RESUMEN
RATIONALE: Amid the pervasive deployment of imidacloprid, the incidence of poisoning from this compound has risen markedly. Those afflicted with imidacloprid poisoning typically exhibit symptoms ranging from headaches, dizziness, nausea, and abdominal pain, to impaired consciousness and breathlessness, yet instances of ocular paralysis induced by this toxin have not previously been documented. PATIENT CONCERNS: When the pesticide spray inadvertently made contact with the patient's eyes, they were seared with a burning sensation and discomfort. Subsequent to this incident, on the second day, the individual began to experience diplopia in the right eye and found it arduous to elevate his eyelids, indicating a challenge in achieving full extension. DIAGNOSES: Based on the medical history, symptoms, and signs, the patient was diagnosed with oculomotor nerve palsy caused by imidacloprid. INTERVENTIONS: The treatment involved intravenous dexamethasone to reduce inflammatory response in the eye tissue; oral pantoprazole enteric-coated tablets to suppress acid production and protect the stomach; Xuesaitong administered intravenously to improve blood supply to the eye and promote metabolism of toxins; vitamin C, cobamamide, and vitamin B1 for nerve nutrition and antioxidant effects; local application of tobramycin-dexamethasone eye drops for anti-inflammatory purposes; and repeated flushing of the conjunctival sac with saline. Finally, the patient improved and was discharged. OUTCOMES: After active treatment, the patient finally improved diplopia and ptosis. LESSONS: This report marks the first documentation of oculomotor nerve palsy induced by imidacloprid, featuring diplopia, and blepharoptosis without substantial limitation of ocular motility. Following therapeutic intervention, the patient showed marked improvement and was discharged from the hospital, providing a point of reference for the treatment of analogous cases in future clinical practice. It also serves as a reminder for the public to take appropriate precautions when using imidacloprid.
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Neonicotinoides , Nitrocompuestos , Enfermedades del Nervio Oculomotor , Humanos , Neonicotinoides/efectos adversos , Nitrocompuestos/efectos adversos , Masculino , Enfermedades del Nervio Oculomotor/inducido químicamente , Enfermedades del Nervio Oculomotor/diagnóstico , Insecticidas/efectos adversosRESUMEN
Intra-amniotic inflammation leading to preterm birth is one of the leading causes of neonatal morbidity and mortality. We recently reported that the mitochondrial levels of MNRR1 (Mitochondrial Nuclear Retrograde, Regulator 1; also called CHCHD2, AAG10, or PARK22), an important bi-organellar regulator of cellular function, are reduced in the context of inflammation and that genetic and pharmacological increases in MNRR1 levels can counter the inflammatory profile. Herein, we show that nitazoxanide, a clinically approved drug, is an activator of MNRR1 and abrogates preterm birth in a well-characterized murine model caused by intra-amniotic lipopolysaccharide (LPS) injection.
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Corioamnionitis , Nacimiento Prematuro , Recién Nacido , Femenino , Humanos , Animales , Ratones , Nacimiento Prematuro/prevención & control , Lipopolisacáridos , Nitrocompuestos/efectos adversos , Inflamación/inducido químicamente , Líquido Amniótico , Proteínas de Unión al ADN , Factores de Transcripción/genéticaRESUMEN
BACKGROUND: This study investigated the clinical outcomes, virological efficacy and safety of nitazoxanide in the treatment of patients with COVID-19. RESEARCH DESIGN AND METHODS: The PubMed, Embase, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov databases were searched for relevant articles written before August 23, 2022. Only randomized controlled trials (RCTs) that assessed the usefulness and safety of nitazoxanide in patients with COVID-19 were included. RESULTS: Five RCTs were included. The overall mortality of COVID-19 patients receiving nitazoxanide (study group) was 1.3% (9/670), which was lower than the control group (1.8%, 12/681), but this difference did not reach statistical significance (risk difference [RD], 0.00; 95% CI: -0.01 to 0.01; P =0.97). However, nitazoxanide was associated with a higher virological eradication rate than placebo or standard care (RD, 0.09; 95% CI: 0.01 to 0.17; P = 0.03). Compared with the placebo or standard care, nitazoxanide were associated with a similar risk of any adverse event (RD, -0.02; 95% CI: -0.07 to 0.03; P = 0.44). CONCLUSIONS: Although nitazoxanide can help virological eradication and is also tolerable, it does not provide additional clinical benefits. Based on these evidences, the use of nitazoxanide in the treatment of patients with COVID-19 is not recommended.
