Toxicity and Pharmacokinetics of Stampidine in Mice and Rats

Uckun, Fatih M.; Chen, Chunlin; Lisowski, Elizabeth; Mitcheltree, Greg C; Venkatachalam, T. K.; Erbeck, Douglas; Chen, Hao; Waurzyniak, Barbara

doi:10.1055/s-0031-1297120

Cited by 14 publications

(24 citation statements)

References 16 publications

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“…We have previously evaluated the in vivo toxicity profiles of stampidine [41−45]. Stampidine was very well tolerated by both mice and rats without any toxicity at cumulative dose levels > 1 g/kg [45]. In mice, daily administration of stampidine intraperitoneally or orally for up to 8 consecutive weeks was not associated with any detectable toxicity at cumulative dose levels as high as 6.4 g/kg.…”

Section: Discussionmentioning

confidence: 99%

In vitro Anti-HIV Potency of Stampidine Alone and in Combination with Standard Anti-HIV Drugs

Uckun

Qazi

Venkatachalam

2011

Arzneimittelforschung

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The purpose of the present study was compare the in vitro anti-HIV potency stampidine (CAS 217178-62-6), a novel aryl phosphate derivative of stavudine (CAS 3056-17-5), and drug combinations containing stampidine to the anti-HIV tency of the standard drugs zidovudine (CAS 30516-87-1), stavudine, lamivudine (CAS 134678-17-4), nelfinavir (CAS 159989-65-8), and nevirapine (CAS 129618-40-2) as well as their combinations. Stampidine inhibited the laboratory HIV-1 strain HTLV(IIIB) (B-envelope subtype) as well as the primary clinical HIV-1 isolates BR/92/025 (C-envelope subtype) and BR/93/20 (F-envelope sub-type) with subnanomolar IC50 values. Stampidine was as effective as zidovudine against HTLV(IIIB) and BR/92/025 and 3-logs more effective than zidovudine against BR/93/20. Stampidine was more effective than stavudine, lamivudine, nelfinavir, and nevirapine against all three HIV-1 isolates. The combination of stampidine with zidovudine + lamivudine was more effective than the combination of nelfinavir or nevirapine with zidovudine lamivudine against all three HIV-1 isolates. The combination of stampidine with nelfinavir was more effective than zidovudine + lamivudine as well as the combination of zidovudine + lamivudine with nelfinavir. The combination of stampidine with lamivudine + nelfinavir was more effective than the combination of zidovudine with lamivudine + nelfinavir. The combination of stampidine with lamivudine + nevirapine was more effective than the combination of stavudine with lamivudine + nevirapine. These findings demonstrate that (a) stampidine, as well as its combinations with the standard anti-HIV drugs zidovudine, lamivudine, nelfinavir or nevirapine, are potent inhibitors of HIV-1 replication in human peripheral blood mononuclear cells, and (b) replacement of either zidcovudine, zidovudine+lamivudine or stavudine in 3-drug cocktails with stampidine resulted in greater anti-HIV potency in vitro.

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Section: Discussionmentioning

confidence: 99%

In vitro Anti-HIV Potency of Stampidine Alone and in Combination with Standard Anti-HIV Drugs

Uckun

Qazi

Venkatachalam

2011

Arzneimittelforschung

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“…[110,111] This compound also showed good activity, tolerability and toxicity profiles in vivo. [112][113][114] Stampidine (44) has been proposed as a treatment for patients infected with highly drug-resistant strains of HIV-1. Despite the impressive in vitro and in vivo activities of stampidine (44), there have been no recent reports regarding its further development, and no clinical trials are underway at present.…”

Section: Thymectacinmentioning

confidence: 99%

Aryloxy Phosphoramidate Triesters: a Technology for Delivering Monophosphorylated Nucleosides and Sugars into Cells

2009

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Prodrug technologies aimed at delivering nucleoside monophosphates into cells (protides) have proved to be effective in improving the therapeutic potential of antiviral and anticancer nucleosides. In these cases, the nucleoside monophosphates are delivered into the cell, where they may then be further converted (phosphorylated) to their active species. Herein, we describe one of these technologies developed in our laboratories, known as the phosphoramidate protide method. In this approach, the charges of the phosphate group are fully masked to provide efficient passive cell-membrane penetration. Upon entering the cell, the masking groups are enzymatically cleaved to release the phosphorylated biomolecule. The application of this technology to various therapeutic nucleosides has resulted in improved antiviral and anticancer activities, and in some cases it has transformed inactive nucleosides to active ones. Additionally, the phosphoramidate technology has also been applied to numerous antiviral nucleoside phosphonates, and has resulted in at least three phosphoramidate-based nucleotides progressing to clinical investigations. Furthermore, the phosphoramidate technology has been recently applied to sugars (mainly glucosamine) in order to improve their therapeutic potential. The development of the phosphoramidate technology, mechanism of action and the application of the technology to various monophosphorylated nucleosides and sugars will be reviewed.

