RESUMEN

Lorcaserin is a serotonin (5-HT)2C receptor-preferring agonist approved by the US Food and Drug Administration to treat obesity. Lorcaserin decreases cocaine self-administration in rats and monkeys. Although this effect is partially inhibited by a 5-HT2C receptor antagonist (SB242084), lorcaserin also has effects at 5-HT2A and 5-HT1A receptors, and the relative contribution of these receptors to its anti-cocaine effects has not been investigated. The goals of this study were to determine 1) the potency and effectiveness of lorcaserin to decrease self-administration of cocaine and 3,4-methylenedioxypyrovalerone (MDPV), a common "bath salts" constituent; and 2) the receptor(s) mediating the effects of lorcaserin on cocaine and MDPV self-administration. Male Sprague-Dawley rats (n = 6) were trained to self-administer MDPV under a progressive ratio schedule of reinforcement and maintained under this schedule with daily access to 0.32 mg/kg per infusion of cocaine or 0.032 mg/kg per infusion of MDPV. Dose-response curves for the effects of lorcaserin on cocaine and MDPV self-administration were generated by administering lorcaserin (0.1-5.6 mg/kg) 25 minutes before the start of the session. To assess the effects of 5-HT2C (SB242084, 0.1 mg/kg), 5-HT2A (MDL100907, 0.1 mg/kg), and 5-HT1A (WAY100635, 0.178 mg/kg) receptor antagonists, they were administered 15 minutes before lorcaserin. Lorcaserin decreased cocaine and MDPV self-administration with equal potency. Antagonism of 5-HT2C (but not 5-HT1A or 5-HT2A) receptors blocked the effects of lorcaserin on cocaine and MDPV self-administration. Taken together, these data provide additional support for further development of 5-HT2C receptor agonists, such as lorcaserin, for the treatment of stimulant abuse.

Asunto(s)

Benzazepinas/farmacología , Benzodioxoles/antagonistas & inhibidores , Cocaína/antagonistas & inhibidores , Pirrolidinas/antagonistas & inhibidores , Receptor de Serotonina 5-HT2C/metabolismo , Agonistas del Receptor de Serotonina 5-HT2/farmacología , Animales , Benzodioxoles/administración & dosificación , Cocaína/administración & dosificación , Relación Dosis-Respuesta a Droga , Masculino , Pirrolidinas/administración & dosificación , Ratas , Ratas Sprague-Dawley , Refuerzo en Psicología , Autoadministración , Cathinona Sintética

RESUMEN

AIMS: To determine proinflammatory mechanisms of Treponema pallidum outer membrane protein Tp92 in the early syphilis infection in human macrophages and HMEC-1 cells. METHODS: Recombinant Tp92 protein was used to stimulate target human macrophages and HMEC-1 cells. PDTC (Pyrrolidinedithiocarbamic acid), SB202190 and Z-YVAD-FMK were used to block the MyD88/NF-κB, MAPKs/p38 and NLRP3/Caspase-1 pathway, respectively. TNF-α, IL-1ß, IL-6, IL-8,NLRP3, casepase-1 were detected by ELISA or Western blot. Lactate dehydrogenase (LDH) activity was measured. RESULTS: Tp92 protein could significantly induced the secretion of proinflammatory cytokines TNF-α, IL-1ß, IL-6 and IL-8 in HMEC-1 cells, but not in macrophages except IL-8. When MyD88/NF-κB pathway was blocked, differences in the secretion of TNF-α, IL-6 and IL-1ß levels and LDH enzyme activity between Tp92 group and Tp92 + PDTC group were not significant (P > 0.05) in HMEC-1 cells and macrophages except IL-8(P < 0.05). When MAPKs/p38 pathway was blocked, differences in the secretion of TNF-α, IL-1ß, IL-6 and IL-8 and LDH enzyme activity both Tp92 group and Tp92 + SB2010190 group were not significant (P > 0.05) in HMEC-1 cells and macrophages. In contrast, when NLRP3/Caspase-1 pathway was blocked with Z-YVAD-FMK, TNF-α, IL-6 and IL-1ß levels, LDH enzyme activity, and Caspase-1 and NLRP3 protein levels were significantly declined (P < 0.05) in HMEC-1 cells except IL-8(P > 0.05). The LDH enzyme activity in macrophages was decreased before and after Z-YVAD-FMK blocking (P < 0.05),however, differences in the secretion of TNF-α, IL-1ß, IL-6 and IL-8 between Tp92 group and Tp92+Z-YVAD-FMK group in macrophages were not significant (P > 0.05). CONCLUSIONS: Tp92 protein may promote proinflammatory cytokines TNF-α, IL-1ß, IL-6 secretion of HMEC-1 cells, but not in macrophages, and increase the LDH enzyme activity of HMEC-1 cells and macrophages through NLRP3/Caspase-1 pathway. However, Tp92 protein may promote IL-8 secretion of HMEC-1 cells and macrophages through MyD88/NF-κB pathway.

Asunto(s)

Antígenos de Superficie/farmacología , Proteínas Bacterianas/farmacología , Línea Celular/efectos de los fármacos , Citocinas/metabolismo , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Proteínas de la Membrana/farmacología , Treponema pallidum/metabolismo , Clorometilcetonas de Aminoácidos/antagonistas & inhibidores , Antígenos de Superficie/genética , Proteínas Bacterianas/genética , Caspasa 1/efectos de los fármacos , Caspasa 1/metabolismo , Clonación Molecular , Citocinas/efectos de los fármacos , Humanos , Imidazoles/antagonistas & inhibidores , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Interleucina-8/metabolismo , L-Lactato Deshidrogenasa/efectos de los fármacos , L-Lactato Deshidrogenasa/metabolismo , Proteínas de la Membrana/genética , Quinasas de Proteína Quinasa Activadas por Mitógenos/efectos de los fármacos , Quinasas de Proteína Quinasa Activadas por Mitógenos/metabolismo , Factor 88 de Diferenciación Mieloide/efectos de los fármacos , Factor 88 de Diferenciación Mieloide/metabolismo , FN-kappa B/efectos de los fármacos , FN-kappa B/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/efectos de los fármacos , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Piridinas/antagonistas & inhibidores , Pirrolidinas/antagonistas & inhibidores , Proteínas Recombinantes/genética , Proteínas Recombinantes/farmacología , Transducción de Señal/efectos de los fármacos , Células THP-1 , Tiocarbamatos/antagonistas & inhibidores , Treponema pallidum/genética , Factor de Necrosis Tumoral alfa/metabolismo

