Inhibitory effect of tea polyphenols on local tissue damage induced by snake venoms.

The methanolic extract of fresh tea leaves of Camellia sinensis L. (Theaceae) (CS) was assayed for its potential to inhibit enzymes with hydrolytic activity in Naja naja kaouthia Lesson (Elapidae) and Calloselasma rhodostoma Kuhl (Viperidae) venoms. These snake venom enzymes are responsible for the early effects of envenomation, such as local tissue damage and inflammation. The CS extract inhibited phospholipase A(2), proteases, hyaluronidase and L-amino acid oxidase in both venoms by in vitro neutralization and inhibited the hemorrhagic and the dermonecrotic activities of the venoms in vivo. It is suggested that the inhibitory potential of the CS extract against local tissue damage induced by snake venoms may be attributed to complexation and chelation between the venom proteins and the phenolic contents of the extract.

In vitro antimicrobial activity of Zingiber cassumunar (Plai) oil and a 5% Plai oil gel.

The essential oil of Zingiber cassumunar (Plai oil) exhibits antimicrobial activity against a wide range of Gram-positive and Gram-negative bacteria, dermatophytes and yeasts. Dermatophytes were found to be the most susceptible microorganisms followed by yeasts, whereas bacteria were the least susceptible. The mean diameter of the inhibition zone determined by the disc diffusion screening method increased with increasing Plai oil concentration between 6.25 and 50 vol %. The minimum bactericidal concentration (MBC) determined by the broth macrodilution method ranged from 0.62 to 2.5 vol % for Plai oil and from 52 to 79 mg/mL for the 5 wt % Plai oil gel, whereas the minimum fungicidal concentration (MFC) ranged from 0.31 to 1.25 vol % for Plai oil and from 13.8 to 39.5 mg/mL for the 5% Plai oil gel.

Conjugate of N4-(4-carboxybutyryl)-ara-C and ethylenediamine-introduced dextran. Drug release profiles and further in vivo study of its antitumor effects.

In vitro and further in vivo work with a conjugate formed from the cytotoxic drug 1-beta-arabinofuranosylcytosine (ara-C) and dextran 2000 are described. In the preparation of this conjugate, functionalisation of ara-C was via N4-(4-carboxybutyryl)-ara-C (glu-ara-C), permitting conjugation with amino groups introduced by prior reaction of the oxidised dextran with ethylenediamine; by varying the proportions of the reaction components, 5.4 to 7.7% w/w loadings of ara-C were obtained. At physiological pH, in vitro, drug release from a 5.4% loaded conjugate was gradual and was dominantly ara-C; at lysosomal pH (pH 5) the release rate was much slower and more ara-U was formed. Antitumour effects were evaluated in L1210 leukaemic mice following single (1 day after inoculation) or double (2 and 6 days after inoculation) intraperitoneal injection of ara-C, glu-ara-C, or a 7.7% loaded conjugate at three dose levels. In all cases, the increase in lifespan was greatest following use of the conjugate, but the differences in the effects of ara-C and the conjugate were only significant at the lowest dose level. Glu-ara-C was virtually inactive under all conditions.

Antitumor characteristics of the conjugate of N4-(4-carboxybutyryl)-ara-C with ethylenediamine-introduced dextran and its resistance to cytidine deaminase.

By oxidation of dextran, and reduction of the Schiff bases formed by reaction of the oxidised dextran with diaminoalkanes, several diaminoalkane-introduced dextrans were prepared and evaluated as drug carriers. Conjugates between N4-(4-carboxyburyryl)-1-beta-D-arabinofuranosylcytosine (glu-ara-C) and such drug carriers were prepared, and selected conjugates were tested in vivo, and investigated for inhibitory effects on cytidine deaminase. Ethylenediamine-introduced dextran prepared under 10% oxidation conditions was found to be most useful as a drug carrier from its chemical characteristics and toxicity evaluation in BDF1 mice. The conjugate obtained from glu-ara-C and ethylenediamine-introduced dextran 2000 showed high antitumor activity, significant at the relatively low dose of 100 mg equivalent ara-C/kg, in BDF1 mice bearing L1210 leukemia cells. Glu-ara-C and the conjugate were unaffected by cytidine deaminase under conditions in which 1-beta-D-arabinofuranosylcytosine was degraded rapidly to 1-beta-D-arabinofuranosyluracil.

In vitro pH-dependent drug release from N4-(4-carboxybutyryl)-1-beta-D-arabinofuranosylcytosine and its conjugate with poly-L-lysine or decylenediamine-dextran T70.

N4-(4-Carboxybutyryl)-1-beta-D-arabinofuranosylcytosine (glu-ara-C), the conjugate of glu-ara-C and poly-L-lysine (PLL), (PLL-glu-ara-C), and the conjugate of glu-ara-C and decylenediamine-dextran T70 (T70-C10), (T70-C10-glu-ara-C), were prepared. Drug regeneration from glu-ara-C and the conjugates was investigated in buffered solutions of pH 4,5,7,7.4 and 8. The character of the drug release from the conjugates was different from that from glu-ara-C. Namely, the release of 1-beta-D-arabinofuranosylcytosine (ara-C) from glu-ara-C was accelerated under both weakly acidic and weakly basic conditions, while it was accelerated only under weakly basic conditions from the conjugates. Overall, the drug release profiles from the conjugates showed similar patterns. However, under neutral and weakly basic conditions, ara-C was regenerated more rapidly from PLL-glu-ara-C than from T70-C10-glu-ara-C. During the incubation of glu-ara-C and the conjugates under weakly acidic conditions, 1-beta-D-arabinofuranosyluracil (ara-U) was detected and its amount increased with time to similar extents.