RESUMEN
AIM: Nitric oxide (NO) prevents the decline of RBC deformability under high altitude and other ischemic and hypoxic conditions, but the clear mechanisms remain unknown. Here, we have carried out a systematic study to find the mechanisms of NO-induced regulation of RBC deformability under hypoxia. METHODS: NO levels, RBCs membrane elongation index (EI), membrane protein band 3 methemoglobin (MetHb) were determined during hypoxia (0 to 120 minutes). To validate the role of NO in regulating RBC deformability, tests were also performed with a NO donor (sodium nitroprusside) or a NO synthase inhibitor (l-nitro-arginine methylester) under 60 minutes hypoxia. RESULTS: Hypoxia for 45 minutes increased NO levels from 25.65 ± 1.95 to 35.26 ± 2.01 µmol/L, and there was a plateau after 60 minutes hypoxia. The EI did not change before 45 minutes hypoxia, but decreased from 0.567 ± 0.019 to 0.409 ± 0.042 (30 Pa) after 60 minutes hypoxia. The cross-linking of band 3 and phosphotyrosine increased after 45 minutes hypoxia. All can be alleviated by supplement NO and aggregated by inhibiting NOS. However, the MetHb was not present this trend. CONCLUSION: NO may prevent decreased of RBCs deformability through reducing the cross-linking of membrane band 3 under hypoxia; this helps microvascular perfusion of RBCs during ischemic and hypoxic disease states.
Asunto(s)
Proteína 1 de Intercambio de Anión de Eritrocito/metabolismo , Hipoxia de la Célula , Deformación Eritrocítica/fisiología , Eritrocitos/fisiología , Óxido Nítrico/metabolismo , Adulto , Inhibidores Enzimáticos/farmacología , Voluntarios Sanos , Humanos , Peroxidación de Lípido , Lípidos de la Membrana/metabolismo , Metahemoglobina/metabolismo , NG-Nitroarginina Metil Éster/farmacología , Donantes de Óxido Nítrico/farmacología , Nitroprusiato/farmacología , Fosfotirosina/metabolismo , Proteína Tirosina Fosfatasa no Receptora Tipo 11/metabolismo , Quinasa Syk/metabolismoRESUMEN
Several studies reported that bisphenol A (BPA) and its metabolite hydroquinone (HQ) have adverse effects on human and animal health. In this work, a comparative study of influence of the BPA and HQ, environment pollutants, on human erythrocytes was carried out. It was shown that BPA and HQ to varying extents caused oxidative damage in human erythrocytes: hemolysis, decreased GSH level, and methemoglobin formation. It was demonstrated that hydrolysable tannins 3,6-bis-O-di-O-galloyl-1,2,4-tri-O-galloyl-ß-D-glucose (C55H40O34) and 1,2,3,4,6-penta-O-galloyl-ß-D-glucose (C41H32O26) (PGG) isolated from the Rhus typhina L. leaves in the range of 1-50 µM concentrations inhibited hemolysis and methemoglobin formation and also increased intracellular reduced glutathione in erythrocytes treated with BPA or HQ. It was revealed by electron paramagnetic resonance (EPR) using 5-doxyl-stearic acid (5-DS) that C55H40O34 and C41H32O26 increased the rigidity of erythrocyte membranes at the depth of 5th carbon atom of the fatty acid hydrocarbon chain. Taken together, these results allow to conclude that tannins from the Rhus typhina L. leaves protect erythrocytes from oxidative stress caused by BPA or HQ both due to their antioxidant activity as well as their interaction with the erythrocyte membrane components.
Asunto(s)
Compuestos de Bencidrilo/toxicidad , Eritrocitos/efectos de los fármacos , Hidroquinonas/toxicidad , Fenoles/toxicidad , Extractos Vegetales/farmacología , Sustancias Protectoras/farmacología , Rhus/química , Taninos/farmacología , Muerte Celular , Eritrocitos/metabolismo , Glutatión/metabolismo , Hemólisis/efectos de los fármacos , Humanos , Metahemoglobina/metabolismo , Estrés Oxidativo/efectos de los fármacos , Hojas de la Planta/químicaRESUMEN
Insufficient nitric oxide (NO) bioavailability plays an important role in endothelial dysfunction and arterial stiffening with aging. Supplementation with sodium nitrite, a precursor of NO, ameliorates age-related vascular endothelial dysfunction and arterial stiffness in mice, but effects on humans, including the metabolic pathways altered, are unknown. The purpose of this study was to determine the safety, feasibility, and efficacy of oral sodium nitrite supplementation for improving vascular function in middle-aged and older adults and to identify related circulating metabolites. Ten weeks of sodium nitrite (80 or 160 mg/day, capsules, TheraVasc; randomized, placebo control, double blind) increased plasma nitrite acutely (5- to 15-fold, P < 0.001 vs. placebo) and chronically (P < 0.10) and was well tolerated without symptomatic hypotension or clinically relevant elevations in blood methemoglobin. Endothelial function, measured by brachial artery flow-mediated dilation, increased 45-60% vs. baseline (P < 0.10) without changes in body mass or blood lipids. Measures of carotid artery elasticity (ultrasound and applanation tonometry) improved (decreased ß-stiffness index, increased cross-sectional compliance, P < 0.05) without changes in brachial or carotid artery blood pressure. Aortic pulse wave velocity was unchanged. Nitrite-induced changes in vascular measures were significantly related to 11 plasma metabolites identified by untargeted analysis. Baseline abundance of multiple metabolites, including glycerophospholipids and fatty acyls, predicted vascular changes with nitrite. This study provides evidence that sodium nitrite supplementation is well tolerated, increases plasma nitrite concentrations, improves endothelial function, and lessens carotid artery stiffening in middle-aged and older adults, perhaps by altering multiple metabolic pathways, thereby warranting a larger clinical trial.
