic drug. Semin Arthritis Rheum.1993 Oct;23(2 Suppl 1):82-91.

CLOROQUINA4-aminoquinolonaHans Andersag y su equipo le descubrieron en 1934, en los laboratorios Bayer de Eberfeld.Nombre cdigo: Resochin. Durante la Segunda Guerra Mundial, se patrocin una serie de ensayos clnicos que demostraron el valor teraputico del frmaco.

En 1947 se autoriz su uso mdico en el tratamiento profilctico de la malaria.Centers for Disease Control and Prevention (2010).The History of Malaria, an Ancient Disease. En United States Department of Health and Human Services.Malaria. Consultado el 3 de noviembre de 2011

HIDROXICLOROQUINA4-aminoquinolona

La hidroxicloroquina se diferencia de la cloroquina por la presencia de un grupo hidroxilo en el extremo de la cadena lateral.

Est disponible para administracin oral como sulfato de hidroxicloroquina, de 200 mg que contiene 155 mg de base en forma quiral.

CLOROQUINA

Nombre sistemtico:(RS)-N'-(7-chloroquinolin-4-yl)-N,N-dietil-pentano-1,4-diamina

Formula: C18H26ClN3Peso Molecular: 319.872g/mol

HIDROXICLOROQUINA4-aminoquinolona

Systematic name:(RS)-2-[{4-[(7-chloroquinolin-4-yl)amino]pentyl}

Formula: C18H26ClN3OPeso Molecular: 335.872g/mol

FARMACOLOGA

Absorcin : Va Oral. Administrar con leche o AlimentosBiodisponibilidad 99%Pico en plasma 1-3 horas.

Distribucin: extendida sobre los tejidos, Unin a protenas ~65%.Embarazo: atraviesa la placenta. Clasificacin C.Lactancia: se reporta concentracion en la leche materna.

FARMACOLOGA

Metabolismo: Parcial en hgado.

Eliminacin: 3 a 5 das (Cloroquina) / 32 a 50 das (Hidroxicloroquina)

Excrecin: 60~70% en orina como droga no metabolizada. Excrecin modificada por acidificacin de la orina.Excrecin urinaria puede persistir en pequeas cantidades, meses posterior a la ultima administracin (120das aprox) (cloroquina)

POSOLOGA CLOROQUINAPresentacin: Va Oral. Tab. 250 y 500mg

POSOLOGIA Artritis Reumatoide o LES: 3-5 mg/kg/da (sulfato) dividido en 1-2 dosis/da (dosis mxima de 500 mg/da).

No se recomienda exceder la dosis de 6,5 mg/kg/da.

POSOLOGA HIDROXICLOROQUINAPresentacin : Va Oral. Tab. 200mg.

POSOLOGIA. Nios: 35 mg/kg/dia dividido 12 veces por dia maximo de 400mg diaAdultos: 200 a 600mg/dia (dosis maxima 600mg)

Artritis reumatoide: Inicial: 400-600mg VO OD por 4 a 12 semanas. Mantenimiento: 200-400mg VO OD.

Lupus Eritematoso Sistemico.Inicial: 400mg VO OD. Mantenimiento: 200-400mg VO OD.

CONVERSIN

200mg de hidroxicloroquina

Equivalen a

155mg de cloroquina

EFECTOS ADVERSOS

CONTRAINDICACIONESContraindicaciones absolutas: Hipersensibilidad de cloroquina o 4-aminoquinolonas.Psoriasis, porfiria, alteraciones retineales o visuales.

VigilanciaDficit de Glucosa-6-deshidrogenasa. Monitoreo en terapia prolongadaAntecedentes de dao auditivoEnfermedad heptica, alcolismo, administracin de drogas hepatotoxicas.Consumo de anticidos disminuye su absorcin, utilizar con separacin de 4 horas. Retinopatia y maculopatia han sido asociadas al uso en larga data.

