Stavudine (d4T)

SB-271046 is a potent, selective and orally active antagonist of 5-HT6 receptor (pKi = 8.9 in HeLa cell in vitro)

5-HT receptor is a G-protein coupled receptor for 5-hydroxytryptamine (serotonin) that found in nerve systems. It also functions as receptor for various alkaloids and psychoactive substances.

In native brain tissue, SB-271046 exhibits high affinity for human recombinant 5-HT6 receptors and 5-HT6 receptors. SB-271046 has a 200 fold greater selectivity over all other 5-HT receptors subtypes tested. [1]

In rat MEST (maximal electroshock seizure threshold) test, SB-271046 increases the seizure threshold over a wide range of dose with a minimum effective dose of 40.1 mg kg71 p.o. and maximum effect at 4 h post-dose. [1] In rat Morris water maze that measuring behavior acquisition and retention, galanthamine and SB-271046 combined treatment reverses the scopolamine- or MK-801-induced learning impairments. [2]

References:
1.  Routledge C, Bromidge SM, Moss SF et al. Characterization of SB-271046: a potent, selective and orally active 5-HT (6) receptor antagonist. Br J Pharmacol. 2000 Aug; 130(7):1606-12.
2.  Marcos B, Chuang TT, Gil-Bea FJ, Ramirez MJ. Effects of 5-HT6 receptor antagonism and cholinesterase inhibition in models of cognitive impairment in the rat. Br J Pharmacol. 2008 Oct;155(3):434-40.

Usage of stavudine (D4T) - a retrospective analysis in a South London hospital.[Pubmed:17362559]

Int J STD AIDS. 2007 Mar;18(3):215-7.

British HIV Association (BHIVA) guidelines are updated on a regular basis with emergence of new clinical evidence. In June 2003, the BHIVA guidelines recommended that Stavudine (d4T)-containing regimens are less preferred if other viable options are available. A retrospective analysis was conducted to establish whether local prescribing practice reflects national guidance offered by BHIVA. This study identifies 28 patients on D4T combinations, which represents 2% of the total treated group in our clinic population. In all, 89% (25/28) of patients had a viral load of <50 copies/mL and CD4 counts ranged from 122 to 1016 cells/mm(3). In this study, 12/28 patients had documented lipodystrophy. Seventeen out of 28 patients had no clear documented reasons for remaining on D4T, eight patients preferred to continue and three patients continued because of genotypic findings. This study shows that a small proportion of patients are still on D4T-containing regimen for the following reason - patient's choice, side-effects, toxicities and interaction. The majority of patients remaining on D4T had documented lipodystrophy changes. Therefore, clinicians continuing to prescribe D4T should document the precise reason for its continued use. If patients prefer to continue D4T, this should be well documented to circumvent any medicolegal consequences, should toxicity develop later.

beta-Estradiol attenuates the anti-HIV-1 efficacy of Stavudine (D4T) in primary PBL.[Pubmed:18808673]

Retrovirology. 2008 Sep 22;5:82.

BACKGROUND: Female hormones are known to play an important role in predisposition for many infectious diseases. Recent work suggests there are gender effects in HIV/AIDS progression. Here we ask whether the sex steroid hormone beta-estradiol affects the replication of HIV-1 or the efficacy of a common anti-retroviral drug, Stavudine (d4T). RESULTS: Human PBL were infected with HIV-1 in the presence or absence of combinations of sex steroid hormones and the anti-retroviral drug, D4T. After seven days in culture, viral supernatants were assayed for HIV-1 p24 protein. beta-estradiol resulted in a modest inhibition of HIV-1 replication of approximately 26%. However, 2 nM beta-estradiol increased the amount of HIV-1 replication in the presence of 50 nM D4T from a baseline of 33% (+/- SE = 5.4) to 74% (+/- SE = 5.4) of control virus levels in the absence of drug. Both results were statistically highly significant (p < 0.001). beta-estradiol did not increase the replication of a D4T-resistant strain of HIV in the presence of D4T. The effects were unlikely to be due to general cell inhibition or toxicity because these concentrations of drug and hormone cause no cytotoxicity in PBL as measured by trypan blue exclusion. CONCLUSION: beta-estradiol inhibited both HIV-1 replication in primary human PBL and the antiretroviral efficacy of D4T in PBL cultures. To optimize antiretroviral drug therapy, it may be necessary to monitor patient hormonal status.

Early nucleoside reverse transcriptase inhibitors for the treatment of HIV: a brief history of stavudine (D4T) and its comparison with other dideoxynucleosides.[Pubmed:19854224]

Antiviral Res. 2010 Jan;85(1):34-8.