Asunto(s)
Envejecimiento/efectos de los fármacos , Aorta/efectos de los fármacos , Arterias Carótidas/efectos de los fármacos , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/metabolismo , Nitrito de Sodio/farmacología , Anciano , Envejecimiento/metabolismo , Aorta/metabolismo , Presión Sanguínea/efectos de los fármacos , Índice de Masa Corporal , Arteria Braquial/efectos de los fármacos , Arteria Braquial/metabolismo , Arterias Carótidas/metabolismo , Suplementos Dietéticos , Método Doble Ciego , Elasticidad/efectos de los fármacos , Femenino , Humanos , Masculino , Metahemoglobina/metabolismo , Persona de Mediana Edad , Óxido Nítrico/metabolismo , Análisis de la Onda del Pulso/métodos , Rigidez Vascular/efectos de los fármacos , Vasodilatación/efectos de los fármacosRESUMEN
A slow-release form of nitrate (encapsulated nitrate [EN]) was investigated for effects on risk of toxicity, feed consumption rates, and feed sorting behavior in 2 experiments. In Exp. 1, 5 beef heifers (806 ± 72 kg BW) were fed once daily at 75% of ad libitum intake. Supplementary EN (85.6% DM; 71.4% NO3(-) on a DM basis) was increased by 1% every 4 d from 0 to 1.0, 2.0, 2.9, 3.9, 4.8, and 5.8% of dietary DM (from 10.3 to 15.6% CP and 0.11 to 4.8% total NO3(-)). During the study, a heifer was removed due to nitrate poisoning with 59% blood methemoglobin (MetHb; % of total hemoglobin) at 2.9% EN and another due to refusal to eat the 2% EN diet. When dietary EN increased from 0 to 5.8%, DMI (8.8 to 7.6 kg/d; P < 0.001) and feed consumption from 0 to 3 h were decreased (70.3 to 48.6% of total feed offered on an as-is basis; P = 0.001) and feed consumption from 12 to 24 h was increased (0.6 to 22.6%; P < 0.001). Blood MetHb at 1% EN was negligible (<1.5% of total hemoglobin). However, MetHb levels were greater (average 9.8 vs. 3.1% and maximum 23.6 vs. 13.6% at 3 h) at 2.0 and 2.9% EN than at 3.9, 4.8, and 5.8% EN. In Exp. 2, 8 beef heifers (451 ± 21 kg BW) were used in a replicated 4 × 4 Latin square design and fed for ad libitum intake, once daily, diets containing 0, 1, 2, and 3% EN (isonitrogenous, 12.7% CP, and 0.15 to 2.5% total NO3(-) in dietary DM). Each period consisted of 14 d for adaption and 14 d for sampling followed by a 7-d washout. During adaptation, EN was provided to heifers in a stepwise manner (an increase by 1% every 4 d). In Exp. 2 with ad libitum feeding, feed consumption rates were not different (41.8% of total feed consumed from 0 to 3 h; P = 0.56) among EN levels, but DMI tended to decrease linearly (0 to 3% EN; 10.4 to 10.1 kg/d; P = 0.06) and feed was sorted (linear, P < 0.05) against concentrates (containing EN) with EN inclusion. Potential toxicity of nitrate based on blood MetHb was not observed (all samples <2.0% of total hemoglobin). In both studies, ruminal pH increased numerically (Exp. 1) and significantly (Exp. 2; linear, P = 0.04) with EN. In conclusion, studies indicated that the organoleptic properties of diets containing >3% EN may have caused lower feed intake, reduced feed consumption rates, and feed sorting. In addition, feed consumption rate, which was altered by restrictive or ad libitum feeding, was an important factor affecting the potential toxicity of nitrate (e.g., MetHb). Ad libitum feeding minimized risks of nitrate toxicity.
