Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving oxidoreductase
Reexamination Certificate
2001-08-24
2004-09-14
Lankford, Jr., Leon B. (Department: 1651)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving oxidoreductase
C435S007100, C435S004000
Reexamination Certificate
active
06790635
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a method for predicting restenosis following coronary intervention by measuring a human lipocalin-type prostaglandin D synthase (hereinafter referred to as L-PGDS) concentration in a body fluid sample. More particularly, the invention relates to the method for predicting restenosis following coronary intervention using changes in the L-PGDS concentration in the sample as an indicator.
BACKGROUND OF THE INVENTION
Methods for treating an ischemic heart disease such as angina, which brings about stenosis in a coronary, include pharmacotherapy, coronary artery bypass graft, and coronary intervention.
Pharmacotherapy is a basic treatment for angina, and is used for improving myocardinal ischemic conditions. Its mechanism of action works in two ways: one expands a coronary artery, improving a bloodflow into the myocardium (e.g. nitrous acid), and the other decreases the heart rate and blood pressure to reduce oxygen consumption of the myocardium, thereby preventing the occurrence of an attack (e.g. &bgr; blocker agent). On the other hand, coronary artery bypass graft is a method in which a blood vessel is newly established for a stenosed part to connect the aorta with peripheries of the stenosed part in a coronary artery, thereby reconstructing the circulation of the coronary artery.
Coronary intervention is a method in which an intravascular catheter is inserted into a femoral artery and directed to a stenosed part, and then a physical treatment is performed locally to ensure blood flow. Various devices are used in coronary intervention. A Percutaneous Transluminal Coronary Angioplasty (referred to as PTCA hereinafter) is a method in which a balloon catheter is inserted into a blood vessel and expanded in a stenosed part, thereby enlarging the stenosed part to recover a normal bloodflow. A coronary stent implantation is a method in which a metal wire-woven tube is implanted in a stenosed part using a catheter to support a lumen of the coronary artery, thereby ensuring a normal bloodflow.
As described above, coronary intervention is not accompanied by a surgical operation such as thoracotomy. Therefore, ever since Gruentig performed the first successful PTCA in 1977, it has become widely used in Japan, not to mention Europe and America. In the early days, the application of coronary intervention was limited to stable angina with a restricted lesion in a single vessel. Its application was then extended to a stable angina with lesions in multiple vessels, and further, to an angina with a complete obstruction. Nowadays, it has become one of the established treatments for ischemic heart diseases. However, there is a significant weak point in PTCA in that an acute and subacute thrombotic occlusion occurs in an early stage following the operation, and that restenosis occurs within 3 to 4 months at 30-40% probability (Nobuyoshi, M. et al. (1988)
Am. Coll. Cardiol
. 12: 616-623).
Among these, for the acute and subacute thrombotic occlusion which occurs at an early stage, a method in which an intracoronary stent is used as a device, and in addition, aspirin and ticlopidine are used together, has been established as a typical prevention (Lincoff, A. M. et al. (1993)
J. Am. Coll. Cardiol
. 21: 866-875).
On the other hand, a step towards solving the restenosis problem was also presented by the development of the intracoronary stent. The restenosis occurrence following intervention in cases where this device is used decreased to 20-30% compared to PTCA using a balloon. Later on, the advent of various stents greatly lowered the probability of restenosis, however, they have fallen short of completely preventing restenosis (Fishman, D. L. et al. (1994)
N. Engl. J. Med
. 331: 496-501; Serruys, P. W. et al. (1994)
N. Engl. J. Med
. 331: 489-501).
Therefore, together with the improvement of such devices, prevention by medication has also been attempted.
Since the restenosis is triggered by platelets accumulating toward an intimal injury caused by coronary intervention as well as the growth of a newly-born intima, and by a platelet-derived growth factor being produced, the effect of antiplatelets was expected. However, none of aspirin, dipyridamole, and ticlopidine could reduce the restenosis occurrence. Furthermore, trapidil, which is an antagonist of the platelet-derived growth factor, was of no effect, and the preventive efficacy of anticoagulants, heparin and warfarin, was not confirmed either. Still further, it was reported that the restenosis rate is higher in the case of coronary spastic angina, and in view of the cause-effect relationship between restenosis and coronary spastic angina, the effect of a calcium antagonist was prospected. However, neither diltiazem nor nifedipine was effective (
Arteriosclerosis
: 122; Medical Aoi Press).
Under such circumstances, drugs that are being recognized as effective for restenosis have recently appeared. It has been reported that drugs that were prescribed as a keloidal drug such as tranilast which is an antiallergic agent and cilostazol which is an antiplatelet agent showed favorable results after PTCA, and basic research concerning these drugs is now proceeding (Ishiwata (1996) Kowa medical report Vol. 39, No. 3: 127-33; Tamal H. et al. (1994)
Circulation
90: I-652; Katsuki et al. (1998)
Medicina
35: 659-661). Although neither drug has been clinically tested on a large-scale yet, it is considered certain that effective drugs including these will emerge in the future.
Thus, an early prediction of the occurrence of restenosis will enable an effective precaution to be taken using drugs. Therefore, a method for early prediction of occurrence of restenosis following coronary intervention has been long expected, however, early prediction is not easy since restenosis following the intervention often occurs asymptomatically.
Nowadays, various factors involved in restenosis are being studied, and their relationship with the mechanism of restenosis is being examined. Since the plasma concentration of angiotensin converting enzyme is correlated with the amount of intimal growth following a stent placement, its potential as an indicator for predicting restenosis has been suggested (Ohishi (1995)
Hypertension
26: 561). Furthermore, based on the assumption that a constrictive remodeling is involved in occurrence of restenosis following PTCA, studies on endothelin (referred to as ET hereinafter) which is a vasoactive substance having a strong vasoconstrictive effect, have been carried out. Doi et al. measured the ET concentration in a coronary artery before/after/three months after PTCA, and reported that a group with significant stenosis showed a greater degree of changes in the concentration compared to a group without significant stenosis was not confirmed, and they reported clinical data indicating that the ET increase in the coronary circulation played an important role in the mechanism of coronary artery restenosis following PTCA (
Journal of Cardiology
vol. 32 Supplement 1: p391). It is suggested that the platelet-derived growth factor also has a potential as a factor for predicting restenosis in view of its involvement in a restoration process after being damaged by PTCA (Haneo et al. (1993)
Journal of Clinical
and
Experimental Medicine
167 No. 6 p512). Naruko et al. carried out an investigation on the expression of natriuretic peptide system in a restenosed part, and confirmed the expression of natriuretic peptide C, natriuretic peptide A receptor, and natriuretic peptide clearance receptor in a newly-born intima of the restenosed part (
Journal of Japan Atherosclerosis society
vol. 25 Supplement 1998: 140).
However, for each agent excepting ET, the data merely indicates its involvement in the mechanism of restenosis, and no clinical findings capable of predicting restenosis at an early stage after coronary intervention have been obtained so far. Additionally, since ET requires a long-term follow-up of the changes in the concentration, it is not practical from the viewpoint of early pred
Inoue Teruo
Nakajima Hiroshi
Oda Hiroshi
Sato Nobuyuki
Seiki Kosuke
Davis Ruth A.
Fish & Richardson P.C.
Lankford , Jr. Leon B.
Maruha Corporation
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