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Tratamiento Farmacológico de COVID-19 , Humanos , Ensayos Clínicos Controlados Aleatorios como Asunto , Nitrocompuestos/efectos adversos , Tiazoles/efectos adversosRESUMEN
Oxidative stress and mitochondrial dysfunction are among the mechanisms expected to explain the pathogenesis of Huntington's disease. Erythropoietin (EPO) and the Bacillus Calmette-Guérin (BCG) vaccine have neuroprotective effects against neurodegenerative diseases; however, the full mechanisms of their action are currently unclear. Here, for the first time, we investigated the neuroprotective effect of BCG vaccination in Huntington-like disease induced by 3-nitropropionic acid (3-NP) and its combination with EPO. Male Wistar rats were randomized into five groups: saline-treated control; 3-NP group (20 mg/kg/day, i.p.) for 7 days; EPO-treated group (5000 IU/kg/day, i.p.) for 14 days after 3-NP administration; live BCG vaccine prophylactic group (5000 cfu/g, i.p.) 10 days prior to 3-NP administration; and live BCG vaccine (5000 cfu/g, i.p.) 10 days before 3-NP administration, followed by EPO treatment (5000 IU/kg/day, i.p.) for 14 days. In a histopathological examination, striatum neurodegeneration was evidenced in the 3-NP injected rats. Administration of 3-NP elevated the levels of p-PI3K, p-Akt, p-mTOR, p-P70S6K, BAX, malondialdehyde, nitric oxide, and cytochrome oxidase while reduced the levels of BCL-2, superoxide dismutase, reduced glutathione, and the autophagy marker microtubule-associated protein light chain 3 in the striatum. EPO and BCG ameliorated the biochemical, histopathological, and behavioral derangements induced by 3-NP, with prominent neuroprotection observed in rats administered the BCG prophylactic combined with EPO treatment. These results highlight the role played by EPO and BCG in the management of 3-NP-induced Huntington-like disease by inhibiting the PI3K/Akt/mTOR/P70S6K pathway and enhancing the autophagy.
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Eritropoyetina , Enfermedad de Huntington , Fármacos Neuroprotectores , Animales , Autofagia , Vacuna BCG , Eritropoyetina/uso terapéutico , Enfermedad de Huntington/inducido químicamente , Enfermedad de Huntington/tratamiento farmacológico , Enfermedad de Huntington/prevención & control , Masculino , Fármacos Neuroprotectores/uso terapéutico , Nitrocompuestos/efectos adversos , Fosfatidilinositol 3-Quinasas , Propionatos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ratas , Ratas Wistar , Proteínas Quinasas S6 Ribosómicas 70-kDa/uso terapéutico , Serina-Treonina Quinasas TOR , VacunaciónRESUMEN
Repurposing approved drugs may rapidly establish effective interventions during a public health crisis. This has yielded immunomodulatory treatments for severe coronavirus disease 2019 (COVID-19), but repurposed antivirals have not been successful to date because of redundancy of the target in vivo or suboptimal exposures at studied doses. Nitazoxanide is a US Food and Drug Administration (FDA) approved antiparasitic medicine, that physiologically-based pharmacokinetic (PBPK) modeling has indicated may provide antiviral concentrations across the dosing interval, when repurposed at higher than approved doses. Within the AGILE trial platform (NCT04746183) an open label, adaptive, phase I trial in healthy adult participants was undertaken with high-dose nitazoxanide. Participants received 1,500 mg nitazoxanide orally twice-daily with food for 7 days. Primary outcomes were safety, tolerability, optimum dose, and schedule. Intensive pharmacokinetic (PK) sampling was undertaken day 1 and 5 with minimum concentration (Cmin ) sampling on days 3 and 7. Fourteen healthy participants were enrolled between February 18 and May 11, 2021. All 14 doses were completed by 10 of 14 participants. Nitazoxanide was safe and with no significant adverse events. Moderate gastrointestinal disturbance (loose stools or diarrhea) occurred in 8 participants (57.1%), with urine and sclera discoloration in 12 (85.7%) and 9 (64.3%) participants, respectively, without clinically significant bilirubin elevation. This was self-limiting and resolved upon drug discontinuation. PBPK predictions were confirmed on day 1 but with underprediction at day 5. Median Cmin was above the in vitro target concentration on the first dose and maintained throughout. Nitazoxanide administered at 1,500 mg b.i.d. with food was safe with acceptable tolerability a phase Ib/IIa study is now being initiated in patients with COVID-19.