Asunto(s)
Bovinos/metabolismo , Conducta Alimentaria/efectos de los fármacos , Fermentación/efectos de los fármacos , Metahemoglobina/metabolismo , Nitratos/farmacología , Rumen/metabolismo , Alimentación Animal , Animales , Cápsulas , Dieta/veterinaria , Suplementos Dietéticos , Relación Dosis-Respuesta a Droga , Ingestión de Alimentos/efectos de los fármacos , Ingestión de Alimentos/fisiología , Conducta Alimentaria/fisiología , Femenino , Fermentación/fisiología , Concentración de Iones de Hidrógeno , Nitratos/administración & dosificación , Rumen/efectos de los fármacos , Factores de TiempoRESUMEN
Methemoglobinemia is a relatively rare, but potentially life-threating medical condition, which may be induced by application of topical anaesthetic agents commonly used during endoscopic procedure. The aim of our study was to assess the influence of lidocaine used prior to transesophageal echocardiography (TEE) on the blood level of methemoglobin in vivo. Additionally we attempted to establish the occurrence rate of clinically evident lidocaine-induced methemoglobinemia on the basis of data collected in our institution. We retrospectively analyzed patient records from 3,354 TEEs performed in our echocardiographic laboratory over the course of 13 years in search for clinically evident methemoglobinemia cases. Additionally, 18 consecutive patients referred for TEE were included in the prospective part of our analysis. Blood samples were tested before and 60 min after pre-TEE lidocaine anesthesia application. Information concerning concomitant conditions and pharmacotherapy were also obtained. In 3,354 patients who underwent TEE in our institution no cases of clinically evident methemoglobinemia occurred. In the prospective part of the study, none of 18 patients [16 (89 %) men, mean age 63 ± 13] was diagnosed with either clinical symptoms of methemoglobinemia or exceeded normal blood concentration of methemoglobin. Initial mean methemoglobin level was 0.5 ± 0.1 % with mild, statistically (but not clinically) significant rise to 0.6 ± 0.1 % after 60 min (p = 0.02). Among the analyzed factors only the relation between the proton pump inhibitors intake and methemoglobin blood level rise was identified as statistically relevant (p = 0.03). In adults, pre-TEE lidocaine anesthesia with recommended dosage results in significant increase in methemoglobin blood level, which however does not exceed normal values and does not result in clinically evident methemoglobinemia.
Asunto(s)
Anestesia Local/efectos adversos , Anestésicos Locales/efectos adversos , Ecocardiografía Transesofágica , Lidocaína/efectos adversos , Metahemoglobina/metabolismo , Metahemoglobinemia/inducido químicamente , Administración Cutánea , Anciano , Anestésicos Locales/administración & dosificación , Biomarcadores/sangre , Femenino , Humanos , Lidocaína/administración & dosificación , Masculino , Metahemoglobinemia/sangre , Metahemoglobinemia/diagnóstico , Persona de Mediana Edad , Estudios Prospectivos , Estudios Retrospectivos , Factores de RiesgoRESUMEN
Methemoglobin (MetHb) is a form of hemoglobin in which heme iron is oxidized and unable to bind oxygen; its normal basal production is counteracted by an efficient MetHb-reduction pathway. The causes of methemoglobinemia are classified as congenital or acquired. Shortly after his birth, the 5-hour-old male Caucasian neonate, whose case we present herein, developed central cyanosis that was unresponsive to supplemental oxygen. Oxygen saturation as determined via pulse oximetry was normal. In contrast, blood gas testing by multiwave CO-oximetry indicated decreased fractional oxyhemoglobin and an elevated MetHb fraction. The patient was subsequently diagnosed with a congenital cytochrome b5 reductase deficiency. This case emphasizes causes of methemoglobinemia and differences among analytical methods used to measure oxygen status when MetHb is present.
Asunto(s)
Cianosis/sangre , Cianosis/etiología , Metahemoglobinemia/complicaciones , Análisis de los Gases de la Sangre , Humanos , Recién Nacido , Masculino , Metahemoglobina/metabolismoRESUMEN
The aim of this study was to evaluate the effects of a high-fat diet (HFD) on oxidative indexes in WistarOttawaKarlsburg W (WOKW) rats used as a model of metabolic syndrome in comparison with Dark Agouti (DA) rats used as a control strain. This syndrome is defined by the occurrence of two or more risk factors including obesity, hypertension, dyslipidemia, and insulin resistance. Forty rats were used in the study and the effect of HFD was evaluated in terms of body weight and both hemoglobin and CoQ oxidative status. Moreover, 16 rats (8 of each strain) were supplemented with 3 mg/100 g b.w. of CoQ10 for 1 month in view of its beneficial properties in cardiovascular disease due to its antioxidant activity in the lipid environment. HFD promoted an increase in body weight, in particular in WOKW males, and in the methemoglobin (met-Hb) index in both strains. Moreover, HFD promoted endogenous CoQ10 oxidation. CoQ10 supplementation was able to efficiently counteract the HFD pro-oxidant effects, preventing met-Hb formation and CoQ oxidation.