INMUNOMODULADORES I COLCHICINA

COLCHICINA

Nombre sistemico:N-[(7S)-1,2,3,10-tetramethoxy-9-oxo-5,6,7,9-tetrahydrobenzo[a]heptalen-7-yl]acetamide

Formula:C22H25NO6Peso Molecular: 399.437g/mol

MECANISMO DE ACCIN COLCHICINA *Genes inducidos por colchicina en negritas.E. Ben-Chetrit, S. Bergmann and R. Sood. Anti-inflammatory effects of colchicine. Rheumatology 2006;45:274282

Grupo gentico Nombre de gen o smboloInflamacinCASP1, GPR146, NOS3, G1P2, IFIT1, MX1, IFITM1, GBP1, TNFSF10, CTSC (cathepsin C), CTSZ (cathepsin Z).Plasminogen activator, urokinase.Citoesqueleto (tubulina, actina, molculas de adhesin) Tubulin 5 beta, Tubulin beta 2, CDC42BPA, MYLIP, Fibronectin, Paracingulin, PIK3C2BMAPK1, RHOB, RHOC, RHOJ, NSE2.Cadherin-like 24, Discoidin, Nexilin, Echinoderm, Podocalyxin, Moesin, Coronin, DUSP8, Stanniocalcin 2.Transcriccion y factores de crecimiento celular.TGFBR3, GATA3, TIMP1, PPP1CA, Hoxa 5, Actin-binding LIM, STAT1, APBB2AKAP12

MECANISMO DE ACCIN COLCHICINA El uso prolongado (>24 horas) de colchicina inhibe la expresin gentica de:

Caspasa-1 eNOS3 (Oxido Nitrico Sintetasa Endoteliasl). Tubulina-beta-5PI3K (fosfoinositol 3-quinasas o fosfoinositida-3-quinasas)CDC42 (protena de control de division cellular 42) E. Ben-Chetrit, S. Bergmann and R. Sood. Anti-inflammatory effects of colchicine. Rheumatology 2006;45:274282

MECANISMO DE ACCIN COLCHICINA Bloquea respuesta inflamatoria asociada a travs de la supresin del inflamosoma NACHT-LRR-PYD-containing protein-3 (NALP3) o Criopirina localizado en el brazo largo del cromosoma 1, activado por Caspasa-1 e Il1- y L-Selectina expresada en neutrfilos.

Disminuye la quimiotaxis de neutrfilos y su adhesin al endotelio al modular la activacin de meloculas de adhesin endoteliales, he inhibe la produccin de aniones superoxido producidos por lisosomas de neutrfilos.

Nuki G Colchicine: its mechanism of action and efficacy in crystal-induced inflammation. Curr Rheumatol Rep.2008 Jul;10(3):218-27.

MECANISMO DE ACCIN COLCHICINA En la divisin celular

Detiene la mitosis durante su metafase y no se forma el huso.

Presenta configuraciones atpicas y anormales del ncleo muriendo las clulas.

Clulas con mayor actividad de divisin y de metabolismo son las primeras en afectarse.AMERICAN JOURNAL OF THERAPEUTICS 8, 123-143 2008

MECANISMO DE ACCIN COLCHICINA En la Gota

Interrumpe el ciclo de deposicin de los cristales de urato monosodicos en las articulaciones y modifica la respuesta inflamatoria asociada a travs de la supresin del inflamosoma activado por Caspasa-1 e Il1- y L-Selectina

Inhibe la formacin y liberacin de glicoprotena quimiotactica que es producida durante la fagocitosis de cristales de urato. Nuki G Colchicine: its mechanism of action and efficacy in crystal-induced inflammation. Curr Rheumatol Rep.2008 Jul;10(3):218-27.

MECANISMO DE ACCIN COLCHICINA

MECANISMO DE ACCIN COLCHICINA En la inflamacin:

Inhibe seales de motilidad de las vesculas intracelular y secrecin de mediadores endgenos tales como citoquinas y quimioquinas.

