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Estesioneuroblastoma Olfatorio/tratamiento farmacológico , Indazoles/uso terapéutico , Cavidad Nasal , Recurrencia Local de Neoplasia/tratamiento farmacológico , Neoplasias Nasales/tratamiento farmacológico , Pirimidinas/uso terapéutico , Sulfonamidas/uso terapéutico , Anciano , Estesioneuroblastoma Olfatorio/genética , Estesioneuroblastoma Olfatorio/secundario , Femenino , Fumarato Hidratasa/genética , Humanos , Mutación , Neoplasias Nasales/genética , Neoplasias Nasales/patología , Inducción de Remisión , Retratamiento , Factores de TiempoRESUMEN
The recent identification of rearrangements of neurotrophic tyrosine receptor kinase (NTRK) genes and the development of specific fusion protein inhibitors, such as larotrectinib and entrectinib, have revolutionised the diagnostic and clinical management of patients presenting with tumours with these alterations. Tumours that harbour NTRK fusions are found in both adults and children; and they are either rare tumours with common NTRK fusions that may be diagnostic, or more prevalent tumours with rare NTRK fusions. To assess currently available evidence on this matter, three key Spanish medical societies (the Spanish Society of Medical Oncology (SEOM), the Spanish Society of Pathological Anatomy (SEAP), and the Spanish Society of Paediatric Haematology and Oncology (SEHOP) have brought together a group of experts to develop a consensus document that includes guidelines on the diagnostic, clinical, and therapeutic aspects of NTRK-fusion tumours. This document also discusses the challenges related to the routine detection of these genetic alterations in a mostly public Health Care System.
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Consenso , Glicoproteínas de Membrana/genética , Neoplasias/genética , Proteínas de Fusión Oncogénica/genética , Receptor trkA/genética , Receptor trkB/genética , Receptor trkC/genética , Adulto , Factores de Edad , Benzamidas/uso terapéutico , Niño , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Inmunohistoquímica , Hibridación Fluorescente in Situ , Indazoles/uso terapéutico , Terapia Molecular Dirigida , Neoplasias/diagnóstico , Neoplasias/terapia , Proteínas de Fusión Oncogénica/análisis , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirazoles/uso terapéutico , Pirimidinas/uso terapéutico , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Sociedades Médicas , EspañaRESUMEN
ROS proto-oncogene 1 (ROS1) encodes a type I integral membrane protein with tyrosine kinase activity and whose activating alterations are involved in the aggressiveness of several tumor types. Fusions involving ROS1 gene are present in 1-2% of lung adenocarcinomas and other solid tumors. Entrectinib, also known as RXDX-101, is a potent second-generation, multitarget oral inhibitor against NTRK1, NTRK2, NTRK3, ALK, and ROS1 with the ability to cross the blood-brain barrier. Results of Phase I and II trials have led the Food and Drug Administration to grant approval to entrectinib for the treatment of patients with metastatic, ROS1-positive non-small cell lung cancer (NSCLC). In this review, we will describe the biology of ROS1, as well as results of the efficacy and safety of different clinical trials evaluating entrectinib in ROS1-positive NSCLC.
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Benzamidas/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas , Indazoles/uso terapéutico , Neoplasias Pulmonares , Proteínas Tirosina Quinasas/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/patología , Ensayos Clínicos Fase I como Asunto , Ensayos Clínicos Fase II como Asunto , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Proto-Oncogenes MasRESUMEN
Metastatic renal cell carcinoma (mRCC) encompasses a heterogeneous group of neoplasms with distinct clinical behavior and prognoses. As a result of the increasing number of therapeutic options in the metastatic setting, it is crucial to improve prognostic stratification ability. We aimed to evaluate the prognostic value of neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) and combination platelet count and neutrophil lymphocyte ratio (COP-NLR) in patients with mRCC. We evaluated a cohort of mRCC patients treated with first-line pazopanib or sunitinib. Levels of NLR, PLR and COP-NLR were measured prior to systemic treatment and evaluated as prognostic predictors. Primary endpoint was overall survival (OS). Data from 276 patients were included, of which 54.7% received first-line pazopanib and 45.3%, sunitinib. Memorial Sloan-Kettering Cancer Center risk classification was intermediate and poor in 50% and 42.6% of patients, respectively. High NLR (> 3.5) was associated with inferior OS (median 9.6 vs 17.8 months, P < 0.001). A high PLR (> 200) was associated with inferior OS (median 10.3 vs 17 months, P = 0.002). The median OS in the COP-NLR 1, 2 and 3 groups were 19.0 months (95% CI 15.3-26.0), 13.1 months (95% CI 9.8-17.0) and 7.4 months (95% CI 3.6-11.9), respectively (P < 0.001). In the multivariate analysis, high NLR and high COP-NLR were associated with inferior OS. Both high NLR and high COP-NLR were associated with poorer OS in our cohort of patients with mRCC treated with first-line pazopanib or sunitinib.