Asunto(s)
Antioxidantes/administración & dosificación , Grasas de la Dieta/efectos adversos , Suplementos Dietéticos , Síndrome Metabólico/dietoterapia , Síndrome Metabólico/etiología , Ubiquinona/análogos & derivados , Animales , Antioxidantes/metabolismo , Peso Corporal/efectos de los fármacos , Dieta Alta en Grasa , Susceptibilidad a Enfermedades , Femenino , Masculino , Síndrome Metabólico/sangre , Síndrome Metabólico/patología , Metahemoglobina/antagonistas & inhibidores , Metahemoglobina/metabolismo , Oxidación-Reducción , Estrés Oxidativo , Ratas , Especificidad de la Especie , Resultado del Tratamiento , Ubiquinona/administración & dosificación , Ubiquinona/sangreRESUMEN
BACKGROUND: Toxin-induced methemoglobinemia is seen in poisoning with oxidizing agents. We report the clinical features and outcome of patients admitted with severe methemoglobinemia due to intentional ingestion of toxicants. METHODS: In this observational case series, patients admitted with toxin-induced methemoglobinemia between September 2011 and January 2014 were identified from the institutional poisoning database. Clinical profile and outcome of patients with methemoglobin concentration greater than or equal to 49% is reported. RESULTS: Of the 824 patients admitted with poisoning, 5 patients with methemoglobin concentration greater than or equal to 49% were included. The implicated compounds were nitrobenzene, benzoylphenylurea, flubendamide and Rishab(TM). One patient refused to name the compound. All patients were managed in the intensive care unit. Altered sensorium [Glasgow coma scale (GCS) < 10] was common (80%); 2 patients presented with a GCS greater than 4. All patients manifested cyanosis, low oxygen saturation and chocolate-brown-colored blood despite supplemental oxygen therapy. The median methemoglobin concentration was 64.7% (range 49.8-91.6%); 2 patients had methemoglobin concentration greater than 70%. One patient needed inotropes. Four patients required mechanical ventilation for 4-14 days. All patients were treated with methylene blue; 4 received more than one dose. Three patients also received intravenous ascorbic acid 500 mg, once daily, for 3 days. Following treatment, there was evidence of haemolysis in all patients; 2 required blood transfusion. All patients survived. CONCLUSION: Patients with severe toxin-induced methemoglobinemia present with altered sensorium and cyanosis and may require ventilatory support and inotropes. Though methemoglobin concentrations greater than 70% are considered fatal, aggressive management with methylene blue and supportive therapy can lead to survival.
Asunto(s)
Metahemoglobinemia/diagnóstico , Venenos/toxicidad , Administración Oral , Adulto , Cianosis/inducido químicamente , Cianosis/diagnóstico , Cianosis/tratamiento farmacológico , Humanos , Metahemoglobina/metabolismo , Metahemoglobinemia/inducido químicamente , Metahemoglobinemia/tratamiento farmacológico , Azul de Metileno/uso terapéutico , Persona de Mediana Edad , Nitrobencenos/toxicidad , Adulto JovenRESUMEN
Hydrogen sulphide (H2S), a chemical hazard in oil and gas production, has recently become a dreadful method of suicide, posing specific risks and challenges for the first responders. Currently, there is no proven effective treatment against H2S poisoning and its severe neurological, respiratory or cardiac after-effects. We have recently described that H2S is present in various compartments, or pools, in the body during sulphide exposure, which have different levels of toxicity. The general goals of our study were to (1) determine the concentrations and kinetics of the various pools of hydrogen sulphide in the blood, i.e., gaseous (CgH2S) versus total sulphide, i.e., reacting with monobromobimane (CMBBH2S), during and following H2S exposure in a small and large mammal and (2) establish the interaction between the pools of H2S and a methemoglobin (MetHb) solution or a high dose of hydroxocobalamin (HyCo). We found that CgH2S during and following H2S infusion was similar in sedated sheep and rats at any given rate of infusion/kg and provoked symptoms, i.e., hyperpnea and apnea, at the same CgH2S. After H2S administration was stopped, CgH2S disappeared within 1 min. CMBBH2S also dropped to 2-3µM, but remained above baseline levels for at least 30 min. Infusion of a MetHb solution during H2S infusion produced an immediate reduction in the free/soluble pool of H2S only, whereas CMBBH2S increased by severalfold. HyCo (70 mg/kg) also decreased the concentrations of free/soluble H2S to almost zero; CgH2S returned to pre-HyCo levels within a maximum of 20 min, if H2S infusion is maintained. These results are discussed in the context of a relevant scenario, wherein antidotes can only be administered after H2S exposure.