Ejerce efectos sobre los leucocitos alterando su adhesin, movilidad y produccin de citoquinas. Disminucin de secrecin de Il1-.

Modula la actividad de la ciclooxygenasas (COX1 COX2) la cual juega un rol importante en la produccin de prostaglandinas

AZATIOPRINA

AZATIOPRINA Droga inmunosupresora usada en el transplante de rganos y enfermedades autoinmunes que pertenece al grupo quimico anlogo de las purinas.

Fue sintetizada originalmente como drogo anticancergena y prodroga de la mercaptopurina, en 1957.

AZATIOPRINA Nombre sistemtico:6-(3-metill-5-nitroimidazol-4-yl)sulfanil-7H-purina

Formula: C9H7N7O2S Peso Molecular: 277.26 g/molMetabolito activo metil-tiosina Monofosfato

MECANISMO DE ACCIN AZATIOPRINAHiptesis actuales.

La produccin de 6-mercaptopurina (6-MP) que acta como un antimetabolito de las purinas.

El dao al ADN a travs de la incorporacin de tio-anlogos purnicos

La inhibicin de mltiples vas en la biosntesis de cidos nucleicos, (ejemplo tioguanosil trifosfato, TGTP, en ARN) previniendo as la proliferacin de clulas involucradas en la determinacin y amplificacin de la respuesta inmune.

MECANISMO DE ACCIN AZATIOPRINAHiptesis actuales.

La induccin deapoptosisen clulas linfociticas anormalmente activas, al inducir la regulacin positiva de Bcl-xL en membrane mitochondrial (la cual actua en celulas B que aumenta su sobrevida)

El posible bloqueo de grupos SH mediante alquilacin.

MECANISMO DE ACCIN AZATIOPRINAMecanismo principal. Es una prodroga que al ser un anloga de las purinas, produce 6-mercaptopurina a travs de la reduccin de glutatin y otros componentes de grupo sulfidrilo, posteriormente convertido en 6-tiurato, 6metil-mercaptopurina y 6-tioguanina (nucletidos de guanina citotxicos) .

Bloquea replicacin de ADN y bloquea la sntesis de Novo de la va de las purinas.

Explica la especificidad de los linfocitos (principalmente para linfocitos T) debido a la carencia de otra va alterna al metabolismo de las purinas en los mismos. Jonathan S. MaltzmanandGary A. Koretzky. Azathioprine: old drug, new actions. J Clin Invest. 2003 Apr 15; 111(8): 11221124.

FARMACOLOGA AZATIOPRINAAbsorcin: Va Oral. Pico en plasma 1-2 horas.

Distribucin: pobre en tejidos. Unin a protenas 30%.Embarazo: atraviesa la placenta. Clasificacin D.Lactancia: se reporta concentracion en la leche materna.

Metabolismo: heptico.

Eliminacin: 12 minutos parcialmente como prodroga, 6-MP 0,7-3 horas.Excrecin: en orina como metabolitos.

EFECTOS BIOLOGICOS: AZATIOPRINAReduccin de la proliferacin de Linfocitos T y B.

Indicaciones: Asociado a esteroides y/u otro agente inmunosupresor, est indicado en el aumento de la supervivencia de los trasplantes de rganos, tales como el rin, el corazn, y el hgado

Enfermedad inflamatoria intestinal de moderada a grave.

Esclerosis mltiple recurrente-remitente clnicamente definida.

EFECTOS BIOLOGICOS: AZATIOPRINAReduccin de la proliferacin de Linfocitos T y B.

Indicaciones: Enfermedades inmunitarias Artritis reumatoidea, lupus eritematoso sistmico, dermatomiositis, polimiositis, hepatitis crnica activa autoinmune, pnfigo vulgar, poliarteritis nodosa, anemia hemoltica autoinmune, prpura trombocitopnica idioptica y pioderma gangrenoso

POSOLOGA AZATIOPRINA

Presentacin: Pharmachemie / Sinergium Tab. 50mg Representaciones Nolver, C.A. Tab. 50mg

Greta de Acquatella, C. Zulay Pastrn, Milka Gonzlez. Vademecum BADAN 2007.

