Coronary artery stent covered with endothelin receptor antagonist
This invention generally relates to expandable intravascular devices, also known as stents, that are implanted in a coronary artery, to maintain the patency of the lumen.
These stents can be coated with a biodegradable polymer to inhibit development of meointimal hyperplasia in the blood vessel in which the stent is implanted. Our invention involves the attachment of an endothelin receptor A antagonist on the surface of a coated stent.
Percutaneous transluminal coronary angioplasty (PTCA) has been established as an efficacious and safe procedure for the alleviation of myocardial ischemia associated with coronary artery atherosclerosis. An increasing number of patients with coronary artery disease now undergo PTCA as an alternative to bypass surgery.
However, the major factor limiting the long term success of the procedure is restenosis of the dilated segment, which occurs in approximately 20-40% of patients.
Animal studies suggest that post-PTCA restenosis results from platelet adhesion to the area of endothelial damage at the dilation site, with subsequent release of potent smooth muscle cell constrictors, mitogens and various growth factors. Restenosis represents a human correlate of the arterial injury technique used to create atherosclerotic plaques in experimental animals. Many studies have shown that, compared to the primary plaque, areas of restenosis tend to have a different, more proliferative histological appearance.
Stents are generally cylindrically shaped devices, which function to hold open and sometimes expand a segment of a blood vessel. They are particularly suitable for supporting and preventing a torn or injured arterial lining from occluding fluid passageway. Intravascular stents are increasingly useful for treatment of coronary artery stenoses, and for prevention of restenosis or closure after balloon angioplasty.
Coronary stenting was introduced to clinical practice in 1986, and was originally intended as a bailout device to treat acute vessel occlusion or sub-optimal results.
During the past 3 years, the indications for stent implantation after PTCA have dramatically expanded, especially after recent trials showed that coronary stents reduce the restenosis rate. The mechanism by which coronary stenting reduces the restenosis rate is most likely by producing large lumens and staving off pathological arterial remodeling.
The success of a stent can be assessed by evaluating a number of factors, such as
* thrombosis (acute, subacute or chronic)
* neointimal hyperplasia, primarily due to smooth muscle cell migration and proliferation following implantation of the stent
* injury to the artery wall
* overall loss of luminal patency * stent diameter in vivo and
* leukocyte adhesion to the luminal lining of stented arteries.
Of these, the chief areas of concern are early subacute thrombosis, and eventual restenosis of the blood vessel due to intimal hyperplasia.
Despite the significant reduction in the restenosis rates with the use of coronary stents, recurrence of coronary artery stenosis inside the stent remains the'Achilles heel'of the procedure. The main mechanism of in-stent restenosis is the neointimal proliferation through the stent struts that accounts for almost all the late loss in lumen diameter, with hardly any evidence of vessel shrinkage or stent collapse.
It is well known that various types of foreign materials can lead to thrombosis and inflammation. Aggressive medical therapy including heparin therapy, as well as the antithrombotic combination of aspirin and ticlopidine have reduced the rate of acute or subacute thrombosis. The current rate of acute and subacute thrombosis is approximately 1%, a percentage deemed acceptable, although farther reduction would be desirable.
The main target remains the reduction of chronic restenosis rates after stent implantation. Restenosis is induced by initial platelet adhesion and thrombus formation followed by immunocyte adhesion on the stent surface and on the injured vessel wall. The thrombus releases factors that activate the proliferation of smooth muscle cells, a process leading to in-stent restenosis.
It would therefore beneficial to provide a coated stent that would
* limit thrombogenicity during a period of re-endothelization following implantation of the stent and
* be conducive to re-endothelization and limit restenosis due to thrombosis and neo intimal hyperplasia.
Materials that support endothelial cell growth are generally biocompatible. Several coatings are now on the market, such as paraxylene polymers, generically known as parylenes, poly-LD-lactid acid and several others.
On the coating, several substances can be attached, that can be released gradually, over a period of months. Several substances have been used, such as heparin, hirudin, hirulog or iloprost with contradictory results. Our invention involves. the attachment of an endothelin-1-receptor A antagonist on the surface of a stent coated with poly-LD-lactic acid.
In order to perform the coating protocol, the following substances in these particular concentrations are needed:
PLA: 100 mg per 3 ml Ethylacetate (solvent for all solutions)
BQ123: 5 mg per 3 ml PLA-Ethylacetate-solution=5%
The procedure is divided in two parts: the non-sterile and the sterile one.