Asunto(s)
Antídotos/administración & dosificación , Sulfuro de Hidrógeno/toxicidad , Hidroxocobalamina/administración & dosificación , Metahemoglobina/administración & dosificación , Intoxicación/sangre , Intoxicación/tratamiento farmacológico , Sulfuros/toxicidad , Animales , Femenino , Gases , Sulfuro de Hidrógeno/sangre , Sulfuro de Hidrógeno/farmacocinética , Hidroxocobalamina/sangre , Masculino , Metahemoglobina/metabolismo , Intoxicación/etiología , Ratas Sprague-Dawley , Ovinos , Sulfuros/sangre , Sulfuros/farmacocinéticaRESUMEN
N1-Benzylated dihydroquinolin-6-ols and their corresponding esters display exceptional activity against African trypanosomes in vitro, and administration of members of this class of compounds to trypanosome-infected mice results in cures in a first-stage African trypanosomiasis model. Since a quinone imine intermediate has been implicated in the antiparasitic mechanism of action of these compounds, evaluation of the hepatotoxic, mutagenic, and methemoglobin-promoting effects of these agents was performed. 1-Benzyl-1,2-dihydro-2,2,4-trimethylquinolin-6-ol hydrochloride and 1-benzyl-1,2-dihydro-2,2,4-trimethylquinolin-6-yl acetate showed outstanding in vitro selectivity for Trypanosoma brucei compared to the HepG2, Hep3B, Huh7, and PLC5 hepatocyte cell lines. 1-Benzyl-1,2-dihydro-2,2,4-trimethylquinolin-6-ol hydrochloride and 1-(2-methoxybenzyl)-1,2-dihydro-2,2,4-trimethylquinolin-6-yl acetate were not mutagenic when screened in the Ames assay, with or without metabolic activation. The latter 2 compounds promoted time- and dose-dependent formation of methemoglobin when incubated in whole human blood, but such levels were below those typically required to produce symptoms of methemoglobinemia in humans. Although compounds capable of quinone imine formation require careful evaluation, these in vitro studies indicate that antitrypanosomal dihydroquinolines merit further study as drug candidates against the neglected tropical disease human African trypanosomiasis.
Asunto(s)
Acetatos/efectos adversos , Drogas en Investigación/efectos adversos , Hepatocitos/efectos de los fármacos , Metahemoglobina/metabolismo , Quinolinas/efectos adversos , Compuestos de Quinolinio/efectos adversos , Tripanocidas/efectos adversos , Acetatos/metabolismo , Acetatos/farmacología , Activación Metabólica , Animales , Línea Celular , Supervivencia Celular/efectos de los fármacos , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Drogas en Investigación/síntesis química , Drogas en Investigación/metabolismo , Drogas en Investigación/farmacología , Hemoglobinas/química , Hemoglobinas/metabolismo , Hepatocitos/enzimología , Hepatocitos/metabolismo , Humanos , Concentración 50 Inhibidora , Cinética , Metahemoglobina/química , Pruebas de Mutagenicidad , Oxidación-Reducción , Quinolinas/síntesis química , Quinolinas/metabolismo , Quinolinas/farmacología , Compuestos de Quinolinio/metabolismo , Compuestos de Quinolinio/farmacología , Ratas , Tripanocidas/síntesis química , Tripanocidas/metabolismo , Tripanocidas/farmacología , Trypanosoma brucei brucei/efectos de los fármacos , Trypanosoma brucei brucei/crecimiento & desarrolloAsunto(s)
Anestésicos Locales/efectos adversos , Manejo de la Enfermedad , Metahemoglobina/metabolismo , Metahemoglobinemia/terapia , Dolor Postoperatorio/terapia , Guías de Práctica Clínica como Asunto , Anestesia Local/efectos adversos , Femenino , Humanos , Metahemoglobinemia/sangre , Metahemoglobinemia/inducido químicamente , Persona de Mediana EdadRESUMEN
The anticancer agent 3-aminopyridine-2-carboxaldehyde thiosemicarbazone is a ribonucleotide reductase inhibitor. It inactivates ribonucleotide reductase by disrupting an iron-stabilized radical in ribonucleotide reductase's small subunits, M2 and M2b (p53R2). Unfortunately, 3-aminopyridine-2-carboxaldehyde thiosemicarbazone also alters iron II (Fe(2+)) in hemoglobin. This creates Fe(3+) methemoglobin that does not deliver oxygen. Fe(2+) in hemoglobin normally auto-oxidizes to inactive Fe(3+) methemoglobin at a rate of nearly 3% per day and this is counterbalanced by a reductase system that normally limits methemoglobin concentrations to less than 1% of hemoglobin. This balance may be perturbed by symptomatic toxicity levels during 3-aminopyridine-2-carboxaldehyde thiosemicarbazone therapy. Indications of 3-aminopyridine-2-carboxaldehyde thiosemicarbazone sequelae attributable to methemoglobinemia include resting dyspnea, headaches and altered cognition. Management of methemoglobinemia includes supplemental oxygen, ascorbate and, most importantly, intravenously administered methylene blue as a therapeutic antidote.
