RESUMEN
BACKGROUND/OBJECTIVE: To assess safety/efficacy of tofacitinib and tumor necrosis factor inhibitors (TNFi) in patients from Latin America (LATAM) in ORAL Surveillance. METHODS: In ORAL Surveillance, 4362 patients with rheumatoid arthritis aged ≥50 years with ≥1 additional cardiovascular risk factor received tofacitinib 5 or 10 mg twice daily or TNFi. This post hoc analysis stratified patients by geographical location (LATAM, n = 1202; non-LATAM, n = 3160). Incidence rates (IRs; patients with first event/100 patient-years) and hazard ratios for adverse events of special interest were reported. Efficacy outcomes included Clinical Disease Activity Index and American College of Rheumatology 20/50/70 responses. RESULTS: Risk factors associated with cardiovascular disease and malignancies were less prevalent in the LATAM cohort compared with the non-LATAM cohort. IRs for patients receiving tofacitinib (combined doses) versus TNFi were 0.54 versus 0.28 (LATAM) and 1.14 versus 0.92 (non-LATAM) for major adverse cardiovascular events; 0.58 versus 0.27 (LATAM) and 1.33 versus 0.95 (non-LATAM) for malignancies excluding nonmelanoma skin cancer; and 0.69 versus 0.35 (LATAM) and 0.63 versus 0.33 (non-LATAM) for all-cause death. IRs for nonmelanoma skin cancer and venous thromboembolism were also numerically higher with tofacitinib versus TNFi and in the non-LATAM cohort versus LATAM. Efficacy was similar across treatment groups within each cohort. CONCLUSIONS: Adverse events of special interest were generally less frequent in LATAM versus non-LATAM patients, reflecting differences in baseline characteristics, and higher with tofacitinib versus TNFi in both cohorts, consistent with the overall findings of ORAL Surveillance. Our findings emphasize the importance of assessing individual risk factors to guide benefit/risk assessment and treatment decisions. CLINICAL TRIAL REGISTRATION NUMBER: NCT02092467.
Asunto(s)
Artritis Reumatoide , Enfermedades Cardiovasculares , Neoplasias , Piperidinas , Pirimidinas , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Antirreumáticos/efectos adversos , Antirreumáticos/administración & dosificación , Antirreumáticos/uso terapéutico , Artritis Reumatoide/tratamiento farmacológico , Enfermedades Cardiovasculares/epidemiología , Enfermedades Cardiovasculares/prevención & control , Incidencia , América Latina/epidemiología , Neoplasias/epidemiología , Neoplasias/tratamiento farmacológico , Piperidinas/administración & dosificación , Piperidinas/efectos adversos , Piperidinas/uso terapéutico , Pirimidinas/efectos adversos , Pirimidinas/administración & dosificación , Pirroles/administración & dosificación , Pirroles/efectos adversos , Resultado del Tratamiento , Inhibidores del Factor de Necrosis Tumoral/efectos adversos , Inhibidores del Factor de Necrosis Tumoral/administración & dosificaciónRESUMEN
The endocannabinoid neurotransmission acting via local CB1 receptor in the bed nucleus of the stria terminalis (BNST) has been implicated in behavioral and physiological responses to emotional stress. However, the neural network related to this control is poorly understood. In this sense, the lateral hypothalamus (LH) is involved in stress responses, and BNST GABAergic neurons densely innervate this hypothalamic nucleus. However, a role of BNST projections to the LH in physiological responses to stress is unknown. Therefore, using male rats, we investigated the role of LH GABAergic neurotransmission in the regulation of cardiovascular responses to stress by CB1 receptors within the BNST. We observed that microinjection of the selective CB1 receptor antagonist AM251 into the BNST decreased the number of Fos-immunoreactive cells within the LH of rats submitted to acute restraint stress. Treatment of the BNST with AM251 also enhanced restraint-evoked tachycardia. Nevertheless, arterial pressure increase and sympathetically-mediated cutaneous vasoconstriction to restraint was not affected by CB1 receptor antagonism within the BNST. The effect of AM251 in the BNST on restraint-evoked tachycardia was abolished in animals pretreated with the selective GABAA receptor antagonist SR95531 in the LH. These results indicate that regulation of cardiovascular responses to stress by CB1 receptors in the BNST is mediated by GABAergic neurotransmission in the LH. Present data also provide evidence of the BNST endocannabinoid neurotransmission as a mechanism involved in LH neuronal activation during stressful events.
Asunto(s)
Endocannabinoides/fisiología , Área Hipotalámica Lateral/fisiología , Distrés Psicológico , Núcleos Septales/fisiología , Animales , Antagonistas de Receptores de Cannabinoides/administración & dosificación , Antagonistas del GABA/administración & dosificación , Neuronas GABAérgicas/efectos de los fármacos , Neuronas GABAérgicas/fisiología , Frecuencia Cardíaca/efectos de los fármacos , Frecuencia Cardíaca/fisiología , Área Hipotalámica Lateral/efectos de los fármacos , Masculino , Modelos Neurológicos , Piperidinas/administración & dosificación , Pirazoles/administración & dosificación , Piridazinas/administración & dosificación , Ratas , Ratas Wistar , Núcleos Septales/efectos de los fármacos , Estrés Psicológico/fisiopatología , Transmisión Sináptica/efectos de los fármacos , Transmisión Sináptica/fisiología , Taquicardia/fisiopatologíaRESUMEN
OBJECTIVE: One-third of patients with severe rheumatoid arthritis (RA) do not achieve remission or low disease activity, or they have side effects from cDMARD and bDMARD. They will need a new treatment option such as the small molecule JAK inhibitors. In this systematic review, we evaluate the efficacy and safety data of the current jakinibs: tofacitinib, peficitinib, decernotinib, upadacitinib, baricitinib and filgotinib in patients in whom treatment with conventional or biological disease-modifying antirheumatic drugs (cDMARD and/or bDMARD) failed. METHODS: We searched for randomized controlled trials comparing efficacy and safety of jakinibs for RA treatment using the Web of Science, Scopus, PubMed, and clinicaltrials.gov databases with the terms: "rheumatoid arthritis" OR "arthritis rheumatoid" OR "RA" AND "inhibitor" OR "jak inhibitor" AND "clinical trial" OR "treatment" OR "therapy". RESULTS: All jakinibs achieved good results in ACR 20, 50, 70 and with CRP-DAS28 for LDA and remission, upadacitinib showed better results compared to the others. In ESR-DAS28 for remission, tofacitinib achieved the best result. Regarding the safety of all jakinibs, peficitinib, baricitinib and filgotinib did not register deaths in their studies unlike tofacitinib that presented 11 deaths. Despite all benefits of jakinibs, the use in patients with severe liver and kidney disease should be avoided. CONCLUSIONS: Jakinibs in monotherapy or in combination with methotrexate can be considered a viable alternative in the treatment of moderate-to-severe RA. Even after failures with combination of cDMARDS and bDMARDS, jakinibs demonstrated efficacy.
