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The purpose of this study was to synthesize and determine the in vitro transdermal penetration of cytarabine and its 5-alkyl esters and to establish a correlation, if any, with selected physicochemical properties. The n-alkyl esters were synthesized by acylation of cytarabine (1) at its pharmacophoric 5-OH. The transdermal flux values of (1) and its esters were determined in vitro using Franz diffusion cell methodology. Aqueous solubility and log D (pH 7.4) values were determined and assessed for correlation to transdermal flux. An inverse relation was observed between the water solubility (Sw) and log D values. Of all esters, (4) exhibited the highest flux value of 22.2 nmol.cm-2.h-1, which is significantly different to that of the parent drug cytarabine (3.70 nmol.cm-2.h-1). No trend was found between water solubility and flux values.

The objective of this study was to determine the in vitro transdermal permeation through the human stratum corneum (SC) of the antiretroviral (ARV) drug lamivudine (3TC) (1) and its synthesised methoxypoly(ethylene glycol) (MPEG) carbamates and carbonates in phosphate buffer solution and with the use of Pheroid™ as delivery system, and to establish a relationship, if any, with selected physicochemical properties. The synthesis and in vitro human skin permeation flux of three N4-methoxypoly(ethylene glycol) carbamates (3)-(5) and three 6-O-methoxypoly(ethylene glycol) carbonates (6)-(8) of lamivudine are reported. The derivatives were synthesised in a two-step process by coupling activated MPEG oligomers of various chain lengths to either the 4-amino or the 6-hydroxy group of lamivudine. Irrespective of the oligomeric series of derivatives (carbamate or carbonate), the aqueous solubility increased as the MPEG chain lengthened while the solubility in octanol (lipophilicity) remained almost constant. Regardless of the mechanism of diffusion, viz. passive (in PBS) or use of enhancer (Pheroid™), no derivative penetrated the skin better than the parent drug itself. The use of Pheroid™ appeared to retard skin permeation.

The objective of this study was to synthesize derivatives of the anti-HIV drug stavudine (d4T) with more favourable physicochemical properties for transdermal delivery in an effort to increase transdermal penetration of stavudine and thus reduce the severe side effects associated with the dose-dependent oral therapy. The synthesis, hydrolytic stability, and in vitro human skin permeation flux of a series of novel methoxypoly(ethylene glycol) (MPEG) carbonates of stavudine are reported. The carbonates were synthesized in a two-step process by coupling the MPEG promoiety of various chain lengths to C-5 of d4T. In kinetic studies the carbonates proved to be markedly stable in weakly acidic phosphate medium (pH 5.0) with half-lives ranging from 16 to 58 days. The aqueous solubility increased as the ethylene oxide chain lengthened. However, there was no significant increase in the estimated solubility in octanol. In vitro in the phosphate buffer (200 mM; pH 5.0) almost all carbonates permeate the human skin. However, the most effective penetrant, the derivative with 3 ethylene oxide units in the side chain, exhibited a flux of 26.1 nmol/cm2/h as compared to 59.15 nmol/cm2/h of the parent drug stavudine. Thus, no permeation enhancement was observed during this study.

An Immunogold labeling procedure and experimental data are presented, which demonstrate that antibodies produced against a bovine serum albumin-abscisic acid conjugate can be used both to characterize the cellular and subcellular localization of abscislc acid (ABA), and to permit quantitative comparisons of this hormone in the subcellular compartments prior to and at times of drought stress. At the control leaf water potential (approximately -0.45 MPa), a quantitatively similar positive labeling pattern was observed in the chloroplasts and apoplast. A twofold drought stress-induced increase in the apoplastic ABA concentration was observed in the drought stressed leaf tissue (i.e., at a leaf water potential of approximately -1.55 MPa), while the ABA concentration in the chloroplasts did not differ from that of the controls. Three histochemical controls and the physiological observations validated the specificity of the procedure. Based on the labeling patterns we observed and literature cited, the validity of the hypothesis that drought stress induces a release of chloroplastic ABA is questioned. We interpreted our results as providing indirect evidence for a drought stress-induced root source origin for the increased apoplastic ABA concentrations.

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