Asunto(s)
Antídotos/uso terapéutico , Antineoplásicos/efectos adversos , Inhibidores Enzimáticos/efectos adversos , Metahemoglobinemia/tratamiento farmacológico , Azul de Metileno/uso terapéutico , Piridinas/efectos adversos , Ribonucleótido Reductasas/antagonistas & inhibidores , Tiosemicarbazonas/efectos adversos , Antineoplásicos/farmacocinética , Inhibidores Enzimáticos/farmacocinética , Hemoglobinas/metabolismo , Humanos , Metahemoglobina/metabolismo , Metahemoglobinemia/inducido químicamente , Metahemoglobinemia/diagnóstico , Piridinas/farmacocinética , Tiosemicarbazonas/farmacocinéticaRESUMEN
BACKGROUND: Recently, nitrite has been rediscovered as a physiologically relevant storage reservoir of nitric oxide in blood and it can readily be converted to nitric oxide under hypoxic and acidic conditions. In this study, the authors evaluated the therapeutic efficacy of nitrite on reperfusion-induced microcirculatory alterations and mitochondrial dysfunction in the microvasculature of skeletal muscle. METHODS: The authors used a vascular pedicle isolated rat cremaster model that underwent 4 hours of warm ischemia followed by 2 hours or 17 hours of reperfusion. At 5 minutes before reperfusion, normal saline, sodium nitrite (0.20 µM/minute/kg), or nitrite mixed with 2-(4-carboxyphenyl)-4,5-dihydro-4,4,5,5-tetramethylimidazoline-3-oxide-1-oxyl (potassium salt) (0.2 mg/minute/kg) was infused into the microcirculation of ischemic cremaster by means of intraarterial infusion. Ischemia-reperfusion-induced microcirculatory alterations were measured after 2 hours of reperfusion. Microvasculature of the cremaster muscle including the vascular pedicle was harvested to determine the mitochondrial dysfunction. The blood concentration of methemoglobin was also measured to determine the toxicity of nitrite. RESULTS: The authors found that nitrite significantly attenuated ischemia-reperfusion-induced vasoconstriction, arteriole stagnation, and capillary no-reflow in the early phase of reperfusion and the depolarization of mitochondrial membrane potential and cytochrome c release in the late phase of reperfusion. Nitrite-induced protection was significantly blocked by a nitric oxide scavenger (potassium salt). The methemoglobin results showed that the doses of nitrite we used in the present study were safe. CONCLUSION: The supplementation of a low dose of nitrite, directly into the microcirculation of ischemic muscle through local intraarterial infusion, significantly attenuated ischemia-reperfusion-induced microcirculatory alterations in vivo and mitochondrial dysfunction in vitro in the microvasculature of skeletal muscle.
Asunto(s)
Isquemia/tratamiento farmacológico , Mitocondrias Musculares/fisiología , Músculo Esquelético/irrigación sanguínea , Nitritos/farmacología , Daño por Reperfusión/prevención & control , Análisis de Varianza , Animales , Citocromos c/metabolismo , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Masculino , Potenciales de la Membrana , Metahemoglobina/efectos de los fármacos , Metahemoglobina/metabolismo , Microcirculación/efectos de los fármacos , Músculo Esquelético/fisiopatología , Distribución Aleatoria , Ratas , Ratas Sprague-Dawley , Valores de Referencia , Daño por Reperfusión/tratamiento farmacológicoRESUMEN
Erythrocytes are excellent model to study the xenobiotic induced oxidative changes. Pyrethroid pesticides are increasingly being used in insecticidal preparations from the simple mosquito coils to house hold aerosols to sophisticated ultra low volume foggers and sprays. Cypermethrin a Type II pyrethroid pesticide is used widely in pest control. Fenugreek is a potent antioxidant. We have evaluated the potential of aqueous extract of germinated fenugreek seeds in counteracting cypermethrin induced oxidative changes in erythrocytes of male Wistar rats. Male Wistar rats were treated with 1/10 LD50 (25mg/kg body weight) of cypermethrin and 10 percent aqueous extract of germinated fenugreek for 60 days. Cypermethrin treatment caused significant decrease in non enzymatic antioxidants, glutathione (GSH), vitamin E, vitamin C, increased methemoglobin formation in erythrocytes and increased their mechanical fragility. Treatment with fenugreek reversed the cypermethrin induced oxidative changes in erythrocytes and restored all the parameters to near normal levels. The overall results reveal the ameliorating effect of aqueous extract of germinated fenugreek on cypermethrin induced toxicity in erythrocytes.
Asunto(s)
Antioxidantes/farmacología , Eritrocitos/metabolismo , Insecticidas/toxicidad , Extractos Vegetales/farmacología , Piretrinas/toxicidad , Trigonella , Animales , Ácido Ascórbico/metabolismo , Suplementos Dietéticos , Glutatión/metabolismo , Humanos , Masculino , Metahemoglobina/metabolismo , Fragilidad Osmótica/efectos de los fármacos , Ratas , Ratas Wistar , Semillas , Vitamina E/metabolismoRESUMEN
A 6-year-old, intact male Schnauzer was referred 2-days after accidental ingestion of baked garlic. Regenerative anemia (Hematocrit 22%) and the elevated methemoglobin (8.7%) concentration were detected upon hematological examination. Eccentrocytes, Heinz bodies and ruptured red blood cells were also noted on blood smear films, which were the results from the oxidative injury of the Allium species. The dog was hypertension (systolic mean 182 mmHg) concurrent with other clinical signs, such as vomiting and dark brown urination. Treatment with continuous oxygen, antioxidant drugs and antihypertensive therapy resulted in good progress. The dog was discharged 4 days after hospitalization. There were no remarkable findings in the follow up hematologic examination 24 days after discharge, but the dog still had a high blood pressure and continued on antihypertensive therapy. No recurrence was noted and the blood pressure returned to normal levels 4 months later.
