Electrochemical degradation of trace antiretroviral drug stavudine was investigated by using a reactive electrochemical membrane (REM) with Ti/SnO 2 -Sb anode. From the results it was evident that the stavudine degradation followed pseudo-first-order kinetics, with the values of the degradation rate constant and half-life being 0.24 min −1 and 2.9 min, respectively, at a current density of 8 mA cm −2 . The degradation rate was obviously decreased under alkaline condition (pH = 11.0) and the degradation was also inhibited in the presence of NO 3 − and Cl − . Five intermediates were identified in the electrochemical degradation of stavudine, and the degradation pathways were proposed. Density functional theory calculation revealed that the double bond carbon atom nearby hydroxymethyl group was the site attacked by OH and the cleavage of C N bond was the rate-determining step in the electrochemical degradation of stavudine. The nitrogen in stavudine was mainly converted to nitrate and ammonium. Quantitative structure-activity relationship model indicated that the toxicity of some intermediates was higher than the parent compound stavudine. The electric energy consumption for 90% stavudine degradation ranged from 0.87 to 2.29 Wh L −1 at the experimental conditions, indicating that stavudine can be degraded efficiently by the REM with Ti/SnO 2 -Sb anode.
Chitosan-stavudine (d4T) conjugate with a succinic spacer was synthesized via carbodiimide coupling reaction and structurally characterized. In order to nanosize it for improving its therapeutic properties, the chitosan-5′- O -succinyl-d4T conjugate was crosslinked with sodium tripolyphosphate (TPP) to obtain the chitosan-d4T conjugate nano-prodrug. The morphologies of chitosan-d4T conjugate nanoparticles were observed by transmission electron microscopy (TEM), and their zeta potential, particle size, and polydispersity (size distribution) were measured by the dynamic light scattering (DLS) techniques. In vitro drug release studies at pH 1.1 and pH 7.4 indicate that the crosslinked chitosan-d4T conjugate nano-prodrug can prevent the coupled d4T from leaking out before entering the target viral reservoirs and provide a mild sustained release without the burst release. The results reveal that constructing conjugated chitosan nano-prodrugs may be a promising approach for improving the therapy efficacy of drugs in antiviral treatment.
Two kinds of chitosan-stavudine (d4T) conjugates, chitosan- O -isopropyl-5′- O -d4T monophosphate conjugate (Cs-P-d4T) with a phosphoramide linkage and chitosan-5′- O -succinyl-d4T conjugate (Cs-S-d4T) with a succinic spacer, were synthesized using an Atherton-Todd reaction and carbodiimide coupling reaction, respectively, and then structurally characterized. Their in vitro drug release behaviors and anti-human immunodeficiency virus (HIV) activity were investigated and compared. Both of the chitosan-d4T conjugates more strongly prefer to release corresponding d4T derivatives rather than free d4T in a prolonged manner but have different hydrolysis routes. The anti-HIV activity and cytotoxicity evaluated in the MT4 cell line revealed that the anti-HIV selectivity index was in the following order: Cs-P-d4T > d4T >> Cs-S-d4T since the released d4T-5′-( O -isopropyl) monophosphate from Cs-P-d4T can bypass the rate-limiting bottleneck of nucleoside phosphorylation, while the released 5′- O -succinyl-d4T from Cs-S-d4T has to be hydrolyzed to d4T and then successively phosphorylated to its active form to exert antiviral activity. The results suggested that constructing a chitosan-nucleoside reverse transcriptase inhibitor (NRTI) conjugate with a phosphoramide linkage may be an efficient approach for improving NRTI therapy efficacy in antiretroviral treatment.
Micellar electrokinetic chromatography (MEKC) with ultraviolet detection was employed for the simultaneous determination of the nucleoside reverse transcriptase inhibitors lamivudine, stavudine and didanosine with the ionic liquid-based cationic surfactant 1-tetradecyl-3-methylimidazolium bromide ([C14MIm]Br) as the pseudostationary phase. The composition, pH, and concentration of running buffer, surfactant concentration, separation voltage, and injection time were optimized. In comparison with conventional cationic surfactants, improved separation was observed using [C14MIm]Br. The applicability of the method was demonstrated by the analysis of human urine. The method exhibited wide linear ranges with limits of quantitation of 0.5, 0.3, and 1.0 μg/mL for lamivudine, stavudine, and didanosine, respectively. The intra-day and inter-day accuracies were from 91.5% to 114.0%. The precision, expressed as relative standard deviation (RSD), was less than 12.6% for the peak area. The recoveries of the analytes in the samples were between 91.8% and 97.3%. This approach is convenient, rapid, and economical for these analytes in biological samples.
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