Coronary heart disease treated with 17.beta.oestradiol

Use of 17.beta.-oestradiol in the treatment of coronary heart disease.

The present invention relates to the treatment of coronary heart disease 
and provides a pharmaceutical composition for such treatment, as well as a 
method for the treatment of coronary heart disease. 
BACKGROUND OF THE INVENTION 
Coronary heart disease arises from damage to the cardiac muscle, the 
myocardium, caused by insufficient flow of blood in the coronary arteries. 
The reduced flow of blood is termed myocardial ischemia, and the resulting 
heart damage is reflected in severe attacks of pain known as angina 
pectoris. The attacks of pain may be relieved or prevented using drugs, 
for example by sublingual administration of nitroglycerin or by the oral 
use of .beta.-blocking agents and calcium antagonists. Apart from 
relieving or preventing the angina, coronary heart disease may be treated 
by a combination of further methods, including the use of other drugs and 
the use of surgery. 
Coronary heart disease is particularly prevalent in women who have past the 
time of menopause. Furthermore, an increase in the incidence of heart 
conditions, including coronary artery disease, angina pectoris and 
vasomotor disturbance, is associated with the menopause. 
SUMMARY OF THE INVENTION 
The present invention provides compositions and methods for the therapeutic 
treatment of coronary heart disease. Such compositions and methods are 
based on the discovery that an oestrogen improves exercise-induced 
myocardial ischaemia in female patients with coronary artery disease. 
Thus, the present invention provides a pharmaceutical composition for 
treatment of coronary heart disease, comprising a synthetic or natural 
oestrogen together with a pharmaceutically acceptable carrier. 
Correspondingly, a method for the treatment of coronary heart disease, 
especially coronary heart disease in post-menopausal women, comprises 
administration of an effective amount of an oestrogen. The treatment will 
generally be chronic but acute treatment is possible. The compositions can 
readily be formulated and administered to suit the mode of treatment. 
Other features and advantages of the invention will be apparent from the 
following description and the claims. 
PREFERRED EMBODIMENTS OF THE INVENTION 
The currently preferred oestrogen is 17.beta.-oestradiol. Another product 
which may be employed is one prepared from the urine of pregnant mares, 
such as that sold by Wyeth under the Trade Name "Premarin" and which 
comprises a number of oestrogens, not all identified. 
In a particularly preferred embodiment, the method of treatment of the 
present invention comprises the steps of: 
diagnosing coronary heart disease in a patient; and then 
administering to said patient an effective amount of an oestrogen. The 
patient can then be monitored for improvement in the heart condition. 
Typically the patient, a male of, say, 40 to 60 years or a female of, say, 
60 to 75 years will exhibit one or more of the symptoms of coronary heart 
disease, including exceptional chest pain and shortness of breath. The 
oestrogen can be administered in various forms, depending upon the patient 
and the desired route of administration which may be oral, parenteral or 
transdermal. Suitable formulations for oral administration include 
tablets, capsules, granules, powders or syrups; and suitable formulations 
for parenteral administration include injections (which may be 
intravenous, intramuscular or subcutaneous), drops or suppositories. These 
various formulations can be prepared by conventional means in which the 
oestrogen is mixed with additives such as those commonly employed in the 
field of pharmaceutical preparations, including vehicles, binders, 
disintegrators, lubricants, corrigents, solubilizers, suspending agents 
and coating agents. Similarly the active ingredient may be formulated as a 
skin patch for transdermal application, e.g. the product Estradern 
manufactured by Ciba Laboratories. 
The dosage may be varied depending on the symptoms, age and body weight of 
the patient, the route of administration and the form of the preparation. 
A daily dose of from 0.1 mg to 10 mg, more typically 0.5 mg to 2 mg, which 
may be administered in a single dose or in divided doses, is usually 
appropriate for an adult human patient. For female patients, if the uterus 
is intact, the oestrogen may be administered in conjunction with added 
progesterone from 14-28 days. 
The present invention also provides for the use of an oestrogen in the 
manufacture of a medicament for the treatment of coronary heart disease, 
and particularly of coronary heart disease and myocardial ischaemia in 
female patients, particularly menopausal and post-menopausal women. 
Oestrogens have previously been administered for several medical 
indications, notably in hormone replacement therapy for menopausal and 
postmenopausal women. However, stemming from a recognition of the adverse 
effects of the contraceptive pill, the administration of oestrogens is 
contra-indicated for patients with coronary heart disease, and the 
pharmacopoeia contain warnings for oestrogen products that they are not to 
be given to patients with cardiac disease. Thus, no medical practitioner 
will prescribe oestrogen for a patient with coronary heart disease. 