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Antineoplásicos/uso terapéutico , Biomarcadores de Tumor/sangre , Carcinoma de Células Renales/inmunología , Neoplasias Renales/inmunología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Células Renales/tratamiento farmacológico , Niño , Femenino , Humanos , Indazoles/uso terapéutico , Inflamación/sangre , Neoplasias Renales/tratamiento farmacológico , Recuento de Linfocitos , Masculino , Persona de Mediana Edad , Neutrófilos , Recuento de Plaquetas , Pronóstico , Pirimidinas/uso terapéutico , Sulfonamidas/uso terapéutico , Sunitinib/uso terapéutico , Adulto JovenRESUMEN
BACKGROUND: Bacterial vaginosis (BV) is an infection that has a prevalence between 10% to 50% worlwide. BV results in an imbalance of the normal vaginal flora. Microorganisms associated with BV have been isolated from the normal flora of the male genital tract, and their presence could be related to the recurrence of BV after antibiotic treatment. Therefore, the treatment of sexual partners could decrease the recurrence of infection and possibly the burden of the disease. OBJECTIVES: To assess the effectiveness in women and the safety in men of concurrent antibiotic treatment for the sexual partners of women treated for BV. SEARCH METHODS: We searched the Cochrane Sexually Transmitted Infections Group Specialized Register (23 July 2016), CENTRAL (1991 to 23 July 2016), MEDLINE (1946 to 23 July 2016), Embase (1974 to 23 July 2016), LILACS (1982 to 23 July 2016), the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (23 July 2016), ClinicalTrials.gov (23 July 2016) and the Web of Science™ (2001 to 23 July 2016). We also handsearched conference proceedings, contacted trial authors and reviewed the reference lists of retrieved studies. SELECTION CRITERIA: Randomized controlled trials (RCTs) that compared the concurrent use of any antibiotic treatment with placebo, no intervention or any other intervention by the sexual partners of women treated for BV. DATA COLLECTION AND ANALYSIS: Three review authors independently assessed trials for inclusion, extracted data and assessed the risk of bias in the included studies. We resolved any disagreements through consensus. We assessed the quality of the evidence using the GRADE approach. MAIN RESULTS: Seven RCTs (1026 participants) met our inclusion criteria, and pharmaceutical industry funded four of these trials. Five trials (854 patients) compared any antibiotic treatment of sexual partners with placebo. Based on high quality evidence, antibiotic treatment does not increase the rate of clinical or symptomatic improvement in women during the first week (risk ratio (RR) 0.99, 95% confidence interval (CI) 0.96 to 1.03; 712 participants, four studies; RR 1.06, 95% CI 1.00 to 1.12; 577 patients, three studies, respectively), between the first and fourth week (RR 1.02, 95% CI 0.94 to 1.11; 590 participants, three studies; RR 0.93, 95% CI 0.84 to 1.03; 444 participants, two studies; respectively) or after the fourth week (RR 0.98, 95% CI 0.90 to 1.07; 572 participants, four studies; RR 1.03, 95% CI 0.90 to 1.17; 296 participants, two studies; respectively). Antibiotic treatment does not led to a lower recurrence during the first and fourth week (RR 1.28, 95% CI 0.68 to 2.43; 218 participants, one study; low quality evidence) or after the fourth week of treatment (RR 1.00, 95% CI 0.67 to 1.52; 372 participants, three studies; low quality evidence) in women, but increases the frequency of adverse events (most frequently gastrointestinal symptoms) reported by sexual partners (RR 2.55, 95% CI 1.55 to 4.18; 477 participants, three studies; low quality evidence). Two trials (172 participants) compared any antibiotic treatment for sexual partners with no intervention. When we compared it with no intervention, the effects of antibiotic treatment on recurrence rate after the fourth week (RR 1.71, 95% CI 0.65 to 4.55; 51 participants, one study), clinical improvement between the first and fourth week (RR 0.93, 95% CI 0.70 to 1.25; 152 participants, two studies) and symptomatic improvement after the fourth week (RR 0.66, 95% CI 0.39 to 1.11; 70 participants, one study) were imprecise and there were no differences between groups. We downgraded the quality of the evidence to low or very low. AUTHORS' CONCLUSIONS: High quality evidence shows that antibiotic treatment for sexual partners of women with BV, compared with placebo, does not increase the rate of clinical or symptomatic improvement during the first, between the first and fourth or after the fourth week into the women. Low quality evidence suggests that antibiotic treatment does not led to a lower recurrence rate during the first and fourth or after the fourth week of treatment into the women, but increases the frequency of adverse events reported by sexual partners. Finally, compared with no intervention, antibiotic treatment does not decrease the recurrence rate after the fourth week and does not increase the frequency of clinical or symptomatic improvement between the first and fourth or after the fourth week into the women, respectively.