Asunto(s)
Enfermedades de los Perros/diagnóstico , Ajo/efectos adversos , Hipertensión/veterinaria , Anemia/sangre , Anemia/inducido químicamente , Anemia/veterinaria , Animales , Antihipertensivos/uso terapéutico , Antioxidantes/uso terapéutico , Culinaria , Enfermedades de los Perros/sangre , Perros , Hematócrito , Hipertensión/sangre , Hipertensión/inducido químicamente , Hipertensión/tratamiento farmacológico , Masculino , Metahemoglobina/metabolismo , Resultado del TratamientoRESUMEN
The athletic performance supplement industry is a multibillion-dollar business and one popular category claims to increase nitric oxide (NO) production. We report three patients presenting to the emergency department with adverse effects. A 33-year-old man presented with palpitations, dizziness, vomiting, and syncope, after the use of NO(2) platinum. His examination and electrocardiogram (ECG) were normal. The dizziness persisted, requiring admission overnight. A 21-year-old man with palpitations and near syncope had used a "nitric oxide" supplement. He was tachycardic to 115 bpm with otherwise normal examination. Laboratory values including methemoglobin, and ECG were unremarkable. He was treated with 1 L of saline with no change in heart rate. He was admitted for observation. A 24-year-old man presented after taking NO-Xplode with palpitations and a headache. His examination, laboratory values, and ECG were normal. He was discharged. The purported active ingredient in these products is arginine alpha-ketoglutarate (AAKG), which is claimed to increase NO production by supplying the precursor L-arginine. The symptoms could be due to vasodilation from increased levels of NO, though other etiologies cannot be excluded. AAKG containing supplements may be associated with adverse effects requiring hospital admission.
Asunto(s)
Arginina/análogos & derivados , Suplementos Dietéticos/efectos adversos , Ácidos Cetoglutáricos/efectos adversos , Adulto , Arginina/efectos adversos , Arginina/metabolismo , Arritmias Cardíacas/inducido químicamente , Presión Sanguínea/efectos de los fármacos , Citrulina/metabolismo , Mareo/inducido químicamente , Electrocardiografía , Frecuencia Cardíaca/efectos de los fármacos , Humanos , Masculino , Metahemoglobina/metabolismo , Óxido Nítrico/metabolismo , Adulto JovenRESUMEN
Extracts from the leaves of Ginkgo biloba have been used in Chinese medicine for thousands of years. Today, various standardized preparations from G. biloba leaf extract have been developed. G. biloba leaf extract, which contains flavonoids and terpenoids as the major biologically active components, has become one of the most popular and commonly used herbal remedies due to its wide spectrum of beneficial effects on health. In this study, we investigated the effects of G. biloba leaf extract on the properties of human red blood cells in the presence and absence of amyloid peptide (Abeta25-35), peroxide and hypotonic stress. The results suggest that G. biloba leaf extract has a dual action, both protective and disruptive, on red blood cells, depending on whether an exogenous stress is present. G. biloba leaf extract has a protective role on red blood cells against Abeta- and hypotonic pressure-induced haemolysis, peroxide-induced lipoperoxidation, as well as glutathione consumption and methaemoglobin formation. On the other hand, G. biloba leaf extract also exhibited damage to red blood cells by increasing cell fragility, changing cellular morphology and inducing glutathione consumption and methaemoglobin formation, especially when applied at high doses. These anti- and pro-oxidative activities of polyphenolic substances are thought to be involved in the dual function of G. biloba leaf extract. The results of this study suggest that high doses of herbal remedies and dietary supplements can be toxic to cells.
Asunto(s)
Eritrocitos/efectos de los fármacos , Ginkgo biloba/química , Estrés Oxidativo/efectos de los fármacos , Extractos Vegetales/efectos adversos , Extractos Vegetales/farmacología , Péptidos beta-Amiloides/toxicidad , Membrana Celular/efectos de los fármacos , Membrana Celular/metabolismo , Células Cultivadas , Relación Dosis-Respuesta a Droga , Eritrocitos/metabolismo , Eritrocitos/patología , Glutatión/metabolismo , Hemólisis/efectos de los fármacos , Humanos , Peroxidación de Lípido/efectos de los fármacos , Fluidez de la Membrana/efectos de los fármacos , Metahemoglobina/metabolismo , Fragilidad Osmótica/efectos de los fármacos , Fragmentos de Péptidos/toxicidad , Extractos Vegetales/aislamiento & purificación , Hojas de la Planta/químicaRESUMEN
Data from 4 randomized, placebo-controlled, double-blind trials in Indonesia, Thailand, and Vietnam, the South-East Asian Multicountry Trial on Iron and Zinc supplementation in Infants (SEAMTIZI), were pooled to investigate the effects of iron and zinc supplementation infant growth. Infants (n = 2451) aged 4-6 mo old were supplemented with iron (10 mg/d) and/or zinc (10 mg/d) for 6 mo. Overall, neither iron nor zinc supplementation prevented the progressive growth faltering during infancy, which is common in many developing countries. However, infants who received zinc were less likely to be stunted at the end of the supplementation period (odds ratio 0.80; 95% CI 0.64-1.0). Boys had a 30% higher risk of being stunted at the end of the study than girls (P < 0.01). Baseline factors modified the effect of supplementation, with infants anemic at baseline (hemoglobin < 105 g/L) benefiting from zinc supplementation, with an estimated increase in height-for-age Z-score (HAZ) score of 0.17 (P < 0.01), but with no effect of zinc supplementation on growth in infants not anemic at baseline. Iron supplementation negatively affected linear growth in infants with a birth weight of >3500 g (estimated effect size, -0. 14 HAZ score; P < 0.01), but with no significant effect in infants with a lower birth weight. This study shows that blanket supplementation of infants with iron or zinc will not be beneficial to all recipients and may have adverse effects in some. Hence, interventions such as iron and zinc supplementation for infants should be restricted to subgroups in which there is a clear benefit and baseline factors should be considered and characterized before implementing new policies.
