Abstract-Dipeptide esters of paracetamol were prepared in high yields. These compounds are quantitatively hydrolyzed to paracetamol and corresponding 2,5-diketopiperazines at pH 7.4 and 37°C. The reactivity is increased in sarcosine and proline peptides and decreased by bulky side chains at both the N-and C-terminal residues of the dipeptide carrier. Moreover, dipeptide esters of paracetamol did not affect the levels of hepatic glutathione. Thus, dipeptides seem promising candidates as carriers for cyclizationactivated prodrugs. Ó 2005 Elsevier Ltd. All rights reserved.Phenol drugs are attractive targets for prodrug design due to their extensive first-pass metabolism. 1 In the case of paracetamol, 1 (Scheme 1), the metabolism can lead to serious hepatic and renal toxic effects. 2 These toxic side-effects have been ascribed to the formation of a N-acetylquinone imine, 3 which is detoxified by reaction with glutathione leading to glutathione depletion and cell death. 3,4 Esterification of paracetamol with amino acids was reported as a means to obviate the severe hepatotoxicity of the drug at high doses 5 as well as to increase aqueous solubility. 6 We now report that dipeptides may also be used as carriers for hydroxyl-containing drugs. Dipeptide esters and amides (2, X = O or NH, Scheme 1) can deliver the parent drug through enzyme-independent processes such as the intramolecular cyclization to form the corresponding diketopiperazines (3, DKPs, Scheme 1). 7,8 The major drawback of using dipeptides as carrier candidates for prodrugs is their susceptibility to non-specific peptidases. However, enzymatically stable dipeptides (e.g., containing 2-aminoisobutyric acid or N-methylglycine as carriers) have been used successfully to improve physico-chemical properties of cytarabine 9 and cyclosporine. 10 Despite the potential of dipeptides as carriers for cyclization-activated prodrugs, there is a lack of systematic information concerning the effect of the peptide structure on the rate of drug release under physiological conditions. Herein we report the synthesis and the chemical reactivity of dipeptide esters of paracetamol, 4, encompassing a wide range of amino acid residues to evaluate the suitability of dipeptide esters as potential cyclization-activated prodrugs of paracetamol. In addition, the potential hepatotoxicity of several paracetamol derivatives was studied by evaluating the effect on the hepatic levels of glutathione in mice.Paracetamol esterification was based on the O-(benzotriazol-1-yl)-N,N,N 0 ,N 0 -tetramethyluronium 0960-894X/$ -see front matter Ó

The objective of this work was to evaluate the growth performance of common snook (Centropomus undecimalis) subjected to different feeding rates and frequencies using automatic feeders. Two experiments of 60 days each were carried out. In the first one, 20 fishes per tank were distributed in three feeding rates of: 5, 10, and 15% body weight per day. In the second experiment, 20 fishes per tank were distributed in nine tanks, in three feeding frequency: once a day, three times a day, and six times a day. Water parameters were maintained at the recommended level for the species. Final weight, body weight gain, specific growth rate, and feed conversion rate did not differ significantly between the 10 and 15% feeding rates. However, both rates differed from the 5% one. The feeding frequency of six times a day resulted in better values for final weight, final biomass, body weight gain, and specific growth rate. Therefore, common snook fingerlings should be fed at the feeding rate of 10% body weight per day, six times a day, in order to achieve the best growth performance.

Resumo -O objetivo deste trabalho foi avaliar o efeito da privação alimentar e a ocorrência de crescimento compensatório sobre o desempenho produtivo de formas jovens do robalo-flecha (Centropomus undecimalis). O experimento teve duração de 60 dias, em que os peixes -35 indivíduos por tanque -foram divididos nos três seguintes grupos de tratamentos: com alimentação todos os dias (controle); com alimentação cinco dias por semana, seguidos de dois dias de jejum; e com alimentação quatro dias por semana, seguidos de três dias de jejum. Os tratamentos de privação alimentar proporcionaram indicadores de desempenho significativamente inferiores aos do controle. Formas jovens da espécie não devem ser submetidas a períodos de privação alimentar, pelos prejuízos que esta prática acarreta ao desempenho produtivo.Termos para indexação: Centropomus undecimalis, hiperfagia, manejo alimentar, maricultura. Compensatory growth and food deprivation in common snook growth performanceAbstract -The objective of this work was to evaluate the effect of food deprivation and the occurrence of compensatory growth on the performance of common snook fingerlings (Centropomus undecimalis). The experiment lasted for 60 days, when fish -35 individuals per tank -were divided into three groups of treatments, as follows: daily feeding (control); feeding for five days a week, followed by two days of fast; and feeding for four days a week, followed by three days of fast. The treatments of alimentary restriction provided performance indicators significantly inferior to those of the control. Common snook fingerlings should not be subjected to food restriction because of the damages that this practice entails to productive performance.

The synthesis of a new series of 3-alkoxy-5-hydroxy-5trifluoromethyl pyrrolidin-2-ones 2a-h from the reaction of 1,1,1trifluoro-4-alkoxyalk-3-en-2-ones 1a-h of the general formula F 3 CC(O)C(R 2)=C(R 1)OR, where: R = Me, Et,-(CH 2) 2- ,-(CH 2) 3-; R 1 = H, Me, Ph, p-Me-Ph, p-F-Ph; and R 2 = H, Me,-(CH 2) 2- ,-(CH 2) 3-with sodium cyanide in hydro-alcoholic medium is reported.

Trifluoro-4-alkoxyalk-3-en-2-ones. -Different substrates react with NaCN in an aqueous-alcoholic medium to yield highly functionalized title compounds, which may be of therapeutic value. -(ZANATTA*, N.; ROSA, L. S.; CORTELINI, M. F. M.; BEUX, S.; SANTOS, A. P. D.; BONACORSO, H. G.; MARTINS, M. A. P.; Synthesis 2002, 16, 2404-2408; Dep. Quim., Univ. Fed. Santa Maria, 97105 Santa Maria, Brazil; Eng.) -Mais 11-114