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Antivirales/administración & dosificación , Nitrocompuestos/administración & dosificación , Nitrocompuestos/efectos adversos , Nitrocompuestos/farmacocinética , Tiazoles/administración & dosificación , Tiazoles/efectos adversos , Tiazoles/farmacocinética , Adulto , Antivirales/efectos adversos , Antivirales/farmacocinética , Reposicionamiento de Medicamentos , Femenino , Voluntarios Sanos , Humanos , Masculino , Persona de Mediana Edad , Adulto Joven , Tratamiento Farmacológico de COVID-19RESUMEN
Understanding the effects of metabolism on the rational design of novel and more effective drugs is still a considerable challenge. To the best of our knowledge, there are no entirely computational strategies that make it possible to predict these effects. From this perspective, the development of such methodologies could contribute to significantly reduce the side effects of medicines, leading to the emergence of more effective and safer drugs. Thereby, in this study, our strategy is based on simulating the electron ionization mass spectrometry (EI-MS) fragmentation of the drug molecules and combined with molecular docking and ADMET models in two different situations. In the first model, the drug is docked without considering the possible metabolic effects. In the second model, each of the intermediates from the EI-MS results is docked, and metabolism occurs before the drug accesses the biological target. As a proof of concept, in this work, we investigate the main antiviral drugs used in clinical research to treat COVID-19. As a result, our strategy made it possible to assess the biological activity and toxicity of all potential by-products. We believed that our findings provide new chemical insights that can benefit the rational development of novel drugs in the future.
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Antivirales/metabolismo , Tratamiento Farmacológico de COVID-19 , Descubrimiento de Drogas , SARS-CoV-2/efectos de los fármacos , Adenina/efectos adversos , Adenina/análogos & derivados , Adenina/metabolismo , Adenina/farmacología , Adenosina/efectos adversos , Adenosina/análogos & derivados , Adenosina/metabolismo , Adenosina/farmacología , Adenosina Monofosfato/efectos adversos , Adenosina Monofosfato/análogos & derivados , Adenosina Monofosfato/metabolismo , Adenosina Monofosfato/farmacología , Alanina/efectos adversos , Alanina/análogos & derivados , Alanina/metabolismo , Alanina/farmacología , Amidas/efectos adversos , Amidas/metabolismo , Amidas/farmacología , Antivirales/efectos adversos , Antivirales/farmacología , COVID-19/metabolismo , Cloroquina/efectos adversos , Cloroquina/análogos & derivados , Cloroquina/metabolismo , Cloroquina/farmacología , Diseño de Fármacos , Humanos , Redes y Vías Metabólicas , Simulación del Acoplamiento Molecular , Nitrocompuestos/efectos adversos , Nitrocompuestos/metabolismo , Nitrocompuestos/farmacología , Pirazinas/efectos adversos , Pirazinas/metabolismo , Pirazinas/farmacología , Pirrolidinas/efectos adversos , Pirrolidinas/metabolismo , Pirrolidinas/farmacología , Ribavirina/efectos adversos , Ribavirina/metabolismo , Ribavirina/farmacología , SARS-CoV-2/metabolismo , Tiazoles/efectos adversos , Tiazoles/metabolismo , Tiazoles/farmacologíaRESUMEN
Huntington's disease (HD) is an inherited neurodegenerative disorder caused by CAG repeat expansion in the huntingtin (HTT) gene. Here, we examined the effects of antioxidants on 3-nitropropionic acid (3-NP; a mitochondrial complex II inhibitor)-induced mitochondrial dysfunction and cell death in STHdhQ111 striatal cells carrying homozygous mutant HTT with extended CAG repeats compared with those in STHdhQ7 striatal cells. 3-NP reduced cell viability and increased cell death both in STHdhQ111 and STHdhQ7, and the cytotoxicity was markedly attenuated by antioxidants (N-acetyl-l-cysteine and edaravone). Furthermore, 3-NP increased intracellular reactive oxygen species (ROS) production in both cell lines, and this increase was inhibited by antioxidants. Mitochondrial ROS was also increased by 3-NP in STHdhQ111 but not in STHdhQ7, and this increase was significantly inhibited by edaravone. Mitochondrial membrane potential (MMP) was lower in STHdhQ111 than that in STHdhQ7, and antioxidants prevented 3-NP-induced MMP decrease in STHdhQ111.3-NP enhanced oligomerization of dynamin-related protein 1 (Drp1), a protein that promotes mitochondrial fission in both cells, and both antioxidants prevented the increase in oligomerization. These results suggest that reduced mitochondrial complex II activity enhances cell death via intracellular ROS production and Drp1 oligomerization in striatal cells with mutant HTT and antioxidants may reduce striatal cell death.