RESUMEN

Overexpression of P-glycoprotein (P-gp) in the brain is an important mechanism involved in drug­resistant epilepsy (DRE). High-mobility group box 1 (HMGB1), an inflammatory cytokine, significantly increases following seizures and may be involved in upregulation of P­gp. However, the underlying mechanisms remain elusive. The aim of the present study was to evaluate the role of HMGB1 and its downstream signaling components, receptor for advanced glycation end­product (RAGE) and nuclear factor­κB (NF­κB), on P­gp expression in rat brains during status epilepticus (SE). Small interfering RNA (siRNA) was administered to rats prior to induction of SE by pilocarpine, to block transcription of the genes encoding HMGB1 and RAGE, respectively. An inhibitor of NF­κB, pyrrolidinedithiocarbamic acid (PDTC), was utilized to inhibit activation of NF­κB. The expression levels of HMGB1, RAGE, phosphorylated­NF­κB p65 (p­p65) and P­gp were detected by western blotting. The relative mRNA expression levels of the genes encoding these proteins were measured using reverse transcription­quantitative polymerase chain reaction and the cellular localization of the proteins was determined by immunofluorescence. Pre­treatment with HMGB1 siRNA reduced the expression levels of RAGE, p­p65 and P­gp. PDTC reduced the expression levels of P­gp. These findings suggested that overexpression of P­gp during seizures may be regulated by HMGB1 via the RAGE/NF­κB signaling pathway, and may be a novel target for treating DRE.

Asunto(s)

Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Encéfalo/metabolismo , Proteína HMGB1/metabolismo , FN-kappa B/metabolismo , Receptor para Productos Finales de Glicación Avanzada/metabolismo , Estado Epiléptico/metabolismo , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/biosíntesis , Animales , Regulación de la Expresión Génica/efectos de los fármacos , Técnicas de Silenciamiento del Gen , Proteína HMGB1/genética , Masculino , Fosforilación , Pilocarpina/farmacología , Pirrolidinas/antagonistas & inhibidores , ARN Mensajero/metabolismo , ARN Interferente Pequeño/metabolismo , Ratas , Ratas Sprague-Dawley , Receptor para Productos Finales de Glicación Avanzada/genética , Transducción de Señal , Estado Epiléptico/genética , Tiocarbamatos/antagonistas & inhibidores , Regulación hacia Arriba

RESUMEN

Despite its low chemical reactivity, the noble gas xenon possesses a remarkable spectrum of biological effects. In particular, xenon is a strong neuroprotectant in preclinical models of hypoxic-ischemic brain injury. In this study, we wished to determine whether xenon retained its neuroprotective potential in experimental settings that model the progressive loss of midbrain dopamine (DA) neurons in Parkinson's disease. Using rat midbrain cultures, we established that xenon was partially protective for DA neurons through either direct or indirect effects on these neurons. So, when DA neurons were exposed to l-trans-pyrrolidine-2,4-dicarboxylic acid so as to increase ambient glutamate levels and generate slow and sustained excitotoxicity, the effect of xenon on DA neurons was direct. The vitamin E analog Trolox also partially rescued DA neurons in this setting and enhanced neuroprotection by xenon. However, in the situation where DA cell death was spontaneous, the protection of DA neurons by xenon appeared indirect as it occurred through the repression of a mechanism mediated by proliferating glial cells, presumably astrocytes and their precursor cells. Xenon also exerted trophic effects for DA neurons in this paradigm. The effects of xenon were mimicked and improved by the N-methyl-d-aspartate glutamate receptor antagonist memantine and xenon itself appeared to work by antagonizing N-methyl-d-aspartate receptors. Note that another noble gas argon could not reproduce xenon effects. Overall, present data indicate that xenon can provide protection and trophic support to DA neurons that are vulnerable in Parkinson's disease. This suggests that xenon might have some therapeutic value for this disorder.

Asunto(s)

Anestésicos por Inhalación/farmacología , Neuronas Dopaminérgicas/efectos de los fármacos , Mesencéfalo/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Xenón/farmacología , Animales , Antioxidantes/farmacología , Muerte Celular/efectos de los fármacos , Células Cultivadas , Cromanos/farmacología , Ácidos Dicarboxílicos/antagonistas & inhibidores , Ácidos Dicarboxílicos/toxicidad , Antagonistas de Aminoácidos Excitadores/farmacología , Memantina/farmacología , Técnicas de Cultivo de Órganos , Pirrolidinas/antagonistas & inhibidores , Pirrolidinas/toxicidad , Ratas , Ratas Wistar

RESUMEN

Anxiety disorders are one of the most common and debilitating mental illnesses worldwide. Growing evidence indicates an age-dependent rise in the incidence of anxiety disorders from adolescence through adulthood, suggestive of underlying neurodevelopmental mechanisms. Kappa opioid receptors (KORs) are known to contribute to the development and expression of anxiety; however, the functional role of KORs in the basolateral amygdala (BLA), a brain structure critical in mediating anxiety, particularly across ontogeny, are unknown. Using whole-cell patch-clamp electrophysiology in acute brain slices from adolescent (postnatal day (P) 30-45) and adult (P60+) male Sprague-Dawley rats, we found that the KOR agonist, U69593, increased the frequency of GABAA-mediated spontaneous inhibitory postsynaptic currents (sIPSCs) in the adolescent BLA, without an effect in the adult BLA or on sIPSC amplitude at either age. The KOR effect was blocked by the KOR antagonist, nor-BNI, which alone did not alter GABA transmission at either age, and the effect of the KOR agonist was TTX-sensitive. Additionally, KOR activation did not alter glutamatergic transmission in the BLA at either age. In contrast, U69593 inhibited sIPSC frequency in the central amygdala (CeA) at both ages, without altering sIPSC amplitude. Western blot analysis of KOR expression indicated that KOR levels were not different between the two ages in either the BLA or CeA. This is the first study to provide compelling evidence for a novel and unique neuromodulatory switch in one of the primary brain regions involved in initiating and mediating anxiety that may contribute to the ontogenic rise in anxiety disorders.

