RESUMEN
In the present study, chitosan-based wound dressings loaded with the extract of Opuntia ficus-indica (OPU) were prepared. OPU is known for its capability to accelerate skin injury repair. Chitosan (Ch) was crosslinked with a low molecular weight diepoxy-poly(ethylene glycol) (diePEG), and hydrogel films with different Ch/PEG composition and OPU content were prepared by casting. The occurrence of crosslinking reaction was confirmed by FTIR spectroscopy. FTIR and DSC analysis suggested that ionic interactions occur between chitosan and OPU. Tensile tests evidenced that the crosslinking caused a decrease of Young's modulus, which approaches the value of the human skin modulus. Swelling characteristics, water vapor transmission rate, and release kinetics demonstrated that these films are adequate for the proposed application. Finally, a scratch test on a keratinocytes monolayer showed that the rate of cell migration in the presence of OPU-loaded samples is about 3-fold higher compared to unloaded films, confirming the repairing activity of OPU.
Asunto(s)
Quitosano/química , Metilgalactósidos/química , Opuntia/química , Extractos Vegetales/farmacología , Polietilenglicoles/química , Cicatrización de Heridas/efectos de los fármacos , Vendajes , Materiales Biocompatibles/química , Reactivos de Enlaces Cruzados/química , Sistemas de Liberación de Medicamentos/métodos , Módulo de Elasticidad , Células HaCaT , Humanos , Hidrogeles/química , Extractos Vegetales/química , Piel/lesiones , Espectroscopía Infrarroja por Transformada de Fourier/métodos , Resistencia a la TracciónRESUMEN
In the present study, a complex of compounds (red orange complex, ROC), obtained from three red orange varieties (Citrus sinensis varieties: Moro, Tarocco and Sanguinello), containing cyanidin glycosides, hydroxycinnamic acids, flavanone glycosides and ascorbic acid, was screened to discover new lead compounds in the suppression of the production of key molecules released during inflammatory events in interleukin-1beta (IL-beta) stimulated human primary chondrocytes. The expression of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX)-2 and intercellular adhesion molecule-1 (ICAM-1), and the release of nitric oxide, prostaglandin (PG)E(2) and interleukin-8 (IL-8) were determined. Indomethacin was used as an anti-inflammatory drug reference. ROC acts as a potent inhibitor of iNOS and COX-2 gene expression while also suppressing the production of PGE(2) and nitrite in human chondrocytes. In addition, ROC induces a significant decrease in ICAM expression and IL-8 release. These findings suggest that ROC exerts anti-inflammatory effects probably through the suppression of COX-2 and iNOS expression.
Asunto(s)
Antiinflamatorios/farmacología , Condrocitos/efectos de los fármacos , Condrocitos/metabolismo , Citrus sinensis/química , Ciclooxigenasa 2/metabolismo , Óxido Nítrico Sintasa de Tipo II/metabolismo , Extractos Vegetales/farmacología , Antiinflamatorios/química , Western Blotting , Células Cultivadas , Humanos , Interleucina-8/metabolismo , Extractos Vegetales/químicaRESUMEN
Allergic diseases represent conditions affecting millions of individuals across the world. The objective of this study was to investigate the potential anti-allergic effects of a new nutraceutical ingredient, Pantescal (Bionap, Italy), contained in different food supplements. Pantescal is a mixture of plant extracts, such as Capparis spinosa, Olea europaea, Panax Ginseng and Ribes nigrum. The study was a randomized, double-blind, placebo controlled design. 60 patients allergic to common aeroallergens were chosen. Allergic patients were divided into two groups: one group was supplemented by Pantescal and the other, using a placebo formulation. Two in vitro tests were performed on blood samples taken from patients before and at 2 h, 2, 3 and 10 days after supplementation: cellular antigen stimulation test (CAST) was used to analyze the amount of sulphidoleukotrienes (SLT) production and flow-cytometric antigen stimulation test (FAST) to measure expression of basophil degranulation marker (CD63) was also performed. CAST showed that after 2 and 3 days, a slight decrease of SLT production was evident but only after 10 days did it become significant with a percentage of inhibition (P.I)=43.3%. FAST revealed that there were no statistical differences for the first 2 days after supplementation although there was an inhibitory trend in the supplemented patients. CD63 expression was significantly reduced after 10 days (P.I.=64.8%). This study suggests that Pantescal is effective in reducing allergic biomarkers such as CD63 protein and SLT in atopic subjects. The higher inhibitory effect on CD63 expression compared to SLT production allows us to hypothesize cell membrane stabilization as the main potential mechanism to explain the observed Pantescal protective effects.