POSOLOGA AZATIOPRINA

Dosis en trasplantes

Dosis inicial 3-5 mg/kg/da por va intravenosa u oral durante el primer da de la terapia.

Mantenimiento de 1-4 mg/kg/da, por va oral, Ajustar de acuerdo a las necesidades clnicas y a la tolerancia hematolgica.

POSOLOGA AZATIOPRINA

Enfermedad Inflamatoria Intestinal:

0.5mg/Kg/da e incrementar cada 10 das hasta alcanzar la dosis efectiva de 2-3 mg/kg/da.

Se recomienda una duracin del tratamiento de al menos 12 meses Respuesta a azatioprina puede no ser clnicamente aparente hasta 3-4 meses del inicio del tratamiento

POSOLOGA AZATIOPRINA

Artritis Idioptica Juvenil:

1mg/Kg/da en una o dos tomas durante 6-8 semanas incrementar 0,5mg/Kg/da cada cuatro semanas hasta: conseguir la respuesta deseada o dosis mxima de 2,5 mg/kg/da

Hepatitis autoinmune: 1-2 mg/kg/da

POSOLOGA AZATIOPRINA

Dosis en otros procesos:

Dosis inicial es de 2-2,5 mg/kg/da ajustar dependiendo de la respuesta clnica y de la tolerancia hematolgica del paciente

EFECTOS ADVERSOS AZATIOPRINA

Efectos adversosFrecuenciaManifestaciones >10%Leucopenia 28-50%Infeccin 20%

No establecidaaplasia medular, melanoma, dolor abdominal, alopecia, artralgia, nauseas, vomitos, diarrea fiebre, hepatotoxicidad, anemia macrocitica, mialgia, rash, trombocitopenia, sndrome dulce (dermatitis neutrofilica febril aguda)

EFECTOS ADVERSOS AZATIOPRINA Sndrome Dulce (Sweet's syndrome)Melanoma

CONTRAINDICACIONES AZATIOPRINA

ContraindicacionesAlergia documentadaInmunosupresionRiesgo mutagenico HemopatiasEmbarazo/lactanciaArtritis reumatoide tratada previamente con agentes alquilantes

CONTRAINDICACIONES AZATIOPRINAVigilancia Riesgo de hepatotoxicidad, infecciones recurrentes y NeoplasiasAnticoagulantes, aminosalicilatos, alopurinol, o otros inmunosupresores.

Teratogenicidad: Estudios en ratas preadas, ratones y conejos usando azatioprina en dosis a partir de 5-15 mg/kg/da durante el periodo de organognesis, ha demostrado varios grados de anomalas fetales.

La teratogenicidad fue evidente en conejos a dosis de 10 mg/kg/da. La evidencia sobre la teratogenicidad de azatioprina en el hombre es controvertida

INMUNOMODULADORES I METOTREXATE

METOTREXATEConocido por las siglasMTX, es unfrmacousado en el tratamiento delcnceryenfermedades autoinmunes. Sidney Farberdel Hospital Infantil de Boston

En la dcada de 1950 se empez a usar para el tratamiento del cncer.

En 1988 fue aprobado enEstados Unidospor laFDA(Administracin de Alimentos y Medicamentos), para su uso en la artritis reumatoide del adulto

METOTREXATE

Nombre sistemtico:cido(2S)-2-[(4-{[(2,4-diaminopteridin-6-il)metil](metil)amino}benzoil)amino]pentanodioico

Formula:C20H22N8O5Peso Molecular: 454.44 g/molMetabolito activo: 7-hidroximethotrexate,

MECANISMO DE ACCIN METOTREXATEActua como un antagonista del acido flico, inhibiendo de forma competitiva la dihidroxifolato-deshidrogenasa, por lo que es capaz de inhibir la sntesis de ADN.