Asunto(s)

Envejecimiento/fisiología , Complejo Nuclear Basolateral/metabolismo , Receptores Opioides kappa/fisiología , Ácido gamma-Aminobutírico/fisiología , Animales , Complejo Nuclear Basolateral/efectos de los fármacos , Bencenoacetamidas/antagonistas & inhibidores , Bencenoacetamidas/farmacología , Ácido Glutámico/fisiología , Potenciales Postsinápticos Inhibidores/efectos de los fármacos , Masculino , Naltrexona/análogos & derivados , Naltrexona/farmacología , Pirrolidinas/antagonistas & inhibidores , Pirrolidinas/farmacología , Ratas , Receptores Opioides kappa/agonistas , Receptores Opioides kappa/antagonistas & inhibidores , Receptores Opioides kappa/biosíntesis , Transmisión Sináptica/efectos de los fármacos

RESUMEN

Novel substituted phenoxyalkyl pyridinium oximes, previously shown to reactivate brain cholinesterase in rats treated with high sublethal dosages of surrogates of sarin and VX, were tested for their ability to prevent mortality from lethal doses of these two surrogates. Rats were treated subcutaneously with 0.6mg/kg nitrophenyl isopropyl methylphosphonate (NIMP; sarin surrogate) or 0.65mg/kg nitrophenyl ethyl methylphosphonate (NEMP; VX surrogate), dosages that were lethal within 24h to all tested rats when they received only 0.65mg/kg atropine at the time of initiation of seizure-like behavior (about 30min). If 146mmol/kg 2-PAM (human equivalent dosage) was also administered, 40% and 33% survival was obtained with NIMP and NEMP, respectively, while the novel Oximes 1 and 20 provided 65% and 55% survival for NIMP and 75 and 65% for NEMP, respectively. In addition, both novel oximes resulted in a highly significant decrease in time to cessation of seizure-like behavior compared to 2-PAM during the first 8h of observation. Brain cholinesterase inhibition was slightly less in novel oxime treated rats compared to 2-PAM in the 24h survivors. The lethality data indicate that 24h survival is improved by two of the novel oximes compared to 2-PAM. The cessation of seizure-like behavior data strongly suggest that these novel oximes are able to penetrate the blood-brain barrier and can combat the hypercholinergic activity that results in seizures. Therefore this oxime platform has exceptional promise as therapy that could both prevent nerve agent-induced lethality and attenuate nerve agent-induced seizures.

Asunto(s)

Antídotos/uso terapéutico , Compuestos Organotiofosforados/antagonistas & inhibidores , Compuestos Organotiofosforados/toxicidad , Oximas/uso terapéutico , Pirrolidinas/antagonistas & inhibidores , Pirrolidinas/toxicidad , Convulsiones/inducido químicamente , Convulsiones/prevención & control , Acetilcolinesterasa/metabolismo , Animales , Conducta Animal/efectos de los fármacos , Encéfalo/enzimología , Inhibidores de la Colinesterasa/toxicidad , Masculino , Compuestos de Pralidoxima/farmacología , Ratas , Ratas Sprague-Dawley , Análisis de Supervivencia

RESUMEN

3,4-methylenedioxypyrovalerone or MDPV is a synthetic cathinone with psychostimulant properties more potent than cocaine. We quantified this drug in the striatum after subcutaneous administration to rats. MDPV reached the brain around 5 min after its administration and peaked at 20-25 min later. The elimination half-life in the striatum (61 min) correlates with the decrease in the psychostimulant effect after 60 min. Around 11% of the administered dose reached the striatum and, considering a homogeneous brain distribution, we determined that around 86% of the plasma MDPV is distributed to the brain. MDPV induced a dose-dependent increase in locomotor activity, rearing behaviour and stereotypies, all prevented by haloperidol. A plot of locomotor activity or stereotypies versus MDPV striatal concentrations over time showed a direct relationship between factors. No free MDPV metabolites were detected in plasma, at any time, but hydrolysis with glucuronidase allowed us to identify mainly three metabolites, one of them for the first time in rat plasma. The present results contribute to evidence that MDPV induces hyperlocomotion mainly through a dopamine-dependent mechanism. Good correlation between behavioural effects and striatal levels of MDPV leads us to conclude that its psychostimulant effect is mainly due to a striatal distribution of the substance. The present research provides useful information on the pharmacokinetics of MDPV, and can help design new experiments with kinetics data as well as provide a better understanding of the effects of MDPV in humans and its potential interactions.

Asunto(s)

Benzodioxoles/farmacología , Benzodioxoles/farmacocinética , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/metabolismo , Actividad Motora/efectos de los fármacos , Pirrolidinas/farmacología , Pirrolidinas/farmacocinética , Conducta Estereotipada/efectos de los fármacos , Animales , Benzodioxoles/antagonistas & inhibidores , Benzodioxoles/sangre , Estimulantes del Sistema Nervioso Central/antagonistas & inhibidores , Estimulantes del Sistema Nervioso Central/sangre , Estimulantes del Sistema Nervioso Central/farmacocinética , Estimulantes del Sistema Nervioso Central/farmacología , Relación Dosis-Respuesta a Droga , Semivida , Haloperidol/farmacología , Inyecciones Subcutáneas , Masculino , Pirrolidinas/antagonistas & inhibidores , Pirrolidinas/sangre , Ratas , Cathinona Sintética

RESUMEN

The incidence of facial trauma is high. This study has the primary objective of documenting and cataloging maxillofacial fractures in polytrauma patients. From a total of 1229 multiple trauma cases treated at the Emergency Room of the Santo Antonio Hospital - Oporto Hospital Center, Portugal, between August 2001 and December 2007, 251 patients had facial wounds and 209 had maxillofacial fractures. Aged ranged form 13 to 86 years. The applied selective method was based on the presence of facial wound with Abbreviated Injury Scale ≥1. Men had a higher incidence of maxillofacial fractures among multiple trauma patients (86.6%) and road traffic accidents were the primary cause of injuries (69.38%). Nasoorbitoethmoid complex was the most affected region (67.46%) followed by the maxilla (57.42%). The pattern and presentation of maxillofacial fractures had been studied in many parts of the world with varying results. Severe multiple trauma patients had different patterns of maxillofacial injuries. The number of maxillofacial trauma is on the rise worldwide as well as the incidence of associated sequelae. Maxillofacial fractures on multiple trauma patients were more frequent among males and in road traffic crashes. Knowing such data is elementary. The society should have a key role in the awareness of individuals and in prevention of road traffic accidents.

