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2.
PLoS One ; 15(5): e0232987, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32407399

RESUMO

Escherichia coli and Staphylococcus aureus are important agents of urinary tract infections that can often evolve to severe infections. The rise of antibiotic-resistant strains has driven the search for novel therapies to replace the use or act as adjuvants of antibiotics. In this context, plant-derived compounds have been widely investigated. Cuminaldehyde is suggested as the major antimicrobial compound of the cumin seed essential oil. However, this effect is not fully understood. Herein, we investigated the in silico and in vitro activities of cuminaldehyde, as well as its ability to potentiate ciprofloxacin effects against S. aureus and E. coli. In silico analyses were performed by using different computational tools. The PASS online and SwissADME programmes were used for the prediction of biological activities and oral bioavailability of cuminaldehyde. For analysis of the possible toxic effects and the theoretical pharmacokinetic parameters of the compound, the Osiris, SwissADME and PROTOX programmes were used. Estimations of cuminaldehyde gastrointestinal absorption, blood brain barrier permeability and skin permeation by using SwissADME; and drug likeness and score by using Osiris, were also evaluated The in vitro antimicrobial effects of cuminaldehyde were determined by using microdilution, biofilm formation and time-kill assays. In silico analysis indicated that cuminaldehyde may act as an antimicrobial and as a membrane permeability enhancer. It was suggested to be highly absorbable by the gastrointestinal tract and likely to cross the blood brain barrier. Also, irritative and harmful effects were predicted for cuminaldehyde if swallowed at its LD50. Good oral bioavailability and drug score were also found for this compound. Cuminaldehyde presented antimicrobial and anti-biofilm effects against S. aureus and E. coli.. When co-incubated with ciprofloxacin, it enhanced the antibiotic antimicrobial and anti-biofilm actions. We suggest that cuminaldehyde may be useful as an adjuvant therapy to ciprofloxacin in S. aureus and E. coli-induced infections.


Assuntos
Antibacterianos/administração & dosagem , Benzaldeídos/administração & dosagem , Ciprofloxacina/administração & dosagem , Cimenos/administração & dosagem , Escherichia coli/efeitos dos fármacos , Staphylococcus aureus/efeitos dos fármacos , Adjuvantes Farmacêuticos/administração & dosagem , Adjuvantes Farmacêuticos/farmacocinética , Adjuvantes Farmacêuticos/toxicidade , Administração Oral , Benzaldeídos/farmacocinética , Benzaldeídos/toxicidade , Biofilmes/efeitos dos fármacos , Biofilmes/crescimento & desenvolvimento , Disponibilidade Biológica , Simulação por Computador , Cimenos/farmacocinética , Cimenos/toxicidade , Sinergismo Farmacológico , Escherichia coli/patogenicidade , Escherichia coli/fisiologia , Infecções por Escherichia coli/tratamento farmacológico , Humanos , Técnicas In Vitro , Testes de Sensibilidade Microbiana , Infecções Estafilocócicas/tratamento farmacológico , Staphylococcus aureus/patogenicidade , Staphylococcus aureus/fisiologia , Infecções Urinárias/tratamento farmacológico
3.
Med Mal Infect ; 50(1): 16-21, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31611133

RESUMO

French people have never been so wary about vaccines. The use of aluminum salts in vaccine adjuvants to enhance effectiveness is one of the major reasons for this lack of confidence. The direct toxicity of aluminum is often put forward. Direct toxicity of aluminum has long been known-especially with occupational exposure-to be associated with characteristic clinical manifestations and increased blood aluminum level. Intoxication related to the excessive amount of an element in the body, whether be it lead poisoning following exposure to lead or mercury poisoning for instance, is always associated with metal increase in biological media. To date no link has been established between the direct toxicity of aluminum and vaccines. Aluminum levels in biological media of vaccinated subjects are not different from those of unvaccinated subjects. This is consistent with the very small amount of aluminum contained in one dose of vaccine. Indirect toxicity of aluminum was suggested to explain macrophagic myofasciitis in humans in 2011, a disease that could be mediated by an autoimmune/autoinflammatory mechanism. This hypothesis has recently been refuted in a large pharmaco-epidemiological study proving that aluminum-containing adjuvants of vaccines are not responsible for this autoimmune/autoinflammatory syndrome.


Assuntos
Adjuvantes Farmacêuticos/toxicidade , Alumínio/toxicidade , Vacinas/efeitos adversos , Alumínio/farmacocinética , Humanos , Sais
4.
Ecotoxicol Environ Saf ; 188: 109883, 2020 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-31704328

RESUMO

In order to develop an understanding of the role of adjuvants in a popular glyphosate-based herbicide - Roundup® Concentrate Plus (RCP), on non-target organisms, the effects of pure glyphosate [N-(phosphonomethyl)-glycine], RCP and a non-ionic surfactant - polyethoxylated tallowamine (POEA) were studied in the fruit fly Drosophila melanogaster. Acute exposure to sub-lethal concentrations of RCP (15 µg/mL) and POEA (45 µg/mL) reduced (p < 0.001) lifespan of female flies compared to untreated controls or glyphosate (100 µg/mL). Negative geotaxis responses in female flies were reduced (p < 0.05) following acute exposure to sub-lethal concentrations of RCP and POEA whereas glyphosate did not significantly affect this response compared to untreated flies. Acute exposure to sub-lethal concentrations of RCP and POEA elevated (p < 0.05) protein carbonyl levels while markedly (p < 0.01) inhibiting carbonyl reductase activity whereas glyphosate treatment did not significantly affect protein carbonyl levels or carbonyl reductase activity. Fecundity was reduced (p < 0.05) following exposure to sub-lethal concentrations of RCP and POEA whereas glyphosate did not affect fecundity. In vitro treatment of ovarian stem sheath (OSS) cells with sub-lethal concentrations of RCP and POEA revealed decreased cell viability and enhanced caspase activity indicative of pro-apoptotic processes after 48 h compared to untreated controls. Glyphosate however was non-toxic at the concentration used. The results suggest that RCP and the surfactant POEA are more toxic than pure glyphosate and inhibit fecundity in Drosophila by impairing cell viability through enhanced apoptosis.