Ovarian hormones, and in particular 17.beta.-oestradiol, are vasoactive 
substances. They have been shown to increase cardiac output and arterial 
flow velocity, and decrease vascular resistance, systolic and diastolic 
blood pressure (see, for example, Am. Heart J. 1987; 114: 1467-1503; N. 
Engl. J. Med. 1987; 316; 1105-1110; and .Circulation 1987; 75:1102-1109).

EXAMPLES OF THE INVENTION 
The present invention is exemplified but not limited by the following 
Examples. 
Example 1 
The acute effect of sublingual 17.beta.-oestradiol on exercise-induced 
myocardial ischaemia was assessed in women with coronary artery disease. 
The study population consisted of 11 female patients with coronary artery 
disease referred for cardiac evaluation during a 3 month period at the 
Royal Brompton National Heart & Lung Hospital, London. Patients were 
included in the study if they had a reproducible positive exercise test 
(.gtoreq.1 mm of ST segment depression), proven coronary artery disease 
(.gtoreq.70% diameter stenosis of one or more coronary arteries) and 
clinical indication of oestrogen deficiency. All but 2 of the women had 
17.beta.-oestradiol plasma concentrations lower than 200 pmol/l (normal 
postmenopausal plasma concentration &lt;200 pmol/1 ). Patients with primary 
valvar congenital heart disease, myocardial or pericardial disease, 
congestive heart failure, left ventricular hypertrophy, ST segment changes 
at rest and left bundle branch block were excluded. Patients with 
uncorrected hypokalaemia and those receiving digitalis or antidepressant 
drugs were also excluded. 
The mean age of the 11 female patients was 58.+-.8 years. Angina had been 
present for 4.6.+-.3 years. Previous myocardial infarction had occurred in 
3 patients and 2 had undergone coronary artery bypass graft surgery. 
Hysterectomy had been performed in 2 patients. Eight patients were 
receiving .beta.-blockers, 6 were receiving calcium channel antagonists 
and 4 were taking long acting nitrates. All patients underwent left 
ventriculography and selective coronary arteriography using the Judkins 
technique. Coronary artery disease (defined as at least 70% narrowing of 
the luminal diameter in one or more of the major coronary arteries or 
their major branches) was found in 3 vessels in 3 patients, in 2 vessels 
in 6 patients and in 1 vessel in 2 patients. 
All 11 patients performed, off therapy, two exercise tests on two different 
days at the same hour of the day (.+-.1 hour) using the modified Bruce 
protocol. Nitrates other than sublingual nitroglycerin were withdrawn 2 
days before the study. Calcium channel blocking and .beta.-adrenergic 
blocking agents were withdrawn 4 and 5 days before respectively. At least 
6 hours elapsed between use of sublingual nitroglycerin and each exercise 
test. Forty minutes prior to each exercise, test patients were given 
either 17.beta.-oestradiol (Estrace 1 mg, Mead Johnson laboratories, 
Evansville, Ind.) or 17.beta.-oestradiol placebo (Mead Johnson 
laboratories, Evansville, Ind.) administered in random order. Both 
investigators and patients were blinded to the therapy taken by the 
patient. A complete 12-lead electrocardiogram was obtained at rest, every 
minute during the test, at the end of each stage, at the onset of 1 mm of 
planar ST segment depression, at peak exercise and every minute during 
recovery. Leads V.sub.2, V.sub.5 and II were continuously monitored. 
Systolic and diastolic blood pressure were measured at rest and monitored 
every minute during exercise and recovery. 
A positive response in the electrocardiogram was defined as a horizontal or 
downsloping ST segment depression .gtoreq.1 mm at 60 ms after the J point 
occurring at least in six consecutive complexes. The exercise test was 
concluded at the point of physical exhaustion, ST segment depression 
.gtoreq.3 min, severe angina, severe dyspnoea or a decline in systolic 
blood pressure greater than 20 mm Hg. Total exercise time, time to 
myocardial ischaemia, heart rate, blood pressure at the onset of 1 min ST 
segment depression, maximal ST segment depression and the development of 
angina during exercise were recorded. 
A blood sample for the evaluation of plasma levels of 17.beta.-oestradiol 
was taken after each test and analyzed using a standard radioimmunoassay 
method. 
The ST segment, 60 ms after the J point, was evaluated after signal 
averaging using a computer assisted system (CASE Marquette 12) in all 12 
leads. The lead showing the greatest ST segment depression in the placebo 
exercise test was selected for analysis. Exercise tests were reviewed in 
random order by independent, experienced investigators blinded to the 
clinical data. 
All patients developed chest pain on exertion after placebo, while only 6 
patients experienced chest pain after 17.beta.-oestradiol. All patients 
had at least 1 mm ST segment depression during the placebo exercise test, 
but only 7 patients had a positive exercise test after 
17.beta.-oestradiol. Blood pressure, heart rate and rate pressure product 
at rest, at the onset of 1 mm of ST depression and at peak exercise are 
shown in the following Table. Statistical significance was tested using 
the two-tailed Mann-Whitney Test. The data are expressed as mean (.+-.ISD) 
and differences with 95% confidence intervals are given. 
