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LOCAL DRUG DELIVERY —IS IT AN ANSWER FOR RESTENOSIS?? (english)
10 Feb 2003
Currently working with Ranbaxy laboratories Ltd and is member of Karnataka State Pharmacy Council.
Email; him_chatt (at) yahoo.com
LOCAL DRUG DELIVERY —IS IT AN ANSWER FOR RESTENOSIS??

By, Himadri Chatterjee,B.Pharm.
Currently working with Ranbaxy laboratories Ltd and is member of Karnataka State Pharmacy Council.
Email; him_chatt (at) yahoo.com

INTRODUCTION
Local drug delivery means delivery of a pharmacological agent which can be a drug, an enzyme, an oligonucleotide or genes. In the context of coronary artery disease, local drug delivery (LDD) means delivery of the pharmacological agent into the intima, media or both. This can be achieved by means of just injecting into the coronary ostia or delivering the drug into the intima and media via specialised devices. The major advantage of LDD would be that the drugs delivered would be very small in quantity and thus the side effects associated with them would be absent or at the most minimal. It can be used as tool in the treatment of thrombosis that is infarction, vessel passivation, e.g. post angioplasty and post stenting and for the prevention of restenosis following intracoronary revascularisation procedures. For thrombolysis this type of therapy holds promise in the treatment of acute myocardial infarction, and it has been successfully used using Streptokinase, Urokinase, t-PA and other thrombolytic agents, but its efficacy vis-a-vis intravenous thrombolytic therapy is not proven and the cost effectiveness in the present time is not there, hence it holds little promise in the treatment of acute myocardial infarction, although it remains a very important tool and modality for exciting research. The most useful indication in the era of percutaneous coronary revascularisation for this therapy remains the prevention of restenosis post coronary revascularisation. Several clinical trials are underway to prove this point. After the introduction of angioplasty in 1976 by Dr. Andres Gruentzig - the most worrisome long term diasbling feature of this therapy was restenosis or progression of the disease at the site of angioplasty. This used to happen in about 30-50% at the end of 3-6 months. [1] To overcome this high restenosis rate Dr. Roubin and Dr. Gianturco thought that if the angioplasty site is scaffolded by metal inside the artery which can give a large luminal diameter, the restenosis may be low or nil. Hence their invention of Gianturco Roubin Stent (Flex stent or GR I). Thereafter many such stents were introduced and many trials well conducted which proved that the restenosis rate can be brought down but not eliminated. [2-12]
OVERVIEW OF LOCAL DRUG DELIVERY

Drug delivery has been the potential Achilles’ heel of biotechnology companies, largely because of the difficulty in manufacturing the device and due to the rapid clearance of the pharmacologic agent. [13] The requirements for clinically usable LDD systems are
1. high percentage of drug or therapeutic agent should reach the vessel wall
2. there should be no escape downstream
3. delivery should be atraumatic
4. procedure should be brief and
5. it should be easy and inexpensive
These five are ideal characteristics for any system but at the moment they are not achievable.
DEVICES FOR LOCAL DRUG DELIVERY
The various devices designed for local drug delivery can be classified into :

A. Delivery catheters
B. Polymeric stents
C. Facilitated diffusion devices

Delivery catheters are essentially PTCA balloon catheters modified in a way by which drugs can be delivered. The earliest had been the double balloon catheter from USCI. It was basically PTCA catheter with 2 balloons separated by a shaft which had a hole. Both the balloons were inflated and drug delivered through the hole in the shaft. It required prolonged inflation time which caused prolonged ischaemia and its related complications, in addition the drug delivered locally would only get absorbed to a very less extent. To overcome this drawback USCI came out with Wolinsky perforated balloon catheter which had 28, 25 mm holes on the balloon drilled using a laser. Drugs used to be delivered through these holes. About 5% of total drug administered persisted in the artery for 8 hrs. This balloon caused a lot of vessel trauma due to jet effect and many cases disruption, dissection and total perforation were found in animal models. To overcome this jet trauma Cordis Corporation came out with a Microporous balloon. Instead of 25 mm diameter hole, this balloon had thousands of 1 micron diameter holes effectively making the whole balloon porous, thus reducing chances of vessel injury. At the same time catheters were designed so that balloon could be kept inflated and myocardial perfusion maintained through central hole. One such catheter was channel balloon catheter by Boston Scientific Corporation. Another cut catheter of same design is transport coronary angioplasty catheter. A novel approach for LDD is the Dispatch Delivery catheter by Scimed Life Systems and approved by FDA for intracoronary drug infusion in humans. It is a helical balloon which allows the drug to be held against the arterial wall in the space formed by the helices while the coronary blood flow is maintained. It can be easily used for 30-60 mins. without clinically causing myocardial ischaemia. Another exciting device made to deliver drug is the Infusion Sleeve made by Localmed. Inc. This is commercially made available and has to be used in conjunction with an angioplasty balloon. Boston Scientific Corporation has also made Hydrogel balloon. It is essentially an angioplasty balloon coated from outside with hydrophyllic polyacrylic acid polymer. This polymer acts as a sponge when dipped in any drug solution. Upon inflation of the balloon the absorbed drug is passively released and gets deposited on the intima. It is the least traumatic device, but the limitation is slow absorption of the drug and rapid wash out. [13]