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Antibacterianos/uso terapéutico , Prevención Secundaria , Parejas Sexuales , Vaginosis Bacteriana/prevención & control , Adolescente , Adulto , Antibacterianos/efectos adversos , Clindamicina/uso terapéutico , Femenino , Humanos , Indazoles/uso terapéutico , Lincosamidas/uso terapéutico , Masculino , Metronidazol/uso terapéutico , Persona de Mediana Edad , Ensayos Clínicos Controlados Aleatorios como Asunto , Recurrencia , Factores de Tiempo , Tinidazol/uso terapéuticoRESUMEN
Amantadine is the noncompetitive antagonist of N-methyl-D-aspartate, receptor activated by the excitatory neurotransmitter glutamate. It is the only effective medication used to alleviate dyskinesia induced by L-3,4-dihydroxyphenylalanine (L-DOPA) in Parkinson's disease patients. Unfortunately, adverse effects as abnormal involuntary movements (AIMs) known as L-DOPA-induced dyskinesia limit its clinical utility. Combined effective symptomatic treatment modalities may lessen the liability to undesirable events. Likewise drugs known to interfere with nitrergic system reduce AIMs in animal models of Parkinson's disease. We aimed to analyze an interaction between amantadine, neuronal nitric oxide synthase inhibitor (7-nitroindazole, 7NI), and nitric oxide donor (sodium nitroprusside, SNP) in 6-hydroxydopamine-(6-OHDA)-lesioned rats (microinjection in the medial forebrain bundle) presenting L-DOPA-induced dyskinesia (20 mg/kg, gavage, during 21 days). We confirm that 7NI-30 mg/kg, SNP-2/4 mg/kg and amantadine-40 mg/kg, individually reduced AIMs. Our results revealed that co-administration of sub-effective dose of amantadine (10 mg/kg) plus sub-effective dose of 7NI (20 mg/kg) potentiates the effect of reducing AIMs scores when compared to the effect of the drugs individually. No superior benefit on L-DOPA-induced AIMs was observed with the combination of amantadine and SNP. The results revealed that combination of ineffective doses of amantadine and 7NI represents a new strategy to increase antidyskinetic effect in L-DOPA-induced AIMs. It may provide additional therapeutic benefits to Parkinson's disease patients from these disabling complications at lower and thus safer and more tolerable doses than required when either drug is used alone. To close, we discuss the paradox of both nitric oxide synthase inhibitor and/or donor produced AIMs reduction by targeting nitric oxide synthase.
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Amantadina/uso terapéutico , Discinesia Inducida por Medicamentos/complicaciones , Discinesia Inducida por Medicamentos/tratamiento farmacológico , Indazoles/uso terapéutico , Levodopa/efectos adversos , Nitroprusiato/uso terapéutico , Enfermedad de Parkinson/complicaciones , Enfermedad de Parkinson/tratamiento farmacológico , Animales , Modelos Animales de Enfermedad , Sinergismo Farmacológico , Quimioterapia Combinada , Masculino , Haz Prosencefálico Medial/efectos de los fármacos , Microinyecciones , Oxidopamina/administración & dosificación , RatasRESUMEN
Abnormal metabolism is another cancer hallmark. The two most characterized altered metabolic pathways are high rates of glycolysis and glutaminolysis, which are natural targets for cancer therapy. Currently, a number of newer compounds to block glycolysis and glutaminolysis are being developed; nevertheless, lonidamine and 6-diazo-5-oxo-L-norleucine (DON) are two old drugs well characterized as inhibitors of glycolysis and glutaminolysis, respectively, whose clinical development was abandoned years ago when the importance of cancer metabolism was not fully appreciated and clinical trial methodology was less developed. In this review, a PubMed search using the words lonidamine and 6-diazo-5-oxo-L-norleucine (DON) was undertaken to analyse existing information on the preclinical and clinical studies of these drugs for cancer treatment. Data show that they exhibit antitumor effects; besides there is also the suggestion that they are synergistic. We conclude that lonidamine and DON are safe and potentially effective drugs that need to be reevaluated in combination as metabolic therapy of cancer.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Diazooxonorleucina/uso terapéutico , Indazoles/uso terapéutico , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Ensayos Clínicos como Asunto , Diazooxonorleucina/efectos adversos , Diazooxonorleucina/farmacocinética , Humanos , Indazoles/efectos adversos , Indazoles/farmacocinéticaRESUMEN
Agmatine, an endogenous cationic amine, has been shown to exert antidepressant-like effects. This study investigated the ability of agmatine administered orally to abolish the depressive-like behavior induced by the administration of the pro-inflammatory cytokine, tumor necrosis factor (TNF-α) in mice. In control animals, agmatine (0.001, 0.01, 0.1, and 1 mg/kg) reduced the immobility time in the tail suspension test (TST). Acute administration of TNF-α (0.001 fg/mouse, i.c.v.) increased immobility time in the TST, indicative of a depressive-like behavior, and agmatine (0.0001, 0.1, and 1 mg/kg) prevented this effect. Additionally, we examined the effects of the combined administration of sub-effective doses of agmatine with antidepressants, the NMDA receptor antagonist MK-801 and the neuronal nitric oxide synthase inhibitor 7-nitroindazole (7-NI) in mice exposed to either TNF-α or saline. In control mice, administration of a sub-effective dose of agmatine (0.0001 mg/kg) combined with sub-effective doses of either fluoxetine (5 mg/kg, p.o.), imipramine (0.1 mg/kg, p.o.), bupropion (1 mg/kg, p.o.), MK-801 (0.001 mg/kg, p.o.) or 7-NI (25 mg/kg, i.p.) produced a synergistic antidepressant-like effect in the TST. All these administrations prevented the increased immobility time induced by TNF-α. The effect of agmatine in the TNF-α model of depression appears to be associated, at least partially, with an activation of the monoaminergic systems and inhibition of NMDA receptors and nitric oxide synthesis, although converging signal transduction pathways that may underlie the effect of agmatine should be further investigated. This set of results indicates that agmatine may constitute a new therapeutic alternative for the treatment of depression associated with inflammation.
