Dizajniranje, sinteza, kinetika hidrolize i farmakodinamski profili konjugata aceklofenaka s histidinom i alaninom

The gastrointestinal toxicity associated with aceclofenac can be reduced by condensing its carboxylic acid group with methyl esters of amino acids like histidine and alanine to give amide linkage by the Schotten-Baumann method. Physicochemical characterization of the conjugates was carried out by various analytical and spectral methods. The synthesized conjugates were also subjected to in vitro hydrolysis in simulated gastric fluid (SGF) at pH 1.2, simulated intestinal fluid (SIF) at pH 7.4 and SIF + 80 % human plasma at pH 7.4. The release of free aceclofenac from histidine and alanine conjugated aceclofenac showed negligible hydrolysis in SGF compared to SIF. This indicated that the conjugates do not break in stomach, but release aceclofenac in SIF. Both synthesized conjugates showed excellent pharmacological response and encouraging hydrolysis rate in SIF and SIF + 80 % human plasma. Marked reduction of the ulcer index and comparable increase in analgesic and anti-inflammatory activities were obtained in both cases compared to aceclofenac alone. These findings suggest that the conjugates are better in action compared to the parent drug and have fewer gastrointestinal side-effects.Gastrointestinalna toksičnost aceklofenaka može se umanjiti kondenzacijom karboksilne skupine aceklofenaka s metilnim esterima aminokiselina poput histidina i alanina, pri čemu se stvaraju nove amidne veze po Schotten-Baumannovoj metodi. Fizikokemijska karakterizacija konjugata provedena je različitim analitičkim i spektralnim metodama. Nadalje, praćena je hidroliza sintetiziranih konjugata in vitro u simuliranoj gastričnoj tekućini (SGF) pri pH 1,2, simuliranoj intestinalnoj tekućini (SIF) pri pH 7,4 i simuliranoj intestinalnoj tekućini s 80 % humane plazme pri pH 7,4. Oslobađanje aceklofenaka iz konjugata s histidinom, odnosno alaninom, bilo je zanemarivo u SGF-u, u odnosu na oslobađanje u SIF-u. To ukazuje da su konjugati stabilni u želucu, dok se u SIF-u iz njih oslobađa aceklofenak. Oba konjugata daju izvrstan farmakološki odgovor i zadovoljavajući stupanj hidrolize u SIF-u i smjesi SIF-a i humane plazme. Oba konjugata pokazala su značajno smanjenu ulcerogenost i pojačano analgetsko i protuupalno djelovanje u odnosu na aceklofenak. Rezultati ukazuju na prednost konjugata u odnosu na samu ljekovitu tvar

Effects of quercetin on kidney injury induced by doxorubicin

OBJECTIVES: The anthracycline antitumor drug doxorubicine causes severe nephrotoxicity in a variety of experimental animals and may be nephrotoxic to humans. The aim of present study was to determine the protective effects of quercetin against doxorubicin-induced kidney injury with light microscopy. METHODS: Forty male Wistar albino rats were divided into four groups: control, doxorubicin, doxorubicin + quercetin and quercetin. A single dose of 20 mg/kg/i.p. doxorubicin was used to induce injury. Quercetin was administrated orally against doxorubicin toxicity. The kidneys were examined under light microscopy after H&E (hematoxylin-eosin) staining and the changes were scored. RESULTS: Significant tissue injury was observed in doxorubicin-administered group. Among these injuries, renal tubular dilatation, tubular vacuolar changes, glomerular vacuolization, decrease in bowman space, bowman capsule thickening, and interstitial infiltration were evident. However, the injury induced by doxorubicin was attenuated with quercetin administration. DISCUSSION: Quercetin decreased doxorubicin-induced kidney damage (Tab. 1, Fig. 4, Ref 27). Text in PDF www.elis.sk.Afyon Kocatepe University Scientific Research Projects Coordination Unit [08.TIP.01]This study was supported by Afyon Kocatepe University Scientific Research Projects Coordination Unit (Project Number: 08.TIP.01)

Effects of caffeic acid phenethyl ester and alpha-tocopherol on reperfusion injury in rat brain

Oxygen-derived free radicals have been implicated in the pathogenesis of cerebral injury after ischaemia-reperfusion. Caffeic acid phenethyl ester (CAPE), an active component of propolis extract, exhibits antioxidant properties. The purpose of the present study was to investigate the effects of ischaemia and subsequent reperfusion on rat brain and to investigate the effects of two free radical scavengers, CAPE and alpha-tocopherol, on this in vivo model of cerebral injury. Ischaemia was induced by bilateral occlusion of the carotid arteries for 20 min and reperfusion was achieved by releasing the occlusion to restore the circulation for 20 min. Control rats underwent a sham operation. CAPE at 10 mumol kg(-1) or alpha-tocopherol at 25 mumol kg(-1) was administered intraperitoneally before reperfusion. Reperfusion led to significant increase in the activity of xanthine oxidase and higher malondialdehyde levels in the brain. Acute administration of both CAPE and alpha-tocopherol suppressed ischaemia-reperfusion-induced cerebral lipid peroxidation and injury, but CAPE seems to offer a better therapeutic advantage over alpha-tocopherol. Copyright (C) 2003 John Wiley Sons, Ltd