As mismo puede modificar otras enzimas que intervienen en el metabolismo de los folatos, produciendo aumento de la adenosina extracelular.

Disminuye la quimiotaxis celular y acciones de diversas citosinas. Bulletin of the NYU Hospital for Joint Diseases 2007;65(3):168-73

MECANISMO DE ACCIN METOTREXATEEfecto Antineoplsico.

Acta inhibiendo competitivamente la dihidrofolato reductasa (DHFR) la cual participa en la sntesis de acido flico. El cual es crucial para la sntesis de novo de timidina requerida para la sntesis de ADN, asi como para la biosntesis de purina, ARN y pirimidina. Bulletin of the NYU Hospital for Joint Diseases 2007;65(3):168-73

MECANISMO DE ACCIN METOTREXATEEfecto Inmunomodulador.

Bulletin of the NYU Hospital for Joint Diseases 2007;65(3):168-73

FARMACOLOGA METOTREXATEAbsorcin: Va Oral. Biodisponibilidad 60% a dosis menores de 30mg/m2 40-50% a dosis mayores de de 80mg/m2Va SC (Ortrexup)Biodisponibilidad 77, 73, 91 y 97% a dosis 10, 15, 20, 25mg respectivamente

Va SC (Rasuvo)Biodisponibilidad 35, 49, 51 y 68% sobre la dosis oral a dosis de 7.5, 15 y 22.5mg respectivamente

Pico en plasma: VO 1-2 horas / IM 30-60min

FARMACOLOGA METOTREXATE

POSOLOGA METOTREXATEPresentacin: EbeweTab. 5mgAmp. 50mg, 500mg, 1g.Bedford Lab. Amp. 50mgPharmachemie / Sinergium Tab. 2,5mg, Amp. 5mg, 50mg, 500mg, Vial. 1 g.Pfizer Venezuela, S.A. Amp. 50mg, Vial. 500mg.Dabur / Biogalenica, C.A. Tab. 2,5mg, Amp. 50mg.Laboratorio Biopas, S.A. Amp. 50mg, 500mg)

Greta de Acquatella, C. Zulay Pastrn, Milka Gonzlez. Vademecum BADAN 2007.

POSOLOGA METOTREXATE

Va Oral:

Adultos y nios: 3.3 mg/m2. diariamente durante 4 - 6 semanas o hasta que se produzca la remisin

Dosis de mantenimiento de 20 - 30 mg/m2 dos veces por semana.

POSOLOGA METOTREXATEVa IV/IM: 50mg/m2/semanal en rgimen de varias drogas. Dosis intermedia entre 100mg y 500mg/m2/cada 15 21 das. Dosis altas mayores de 1g/m2 hasta 12gr/m2/infusin. Dosis mayores de 100mg/m2 deben ser administradas en 1000 cc de solucin glucosada al 5% y en un tiempo de 4 horas con hidratacin previa y alcalinizacin con Bicarbonato de Sodio. NOTA: 24 horas de terminada la infusin, comenzar rescate con Leucovorina a dosis entre 15-30mg/m2/dosis/VO/cada 6 horas por un mnimo de 8 dosis de acuerdo al protocolo usado.Greta de Acquatella, C. Zulay Pastrn, Milka Gonzlez. Vademecum BADAN 2007.

POSOLOGA METOTREXATE

Va IT:Dosis por va I.T., 12mg/m2 no sobrepasar 15mg

En este caso de leucemia menngea se administran 2 dosis semanales hasta la desaparicin de clulas neoplsicas del LCR y se consolidar con dos dosis subsiguientes.Greta de Acquatella, C. Zulay Pastrn, Milka Gonzlez. Vademecum BADAN 2007.

INDICACIONES METOTREXATE

Esta indicado su uso en:

Artritis reumatoideDermatomiocitis juvenilArtritis psoriaticaLupusSarcoidosisEnfermedad de CrohnEczema y varias formas de vasculitis.