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Agmatina/uso terapéutico , Antidepresivos/uso terapéutico , Depresión/inducido químicamente , Depresión/tratamiento farmacológico , Factor de Necrosis Tumoral alfa/toxicidad , Análisis de Varianza , Animales , Modelos Animales de Enfermedad , Maleato de Dizocilpina/uso terapéutico , Relación Dosis-Respuesta a Droga , Conducta Exploratoria/efectos de los fármacos , Femenino , Suspensión Trasera , Pérdida de Tono Postural/efectos de los fármacos , Indazoles/uso terapéutico , RatonesRESUMEN
For years, Chagas disease treatment has been limited to only two drugs of highly questionable and controversial use (Nifurtimox(®) and Benznidazole(®)). In the search of effective drugs, many efforts have been made, but only a few structures have emerged as actual candidates. Heading into this, the multitarget-directed approach appears as the best choice. In this framework, indazoles were shown to be potent Trypanosoma cruzi growth inhibitors, being able to lead both the formation of reactive oxygen species and the inhibition of trypanothione reductase. Herein, we discuss the main structural factors that rule the anti-T. cruzi properties of indazoles, and how they would be involved in the biological properties as well as in the action mechanisms, attempting to make parallels between the old paradigms and current evidences in order to outline what could be the next steps to follow in regard to the future drug design for Chagas disease treatment.
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Indazoles/química , Tripanocidas/química , Trypanosoma cruzi/metabolismo , Enfermedad de Chagas/tratamiento farmacológico , Enfermedad de Chagas/parasitología , Diseño de Fármacos , Humanos , Indazoles/farmacología , Indazoles/uso terapéutico , NADH NADPH Oxidorreductasas/antagonistas & inhibidores , NADH NADPH Oxidorreductasas/metabolismo , Nifurtimox/química , Nifurtimox/farmacología , Nifurtimox/uso terapéutico , Nitroimidazoles/química , Nitroimidazoles/farmacología , Nitroimidazoles/uso terapéutico , Proteínas Protozoarias/antagonistas & inhibidores , Proteínas Protozoarias/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Tripanocidas/farmacología , Tripanocidas/uso terapéutico , Trypanosoma cruzi/efectos de los fármacos , Trypanosoma cruzi/enzimologíaRESUMEN
Rodents with lesion of dopaminergic pathway when receiving repeated l-3,4-dihydroxiphenylalanine (l-DOPA) treatment develop abnormal involuntary movements called dyskinesia. We demonstrated that nitric oxide synthase (NOS) inhibitors mitigate l-DOPA-induced dyskinesia in rodents. The aim of the present study was to verify if the in vivo preferential neuronal NOS (nNOS) inhibitor 7-nitroindazole (7-NI) affect the expression of the transcription factor FosB/ΔFosB in the lesioned striatum, an indicator of neuronal activity associated with dyskinesia. Male Wistar rats with unilateral microinjection (medial forebrain bundle) of either the neurotoxin 6-hydroxidopamine (6-OHDA; n=4-6/group) or saline (sham; n=6/group) were provided with l-DOPA (30mg/kg plus benserazide 7.5mg/kg/day, oral gavage), once a day during 22 days. 6-OHDA-lesioned animals developed abnormal involuntary movements (AIMs) classified as axial, limb, orofacial and locomotive dyskinesia and presented FosB/ΔFosB increase in the dopamine-depleted striatum. Administration of 7-NI (30mg/kg, i.p.), 30min prior to l-DOPA reduced the severity of AIMs (≈65% for axial, limb and orofacial and 74% for locomotive AIMs scores), without interfering with the rotarod performance. Simultaneously, 7-NI attenuated the expression of FosB/ΔFosB in dopamine-depleted striatum (≈65% in medial and ≈54% in lateral striatum, bregma 0.48mm). FosB/ΔFosB expression in lateral striatum was correlated with l-DOPA-induced dyskinesia. The findings described here corroborate a new approach to the management of l-DOPA-therapy in Parkinson's disease (PD) treatment.
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Discinesia Inducida por Medicamentos/metabolismo , Indazoles/farmacología , Óxido Nítrico Sintasa de Tipo I/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-fos/metabolismo , Animales , Antiparkinsonianos/efectos adversos , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/metabolismo , Discinesia Inducida por Medicamentos/tratamiento farmacológico , Discinesia Inducida por Medicamentos/psicología , Indazoles/uso terapéutico , Levodopa/efectos adversos , Masculino , Microinyecciones , Actividad Motora/efectos de los fármacos , Oxidopamina , Ratas , Ratas WistarRESUMEN
Degeneração Macular Relacionada à Idade (DMRI) exsudativa é a principal causa de perda visual severa em indivíduos acima de 50 anos nos países desenvolvidos. O fator de crescimento endotelial (VEGF) é considerado um dos mais importantes reguladores da angiogênese e da permeabilidade vascular . Drogas com atividade antiVEGF tem se mostrado eficaz em preservar ou melhorar a acuidade visual (AV) ao inibir a permeabilidade vascular e o crescimento neovascular nos pacientes tratados. Este artigo de revisão descreve o atual uso terapêutico das medicações antiVEGF para DMRI exsudativa e fornece uma visão geral do futuro da terapia antiangiogênica.