POLYMERIC STENTS OR COATED STENTS

Metallic stents have been well tolerated in long term clinical studies and studies to coat them with drugs, etc., have been tried and many human trials are currently in progress. (Heparin, Phosphorylcholine, Colchicine coated and even Irradiated stents). Improvement over metallic stents is the biodegradable blood release polymer systems (biodegradable stents). The principle being gradual biological elimination without any residual implant stenosis may be effective in reducing the smooth muscle cell hyperplasia associated with prolonged exposure to non degradable stents. [14-18]
FACILITATED DIFFUSION DEVICES
A prototype of this type of device is the iontophoresis catheter. In this type of device the external surface of the balloon, an electrical charge is applied which causes the diffusion of the drug particles which is charged opposite to that of the balloon. In a way it is a modification of the hydrogen balloon. In hydrogen balloon the diffusion is passive whereas in iontophoresis the extrusion of drug is an active process. The potential side effects of the electrical current on the coronary artery are not known at present but deliterous effects have been seen with dermal applications which includes burns, fibrosis, etc. [19, 20]

PHARMACOLOGICAL AGENTS FOR LDD

Agents which have been delivered or can be delivered to treat or to prevent actively tried are streptokinase, urokinase, heparin, enoxaparine, doxorubicin, progesterone, prednisolone, luprolide and abxicimab. Monoclonal antibodies e.g. antisense oligonucleotides, haemaglutinating virus of Japan, FGF (basic fibroblast growth factor), transforming growth factor b and endothelial growth factor are being actively pursued. [21-23] Other experimental things being tried are transfection of endothelial cells by low virulence vectors from liposomes, retroviruses and adenoviruses. [24-26] Proto oncogenes C-myc, C-myg, CDC-2 and PCNA are also being tried. [27-30] Other agents being tried are a and g interferon, HMGCoA inhibitor and anti oxidants in addition to Herudin and related compounds. [31-35] Inspite of all the high profile, high tech and expensive research going on LDD, it remains to be established as an effective and accepted means of therapy. Inspite of the challenges due to wide variation in devices, drugs, other agents and the mode of delivery, substantial progress has been made specially in research pertaining to animals as a result of which few human trials have been conducted and few are going on. (Urodispatch study; local PAM, corami, distress, duet, hips, etc.). It is a matter of time when LDD would be the main mode of management in acute coronary syndromes as well as for the prevention of disease elsewhere in coronary arteries.
REFERENCES
1. Popma JJ, et al. Clinical trials of restenosis after coronary angioplasty. Circulation 1991; 84 : 1426-36.
2. Topol EJ, et al. Analysis of coronary angioplasty practice in the United States with an insurance-claims data base. Circulation 1993; 87 : 1489-97.
3. Waller BF, et al. Restenosis 1 to 24 months after clinically successful coronary balloon angioplasty : a necropsy study of 20 patients. J Am Coll Cardiol 1991; 17 : 58B-70B.
4. Noboyoshi M, et al. Restenosis after percutaneous transluminal coronary angioplasty : pathologic observations in 20 patients. J Am Coll Cardiol 1991; 17 : 433-39.
5. Kovach JA, et al. Sequential intravascular ultrasound characterization of the mechanisms of rotational atherectomy and adjunct balloon angioplasty. J Am Coll Cardiol 1993; 22 : 1024-32.
6. Mintz GS, et al. Intravascular ultrasound comparison of de novo and restenoic coronary lesions. J Am Coll Cardiol 1993; 21 : 118A. Abstract.
7. Ip JH, et al. Syndromes of accelerated atherosclerosis : role of vascular injury and smooth muscle cell proliferation. J Am Coll Cardiol 1990; 15 : 1667-87.
8. Forrester JS, et al. A paradigm for restenosis based on cell biology : clues for the development of new preventive therapies. J Am Coll Cardiol 1991; 17 : 578B-769.
9. Ellis SG, et al. Restenosis after placement of Palmaz-Schatz in native coronary arteries : initial results of a multicenter experience. Circulation 1992; 86 : 1836-44.
10. Bittl JA, et al. Clinical success complications and restenosis rates with excimer laser coronary angioplasty. J Am Cardiol 1992; 70 : 1533-39.
11. Schatz RA, et al. For STRESS Investigators Stent Restenosis Study (STRESS) : analysis of in-hospital results. Circulation 1993; 88 (suppl I) : 1-594. Abstract.
12. Serruys PW, et al. On behalf of the Benestent study group : interim analysis of the BENESTENT Trial. Circulation 1993; 88 (suppl I) : I-594. Abstract.
13. A Michael Lincoff, et al. Local Drug Delivery for the Prevention of Restenosis - Fact, Fancy and Future. Circulation 1994; 90 : 2070-84.
14. Langer R. New methods of drug delivery. Science 1990; 249
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