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Antioxidantes/farmacología , Muerte Celular/efectos de los fármacos , Muerte Celular/genética , Complejo II de Transporte de Electrones/metabolismo , Proteína Huntingtina/genética , Enfermedad de Huntington/genética , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Mutación/genética , Especies Reactivas de Oxígeno/metabolismo , Expansión de Repetición de Trinucleótido/genética , Animales , Edaravona/farmacología , Complejo II de Transporte de Electrones/antagonistas & inhibidores , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Ratones Transgénicos , Dinámicas Mitocondriales/efectos de los fármacos , Nitrocompuestos/efectos adversos , Nitrocompuestos/antagonistas & inhibidores , Propionatos/efectos adversos , Propionatos/antagonistas & inhibidoresRESUMEN
The soybean aphid Aphis glycines Matsumura (Hemiptera: Aphididae) is a primary pest of soybeans and poses a serious threat to soybean production. Our studies were conducted to understand the effects of different concentrations of insecticides (imidacloprid and thiamethoxam) on A. glycines and provided critical information for its effective management. Here, we found that the mean generation time and adult and total pre-nymphiposition periods of the LC50 imidacloprid- and thiamethoxam-treatment groups were significantly longer than those of the control group, although the adult pre-nymphiposition period in LC30 imidacloprid and thiamethoxam treatment groups was significantly shorter than that of the control group. Additionally, the mean fecundity per female adult, net reproductive rate, intrinsic rate of increase, and finite rate of increase of the LC30 imidacloprid-treatment group were significantly lower than those of the control group and higher than those of the LC50 imidacloprid-treatment group (P < 0.05). Moreover, both insecticides exerted stress effects on A. glycines, and specimens treated with the two insecticides at the LC50 showed a significant decrease in their growth rates relative to those treated with the insecticides at LC30. These results provide a reference for exploring the effects of imidacloprid and thiamethoxam on A. glycines population dynamics in the field and offer insight to agricultural producers on the potential of low-lethal concentrations of insecticides to stimulate insect reproduction during insecticide application.
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Áfidos/crecimiento & desarrollo , Glycine max/parasitología , Insecticidas/efectos adversos , Neonicotinoides/efectos adversos , Nitrocompuestos/efectos adversos , Tiametoxam/efectos adversos , Animales , Áfidos/efectos de los fármacos , Productos Agrícolas/efectos de los fármacos , Productos Agrícolas/crecimiento & desarrollo , Femenino , Fertilidad/efectos de los fármacos , Dosificación Letal Mediana , Masculino , Dinámica PoblacionalRESUMEN
Nitazoxanide (NTZ) is a broad-spectrum antiparasitic and antiviral drug (thiazole). However, although NTZ has been extensively used, there are no reports concerning its toxicology in vertebrates. This study used the zebrafish as a vertebrate model to evaluate the safety of NTZ and to analyse the related molecular mechanisms. The experimental results showed that zebrafish embryos exposed to NTZ had cardiac malformation and dysfunction. NTZ also significantly inhibited proliferation and promoted apoptosis in cardiomyocytes. Transcriptomic analysis used compared gene expression levels between zebrafish embryos in the NTZ treatment and the control groups identified 200 upregulated genes and 232 downregulated genes. Analysis by Kyoto encyclopaedia of genes and genomes (KEGG) and gene ontology (GO) showed that signal pathways on cardiomyocyte development were inhibited while the oxidative stress pathways were activated. Further experiments showed that NTZ increased the content of reactive oxygen species (ROS) in the hearts of zebrafish. Antioxidant gadofullerene nanoparticles (GFNPs) significantly alleviated the developmental toxicity to the heart, indicating that NTZ activated the oxidative stress response to cause embryonic cardiomyocyte injury in zebrafish. This study provides evidence that NTZ causes developmental abnormalities in the cardiovascular system of zebrafish.
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Lesiones Cardíacas/etiología , Lesiones Cardíacas/metabolismo , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Nitrocompuestos/efectos adversos , Estrés Oxidativo/efectos de los fármacos , Tiazoles/efectos adversos , Animales , Animales Modificados Genéticamente , Apoptosis/efectos de los fármacos , Cardiotoxicidad , Biología Computacional/métodos , Modelos Animales de Enfermedad , Susceptibilidad a Enfermedades , Embrión no Mamífero/efectos de los fármacos , Embrión no Mamífero/metabolismo , Perfilación de la Expresión Génica , Ontología de Genes , Especies Reactivas de Oxígeno/metabolismo , Superóxido Dismutasa/metabolismo , Pez CebraRESUMEN
Recently, we reported a novel mode of action in monarch butterfly (Danaus plexippus) larvae exposed to neonicotinoid insecticides: arrest in pupal ecdysis following successful larval ecdysis. In this paper, we explore arrested pupal ecdysis in greater detail and propose adverse outcome pathways to explain how neonicotinoids cause this effect. Using imidacloprid as a model compound, we determined that final-instar monarchs, corn earworms (Helicoverpa zea), and wax moths (Galleria mellonella) showed high susceptibility to arrested pupal ecdysis while painted ladies (Vanessa cardui) and red admirals (Vanessa atalanta) showed low susceptibility. Fall armyworms (Spodoptera frugiperda) and European corn borers (Ostrinia nubilalis) were recalcitrant. All larvae with arrested ecdysis developed pupal cuticle, but with incomplete shedding of larval cuticle and unexpanded pupal appendages; corn earworm larvae successfully developed into adults with unexpanded appendages. Delayed initiation of pupal ecdysis was also observed with treated larvae. Imidacloprid exposure was required at least 26 h prior to pupal ecdysis to disrupt the molt. These observations suggest neonicotinoids may disrupt the function of crustacean cardioactive peptide (CCAP) neurons, either by directly acting on their nicotinic acetylcholine receptors or by acting on receptors of inhibitory neurons that regulate CCAP activity.
