RESUMO
Myocardial reperfusion injury (MRI) accounts for up to 50% of the final size in acute myocardial infarction and other conditions associated with ischemia-reperfusion. Currently, there is still no therapy to prevent MRI, but it is well known that oxidative stress has a key role in its mechanism. We previously reduced MRI in rats through a combined antioxidant therapy (CAT) of ascorbic acid, N-acetylcysteine, and deferoxamine. This study determines the safety and pharmacokinetics of CAT in a Phase I clinical trial. Healthy subjects (n = 18) were randomized 2:1 to CAT or placebo (NaCl 0.9% i.v.). Two different doses/infusion rates of CATs were tested in a single 90-minute intravenous infusion. Blood samples were collected at specific times for 180 minutes to measure plasma drug concentrations (ascorbic acid, N-acetylcysteine, and deferoxamine) and oxidative stress biomarkers. Adverse events were registered during infusion and followed for 30 days. Both CAT1 and CAT2 significantly increased the CAT drug concentrations compared to placebo (P < .05). Most of the pharmacokinetic parameters were similar between CAT1 and CAT2. In total, 6 adverse events were reported, all nonserious and observed in CAT1. The ferric-reducing ability of plasma (an antioxidant biomarker) increased in both CAT groups compared to placebo (P < .001). The CAT is safe in humans and a potential treatment for patients with acute myocardial infarction undergoing reperfusion therapy.
Assuntos
Acetilcisteína , Antioxidantes , Ácido Ascórbico , Desferroxamina , Traumatismo por Reperfusão Miocárdica , Estresse Oxidativo , Humanos , Antioxidantes/farmacocinética , Antioxidantes/administração & dosagem , Antioxidantes/efeitos adversos , Antioxidantes/farmacologia , Masculino , Acetilcisteína/administração & dosagem , Acetilcisteína/farmacocinética , Acetilcisteína/efeitos adversos , Ácido Ascórbico/administração & dosagem , Ácido Ascórbico/farmacocinética , Ácido Ascórbico/efeitos adversos , Adulto , Estresse Oxidativo/efeitos dos fármacos , Feminino , Desferroxamina/farmacocinética , Desferroxamina/administração & dosagem , Desferroxamina/efeitos adversos , Voluntários Saudáveis , Adulto Jovem , Infusões Intravenosas , Pessoa de Meia-Idade , Método Duplo-Cego , Quimioterapia Combinada , Biomarcadores/sangueRESUMO
BACKGROUND: The aim of this work was evaluate the antioxidant effect of ascorbyl laurate (ASC12) based nanostructures applied topically to the cornea of ocular normotensive and hypertensive rabbits. The ASC12 was chosen for its capacity to form liquid lyotropic crystal and keeps its free radical trapping power. METHODS: The hypertension model was performed in six rabbits and was obtained by the application of intracameral injections of alpha-chymotrypsin in the right eye. A single 50 ml dose of ascorbyl laurate coagel 2% w/v (COA-ASC12) was applied topically to the cornea of six normotensive and six hypertensive rabbits. The aqueous humor samples were obtained before and after instillation of COA-ASC12 at different times (2 h and 4 h). Antioxidant capacity was determined via the reduction reaction with iron and tripyridyltriazine (FRAP) and the total proteins were measured using the Bradford reagent. RESULTS: The kinetic antioxidant capacity in the aqueous humor of normotensive and hypertensive rabbits showed a maxim increment at 4 h instillation. Also, the antioxidant capacity in the aqueous humor of hypertensive rabbits was ten times lower than in normotensive rabbits. CONCLUSION: This type of nanostructures has the potential to significantly improve the topical formulation for the prophylaxis and treatment of several eye diseases.