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É alta a incidência de traumas na face. Este estudo teve por objetivo documentar e catalogar as fraturas maxilofaciais em pacientes com politraumatismos. De um total de 1229 casos de politraumatizados tratados na Sala de Emergência do Hospital de Santo António - Centro Hospitalar do Porto, Portugal, entre Agosto de 2001 e Dezembro de 2007, 251 pacientes tiveram ferimentos na face e 209 apresentaram fraturas maxilofaciais. As idades variaram de 13 a 86 anos. O método de seleção baseou-se na presença de ferimentos na face com Abreviated Injury Scale ≥1. Os homens apresentaram maior incidência de fraturas maxilofaciais (86,6%) entre os pacientes com múltiplos traumatismos na face e os acidentes de trânsito foram a causa principal dos traumatismos (69,38%). A região mais afetada foi o complexo naso-órbito-etmoidal (67,46%), seguido pela maxila (57,42%). O padrão e a apresentação das fraturas maxilofaciais tem sido estudado em muitas regiões do mundo com resultados variados. Pacientes com politraumatizados graves apresentaram padrões diferentes de traumatismos maxilofaciais. O número de traumatismos maxilofaciais tem aumentado à escala mundial, assim como a incidência das sequelas associadas. Entre os pacientes com traumatismos múltiplos, a maioria pertencia ao sexo masculino, assim como a causa mais frequente foram os acidentes automobilísticos. É elementar o conhecimento destes dados. A sociedade tem um papel primordial nos cuidados individuais e na prevenção dos acidentes de trânsito.

Asunto(s)

Animales , Masculino , Ratones , Ratas , Reactivadores de la Colinesterasa , Colina/análogos & derivados , Diazinón/antagonistas & inhibidores , Neurotransmisores/farmacología , Fisostigmina/antagonistas & inhibidores , Pirrolidinas/antagonistas & inhibidores , Colina/metabolismo , Colina/farmacología , Inhibidores de la Colinesterasa/toxicidad , Diazinón/toxicidad , Ratones Endogámicos ICR , Fisostigmina/toxicidad , Pirrolidinas/toxicidad , Ratas Endogámicas , Receptores Colinérgicos/efectos de los fármacos , Receptores Colinérgicos/metabolismo

RESUMEN

BACKGROUND: Anti-atherosclerotic effects of dipeptidyl peptidase-4 (DPP-4) inhibitors have been shown in many studies. Since inflammation and immune response play a key role in atherogenesis, we examined the effect of DPP-4 inhibitors on the expression of nod-like receptor family, pyrin domain containing 3 (NLRP3) Inflammasome and Interleukin-1beta (IL-1ß) in human macrophages. METHODS AND RESULTS: THP-1 macrophages were incubated with oxidized low density lipoprotein (ox-LDL) with or without DPP-4 inhibitors (sitagliptin and NVPDPP728). The effects of DPP-4 inhibitors on the expression of NLRP3, toll-like receptor 4 (TLR4) and pro-inflammatory cytokine IL-1ß were studied. Both DPP-4 inhibitors induced a significant reduction in NLRP3, TLR4 and IL-1ß expression; concurrently, there was an increase in glucagon like peptide 1 receptor (GLP-1R) expression. Simultaneously, DPP-4 inhibitors reduced phosphorylated-PKC, but not PKA, levels. To determine the role of PKC activation in the effects of DPP-4 inhibitors, cells were treated with PMA- which blocked the effect of DPP-4 inhibitors on NLRP3 and IL-1ß as well as TLR4 and GLP-1R. Over-expression of GLP-1R in macrophages with its agonist liraglutide also blocked the effects of PMA. CONCLUSION: DPP-4 inhibitors suppress NLRP3, TLR4 and IL-1ß in human macrophages through inhibition of PKC activity. This study provides novel insights into the mechanism of inhibition of inflammatory state and immune response in atherosclerosis by DPP-4 inhibitors.

Asunto(s)

Proteínas Portadoras/metabolismo , Inhibidores de la Dipeptidil-Peptidasa IV/farmacología , Inflamasomas/biosíntesis , Interleucina-1beta/biosíntesis , Macrófagos/efectos de los fármacos , Proteína Quinasa C/metabolismo , Receptores de Glucagón/metabolismo , Proteínas Portadoras/biosíntesis , Técnicas de Cultivo de Célula , Proteínas Quinasas Dependientes de AMP Cíclico/biosíntesis , Regulación de la Expresión Génica/efectos de los fármacos , Péptido 1 Similar al Glucagón/análogos & derivados , Péptido 1 Similar al Glucagón/farmacología , Receptor del Péptido 1 Similar al Glucagón , Humanos , Liraglutida , Macrófagos/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR , Nitrilos/antagonistas & inhibidores , Nitrilos/farmacología , Fosforilación/efectos de los fármacos , Pirazinas/antagonistas & inhibidores , Pirazinas/farmacología , Pirrolidinas/antagonistas & inhibidores , Pirrolidinas/farmacología , Receptores de Glucagón/biosíntesis , Transducción de Señal/efectos de los fármacos , Fosfato de Sitagliptina , Acetato de Tetradecanoilforbol/análogos & derivados , Acetato de Tetradecanoilforbol/farmacología , Receptor Toll-Like 4/biosíntesis , Triazoles/antagonistas & inhibidores , Triazoles/farmacología

RESUMEN

Prolactin is the key hormone to stimulate milk synthesis in mammary epithelial cells. It signals through the Jak2-Stat5 pathway to induce the expression of ß-casein, a milk protein which is often used as a marker for mammary differentiation. Here we examined the effect of pyrrolidine dithiocarbamate (PDTC) on prolactin signaling. Our results show that PDTC downregulates prolactin receptor levels, and inhibits prolactin-induced Stat5 tyrosine phosphorylation and ß-casein expression. This is not due to its inhibitory action on NF-κB since application of another NF-κB inhibitor, BAY 11-7082, and overexpression of I-κBα super-repressor do not lead to the same results. Instead, the pro-oxidant activity of PDTC is involved as inclusion of the antioxidant N-acetylcysteine restores prolactin signaling. PDTC triggers great extents of activation of ERK and JNK in mammary epithelial cells. These do not cause suppression of prolactin signaling but confer serine phosphorylation of insulin receptor substrate-1, thereby perturbing insulin signal propagation. As insulin facilitates optimal ß-casein expression, blocking insulin signaling by PDTC might pose additional impediment to ß-casein expression. Our results thus imply that lactation will be compromised when the cellular redox balance is dysregulated, such as during mastitis.