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Insecticidas/efectos adversos , Muda/efectos de los fármacos , Neonicotinoides/efectos adversos , Nitrocompuestos/efectos adversos , Pupa/efectos de los fármacos , Pupa/fisiología , Animales , Larva/efectos de los fármacos , Larva/fisiología , Neuronas/metabolismo , Neuronas/fisiología , Neuropéptidos/metabolismo , Receptores Nicotínicos/metabolismoRESUMEN
Drug combinations have been evaluated for Chagas disease in an attempt to improve efficacy and safety. In this line, the objective of this work is to assess the effects of treatment with nitro drugs combinations using benznidazole (BZ) or nifurtimox (NFX) plus the sulfone metabolite of fexinidazole (fex-SFN) in vitro and in vivo on Trypanosoma cruzi infection. The in vitro interaction of fex-SFN and BZ or NFX against infected H9c2 cells by the Y strain was classified as an additive (0.5⩾ΣFIC<4), suggesting the possibility of a dose reduction in the in vivo T. cruzi infection. Next, the effect of combining suboptimal doses was assessed in an acute model of murine T. cruzi infection. Drug combinations led to a faster suppression of parasitemia than monotherapies. Also, the associations led to higher cure levels than those in the reference treatment BZ 100 mg day−1 (57.1%) (i.e. 83.3% with BZ/fex-SFN and 75% with NFX/fex-SFN). Importantly, toxic effects resulting from the associations were not observed, according to weight gain and hepatic enzyme levels in the serum of experimental animals. Taken together, this study is a starting point to explore the potential effects of nitro drugs combinations in preclinical models of kinetoplastid-related infections.
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Enfermedad de Chagas/tratamiento farmacológico , Nitrocompuestos/uso terapéutico , Animales , Quimioterapia Combinada , Femenino , Humanos , Concentración 50 Inhibidora , Ratones , Enfermedades Desatendidas/tratamiento farmacológico , Nifurtimox/efectos adversos , Nifurtimox/uso terapéutico , Nitrocompuestos/efectos adversos , Nitroimidazoles/efectos adversos , Nitroimidazoles/metabolismo , Nitroimidazoles/uso terapéutico , Reacción en Cadena en Tiempo Real de la Polimerasa , Sulfonas/efectos adversos , Sulfonas/uso terapéuticoRESUMEN
Neuron-glia antigen 2 (NG2) proteoglycan and platelet-derived growth factor receptor beta (PDGFR-ß) are widely used markers of pericytes, which are considered cells that form fibrotic scars in response to central nervous system insults. However, the exact phenotypes of NG2- and PDGFR-ß-expressing cells, as well as the origin of the fibrotic scar after central nervous system insults, are still elusive. In the present study, we directly examined the identities and distributions of NG2- and PDGFR-ß-positive cells in the control and lesioned striatum injured by the mitochondrial toxin 3-nitropropionic acid. Immunoelectron microscopy and correlative light and electron microscopy clearly distinguished NG2 and PDGFR-ß expression in the vasculature during the post-injury period. Vascular smooth muscle cells and pericytes expressed NG2, which was prominently increased after the injury. NG2 expression was restricted to these vascular mural cells until 14 days post-lesion. By contrast, PDGFR-ß-positive cells were perivascular fibroblasts located abluminal to smooth muscle cells or pericytes. These PDGFR-ß-expressing cells formed extravascular networks associated with collagen fibrils at 14 days post-lesion. We also found that in the injured striatal parenchyma, PDGFR-ß could be used as a complementary marker of resting and reactive NG2 glia because activated microglia/macrophages shared only the NG2 expression with NG2 glia in the lesioned striatum. These data indicate that NG2 and PDGFR-ß label different vascular mural and parenchymal cells in the healthy and injured brain, suggesting that fibrotic scar-forming cells most likely originate in PDGFR-ß-positive perivascular fibroblasts rather than in NG2-positive pericytes.
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Lesiones Encefálicas/inducido químicamente , Encéfalo/fisiopatología , Fibroblastos/metabolismo , Fibrosis/metabolismo , Nitrocompuestos/efectos adversos , Propionatos/efectos adversos , Receptor beta de Factor de Crecimiento Derivado de Plaquetas/metabolismo , Animales , Humanos , Masculino , Ratas , Ratas Sprague-DawleyRESUMEN
Introduction: The CD47 and SIRPα checkpoint pathway has garnered much interest within the anti-cancer research community, with multiple experimental checkpoint inhibitors targeting CD47 and SIRPα in development. The use of such checkpoint inhibitors may however be limited by hematologic toxicity.Areas covered: We report on RRx-001, the first known small molecule downregulator of CD47 and SIRPα, which has shown a lack of hematologic toxicity in clinical trials.Expert opinion: RRx-001 is the first reported small molecule downregulator of CD47 and SIRPα and lacks any notable hematologic or systemic toxicity as demonstrated in clinical trials to date. Small molecule RRx-001 could be used in combination with or in place of CD47 targeting antibodies for anti-cancer treatment.
