GB2270841A

GB2270841A - Compositions for Treating vascular restenosis

Info

Publication number: GB2270841A
Application number: GB9318000A
Authority: GB
Inventors: Robert G Johnson; Christopher F Reilly
Original assignee: Merck and Co Inc
Current assignee: Merck and Co Inc
Priority date: 1992-09-09
Filing date: 1993-08-31
Publication date: 1994-03-30
Also published as: GB9318000D0

Abstract

Angiotensin-II Antagonists in combination with heparin suppress vascular stenosis which commonly occurs during the development of atherosclerosis and the restenosis following arterial angioplasty, stent placement, bypass surgery, heart transplantation and endarterectomy.

Description

TITLE OF THE INVENTION INHIBITION OF VASCULAR RESTENOSIS BACKGROUND OF THE INVENTION Restenosis occurs after a variety of arterial insults such as angioplasty, stent placement, bypass surgery, heart transplantation and endarterectomy.

Some of these procedures have been practiced for years for the treatment of coronary artery disease. Despite good initial successes and few complications, physiologically significant restenosis occurs between one and six months at the site of the procedures in a number of patients, and continues to be the main problem associated with the procedures.

To date, pharmacological intervention directed toward inhibiting restenosis has been largely unsuccessful including the use of corticosteroids, antiplatelet agents, calcium channel blockers, anticoagulant therapy, hypocholesterolemic agents and fish oil preparations.

There are data to indicate that there are similarities between native arterial lesions and those induced by surgical procedures and that treatment with angiotensin II receptor antagonists alone or in combination with heparin or a derivative thereof will prevent or at least slow down the rate of restenosis.

DETAILED DESCRIPTION OF THE INVENTION The novel- method of treatment of this invention comprises the administration to a patient scheduled to undergo an arterial surgical procedure such as arterial angioplasty, stent placement, bypass surgery, heart transplantation or endarterectomy with an angiotensin II (A-II) receptor antagonist in combination with heparin or a derivative thereof about 0-48 hours before the surgical procedure and for an indefinite period of time after the procedure, whereby restenosis is inhibited.

In the novel method of this invention the patient is a human scheduled for the arterial surgery.

The dose of A-Il -antagonist is about 50 to about 200 mg/day preferably about 100 mg/day, both before and after the surgical procedure. Treatment with the A-II antagonist after the angioplasty continues for at least 6 months and may be required indefinitely to prevent restenosis.

The A-II antagonist is administered concomitantly with about 15,000 to 45,000 units/kg/day of heparin (140-170 USP units/mg) which serves to augment the effect of the A-II antagonist.

The identity of the A-II antagonist is not critical provided it has an intrinsic activity of about IC50 < lOnfl and includes known A-II antagonists of the imidazole type, imidazopyridine type, benzimidazole type or the quinoline type and the like, such as the following:

EXAMPLE 1 INHIBITION OF VASCULAR RESTENOSIS WITH COMPOUND VII The A-II antagonist, VII, was delivered as an iv loading dose of 0.1, 0.3 and 1.0 mg/kg to groups of rats at the time of balloon angioplasty of their left carotid arteries followed by continuous iv delivery via Alzet minipumps of 0.1, 0.3 and 1.0 mg/kg/day until sacrifice on day 14. The sizes of the neointimal areas were measured and compared to controls.The data are reported in Table I where it can be seen that the restenosis was inhibited in a dose related manner and that the two highest doses, 0.3 and 1 mg/kg significantly inhibited restenosis (27-30% inhibition) 14 days after angioplasty. These data indicate that blockade of the A-II recepter suppresses vascular restenosis.

TABLE 1 COMPOUND VII TREATMENT AND RESTENOSIS IN THE RAT VII n Neointimal Area + sem % Inhibition (mg/kg/day) (mm) - 7 0.231 + 0.018 0.1 4 0.243 + 0.15 0 0.3 8 0.169 + 0.016* 27 1.0 5 0.163 + 0.011* 30 *p < 0.05 vs. controls (l-way ANOVA with 2-sided Dunnetts Multiple Comparison Test) EXAMPLE 2 INHIBITION OF RESTENOSIS WITH VII AND HEPARIN COMBINATION The A-II antagonist, VII; and VII plus heparin and heparin alone were delivered as iv loading doses of 1 mg/kg of VII and 0.3 mg/kg of heparin to separate groups of rats at the time of balloon angioplasty of their left carotid arteries followed by continuous i.v. delivery via Alzet minipumps of 1 mg/kg/day of VII and 0.3 mg/kg/hour of heparin.