Asunto(s)
Alérgenos/inmunología , Antígenos CD/biosíntesis , Suplementos Dietéticos , Hipersensibilidad/terapia , Leucotrienos/biosíntesis , Extractos Vegetales/uso terapéutico , Glicoproteínas de Membrana Plaquetaria/biosíntesis , Adolescente , Adulto , Anciano , Basófilos/inmunología , Niño , Método Doble Ciego , Femenino , Humanos , Hipersensibilidad/inmunología , Masculino , Persona de Mediana Edad , Extractos Vegetales/administración & dosificación , Tetraspanina 30 , Adulto JovenRESUMEN
Chitosan is a natural polymer whose bioadhesive properties make it a useful material for filming over and protecting damaged or sensitive mucosae. Much effort has been expended to develop this employ, and new applications are in the offing. The aim of the present study was to optimize the synthesis under sonochemical conditions of water-soluble chitosan tetraalkylammonium salts and to assess the mucoadhesive properties of the resulting water-soluble cationic polyelectrolytes. Aqueous solutions of several tetralkylammonium chitosan derivatives, viz. N-trimethyl- (1), N-diethylmethyl- (2), N-carboxymethyl- (3) and N-[N,N-diethylaminomethyl(diethyldimethylene ammonium)(n)]methylchitosan (4) were tested along with the parent biopolymer and its citric acid salt (5), both at neutral and acidic pH. We used a published technique for evaluating in vitro bioadhesion to isolated buccal cells, a mucosal model that can predict bioadhesive behavior in vivo. Derivatives 1 and 4 gave the best results.
Asunto(s)
Quitosano/análogos & derivados , Quitosano/farmacología , Portadores de Fármacos/farmacología , Mucosa Bucal/metabolismo , Compuestos de Amonio Cuaternario/farmacología , Adhesividad , Aminación , Quitosano/química , Portadores de Fármacos/química , Femenino , Humanos , Masculino , Compuestos de Amonio Cuaternario/química , Solubilidad , AguaRESUMEN
Herpes simplex virus type 1 (HSV-1) and herpes simplex virus type 2 (HSV-2) are common human pathogens that in particular cases can also cause severe problems especially in immunodeficient patients. The present paper reports the antiviral and immunomodulatory properties of a methanolic extract of C. spinosa buds (CAP), rich in flavonoids, including several quercetin and kaempferol glycosides. In particular we have investigated whether the in vitro exposure of human peripheral blood mononuclear cells (PBMCs) to CAP might inhibit the replication of HSV-2 and modulate the induction kinetics of IL-12, TNF-alpha IFN-gamma. Our findings have shown that CAP treatment interferes with HSV-2 replication in PBMCs inhibiting the extracellular virus release upregulating their production of IL-12, IFN-gamma and TNF-alpha. One could speculate that CAP may contribute in improving immune surveillance of PBMCs toward virus infection by up-regulating expression of peculiar proinflammatory cytokines; it should thus be successfully employed for treatment of HSV-2 infections in immunocompromised hosts.
Asunto(s)
Antivirales/farmacología , Capparis/química , Factores Inmunológicos/farmacología , Leucocitos Mononucleares/efectos de los fármacos , Regulación hacia Arriba/efectos de los fármacos , Células Cultivadas , Citocinas/análisis , Citocinas/biosíntesis , Flores/química , Liofilización , Herpesvirus Humano 2/crecimiento & desarrollo , Leucocitos Mononucleares/inmunología , Leucocitos Mononucleares/virología , Metanol/química , Replicación Viral/efectos de los fármacosRESUMEN
Conventional medications in articular disease are often effective for symptom relief, but they can also cause significant side effects and do not slow the progression of the disease. Several natural substances have been shown to be effective as non-steroidal anti-inflammatory drugs at relieving the symptoms of osteoarthritis (OA), and preliminary evidence suggests that some of these compounds may exert a favourable influence on the course of the disease. In this study, we assay the anti-inflammatory/chondroprotective effect of some lyophilised extracts obtained from Opuntia ficus indica (L.) cladodes and of hyaluronic acid (HA) on the production of key molecules released during chronic inflammatory events such as nitric oxide (NO), glycosaminoglycans (GAGs), prostaglandins (PGE(2)) and reactive oxygen species (ROS) in human chondrocyte culture, stimulated with proinflammatory cytokine interleukin-1 beta (IL-1 beta). Further the antioxidant effect of these extracts was evaluated in vitro employing the bleaching of the stable 1,1-diphenyl-2-picrylhydrazyl radical (DPPH test). All the extracts tested in this study showed an interesting profile in active compounds. Particularly some of these extracts were characterized by polyphenolic and polysaccharidic species. In vitro results pointed out that the extracts of Opuntia ficus indica cladodes were able to contrast the harmful effects of IL-1 beta. Our data showed the protective effect of the extracts of Opuntia ficus indica cladodes in cartilage alteration, which appears greater than that elicited by hyaluronic acid (HA) commonly employed as visco-supplementation in the treatment of joint diseases.