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Antineoplásicos/efectos adversos , Azetidinas/efectos adversos , Nitrocompuestos/efectos adversos , Anemia/epidemiología , Anemia/etiología , Antígenos de Diferenciación/metabolismo , Antineoplásicos/administración & dosificación , Antineoplásicos/farmacología , Azetidinas/administración & dosificación , Azetidinas/farmacología , Antígeno CD47/metabolismo , Humanos , Nitrocompuestos/administración & dosificación , Nitrocompuestos/farmacología , Receptores Inmunológicos/metabolismo , Trombocitopenia/epidemiología , Trombocitopenia/etiologíaRESUMEN
Background: In a Phase II study RRx-001 was combined with Etoposide platinum (EP) in previously platinum treated SCLC. We correlated expression of the M2 marker, CD206, on HLA-DRlow/- monocytes, a phenotype that correlates with a poor prognosis, with response to RRx-001. Research design and methods: Patients received 4 mg RRx-001 once weekly until progression followed by the start of EP (etoposide 100 mg/m2 IV on days 1-3 of a 21-day cycle and either cisplatin 80 mg/m2 IV on day 1 or carboplatin AUC 5-6 IV on day 1). Treatment continued until progression or intolerable toxicity. Peripheral blood was collected in Cell Preparation Tubes with sodium citrate from 14 patients for exploratory studies during screening and after therapy on Days 1, 8, and 15. Peripheral blood mononuclear cells (PBMCs) were isolated from blood by centrifugation and multiparameter flow cytometric analysis was performed. Results: CD206 expression on HLA-DRlow/- monocytes was associated with response to chemotherapy and overall survival. Conclusion: During treatment with RRx-001, reduced expression of the protumorigenic M2 marker CD206 on peripheral monocytes positively correlated with increased response and survival.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Azetidinas/uso terapéutico , Carboplatino/uso terapéutico , Cisplatino/uso terapéutico , Etopósido/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Nitrocompuestos/uso terapéutico , Carcinoma Pulmonar de Células Pequeñas/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Azetidinas/efectos adversos , Carboplatino/efectos adversos , Cisplatino/efectos adversos , Progresión de la Enfermedad , Etopósido/efectos adversos , Antígenos HLA-DR/sangre , Humanos , Neoplasias Pulmonares/sangre , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/patología , Glicoproteínas de Membrana/sangre , Nitrocompuestos/efectos adversos , Receptores Inmunológicos/sangre , Carcinoma Pulmonar de Células Pequeñas/sangre , Carcinoma Pulmonar de Células Pequeñas/mortalidad , Carcinoma Pulmonar de Células Pequeñas/patología , Factores de Tiempo , Resultado del Tratamiento , Macrófagos Asociados a Tumores/efectos de los fármacos , Macrófagos Asociados a Tumores/metabolismoRESUMEN
Striatal neurons depends on an afferent supply of brain-derived neurotrophic factor-(BDNF) that explicitly interacts with tropomyosin receptor kinase B (TrkB) receptor and performs sundry functions including synaptic plasticity, neuronal differentiation and growth. Therefore, we aimed to scrutinize an active molecule that functions identical to BDNF in activating TrkB receptor and it's downstream targets for restoring neuronal survival in Huntington disease (HD). Data from in vitro Neuro-2a cell line showed that treatment with 7,8-dihydroxyflavone (7,8-DHF), improved 3-nitropropionic acid (3-NP) induced neuronal death by stabilizing the loss of mitochondrial membrane potential and transiently increased the activity of cAMP-response element-binding protein (CREB) and BDNF via TrkB receptor activation. Consistent with in vitro findings, our in vivo results stated that treatment with 7,8-DHF at a dose of 10 mg/kg body weight ameliorated various behavior alterations caused by 3-NP intoxication. Further histopathological and electron microscopy evidences from striatal region of 3-NP mice brain treated with 7,8-DHF showed more improved neurons with intact mitochondria and less autophagic vacuoles. Protein expression analysis of both in vitro and in vivo study showed that 7,8-DHF promotes neuronal survival through upregulation and phosphorylation of phosphatidylinositol 3-kinase (PI3K) and Akt at serine-473/threonine-308). Akt phosphorylation additionally phosphorylates Bad at serine-136 and inhibits its translocation to mitochondria thereby promoting mitochondrial biogenesis, enhanced ATP production and inhibit apoptosis mediated neuronal death. These aforementioned findings help in strengthening our hypothesis and has come up with a novel neuroprotective mechanism of 7,8-DHF against 3-NP induced neuronal death.