Assuntos
Adjuvantes Farmacêuticos/toxicidade , Drosophila melanogaster/efeitos dos fármacos , Herbicidas/toxicidade , Polietilenoglicóis/toxicidade , Tensoativos/toxicidade , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular , Drosophila melanogaster/fisiologia , Feminino , Fertilidade/efeitos dos fármacos , Glicina/análogos & derivados , Glicina/toxicidade , Longevidade/efeitos dos fármacos , Glifosato
5.
Life Sci ; 212: 159-167, 2018 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-30290186

RESUMO

AIMS: We investigate the consequence of adjuvant anastrozole (ANA) in monotherapy or associated with biochanin A (BCA) in ovariectomized (OVX) rat model and the degree of developing bone loss in both conditions. MATERIALS AND METHODS: Sixty female rats were assigned to six groups. Five groups were bilaterally OVX, and one was sham operated. The five groups were; ANA group (0.5 mg/kg b.wt orally), BCA (5 mg/kg b.wt intraperitoneally (I/P), co-treated group (BCA + ANA), two control groups receiving even distilled water orally or DMSO I/P for twenty weeks. Bone turnover biomarkers BALP, OC, PTH, TRAP and TNFα were determined in serum. Bone mineral content, histological and morphometric measurements on rat femurs were performed. BMD by X-ray technique on tibias of rats and CT analysis of lumbar vertebrae of all treated and sham groups were applied. KEY FINDINGS: There was marked elevation in bone turnover biomarkers with high serum Ca and P content in the ANA-treated rats. Moreover marked elevation of TNFα, PTH, TC and TG, ANA caused severe changes in the BMD detected by X-ray in tibial bones and CT analysis of lumbar vertebrae of OVX rats. While I/P injection of BCA ameliorated the adverse bone health decrements caused by ANA. SIGNIFICANCE: The study highlights the importance of the BCA supplementation in accordance with the ANA therapy in case of ovariectomized rat model of osteoporosis which is clinically presented in Postmenopausal women with breast cancer during which considerable risk of developing osteoporosis is predicted during treatment.


Assuntos
Adjuvantes Farmacêuticos/toxicidade , Anastrozol/toxicidade , Genisteína/farmacologia , Osteoporose/tratamento farmacológico , Ovariectomia/efeitos adversos , Fitoestrógenos/farmacologia , Animais , Feminino , Osteoporose/etiologia , Ratos , Ratos Sprague-Dawley
6.
Physiol Behav ; 173: 132-143, 2017 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-28185878

RESUMO

Depression is frequently encountered during Parkinson's disease (PD) as a non-motor feature, which has been reported to cause and exaggerate motor deficits and neurodegenerative events in experimental PD models. We studied the effect of chronic mild stress (CMS) (pre, post and pre & post) exposure mediated depression on motor and non-motor symptoms, oxidative stress, inflammation and brain derived neurotrophic factor (BDNF) levels and its related signalling molecules against the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/probenecid (MPTP/p) induced neurotoxicity in mice. CMS and MPTP/p-coexposed C57BL/6 mice exhibited low neuromuscular strength and stride length with enhanced oxidative stress and inflammation as compared to CMS or MPTP/p alone exposed mice. Coexposure diminished the levels of BDNF and expressions of p-TrkB, p-ERK/ERK, p-AKT/AKT and p-CREB in nigrostriatal regions as compared to those of the alone exposure. CMS alone exposed mice showed more anxiety related behaviour with diminished expression of serotonin transporter as compared to MPTP/p alone injected group. Post-stress exposure to MPTP/p mice exhibited lowest motor and reflecting higher anxiety state with greatest enhancement in inflammation and reduction in the protein expression of stress and cell signalling markers as compared to pre and pre & post stress exposed PD mice. However, pre- and pre & post CMS exposed PD animals are more vulnerable to oxidative stress as compared with post-stress experienced MPTP/p mice. CMS mediated depression exacerbates motor/non-motor symptoms in MPTP/p-PD animals by modulating oxidative stress and various signalling molecules. Our results suggested that stress induced NMS can accelerate neurodegenerative processes in the PD in a progressive or expedited manner.