Asunto(s)
Antiinflamatorios/farmacología , Condrocitos/efectos de los fármacos , Ácido Hialurónico/farmacología , Opuntia/química , Polisacáridos/farmacología , Antiinflamatorios/química , Antioxidantes/metabolismo , Cartílago Articular/citología , Técnicas de Cultivo de Célula , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Condrocitos/citología , Condrocitos/metabolismo , Medios de Cultivo Condicionados/química , Dinoprostona/análisis , Evaluación Preclínica de Medicamentos , Fracturas del Cuello Femoral/patología , Fracturas del Cuello Femoral/cirugía , Glicosaminoglicanos/análisis , Humanos , Nitritos/análisis , Extractos Vegetales/química , Extractos Vegetales/farmacología , Tallos de la Planta/química , Polisacáridos/química , Especies Reactivas de Oxígeno/análisis , Especies Reactivas de Oxígeno/metabolismo , Espectrofotometría/métodosRESUMEN
Several studies have shown that UV radiation on the skin results in the formation of reactive oxygen species (ROS) that interact with proteins, lipids and DNA, thus altering cellular functions. The epidermis is composed mainly of keratinocytes, rich in ROS detoxifying enzymes and in low-molecular-mass antioxidant molecules. However, the increased generation of ROS can overwhelm the natural defences against oxidative stress. Therefore treatment of the skin with products containing plant-derived antioxidant ingredients may be a useful strategy for the prevention of UV-mediated cutaneous damage. In the present study we have investigated the in vitro capability of a Jacquez grapes wine extract (containing a significant level of proanthocyanidins, together with lower amounts of anthocyanins and hydroxycinnamic acids; JW-E), to protect skin against UVB-induced oxidative damage by using a three-dimensional tissue culture model of human epidermis. The endpoints of our experiments were cell viability, release of interleukin-1alpha and prostaglandin E(2) (well-known mediators of cutaneous inflammatory processes), accumulation in the epidermis of malondialdehyde/4-hydroxynonenal and protein carbonyl groups (derived by the oxidative damage respectively of lipids and proteins) and tissue redox balance (expressed by the levels of reduced glutathione, oxidized glutathione, glutathione peroxidase and glutathione reductase). Taken together, our findings demonstrate that the JW-E is an efficient botanical mixture able to prevent skin oxidative damage induced by UV-B exposure and may thus be a potential promising candidate as a skin photoprotective agent.
Asunto(s)
Protectores contra Radiación/farmacología , Envejecimiento de la Piel/efectos de los fármacos , Vitis/química , Aldehídos/metabolismo , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Dinoprostona/metabolismo , Liofilización , Glutatión/metabolismo , Glutatión Peroxidasa/metabolismo , Glutatión Reductasa/metabolismo , Humanos , Interleucina-1alfa/metabolismo , Peroxidación de Lípido/efectos de los fármacos , Malondialdehído/metabolismo , Estrés Oxidativo/efectos de los fármacos , Extractos Vegetales/uso terapéutico , Rayos UltravioletaRESUMEN
The present work was aimed at evaluating the in vitro effects of a lyophilized extract of wine (JW-E) obtained from Jacquez grapes (Vitis aestivalis-cinereaxVitis vinifera grapes) on the production of key molecules released in inflammatory disease utilising interleukin-1beta (IL-1beta) activated chondrocytes. The extract contains large amounts of phenolic components, in particular some flavonoids (flavan-3-ols, also known as catechins) and proanthocyanidins, as hydroxycinnamic acids and anthocyanins, that possess several biological features such as antiinflammatory and antioxidant effects and a "radical scavenger" activity too. In this study, we assayed the effect of JW-E on the production of key molecules released during chronic inflammatory events as nitric oxide (NO), prostaglandins E(2) (PGE(2)) and reactive oxygen species (ROS) in human chondrocytes culture, stimulated with proinflammatory cytokine interleukin-1beta. The JW-E proved to possess good ability against the harmfull effects of IL-1beta. Our data showed the protective effects of JW-E in cartilage alteration, that appears greater than that elicited by indomethacin, a not steroidal antiinflammatory drug (NSAID), commonly employed in joint diseases.