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“…The virus was added first for a 2 h incubation time prior to addition of the antiviral agents. The cells were cultured for 3 days and cultures were assayed for syncytium formation by submerging the plates in 100 % methanol for 15 min, staining with 0.3 % crystal violet for 5 min, and counting the plaques in each well with an inverted microscope [33]. Percent inhibition of plaque formation was calculated by comparing the plaque numbers from the test substance-treated infected cells with the plaque numbers from untreated infected cells (i.e.…”

Section: Plaque Formation Assaysmentioning

confidence: 99%

“…As shown in Table 3, STAMP was active against each of these isolates at nanomolar concentrations regardless of the degree of their phenotypic or genotypic zidovudine resistance with an average IC 50 value of 8.7 a) Syncytial focus (plaque) formation assays were performed using the CD4-positive HeLa cell line HT4-6C (AIDS Research and Reference Reagent Program, NIAID), as described in Materials and methods. b) The IC 50 values were calculated using the median effect equation by comparing the plaque numbers from the test substance-treated cultures with plaque numbers from untreated cultures (i.e., virus controls) [33]. P-values were calculated using paired t-tests on log 10 -transformed IC 50 values.…”

Section: Activity Of Stampidine Against Nrti-resistant Primary Clinicmentioning

confidence: 99%

“…STAMP was very well tolerated in rats, BALB/c, CD-1 as well as CB17-SCID mice without any detectable acute or subacute toxicity at single intrapertitoneal or oral bolus dose levels as high as 500 mg/ kg [33]. Notably, daily administration of STAMP intraperitoneally or orally for up to 8 consecutive weeks was not associated with any detectable toxicity at cumulative dose levels as high as 6.4 g/kg [33]. STAMP exhibited significant and dose-dependent in vivo anti-HIV activity in Hu-PBL-SCID mice [34].…”

Section: Introductionmentioning

confidence: 99%

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In vitro Activity of Stampidine against Primary Clinical Human Immunodeficiency Virus Isolates

Uckun

Pendergrass

Qazi

et al. 2011

Arzneimittelforschung

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The in vitro activity profile of stampidine (CAS 217178-62-6, STAMP) was examined against clinical isolates of HIV-1. In a side-by-side comparison against 10 zidovudine-sensitive clinical HIV-1 isolates, STAMP was 100-fold more potent than stavudine (CAS 3056-17-5) and twice as effective as zidovudine (CAS 30516-87-1). STAMP was also active against phenotypically and/or genotypically NRTI (nucleoside analog inhibitors of reverse transcriptase) -resistant HIV and inhibited the replication of 20 zidovudine-resistant clinical HIV-1 isolates with low nanomolar to subnanomolar IC50 values. Similarly, STAMP inhibited the replication of 9 genotypically NNRTI (non-nucleoside analog inhibitors of reverse transcriptase)-resistant clinical HIV-1 isolates (n = 9) with an average IC50 value of 11.2 +/- 6.5 nmol/L. The remarkable potency of STAMP against clinical HIV-1 isolates with NRTI- or NNRTI-resistance warrants the further development of this promising new antiviral agent.

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Toxicity and Pharmacokinetics of Stampidine in Mice and Rats

Cited by 14 publications

References 16 publications

In vitro Anti-HIV Potency of Stampidine Alone and in Combination with Standard Anti-HIV Drugs

In vitro Anti-HIV Potency of Stampidine Alone and in Combination with Standard Anti-HIV Drugs

Aryloxy Phosphoramidate Triesters: a Technology for Delivering Monophosphorylated Nucleosides and Sugars into Cells

In vitro Activity of Stampidine against Primary Clinical Human Immunodeficiency Virus Isolates

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