Asunto(s)

Acetilcisteína/farmacología , Células Epiteliales/citología , Células Epiteliales/efectos de los fármacos , Prolactina/metabolismo , Pirrolidinas/antagonistas & inhibidores , Pirrolidinas/farmacología , Transducción de Señal/efectos de los fármacos , Tiocarbamatos/antagonistas & inhibidores , Tiocarbamatos/farmacología , Animales , Caseínas/genética , Bovinos , Células Epiteliales/metabolismo , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Insulina/metabolismo , Proteínas Sustrato del Receptor de Insulina/química , Proteínas Sustrato del Receptor de Insulina/metabolismo , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Glándulas Mamarias Animales/citología , Ratones , FN-kappa B/antagonistas & inhibidores , Fosforilación/efectos de los fármacos , Embarazo , Serina/metabolismo

RESUMEN

Kappa-opioid receptors (KORs) are important for motivation and other medial prefrontal cortex (mPFC)-dependent behaviors. Although KORs are present in the mPFC, their role in regulating transmission in this brain region and their contribution to KOR-mediated aversion are not known. Using in vivo microdialysis in rats and mice, we demonstrate that intra-mPFC administration of the selective KOR agonist U69,593 decreased local dopamine (DA) overflow, while reverse dialysis of the KOR antagonist nor-Binaltorphimine (nor-BNI) enhanced mPFC DA overflow. Extracellular amino-acid levels were also affected by KORs, as U69,593 reduced glutamate and GABA levels driven by the glutamate reuptake blocker, l-trans-pyrrolidine-2,4-dicarboxylate. Whole-cell recordings from mPFC layer V pyramidal neurons revealed that U69,593 decreased the frequency, but not amplitude, of glutamatergic mini EPSPs. To determine whether KOR regulation of mPFC DA overflow was mediated by KOR on DA terminals, we utilized a Cre recombinase-driven mouse line lacking KOR in DA neurons. In these mice, basal DA release or uptake was unaltered relative to controls, but attenuation of mPFC DA overflow by local U69,593 was not observed, indicating KOR acts directly on mPFC DA terminals to locally inhibit DA levels. Conditioning procedures were then used to determine whether mPFC KOR signaling was necessary for KOR-mediated aversion. U69,593-mediated conditioned place aversion was blocked by intra-mPFC nor-BNI microinjection. These findings demonstrate that mPFC KORs negatively regulate DA and amino-acid neurotransmission, and are necessary for KOR-mediated aversion.

Asunto(s)

Reacción de Prevención/fisiología , Corteza Prefrontal/fisiología , Receptores Opioides kappa/fisiología , Transmisión Sináptica/fisiología , Analgésicos/administración & dosificación , Analgésicos/farmacología , Animales , Reacción de Prevención/efectos de los fármacos , Bencenoacetamidas/administración & dosificación , Bencenoacetamidas/farmacología , Ácidos Dicarboxílicos/antagonistas & inhibidores , Ácidos Dicarboxílicos/farmacología , Dopamina/metabolismo , Interacciones Farmacológicas , Potenciales Postsinápticos Excitadores/efectos de los fármacos , Potenciales Postsinápticos Excitadores/fisiología , Ácido Glutámico/metabolismo , Ácido Glutámico/farmacología , Masculino , Ratones , Ratones Noqueados , Microinyecciones , Potenciales Postsinápticos Miniatura/efectos de los fármacos , Naltrexona/administración & dosificación , Naltrexona/análogos & derivados , Naltrexona/farmacología , Antagonistas de Narcóticos/administración & dosificación , Antagonistas de Narcóticos/farmacología , Inhibidores de la Captación de Neurotransmisores/antagonistas & inhibidores , Inhibidores de la Captación de Neurotransmisores/farmacología , Corteza Prefrontal/efectos de los fármacos , Corteza Prefrontal/metabolismo , Células Piramidales/efectos de los fármacos , Células Piramidales/fisiología , Pirrolidinas/administración & dosificación , Pirrolidinas/antagonistas & inhibidores , Pirrolidinas/farmacología , Ratas , Receptores Opioides kappa/agonistas , Receptores Opioides kappa/antagonistas & inhibidores , Receptores Opioides kappa/genética , Transmisión Sináptica/efectos de los fármacos , Ácido gamma-Aminobutírico/metabolismo

RESUMEN

The design of a new clinical candidate histamine-H(3) receptor antagonist for the potential treatment of excessive daytime sleepiness (EDS) is described. Phenethyl-R-2-methylpyrrolidine containing biphenylsulfonamide compounds were modified by replacement of the sulfonamide linkage with a sulfone. One compound from this series, 2j (APD916) increased wakefulness in rodents as measured by polysomnography with a duration of effect consistent with its pharmacokinetic properties. The identification of a suitable salt form of 2j allowed it to be selected for further development.