Asunto(s)
Condrocitos/efectos de los fármacos , Extractos Vegetales/farmacología , Vitis , Vino , Cartílago Articular/citología , Células Cultivadas , Dinoprostona/metabolismo , Frutas , Humanos , Inflamación/tratamiento farmacológico , Interleucina-1/farmacología , Óxido Nítrico/metabolismo , Osteocondritis/tratamiento farmacológico , Extractos Vegetales/uso terapéutico , Especies Reactivas de Oxígeno/metabolismoRESUMEN
In traditional medicine extracts of polysaccharide-containing plants are widely employed for the treatment of skin and epithelium wounds and of mucous membrane irritation. The extracts of Opuntia ficus-indica cladodes are used in folk medicine for their antiulcer and wound-healing activities. The present study describes the wound-healing potential of two lyophilized polysaccharide extracts obtained from O. ficus-indica (L.) cladodes applied on large full-thickness wounds in the rat. When topically applied for 6 days, polysaccharides with a molecular weight (MW)>10(4)Da from O. ficus-indica cladodes induce a beneficial effect on cutaneous repair in this experimental model; in particular the topical application of O. ficus-indica extracts on skin lesions accelerates the reepithelization and remodelling phases, also by affecting cell-matrix interactions and by modulating laminin deposition. Furthermore, the wound-healing effect is more marked for polysaccharides with a MW ranging 10(4)-10(6)Da than for those with MW>10(6)Da, leading us to suppose that the fine structure of these polysaccharides and thus their particular hygroscopic, rheologic and viscoelastic properties may be essential for the wound-healing promoter activity observed.
Asunto(s)
Laminina/efectos de los fármacos , Opuntia/química , Polisacáridos/farmacología , Piel/lesiones , Cicatrización de Heridas/efectos de los fármacos , Animales , Ácido Hialurónico/farmacología , Técnicas para Inmunoenzimas , Laminina/metabolismo , Masculino , Extractos Vegetales/química , Extractos Vegetales/farmacología , Tallos de la Planta/química , Polisacáridos/química , Ratas , Ratas Sprague-Dawley , Piel/efectos de los fármacos , Piel/patologíaRESUMEN
The aim of the present study was to evaluate the in vitro chondroprotective effects of the lyophilised methanolic extract from flowering buds of Capparis Spinosa L (LECS). This plant, common to the Mediterranean basin, has been used by the traditional medicine for its diuretic and antihypertensive effects and also in certain pathological conditions related to uncontrolled lipid peroxidation. The extract contains many constituents, in particular some flavonoids (kaempferol and quercetin derivatives) and hydrocinammic acids with several known biological effects such as the anti-inflammatory and the antioxidant ones. In this study, we assayed the effect of LECS on human chondrocytes cultures stimulated by proinflammatory cytokine interleukin-1beta (IL-1beta) and we determined the production of key molecules released during chronic inflammatory events (nitric oxide, glycosaminoglycans, prostaglandins and reactive oxygen species). We observed that LECS was able to counteract the harmful effects induced by IL-1beta. This protection appeared to be greater than that elicited by indomethacin, which is usually employed in joint diseases. Since LECS possess a chondroprotective effect, it might be used in the management of cartilage damage during the inflammatory processes.
Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Capparis/química , Condrocitos/efectos de los fármacos , Interleucina-1/toxicidad , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Condrocitos/metabolismo , Dinoprostona/metabolismo , Flores/química , Glicosaminoglicanos/metabolismo , Humanos , Óxido Nítrico/metabolismo , Extractos Vegetales/farmacología , Especies Reactivas de Oxígeno/metabolismoRESUMEN
Polyoxyethylene esters of ketoprofen (1a-e), naproxen (2a-e) and diclofenac (3a-e) were tested in vitro to determine their stability in pH 7.4 phosphate buffer and in simulated gastric fluid (pH 2.0 buffer) and their susceptibility in undergoing enzymatic cleavage in human plasma. Furthermore their in vivo antiinflammatory and analgesic activity and GI toxicity were evaluated in rodents. All the prodrugs showed a good stability both in pH 7.4 phosphate buffer and in pH 2.0 buffer. They were readily hydrolyzed by human plasma and, for each group of prodrugs, no significant difference in hydrolysis rate was observed as the length of the oligoethylene chain increased. Esters 1a-e, 2a-e and 3a-e showed an anti-inflammatory activity (expressed as inhibition percent of carrageenan-induced edema in the rat) similar to that of their respective parent drug although at higher doses. The results obtained in the writhing test in mice demonstrated that all the prodrugs tested exhibited, following acute administration, a good analgesic effect. Furthermore these esters were significantly less irritating to the gastric mucosa, although administered at doses higher than the respective parent drug.
Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Diclofenaco/farmacología , Cetoprofeno/farmacología , Naproxeno/farmacología , Polietilenglicoles , Profármacos/farmacología , Ácido Acético , Animales , Antiinflamatorios no Esteroideos/administración & dosificación , Antiinflamatorios no Esteroideos/toxicidad , Carragenina , Diclofenaco/administración & dosificación , Diclofenaco/toxicidad , Edema/inducido químicamente , Edema/prevención & control , Ésteres , Hidrólisis , Cetoprofeno/administración & dosificación , Cetoprofeno/toxicidad , Masculino , Ratones , Naproxeno/administración & dosificación , Naproxeno/toxicidad , Dimensión del Dolor/efectos de los fármacos , Vehículos Farmacéuticos , Profármacos/toxicidad , Ratas , Ratas Sprague-Dawley , Úlcera Gástrica/inducido químicamenteRESUMEN
Diabetes mellitus is associated with a high oxidative stress level, resulting from an imbalance between free radicals or reactive oxygen species production and the antioxidant systems. Inhibition of these oxidative processes by co-adjuvant therapy could therefore prevent, or at least delay, the onset and/or the development of long-term diabetic complications. Dietary supplementation with plant biophenols may be a successful strategy to decrease this risk of pathological complications. The Red Orange Complex (ROC) is a standardized red orange extract containing, as its main active principles, phenolic compounds (anthocyanins, flavanones and hydroxycinnamic acids) as well as ascorbic acid. The aim of the present preliminary study was to evaluate the effects of short-term (2 mo) dietary supplementation with ROC (50 mg/d, orally) on some serum non-invasive biomarkers of oxidative stress (total antioxidant status, or TAS, levels of thiol groups and levels of free radicals) in a group of 33 patients with Type 2 diabetes, in comparison with a group of 28 healthy volunteers. The results obtained demonstrate that in diabetic patients supplementation with ROC can improve blood levels of thiol groups on proteins (an indirect measurement of glutathione activity in serum); furthermore, it can elicit a marked decrease in serum free radical levels, in patients with high blood oxidative stress status. However, ROC supplementation appeared unable to modify serum TAS. Finally, the glycemic profile remained stable during the study period in all subjects, and no unpleasant side effects were reported. In conclusion, the treatment of diabetic patients with ROC might be of therapeutic benefit in order to protect against diabetes complications that are partially due to uncontrolled lipid oxidation. D
Asunto(s)
Citrus/química , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Estrés Oxidativo , Extractos Vegetales/uso terapéutico , Anciano , Antioxidantes/análisis , Ácido Ascórbico/administración & dosificación , Biomarcadores/sangre , Glucemia/análisis , Proteínas Sanguíneas/análisis , Suplementos Dietéticos , Ayuno , Femenino , Radicales Libres/sangre , Glutatión/sangre , Humanos , Masculino , Persona de Mediana Edad , Fenoles/administración & dosificación , Compuestos de Sulfhidrilo/sangreRESUMEN
The aim of the present study was to evaluate the in vitro antioxidant and in vivo photoprotective activities of a lyophilized extract of Capparis spinosa L. (LECS) obtained by methanolic extraction from the flowering buds of this plant. For the in vitro experiments, LECS was tested employing three different models: (a). bleaching of the stable 1,1-diphenyl-2-picrylhydrazyl radical (DPPH test); (b). peroxidation, induced by the water-soluble radical initiator 2,2'-azobis(2-amidinopropane) hydrochloride, of mixed dipalmitoylphosphatidylcholine/linoleic acid unilamellar vesicles (LUVs) (LP-LUV test); and (c). UV-induced peroxidation of phosphatidylcholine multilamellar vesicles (UV-IP test). The in vivo antioxidant/radical scavenger activity was assessed by determining the ability of topically applied LECS to reduce UVB-induced skin erythema in healthy human volunteers. From the results obtained in in vitro and in vivo tests, LECS showed a significant antioxidant effect. Furthermore, by chromatographic fractionation and spectroscopic methods, we identified the major constituents of LECS, and particularly some flavonols (kaempferol and quercetin derivatives) and hydroxycinnamic acids (caffeic acid, ferulic acid, p-cumaric acid, and cinnamic acid).
Asunto(s)
Antioxidantes/farmacología , Brassicaceae/química , Extractos Vegetales/farmacología , Protectores contra Radiación/farmacología , Adulto , Femenino , Liofilización , Humanos , Masculino , Espectrofotometría/métodosRESUMEN
Thiocolchicoside, a semi-synthetic derivative of colchicoside, is used in topical formulations for its anti-inflammatory and muscle-relaxant properties. The objective of this study was to evaluate the effect of a (propylene glycol diperlagonate) DPPG and (propylene glycol) PG mixture present in an innovative foam formulation (Miotens) on the flux of thiocolchicoside through excised human skin. Furthermore, the in vitro permeation behaviour of this new formulation (Miotens foam) was compared to another commercial product (Muscoril ointment) and to a control gel formulation (thiogel), both enhancer free. The best permeation profile was obtained from the foam formulation (Miotens) which was able to increase the thiocolchicoside flux about three fold compared to control formulation (thiogel) and about two fold compared to the commercial formulation Muscoril ointment.