Assuntos
Antioxidantes/farmacologia , Humor Aquoso/efeitos dos fármacos , Ácido Ascórbico/análogos & derivados , Pressão Intraocular/efeitos dos fármacos , Nanoestruturas/química , Hipertensão Ocular/tratamento farmacológico , Administração Oftálmica , Animais , Antioxidantes/administração & dosagem , Antioxidantes/química , Antioxidantes/farmacocinética , Humor Aquoso/metabolismo , Ácido Ascórbico/administração & dosagem , Ácido Ascórbico/química , Ácido Ascórbico/farmacocinética , Ácido Ascórbico/farmacologia , Modelos Animais de Doenças , Géis , Hipertensão Ocular/metabolismo , CoelhosRESUMO
The aim of this study was to design a nanocarrier system for inhalation delivery of rifampicin (RIF) in combination with ascorbic acid (ASC), namely constituted of sodium alginate coated with chitosan and Tween 80 (RIF/ASC NPs) as a platform for the treatment of pulmonary tuberculosis infection. A Box-Behnken experimental design and response surface methodology (RSM) were applied to elucidate and evaluate the effects of several factors on the nanoparticle properties. On the other hand, it was found that RIF/ASC NPs were less cytotoxic than the free RIF, showing a significantly improved activity against nine clinical strains of Mycobacterium tuberculosis (M. tb) in comparison with the free drug. RIF/ASC NPs had an average particle size of 324.0 ± 40.7 nm, a polydispersity index of 0.226 ± 0.030, and a zeta potential of - 28.52 ± 0.47 mV and the surface was hydrophilic. The addition of sucrose (1% w/v) to the nanosuspension resulted in the formation of a solid pellet easily redispersible after lyophilization. RIF/ASC NPs were found to be stable at different physiological pH values. In summary, findings of this work highlight the potential of the RIF/ASC NP-based formulation development herein to deliver RIF in combination with ASC through pulmonary route by exploring a non-invasive route of administration of this antibiotic, increasing the local drug concentrations in lung tissues, the primary infection site, as well as reducing the risk of systemic toxicity and hence improving the patient compliance.
Assuntos
Alginatos/administração & dosagem , Ácido Ascórbico/administração & dosagem , Quitosana/administração & dosagem , Mycobacterium tuberculosis/efeitos dos fármacos , Nanopartículas/administração & dosagem , Rifampina/administração & dosagem , Alginatos/química , Alginatos/farmacocinética , Animais , Antibióticos Antituberculose/administração & dosagem , Antibióticos Antituberculose/química , Antibióticos Antituberculose/farmacocinética , Ácido Ascórbico/química , Ácido Ascórbico/farmacocinética , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Quitosana/química , Quitosana/farmacocinética , Chlorocebus aethiops , Relação Dose-Resposta a Droga , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/química , Portadores de Fármacos/metabolismo , Sistemas de Liberação de Medicamentos/métodos , Humanos , Mycobacterium tuberculosis/metabolismo , Nanopartículas/química , Nanopartículas/metabolismo , Tamanho da Partícula , Rifampina/química , Rifampina/farmacocinética , Células VeroRESUMO
Ascorbic acid (AA) is widely used in cosmetic formulations due to its antioxidant property and ability to increase collagen synthesis. Here, we encapsulated AA in vesicles with different lipid compositions. Negative liposome charge favored AA skin retention, with accumulation of 37 ± 12 and 74 ± 23 µg/cm2 in the epidermis and dermis, respectively, after 6 hours. Drug flux was influenced by the formulation composition, and both the presence of cholesterol and the liposomes surface charge were able to increase the amount of AA crossing the skin. The formulation was stable for at least 30 days and promoted a 7-fold increase in flux compared to free AA. Additionally, liposomes were able to interact better with keratinocytes and fibroblasts membranes. In vitro efficacy studies demonstrated that associating AA to these liposomes resulted in increased effectiveness of type I collagen synthesis by fibroblasts and regeneration of UVA-induced damage in keratinocytes. Our results demonstrate the applicability of AA-negatively charged liposomes in promoting AA cutaneous permeation and increasing the retention and flux of this molecule in the skin. This formulation also increased AA stability and effectiveness, opening new perspectives for its application in view of reducing certain skin ageing outcomes.
