Vascular remodeling agent

Details Vascular remodeling agent Vascular remodeling agent

1998-09-08

2001-04-10

Reamer, James H. (Department: 1614)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Sulfur, selenium or tellurium compound

Reexamination Certificate

active

06214887

ABSTRACT:

INTRODUCTION AND BACKGROUND
Restenosis post-coronary dilation is a common disease of iatrogenic etiology that occurs as a direct consequence of arterial injury induced at the time of angioplasty. In the United States, over 500,000 coronary angioplasty procedures are performed annually and this number has been increasing steadily. Despite technical advances and multiple pharmacologic interventions, most studies have found that the incidence of angiographic restenosis remains in the range of 40%. The presenting symptom in the majority of patients with restenosis is exertional angina. Although clinical evidence for restenosis (MI, coronary revascularization, or recurrent angina) may vary from one study to another, clinical restenosis is generally seen in 25 to 35% of the patients within 6 months of their procedure (Circulation 1992; 86:100-110). Restenosis is a time-limited event. Serial angiographic follow-ups have shown that restenosis is most prevalent between 1 and 4 months and rarely occurs beyond 6 months after coronary angioplasty (
J Am Coll Cardiol
1988; 12:616-23). The most common treatment strategy for restenosis is repeat angioplasty.
In the past decade, research on prevention of restenosis with pharmacological agents has been almost uniformly disappointing, except for some positive findings with a few drugs yielding conflicting results. The classes of agents tested in a placebo-controlled, randomized study have included antithrombotic agents, fish oil, calcium channel blockers, angiotensin-converting enzyme inhibitors, lipid-lowering agents, steroids, other antiproliferative agents, and magnesium.
Several studies have examined the efficacy of other methods of percutaneous revascularization in the prevention or the treatment of coronary restenosis. Such modalities include: directional and rotational atherectomy, excimer laser-assisted angioplasty, cutting-balloon angioplasty, heat-generating angioplasty devices and coronary stenting.
Other than coronary stenting, no other percutaneous revascularization procedure offers demonstrated advantage over conventional PTCA in preventing or limiting recurring restenosis. Although stent implantation may, in some patients (de novo lesion, native coronary artery with a reference diameter larger than 3.0 mm) prove beneficial (
N Engl J Med
1994; 331:489-495) (
N Engl J Med
1994; 331:496-501), its clinical or angiographic superiority in vessels smaller than 3.0 mm in diameter has never been shown (
Semin Intervent Cardiol
1996; 1:255-262).
Our understanding of the pathophysiology of restenosis has been steadily improving. Once believed to be initiated by an early thrombotic phenomenon, restenosis has been considered in the past 7 years essentially a proliferative process taking place in the weeks following angioplasty at the site of arterial injury. Cytologic analyses of post mortem and atherectomy samples have revealed that smooth muscle cells are the predominant cells responsible for this hyperplastic response. One possible explanation for the negative results with the pharmacologic studies aimed at reducing neointimal hyperplasia is that these strategies targeted the wrong mechanism.
More recently, animal and clinical studies have begun to question the predominant role of cellular proliferation in restenosis and indicate that arterial remodeling is, in fact, an important aspect of the restenosis process (
Circulation
1994; 89:2809-15). Inadequate vascular remodeling has been described not only after coronary balloon angioplasty but also after directional and rotational atherectomy and laser angioplasty (
Circulation
1996; 94:35-43). Arterial remodeling is defined as a change in total arterial or external elastic membrane (EEM) cross-sectional area (CSA) over time. Arterial remodeling can be bi-directional. Adaptive positive arterial remodeling (an increase in arterial CSA) may represent a compensatory response of blood vessels to hemodynamic stress, arterial injury, and cellular proliferation. Adaptive arterial remodeling has first been described in early coronary artery atherosclerotic disease process (
N Engl J Med
1987; 316:1371-5). Adaptive positive arterial remodeling in non-instrumented arteries prevents the reduction in lumen dimensions until plaque occupies 20% to 40% of the CSA within the internal elastic membrane (20% to 40% cross-sectional narrowing or plaque burden) (
Am J Cardiol
1997; 80:1408-13). Alternatively, pathologic negative arterial remodeling (a decrease in arterial CSA or chronic arterial constriction) has been shown to contribute to lumen compromise in chronic, focal de novo stenosis in femoral and coronary arteries (
Circulation
1995; 91:1444-9 and
Circulation
1997; 95:1791-8).
SUMMARY OF THE INVENTION
This invention concerns methods and devices for promoting vascular remodeling. By the invention, vascular remodeling is accomplished by the systemic or local administration of the drug, probucol; 4,4′-([1-methylethylidene)bis(thio)]bis-[2,6-bis(1,1-dimethylethyl)phenol]. The preparation of probucol has been described in U.S. Pat. No. 3,576,883 and its use as a cholesterol-lowering agent has also been described in U.S. Pat. No. 3,862,332. Its use to inhibit angiographic and clinical restenosis, i.e., death from cardiac cause, acute myocardial infarction, recurrence or exacerbation of angina pectoris and the need for revascularization (coronary bypass surgery or re-angioplasty) post-coronary angioplasty by promoting positive vascular remodeling has not previously been described. By using probucol to promote vascular remodeling by the method of the invention, favorable results can be obtained in treating diseases and conditions such as restenosis following balloon angioplasty, directional or rotational atherectomy, laser angioplasty and post-stent implantation. Promoting positive vascular remodeling would be favorable not only for interventions performed in the coronary arteries but also when these procedures are performed in any vascular structure, i.e., peripheral vessels (iliac, femoral etc.), renal, mesenteric, or carotid arteries, etc. Furthermore, promoting positive vascular remodeling would be favorable in the long-term treatment of patients with ischemic syndromes as seen in coronary artery disease, peripheral vascular disease, mesenteric vascular disease, cerebro-vascular disease, etc. The benefit of a positive vascular remodeling agent would also be desirable for the treatment of conditions such as chronic arterial hypertension, post-heart transplant, post-bypass surgery, etc.
Five small clinical studies have suggested that probucol started before angioplasty may prevent restenosis (
Circulation
1991; 84: II-299 (abstract),
Clin Ther
1993; 15:374-382
, Jpn Heart J
1996; 37:327-32
, Am Heart J
1996; 132:23-29
, J Am Coll Cardiol
1997; 30:855-62). Recently, we have shown in the MultiVitamins and Probucol (MVP) randomized clinical trial that probucol, a drug with strong antioxidant properties, given alone reduced angiographic lumen loss by 68%, restenosis rate per segment by 47% and the need for repeat angioplasty at 6 month by 58% compare to placebo. These results have been recently published (Multivitamins and probucol in the prevention of restenosis after coronary angioplasty: Results of the MVP randomized trial.
N Engl J Med
1997; 365-372) and the publication is incorporated herein by reference. It was not possible to determine with angiography alone whether probucol acted via inhibition of tissue hyperplasia or improvement in vascular remodeling. Determination of this mechanistic question was necessary to help identify the appropriate targets in the periangioplasty period and, as taught by the present invention, lead to more effective strategies to prevent restenosis. In addition, the invention enables the skilled practitioner to use probucol in conjunction with other percutaneous coronary interventions such as stenting if it is deemed appropriate.
We have performed serial intravascular ultrasound (IVUS) examinations in a consecutive series of patients

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