Asunto(s)

Compuestos de Bifenilo/química , Compuestos de Bifenilo/farmacología , Antagonistas de los Receptores Histamínicos/química , Pirrolidinas/química , Pirrolidinas/farmacología , Receptores Histamínicos H3/química , Sulfonas/química , Animales , Área Bajo la Curva , Encéfalo/metabolismo , Sistema Nervioso Central/efectos de los fármacos , Química Farmacéutica/métodos , Diseño de Fármacos , Canal de Potasio ERG1 , Canales de Potasio Éter-A-Go-Go/química , Antagonistas de los Receptores Histamínicos/farmacocinética , Humanos , Concentración 50 Inhibidora , Ratones , Modelos Químicos , Pirrolidinas/antagonistas & inhibidores , Ratas , Sueño/efectos de los fármacos , Temperatura , Vigilia/efectos de los fármacos

RESUMEN

The transient receptor potential vanilloid 1 (TRPV1) receptor is activated by noxious heat, various endogenous mediators and exogenous irritants. The aim of the present study was to compare three TRPV1 receptor antagonists (SB705498, BCTC and AMG9810) in rat models of heat hyperalgesia. The behavioural noxious heat threshold, defined as the lowest temperature evoking nocifensive reaction, was measured with an increasing-temperature water bath. The effects of TRPV1 receptor antagonists were assessed in thermal hyperalgesia induced by the TRPV1 agonist resiniferatoxin (RTX), mild heat injury (51 degrees C, 20s) or plantar incision in rats. The control heat threshold was 43.2+/-0.4 degrees C. RTX induced an 8-10 degrees C decrease in heat threshold which was dose-dependently inhibited by oral pre-treatment with any of the TRPV1 receptor antagonists with a minimum effective dose of 1mg/kg. The mild heat injury-evoked 7-8 degrees C heat threshold drop was significantly reversed by all three antagonists injected i.p. as post-treatment. The minimum effective doses were as follows: SB705498 10, BCTC 3 and AMG9810 1mg/kg. Plantar incision-induced heat threshold drop (7-8 degrees C) was dose-dependently diminished by an oral post-treatment with any of the antagonists with minimum effective doses of 10, 3 and 3mg/kg, respectively. Assessment of RTX hyperalgesia by measurement of the paw withdrawal latency with a plantar test apparatus yielded 30 mg/kg minimum effective dose for each antagonist. In conclusion, measurement of the noxious heat threshold with the increasing-temperature water bath is suitable to sensitively detect the effects of TRPV1 receptor antagonists in thermal hyperalgesia models.

Asunto(s)

Acrilamidas/antagonistas & inhibidores , Compuestos Bicíclicos Heterocíclicos con Puentes/antagonistas & inhibidores , Calor/efectos adversos , Hiperalgesia/tratamiento farmacológico , Pirazinas/antagonistas & inhibidores , Piridinas/antagonistas & inhibidores , Canales Catiónicos TRPV/antagonistas & inhibidores , Animales , Frío , Modelos Animales de Enfermedad , Diterpenos/farmacología , Relación Dosis-Respuesta a Droga , Femenino , Hiperalgesia/inducido químicamente , Dolor/tratamiento farmacológico , Pirrolidinas/antagonistas & inhibidores , Ratas , Ratas Sprague-Dawley , Urea/análogos & derivados , Urea/antagonistas & inhibidores

RESUMEN

RATIONALE: H(3)-receptor inverse agonists raise a great interest as innovative therapeutics in several central disorders. Whereas their procognitive properties are well established, their antipsychotic-like properties are still debated. OBJECTIVES: We further explored the effect of maximal doses (3-10 mg/kg) of ciproxifan, BF2.649, and ABT-239, three selective H(3)-receptor inverse agonists, on deficits of prepulse inhibition (PPI) induced by apomorphine, MK-801, and phencyclidine (PCP). Their effect was also investigated on stereotypies induced by apomorphine and methamphetamine. RESULTS: Ciproxifan, BF2.649, and ABT-239 did not reverse the PPI impairment produced by apomorphine (0.5 mg/kg, subcutaneous) in rats. Ciproxifan and BF2.649 did not reverse the impairment induced in mice by MK-801 (0.3 mg/kg). Ciproxifan and BF2.649 also failed to reverse the disruption induced in mice by PCP (5-10 mg/kg). Low to moderate doses of haloperidol (0.1-0.4 mg/kg, intraperitoneal), alone or co-administered with BF2.649, did not reverse MK-801-induced PPI disruption. A high dose (1 mg/kg) of haloperidol partially reversed the MK-801-induced deficit and BF2.649 tended to increase this effect, although nonsignificantly. Whereas stereotypies induced in mice by apomorphine and methamphetamine were totally suppressed by haloperidol, the decrease induced by ciproxifan was partial against apomorphine and very low, if any, against methamphetamine. CONCLUSIONS: Their total absence of effect in several validated animal models of the disease does not support antipsychotic properties of H(3)-receptor inverse agonists. However, their positive effects previously reported in behavioral tasks addressing learning, attention, and memory maintain the interest of H(3)-receptor inverse agonists for the treatment of cognitive symptoms of schizophrenia as adjunctive medications.

Asunto(s)

Antipsicóticos/antagonistas & inhibidores , Apomorfina/antagonistas & inhibidores , Maleato de Dizocilpina/antagonistas & inhibidores , Agonismo Inverso de Drogas , Inhibición Psicológica , Fenciclidina/antagonistas & inhibidores , Conducta Estereotipada/efectos de los fármacos , Animales , Antipsicóticos/farmacología , Apomorfina/farmacología , Benzofuranos/antagonistas & inhibidores , Maleato de Dizocilpina/farmacocinética , Haloperidol/farmacología , Antagonistas de los Receptores Histamínicos/farmacología , Imidazoles/antagonistas & inhibidores , Masculino , Metanfetamina/antagonistas & inhibidores , Metanfetamina/farmacología , Ratones , Fenciclidina/farmacología , Piperidinas/antagonistas & inhibidores , Pirrolidinas/antagonistas & inhibidores , Ratas , Ratas Sprague-Dawley , Reflejo de Sobresalto/efectos de los fármacos

RESUMEN

The selective estrogen receptor modulator raloxifene is therapeutically beneficial for postmenopausal connective tissue degradation, such as osteoporosis, vascular sclerosis, and dermal degradation; however, the effects of raloxifene on postmenopausal tendon metabolism have not been clarified. In this study, we investigated the effects of raloxifene analogue (LY117018) on cell proliferation and collagen metabolism using cultured rat Achilles tendon fibroblasts. 17beta-Estradiol (E(2); 10(-11)-10(-9) M) and LY117018 (10(-9)-10(-7) M) had no significant effects on tendon fibroblast proliferation, based on a BrdU (5-bromo-2'-deoxyuridine) incorporation assay (24 hr) and a WST-8 colorimetric assay (2 or 6 days). Neither E(2) nor LY117018 significantly altered the expression of type I collagen, which is a main component of the tendon extracellular matrix (ECM), whereas both E(2) and LY117018 significantly increased the expression of matrix metalloproteinase (MMP)-13, which is responsible for tendon collagen degradation in rat. Also, both E(2) and LY117018 increased the expression of type III collagen and elastin, which are minor components of tendon ECM, but are considered to govern the elastic properties of tendons. These changes in collagen and MMP induced by either E(2) or LY117018 were attenuated by the estrogen receptor alpha blocker ICI 182,780. The results of this study suggest that postmenopausal estrogen deficiency might downregulate tendon collagen turnover and decrease tendon elasticity. Further, raloxifene treatment might restore these changes to premenopausal levels.