EFECTOS ADVERSOS METOTREXATE

Efectos adversosFrecuenciaManifestaciones >10%Aracnoiditis, toxicidad subaguda [(con administracin intratecal) paralisis de extremidades paralisis de nervios craneales, convulsiones, coma.Demielinizacion, encefalopata con irritacin craneal, eritema cutneo, Hiperuremia, estomatitis ulcerativa, Glositis, Gingivitis, Vausea, Diarrea y Vomito, perforacin intestinal, mucositis, anorexia, leucopenia, fallo renal, nefropata, faringitis.

CONTRAINDICACIONES METOTREXATEAlergia al medicamento

Sindrome de lisis tumoral

Supresion de medula osea / sndromes de inmunodeficiencia.

Fallo renal.

Insuficiencia heptica, enfermedad heptica, alcoholismo.

CONCLUSIONES

El uso de inmunomoduladores como tratamiento extendido de enfermedades reumatolgicas e e inflamatorias de larga data es efectivo y seguro a dosis adecuadas sin embargo se desconoce en mucho de los casos sus efectos y mecanismos biolgicos in vivo.

Se Amerita de personalizar la atencin de cada paciente para proporcionar la mejor opcin de tratamiento

Continuara

The antimalarial agentschloroquineand hydroxychloroquine have been used widely for the treatment of rheumatoid arthritis and systemic lupus erythematosus. These compounds lead to improvement of clinical and laboratory parameters, but their slow onset of action distinguishes them from glucocorticoids and nonsteroidal antiinflammatory agents.Chloroquineand hydroxychloroquine increase pH within intracellular vacuoles and alter processes such as protein degradation by acidic hydrolases in the lysosome, assembly of macromolecules in the endosomes, and posttranslation modification of proteins in the Golgi apparatus. It is proposed that the antirheumatic properties of these compounds results from their interference with "antigen processing" in macrophages and other antigen-presenting cells. Acidic cytoplasmic compartments are required for the antigenic protein to be digested and for the peptides to assemble with the alpha and beta chains of MHC class II proteins. As a result, antimalarials diminish the formation of peptide-MHC protein complexes required to stimulate CD4+ T cells and result in down-regulation of the immune response against autoantigenic peptides. Because this mechanism differs from other antirheumatic drugs, antimalarials are well suited to complement these other compounds in combination drug therapy.*The antimalarial agentschloroquineand hydroxychloroquine have been used widely for the treatment of rheumatoid arthritis and systemic lupus erythematosus. These compounds lead to improvement of clinical and laboratory parameters, but their slow onset of action distinguishes them from glucocorticoids and nonsteroidal antiinflammatory agents.Chloroquineand hydroxychloroquine increase pH within intracellular vacuoles and alter processes such as protein degradation by acidic hydrolases in the lysosome, assembly of macromolecules in the endosomes, and posttranslation modification of proteins in the Golgi apparatus. It is proposed that the antirheumatic properties of these compounds results from their interference with "antigen processing" in macrophages and other antigen-presenting cells. Acidic cytoplasmic compartments are required for the antigenic protein to be digested and for the peptides to assemble with the alpha and beta chains of MHC class II proteins. As a result, antimalarials diminish the formation of peptide-MHC protein complexes required to stimulate CD4+ T cells and result in down-regulation of the immune response against autoantigenic peptides. Because this mechanism differs from other antirheumatic drugs, antimalarials are well suited to complement these other compounds in combination drug therapy.*The antimalarial agentschloroquineand hydroxychloroquine have been used widely for the treatment of rheumatoid arthritis and systemic lupus erythematosus. These compounds lead to improvement of clinical and laboratory parameters, but their slow onset of action distinguishes them from glucocorticoids and nonsteroidal antiinflammatory agents.Chloroquineand hydroxychloroquine increase pH within intracellular vacuoles and alter processes such as protein degradation by acidic hydrolases in the lysosome, assembly of macromolecules in the endosomes, and posttranslation modification of proteins in the Golgi apparatus. It is proposed that the antirheumatic properties of these compounds results from their interference with "antigen processing" in macrophages and other antigen-presenting cells. Acidic cytoplasmic compartments are required for the antigenic protein to be digested and for the peptides to assemble with the alpha and beta chains of MHC class II proteins. As a result, antimalarials diminish the formation of peptide-MHC protein complexes required to stimulate CD4+ T cells and result in down-regulation of the immune response against autoantigenic peptides. Because this mechanism differs from other antirheumatic drugs, antimalarials are well suited to complement these other compounds in combination drug therapy.*The antimalarial agentschloroquineand hydroxychloroquine have been used widely for the treatment of rheumatoid arthritis and systemic lupus erythematosus. These compounds lead to improvement of clinical and laboratory parameters, but their slow onset of action distinguishes them from glucocorticoids and nonsteroidal antiinflammatory agents.Chloroquineand hydroxychloroquine increase pH within intracellular vacuoles and alter processes such as protein degradation by acidic hydrolases in the lysosome, assembly of macromolecules in the endosomes, and posttranslation modification of proteins in the Golgi apparatus. It is proposed that the antirheumatic properties of these compounds results from their interference with "antigen processing" in macrophages and other antigen-presenting cells. Acidic cytoplasmic compartments are required for the antigenic protein to be digested and for the peptides to assemble with the alpha and beta chains of MHC class II proteins. As a result, antimalarials diminish the formation of peptide-MHC protein complexes required to stimulate CD4+ T cells and result in down-regulation of the immune response against autoantigenic peptides. Because this mechanism differs from other antirheumatic drugs, antimalarials are well suited to complement these other compounds in combination drug therapy.***Dosis cloroquina 5 mg/kg de peso sin exceder los 500 mg (300mg)