Asunto(s)
Antiinflamatorios no Esteroideos/administración & dosificación , Antiinflamatorios no Esteroideos/farmacocinética , Colchicina/análogos & derivados , Colchicina/administración & dosificación , Colchicina/farmacocinética , Absorción Cutánea/efectos de los fármacos , Administración Cutánea , Adulto , Cromatografía Líquida de Alta Presión , Geles , Humanos , Técnicas In Vitro , Membranas Artificiales , Pomadas , Vehículos Farmacéuticos , Fosfatidilgliceroles , Glicoles de Propileno , Espectrofotometría UltravioletaRESUMEN
Clonazepam and lorazepam are two anxiolytics, antidepressant agents, having suitable features for transdermal delivery. The objectives of this study were to evaluate the in vitro percutaneous absorption of these drugs through excised human skin (stratum corneum and epidermis, SCE) and to determine their in vitro permeation behavior from a series of hydro-alcoholic gel formulations containing various enhancing agents. The best permeation profile was obtained for both drugs applying them together with Azone in combination with propylene glycol (PG): these enhancers were able to increase the clonazepam and lorazepam percutaneous fluxes at steady-state about threefold, compared to the free enhancer formulations (Control). To explain the mechanism of the used promoters, the benzodiazepine diffusion and partitioning coefficients from the gel containing the enhancers were calculated. The results indicated that the Azone in combination with PG could act by increasing the benzodiazepine diffusion coefficients, Transcutol increased only the SC/vehicle partition coefficients, limonene in combination with PG appeared to increase both partition and diffusion coefficients moderately, while PG did not increase both the parameters. Furthermore, to evaluate the potential application of tested benzodiazepine formulations containing Azone in combination with PG using the flux values from the in vitro experiments, the corresponding steady-state plasma concentrations (C(SS)) were calculated. The obtained calculated C(SS) values are within the lorazepam therapeutic range and suggest that transdermal delivery of this drug could be regarded as feasible.
Asunto(s)
Clonazepam/farmacocinética , Moduladores del GABA/farmacocinética , Lorazepam/farmacocinética , Absorción Cutánea , Adulto , Alcoholes , Azepinas , Cromatografía Líquida de Alta Presión , Clonazepam/administración & dosificación , Ciclohexenos , Femenino , Moduladores del GABA/administración & dosificación , Geles , Humanos , Técnicas In Vitro , Cinética , Limoneno , Lorazepam/administración & dosificación , Membranas/efectos de los fármacos , Membranas/metabolismo , Terpenos , AguaRESUMEN
Novel polyoxyethylene esters of ketoprofen (1(a-e)), naproxen (2(a-e)) and diclofenac (3(a-e)) were synthesized and evaluated as potential dermal prodrugs of naproxen, ketoprofen and diclofenac. These esters were obtained by coupling these drugs with polyoxyethylene glycols by a succinic acid spacer. The aqueous solubilities, lipophilicities and hydrolysis rates of esters 1(a-e), 2(a-e) and 3(a-e) were determined in a buffered solution and in porcine esterase. The permeation of these prodrugs through excised human skin was studied in vitro. Furthermore we investigated the in vivo topical anti-inflammatory activity of esters 1(d), 2(e) and 3(e), which showed the best in vitro profile, evaluating the ability of these compounds to inhibit methyl nicotinate (MN)-induced skin erythema on healthy human volunteers. Esters 1(a-e), 2(a-e) and 3(a-e) showed good water stability and rapid enzymatic cleavage and their hydrolysis rates, both chemical and enzymatic, were not significantly affected by the length of the polyoxyethylenic chain used as promoiety. Concerning in vitro percutaneous absorption studies, only esters 1(d-e), 2(d-e) and 3(c-e) showed an increased flux through stratum corneum and epidermis membranes compared to their respective parent drugs. In vivo results showed an interesting delayed and sustained activity of esters 1(d) and 3(e) compared to the parent drugs. In conclusion polyoxyethylene glycols could prove to be suitable promoieties for ketoprofen, naproxen and diclofenac design since esters 1(d-e), 2(d-e) and 3(c-e) showed some requirements (chemical stability, enzymatic lability and an increased skin permeation) needed to obtain successful dermal prodrugs. Furthermore, was observed an appreciable and sustained in vivo topical anti-inflammatory activity of esters 1(d) and 3(e), compared to the parent drugs, using MN-induced erythema in human volunteers as inflammation model.
