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Predicting in vivo efficacy of potential restenosis therapies by cell culture studies: species-dependent susceptibility of vascular smooth muscle cells.

Epstein H, Rabinovich L, Banai S, Elazar V, Gao J, Chorny M, Danenebrg HD, Golomb G - Open Cardiovasc Med J (2008)

Bottom Line: Elucidation of different species sensitivity (rat, rabbit, porcine and human) to diverse drugs (tyrphostins, heparin and bisphsophonates) and a delivery system (nanoparticles) could provide a valuable screening tool for further in vivo studies.The anticipated sensitivity ranking from the explant outgrowth model and SMC mitotic rates (porcine>rat>rabbit>human) do not correlate with the observed relative sensitivity of those animals to antiproliferative therapy in restenosis models (rat>/=rabbit>porcine>human).Similarly, the inhibitory profile of the various antirestenotic drugs in SMC cultures (rabbit>porcine>rat>human) do not correlate with animal studies, the rabbit- and porcine-derived SMC being highly sensitive.

View Article: PubMed Central - PubMed

Affiliation: Dept. of Pharmaceutics, School of Pharmacy, The Hebrew University of Jerusalem, Jerusalem 91120, Israel.

ABSTRACT
Although drug-eluting stents (DES) are successfully utilized for restenosis therapy, the development of local and systemic therapeutic means including nanoparticles (NP) continues. Lack of correlation between in vitro and in vivo studies is one of the major drawbacks in developing new drug delivery systems. The present study was designed to examine the applicability of the arterial explant outgrowth model, and of smooth muscle cells (SMC) cultures for prescreening of possible drugs. Elucidation of different species sensitivity (rat, rabbit, porcine and human) to diverse drugs (tyrphostins, heparin and bisphsophonates) and a delivery system (nanoparticles) could provide a valuable screening tool for further in vivo studies. The anticipated sensitivity ranking from the explant outgrowth model and SMC mitotic rates (porcine>rat>rabbit>human) do not correlate with the observed relative sensitivity of those animals to antiproliferative therapy in restenosis models (rat>/=rabbit>porcine>human). Similarly, the inhibitory profile of the various antirestenotic drugs in SMC cultures (rabbit>porcine>rat>human) do not correlate with animal studies, the rabbit- and porcine-derived SMC being highly sensitive. The validity of in vitro culture studies for the screening of controlled release delivery systems such as nanoparticles is limited. It is suggested that prescreening studies of possible drug candidates for restenosis therapy should include both SMC cell cultures of rat and human, appropriately designed with a suitable serum.

No MeSH data available.


Related in: MedlinePlus

Inhibition effect of AG-1295, alendronate and heparin on SMC outgrowing from arterial porcine explants. Medium (with or without drug) was changed every 2 days after the first week.
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Figure 2: Inhibition effect of AG-1295, alendronate and heparin on SMC outgrowing from arterial porcine explants. Medium (with or without drug) was changed every 2 days after the first week.

Mentions: The effect of various drugs on SMC outgrowth rate was examined on porcine arterial-explants that exhibited the fastest outgrowth rate (Fig. 2). A marked prolongation of the time, from plating of the arterial tissue to the appearance of cells around the explants, was observed following treatment with heparin or AG-1295, but not after ALN or control treatment (Fig. 2). Heparin, and to some lower extent, AG-1295 treatments resulted in ~50% inhibition of replication rate after 10 days. among the species examined. p<0.001 and p<0.05, porcine and human SMC vs. other species, respectively.


Predicting in vivo efficacy of potential restenosis therapies by cell culture studies: species-dependent susceptibility of vascular smooth muscle cells.

Epstein H, Rabinovich L, Banai S, Elazar V, Gao J, Chorny M, Danenebrg HD, Golomb G - Open Cardiovasc Med J (2008)

Inhibition effect of AG-1295, alendronate and heparin on SMC outgrowing from arterial porcine explants. Medium (with or without drug) was changed every 2 days after the first week.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2570571&req=5

Figure 2: Inhibition effect of AG-1295, alendronate and heparin on SMC outgrowing from arterial porcine explants. Medium (with or without drug) was changed every 2 days after the first week.
Mentions: The effect of various drugs on SMC outgrowth rate was examined on porcine arterial-explants that exhibited the fastest outgrowth rate (Fig. 2). A marked prolongation of the time, from plating of the arterial tissue to the appearance of cells around the explants, was observed following treatment with heparin or AG-1295, but not after ALN or control treatment (Fig. 2). Heparin, and to some lower extent, AG-1295 treatments resulted in ~50% inhibition of replication rate after 10 days. among the species examined. p<0.001 and p<0.05, porcine and human SMC vs. other species, respectively.

Bottom Line: Elucidation of different species sensitivity (rat, rabbit, porcine and human) to diverse drugs (tyrphostins, heparin and bisphsophonates) and a delivery system (nanoparticles) could provide a valuable screening tool for further in vivo studies.The anticipated sensitivity ranking from the explant outgrowth model and SMC mitotic rates (porcine>rat>rabbit>human) do not correlate with the observed relative sensitivity of those animals to antiproliferative therapy in restenosis models (rat>/=rabbit>porcine>human).Similarly, the inhibitory profile of the various antirestenotic drugs in SMC cultures (rabbit>porcine>rat>human) do not correlate with animal studies, the rabbit- and porcine-derived SMC being highly sensitive.

View Article: PubMed Central - PubMed

Affiliation: Dept. of Pharmaceutics, School of Pharmacy, The Hebrew University of Jerusalem, Jerusalem 91120, Israel.

ABSTRACT
Although drug-eluting stents (DES) are successfully utilized for restenosis therapy, the development of local and systemic therapeutic means including nanoparticles (NP) continues. Lack of correlation between in vitro and in vivo studies is one of the major drawbacks in developing new drug delivery systems. The present study was designed to examine the applicability of the arterial explant outgrowth model, and of smooth muscle cells (SMC) cultures for prescreening of possible drugs. Elucidation of different species sensitivity (rat, rabbit, porcine and human) to diverse drugs (tyrphostins, heparin and bisphsophonates) and a delivery system (nanoparticles) could provide a valuable screening tool for further in vivo studies. The anticipated sensitivity ranking from the explant outgrowth model and SMC mitotic rates (porcine>rat>rabbit>human) do not correlate with the observed relative sensitivity of those animals to antiproliferative therapy in restenosis models (rat>/=rabbit>porcine>human). Similarly, the inhibitory profile of the various antirestenotic drugs in SMC cultures (rabbit>porcine>rat>human) do not correlate with animal studies, the rabbit- and porcine-derived SMC being highly sensitive. The validity of in vitro culture studies for the screening of controlled release delivery systems such as nanoparticles is limited. It is suggested that prescreening studies of possible drug candidates for restenosis therapy should include both SMC cell cultures of rat and human, appropriately designed with a suitable serum.

No MeSH data available.


Related in: MedlinePlus