The occasion of this 25th anniversary issue encouraged us to reminisce about the important history of the discovery of the dideoxynucleoside analogues for the treatment of HIV/AIDS and to chronicle our thoughts about a particular exciting and rewarding period of our scientific careers. Following the identification of the anti-HIV activity of zidovudine (AZT), we participated in the urgent quest to discover optimal treatments of HIV infection and AIDS. A number of previously synthesized nucleoside analogues were comparatively evaluated, and Stavudine (d4T) emerged as a promising candidate for development. Following clinical evaluation, D4T became a mainstay of the initial antiretroviral combination therapy, prolonging and saving numerous lives. It has only recently been supplanted by better-tolerated treatments. This article forms part of a special issue of Antiviral Research marking the 25th anniversary of antiretroviral drug discovery and development, vol. 85, issue 1, 2010.

Changing utilization of Stavudine (d4T) in HIV-positive people in 2006-2013 in the EuroSIDA study.[Pubmed:25988795]

HIV Med. 2015 Oct;16(9):533-43.

OBJECTIVES: The long-term side effects of Stavudine (d4T) led to recommendations in 2009 to phase out use of this drug. We aimed to describe temporal patterns of d4T use across Europe. METHODS: Patients taking combination antiretroviral therapy (cART) in EuroSIDA with follow-up after 1 January 2006 were included in the study. cART was defined as d4T-containing [d4T plus at least two other antiretrovirals (ARVs) from any class] or non-d4T-containing (at least three ARVs from any class, excluding d4T). Poisson regression was used to describe temporal changes in the prevalence of d4T use and factors associated with initiating d4T. RESULTS: A total of 5850 patients receiving cART on 1 January 2006 were included in the current analysis, rising to 7768 patients on January 1 2013. During this time, the prevalence of d4T use fell from 11.2% to 0.7%, with an overall decline of 19% per 6 months [95% confidence interval (CI) 19-20%]. d4T use declined fastest in Northern Europe [26% (95% CI 23-29%) per 6 months], and slowest in Eastern Europe [17% (95% CI 16-19%) per 6 months]. In multivariable Poisson regression models, new d4T initiations decreased by 14% per 6 months [adjusted incidence rate ratio (aIRR) 0.86; 95% CI 0.80-0.91]. Factors associated with initiating d4T were residence in Eastern Europe (aIRR 4.31; 95% CI 2.17-9.98) versus other European regions and HIV RNA > 400 copies/mL (aIRR 3.11; 95% CI 1.60-6.02) versus HIV RNA < 400 copies/mL. CONCLUSIONS: d4T use has declined sharply since 2006 to low levels in most regions; however, a low but persistent level of d4T use remains in Eastern Europe, where new d4T initiations post 2006 are also more common. The reasons for the regional differences may be multifactorial, but it is important to ensure that all clinicians treating HIV-positive patients are aware of the potential harmful effects associated with d4T.

Antiretroviral activity of stavudine (2',3'-didehydro-3'-deoxythymidine, D4T).[Pubmed:8540743]

Antiviral Res. 1995 Jun;27(3):189-203.

Stavudine, 2',3'-didehydro-3'-deoxythymidine (D4T), is a potent inhibitor of HIV-1 reverse transcriptase in vitro. In clinical studies, stavudine has excellent oral bioavailability in excess of 80%. The dose-limiting toxicity is peripheral neuropathy, which occurred in 15% of stavudine versus 6% of zidovudine-treated patients for 80 weeks in a randomized, blinded, phase III trial. Stavudine-treated groups have experienced significant increases in mean CD4 cell counts and decreases in both mean serum p24 antigen levels and infectious HIV titers in peripheral blood mononuclear cells. In subjects with prior zidovudine treatment, the duration of these responses is limited; CD4 counts and serum p24 antigen levels return to baseline after approximately 6 months. The effect of stavudine on clinical outcome and survival has not yet been established in comparative trials. Stavudine offers an additional therapeutic option to those individuals who are refractory to or intolerant of other available antiretrovirals.

Both 2',3'-dideoxythymidine and its 2',3'-unsaturated derivative (2',3'-dideoxythymidinene) are potent and selective inhibitors of human immunodeficiency virus replication in vitro.[Pubmed:3028398]

Biochem Biophys Res Commun. 1987 Jan 15;142(1):128-34.

2',3'-Dideoxythymidine (ddThd) and its 2',3'-unsaturated derivative 2',3'-dideoxythymidinene (ddeThd) are potent and selective inhibitors of human immunodeficiency virus (HIV) in vitro. When evaluated for their inhibitory effects on the cytopathogenicity of HIV in MT-4 cells, ddThd and ddeThd completely protected the cells against destruction by the virus at a concentration of 1 microM and 0.04 microM, respectively. In this aspect, ddeThd was about 5 times more potent than 2',3'-dideoxycytidine (ddCyd), one of the most potent and selective anti-HIV compounds now pursued for its therapeutic potential in the treatment of AIDS. ddThd and ddeThd also suppressed HIV antigen expression at 1 microM and 0.04 microM, respectively. Their selectivity indexes, as based on the ratio of the 50% cytotoxic dose to the 50% antiviral effective dose, were 120 (ddeThd) and greater than 625 (ddThd).