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Factor Neurotrófico Derivado del Encéfalo/metabolismo , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Flavonas/administración & dosificación , Enfermedad de Huntington/fisiopatología , Glicoproteínas de Membrana/agonistas , Neuronas/citología , Fosfatidilinositol 3-Quinasa/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Animales , Apoptosis/efectos de los fármacos , Factor Neurotrófico Derivado del Encéfalo/genética , Muerte Celular/efectos de los fármacos , Supervivencia Celular , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/genética , Humanos , Enfermedad de Huntington/tratamiento farmacológico , Enfermedad de Huntington/genética , Enfermedad de Huntington/metabolismo , Masculino , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Mitocondrias/efectos de los fármacos , Mitocondrias/genética , Mitocondrias/metabolismo , Neuronas/metabolismo , Fármacos Neuroprotectores/administración & dosificación , Nitrocompuestos/efectos adversos , Fosfatidilinositol 3-Quinasa/genética , Propionatos/efectos adversos , Proteínas Tirosina Quinasas/genética , Proteínas Tirosina Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/genética , Transducción de SeñalRESUMEN
Modulation of subthalamic nucleus (STN) firing patterns with injections of depolarizing currents into the STN is an important advance for the treatment of hypokinetic movement disorders, especially Parkinson's disease (PD). Chorea, ballism and dystonia are prototypical examples of hyperkinetic movement disorders. In our previous study, normal rats without nigro-striatal lesion were rendered hypokinetic with hyperpolarizing currents injected into the STN. Therefore, modulation of the firing pattern by injection of a hyperpolarizing current into the STN could be an effective treatment for hyperkinetic movement disorders. We investigated the effect of injecting a hyperpolarizing current into the STNs of two different types of hyperkinetic animal models and a patient with an otherwise uncontrollable hyperkinetic disorder. The two animal models included levodopa-induced hyperkinetic movement in parkinsonian rats (L-DOPA-induced dyskinesia model) and hyperkinesia induced by an intrastriatal injection of 3-nitropropionic acid (Huntington disease model), covering neurodegeneration-related as well as neurotoxin-induced derangement in the cortico-subcortical re-entrant loops. Delivering hyperpolarizing currents into the STN readily alleviated the hyperkinetic behaviors in the two animal models and in the clinical case, with an evident increase in subthalamic burst discharges in electrophysiological recordings. Application of a hyperpolarizing current into the STN via a Deep brain stimulation (DBS) electrode could be an effective general therapy for a wide spectrum of hyperkinetic movement disorders.
Asunto(s)
Estimulación Encefálica Profunda/métodos , Hipercinesia/terapia , Levodopa/efectos adversos , Nitrocompuestos/efectos adversos , Propionatos/efectos adversos , Núcleo Subtalámico/fisiología , Animales , Polaridad Celular , Modelos Animales de Enfermedad , Humanos , Hipercinesia/inducido químicamente , Masculino , Ratas , Resultado del TratamientoRESUMEN
The rhizome of Anemarrhena asphodeloides Bunge, used in Traditional Chinese Medicine as a brain function-improving herb, is a promising source of neuroprotective substances. The aim of this study was to evaluate the protective action of xanthones from A. asphodeloides rhizomes on the PC12 cell line exposed to the neurotoxic agent-3-nitropropionic acid (3-NP). The xanthone-enriched fraction of the ethanolic extract of A. asphodeloides (abbreviated from now on as XF, for the Xanthone Fraction), rich in polyphenolic xanthone glycosides, in concentrations from 5 to 100 µg/mL, and 3-NP in concentrations from 2.5 to 15 mM, were examined. After 8, 16, 24, 48, and 72 h of exposure of cells to various combinations of 3-NP and XF, the MTT viability assay was performed and morphological changes were estimated by confocal fluorescence microscopy. The obtained results showed a significant increase in the number of cells surviving after treatment with XF with exposure to neurotoxic 3-NP and decreased morphological changes in PC12 cells in a dose and time dependent manner. The most effective protective action was observed when PC12 cells were pre-incubated with the XF. This effect may contribute to the traditional indications of this herb for neurological and cognitive complaints. However, a significant cytotoxicity observed at higher XF concentrations (over 10 µg/mL) and longer incubation time (48 h) requires caution in future research and thorough investigation into potential adverse effects.