Asunto(s)
Antirreumáticos/administración & dosificación , Artritis Reumatoide/diagnóstico , Artritis Reumatoide/tratamiento farmacológico , Inhibidores de las Cinasas Janus/administración & dosificación , Antirreumáticos/efectos adversos , Artritis Reumatoide/enzimología , Azetidinas/administración & dosificación , Enfermedad Hepática Inducida por Sustancias y Drogas/diagnóstico , Quimioterapia Combinada , Compuestos Heterocíclicos con 3 Anillos/administración & dosificación , Humanos , Inhibidores de las Cinasas Janus/efectos adversos , Enfermedades Renales/inducido químicamente , Enfermedades Renales/diagnóstico , Metotrexato/administración & dosificación , Piperidinas/administración & dosificación , Purinas/administración & dosificación , Pirazoles/administración & dosificación , Pirimidinas/administración & dosificación , Ensayos Clínicos Controlados Aleatorios como Asunto/métodos , Sulfonamidas/administración & dosificación , Resultado del TratamientoRESUMEN
The endocannabinoid system is implicated in anxiety, but the brain sites involved are not completely understood. The bed nucleus of the stria terminalis (BNST) has been related to anxiety and responses to aversive threats. Besides, endocannabinoid neurotransmission acting via CB1 receptors was identified in the BNST. However, the presence of CB2 receptors and the role of BNST endocannabinoid system in anxiety-like behaviors have never been reported. Therefore, this study investigated the presence of CB1 and CB2 receptors in the BNST and their role in anxiety-like behaviors. For this, gene expression of the endocannabinoid receptors was evaluated in samples from anterior and posterior BNST. Besides, behaviors were evaluated in the elevated plus-maze (EPM) in unstressed rats (trait anxiety-like behavior) and after exposure to restraint stress (restraint-evoked anxiety-like behavior) in rats treated with either the CB1 receptor antagonist AM251 or the CB2 receptor antagonist JTE907 into the anterior BNST. The presence of CB1 and CB2 receptors gene expression was identified in anterior and posterior divisions of the BNST. Bilateral microinjection of AM251 into the anterior BNST dose-dependently increased EPM open arms exploration in unstressed animals and inhibited the anxiety-like behavior in the EPM evoked by restraint. Conversely, intra-BNST microinjection of JTE907 decreased EPM open arms exploration in a dose-dependent manner and inhibited restraint-evoked behavioral changes in the EPM. Taken together, these results indicate that CB1 and CB2 receptors present in the BNST are involved in control of anxiety-like behaviors, and control by the latter is affected by previous stress experience.
Asunto(s)
Ansiedad/psicología , Endocannabinoides/metabolismo , Núcleos Septales/efectos de los fármacos , Estrés Psicológico/metabolismo , Transmisión Sináptica/efectos de los fármacos , Animales , Antagonistas de Receptores de Cannabinoides , Dioxoles/administración & dosificación , Expresión Génica , Masculino , Modelos Neurológicos , Piperidinas/administración & dosificación , Pirazoles/administración & dosificación , Quinolonas/administración & dosificación , Ratas , Ratas Wistar , Restricción Física/efectos adversos , Núcleos Septales/metabolismoRESUMEN
Cocaine addiction is a severe mental disorder for which few treatment options are available. The underlying mechanisms include facilitation of monoamine-neurotransmission, particularly dopamine. Here, we tested the hypothesis that the monoamine stabilizers, (-)-OSU6162 ((3S)-3-(3-methylsulfonylphenyl)-1-propylpiperidine) and aripiprazole (7-[4-[4-(2,3-dichlorophenyl)piperazin-1-yl]butoxy]-3,4-dihydro-1H-quinolin-2-one), prevent cocaine-induced behaviors. Male Swiss mice received injections of (-)-OSU6162 or aripiprazole and cocaine and were tested for cocaine-induced hyperlocomotion, locomotor sensitization, and acquisition and expression of conditioned place preference (CPP). The increase in the distance traveled induced by cocaine (20 mg/kg) was prevented by pretreatment with aripiprazole (1 and 10 mg/kg), whereas (-)-OSU6162 (3 mg/kg) exerted a minor effect. Aripiprazole, however, also impaired spontaneous locomotion. Neither (-)-OSU6162 nor aripiprazole interfered with the locomotor sensitization and expression of CPP induced by cocaine (15 mg/kg). (-)-OSU6162 (3 mg/kg), but not aripiprazole, prevented the acquisition of CPP induced by cocaine (15 mg/kg). (-)-OSU6162 exerts a minor effect in reducing cocaine-induced stimulatory activity and context-related memories, which are responsible for triggering drug seeking. Further studies are required to establish whether (-)-OSU6162 could be a candidate drug for the treatment of cocaine addiction.