Neovascular age-related macular degeneration is the leading cause of severe, irreversible vision loss in individuals over 50 years in developed countries. Vascular endothelial growth factor (VEGF) has been shown to play a role in the regulation of choroidal neovascularization and vascular permeability. Anti-VEGF drugs have been shown to preserve or improve visual acuity by inhibiting vascular permeability and arresting the growth of neovascularization in the vast majority of treated patients. This review describes the current literature on the use of this therapeutic approach in the management of neovascular AMD and gives an overview of the future directions.
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Humanos , Proteínas Recombinantes de Fusión/uso terapéutico , Neovascularización Coroidal/tratamiento farmacológico , Inhibidores de la Angiogénesis/uso terapéutico , Receptores de Factores de Crecimiento Endotelial Vascular/uso terapéutico , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Aptámeros de Nucleótidos/uso terapéutico , Degeneración Macular Húmeda/tratamiento farmacológico , Pirimidinas/uso terapéutico , Sulfonamidas/uso terapéutico , Agudeza Visual/fisiología , Neovascularización Coroidal/etiología , Factor A de Crecimiento Endotelial Vascular/metabolismo , Degeneración Macular Húmeda/complicaciones , Degeneración Macular Húmeda/metabolismo , Bevacizumab/uso terapéutico , Ranibizumab/uso terapéutico , Indazoles/uso terapéutico , Neovascularización Patológica/metabolismoRESUMEN
Myricitrin is a nitric oxide (NO) and protein kinase C (PKC) inhibitor that has central nervous system activity, including anxiolytic-like action. Nitric oxide inhibitors blocked the behavioral effects of apomorphine, suggesting an antipsychotic-like effect. Furthermore, PKC inhibition reduced psychotic symptoms in acute mania patients and blocked amphetamine-induced hyperlocomotion, suggesting a potential antipsychotic-like effect. The present study evaluated the effects of myricitrin in animal models that assess antipsychotic-like effects (apomorphine-induced stereotypy and climbing and the paw test) and extrapyramidal side effects (catalepsy test and paw test). Olanzapine was used as a positive control. 7-Nitroindazole (7-NI), a NOS inhibitor, and l-arginine, a NO precursor, were used to evaluate nitrergic modulation, and tamoxifen was used to test the effect of PKC inhibition. In mice, myricitrin dose-dependently and olanzapine blocked the stereotypy and climbing induced by apomorphine at doses that did not induce catalepsy. 7-Nitroindazole also blocked apomorphine-induced stereotypy and climbing, which were reversed by l-arginine pretreatment. l-arginine only attenuated the effects of myricitrin on apomorphine's effects. Tamoxifen also blocked apomorphine-induced stereotypy and climbing. In the paw test in rats, myricitrin and olanzapine increased hindlimb retraction time at doses that did not affect forelimb reaction time, whereas haloperidol affected both parameters at the same dose. Myricitrin did not induce catalepsy in the bar test. Tamoxifen did not affect hindlimb retraction time or forelimb retraction time, whereas 7-NI significantly increased hindlimb reaction time. Thus, myricitrin exhibited an antipsychotic-like profile at doses that did not induce catalepsy, and this effect may be related to nitrergic action.
