Preparation, Characterization and in vitro Release of Chitosan-stavudine Conjugate Nano-prodrug

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.

世界卫生组织力促阶段性停用Stavudine药物

据美国BIOCOMPARE科技新闻网（2009—12—25）报道，根据日内瓦路透社（Geneva，Reuters）的报道，世界卫生组织（WHO）力促阶段性地停用胸腺嘧啶核苷类似物（sta、rudine）这种最常见的AIDS药物，原因是stavudine会导致长期、不可恢复的不良反应，包括破坏神经的功能等。此外，WHO也建议感染HIV的患者，包括怀孕妇女在内，应尽早使用AIDS药物，以避免病毒垂直传染给胎儿。

An antiretroviral regimen containing 6 months of stavudine followed by long-term zidovudine for first-fine HIV therapy is optimal in resource-limited settings： a prospective, multicenter study in China

Background An zidovudine （AZT）-substitution regimen containing 24-week stavudine （d4T） followed by long-term AZT for HIV therapy is potential to trade off short-term AZT-related anemia and long-term risks associated with d4T in resourcelimited settings.However,evidence is scarce.This study aims to assess the efficacy and safety of AZT-substitution regimen,aiming to find a regimen with better efficacy,less adverse events,and more affordability in resource-limited settings.Methods This prospective,multicenter study enrolled 499 （190 on d4T regimen,172 on AZT regimen,and 137 on AZT-substitution regimen） HIV-1-infected subjects who initiated combined antiretroviral therapy and attended follow-up visits over 96 weeks from 2009 to 2011.Lamivudine （3TC） and either nevirapine （NVP） or efavirenz （EFV） were the other two drugs in the antiretroviral regimens.Virologic and immunologic responses and adverse events were monitored at baseline and at weeks 4,12,24,36,48,60,72,84,and 96.Results In terms of hematological adverse effects,AZT-substitution group had similar safety profiles to d4T group and was superior to AZT group.In comparison with AZT-substitution group,AZT group was associated with higher risk of developing anemia （adjusted hazard ratio （aHR）for anemia ≥ grade Ⅱ,8.44,95％ CI 1.81-39.46） and neutropenia （aHR for neutropenia ≥ grade Ⅱ,1.86,95％ CI 1.19-2.93）.The prevalence of lipodystrophy in d4T group was 19.5％,while that in AZT-substitution group was zero.As to antiretroviral efficacy,these three groups showed no differences.Conclusion AZT-substitution regimen provides a relatively safe and effective first-line antiretroviral strategy in resource-limited settings.

A one-year clinical trial using didanosine, stavudine and nevirapine for highly active antiretroviral therapy

Antiretroviral therapy is a key determinant in the treatment and prevention of human immunodeficiency virus (HIV) infection. Initial treatment for patients with HIV infection generally includes two nucleoside reverse transcriptase inhibitors (NRTI) and a protease inhibitor (PI) or a nonnucleoside reverse transcriptase inhibitor (NNRTI). The combination antiretroviral therapy (refers to highly active antiretroviral therapy or HAART) showed a significant effect upon reducing morbidity and mortality of HIV disease. Cao and colleagues^1 began the clinical application of HAART in 1999 and completed the first clinical trial in China using a combination of two NRTIs and one PI. The result in using combivir (AZT+3TC) and indinavir (2 NRTIs+1 PI) are consistent with those reported in the literature.~2 In this study, we report the first virological and immunological outcomes in HIV infected Chinese patients treated with a combination of didanosine, stavudine and nevirapine (2 NRTIs+1 NNRTI) for 52 weeks.

Studies on the Compounds of d4T Combined with Nitric Oxide Donors and Nitric Oxide Synthase Inhibitors and their Anti-HIV and AIDS Activity

Stavudine, a potent anti HIV and AIDS related complex, is one of the Nucleoside Analogue Reverse Transcriptase Inhibitors (NARTIs). It is phosphorylated intracellularly and then inhibits the viral reverse transcriptase by acting as a false substrate. Modifications made on the hydrogen labile at the 5' position on the sugar is an interesting template for the elaboration of new potent anti HIV and AIDS drugs. The expected advantages of the modified stavudine prodrugs can be multiple: synergistic drug activities, enhancement of stavudine intracellular uptake, increase of stavudine brain delivery, and bypass of the first stavudine phosphorylation step into the cells. Nitric oxide synthase inhibitors of stavudine and nitric oxide donors of stavudine may hold significant promise for the treatment of HIV and AIDS.

Melanonychia in Patients Infected with Human Immunodeficiency Virus Original Communication

This study examined whether melanonychia was more prevalent in 1) HIV positive individuals compared to HIV negative persons, 2) HIV positives exposed to zidovudine and/or stavudine and 3) those with darker skin pigmentation. Procedures. 267 HIV positive and 273 HIV negative patients were examined for presence or absence of melanonychia and level of skin pigmentation using the Fitzgerald scale. Pharmacy records were examined for determining exposure to zidovudine or stavudine. Chi square, odds ratios and logistic regression were used to examine the study questions Main Findings. Melanonychia appeared in 49.1% of 267 HIV positive and 21.8% of 273 HIV negative subjects. Adjusting for skin pigmentation, HIV positives were 4.1 times more likely to have melanonychia than HIV negatives. Melanonychia was present in 54% of those receiving zidovudine and in 42% of those receiving stavudine (OR = 2.73, p = 0.05). In a multivariate model in HIV positives which included skin type, prescription of zidovudine and/or Stavudine, only dark skin (OR = 14.62, p < 0.001) and zidovudine (OR = 2.65, p < 0.03) were significant. Principal Conclusions. HIV infected persons are prone to melanonychia. This is more frequent in darker skinned persons and is enhanced in those exposed to zidovudine.

An Odyssey in antiviral drug development—50 years at the Rega Institute:1964–2014

I.How it started I entered the Rega Institute for Medical Research in August 1964,as a medical student,to start working under the guidance of Prof.Piet De Somer,then professor of microbiology at the Leuven School of Medicine.When I graduated