Asunto(s)
Aripiprazol/farmacología , Cocaína/farmacología , Locomoción/efectos de los fármacos , Piperidinas/farmacología , Animales , Aripiprazol/administración & dosificación , Conducta Animal/efectos de los fármacos , Cocaína/administración & dosificación , Condicionamiento Psicológico/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Comportamiento de Búsqueda de Drogas/efectos de los fármacos , Masculino , Ratones , Piperidinas/administración & dosificaciónRESUMEN
Metabolic Syndrome (MetS) is increasing worldwide regardless of culture, genetic, gender, and geographic differences. While multiple individual risk factors, such as obesity, hypertension, diabetes, and hyperlipidemia, can cause cardiovascular disease (CVD), it is the intercurrence of these risk factors that defines MetS as a cluster that creates an environment for atherosclerosis and other manifestations of CVD. Despite the advances in the knowledge and management of each of the components of MetS, there are two molecular biology processes, chronic inflammation and oxidative stress, which are still underdiagnosed and undertreated. In order to assess the effect of a dietary supplement on chronic inflammation in MetS, we conducted a clinical trial with volunteers receiving a formula composed of resveratrol, piperine and alpha tocopherol (FRAMINTROL®), together with their habitual treatment, for three months. The inflammatory state was evaluated by ultrasensitive C reactive protein (US CRP) and ferritin in plasma, and oxygen consumption and chemiluminescence in neutrophils. The results showed that ferritin decreased by 10% (p < 0.05), US-CRP by 33% (p < 0.0001), oxygen consumption by 55% (p < 0.0001), and spontaneous chemiluminiscence was by 25% (p < 0.005) after treatment. As far as we know, this is the first study showing a chronic inflammation decrease in MetS patients due to the administration of a biopower Resveratrol-piperine and alpha tocopherol dietary supplement together with conventional therapy.
Asunto(s)
Alcaloides/administración & dosificación , Benzodioxoles/administración & dosificación , Suplementos Dietéticos , Inflamación/terapia , Síndrome Metabólico/complicaciones , Piperidinas/administración & dosificación , Alcamidas Poliinsaturadas/administración & dosificación , Resveratrol/administración & dosificación , alfa-Tocoferol/administración & dosificación , Anciano , Alcaloides/farmacología , Benzodioxoles/farmacología , Biomarcadores/análisis , Biomarcadores/sangre , Proteína C-Reactiva/análisis , Enfermedad Crónica , Femenino , Ferritinas/sangre , Humanos , Inflamación/diagnóstico , Inflamación/etiología , Mediciones Luminiscentes , Masculino , Persona de Mediana Edad , Neutrófilos , Estrés Oxidativo/efectos de los fármacos , Consumo de Oxígeno , Piperidinas/farmacología , Alcamidas Poliinsaturadas/farmacología , Resveratrol/farmacología , Factores de Tiempo , alfa-Tocoferol/farmacologíaAsunto(s)
Transdiferenciación Celular , Inmunoterapia/efectos adversos , Linfoma de Células del Manto/terapia , Neoplasias Primarias Secundarias/etiología , Sarcoma/etiología , Adenina/administración & dosificación , Adenina/efectos adversos , Adenina/análogos & derivados , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Transdiferenciación Celular/genética , Transdiferenciación Celular/inmunología , Reprogramación Celular/genética , Reprogramación Celular/inmunología , Reprogramación Celular/fisiología , Terapia Combinada , Epigénesis Genética/fisiología , Epigenoma/inmunología , Reordenamiento Génico , Genes de las Cadenas Pesadas de las Inmunoglobulinas/genética , Humanos , Inmunoterapia/métodos , Ganglios Linfáticos/patología , Linfoma de Células del Manto/genética , Linfoma de Células del Manto/inmunología , Neoplasias Primarias Secundarias/diagnóstico , Piperidinas/administración & dosificación , Piperidinas/efectos adversos , Receptores de Antígenos de Linfocitos T/uso terapéutico , Rituximab/administración & dosificación , Rituximab/efectos adversos , Sarcoma/genética , Sarcoma/inmunología , Sarcoma/patología , Trasplante Autólogo/efectos adversos , Células Tumorales CultivadasRESUMEN
RATIONALE: Prepulse inhibition of the startle reflex (PPI) is disrupted in several psychiatric disorders including schizophrenia. Understanding PPI pharmacology may help elucidate the pathophysiology of these disorders and lead to better treatments. Given the advantages of multi-target approaches for complex mental illnesses treatment, we have investigated the interaction between receptors known to modulate PPI (5-HT1A and 5-HT2A) and the neuromodulatory endocannabinoid system. OBJECTIVES: To investigate serotonin and cannabinoid receptor (CBR) co-modulation in a model of PPI disruption relevant to schizophrenia METHODS: Male Swiss mice were pretreated with WIN 55,212-2 (CBR agonist), rimonabant (CB1R inverse agonist), 8-OH-DPAT (5-HT1A/7 agonist), and volinanserin (5-HT2A antagonist) or with a combination of a cannabinoid and a serotonergic drug. PPI disruption was induced by acute administration of MK-801. RESULTS: WIN 55,212-2 and rimonabant did not change PPI nor block MK-801-induced deficits. 8-OH-DPAT increased PPI in control mice and, in a higher dose, inhibited MK-801-induced impairments. Volinanserin also increased PPI in control and MK-801-treated mice, presenting an inverted U-shaped dose-response curve. Co-administration of either cannabinoid ligand with 8-OH-DPAT did not change PPI; however, the combination of volinanserin with rimonabant increased PPI in both control and MK-801-exposed mice. CONCLUSIONS: WIN 55,212-2 and rimonabant had similar effects in PPI. Moreover, serotonin and cannabinoid receptors interact to modulate PPI. While co-modulation of CBR and 5-HT1A receptors did not change PPI, a beneficial effect of 5-HT2A and CB1R antagonist combination was detected, possibly mediated through potentiation of 5-HT2A blockade effects by concomitant CB1R blockade.