Asunto(s)

Tendón Calcáneo/efectos de los fármacos , Fibroblastos/efectos de los fármacos , Pirrolidinas/farmacología , Clorhidrato de Raloxifeno/análogos & derivados , Moduladores Selectivos de los Receptores de Estrógeno/farmacología , Tiofenos/farmacología , Tendón Calcáneo/citología , Animales , Bromodesoxiuridina/metabolismo , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Colágeno Tipo I/metabolismo , Colágeno Tipo III/metabolismo , Elastina/metabolismo , Estradiol/análogos & derivados , Estradiol/farmacología , Antagonistas de Estrógenos/farmacología , Matriz Extracelular/efectos de los fármacos , Matriz Extracelular/metabolismo , Femenino , Fibroblastos/metabolismo , Fibroblastos/patología , Fulvestrant , Metaloproteinasa 13 de la Matriz/metabolismo , Pirrolidinas/antagonistas & inhibidores , Ratas , Sales de Tetrazolio/metabolismo , Tiofenos/antagonistas & inhibidores

RESUMEN

OBJECTIVE: The aim of this study was to assess the drug interaction potential of psychotropic medication on methadone N-demethylation using cDNA-expressed cytochrome P450 CYP enzymes. METHODS: Methadone was incubated with various drugs (n = 10) and cDNA-expressed CYP3A4, CYP2D6, CYP2B6, CYP2C19 and CYP1A2 enzymes to screen for their inhibition potency. The nature of enzyme selective activity for inhibition was further investigated for potent inhibitors. To test for a mechanism-based component in inhibition, all substances were tested with preincubation and without. 2-Ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) concentration was determined by liquid chromatography/tandem mass spectrometry following liquid/liquid extraction. RESULTS: Formation of EDDP was catalysed by CYP3A4, CYP2D6 and CYP2C19. The N-demethylation of methadone was preferentially inhibited by amitriptyline, buprenorphine, methylenedioxymethamphetamine (MDMA) and zolpidem. Both amitriptyline and buprenorphine were strong, reversible inhibitors of CYP3A4. Similarly, amitriptyline and MDMA were identified as inhibitors of CYP2D6. Zolpidem revealed a mechanism-based inhibition of CYP3A4. CONCLUSION: Amitriptyline, MDMA and zolpidem are likely to slow down conversion of methadone and to increase its area under the curve (AUC). A consideration of the in vitro evidence of drug-methadone interactions should help to improve patient care during methadone maintenance treatment.

Asunto(s)

Sistema Enzimático del Citocromo P-450/metabolismo , Metadona/metabolismo , Algoritmos , Amitriptilina/metabolismo , Amitriptilina/farmacología , Analgésicos Opioides/metabolismo , Analgésicos Opioides/farmacología , Clorhidrato de Atomoxetina , Cromatografía Liquida/métodos , Citalopram/metabolismo , Citalopram/farmacología , Clozapina/metabolismo , Clozapina/farmacología , Inhibidores Enzimáticos del Citocromo P-450 , Sistema Enzimático del Citocromo P-450/genética , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Isoenzimas/antagonistas & inhibidores , Isoenzimas/genética , Isoenzimas/metabolismo , Cinética , Metadona/farmacología , Metilación , N-Metil-3,4-metilenodioxianfetamina/metabolismo , N-Metil-3,4-metilenodioxianfetamina/farmacología , Oxidorreductasas N-Desmetilantes/antagonistas & inhibidores , Oxidorreductasas N-Desmetilantes/metabolismo , Oxidorreductasas N-Desmetilantes/farmacología , Propilaminas/metabolismo , Propilaminas/farmacología , Psicotrópicos/metabolismo , Psicotrópicos/farmacología , Piridinas/metabolismo , Piridinas/farmacología , Pirrolidinas/antagonistas & inhibidores , Pirrolidinas/metabolismo , Espectrometría de Masas en Tándem/métodos , Zolpidem

RESUMEN

The SAR development is described for a series of N-acyl pyrrolidine inhibitors of the Hepatitis C virus RNA-dependent RNA polymerase, NS5B, from tractable Delta21 enzyme inhibitors to an example with antiviral activity in a cellular assay (HCV replicon).

Asunto(s)

Antivirales/farmacología , Química Farmacéutica/métodos , Hepacivirus/química , Hepacivirus/genética , Pirrolidinas/antagonistas & inhibidores , ARN Polimerasa Dependiente del ARN/antagonistas & inhibidores , Replicón/genética , Proteínas no Estructurales Virales/farmacología , Antivirales/química , Diseño de Fármacos , Inhibidores Enzimáticos/farmacología , Concentración 50 Inhibidora , Modelos Químicos , Conformación Molecular , ARN Viral/química , Proteínas no Estructurales Virales/química , Replicación Viral/efectos de los fármacos

RESUMEN

BACKGROUND: Lower admission heart rate (HR) is known to predict favorable outcome in ST-elevation acute myocardial infarction. However, there are limited short-term and no long-term data available regarding the prediction value of the initial HR in patients with the full spectrum of acute coronary syndromes (ACS). In addition, it is unknown whether the HR obtained later during hospitalization for ACS (i.e., Day 2 or 3) remains prognostically valuable. HYPOTHESIS: The aim of this study was to investigate the utility of the initial and delayed HR in predicting outcome in patients with ACS. METHODS: We examined mortality at 30 days and 10 months in 10,267 patients with ACS enrolled in the oral glycoprotein IIb/IIIa inhibition with Orofiban in Patients with Unstable coronary Syndromes-Thrombolysis In Myocardial Infarction (OPUS-TIMI) 16 trial. Patients were stratified by HR and day from onset of ACS into the following groups: (1) HR < 60 beats/min, (2) HR 60-80 beats/min, (3) HR 80-100 beats/min, (4) HR > 100 beats/min; and HR obtained on (1) Day 1, (2) Day 2, and (3) Day 3. RESULTS: By univariate analysis, mortality at 30 days and at 10 months increased progressively with higher HR strata (1.4 vs. 1.6 vs. 2.3 vs. 5.6%, p < 0.001, and 2.6 vs. 4.2 vs. 6.5 vs. 11.8%, p < 0.001, respectively). Elevated HR remained associated with mortality irrespective of time from onset of ACS. CONCLUSIONS: Higher initial and delayed HR is highly predictive of higher short- and long-term mortality in patients with ACS. This is a simple marker that could be easily used in risk assessment.

