<%@LANGUAGE="JAVASCRIPT" CODEPAGE="1252"%> Drug Eluting Stents
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Drug types used in drug eluting stents

The drugs that may be useful in preventing in-stent restenosis (ISR) fall into four major categories; anti-neoplastics, immunosupressives, migration inhibitors, and enhanced healing factors. ISR is primarily due to natural healing mechanisms including endothelial cell migration and extracellular matrix formation, collectively know as intimal hyperplasia. Platelets are attracted by the damaged tissue and they further the endothelial cell response as well as form thrombosis in the area around the stent [1]. Compounds that can inhibit ISR and intimal hyperplasia are excellent candidates for drug eluting stents.

Anti-Neoplastics

Anti-Proliferative

Migration Inhibitors

 

Enhanced Healing Factors

Sirolimus

Taxol (paclitaxel)

Batimistat

BCP671

Tacrolimus

Actinomycin

Prolyl Hydrosylase Inhibitors

VEGF

Everolimus

Methotraxate

Halofunginone

Estradiols

Leflunomide

Angiopeptin

C-preteinase Inhibitors

NO Donor Compounds

M-Prednisolone

Vincristine

Probucol

EPC antibodies

Dexamethasone

Mitmycine

 

 

Cyclosporine

Statins

 

 

Mycophenolic Acid

C MYC antisense

 

 

Mizoribine

Abbott ABT-578

 

 

Interferon ?-1b

RestenASE

 

 

Tranilast

2-choloro-deoxyadenosine

 

 

 

PCNA Ribozyme

 

 

  • Anti-neoplastics : Anti-proliferative compounds include paclitaxel, QP-2, actinomycin, statins and many others. Paclitaxel was originally used to inhibit tumor growth by assembling microtubules that prevent cells from dividing. It has also recently been observed to attenuate neointimal growth [2].
  • Immunosupressives : Immunosupressives are generally used to prevent the immune rejection of allogenic organ transplants. The general mechanism of action of most of these drugs is to stop cell cycle progression by inhibiting DNA synthesis. Everolimus, sirolimus, tacrolimus (FK-506), ABT-578, interferon, dexamethasone, and cyclosporine all fall into this category. The sirolimus derived compounds appear especially promising in their ability to reduce intimal thickening [2].
  • Migration Inhibitors : These compounds are aimed at preventing endothelial cell migration to the inside of the stent. Once smooth muscle cells migrate to the luminal side of the stent, they can produce extracellular matrix and begin to occlude blood flow. Therefore, inhibiting their migration can have great therapeutic applications for preventing in stent restenosis. Examples of these compounds are batimastat and halofuginone. Batimastat, for example, is a potent inhibitor of matrix metalloproteinase enzymes. It can prevent the matrix degradation that is necessary for cells to free themselves to move. If the cells cannot move, they can not invade the stent area.
  • Enhanced Healing Factors : Vascular endothelial growth factor (VEGF) promotes healing of the vasculature. In the context of stents, this would heal the implantation site and reduce platelet sequestration due to injury related chemotaxis. Nitrous oxide donor compounds may also replicate this effect. Healing of the vessel wall seems to be the gentlest approach to preventing ISR, but healing factors are still in the early stages of development for this application.

Sirolimus (rampamycin) and paclitaxel are the two drugs that are used in the Cordis and Boston Scientific drug eluting stents, respectively. Sirolimus is a macrocyclic lactone immunosuppressive agent that inhibits the cell division cycle and cellular proliferation by promoting kinase activation and halting the cellular growth phase.

Paclitaxel also inhibits the cell cycle, but works via a different mechanism than Sirolimus. Paclitaxel binds to microtubules in dividing cells and causes them to assemble, thereby preventing mitosis. Paclitaxel is in the anti-neoplastic family of compounds [1]. Together Paclitaxel and Sirolimus are two of the most promising drugs for use in stents, as several others have run into problems with lumen loss [2], late thrombosis, delayed restenosis, and aneurysm formation [1].

To see an animation showing the mechanism of action of paclitaxel click here and select the "Multimedia" tab and click "Microtubules".

Pharmacokinetics

Sirolimus is released from the CYPHER stent from the PEVA/PBMA polymer into the surrounding area by diffusion. [3] This mechanism can be described by Fick's law of diffusion, and is dependent upon concentration of drug both inside and outside the polymer matrix. The greater the difference between drug concentration inside and outside the polymer matrix, the faster the release of drug will occur. As mentioned previously, the outer layer of PEVA/PBMA minimizes the burst effect following stent implantation. The outer PEVA/PBMA layer also slows the rate of sirolimus diffusion allowing the drug to be released gradually over a longer period. [4] The concentration of drug decreases with first order elimination kinetics. Approximately 50 percent of the total drug is eliminated within the first 10 days of implantation. The drug is 90 percent removed from the stent by about 60 days, and is completely removed by about 90 days following implantation. [5] The peak drug concentration occurs about 4 hours after implantation. [6] This release profile provides just enough drug release immediately after stent implantation to prevent neointimal hyperplasia, without any of the side effects of systemic administration.

Drugs and Pharmacokinetics
 
 
   
   
   

 

Copyright © 2004 Nick Mark