Asunto(s)
Antagonistas de Receptores de Cannabinoides/administración & dosificación , Inhibición Prepulso/fisiología , Receptor de Serotonina 5-HT2A/fisiología , Receptores de Cannabinoides/fisiología , Esquizofrenia/tratamiento farmacológico , Antagonistas del Receptor de Serotonina 5-HT2/administración & dosificación , 8-Hidroxi-2-(di-n-propilamino)tetralin/administración & dosificación , Animales , Benzoxazinas/administración & dosificación , Moduladores de Receptores de Cannabinoides/administración & dosificación , Cannabinoides/administración & dosificación , Relación Dosis-Respuesta a Droga , Quimioterapia Combinada , Fluorobencenos/administración & dosificación , Masculino , Ratones , Morfolinas/administración & dosificación , Naftalenos/administración & dosificación , Piperidinas/administración & dosificación , Inhibición Prepulso/efectos de los fármacos , Reflejo de Sobresalto/efectos de los fármacos , Reflejo de Sobresalto/fisiología , Agonistas del Receptor de Serotonina 5-HT2/administración & dosificación , Resultado del TratamientoRESUMEN
RATIONALE: The behavioural effects elicited by chemical constituents of Cannabis sativa, such as cannabidiol (CBD), on the ventromedial hypothalamus (VMH) are not well understood. There is evidence that VMH neurons play a relevant role in the modulation of unconditioned fear-related defensive behavioural reactions displayed by laboratory animals. OBJECTIVES: This study was designed to explore the specific pattern of distribution of the CB1 receptors in the VMH and to investigate the role played by this cannabinoid receptor in the effect of CBD on the control of defensive behaviours and unconditioned fear-induced antinociception. METHODS: A panic attack-like state was triggered in Wistar rats by intra-VMH microinjections of N-methyl-D-aspartate (NMDA). One of three different doses of CBD was microinjected into the VMH prior to local administration of NMDA. In addition, the most effective dose of CBD was used after pre-treatment with the CB1 receptor selective antagonist AM251, followed by NMDA microinjections in the VMH. RESULTS: The morphological procedures demonstrated distribution of labelled CB1 receptors on neuronal perikarya situated in dorsomedial, central and ventrolateral divisions of the VMH. The neuropharmacological approaches showed that both panic attack-like behaviours and unconditioned fear-induced antinociception decreased after intra-hypothalamic microinjections of CBD at the highest dose (100 nmol). These effects, however, were blocked by the administration of the CB1 receptor antagonist AM251 (100 pmol) in the VMH. CONCLUSION: These findings suggest that CBD causes panicolytic-like effects and reduces unconditioned fear-induced antinociception when administered in the VMH, and these effects are mediated by the CB1 receptor-endocannabinoid signalling mechanism in VMH.
Asunto(s)
Cannabidiol/toxicidad , Miedo/fisiología , Dimensión del Dolor/métodos , Trastorno de Pánico/metabolismo , Receptor Cannabinoide CB1/metabolismo , Núcleo Hipotalámico Ventromedial/metabolismo , Animales , Cannabidiol/administración & dosificación , Miedo/efectos de los fármacos , Miedo/psicología , Inyecciones Intraventriculares , Masculino , N-Metilaspartato/administración & dosificación , Dimensión del Dolor/efectos de los fármacos , Dimensión del Dolor/psicología , Trastorno de Pánico/inducido químicamente , Piperidinas/administración & dosificación , Pirazoles/administración & dosificación , Ratas , Ratas Wistar , Receptor Cannabinoide CB1/antagonistas & inhibidores , Núcleo Hipotalámico Ventromedial/efectos de los fármacosRESUMEN
BACKGROUND: Endocannabinoid neurotransmission in the bed nucleus of the stria terminalis is involved in the control of cardiovascular responses to stress. However, the local mechanisms involved is this regulation are not known. AIMS: The purpose of this study was to assess an interaction of bed nucleus of the stria terminalis endocannabinoid neurotransmission with local nitrergic signaling, as well as to investigate the involvement of local N-methyl-D-aspartate glutamate receptor and nitric oxide signaling in the control of cardiovascular responses to acute restraint stress by bed nucleus of the stria terminalis endocannabinoid neurotransmission in rats. METHODS: The first protocol evaluated the effect of intra-bed nucleus of the stria terminalis microinjection of the selective cannabinoid receptor type 1 receptor antagonist AM251 in nitrite/nitrate content in the bed nucleus of the stria terminalis following restraint stress. The other protocols evaluated the impact of local pretreatment with the selective N-methyl-D-aspartate glutamate receptor antagonist LY235959, the selective neuronal nitric oxide synthase inhibitor Nω-propyl-L-arginine, the soluble guanylate cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one, or the protein kinase G inhibitor KT5823 in restraint-evoked cardiovascular changes following bed nucleus of the stria terminalis treatment with AM251. RESULTS: Bilateral microinjection of AM251 into the bed nucleus of the stria terminalis increased local nitric oxide release during restraint stress. Bed nucleus of the stria terminalis treatment with the cannabinoid receptor type 1 receptor antagonist also enhanced the tachycardia caused by restraint stress, but without affecting arterial pressure increase and sympathetic-mediated cutaneous vasoconstriction. The facilitation of restraint-evoked tachycardia following bed nucleus of the stria terminalis treatment with the cannabinoid receptor type 1 receptor antagonist was completely inhibited by local pretreatment with LY235959, Nω-propyl-L-arginine, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one, or KT5823. CONCLUSIONS: Our results provide evidence that bed nucleus of the stria terminalis endocannabinoid neurotransmission inhibits local N-methyl-D-aspartate/neuronal nitric oxide synthase/soluble guanylate cyclase/protein kinase G signaling, and this mechanism is involved in the control of the cardiovascular responses to stress.