Asunto(s)
Antiinflamatorios no Esteroideos/administración & dosificación , Polietilenglicoles/administración & dosificación , Profármacos/administración & dosificación , Absorción Cutánea/efectos de los fármacos , Administración Cutánea , Adulto , Antiinflamatorios no Esteroideos/química , Antiinflamatorios no Esteroideos/metabolismo , Área Bajo la Curva , Diclofenaco/administración & dosificación , Diclofenaco/química , Diclofenaco/metabolismo , Eritema/tratamiento farmacológico , Femenino , Geles , Humanos , Cetoprofeno/administración & dosificación , Cetoprofeno/química , Cetoprofeno/metabolismo , Masculino , Persona de Mediana Edad , Naproxeno/administración & dosificación , Naproxeno/química , Naproxeno/metabolismo , Polietilenglicoles/química , Polietilenglicoles/metabolismo , Profármacos/química , Profármacos/metabolismo , Absorción Cutánea/fisiología , Solubilidad , Solventes/administración & dosificación , Solventes/química , Solventes/metabolismoRESUMEN
Sedum telephium L. is a medicinal plant used in antiquity to cure many types of inflammatory skin diseases. The leaves (without the external cuticle), are used to promote healing and reduce skin inflammation and pain, and contain various components. We found two major components: flavonol glycosides and polysaccharides, with molecular weight between 13,000 and 13,500 Da. We evaluated the in-vitro antioxidant and in-vivo skin photoprotective effects of three lyophilized extracts obtained from the juice of S. telephium L. leaves: a total lyophilized juice, a lyophilized flavonolic fraction, and a lyophilized polysaccharidic fraction. Two in-vitro models were used: the bleaching of the stable 2,2-diphenyl-1-picrylhydrazyl (DPPH*) radical, and the protective effect against UV-induced peroxidation on phosphatidylcholine multilamellar vesicles, as model membranes. The antioxidant/radical scavenging activity of each lyophilized extract was also assessed in-vivo by determining their ability to reduce UVB-induced skin erythema (monitored by reflectance spectrophotometry) in healthy human volunteers. The findings of the in-vitro experiments clearly demonstrated that, unlike the lyophilized polysaccharidic fraction, the lyophilized flavonolic fraction and total lyophilized juice possess strong antioxidant/free radical scavenging properties, which are likely due to phenolic compounds. Consistent with these findings, gel formulations of both the total lyophilized juice and, to a greater degree, the lyophilized flavonolic fraction appeared to possess a strong protective effect against UV-induced skin erythema in-vivo, whereas the lyophilized polysaccharidic fraction was completely ineffective. The in-vitro and in-vivo results suggest that, both the total lyophilized juice and, in particular, the lyophilized flavonolic fraction, but not the lyophilized polysaccharidic fraction of S. telephium L. leaves, have photoprotective effects against UVB-induced skin damage.
Asunto(s)
Eritema/tratamiento farmacológico , Flavonoides/uso terapéutico , Glicósidos/uso terapéutico , Polisacáridos/uso terapéutico , Adulto , Antioxidantes/farmacocinética , Intervalos de Confianza , Femenino , Flavonoides/farmacocinética , Radicales Libres/farmacocinética , Liofilización , Glicósidos/farmacocinética , Humanos , Masculino , Fitoterapia , Hojas de la Planta/uso terapéutico , Plantas Medicinales/uso terapéutico , Polisacáridos/farmacocinética , Rayos Ultravioleta/efectos adversosRESUMEN
7-Chlorokynurenic acid 1 is a potent glycine-N-methyl-D-aspartate (NMDA) receptor antagonist, but it shows weak activity after systemic administration. In order to overcome the Blood-brain barrier (BBB), we synthetized three new esters 2-4 of 1 obtained by chemical conjugation with essential nutrients such as glucose and galactose, that are actively transported across the BBB. These compounds were assayed to evaluate their in vitro chemical and enzymatic hydrolysis. In addition the prodrugs 2-4 were tested for their ability to protect mice against NMDA-induced seizures after systemic administration. All the prodrugs 2-4 appeared moderately stable in pH 7.4 buffered solution and were susceptible to in vitro enzymatic hydrolysis. Intraperitoneal administration of either esters 2 or 4 was highly protective against seizures induced by NMDA in mice, with the latter prodrug showing the highest anticonvulsive activity. In addition, ester 4 undergoes a time-dependent extracellular hydrolysis into 1 when applied to mixed cultures of mouse cortical cells, a model that reproduces in vitro the cellular milieu encountered by the prodrugs once they penetrate the brain parenchyma.