Assuntos
Antioxidantes/administração & dosagem , Ácido Ascórbico/administração & dosagem , Colágeno/metabolismo , Fibroblastos/efeitos dos fármacos , Absorção Cutânea , Administração Cutânea , Animais , Antioxidantes/farmacocinética , Antioxidantes/farmacologia , Ácido Ascórbico/farmacocinética , Ácido Ascórbico/farmacologia , Células 3T3 BALB , Linhagem Celular , Fibroblastos/metabolismo , Humanos , Lipossomos/química , Camundongos , Pele/efeitos dos fármacos , Pele/metabolismoRESUMO
The molecular response of the antioxidant system and the effects of antioxidant supplementation against oxidative insult in lead-exposed workers has not been sufficiently studied. In this work, antioxidants (vitamin E 400 IU+vitamin C 1g/daily) were supplemented for one year to 15 workers exposed to lead (73 µg of lead/dl of blood) and the results were compared with those on 19 non-lead exposed workers (6.7 µg of lead/dl). Lead intoxication was accompanied by a high oxidative damage and an increment in the erythrocyte antioxidant response due to increased activity of catalase and superoxide dismutase. Antioxidant supplementations decreased significantly the oxidative damage as well as the total antioxidant capacity induced by lead intoxication with reduction of the antioxidant enzyme activities. We conclude that antioxidant supplementation is effective in reducing oxidative damage and induces modifications in the physiopathological status of the antioxidant response in lead-exposed workers.
Assuntos
Poluentes Ocupacionais do Ar/toxicidade , Antioxidantes/farmacologia , Ácido Ascórbico/farmacologia , Chumbo/toxicidade , Vitamina E/farmacologia , Adulto , Poluentes Ocupacionais do Ar/sangue , Antioxidantes/farmacocinética , Ácido Ascórbico/sangue , Ácido Ascórbico/farmacocinética , Catalase/sangue , Suplementos Nutricionais , Glutationa Peroxidase/sangue , Glutationa Redutase/sangue , Humanos , Chumbo/sangue , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Exposição Ocupacional/efeitos adversos , Exposição Ocupacional/análise , Estresse Oxidativo/efeitos dos fármacos , Sintase do Porfobilinogênio/sangue , Superóxido Dismutase/sangue , Vitamina E/sangue , Vitamina E/farmacocinéticaRESUMO
The adjuvants approved in human vaccine with recombinant/purified antigens induce weak cellular immune response and so the development of new adjuvant strategies is critical. CpG-ODN has successfully been used as an adjuvant (phase I-III clinical trials) but its bioavailability needs to be improved. We investigated the adjuvant ability of CpG-ODN formulated with a liquid crystal nanostructure of 6-O-ascorbyl palmitate (Coa-ASC16). Mice immunized with OVA/CpG-ODN/Coa-ASC16 elicited a potent specific IgG1, IgG2a, Th1 and Th17 cellular response without systemic adverse effects. These responses were superior to those induced by OVA/CpG-ODN (solution of OVA with CpG-ODN) and to those induced by the formulation OVA/CpG-ODN/Al(OH)3. Immunization with OVA/CpG-ODN/Coa-ASC16 resulted in a long-lasting cell-mediated immune response (at least 6.5 months). Furthermore, Coa-ASC16 alone allows a controlled release of CpG-ODN in vitro and induces local inflammatory response, independent of TLR4 signaling, characterized by an influx of neutrophils and Ly6C(high) monocytes and pro-inflammatory cytokines. Remarkably, the adjuvant capacity of CpG-ODN co-injected with Coa-ASC16 (OVA/CpG-ODN plus Coa-ASC16) was similar to the adjuvant activity of OVA/CpG-ODN, supporting the requirement for whole formulation to help CpG-ODN adjuvanticity. These results show the potential of this formulation, opening a new avenue for the development of better vaccines.