Asunto(s)
Hemodinámica/efectos de los fármacos , Receptor Cannabinoide CB1/efectos de los fármacos , Núcleos Septales/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Estrés Psicológico/complicaciones , Estrés Psicológico/tratamiento farmacológico , Animales , Proteínas Quinasas Dependientes de GMP Cíclico/antagonistas & inhibidores , Proteínas Quinasas Dependientes de GMP Cíclico/efectos de los fármacos , Guanilato Ciclasa/antagonistas & inhibidores , Guanilato Ciclasa/efectos de los fármacos , Masculino , Microinyecciones , Óxido Nítrico Sintasa de Tipo I/antagonistas & inhibidores , Óxido Nítrico Sintasa de Tipo I/efectos de los fármacos , Piperidinas/administración & dosificación , Piperidinas/farmacología , Pirazoles/administración & dosificación , Pirazoles/farmacología , Ratas , Ratas Wistar , Receptor Cannabinoide CB1/antagonistas & inhibidores , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Receptores de N-Metil-D-Aspartato/efectos de los fármacos , Restricción Física , Transmisión Sináptica/efectos de los fármacosRESUMEN
Flavonoids have been proposed as potential chemotherapeutic agents because they are toxic against cancer cells but not harmful to healthy cells. This systematic review analyzed flavonoid effectiveness in human cancer chemotherapy. Overall, 22 phase II and 1 phase III clinical trials (PubMed, Scopus, and Web of Science) that used flavonoids as a single agent or combined with other therapeutics against hematopoietic/lymphoid or solid cancer published by January 2019 were selected for analysis. Flavopiridol was the most commonly used flavonoid (at a dose of 50-mg/m2 IV) for all tumor types. Aside from the relatively low rate of complete response (CR) or partial response (PR) with any administration protocol, flavonoids showed higher positive outcomes for hematopoietic and lymphoid tissues (140 patients with CR and 88 with PR among 615 patients in 11 trials) than for solid tumors (4 patients with CR and 21 with PR among 525 patients in 12 trials). However, because of the high variety in administration schedule, more studies are needed to further understand how flavonoids can promote positive outcomes for cancer patients.
Asunto(s)
Antineoplásicos/administración & dosificación , Flavonoides/administración & dosificación , Neoplasias/tratamiento farmacológico , Piperidinas/administración & dosificación , Polifenoles/administración & dosificación , Ensayos Clínicos como Asunto , HumanosRESUMEN
LiTCTP is a toxin from the Translationally Controlled Tumor Protein (TCTP) family identified in Loxosceles brown spider venoms. These proteins are known as histamine-releasing factors (HRF). TCTPs participate in allergic and anaphylactic reactions, which suggest their potential role as therapeutic targets. The histaminergic effect of TCTP is related to its pro-inflammatory functions. An initial characterization of LiTCTP in animal models showed that this toxin can increase the microvascular permeability of skin vessels and induce paw edema in a dose-dependent manner. We evaluated the role of LiTCTP in vitro and in vivo in the inflammatory and allergic aspects that undergo the biological responses observed in Loxoscelism, the clinical condition after an accident with Loxosceles spiders. Our results showed LiTCTP recombinant toxin (LiRecTCTP) as an essential synergistic factor for the dermonecrotic toxin actions (LiRecDT1, known as the main toxin in the pathophysiology of Loxoscelism), revealing its contribution to the exacerbated inflammatory response clinically observed in envenomated patients.
Asunto(s)
Biomarcadores de Tumor/inmunología , Hipersensibilidad/inmunología , Inflamación/inmunología , Hidrolasas Diéster Fosfóricas/química , Hidrolasas Diéster Fosfóricas/inmunología , Enfermedades de la Piel/inmunología , Venenos de Araña/química , Venenos de Araña/inmunología , Animales , Biomarcadores de Tumor/antagonistas & inhibidores , Biomarcadores de Tumor/genética , Cimetidina/administración & dosificación , Cimetidina/farmacología , Cromolin Sódico/administración & dosificación , Cromolin Sódico/farmacología , Relación Dosis-Respuesta a Droga , Hipersensibilidad/tratamiento farmacológico , Inflamación/tratamiento farmacológico , Inyecciones Intraperitoneales , Inyecciones Intravenosas , Mastocitos/efectos de los fármacos , Mastocitos/inmunología , Ratones , Piperidinas/administración & dosificación , Piperidinas/farmacología , Prometazina/administración & dosificación , Prometazina/farmacología , Conejos , Ratas , Enfermedades de la Piel/tratamiento farmacológico , Células Tumorales Cultivadas , Proteína Tumoral Controlada Traslacionalmente 1RESUMEN
The activity of rifampin (RIF) and piperine was evaluated at the relative transcript levels of 12 efflux pumps (EPs), and an additional mechanism was proposed to be behind the synergic interactions of piperine plus RIF in Mycobacterium tuberculosis AutoDock v4.2.3 and Molegro v6 programs were used to evaluate PIP binding in M. tuberculosis RNA polymerase (RNAP). A hypothesis has been raised that piperine interferes in M. tuberculosis growth through RNAP inhibition, differently from what was previously endorsed for EP inhibition only.