Assuntos
1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina/efeitos adversos , Transtornos Parkinsonianos/fisiopatologia , Estresse Psicológico/fisiopatologia , Adjuvantes Farmacêuticos/toxicidade , Animais , Peso Corporal/efeitos dos fármacos , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Proteínas de Ligação ao Cálcio/metabolismo , Catalase/metabolismo , Modelos Animais de Doenças , Comportamento Exploratório/efeitos dos fármacos , Proteína Glial Fibrilar Ácida/metabolismo , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Proteínas dos Microfilamentos/metabolismo , Força Muscular/efeitos dos fármacos , Probenecid/toxicidade , Transdução de Sinais/efeitos dos fármacos , Superóxido Dismutase/metabolismo , Tiobarbitúricos/toxicidade , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismo
7.
Toxicol Mech Methods ; 26(4): 270-5, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-27098016

RESUMO

Safety assessment evaluating the presence of impurities, residual materials, and contaminants in vaccines is a focus of current research. Thresholds of toxicological concern (TTCs) are mathematically modeled levels used for assessing the safety of many food and medication constituents. In this study, six algorithms are selected from the open-access ToxTree software program to derive a method for calculating TTCs for vaccine constituents: In Vivo Rodent Micronucleus assay/LD50, Benigni-Bossa/LD50, Cramer Extended/LD50, In Vivo Rodent Micronucleus assay/TDLo, Benigni-Bossa/TDLo, and the Cramer Extended/TDLo. Using an initial dataset (n = 197) taken from INCHEM, RepDose, RTECS, and TOXNET, the chemicals were divided into two families: "positive" - based on the presence of structures associated with adverse outcomes, or "negative" - no such structures or having structures that appear to be protective of health. The final validation indicated that the Benigni-Bossa/LD50 method is the most appropriate for calculating TTCs for vaccine constituents. Final TTCs were designated as 18.06 µg/person and 20.61 µg/person for the Benigni-Bossa/LD50 positive and negative structural families, respectively.


Assuntos
Contaminação de Medicamentos , Modelos Teóricos , Software , Toxicologia/métodos , Vacinas/química , Vacinas/toxicidade , Adjuvantes Farmacêuticos/química , Adjuvantes Farmacêuticos/toxicidade , Algoritmos , Dose Letal Mediana , Conservantes Farmacêuticos/química , Conservantes Farmacêuticos/toxicidade , Relação Quantitativa Estrutura-Atividade
8.
Int J Toxicol ; 33(1): 29-38, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24434723

RESUMO

In the present study, the effects on oxidative balance and cellular end points of glyphosate, aminomethylphosphonic acid (AMPA), and a glyphosate formulation (G formulation) were examined in HepG2 cell line, at dilution levels far below agricultural recommendations. Our results show that G formulation had toxic effects while no effects were found with acid glyphosate and AMPA treatments. Glyphosate formulation exposure produced an increase in reactive oxygen species, nitrotyrosine formation, superoxide dismutase activity, and glutathione (GSH) levels, while no effects were observed for catalase and GSH-S-transferase activities. Also, G formulation triggered caspase 3/7 activation and hence induced apoptosis pathway in this cell line. Aminomethylphosphonic acid exposure produced an increase in GSH levels while no differences were observed in other antioxidant parameters. No effects were observed when the cells were exposed to acid glyphosate. These results confirm that G formulations have adjuvants working together with the active ingredient and causing toxic effects that are not seen with acid glyphosate.


Assuntos
Adjuvantes Farmacêuticos/toxicidade , Apoptose/efeitos dos fármacos , Glicina/análogos & derivados , Hepatócitos/efeitos dos fármacos , Herbicidas/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos , Química Farmacêutica , Sinergismo Farmacológico , Glutationa/agonistas , Glutationa/metabolismo , Glicina/toxicidade , Células Hep G2 , Hepatócitos/citologia , Hepatócitos/metabolismo , Herbicidas/química , Humanos , Isoxazóis , Dose Letal Mediana , Organofosfonatos/toxicidade , Concentração Osmolar , Oxirredução , Espécies Reativas de Oxigênio/agonistas , Espécies Reativas de Oxigênio/metabolismo , Superóxido Dismutase/química , Superóxido Dismutase/metabolismo , Tetrazóis , Tirosina/agonistas , Tirosina/análogos & derivados , Tirosina/metabolismo , Glifosato
9.
J Econ Entomol ; 106(5): 1952-7, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24224234

RESUMO

Commercial producers of honey bee queens (Apis mellifera L.) have reported unexplained loss of immature queens during the larval or pupal stage. Many affected queen-rearing operations are situated among the almond orchards of California and report these losses in weeks after almond trees bloom. Almond flowers are a rich foraging resource for bees, but are often treated with fungicides, insecticides, and spray adjuvants during bloom. Anecdotal reports by queen producers associate problems in queen development with application of the fungicide Pristine (boscalid and pyraclostrobin) and spray adjuvants that are tank-mixed with it. To test the effect of these compounds on queen development, a new bioassay was developed in which queens are reared in closed swarm boxes for 4 d, until capping, with nurse bees fed exclusively on artificially contaminated pollen. Pollen was treated with four concentrations of formulated Pristine (0.4, 4, 40, and 400 ppm), a spray adjuvant (Break-Thru, 200 ppm), the combination of Pristine and spray adjuvant (400:200 ppm), the insect growth regulator insecticide diflubenzuron (100 ppm) as a positive control, or water as negative control. Chemical analysis revealed that low concentrations of pyraclostrobin (50 ppb), but no boscalid, were detectable in royal jelly secreted by nurse bees feeding on treated pollen. No significant difference in queen development or survival was observed between any of the experimental treatments and the negative control. Only diflubenzuron, the positive control, caused a substantial reduction in survival of immature queens.