In the non-sterile one, the appropriate quantity of PLA is weighted and being dissolved in the correlated volume of ethylacetate. BQ123 is added subsequently in the given concentrations. For groups without BQ123, procedure remains the same.
In the sterile step, the BQ123-PLA-Ethylacetate solution is being sterilized by the method of filtration with a 20 llm pore-filter. The procedure will be repeated and the stent will be dried, for 5 min additionally without swiveling this time and finally, sealed in sterile cups and bags.
It also should be mentioned, that 3 ml of the coating solution are sufficient forl5 stents
Endothelin-1 (ET-1) belongs to a family of structurally related 21-aminoacid peptides that include 3 isoforms : ET-1, ET-2 and ET-3. ET-1 produces a very potent and long-lasting vasoconstriction in vitro and in vivo, whereas ET-3 is a much weaker vasoconstrictor. ET-1 has been shown to exert a potent mitogenic effect in cultured smooth muscle cells and mesangial cells. ET-1 also induces the expression and release of several protooncogenes and growth factors, which may act synergistically.
Two receptors for ET, termed ETA and ETB, have been identified and shown to be expressed on several cardiovascular cell types, including endothelial cells, vascular smooth muscle cells, cardiac myocytes and fibroblasts. ETA receptors are abundant in cardiovascular tissues, whereas ETB receptors are abundant in non-cardiovascular tissues, including kidney, adrenal glands and central nervous system. The ETA receptor is selective for ET-1 and ET-2 and is believed to mediate vasoconstriction.
The vasoconstriction is related to the ability of ET activated receptors to stimulate phospholipase C, which leads to the formation of inositol 1,4,5-triphosphate and diaglycerol. Inositol increases the intracellular calcium concentration, which in turn causes vasoconstriction.
Enhanced understanding of the biology of angioplasty will be required to prevent restenosis of the dilated segment. Among the various neurohumoral factors which have been implicated in neointima formation, ET-1 levels have also been found to be elevated in the human coronary circulation. ETl, therefore, may be involved in the pathogenesis of coronary artery restenosis.
ET-1 induced mitogenesis is mediated by the ETA receptor subtype in rat and human smooth muscle cells. Diaglycerol and calcium stimulate protein kinase C, which mediates the mitogenic action of ET-1. The selective ETA receptor antagonist BQ-123 delays the mitogenic proliferative responsiveness of human and rat aortic smooth muscle cells cultured in vitro. This synthetic compound has no effect on blood pressure in vivo even at a high dose.
ETB is a non-selective subtype that binds to ET-1, ET-2 and ET-3 with the same affinity and mediates the formation of nitric oxide and prostacyclin. It is thought that the ET-1 transient depressor response may be dependent on vasodilation mediated by ETB receptors on the endothelium. However, the smooth muscle layer also contains small amounts of ETB receptors, which mediate vasoconstriction.
Although ETB receptors have been implicated in the pathologic process of restenosis, no direct proof exists towards this notion. Therefore, in our invention, we advocate the use of selective ETA receptor on the stent-coating, in order to reduce the restenosis rates.
Our invention involves the adhesion of-123, a selective ETA antagonist, on the surface of a coated coronary stent, with a view to delivering the drug selectively and precisely at the site of the atherosclerotic plaque, where it will be released locally' over a long period of time. ET is released locally in the endothelium and acts as an autocrine, paracrine hormone, with a very short plasma half life, although its potent vascular actions are extremely prolonged. BQ123, therefore, might be expected to exert an effect preventing restenosis when administered locally at the site of the plaque after angioplasty.
Figure 1 shows a coronary artery stent in detail. Figure 2 depicts the process of stent delivery in the coronary artery. Figure 3 is a schematic illustration of a coated stent with the endothelin receptor A antagonist.
As shown in figure 1, the stent generally comprises a plurality of radially expandable cylindrical elements (11), disposed generally coaxially and interconnected by members (12) disposed between adjacent cylindrical elements. As illustrated in Fig. 2, a stent is mounted onto a delivery catheter (21). The irregular serpentine pattern has a plurality peaks and valleys which aids in the even distribution of expansion forces. The delivery catheter (21) has an expandable balloon (22) for expanding of the stent (23) within the coronary artery (24).
The delivery catheter, is essentially the same as a conventional balloon dilatation catheter used for angioplasty procedures. The balloon (22) can be formed of suitable materials such as polyethylene, polyethylene terephthalate, polyvinyl chloride, nylon and ionomers. The delivery of the stent (23) is accomplished in the following manner: The stent (23) is first mounted onto the inflatable balloon (22) on the distal end of the delivery catheter. The stent may be"crimped"down on the balloon to ensure a low profile.-The catheter-stent assembly can be introduced into the vasculature of the patient in a conventional Seldinger technique through a guiding catheter.