Asunto(s)
Alcaloides/farmacología , Antineoplásicos/farmacología , Benzodioxoles/farmacología , ARN Polimerasas Dirigidas por ADN/metabolismo , Mycobacterium tuberculosis/efectos de los fármacos , Piperidinas/farmacología , Alcamidas Poliinsaturadas/farmacología , Rifampin/farmacología , Alcaloides/administración & dosificación , Alcaloides/metabolismo , Antineoplásicos/administración & dosificación , Antineoplásicos/metabolismo , Benzodioxoles/administración & dosificación , Benzodioxoles/metabolismo , Sitios de Unión , Sinergismo Farmacológico , Quimioterapia Combinada , Simulación del Acoplamiento Molecular , Mycobacterium tuberculosis/enzimología , Mycobacterium tuberculosis/metabolismo , Piperidinas/administración & dosificación , Piperidinas/metabolismo , Alcamidas Poliinsaturadas/administración & dosificación , Alcamidas Poliinsaturadas/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Rifampin/administración & dosificación , Rifampin/metabolismoRESUMEN
Resumen Introducción: Actualmente no existe un tratamiento estandarizado para la alopecia areata (AA) grave. Se han reportado numerosos casos exitosos del uso de tofacitinib; sin embargo, no existen publicaciones en México. En este trabajo se reportan cuatro casos de pacientes mexicanos con AA grave tratados con tofacitinib oral. Métodos: Serie de casos de adolescentes con alopecia grave tratados con tofacitinib oral. Para determinar la respuesta al tratamiento se utilizó la Escala de gravedad de alopecia (Severity of alopecia tool). Resultados: Se incluyeron cuatro pacientes de entre 13 y 19 años con AA. En todos los casos se observó crecimiento de cabello y disminución de la gravedad de la alopecia después del tratamiento con tofacitinib. En dos pacientes se observó una respuesta intermedia (del 51 al 90%), y en los otros, moderada (del 6 al 50%), sin efectos adversos serios. Las limitaciones del estudio fueron el tamaño reducido de la muestra y la naturaleza retrospectiva de la recolección de los datos. Conclusiones: El tofacitinib demostró ser una buena alternativa de tratamiento para la AA, total y universal, refractarias a otras terapias.
Abstract Background: Currently, no standardized treatment for severe alopecia areata (AA) exists. Numerous successful cases of the use of tofacitinib have been reported in the world literature, but not in Mexico. Four Mexican adolescents with severe AA treated with oral tofacitinib are reported in the present work. Methods: Series of cases of adolescents with severe AA treated with oral tofacitinib. The severity of alopecia tool was used to determine the response to treatment. Results: Four patients from 13 to 19 years old, were included. In all cases, hair growth was observed, and the alopecia severity decreased after the treatment with tofacitinib. In two patients, an intermediate response (from 51 to 90%) was observed; in the other, a moderate response (from 6 to 50%) was observed, without serious adverse effects. The limitations of the study were the small sample size and the retrospective nature of data collection. Conclusions: Tofacitinib showed to be a good treatment alternative for AA, total and universal, refractory to other therapies.
Asunto(s)
Adolescente , Femenino , Humanos , Masculino , Adulto Joven , Piperidinas/administración & dosificación , Pirimidinas/administración & dosificación , Pirroles/administración & dosificación , Inhibidores de Proteínas Quinasas/administración & dosificación , Alopecia Areata/tratamiento farmacológico , Índice de Severidad de la Enfermedad , Administración Oral , Estudios Retrospectivos , Resultado del Tratamiento , Alopecia Areata/patología , MéxicoRESUMEN
Background: Currently, no standardized treatment for severe alopecia areata (AA) exists. Numerous successful cases of the use of tofacitinib have been reported in the world literature, but not in Mexico. Four Mexican adolescents with severe AA treated with oral tofacitinib are reported in the present work. Methods: Series of cases of adolescents with severe AA treated with oral tofacitinib. The severity of alopecia tool was used to determine the response to treatment. Results: Four patients from 13 to 19 years old, were included. In all cases, hair growth was observed, and the alopecia severity decreased after the treatment with tofacitinib. In two patients, an intermediate response (from 51 to 90%) was observed; in the other, a moderate response (from 6 to 50%) was observed, without serious adverse effects. The limitations of the study were the small sample size and the retrospective nature of data collection. Conclusions: Tofacitinib showed to be a good treatment alternative for AA, total and universal, refractory to other therapies.
Introducción: Actualmente no existe un tratamiento estandarizado para la alopecia areata (AA) grave. Se han reportado numerosos casos exitosos del uso de tofacitinib; sin embargo, no existen publicaciones en México. En este trabajo se reportan cuatro casos de pacientes mexicanos con AA grave tratados con tofacitinib oral. Métodos: Serie de casos de adolescentes con alopecia grave tratados con tofacitinib oral. Para determinar la respuesta al tratamiento se utilizó la Escala de gravedad de alopecia (Severity of alopecia tool). Resultados: Se incluyeron cuatro pacientes de entre 13 y 19 años con AA. En todos los casos se observó crecimiento de cabello y disminución de la gravedad de la alopecia después del tratamiento con tofacitinib. En dos pacientes se observó una respuesta intermedia (del 51 al 90%), y en los otros, moderada (del 6 al 50%), sin efectos adversos serios. Las limitaciones del estudio fueron el tamaño reducido de la muestra y la naturaleza retrospectiva de la recolección de los datos. Conclusiones: El tofacitinib demostró ser una buena alternativa de tratamiento para la AA, total y universal, refractarias a otras terapias.