Asunto(s)
Anemia/tratamiento farmacológico , Estatura/efectos de los fármacos , Suplementos Dietéticos , Crecimiento/efectos de los fármacos , Hierro/uso terapéutico , Zinc/uso terapéutico , Método Doble Ciego , Femenino , Humanos , Lactante , Hierro/administración & dosificación , Lactancia , Masculino , Metahemoglobina/análogos & derivados , Metahemoglobina/metabolismo , Caracteres Sexuales , Zinc/administración & dosificaciónRESUMEN
OBJECTIVE: beta-thalassemia major, or Cooley's anemia, is a red blood cell disorder requiring lifelong blood transfusions for survival. Erythrocytes accumulate toxic iron at their membranes, triggering an oxidative cascade that leads to their premature destruction in high numbers. We hypothesized that removing this proximate iron compartment as a primary treatment, using standard and alternative orally active iron chelators, could prevent hastened red cell removal and, clinically, perhaps alleviate the need for transfusion. MATERIALS AND METHODS: Iron chelators of the pyridoxal isonicotinoyl hydrazone family (pyridoxal isonicotinoyl hydrazone and its analog pyridoxal ortho-chlorobenzoyl hydrazone) were evaluated in addition to the present mainstay, desferrioxamine and deferiprone, in vitro and in vivo. RESULTS: Treatment of human beta-thalassemic erythrocytes with chelators resulted in significant depletion of membrane-associated iron and reduction of oxidative stress, as evaluated by methemoglobin levels. When administered to beta-thalassemic mice, iron chelators mobilized erythrocyte membrane iron, reduced cellular oxidation, and prolonged erythrocyte half-life. The treated thalassemic mice also showed improved hematological abnormalities. Remarkably, a beneficial effect as early as the erythroid precursor stage was manifested by normalized proportions of mature vs immature reticulocytes. All four compounds were also found to mitigate iron accumulation in target organs, a critical determinant for patient survival. In this respect, pyridoxal ortho-chlorobenzoyl hydrazone displayed higher activity relative to other chelators tested, further diminishing iron in liver and spleen by up to approximately fivefold and twofold, respectively. CONCLUSION: Our study demonstrates the ability of iron chelators to improve several of the fundamental pathological disturbances of thalassemia, and reveals their potential for clinical use in diminishing requirement for transfusion when administered early in disease development.
Asunto(s)
Membrana Eritrocítica/metabolismo , Quelantes del Hierro/farmacología , Hierro/metabolismo , Metahemoglobina/metabolismo , Estrés Oxidativo/efectos de los fármacos , Talasemia beta/terapia , Animales , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Membrana Eritrocítica/patología , Transfusión de Eritrocitos , Humanos , Quelantes del Hierro/uso terapéutico , Ratones , Ratones Transgénicos , Oxidación-Reducción/efectos de los fármacos , Reticulocitos/metabolismo , Reticulocitos/patología , Talasemia beta/metabolismo , Talasemia beta/patologíaRESUMEN
BACKGROUND: Tumescent anaesthesia is currently used for several dermatological procedures. The objective of this study was to determine the plasma concentrations of local anaesthetics under real operating conditions with this anaesthetic technique. METHODS: A total of 31 patients received 3 different anaesthetic solutions with prilocaine and lidocaine for several surgical procedures. The concentrations of local anaesthetics, methemoglobin, epinephrine as well as the occurrence of adverse reactions were determined 30 min, 1 h, 3 h, 6 h, 12 h and 24 h after administration RESULTS: Maximum plasma concentrations of prilocaine were measured predominantly after 3 and 6 h, for lidocaine after 6 h. In two patients maximum plasma levels occurred 24 h after infiltration. Although toxic concentrations were not exceeded, side-effects could be observed in four patients. CONCLUSIONS: Even if the measured concentrations of local anaesthetics appeared to be safe, slight and moderate side-effects could be observed in 12.9% of cases. Maximum plasma levels of local anaesthetics may still occur 24 h after administration.