A guidewire (25) is passed across the narrowed part of the coronary artery and then the catheter-stent assembly is advanced over the guldewire (25) in the artery (24), until the stent (23) is directly under the narrowed part of the coronary artery (26). The balloon (22) of the catheter is expanded, expanding the stent (23) against the artery (24), which is, illustrated in Fig. 2B. The artery (24) is preferably expanded slightly by the expansion of the stent (23) to seat or otherwise fix the stent (23) to prevent movement.
Due to the formation of the stent (23) from an elongated tubular member, the undulating component of the cylindrical elements of the stent (23) is relatively flat in transverse cross-section, so that when the stent is expanded, the cylindrical elements are pressed into the wall of the artery (24). As a result, the stent does not interfere with the blood flow through the artery 15. The cylindrical elements (11) of the stent, which are pressed into the wall of the artery (24), eventually will be covered with endothelial cell growth. The serpentine pattern of the cylindrical sections (11) provides good tacking characteristics to prevent stent movement within the artery. Furthermore, the closely spaced cylindrical elements (11) at regular intervals, provide uniform support for the wall of the artery (24).
Consequently, the stents are well adapted to hold in place small flaps or dissections in the wall of the artery (24).
After expansion of the stent (fig 2C), portions of the various elements will turn outwardly, forming small projections which will embed in the vessel wall. For example, the tip of peak portion tips outwardly upon expansion a sufficient amount to embed into the vessel wall and help secure the implanted stent. Upon expansion, the projecting peak provides an outer wall surface on the stent that is not smooth, but instead has a plurality of projecting peaks all along the outer wall surface. While the projections assist in securing the stent in the vessel wall, they are not sharp so as to cause trauma or damage to the vessel wall.
One important feature of the illustrated embodiment is the capability of the stent to expand from a low-profile diameter to a diameter much greater than heretofore was available, while still maintaining structural integrity in its expanded state. Thus, the stent has an overall expansion ratio of 1.0 up to about 4.0 using certain compositions of stainless steel.
The illustrated stent (23) can be made in many ways. One method of making the stent is to coat a thin-walled tubular member, such as a stainless steel hypotube, with a material which is resistive to chemical enchants. Subsequently, portions of the surface are removed, to expose underlying hypotubing, which is further removed by subsequent etching. The coated portion of the metallic tube is in the desired shape of the stent. An etching process avoids the necessity of removing burrs or slag inherent in conventional or laser machining processes.
A coating, is applied preferably by electrophoretic deposition to a length of tubing, which is resistive to chemical etchants. Substances can be attached on the surface of the coating. In this way, these substances are released in slow, controllable manner.
In our invention, the coated surface has the advantage of delivering the endothelin receptor A antagonist BQ-123 over a period of one month. Several coatings are now available on the market, similar to the one used in our study (PLA).
To ensure that the surface finish is reasonably uniform, one of the electrodes used for the electrochemical polishing is a doughnut-shaped electrode, which is placed about the central portion of the tubular member. The tubing may be made of suitable biocompatible material such as stainless steel, titanium, tantalum, super-elastic nickel-titanium (NiTi) alloys and even high strength polymers. The stent diameter is very small, so the tubing from which it is made must necessarily also have a small diameter, in the order of about 1.5 mm in the unexpanded condition, and can be expanded to have an outer diameter of 5mm. The wall thickness of the hypotubing is typically about 0.08 mm (0.003 inch).
We have already set-up an experimental animal study to test the effects of our invention. To our knowledge, this is the first study to examine the effects. of ETA antagonism on restenosis after implantation of a coated stent with BQ123. The clinical implications might be important for the therapeutic strategy for the prevention of restenosis, a disorder characterised by abnormal smooth muscle cell proliferation.
This study has been approved by the appropriate Greek authorities. The study involves the implantation of two types of coronary stents in pigs. Six juvenile pigs were used for the biocompatibility of the coating which will be compared to that of uncoated stainless steel stents. These initial implantations indicated no adverse effects of the stent coating in terms of animal morbidity and mortality or excessive local tissue reaction. As a result, we have proceeded to the main part of the study.
The main part of the study comprises sixty juvenile male farm pigs weighing 25-35 kg and will compare two types of stents:
1) stainless steel
2) stainless steel coated with PLA coating with BQ-123 attachment
The results of this study will be submitted for publication in peer-reviewed medical journals.