Compound VII was delivered continuously until sacrifice at 14 days. Heparin administration was discontinued on day 4 following angioplasty.

The sizes of the neointinal areas were compared to each other and to saline controls. The data are reported in Table II where it can be seen that relative to saline controls (n=6), restenosis measured 4 days later was inhibited 23% in the 809 only group (n=7), 19% in the heparin only group (n=4) and 60% in the 809 plus heparin group (n=3). These data indicate that heparin and A-II receptor antagonists interact in a synergistic or additive manner to reduce vascular restenosis.

TABLE II COMBINED HEPARIN AND VII TREATMENT AND RESTENOSIS IN THE RAT TREATMENT N INTIMA (mm2) % Inhibition saline 6 .199 + .141 VII 7 .153 + .028 23 heparin 4 .162 + .064 19 (4 days) heparin + 3 .079 + .071 60 VII Protocol 1. VII was delivered as a 1 mg/kg loading dose prior to angioplasty followed by continuous i.v. infusion at 1 mg/kg/day until termination at 14 days.

2. Heparin was delivered as a 0.3 mg/kg loading dose prior to angioplasty followed by continuous i.v.

infusion at 0.3 mg/kg/day for 4 days.

EXAMPLE 3 INHIBITION OF RESTENOSIS WITH VII PRETREATMENT AND HEPARIN COMBINATION A vehicle treatment group was compared to groups treated with VII (1 mg/kg/day, continuous i.v.) begun at the time of angioplasty, VII begun 2 days prior to angioplasty (1 mg/kg/day, i.v. bolus), or VII in conjunction with heparin (0.3 mg/kg i.v. bolus at the time of angioplasty followed by continuous i.v.

delivery at 0.3 mg/kg/hr by ALZET minipumps. Heparin delivery was discontinued either 2 or 4 days later. In all cases, VII treatment was continued for the duration of the experiments (14 days). Fourteen days after balloon angioplasty, the rats were sacrificed and the extent of restenosis was determined by morphometric measurements of the newly-formed intima.

The data shown in Table 3 indicates that monotherapy with VII inhibited restenosis by 23% and that the antirestenotic effect of VII was enhanced when VII was preadministered for the 48 hr period prior to surgery (45% inhibition). The most pronounced inhibition was observed in the groups where heparin was coadministered. Heparin administration alone (hep 4d) did not significantly inhibit restenosis. The maximal inhibition (59%) was obtained in the VII pretreatment group where heparin was delivered for 4 days post-angioplasty.

TABLE III THE EFFECT OF VII PRETREATMENT + BEPARIN ON RESTENOSIS IN THE RAT Treatment n Intimal Area + sd (mm) % Inhibition vehicle 8 0.193 + 0.037 VII 9 0.149 + 0.026* 23 VIIpta 5 0.106 + 0.023* 45 VII + hep 4d 8 0.096 + 0.056*# 50 VII + hep 2d 5 0.112 + 0.035* 42 VIIpt + hep 4d 5 0.079 + 0.037*# 59 hep 4d1 4 0.162 + 0 064 16 1data from Table 2 :p k 0.05 vs. vehicle, Duncan's multiple range test #p < 0.05 vs. 809, Duncan's multiple range test apt = pretreatment

Claims

WHAT IS CLAIMED IS:

1. A method of inhibiting vascular restenosis in a patient in need of a vascular surgery which comprises the administration of a combination of heparin and an A-II antagonist with intrinsic activity of IC50 < 10 nM prior to or at the time of the surgery and administration of the A-II antagonist for at least 6 months following the angioplasty.

2. The method of claim 1, wherein the amount of A-II antagonist delivered at or prior to the time of the vascular surgery is 50 to 200 mg/kg and following angioplasty is 50 to 200 mg/kg/day and the amount of heparin delivered at or prior to the time of vascular surgery is about 15,000 to 45,000 units/kg/day (140-170 USP units/mg).

3. The method of claim 2 wherein the A-II antagonist is an imidazole derivative, an imidazopyridine derivative, a benzimidazole derivative or a quinoline derivative.

4. The method of claim 3 wherein the A-II antagonist is selected from the group consisting of the following compounds:

5. The method of claim 4.wherein the A-II antagonist is compound IV or VII.

6. The method of claim 5 wherein the A-II antagonist is compound VII.