Asunto(s)

Frecuencia Cardíaca/fisiología , Infarto del Miocardio/mortalidad , Complejo GPIIb-IIIa de Glicoproteína Plaquetaria/antagonistas & inhibidores , Enfermedad Aguda , Alanina/antagonistas & inhibidores , Femenino , Humanos , Masculino , Persona de Mediana Edad , Infarto del Miocardio/tratamiento farmacológico , Valor Predictivo de las Pruebas , Pronóstico , Pirrolidinas/antagonistas & inhibidores , Síndrome

RESUMEN

This study investigated whether D,L-cis-2,3-Pyrrolidine dicarboxylate (D,L-cis-2,3-PDC), a new glutamate analogue, alters glutamate binding to cerebral plasma membranes and whether N-methyl-D-aspartate (NMDA) receptors are involved in the convulsant effect of this compound. D,L-cis-2,3-PDC reduced sodium-independent [3H]-L-glutamate binding to lysed membrane preparations from adult rat cortex and had no effect on sodium-dependent glutamate binding. Intracerebroventricular administration of D,L-cis-2,3-PDC (7.5-25 nmol/5 microl) induced generalized tonic-clonic convulsions in mice in a dose-dependent manner. The coadministration of MK-801 (7 nmol/2.5 microl), with D,L-cis-2,3-PDC (16.5 nmol/2.5 microl), fully protected the animals against D,L-cis-2,3-PDC-induced convulsions, while the coadministration of DNQX (10 nmol/2.5 microl) increased the latency to convulsions but did not alter the percentage of animals that had convulsions. These results suggest that D,L-cis-2,3-PDC-induced effects are mediated predominantly by NMDA receptors.

Asunto(s)

Convulsivantes , Ácidos Dicarboxílicos/farmacología , Ácidos Dicarboxílicos/toxicidad , Ácido Glutámico/metabolismo , Pirrolidinas/farmacología , Pirrolidinas/toxicidad , Convulsiones/inducido químicamente , Animales , Conducta Animal/efectos de los fármacos , Química Encefálica/efectos de los fármacos , Ácidos Dicarboxílicos/antagonistas & inhibidores , Maleato de Dizocilpina/farmacología , Antagonistas de Aminoácidos Excitadores/farmacología , Masculino , Membranas/efectos de los fármacos , Membranas/metabolismo , Ratones , Fármacos Neuroprotectores/farmacología , Pirrolidinas/antagonistas & inhibidores , Quinoxalinas/farmacología , Ratas , Receptores de N-Metil-D-Aspartato/efectos de los fármacos , Estereoisomerismo , Relación Estructura-Actividad

RESUMEN

AIM: To investigate the effects of two antioxidants on the alterations of nuclear factor kappaB (NF-kappaB) activity and p65, p50 protein expression and phosphorylation of IkappaBalpha in rat hippocampus following global brain ischemia. METHODS: Using a 4-vessel occlusion (4-VO) as brain ischemia model, NF-kappaB protein (p65 or p50 subunit) expression was examined by Western blot analysis, and NF-kappaB activity was assayed by electrophoretic mobility shift assay (EMSA), and neuronal loss was observed by histology. RESULTS: NF-kappaB activity displayed a time-dependent manner, and p65, p50 proteins showed their peak levels after ischemia/reperfusion 6 h. NF-kappaB inductions (p65: 4.79+/-0.78, p50: 5.50+/-0.33, sham control=1) and activity (4.93+/-0.95) after 6 h of reperfusion were markedly reduced by pretreatment with antioxidants pyrrolidine dithiocarbamate (PDTC, 200 mg/kg) (p65: 1.11+/-0.74, p50: 1.38+/-0.98, activity: 2.20+/-0.86, respectively) or N-acetylcysteine (NAC, 300 mg/kg) (p65: 0.64+/-0.39, p50: 1.89+/-0.87, activity: 0.61+/-0.65), and histological observations of the pyramidal layer of CA1 also showed a reduction of neuronal loss in rat hippocampus (70 %+/-5 % or 92 %+/-4 % cells are survival, respectively). Furthermore, PDTC and NAC prevented the decrease (from 0.50+/-0.10 to 0.80+/-0.20 or 1.20+/-0.24, respectively) and phosphorylation (from 2.00+/-0.15 to 0.46+/-0.10 or 0.41+/-0.10, respectively) of IkappaBalpha protein in the cytoplasm. CONCLUSION: The protective effects of antioxidants against ischemia/reperfusion-induced injury may be mediated by down-regulation of NF-kappaB activity. NF-kappaB activation and deactivation are controlled mainly through phosphorylation and degradation of IkappaBalpha following brain ischemia.

Asunto(s)

Antioxidantes/farmacología , FN-kappa B/metabolismo , Pirrolidinas/farmacología , Daño por Reperfusión/metabolismo , Tiocarbamatos/farmacología , Acetilcisteína/farmacología , Animales , Apoptosis/efectos de los fármacos , Isquemia Encefálica/complicaciones , Hipocampo/patología , Proteínas I-kappa B/metabolismo , Masculino , Inhibidor NF-kappaB alfa , FN-kappa B/antagonistas & inhibidores , Subunidad p50 de NF-kappa B , Neuronas/patología , Fosforilación , Pirrolidinas/antagonistas & inhibidores , Ratas , Ratas Sprague-Dawley , Daño por Reperfusión/etiología , Tiocarbamatos/antagonistas & inhibidores , Factor de Transcripción ReIA