Asunto(s)
Anemarrhena/química , Fármacos Neuroprotectores/farmacología , Nitrocompuestos/efectos adversos , Células PC12/citología , Propionatos/efectos adversos , Xantonas/farmacología , Animales , Apoptosis/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Medicamentos Herbarios Chinos/química , Medicamentos Herbarios Chinos/farmacología , Estructura Molecular , Fármacos Neuroprotectores/química , Células PC12/efectos de los fármacos , Ratas , Rizoma/química , Factores de Tiempo , Xantonas/químicaRESUMEN
Mechanisms responsible for neuronal vulnerability in the brain remain unclear. Striatal neurons are preferentially damaged by 3-nitropropionic acid (3-NP), a mitochondrial complex-II inhibitor, causing striatal damage reminiscent of Huntington's disease (HD), but the mechanisms of the selectivity are not as well understood. We have discovered that Rhes, a protein enriched in the striatum, removes mitochondria via the mitophagy process. The process becomes intensified in the presence of 3-NP, thereby eliminating most of the mitochondria from the striatum. We put forward the hypothesis that Rhes acts as a 'mitophagy ligand' in the brain and promotes mitophagy via NIX, a mitophagy receptor. Since Rhes interacts and promotes toxicity in association with mutant huntingtin (mHTT), the genetic cause of HD, it is tempting to speculate on whether the exaggerated mitophagy may be a contributing factor to the striatal lesion found in HD. Thus, Rhes-mediated exaggerated mitophagy may act as a weapon of striatal destruction in the brain.
Asunto(s)
Encéfalo/efectos de los fármacos , Encéfalo/patología , Enfermedad de Huntington/tratamiento farmacológico , Mitofagia , Nitrocompuestos/efectos adversos , Propionatos/efectos adversos , Animales , Cuerpo Estriado/metabolismo , Desarrollo de Medicamentos , Hipocampo/metabolismo , Humanos , Proteína Huntingtina/genética , Lisosomas/metabolismo , Proteínas de la Membrana/metabolismo , Mitocondrias/metabolismo , Neuronas/metabolismo , Dominios Proteicos , Proteínas Proto-Oncogénicas/metabolismoRESUMEN
This study was conducted in treatment-naive adults with drug-susceptible pulmonary tuberculosis in Port-au-Prince, Haiti, to assess the safety, bactericidal activity, and pharmacokinetics of nitazoxanide (NTZ). This was a prospective phase II clinical trial in 30 adults with pulmonary tuberculosis. Twenty participants received 1 g of NTZ orally twice daily for 14 days. A control group of 10 participants received standard therapy over 14 days. The primary outcome was the change in time to culture positivity (TTP) in an automated liquid culture system. The most common adverse events seen in the NTZ group were gastrointestinal complaints and headache. The mean change in TTP in sputum over 14 days in the NTZ group was 3.2 h ± 22.6 h and was not statistically significant (P = 0.56). The mean change in TTP in the standard therapy group was significantly increased, at 134 h ± 45.2 h (P < 0.0001). The mean NTZ MIC for Mycobacterium tuberculosis isolates was 12.3 µg/ml; the mean NTZ maximum concentration (Cmax) in plasma was 10.2 µg/ml. Negligible NTZ levels were measured in sputum. At the doses used, NTZ did not show bactericidal activity against M. tuberculosis Plasma concentrations of NTZ were below the MIC, and its negligible accumulation in pulmonary sites may explain the lack of bactericidal activity. (This study has been registered at ClinicalTrials.gov under identifier NCT02684240.).
Asunto(s)
Antituberculosos/farmacocinética , Antituberculosos/uso terapéutico , Mycobacterium tuberculosis/efectos de los fármacos , Nitrocompuestos/farmacocinética , Nitrocompuestos/uso terapéutico , Tiazoles/farmacocinética , Tiazoles/uso terapéutico , Tuberculosis Pulmonar/tratamiento farmacológico , Adulto , Antituberculosos/efectos adversos , Femenino , Haití , Humanos , Masculino , Pruebas de Sensibilidad Microbiana , Nitrocompuestos/efectos adversos , Esputo/microbiología , Tiazoles/efectos adversos , Adulto JovenRESUMEN
Neonicotinoids are pesticides used to protect crops but with known secondary influences at sublethal doses on bees. Honeybees use their sense of smell to identify the queen and nestmates, to signal danger and to distinguish flowers during foraging. Few behavioural studies to date have examined how neonicotinoid pesticides affect the ability of bees to distinguish odours. Here, we used a differential learning task to test how neonicotinoid exposure affects learning, memory and olfactory perception in foraging-age honeybees. Bees fed with thiamethoxam could not perform differential learning and could not distinguish odours during short- and long-term memory tests. Our data indicate that thiamethoxam directly impacts the cognitive processes involved in working memory required during differential olfactory learning. Using a combination of behavioural assays, we also identified that thiamethoxam has a direct impact on the olfactory perception of similar odours. Honeybees fed with other neonicotinoids (clothianidin, imidacloprid, dinotefuran) performed the differential learning task, but at a slower rate than the control. These bees could also distinguish the odours. Our data are the first to show that neonicotinoids have compound specific effects on the ability of bees to perform a complex olfactory learning task. Deficits in decision making caused by thiamethoxam exposure could mean that this is more harmful than other neonicotinoids, leading to inefficient foraging and a reduced ability to identify nestmates.