Assuntos
Adjuvantes Farmacêuticos/toxicidade , Abelhas/efeitos dos fármacos , Compostos de Bifenilo/toxicidade , Carbamatos/toxicidade , Fungicidas Industriais/toxicidade , Niacinamida/análogos & derivados , Compostos de Organossilício/toxicidade , Pirazóis/toxicidade , Animais , Abelhas/crescimento & desenvolvimento , Abelhas/fisiologia , California , Diflubenzuron/farmacologia , Feminino , Inseticidas/farmacologia , Hormônios Juvenis/farmacologia , Larva/efeitos dos fármacos , Larva/crescimento & desenvolvimento , Larva/fisiologia , Niacinamida/toxicidade , Estrobilurinas
10.
J Ocul Pharmacol Ther ; 28(5): 497-501, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22690870

RESUMO

PURPOSE: To investigate the varied effects of sperminated pullulans (SP) with different amino residues on cornea permeability and its local toxicity. METHODS: Three groups of rabbits were used: control, low-amino residue content SP (SP-L), and high-amino residue content SP (SP-H). The in vitro and in vivo spreading assays were combined with high performance liquid chromatography (HPLC) to measure the concentration of puerarin in the external medium or aqueous humor when 0% SP, 0.2% SP-L, and 0.2% SP-H were included. The toxicity of SP was determined by corneal hydration values, Draize score, aqueous humor protein concentration, corneal endothelial evaluation, as well as light microscopy and electron microscopy. RESULTS: The application of 0.2% SP-L and 0.2% SP-H to the cornea in vitro increased puerarin apparent permeability coefficient by 1.96-fold (P<0.05) and 2.95-fold (P<0.01), respectively. SP-H showed stronger effect than SP-L (P<0.05). For the in vivo assay, those were 1.81-fold (P<0.05) and 3.71-fold (P<0.01), respectively. With the SP application, the corneal hydration values were <83% and Draize scores were <4, with no apparent changes in histological observations. CONCLUSION: SP is one potential adjuvant promoting puerarin permeability to the cornea, and the high-content amino residue SP showed stronger effect, without ocular toxicity.


Assuntos
Adjuvantes Farmacêuticos/química , Córnea/efeitos dos fármacos , Glucanos/química , Isoflavonas/farmacocinética , Espermina/química , Adjuvantes Farmacêuticos/toxicidade , Animais , Humor Aquoso/efeitos dos fármacos , Humor Aquoso/metabolismo , Contagem de Células , Cromatografia Líquida de Alta Pressão , Córnea/metabolismo , Interpretação Estatística de Dados , Células Endoteliais/diagnóstico por imagem , Células Endoteliais/efeitos dos fármacos , Endotélio Corneano/diagnóstico por imagem , Endotélio Corneano/efeitos dos fármacos , Endotélio Corneano/metabolismo , Proteínas do Olho/metabolismo , Glucanos/toxicidade , Técnicas In Vitro , Isoflavonas/administração & dosagem , Isoflavonas/química , Microscopia Eletrônica de Transmissão , Estrutura Molecular , Soluções Oftálmicas , Coelhos , Distribuição Tecidual , Ultrassonografia
11.
Pest Manag Sci ; 68(8): 1107-10, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22588845

RESUMO

The concept 'green adjuvants' is difficult to define. This paper formulates an answer based on two approaches. Starting from the Organisation for Economic Cooperation and Development (OECD) definition for green chemistry, production-based and environmental-impact-based definitions for green adjuvants are proposed. According to the production-based approach, adjuvants are defined as green if they are manufactured using renewable raw materials as much as possible while making efficient use of energy, preferably renewable energy. According to the environmental impact approach, adjuvants are defined as green (1) if they have a low human and environmental impact, (2) if they do not increase active ingredient environmental mobility and/or toxicity to humans and non-target organisms, (3) if they do not increase the exposure to these active substances and (4) if they lower the impact of formulated pesticides by enhancing the performance of active ingredients, thus potentially lowering the required dosage of active ingredients. Based on both approaches, a tentative definition for 'green adjuvants' is given, and future research and legislation directions are set out.


Assuntos
Adjuvantes Farmacêuticos/química , Praguicidas/química , Adjuvantes Farmacêuticos/toxicidade , Animais , Química Farmacêutica , Meio Ambiente , Química Verde , Humanos , Praguicidas/toxicidade
12.
Drug Chem Toxicol ; 35(3): 310-5, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22292413

RESUMO

Biofilm formation is a ubiquitous bacterial defense mechanism and has been shown to be a primary element in the antibiotic resistance of many human diseases, especially in the case of nosocomial infections. Recently, we have developed several compound libraries that are extremely effective at both dispersing preexisting biofilms and also inhibiting their initial formation. In addition to their antibiofilm properties, some of these molecules are able to resensitize resistant bacterial strains to previously ineffective antibiotics and are being assessed as adjuvants. In this study, we evaluated the toxic effects of three of our most effective 2-aminoimidazole compounds (dihydrosventrin, RA, and SPAR) using a rapid pipeline that combines a series of assays. A methylthiazolyldiphenyl-tetrazolium assay, using the HaCaT keratinocyte cell line was used to determine epidermal irritants and was combined with Caenorhabditis elegans fecundity assays that demonstrated the effects of environmental exposure to various concentrations of these molecules. In each case, the assays showed that the compounds did not exhibit toxicity until they reached well above their current biofilm dispersion/inhibition concentrations. The most effective antibiofilm compound also had significant effects when used in conjunction with several standard antibiotics against resistant bacteria. Consequently, it was further investigated using the C. elegans assay in combination with different antibiotics and was found to maintain the same low level of toxicity as when acting alone, bolstering its candidacy for further testing as an adjuvant.