Asunto(s)
Alopecia Areata/tratamiento farmacológico , Piperidinas/administración & dosificación , Inhibidores de Proteínas Quinasas/administración & dosificación , Pirimidinas/administración & dosificación , Pirroles/administración & dosificación , Administración Oral , Adolescente , Alopecia Areata/patología , Femenino , Humanos , Masculino , México , Estudios Retrospectivos , Índice de Severidad de la Enfermedad , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: The peptide nociceptin/orphanin FQ (N/OFQ) and its receptor (NOP) are implicated in the modulation of emotional states. Previous human and rodent findings support NOP antagonists as antidepressants. However, the role played by the N/OFQ-NOP receptor system in resilience to stress is unclear. AIMS: The present study investigated the effects of activation or blockade of NOP receptor signaling before exposure to acute stress. METHODS: The behavioral effects of the administration before stress of the NOP agonists Ro 65-6570 (0.01-1 mg/kg) and MCOPPB (0.1-10 mg/kg), and the NOP antagonist SB-612111 (1-10 mg/kg) were assessed in mice exposed to inescapable electric footshock and forced swim as stressors. The behavioral phenotype of mice lacking the NOP receptor (NOP(-/-)) exposed to inescapable electric footshock was also investigated. RESULTS: The activation of NOP receptor signaling with the agonists increased the percentage of mice developing helpless behavior and facilitated immobile posture. In contrast, the blockade of NOP receptor reduced the acquisition of depressive-like phenotypes, and similar resistance to develop helpless behaviors was observed in NOP(-/-) mice. Under the same stressful conditions, the antidepressant nortriptyline (20 mg/kg) did not change the acquisition of helpless behavior and immobile posture. CONCLUSIONS: These findings support the view that NOP activation during acute stress facilitates the development of depressive-related behaviors, whereas NOP blockade has a protective outcome. This study showed for first time that NOP antagonists are worthy of investigation as preemptive treatments in patients with severe risk factors for depression.
Asunto(s)
Péptidos Opioides/metabolismo , Receptores Opioides/metabolismo , Resiliencia Psicológica/efectos de los fármacos , Estrés Psicológico/tratamiento farmacológico , Animales , Conducta Animal/efectos de los fármacos , Bencimidazoles/administración & dosificación , Bencimidazoles/farmacología , Cicloheptanos/administración & dosificación , Cicloheptanos/farmacología , Depresión/tratamiento farmacológico , Depresión/fisiopatología , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Femenino , Imidazoles/administración & dosificación , Imidazoles/farmacología , Masculino , Ratones , Ratones Noqueados , Nortriptilina/farmacología , Piperidinas/administración & dosificación , Piperidinas/farmacología , Receptores Opioides/efectos de los fármacos , Receptores Opioides/genética , Compuestos de Espiro/administración & dosificación , Compuestos de Espiro/farmacología , Estrés Psicológico/fisiopatología , Receptor de Nociceptina , NociceptinaRESUMEN
OBJECTIVE: To estimate the incremental cost-utility ratio (ICUR) of isolated and combined targeted therapy regimens compared to dacarbazine for first-line treatment of advanced and metastatic melanoma with BRAF V600 mutation. METHODS: A Markov model with three health states (no progression, progression and death), monthly duration cycle and 10-year time horizon was constructed to compare targeted therapy regimens (vemurafenib, dabrafenib, vemurafenib/cobimetinib and dabrafenib/trametinib) with dacarbazine chemotherapy under the Brazilian public health perspective. One-way and probabilistic sensitivity analyses were performed. RESULTS: Mean cost was R$5662.50 ($1490.13) for dacarbazine, R$175 937.18 (46 299.26) for vemurafenib, R$167 461.70 ($44 068.87) for dabrafenib, R$425 901 ($112 079.21) for vemurafenib/cobimetinib and R$411 799.81 ($108 368.37) for dabrafenib/trametinib, whereas QALY was 0.91 for dacarbazine, 1.08 for vemurafenib, 1.12 for dabrafenib, 1.64 for vemurafenib/cobimetinib and 1.56 for dabrafenib/trametinib. The ICUR was estimated from R$572 165.76 ($150 569.94) to R$1 012 524.56 ($266 453.83) per patient, and the most impactful parameters were risk of progression and death, and treatment cost. CONCLUSION: The incorporation of targeted therapies in the Brazilian public health system would produce an additional expenditure of at least 19 times the national GDP per capita to increase in one year the quality-adjusted survival of each patient with advanced/metastatic BRAF-mutant melanoma.
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Antineoplásicos/uso terapéutico , Dacarbazina/uso terapéutico , Costos de la Atención en Salud/estadística & datos numéricos , Melanoma/tratamiento farmacológico , Antineoplásicos/economía , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/economía , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Azetidinas/administración & dosificación , Azetidinas/economía , Azetidinas/uso terapéutico , Brasil , Análisis Costo-Beneficio , Dacarbazina/economía , Costos de los Medicamentos , Humanos , Imidazoles/administración & dosificación , Imidazoles/economía , Imidazoles/uso terapéutico , Melanoma/economía , Oximas/administración & dosificación , Oximas/economía , Oximas/uso terapéutico , Piperidinas/administración & dosificación , Piperidinas/economía , Piperidinas/uso terapéutico , Piridonas/administración & dosificación , Piridonas/economía , Piridonas/uso terapéutico , Pirimidinonas/administración & dosificación , Pirimidinonas/economía , Pirimidinonas/uso terapéutico , Vemurafenib/administración & dosificación , Vemurafenib/economía , Vemurafenib/uso terapéuticoRESUMEN
RATIONALE: Histamine H3 receptors (H3Rs) are co-expressed with dopamine D1 receptors (D1Rs) by striato-nigral medium spiny GABAergic neurons, where they functionally antagonize D1R-mediated responses. OBJECTIVES AND METHODS: We examined whether the chronic administration of the H3R agonist immepip modifies dyskinesias induced by L-3,4-dihydroxyphenylalanine, L-Dopa (LIDs), in rats lesioned with 6-hydroxydopamine in the substantia nigra pars compacta, and the effect of D1R and H3R co-activation on glutamate and GABA content in dialysates from the dorsal striatum of naïve rats. RESULTS: The systemic administration (i.p.) of L-Dopa for 14 days significantly increased axial, limb, and orolingual abnormal involuntary movements (AIMs) compared with the vehicle group. The chronic administration of the H3R agonist immepip alongside L-Dopa significantly decreased axial, limb, and orolingual AIMs compared with L-Dopa alone, but AIMs returned to previous values on immepip withdrawal. Chronic immepip was ineffective when administered prior to L-Dopa. The chronic administration of immepip significantly decreased GABA and glutamate content in striatal dialysates, whereas the administration of L-Dopa alone increased GABA and glutamate content. CONCLUSIONS: These results indicate that chronic H3R activation reduces LIDs, and the effects on striatal GABA and glutamate release provide evidence for a functional interaction between D1Rs and H3Rs.