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Antipsicóticos/farmacología , Flavonoides/farmacología , Óxido Nítrico/antagonistas & inhibidores , Preparaciones de Plantas/farmacología , Proteína Quinasa C/antagonistas & inhibidores , Trastornos Psicóticos/tratamiento farmacológico , Animales , Antipsicóticos/uso terapéutico , Apomorfina/farmacología , Apomorfina/uso terapéutico , Arginina/farmacología , Arginina/uso terapéutico , Catalepsia/inducido químicamente , Modelos Animales de Enfermedad , Agonistas de Dopamina/farmacología , Agonistas de Dopamina/uso terapéutico , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Flavonoides/uso terapéutico , Indazoles/antagonistas & inhibidores , Indazoles/farmacología , Indazoles/uso terapéutico , Masculino , Ratones , Actividad Motora/efectos de los fármacos , Óxido Nítrico/fisiología , Fitoterapia , Hojas de la Planta , Preparaciones de Plantas/uso terapéutico , Proteína Quinasa C/fisiología , Trastornos Psicóticos/fisiopatología , Ratas , Ratas Wistar , Conducta Estereotipada/efectos de los fármacos , Conducta Estereotipada/fisiología , Syzygium , Tamoxifeno/farmacología , Tamoxifeno/uso terapéuticoRESUMEN
7-Nitroindazole (7-NI) inhibits neuronal nitric oxide synthase in vivo and reduces l-DOPA-induced dyskinesias in a rat model of parkinsonism. The aim of the present study was to determine if the anti-dyskinetic effect of 7-NI was subject to tolerance after repeated treatment and if this drug could interfere with the priming effect of l-DOPA. Adult male Wistar rats (200-250 g) with unilateral depletion of dopamine in the substantia nigra compacta were treated with l-DOPA (30 mg/kg) for 34 days. On the 1st day, 6 rats received ip saline and 6 received ip 7-NI (30 mg/kg) before l-DOPA. From the 2nd to the 26th day, all rats received l-DOPA daily and, from the 27th to the 34th day, they also received 7-NI before l-DOPA. Animals were evaluated before the drug and 1 h after l-DOPA using an abnormal involuntary movement scale and a stepping test. All rats had a similar initial motor deficit. 7-NI decreased abnormal involuntary movement induced by l-DOPA and the effect was maintained during the experiment before 7-NI, median (interquartile interval), day 26: 16.75 (15.88-17.00); day 28: 0.00 (0.00-9.63); day 29: 13.75 (2.25-15.50); day 30: 0.5 (0.00-6.25); day 31: 4.00 (0.00-7.13), and day 34: 0.5 (0.00-14.63), Friedman followed by Wilcoxon test,vs day 26, P < 0.05;. The response to l-DOPA alone was not modified by the use of 7-NI before the first administration of the drug (l-DOPA vs time interaction, F1,10 = 1.5, NS). The data suggest that tolerance to the anti-dyskinetic effects of a neuronal nitric oxide synthase inhibitor does not develop over a short-term period of repeated administration. These observations open a possible new therapeutic approach to motor complications of chronic l-DOPA therapy in patients with Parkinson's disease.
Asunto(s)
Antidiscinéticos/uso terapéutico , Discinesia Inducida por Medicamentos/tratamiento farmacológico , Inhibidores Enzimáticos/uso terapéutico , Indazoles/uso terapéutico , Óxido Nítrico Sintasa/antagonistas & inhibidores , Animales , Cuerpo Estriado/efectos de los fármacos , Modelos Animales de Enfermedad , Levodopa/farmacología , Masculino , Ratas , Ratas Wistar , Sustancia Negra/efectos de los fármacosRESUMEN
7-Nitroindazole (7-NI) inhibits neuronal nitric oxide synthase in vivo and reduces l-DOPA-induced dyskinesias in a rat model of parkinsonism. The aim of the present study was to determine if the anti-dyskinetic effect of 7-NI was subject to tolerance after repeated treatment and if this drug could interfere with the priming effect of l-DOPA. Adult male Wistar rats (200-250 g) with unilateral depletion of dopamine in the substantia nigra compacta were treated with l-DOPA (30 mg/kg) for 34 days. On the 1st day, 6 rats received ip saline and 6 received ip 7-NI (30 mg/kg) before l-DOPA. From the 2nd to the 26th day, all rats received l-DOPA daily and, from the 27th to the 34th day, they also received 7-NI before l-DOPA. Animals were evaluated before the drug and 1 h after l-DOPA using an abnormal involuntary movement scale and a stepping test. All rats had a similar initial motor deficit. 7-NI decreased abnormal involuntary movement induced by l-DOPA and the effect was maintained during the experiment before 7-NI, median (interquartile interval), day 26: 16.75 (15.88-17.00); day 28: 0.00 (0.00-9.63); day 29: 13.75 (2.25-15.50); day 30: 0.5 (0.00-6.25); day 31: 4.00 (0.00-7.13), and day 34: 0.5 (0.00-14.63), Friedman followed by Wilcoxon test,vs day 26, P < 0.05;. The response to l-DOPA alone was not modified by the use of 7-NI before the first administration of the drug (l-DOPA vs time interaction, F1,10 = 1.5, NS). The data suggest that tolerance to the anti-dyskinetic effects of a neuronal nitric oxide synthase inhibitor does not develop over a short-term period of repeated administration. These observations open a possible new therapeutic approach to motor complications of chronic l-DOPA therapy in patients with Parkinson’s disease.
Asunto(s)
Animales , Masculino , Ratas , Antidiscinéticos/uso terapéutico , Discinesia Inducida por Medicamentos/tratamiento farmacológico , Inhibidores Enzimáticos/uso terapéutico , Indazoles/uso terapéutico , Óxido Nítrico Sintasa/antagonistas & inhibidores , Cuerpo Estriado/efectos de los fármacos , Modelos Animales de Enfermedad , Levodopa/farmacología , Ratas Wistar , Sustancia Negra/efectos de los fármacosRESUMEN
Ruthenium compounds have been actively studied as metallodrugs for cancer therapy. Representatives of ruthenium-based antitumor drugs are the classes of ruthenium(III)-chlorido-(N-ligand) complexes, including the drugs namely NAMI-A and KP1019 in clinical trials, and ruthenium(II)-arene organometallics, with some compounds currently undergoing advanced preclinical testing. An alternative approach for tumor-inhibiting metallodrugs is the coordination of metal ions to organic pharmaceuticals. The combination of antitumor-active ruthenium ion with biologically-active pro-ligands in single compounds can result in the enhancement of activity, for example through synergistic effects. In the present article, some developments in the ruthenium-based antitumor drugs field are briefly highlighted and recent studies on mixed diruthenium-organic drugs as metallopharmaceuticals in cancer therapy are described. Novel organic pharmaceuticals-containing diruthenium(II,III) complexes have shown promising antitumor activity for C6 rat glioma - a model for glioblastoma multiforme (GBA).