Assuntos
Adjuvantes Imunológicos/farmacocinética , Imunidade Celular , Cristais Líquidos/química , Oligodesoxirribonucleotídeos/farmacocinética , Adjuvantes Imunológicos/química , Alanina Transaminase/sangue , Animais , Antígenos/imunologia , Ácido Ascórbico/análogos & derivados , Ácido Ascórbico/química , Ácido Ascórbico/farmacocinética , Aspartato Aminotransferases/sangue , Disponibilidade Biológica , Células Cultivadas , Feminino , Imunização , Imunoglobulina G/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Nanoestruturas/química , Oligodesoxirribonucleotídeos/química , Ovalbumina/imunologia , Transdução de Sinais , Baço/citologia , Baço/metabolismo , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/metabolismo , Vacinas/química , Vacinas/imunologiaRESUMO
Tobacco smoke is known to cause nitric oxide ((*)NO) inactivation and endothelial dysfunction. In this work we evaluated the interplay between (.)NO and superoxide (O(2)(*-)) radicals and the consequent impact on (*)NO bioavailability and nitroxidative stress in bovine aortic endothelial cells exposed to cigarette smoke extract (CSE) and in smokers. Bovine aortic endothelial cells in the presence of CSE triggered O(2)(*-) production as indicated by spin-trapping electron paramagnetic resonance experiments. O(2)(*-) was produced both extracellulary (3.4 vs. 1.0 nmol.h(-1)*mg(-1); CSE vs. control; cytochrome c(3+) reduction assay) and intracellularly (40% inhibition of cytosolic aconitase). CSE also led to the production of peroxynitrite as evaluated by dihydrorhodamine oxidation and protein tyrosine nitration on cells. O(2)(*-) and peroxynitrite formation were decreased by ascorbate and alpha-tocopherol. Additionally, CSE led to the oxidation of endothelial nitric oxide synthase increasing the monomeric inactive form of endothelial nitric oxide synthase. Smokers and age-matched healthy volunteers were supplemented orally with 500 mg ascorbate plus 400 IU all-rac-alpha-tocopherol every 12 h for 165 days. Smokers had endothelial dysfunction compared with control subjects (95% confidence interval: 2.5, 8.3 vs. 10.6, 14.2; P < 0.05) as assessed by flow-mediated dilation of the brachial artery, and plasma levels of protein 3-nitrotyrosine were 1.4-fold higher. The loss of flow-mediated dilation in smokers reverted after a long-term antioxidant supplementation (95% confidence interval: 13.9, 19.9; P < 0.05), reaching values comparable with the control population. Our data indicate that elements on tobacco smoke, most likely through redox cycling, divert (*)NO toward peroxynitrite by inducing O(2)(*-) production in vascular endothelial cells both in vitro and in vivo.
Assuntos
Antioxidantes/administração & dosagem , Células Endoteliais/metabolismo , Óxido Nítrico/metabolismo , Ácido Peroxinitroso/metabolismo , Fumar/metabolismo , Superóxidos/metabolismo , Adulto , Animais , Antioxidantes/metabolismo , Antioxidantes/farmacocinética , Aorta/citologia , Ácido Ascórbico/administração & dosagem , Ácido Ascórbico/sangue , Ácido Ascórbico/farmacocinética , Artéria Braquial/fisiologia , Bovinos , Células Cultivadas , Células Endoteliais/citologia , Feminino , Humanos , Masculino , Óxido Nítrico Sintase Tipo III/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologia , Fumar/efeitos adversos , Adulto Jovem , alfa-Tocoferol/administração & dosagem , alfa-Tocoferol/sangue , alfa-Tocoferol/farmacocinéticaRESUMO
Fe (II) is a potential prooxidant in vivo and can induce cellular oxidative stress. Ascorbic acid (AA) is a powerful physiological antioxidant and, in the presence of free Fe (II), can exhibit prooxidant effects in vitro. However, in vivo prooxidant effects of Fe (II) and AA have not yet been indisputably demonstrated. Here we evaluate the potential toxic effect of supplementation of Fe (II) associated with AA. Nine healthy, nonsmoking male volunteers (20-31 years old) participated in the crossover study design. The volunteers were supplemented with either a dose of 2 g of AA, 150 mg of iron carbonyl or 2 g of AA plus 150 mg of iron carbonyl with a washout period of 15 days between each treatment. AA, iron, ferritin, thiobarbituric acid-reactive substances, catalase, delta-aminolevulinic dehydratase and SH thiol groups were measured in the blood of the volunteers. Plasma AA levels were increased at 2, 5 and 24 h after AA or AA plus iron ingestion. Plasma Fe levels were increased at 2 and 5 h in the AA plus iron group. Erythrocyte malondialdehyde levels decreased at 5 and 24 h after AA and 5 h after AA plus iron ingestion. Catalase activity from erythrocytes was increased 5 h after supplementation with AA plus iron. There was no significant difference between groups in the other biochemical parameters evaluated. Thus, the present study does not support the hypothesis that the combination of high plasma concentrations of AA and iron, or iron alone, could cause in vivo oxidative damage after a single supplementation dose.