*s 35 mg/kg kg/day divided 12 times per day with a maximum of 400mg per day*s 35 mg/kg kg/day divided 12 times per day with a maximum of 400mg per day*Colchicine consists of three hexameric rings termed A, B and C. The tropolone methyl ester, which is a precise analogue of the ring C of colchicine, can bind the tubulin molecule thereby inhibiting its polymerization into microtubulesin vitro[5]. Since microtubules are part of the cytoskeleton in almost every eukaryotic cell, the effect of colchicine at the cellular level is generally assumed to stem from its direct interaction with microtubules. Specifically, its anti-inflammatory effect has been attributed to its disruption of microtubules in neutrophils, thereby inhibiting their migration toward the chemotactic factors. Furthermore, Cronsteinet al.[6] showed that colchicine may also alter the distribution of adhesion molecules on the surface of both neutrophils and endothelial cells, leading to a significant inhibition of interaction between white blood cells (WBC) and endothelial cells interfering with their transmigration. Thus, there is growing evidence that the anti-inflammatory effect of colchicine is multifaceted.

*Among the suppressed genes were those coding for caspase-1, eNOS3, tubulin-beta-5, PI3K, CDC42, BPA and MAPK 1, all of which are likely to participate in inflammation and neutrophil migration as well as in many other intracellular functions.*apparently interrupts the cycle of monosodium urate crystal deposition in joint tissues and the resultant inflammatory response that initiates and sustains an acute attack. Colchicine decreases leukocyte chemotaxis and phagocytosis and inhibits the formation and release of a chemotactic glycoprotein that is produced during phagocytosis of urate crystals. Colchicine also inhibits urate crystal deposition, which is enhanced by a low pH in the tissues, probably by inhibiting oxidation of glucose and subsequent lactic acid production in leukocytes. Colchicine has no analgesic or antihyperuricemic activity. Colchicine inhibits microtubule assembly in various cells, including leukocytes, probably by binding to and interfering with polymerization of the microtubule subunit tubulin. Although some studies have found that this action probably does not contribute significantly to colchicine's antigout action, a recent in vitro study has shown that it may be at least partially involved.*apparently interrupts the cycle of monosodium urate crystal deposition in joint tissues and the resultant inflammatory response that initiates and sustains an acute attack. Colchicine decreases leukocyte chemotaxis and phagocytosis and inhibits the formation and release of a chemotactic glycoprotein that is produced during phagocytosis of urate crystals. Colchicine also inhibits urate crystal deposition, which is enhanced by a low pH in the tissues, probably by inhibiting oxidation of glucose and subsequent lactic acid production in leukocytes. Colchicine has no analgesic or antihyperuricemic activity. Colchicine inhibits microtubule assembly in various cells, including leukocytes, probably by binding to and interfering with polymerization of the microtubule subunit tubulin. Although some studies have found that this action probably does not contribute significantly to colchicine's antigout action, a recent in vitro study has shown that it may be at least partially involved.