Asunto(s)
Antineoplásicos/uso terapéutico , Compuestos Organometálicos/uso terapéutico , Rutenio/uso terapéutico , Animales , Antiinflamatorios no Esteroideos/química , Dimetilsulfóxido/análogos & derivados , Dimetilsulfóxido/uso terapéutico , Glioblastoma/tratamiento farmacológico , Humanos , Indazoles/uso terapéutico , Ligandos , Neoplasias/tratamiento farmacológico , Compuestos Organoplatinos/uso terapéutico , Ratas , Rutenio/química , Compuestos de Rutenio , SolubilidadRESUMEN
Thyroid cancer incidence has significantly increased in the last three decades and many patients seek medical attention for its treatment every year. Among follicular cell-derived tumors, the majority are differentiated thyroid carcinomas (DTC), whose prognosis is very good with only 15 percent of the cases presenting disease persistence or recurrence after initial treatment. Medullary thyroid carcinoma has a worse prognosis, especially in patients with diffused cancers at the time of initial surgery. Traditional treatment options for persistent or recurrent disease include additional surgery, radioiodine treatment and TSH-suppression in DTC patients; external beam radiotherapy, and cytotoxic chemotherapy, often have low efficacy and many patients with advanced disease ultimately die. In the last two decades many of the molecular events involved in cancer formation have been uncovered. This knowledge has prompted the development of novel therapeutic strategies mainly based on the inhibition of key molecular mediators of the tumorigenic process. In particular the class of small-molecule tyrosine kinase inhibitors was enriched by many compounds that have reached clinical trials and in some cases have had approval for clinical use in specific cancers. Many of these compounds entered clinical trials also for locally advanced or metastatic thyroid carcinomas showing very promising results.
O câncer de tireoide tem aumentado significativamente nas últimas três décadas e muitos pacientes têm buscado cuidados médicos para o tratamento a cada ano. Entre os tumores derivados de células foliculares, a maioria é carcinoma diferenciado de tireoide (CDT), cujo prognóstico é muito bom, em que somente em 15 por cento dos casos a doença é persistente ou recorrente após o tratamento inicial. O carcinoma medular de tireoide tem um prognóstico pior, especialmente em pacientes com câncer difuso no momento da cirurgia inicial. As opções no tratamento tradicional para a doença persistente ou recorrente incluem cirurgia adicional, radioiodoterapia e supressão de TSH em pacientes CDT; a radioterapia externa e a quimioterapia citotóxica apresentam com frequência uma baixa eficácia e muitos pacientes com doença avançada não sobrevivem. Nas últimas duas décadas, muitos dos eventos envolvidos na formação do câncer tornaram-se conhecidos. Esse conhecimento possibilitou o desenvolvimento de novas estratégias terapêuticas, baseadas principalmente na inibição de mediador molecularchave no processo tumorigênico. Em particular, a classe das pequenas moléculas inibidoras de tirosina-quinase foi enriquecida por muitos compostos investigados em estudos clínicos e alguns casos foram aprovados para uso clínico em tipos específicos de câncer. Muitos desses compostos foram aplicados em estudos clínicos de câncer de tireoide com extensa invasão local ou metástase, mostrando resultados muito promissores.
Asunto(s)
Humanos , Antineoplásicos/uso terapéutico , Carcinoma Medular/tratamiento farmacológico , Carcinoma Papilar/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Neoplasias de la Tiroides/tratamiento farmacológico , Bencenosulfonatos/uso terapéutico , Carcinoma Medular/genética , Carcinoma Papilar/genética , Imidazoles/uso terapéutico , Indazoles/uso terapéutico , Indoles/uso terapéutico , Niacinamida/análogos & derivados , Niacinamida/uso terapéutico , Piperidinas/uso terapéutico , Inhibidores de Proteínas Quinasas/clasificación , Piridinas/uso terapéutico , Pirroles/uso terapéutico , Quinazolinas/uso terapéutico , Neoplasias de la Tiroides/genéticaRESUMEN
New 5-nitroindazole derivatives were developed and their antichagasic properties studied. Eight compounds (14-18, 20, 26 and 28) displayed remarkable in vitro activities against Trypanosoma cruzi (T. cruzi). Its unspecific cytotoxicity against macrophages was evaluated being not toxic at a concentration at least twice that of T. cruzi IC(50), for some derivatives. The electrochemical studies, parasite respiration studies and ESR experiment showed that 5-nitroindazole derivatives not be able to yield a redox cycling with molecular oxygen such as occurs with nifurtimox (Nfx). The study on the mechanism of action proves to be related to the production of reduced species of the nitro moiety similar to that observed with benznidazole.