Assuntos
Adjuvantes Farmacêuticos/toxicidade , Antibacterianos/toxicidade , Biofilmes/efeitos dos fármacos , Exposição Ambiental , Imidazóis/toxicidade , Animais , Antibacterianos/farmacologia , Caenorhabditis elegans , Linhagem Celular , Relação Dose-Resposta a Droga , Fertilidade/efeitos dos fármacos , Humanos , Imidazóis/farmacologia , Queratinócitos/metabolismo , Sais de Tetrazólio , Tiazóis , Testes de Toxicidade
13.
Neurosci Lett ; 505(3): 268-72, 2011 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-22040668

RESUMO

The etiology of neurodegenerative disorders like Parkinson's disease remains unknown, although many genetic and environmental factors are suggested as likely causes. Neuronal oxidative stress and mitochondrial dysfunction have been implicated as possible triggers for the onset and progression of Parkinson's neurodegeneration. We have recently shown that long-term treadmill exercise prevented neurological, mitochondrial and locomotor deficits in a chronic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and probenecid-induced mouse model of Parkinson's disease that was originally established in our laboratory. In the present study, we further demonstrated that long-term exercise attenuated both cytochrome c release and elevated levels of p53, which are known to be associated with mitochondrial dysfunction in the striatum of this chronic model. On the other hand, the expressions of mitochondrial transcription factor A and peroxisome proliferator-activated receptor gamma coactivator 1α were unexpectedly upregulated in the striatum of this chronic model, but long-term exercise training brought their levels down closer to normal. Our findings suggest that maintaining normal mitochondrial function is essential for preventing the process of Parkinson's disease-like neurodegeneration, whereas stimulating the mitochondrial transcription factors for biogenesis is not obligatory.


Assuntos
Corpo Estriado/metabolismo , Intoxicação por MPTP/patologia , Intoxicação por MPTP/reabilitação , Condicionamento Físico Animal/métodos , Fatores de Transcrição/metabolismo , Adjuvantes Farmacêuticos/toxicidade , Análise de Variância , Animais , Doença Crônica , Corpo Estriado/patologia , Citocromos c/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Modelos Animais de Doenças , Teste de Esforço , Proteínas de Grupo de Alta Mobilidade/genética , Proteínas de Grupo de Alta Mobilidade/metabolismo , Intoxicação por MPTP/induzido quimicamente , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo , Probenecid/toxicidade , RNA Mensageiro/metabolismo , Transativadores/genética , Transativadores/metabolismo , Fatores de Transcrição/genética
14.
J Pharm Sci ; 100(8): 3186-3195, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21416467

RESUMO

The objective of this study was to investigate the application of Gelucire44/14 as a novel absorption enhancer in ophthalmic drug delivery system. Six compounds, namely ribavirin, puerarin, mangiferin, berberin hydrochloride, baicalin, and curcumin in the order of increasing lipophilicity were selected as model drugs. The effect of Gelucire44/14 on transcorneal permeation was evaluated across excised rabbit cornea. Ocular irritation and precorneal retention time were assessed. Additionally, aqueous humor pharmacokinetic test was performed by microdialysis. The results indicated that Gelucire44/14, at a concentration of 0.05% or 0.1% (w/v), was found to maximally increase the apparent permeability coefficient by 6.47-, 4.14-, 3.50-, 3.97-, 2.92-, and 1.86-fold for ribavirin, puerarin, mangiferin, berberin hydrochloride, baicalin, and curcumin, respectively (p < 0.05). Moreover, Gelucire44/14 was nonirritant at broad concentrations of 0.025%-0.4% (w/v). Pharmacokinetic tests showed that Gelucire44/14 promoted ocular bioavailability of the compounds as indicated by 5.40-, 4.03-, 3.46-, 3.57-, 2.77-, and 1.77-fold maximal increase in the area under the curve for the drugs aforementioned, respectively (p < 0.01). Therefore, Gelucire44/14 exerted a significant improvement on the permeation of both hydrophilic and lipophilic compounds, especially hydrophilic ones. Hence, Gelucire44/14 can be considered as a safe and effective absorption enhancer for ophthalmic drug delivery system.


Assuntos
Adjuvantes Farmacêuticos/farmacocinética , Córnea/metabolismo , Preparações Farmacêuticas , Polietilenoglicóis/farmacocinética , Absorção , Adjuvantes Farmacêuticos/química , Adjuvantes Farmacêuticos/farmacologia , Adjuvantes Farmacêuticos/toxicidade , Animais , Humor Aquoso/metabolismo , Disponibilidade Biológica , Cromatografia Líquida de Alta Pressão , Córnea/efeitos dos fármacos , Córnea/patologia , Sistemas de Liberação de Medicamentos , Interações Hidrofóbicas e Hidrofílicas , Instilação de Medicamentos , Microdiálise , Permeabilidade , Preparações Farmacêuticas/administração & dosagem , Preparações Farmacêuticas/química , Polietilenoglicóis/química , Polietilenoglicóis/farmacologia , Polietilenoglicóis/toxicidade , Coelhos , Solubilidade , Fatores de Tempo
15.
J Toxicol Environ Health A ; 72(15-16): 930-6, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-19672761

