Encapsulation of foscarnet in liposomes modifies drug intracellular accumulation, in vitro anti-HIV-1 activity, tissue distribution, and pharmacokinetics

The purpose of the present research was to investigate the mechanism for improved intercellular and intracellular drug delivery from ethosomes using visualization techniques and cell line study. Ethosomal formulations were prepared using lamivudine as model drug and characterized in vitro, ex vivo and in vivo. Transmission electron microscopy, scanning electron microscopy, and fluorescence microscopy were employed to determine the effect of ethosome on ultrastructure of skin. Cytotoxicity and cellular uptake of ethosome were determined using T-lymphoid cell line (MT-2). The optimized ethosomal formulation showed 25 times higher transdermal flux (68.4 ± 3.5 μg/cm 2 /h) across the rat skin as compared with that of lamivudine solution (2.8 ± 0.2 μg/cm 2 /h). Microscopic studies revealed that ethosomes influenced the ultrastructure of stratum corneum. Distinct regions with lamellar stacks derived from vesicles were observed in intercellular region of deeper skin layers. Results of cellular uptake study showed significantly higher intracellular uptake of ethosomes (85.7% ± 4.5%) as compared with drug solution (24.9% ± 1.9%). The results of the characterization studies indicate that lipid perturbation along with elasticity of ethosomes vesicles seems to be the main contributor for improved skin permeation.

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“…This mixture was filtered through 0.45-μm filter, and drug uptake was determined by analyzing the drug content by HPLC assay. 15 …”

Section: Drug Uptake Studiesmentioning

confidence: 99%

Formulation and evaluation of ethosomes for transdermal delivery of lamivudine

et al. 2007

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“…From these data it can be concluded that the heterodimers offer the potential to deliver higher levels of AZT equivalents than AZT alone to the organs of the MPS but not that there is any preferential accumulation. As shown by Dusserre et al (1995), encapsulation of the antiviral drug foscarnet in liposomes modified intracellular drug accumulation, antiviral activity and pharmacokinetic parameters. Thus, a reduction of the dose required to exert antiviral effects in vivo can be achieved with liposome formulations of antiviral compounds, including the amphiphilic heterodimers.…”

Section: Discussionmentioning

confidence: 95%

In vitroAnti-Human Immunodeficiency Virus and Anti-Hepatitis B Virus Activities and Pharmacokinetic Properties of Heterodinucleoside Phosphates Containing AZT or ddC

Zahner

Küster

et al. 1998

Antivir Chem Chemother

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In vitro activities, against human immunodeficiency virus (HIV)- and hepatitis B virus (HBV)-infected cells, of four amphiphilic heterodinucleoside phosphates containing 3′-azido-2′,3′-dideoxythymidine (AZT) or 2′,3′-dideoxycytidine (ddC) as antiviral monomers were evaluated. The four compounds were N4-hexadecyl-2′-deoxyribocytidylyl-(3′→5′)-3′-azido-2′,3′-deoxythymidine (N4-hxddC-AZT), N4-palmitoyl-2′-deoxyribocytidylyl-(3′→5′)-3′-azido-2′,3′-deoxythymidine (N4-pamdC-AZT), N4-hexadecyl-2′-deoxycytidylyl-(3′→5′)-2′,3′-dideoxycytidine (N4-hxddC-ddC) and 2′-deoxythymidylyl-(3′→5′)-N4-palmitoyl-2′,3′-dideoxycytidine (dT-N4-pamddC). All four dimers were active against HIV, dT-N4-pamddC being the most active and least toxic. dT-N4-pamddC also exhibited strong antiviral effects against a panel of eight AZT-resistant HIV strains. The ddC-containing heterodimers incorporated in liposomes additionally inhibited HBV replication by 50–80% in HepG2 2.2.15 cells. AZT and the AZT-containing dimers were ineffective. Differences in pharmacokinetic properties between the antiviral monomers and the heterodimers were evaluated using liposomal formulations of3H-labelled AZT heterodimers as model compounds. The cellular distribution of AZT in H9 cells was predominantly cytoplasmic, whereas the amphiphilic dimers were distributed more evenly throughout the cytoplasm, nuclear membranes and microsomes. Blood levels of the heterodimers decreased at a rate two- to threefold slower than AZT and the areas-under-the-curves were five- to sevenfold higher for N4-pamdC-AZT and N4-hxddC-AZT, respectively. Compared to AZT, the peak levels of the dimers were three to four times higher in blood and five to six times higher in the liver. Analysis of blood samples showed that 34% of N4-pamdC-AZT was metabolized to AZT, whereas only 9% of N4-hxddC-AZT released AZT. Considering the antiviral potency and the favourable pharmacokinetic properties of the heterodimers, these compounds merit further exploration as antiviral drugs.

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“…However, the efficacy of the formulation of foscarnet was lower than that of acyclovir, irrespective of the schedules of administration tested. This result can be attributed to its high anionic character, which limits its intracellular penetration and thereby limits its efficacy compared to that of acyclovir, which is neutral at a physiological pH (8). In that respect, studies performed in our laboratory with Franz diffusion cells and a polytetrafluoroethylene membrane (pore size, 5 m), which mimics the hydrophobic property of human skin (12,37), have indicated that acyclovir incorporated within the polymer diffuses at least 30 times more efficiently than foscarnet through such a membrane (data not shown).…”

Section: Discussionmentioning

confidence: 99%

Efficacies of Topical Formulations of Foscarnet and Acyclovir and of 5-Percent Acyclovir Ointment (Zovirax) in a Murine Model of Cutaneous Herpes Simplex Virus Type 1 Infection

Piret

Désormeaux

Gourde

et al. 2000

Antimicrob Agents Chemother

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The topical efficacies of foscarnet and acyclovir incorporated into a polyoxypropylene-polyoxyethylene polymer were evaluated and compared to that of 5% acyclovir ointment (Zovirax) by use of a murine model of cutaneous herpes simplex virus type 1 infection. All three treatments given three times daily for 4 days and initiated 24 h after infection prevented the development of the zosteriform rash in mice. The acyclovir formulation and the acyclovir ointment reduced the virus titers below detectable levels in skin samples from the majority of mice, whereas the foscarnet formulation has less of an antiviral effect. Reducing the number of treatments to a single application given 24 h postinfection resulted in a significantly higher efficacy of the formulation of acyclovir than of the acyclovir ointment. Acyclovir incorporated within the polymer was also significantly more effective than the acyclovir ointment when treatment was initiated on day 5 postinfection. The higher efficacy of the acyclovir formulation than of the acyclovir ointment is attributed to the semiviscous character of the polymer, which allows better penetration of the drug into the skin.

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Encapsulation of foscarnet in liposomes modifies drug intracellular accumulation, in vitro anti-HIV-1 activity, tissue distribution, and pharmacokinetics

Cited by 41 publications

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Formulation and evaluation of ethosomes for transdermal delivery of lamivudine

Formulation and evaluation of ethosomes for transdermal delivery of lamivudine

In vitroAnti-Human Immunodeficiency Virus and Anti-Hepatitis B Virus Activities and Pharmacokinetic Properties of Heterodinucleoside Phosphates Containing AZT or ddC

Efficacies of Topical Formulations of Foscarnet and Acyclovir and of 5-Percent Acyclovir Ointment (Zovirax) in a Murine Model of Cutaneous Herpes Simplex Virus Type 1 Infection

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