*apparently interrupts the cycle of monosodium urate crystal deposition in joint tissues and the resultant inflammatory response that initiates and sustains an acute attack. Colchicine decreases leukocyte chemotaxis and phagocytosis and inhibits the formation and release of a chemotactic glycoprotein that is produced during phagocytosis of urate crystals. Colchicine also inhibits urate crystal deposition, which is enhanced by a low pH in the tissues, probably by inhibiting oxidation of glucose and subsequent lactic acid production in leukocytes. Colchicine has no analgesic or antihyperuricemic activity. Colchicine inhibits microtubule assembly in various cells, including leukocytes, probably by binding to and interfering with polymerization of the microtubule subunit tubulin. Although some studies have found that this action probably does not contribute significantly to colchicine's antigout action, a recent in vitro study has shown that it may be at least partially involved.**Dosis cloroquina 5 mg/kg de peso sin exceder los 500 mg (300mg)

*Dosis cloroquina 5 mg/kg de peso sin exceder los 500 mg (300mg)

*through reduction by glutathione and other sulphydryl-containing compounds and then enzymatically converted into 6-thiouric acid, 6-methyl-MP, and 6-thioguanine (6-TG) (1,3). Ultimately, azathioprine can then become incorporated into replicating DNA and can also block the de novo pathway of purine synthesis. It is this action that is thought to contribute to its relative specificity to lymphocytes due to their lack of a salvage pathway. However, the effects on the blockade of DNA replication have never fully explained all of the laboratory and clinical findings of azathioprine-induced immunosuppression**Dosis cloroquina 5 mg/kg de peso sin exceder los 500 mg (300mg)

*Dosis cloroquina 5 mg/kg de peso sin exceder los 500 mg (300mg)

**For cancer, methotrexate competitively inhibitsdihydrofolate reductase(DHFR), anenzymethat participates in thetetrahydrofolatesynthesis.[20][21]The affinity of methotrexate for DHFR is about one thousand-fold that of folate. DHFR catalyses the conversion ofdihydrofolateto the activetetrahydrofolate.[20]Folic acid is needed for thedenovosynthesisof thenucleosidethymidine, required forDNA synthesis.[20]Also, folate is essential for purine and pyrimidine base biosynthesis, so synthesis will be inhibited. Methotrexate, therefore, inhibits the synthesis ofDNA,RNA,thymidylates, andproteins.[20]*For the treatment of rheumatoid arthritis, inhibition of DHFR is not thought to be the main mechanism, but rather multiple mechanisms appear to be involved including: the inhibition ofenzymesinvolved inpurine metabolism, leading to accumulation ofadenosine; inhibition ofT cellactivation and suppression ofintercellular adhesion moleculeexpression byT cells; selective down-regulation ofB cells; increasingCD95sensitivity of activated T cells; inhibition of methyltransferase activity, leading to (de)-activation of enzyme activity relevant to immune system function.[22][23]Another mechanism of MTX is the inhibition of the binding of Interleukin 1 beta to its cell surface receptor.[24]

******