RESUMO

The aerial spray program for the eradication of coca in Colombia uses Glyphos, a local formulation of glyphosate tank-mixed with an adjuvant product, Cosmo-Flux. There are some potential risks to amphibians from direct overspraying of shallow waters. In order to evaluate potential alternative mixtures, a field experiment was conducted at the Center of National Training of Police Operations in Tolima province, Colombia. Plants of coca were established with irrigation and grown to 75 cm tall. A randomized split-plot design experiment was laid out and sprayed with a range of glyphosate formulations and different adjuvants using an experimental ground sprayer. Assessments were made of plant vigor, height, and above-ground standing crop (fresh weight) 3 wk after application. Resprouting of plants was assessed at 9 wk after treatment. Unformulated glyphosate applied as the product Rodeo gave poorer control of coca than two formulated products, Roundup Biactive (from Europe) and Colombian Glyphos. In general, these products performed well without added adjuvants, giving control similar to that of the eradication mixture with Cosmo-Flux. There was some evidence that addition of the adjuvant Silwet L-77 and to a lesser extent Mixture B (from the United Kingdom) gave more rapid herbicide symptoms. There were also indications that glyphosate rates of less than 3.69 kg acid equivalents (a.e.)/ha could give control in the range of 95%. Depending on the environmental risk requirements, the experiment indicates that, should other spray mixtures be required, there are potential alternatives. These would require extensive field testing to cover different environmental conditions, different coca varieties, and particularly aerial application, prior to a recommendation. Should the glyphosate product require changing, Roundup Biactive may be considered. Should the adjuvant require changing, then on the basis of this research, Silwet L-77 and Mixture B would be good candidates for further evaluation.


Assuntos
Coca/efeitos dos fármacos , Desfolhantes Químicos/toxicidade , Controle de Medicamentos e Entorpecentes/métodos , Glicina/análogos & derivados , Poluentes Químicos da Água/toxicidade , Adjuvantes Farmacêuticos/toxicidade , Aeronaves , Coca/crescimento & desenvolvimento , Colômbia , Composição de Medicamentos/métodos , Exposição Ambiental/efeitos adversos , Glicina/toxicidade , Compostos de Organossilício/toxicidade , Tensoativos/toxicidade , Glifosato
16.
J Toxicol Environ Health A ; 72(15-16): 937-48, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-19672762

RESUMO

This study evaluates the cumulative multifactorial physical and chemical impacts resulting from coca production on amphibian populations in comparison with the potential impacts produced by the herbicide glyphosate (Glyphos), which, mixed with the surfactant Cosmo-Flux, is used in the spray control program for illicit crops in Colombia. Using similar worst-case assumptions for exposure, several other pesticides used for coca production, including mancozeb, lambda cyhalothrin, endosulfan, diazinon, malathion, and chlorpyrifos, were up to 10- to 100-fold more toxic to frogs than the Glyphos-Cosmo-Flux mixture. Comparing hazard quotients based on application rates, several of these compounds demonstrated hazards 3-383 times that of formulated glyphosate. Secondary effects, particularly of insecticides, are also a concern, as these agents selectively target the primary food source of amphibians, which may indirectly impact growth and development. Although the potential chemical impacts by other pesticides are considerable, physical activities associated with coca production, particularly deforestation of primary forests for new coca plots, portend the greatest hazard to amphibian populations. The entire production cycle of cocaine has been linked to ecosystem degradation. The clearing of pristine forests for coca propagation in Colombia is well documented, and some of these regions coincide with those that contain exceptional amphibian biodiversity. This is particularly problematic as coca production encroaches more deeply into more remote areas of tropical rain forest. Transportation of disease, including the chitrid fungus, to these remote regions via human intrusion may also adversely affect amphibian populations. Therefore, the cumulative impacts of coca production, through habitat destruction, application of agrochemicals, and potential transmission of disease, are judged to pose greater risks to amphibian populations in coca-growing regions than the glyphosate spray control program.


Assuntos
Coca/crescimento & desenvolvimento , Desfolhantes Químicos/toxicidade , Controle de Medicamentos e Entorpecentes/métodos , Glicina/análogos & derivados , Ranidae , Poluentes Químicos da Água/toxicidade , Adjuvantes Farmacêuticos/toxicidade , Agricultura , Aeronaves , Animais , Colômbia , Relação Dose-Resposta a Droga , Ecossistema , Exposição Ambiental/efeitos adversos , Exposição Ambiental/análise , Monitoramento Ambiental , Glicina/toxicidade , Medição de Risco , Tensoativos/toxicidade , Testes de Toxicidade , Glifosato
17.
J Toxicol Environ Health A ; 72(15-16): 961-5, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-19672764

RESUMO

The spraying of coca (Erythroxylum coca) with glyphosate in Colombia has raised concerns about possible impacts on amphibians. There are few toxicity data for species other than those from temperate regions, and these have not been generated with the combination of formulated glyphosate (Glyphos) and the adjuvant, Cosmo-Flux (coca mix) as used in coca control in Colombia. In order to characterize toxicity of the spray mixture to frogs from Colombia, Gosner stage-25 tadpoles of Scinax ruber, Dendropophus microcephalus, Hypsiboas crepitans, Rhinella granulosa, Rhinella marina, Rhinella typhonius, Centrolene prosoblepon, and Engystomops pustulosus were exposed to the coca mix at concentrations of glyphosate ranging from 1 to 4.2 mg a.e./L diluted in dechlorinated tap water in glass containers. Cosmo-Flux was added to Glyphos in the proportion of 2.3% v/v, as used in aerial application for coca control. Exposures were for 96 h at 23 +/- 1.5 degrees C with 12:12-h light/dark cycle. Test solutions were renewed every 24 h. Concentrations, measured within the first hour and at 24 and 96 h using enzyme-linked immunosorbent assay (ELISA) (Abraxis, LLC), ranged from 70 to 130% of nominal values. LC50 values ranged from 1200 to 2780 microg glyphosate acid equivalents (a.e.)/L for the 8 species tested. Data suggest that sensitivity to Roundup-type formulations of glyphosate in these species is similar to that observed in other tropical and temperate species. In addition, sensitivity of larval amphibians to Roundup-type formulations spans a relatively narrow range. Finally, toxicity of the mixture as used to spray coca was likely driven by the surfactant in the glyphosate formulation, as the addition of Cosmo-Flux did not enhance toxicity above those reported for Vision = Roundup.