Asunto(s)
Antagonistas de Aminoácidos Excitadores/uso terapéutico , Ácido Quinurénico/análogos & derivados , Profármacos/uso terapéutico , Convulsiones/tratamiento farmacológico , Animales , Barrera Hematoencefálica/efectos de los fármacos , Células Cultivadas , Ésteres , Agonistas de Aminoácidos Excitadores , Antagonistas de Aminoácidos Excitadores/síntesis química , Ácido Quinurénico/síntesis química , Ácido Quinurénico/uso terapéutico , Ratones , N-Metilaspartato , Neuronas/efectos de los fármacos , Profármacos/síntesis química , Convulsiones/inducido químicamenteRESUMEN
Topically-applied antioxidant drugs represent a successful strategy for protecting the skin against UV-mediated oxidative damage. However, they can afford to the skin a satisfactory photoprotection only if able to permeate through the stratum corneum and thus to reach deeper cutaneous layers. Caffeic and ferulic acids, dissolved in saturated aqueous solutions at pH 3 or 7.2, have been tested for their capability to permeate through excised human skin mounted in Franz cells. At both pH values, ferulic and, at a lower degree, caffeic acids appeared able to permeate through the stratum corneum. The known higher lipophilicity of ferulic acid may explain the fact that it permeates through the stratum corneum better than caffeic acid. However, vehicle pH values proved to have no influence on biophenol skin permeation profile; this observed lack of pH effect may reflect the drug higher concentration attainable in saturated solutions at high pH. On the basis of the findings obtained in these in vitro experiments, we designed the schedule of a series of in vivo experiments, carried out to evaluate the ability of caffeic and ferulic acids to reduce, in healthy human volunteers, UVB-induced skin erythema, monitored by means of reflectance spectrophotometry. Caffeic and ferulic acids, dissolved in saturated aqueous solution pH 7.2, proved to afford a significant protection to the skin against UVB-induced erythema. To conclude, we have confirmed, by means of in vitro and in vivo experiments, that caffeic and ferulic acids may be successfully employed as topical protective agents against UV radiation-induced skin damage; however their skin absorption is not influenced by the pH of the formulation.
Asunto(s)
Ácidos Cafeicos/farmacología , Ácidos Cumáricos/farmacología , Protectores Solares/farmacología , Administración Tópica , Adulto , Área Bajo la Curva , Ácidos Cafeicos/administración & dosificación , Cromatografía Líquida de Alta Presión , Ácidos Cumáricos/administración & dosificación , Eritema/prevención & control , Femenino , Humanos , Concentración de Iones de Hidrógeno , Técnicas In Vitro , Absorción Cutánea , Espectrofotometría Ultravioleta , Protectores Solares/administración & dosificación , Rayos UltravioletaRESUMEN
We have synthesized D-glucose or D-galactose esters of 7-chlorokynurenic acid (7ClKynA) as prodrugs to facilitate the transport of 7ClKynA across the blood-brain barrier. Intraperitoneal (i.p.) administration of either 7ClKynA-D-glucopyranos-6'-ylester (7ClKynA/Glu6) or 7ClKynA-D-glucopyranos-3'-yl ester (7ClKynA/Glu3) was protective against seizures induced by N-methyl-D-aspartate (NMDA) in mice, with the former drug showing the highest anticonvulsive activity. Systemic injection of equal amounts of 7ClKynA-D-galactopyranos-6'-yl ester (7ClKynA/Gal6) or free 7ClKynA did not protect against NMDA seizures. Microdialysis in freely moving rats showed the presence of significant amounts of 7ClKynA/Glu6, as well as of 7ClKynA or KynA, in cortical perfusates after i.p. injections of 7ClKynA/Glu6. In contrast, only small amounts of 7ClKynA or KynA were detected after i.p. injection of unconjugated 7ClKynA. Prodrug metabolism has also been examined in mouse cortical cultures containing both neurons and astrocytes. 7ClKynA/Glu6 and 7ClKynA/Gal6 were rapidly metabolized into 7ClKynA and KynA, whereas 7ClKynA/Glu3 was metabolized with a slower kinetics. As a result of its conversion into 7ClKynA and KynA, 7ClKynA/Glu6 protected cortical neurons against NMDA toxicity. We conclude that sugar conjugates of 7ClKynA (and perhaps of other excitatory amino acid receptor antagonists) are prodrugs of potential interest in the experimental therapy of epilepsy and acute or chronic neurodegenerative disorders.