Asunto(s)
Discinesia Inducida por Medicamentos/tratamiento farmacológico , Agonistas de los Receptores Histamínicos/administración & dosificación , Imidazoles/administración & dosificación , Levodopa/toxicidad , Oxidopamina/toxicidad , Piperidinas/administración & dosificación , Receptores Histamínicos H3/fisiología , Animales , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/metabolismo , Discinesia Inducida por Medicamentos/metabolismo , Masculino , Ratas , Ratas Wistar , Sustancia Negra/efectos de los fármacos , Sustancia Negra/metabolismoRESUMEN
RATIONALE: The endocannabinoid system plays an important role in the organization of panic-like defensive behavior. Threatening situations stimulate brain areas, such as the dorsomedial hypothalamus (DMH). However, there is a lack of studies addressing the role of the DMH endocannabinoid system in panic-like responses. OBJECTIVES: We aimed to verify which mechanisms underlie anandamide-mediated responses in the DMH. METHODS: To test the hypothesis that the anandamide produces panicolytic-like effects, we treated mice with intra-DMH microinjections of vehicle or increasing doses of anandamide (0.5, 5, or 50 pmol) and then performed confrontation with the South American snake Epicrates cenchria assisi. RESULTS: Intra-DMH anandamide treatment yielded a U-shaped dose-response curve with no effect of the lowest (0.5 pmol) or the highest (50 pmol) dose and significant inhibition of panic-like responses at the intermediate (5 pmol) dose. In addition, this panicolytic-like effect was prevented by pretreatment of the DMH with the CB1 receptor antagonist AM251 (100 pmol). However, pretreatment of the DMH with the TRPV1 receptor antagonist 6-iodo-nordihydrocapsaicin (3 nmol) restored the panicolytic-like effect of the highest dose of anandamide. Immunohistochemistry revealed that CB1 receptors were present primarily on axonal fibers, while TRPV1 receptors were found almost exclusively surrounding the perikarya in DMH. CONCLUSIONS: The present results suggest that anandamide exerts a panicolytic-like effect in the DMH by activation of CB1 receptors and that TRPV1 receptors are related to the lack of effect of the highest dose of anandamide.
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Ácidos Araquidónicos/administración & dosificación , Agonistas de Receptores de Cannabinoides/administración & dosificación , Núcleo Hipotalámico Dorsomedial/metabolismo , Endocannabinoides/administración & dosificación , Pánico/fisiología , Alcamidas Poliinsaturadas/administración & dosificación , Receptor Cannabinoide CB1/biosíntesis , Canales Catiónicos TRPV/biosíntesis , Animales , Boidae , Brasil , Núcleo Hipotalámico Dorsomedial/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Inyecciones Intraventriculares , Masculino , Ratones , Ratones Endogámicos C57BL , Pánico/efectos de los fármacos , Piperidinas/administración & dosificación , Pirazoles/administración & dosificación , Ratas , Receptor Cannabinoide CB1/agonistas , Receptor Cannabinoide CB1/antagonistas & inhibidores , Canales Catiónicos TRPV/antagonistas & inhibidoresRESUMEN
OBJECTIVES: Studies have documented the anti-inflammatory effects of spices, which may be related to treatment of chronic diseases. The purpose of this study was to evaluate the influence of curcumin and piperine and their association on experimental periodontal repair in rats. MATERIALS AND METHODS: Periodontitis was induced via the installation of a ligature around the first molar. After 15 days, the ligatures were removed, and the rats were separated into groups (12 animals per group): (i) curcumin, (ii) piperine, (iii) curcumin+piperine, (iv) corn oil vehicle, and (v) control group (animals had ligature-induced periodontitis but were not treated). The compounds were administered daily, for 15 days by oral gavage. Animals were euthanized at 5 and 15 days, and hemimaxillae and gingival tissues were harvested. Bone repair was assessed by µCT (microcomputer tomography). Histological sections were stained with hematoxylin/eosin (H/E) for the assessment of cellular infiltrate or picrosirius red for quantification of collagen content, and subjected to immunohistochemistry for detecting NF-ĸB. Gingival tissues were used to evaluate levels of TGF-ß and IL-10 (ELISA). RESULTS: Curcumin and piperine increased the TGF-ß level, significantly improved the collagen repair, and decreased the cellularity and activation of NF-ĸB in the periodontal tissues, but only curcumin caused a significant increase in early bone repair. CONCLUSION: Curcumin and piperine promoted a substantive effect on tissue repair; however, there was not synergistic effect of compounds administered in combination. CLINICAL RELEVANCE: Curcumin and piperine stimulates the tissue repair and may be potential candidates for the treatment of periodontal disease.