Assuntos
Anuros/fisiologia , Desfolhantes Químicos/toxicidade , Controle de Medicamentos e Entorpecentes/métodos , Glicina/análogos & derivados , Poluentes Químicos da Água/toxicidade , Adjuvantes Farmacêuticos/toxicidade , Aeronaves , Animais , Combinação de Medicamentos , Glicina/toxicidade , Larva/efeitos dos fármacos , Larva/fisiologia , Dose Letal Mediana , Especificidade da Espécie , Tensoativos/toxicidade , Testes de Toxicidade Aguda , Glifosato
18.
J Toxicol Environ Health A ; 72(15-16): 966-73, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-19672765

RESUMO

The spraying of coca (Erythroxylum coca) with glyphosate (coca mixture, a combination of formulated glyphosate, Glyphos, and an adjuvant, Cosmo-Flux) in Colombia has raised concerns about possible impacts on amphibians. Although acute LC50 for 8 species of Colombian frogs ranged from 1.2 to 2.78 mg acid equivalents (a.e.)/L, these exposures were conducted in the laboratory in the absence of sediments and organic matter such as would occur under realistic field conditions. In order to assess the effects of overspray of frog habitat under field conditions, Gosner stage 25 tadpoles of Rhinella granulosa, R. marina, Hypsiboas crepitans, and Scinax ruber were placed in outdoor microcosms made from polyethylene plastic fish ponds (2.07 m in diameter, 37 cm high) in an experimental area in Tolima, Colombia. The bottoms of the microcosms were covered with a 3-cm layer of local soil and they were filled to a depth of 15 cm (above the sediment) with local spring water. After up to 100 tadpoles of each frog species were placed in the microcosms, they were sprayed with the coca mixture at concentrations greater and less than the normal application rate (3.69 kg glyphosate a.e./ha). Mortality at 96 h in the control microcosms was between 0 and 16% and LC50 values were between 8.9 and 10.9 kg glyphosate a.e./ha (equivalent to initial concentrations of 5963 to 7303 microg glyphosate a.e./L). Mortality >LC50 was only observed in the tested species when the application rate was >2-fold the normal application rate. In other experiments, juvenile and adult terrestrial stages of frogs were exposed by direct spraying to a range of concentrations of coca mixture. Juveniles and adults were exposed in plastic food containers (19 x 19 cm). The bottom of the container was filled with moistened soil and leaf litter to a depth of 1 cm and 0.5 cm, respectively. Mortality in the controls was low, from 0 to 10%, and from 0 to 35% at the normal application rate. LC50 values ranged between 4.5 kg a.e./ha and 22.8 kg a.e./ha, 1.5- to 6-fold greater than the normal application rate. Data indicate that, under realistic worst-case exposure conditions, the mixture of Glyphos and Cosmo-Flux as used for control of coca in Colombia exerts a low toxicity to aquatic and terrestrial stages of anurans and that risks to these organisms under field conditions are small.


Assuntos
Anuros/fisiologia , Desfolhantes Químicos/toxicidade , Controle de Medicamentos e Entorpecentes/métodos , Glicina/análogos & derivados , Poluentes Químicos da Água/toxicidade , Adjuvantes Farmacêuticos/análise , Adjuvantes Farmacêuticos/toxicidade , Aeronaves , Animais , Desfolhantes Químicos/análise , Combinação de Medicamentos , Sedimentos Geológicos/química , Glicina/análise , Glicina/toxicidade , Larva/efeitos dos fármacos , Larva/fisiologia , Dose Letal Mediana , Modelos Biológicos , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , Medição de Risco , Especificidade da Espécie , Tensoativos/análise , Tensoativos/toxicidade , Testes de Toxicidade Aguda , Poluentes Químicos da Água/análise , Glifosato
19.
J Toxicol Environ Health A ; 72(15-16): 974-85, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-19672766

RESUMO

The Colombian amphibian fauna is among the richest known in the world, with about 20 species of salamanders (order Caudata), 35 of the limbless caecilians (order Gymnophiona), and more than 700 species of frogs and toads (order Anura) recorded from localities within the country. The potential effects of exposure to glyphosate on amphibians arising from production of illegal crops (coca) were examined. The analysis was based on (1) behavior and ecology of species and (2) proximities of actual museum records to localities in which illegal crops are being grown and the subset of those that have been sprayed with glyphosate. Based on data on the location of amphibians collected in Colombia, records were obtained for 193 species (28% of the national diversity) of frogs and toads found in localities within 10 km of areas where coca is grown. Further analyses with ARC MAP software allowed for measurement of the direct distance separating collection locations for frogs, known coca fields, and areas where aerial spraying was being conducted. Records in or near coca fields included data for 11 of 13 families of frogs and toads known to be present in Colombia. Only Ceratophryidae and Pipidae were not reported from these locations and appear not to be at risk. For eight species (Dendrobates truncatus, Craugastor raniformis, Pristimantis gaigeae, Smilisca phaeota, Elachistocleis ovale, Hypsiboas crepitans, Trachycephalus venulosus, and Pseudis paradoxa) selected to represent several habitat preferences and life-cycle strategies, large areas of their distributions lie outside coca production regions and their populations as a whole are at low risk. For a limited number of species that barely enter Colombian territory, the consequences of coca production may be more serious and may have placed several species of frogs at risk. These include Ameerega bilingua, Dendropsophus bifurcus, Pristimantis colomai, P. degener, P. diadematus, P. quaquaversus, P. variabilis, and Trachycephalus jordani. Other species may also be at risk but exact numbers are unknown since few investigations were undertaken in these areas during the past 30 yr. The main ranges for these species were assumed to be in Ecuador.