Assuntos
Ácido Ascórbico/farmacologia , Ferro da Dieta/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Adulto , Antioxidantes/metabolismo , Ácido Ascórbico/efeitos adversos , Ácido Ascórbico/sangue , Ácido Ascórbico/farmacocinética , Catalase/sangue , Estudos Cross-Over , Interações Medicamentosas , Ferritinas/sangue , Humanos , Ferro/sangue , Ferro da Dieta/efeitos adversos , Ferro da Dieta/sangue , Ferro da Dieta/farmacocinética , Masculino , Oxirredução , Sintase do Porfobilinogênio/sangue , Substâncias Reativas com Ácido Tiobarbitúrico/análise , Adulto JovemRESUMO
There is a strong advocacy movement for large doses of vitamin C. Some authors argue that the biological half-life for vitamin C at high plasma levels is about 30 minutes, but these reports are the subject of some controversy. NIH researchers established the current RDA based upon tests conducted 12 hours (24 half lives) after consumption. The dynamic flow model refutes the current low-dose recommendations for dietary intakes and links Pauling's mega-dose suggestions with other reported effects of massive doses of ascorbate for the treatment of disease. Although, a couple of controlled clinical studies conducted at The Mayo Clinic did not support a significant benefit for terminal cancer patients after 10 grams of once-a-day oral vitamin C, other clinical trials have demonstrated that ascorbate may indeed be effective against tumors when administered intravenously. Recent studies confirmed that plasma vitamin C concentrations vary substantially with the route of administration. Only by intravenous administration, the necessary ascorbate levels to kill cancer cells are reached in both plasma and urine. Because the efficacy of vitamin C treatment cannot be judged from clinical trials that use only oral dosing, the role of vitamin C in cancer treatment should be reevaluated. One limitation of current studies is that pharmacokinetic data at high intravenous doses of vitamin C are sparse, particularly in cancer patients. This fact needs prompt attention to understand the significance of intravenous vitamin C administration. This review describes the current state-of-the-art in oral and intravenous vitamin C pharmacokinetics. In addition, the governmental recommendations of dose and frequency of vitamin C intake will also be addressed.
Assuntos
Ácido Ascórbico/administração & dosagem , Ácido Ascórbico/farmacocinética , Administração Oral , Ácido Ascórbico/metabolismo , Disponibilidade Biológica , Humanos , Injeções IntravenosasRESUMO
There is a strong advocacy movement for large doses of vitamin C. Some authors argue that the biological half-life for vitamin C at high plasma levels is about 30 minutes, but these reports are the subject of some controversy. NIH researchers established the current RDA based upon tests conducted 12 hours (24 half lives) after consumption. The dynamic flow model refutes the current low-dose recommendations for dietary intakes and links Pauling's mega-dose suggestions with other reported effects of massive doses of ascorbate for the treatment of disease. Although, a couple of controlled clinical studies conducted at The Mayo Clinic did not support a significant benefit for terminal cancer patients after 10 grams of once-a-day oral vitamin C, other clinical trials have demonstrated that ascorbate may indeed be effective against tumors when administered intravenously. Recent studies confirmed that plasma vitamin C concentrations vary substantially with the route of administration. Only by intravenous administration, the necessary ascorbate levels to kill cancer cells are reached in both plasma and urine. Because the efficacy of vitamin C treatment cannot be judged from clinical trials that use only oral dosing, the role of vitamin C in cancer treatment should be reevaluated. One limitation of current studies is that pharmacokinetic data at high intravenous doses of vitamin C are sparse, particularly in cancer patients. This fact needs prompt attention to understand the significance of intravenous vitamin C administration. This review describes the current state-of-the-art in oral and intravenous vitamin C pharmacokinetics. In addition, the governmental recommendations of dose and frequency of vitamin C intake will also be addressed.