Asunto(s)
Enfermedad de Chagas/tratamiento farmacológico , ADN Protozoario/efectos de los fármacos , Indazoles/farmacología , Nitroimidazoles/farmacología , Pruebas de Sensibilidad Parasitaria , Tripanocidas/envenenamiento , Trypanosoma cruzi/efectos de los fármacos , Enfermedad de Chagas/genética , Cristalografía por Rayos X , Células HeLa , Humanos , Indazoles/química , Indazoles/uso terapéutico , Nitroimidazoles/síntesis química , Oxidación-Reducción/efectos de los fármacos , Relación Estructura-Actividad , Tripanocidas/farmacocinéticaRESUMEN
Chronic L-DOPA pharmacotherapy in Parkinson's disease is often accompanied by the development of abnormal and excessive movements known as L-DOPA-induced dyskinesia. Rats with 6-hydroxydopamine lesion of dopaminergic neurons chronically treated with L-DOPA develop a rodent analog of this dyskinesia characterized by severe axial, limb, locomotor and orofacial abnormal involuntary movements. While the mechanisms by which these effects occur are not clear, they may involve the nitric oxide system. In the present study we investigate if nitric oxide synthase inhibitors can prevent dyskinesias induced by repeated administration of L-DOPA in rats with unilateral 6-hydroxydopamine lesion. Chronic L-DOPA (high fixed dose, 100 mg/kg; low escalating dose, 10-30 mg/kg) treatment induced progressive dyskinesia changes. Two nitric oxide synthase inhibitors, 7-nitroindazole (1-30 mg/kg) and NG-nitro-L-arginine (50 mg/kg), given 30 min before L-DOPA, attenuate dyskinesia. 7-Nitroindazolee also improved motor performance of these animals in the rota-rod test. These results suggest the possibility that nitric oxide synthase inhibitors may be useful to treat L-DOPA-induced dyskinesia.
Asunto(s)
Antiparkinsonianos/efectos adversos , Discinesia Inducida por Medicamentos/tratamiento farmacológico , Inhibidores Enzimáticos/uso terapéutico , Levodopa/efectos adversos , Óxido Nítrico Sintasa/antagonistas & inhibidores , Enfermedad de Parkinson/tratamiento farmacológico , Animales , Antiparkinsonianos/uso terapéutico , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/patología , Modelos Animales de Enfermedad , Indazoles/uso terapéutico , Levodopa/uso terapéutico , Masculino , Actividad Motora/efectos de los fármacos , Nitroarginina/uso terapéutico , Oxidopamina , Ratas , Ratas Wistar , Sustancia Negra/efectos de los fármacos , Sustancia Negra/patologíaRESUMEN
Thyroid cancer incidence has significantly increased in the last three decades and many patients seek medical attention for its treatment every year. Among follicular cell-derived tumors, the majority are differentiated thyroid carcinomas (DTC), whose prognosis is very good with only 15% of the cases presenting disease persistence or recurrence after initial treatment. Medullary thyroid carcinoma has a worse prognosis, especially in patients with diffused cancers at the time of initial surgery. Traditional treatment options for persistent or recurrent disease include additional surgery, radioiodine treatment and TSH-suppression in DTC patients; external beam radiotherapy, and cytotoxic chemotherapy, often have low efficacy and many patients with advanced disease ultimately die. In the last two decades many of the molecular events involved in cancer formation have been uncovered. This knowledge has prompted the development of novel therapeutic strategies mainly based on the inhibition of key molecular mediators of the tumorigenic process. In particular the class of small-molecule tyrosine kinase inhibitors was enriched by many compounds that have reached clinical trials and in some cases have had approval for clinical use in specific cancers. Many of these compounds entered clinical trials also for locally advanced or metastatic thyroid carcinomas showing very promising results.
Asunto(s)
Antineoplásicos/uso terapéutico , Carcinoma Medular/tratamiento farmacológico , Carcinoma Papilar/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Neoplasias de la Tiroides/tratamiento farmacológico , Axitinib , Bencenosulfonatos/uso terapéutico , Carcinoma Medular/genética , Carcinoma Papilar/genética , Humanos , Imidazoles/uso terapéutico , Indazoles/uso terapéutico , Indoles/uso terapéutico , Niacinamida/análogos & derivados , Niacinamida/uso terapéutico , Oligonucleótidos , Compuestos de Fenilurea , Piperidinas/uso terapéutico , Inhibidores de Proteínas Quinasas/clasificación , Piridinas/uso terapéutico , Pirroles/uso terapéutico , Quinazolinas/uso terapéutico , Sorafenib , Sunitinib , Neoplasias de la Tiroides/genéticaRESUMEN
Lonidamine (1-[2,4-dichlorophenyl methyl]-1H indazole-3-carboxylic acid), Ind, is an antitumoral drug acting on mitochondria and glucose metabolism. Cell growth and metabolic effects of Ind and drug post-treatment effect were investigated in undifferentiated HT-29 human colonic carcinoma cell line which requires high glucose medium concentration for growth. 0.2 mM Ind significantly decreased cell spreading and growth in monolayer or agar cell culture. After drug treatment cell growth was reestablished to control value within 24 h. Ind modified glycoconjugates and mannose-receptor distribution (analyzed by confocal microscopy), while glucose-glycogen and protein synthesis were not affected, these being the possible reasons for the fast reversible effect.