Assuntos
Agricultura , Anuros/fisiologia , Desfolhantes Químicos/toxicidade , Controle de Medicamentos e Entorpecentes/métodos , Poluentes Ambientais/toxicidade , Glicina/análogos & derivados , Adjuvantes Farmacêuticos/análise , Adjuvantes Farmacêuticos/toxicidade , Aeronaves , Animais , Colômbia , Desfolhantes Químicos/análise , Combinação de Medicamentos , Ecossistema , Monitoramento Ambiental , Poluentes Ambientais/análise , Glicina/análise , Glicina/toxicidade , Estágios do Ciclo de Vida/efeitos dos fármacos , Estágios do Ciclo de Vida/fisiologia , Medição de Risco , Tensoativos/análise , Tensoativos/toxicidade , Glifosato
20.
Farm. hosp ; 33(2): 89-95, mar.-abr. 2009. tab
Artigo em Espanhol | IBECS | ID: ibc-105282

RESUMO

Introducción: Desde la publicación de los resultados del estudio MOSAIC en 2004, el esquema FOLFOX4 se ha establecido como un tratamiento adyuvante recomendado en los cánceres colorrectales estadio III. El objetivo de este estudio es valorar la utilización de este esquema en nuestro ámbito y describir su toxicidad. Métodos: Estudio descriptivo de los tratamientos con FOLFOX4 prescritos desde abril de 2005 a marzo de 2007. Los datos se obtuvieron del programa Farhos Oncología® y las historias clínicas. Se recogieron las variables siguientes: edad, sexo, diagnóstico, estadio de la enfermedad (clasificación TNM) y reacciones adversas, expresando su gravedad según los Common Toxicity Criteria 2.0. Resultados: El esquema FOLFOX4 ha sido prescrito a 39 pacientes (24 varones y 15 mujeres), con una mediana de edad de 59 años. Los diagnósticos fueron: 28 cáncer de colon (4 estadio II, 17 III y 7 IV), 10 cáncer de recto (1 estadio II, 4 III y 5 IV) y 1 cáncer gástrico estadio IV. Las reacciones adversas más frecuentes fueron neuropatía periférica (82 %), neutropenia (56,4 %) y diarrea (53,9 %). Al finalizar el estudio 9 pacientes seguían en tratamiento activo con este esquema (media, 6,8 ciclos). De los 30 restantes, sólo 16 completaron los 12 ciclos previstos. En 14 pacientes se suspendió el tratamiento (media, 8,1 ciclos), siendo los motivos: toxicidad en 10 casos, progresión clínica en 3 y fallecimiento en 1. Del total de los 368 ciclos administrados, 68 tuvieron retrasos en la administración y en 22 se redujo la dosis. Conclusión: La utilización del esquema FOLFOX4 se ha ajustado a usos con unas evidencias científicas sólidas, pero su toxicidad ha limitado el uso y dificultado la administración de la intensidad de dosis prevista (AU)


Introduction: Since the publication of the MOSAIC test results in 2004, the FOLFOX4 regimen has been established as an adjuvant treatment which is recommended in stage III colorectal cancer. The aim of this study is to assess the use of this regimen in our field and to describe its toxicity. Methods: Descriptive study of treatments with FOLFOX4 prescribed between April 2005 and March 2007. The data was obtained from the Farhos Oncología® programme and clinical records. The following data was collected: age, gender, diagnosis, stage of the illness (TNM classification) and adverse reactions, expressing severity according to Common Toxicity Criteria 2.0. Results: The FOLFOX4 regimen was prescribed for 39 patients (24 men and 15 women) with an average age of 59. The diagnoses were: 28 colon cancer (4 stage II, 17 stage III, and 7 stage IV), 10 rectal cancer (1 stage II, 4 stage III, and 5 stage IV) and 1 stage IV gastric cancer. The most frequent adverse reactions were peripheral neuropathy (82 %), neutropenia (56.4 %) and diarrhoea (53.9 %.) When the study was completed, 9 patients continued active treatment with the regimen (average 6.8 cycles.) Of the 30 remaining patients only 16 people completed the 12 planned cycles. 14 patients stopped their treatment (an average of 8.1 cycles) due to toxicity in 10 cases, clinical progression in 3 cases and one patient died. Of the total 368 cycles administered, 68 suffered administration delays and 22 had the dosage reduced. Conclusion: The use of the FOLFOX4 regimen has been adjusted to uses with some solid scientific evidence, but its toxicity has limited its use and has made administering the planned dosage levels difficult (AU)


Assuntos
Humanos , Neoplasias Colorretais/tratamento farmacológico , Antineoplásicos/toxicidade , /diagnóstico , Esquema de Medicação , Quimioterapia Adjuvante , Adjuvantes Farmacêuticos/toxicidade
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