__________________________________________________________________________ 
Difference 
Placebo 
17-.beta. Oestradiol 
(n = 11) 
(n = 11) 
(n = 11) (95% Confidence 
mean (SD) 
mean (SD) 
p Intervals) 
__________________________________________________________________________ 
Resting 
Heart Rate beats/min! 
75 (13) 
80 (12) 0.08 
-5 (-10 to 0.2) 
Blood Pressure mm Hg! 
141 (23) 
132 (22) 
0.06 
9 (-04 to 20) 
Rate Pressure Product 
10681 (2810) 
10675 (3109) 
0.1 
7 (-1163 to 1745) 
mm Hg x (beats/min)! 
1 mm ST Depression 
Heart Rate beats/min! 
117 (18) 
124 (20)* 
0.02 
-10 (-15 to -5)* 
Blood Pressure mm Hg! 
164 (19) 
161 (20)* 
0.09 
-10 (-18 to 23)* 
Rate Pressure Product 
19360 (4243) 
19897 (4410)* 
0.07 
-1600 (-3483 to 59)* 
mm Hg x (beats/min)! 
Time seconds! 
456 (214) 
550 (166)* 
0.02 
-101 (-154 to -39)* 
Peak Exercise 
Heart Rate beats/min) 
140 (34) 
139 (19) 
0.5 
1 (-13 to 11) 
Blood Pressure mm Hg! 
165 (31) 
171 (20) 
0.7 
-6 (-21 to 30) 
Rate Pressure Product 
22079 (5994) 
24010 (4662) 
0.3 
-1930 (-4265 to 2224 
mm Hg x (beats/min)! 
Time seconds! 
569 (249) 
658 (193) 
0.01 
-89 (-154 to -9) 
Max ST Depression mm! 
1.6 (0.4) 
1.2 (0.05) 
0.07 
-0.4 (0 to 0.7) 
__________________________________________________________________________ 
n = 7 
It can be seen that the time to 1 mm ST segment depression (p&lt;0.02) and 
total exercise time (p&lt;0.01) were increased by 17.beta.-oestradiol. Heart 
rate at the onset of 1 mm ST segment depression was increased by 
17.beta.-oestradiol (p&lt;0.05). If the peak exercise time was substituted 
for the time to 1 mm ST segment depression in those 4 patients who did not 
achieve 1 mm ST segment depression on exercise after 17.beta.-oestradiol, 
then time to 1 mm ST segment depression increased (p&lt;0.004). 
17.beta.-oestradiol plasma concentrations increased from 155.+-.168 to 
2531.+-.1192 pmol/l after administration of sublingual 17.beta.-oestradiol 
(normal premenopausal physiological ranges; luteal 368 to 1100 pmol/l, 
midcycle 785 to 1840 pmol/l, follicular 74 to 368 pmol/1 ). No patients 
reported any adverse symptoms after administration of either 
17.beta.-oestradiol or placebo. 
In general, patients who responded to 17.beta.-oestradiol had a low control 
plasma oestradiol concentration. The two patients with the smallest 
increase in time to 1 mm ST segment depression had higher plasma 
oestradiol concentrations. 
In summary, patients were randomized to receive either sublingual 
17.beta.-oestradiol or placebo 40 minutes before a treadmill exercise 
test. Plasma 17.beta.-oestradiol concentrations were confirmed to be 
higher after sublingual 17.beta.-oestradiol when compared with sublingual 
placebo (2531.+-.1192 vs 155.+-.168 pmol/l, p&lt;0.001). 17.beta.-Oestradiol 
increased both time to 1 mm ST depression (449.+-.158 vs 550.+-.166 
seconds, p&lt;0.02, difference 101, 95% confidence intervals 39 to 154) and 
total exercise time (569.+-.249 vs 658.+-.193 seconds, p&lt;0.01, difference 
89, 95% confidence intervals 9 to 154). Heart rate and blood pressure were 
lower at rest after 17.beta.-oestradiol (p&lt;0.08). There were no 
differences in the haemodynamic variables either at the time of 1 mm ST 
segment depression or at peak exercise apart from the heart rate at 1 mm 
ST segment depression which was higher after 17.beta.-oestradiol (p&lt;0.02). 
The results are similar to those obtained using acutely administered 
nitroglycerin or nitrates in patients with coronary artery diseases, and 
may explain some of the protection against coronary artery disease 
apparent in females before the menopause, and the protective effects of 
oestrogen replacement therapy in menopausal women. 
Other embodiments and within the following claims.