MXPA97009163A - The use of a dopamine / proluctine reduction compound to prepare compositions to prevent associated stenosis with intervention after invasive interventions without deriva - Google Patents

Abstract

The present invention relates to the use of a dopamine enhancer / prolactin reducing compound for preparing compositions for preventing stenosis after an invasive intervention without bypass, the invention relates to the use of said compound to decrease symptomatic chest pains after an invasive intervention without derivation, the use of the compositions comprises administering a daily amount thereof, so as to provide the dopamine enhancing compound / prolactin reducer at a predetermined time, and continue the administration for a period at least sufficient for allow the vascular injury to heal

Description

THE USE OF A PROLUCTINE DOPAMINE / REDUCER COMPOUND TO PREPARE COMPOSITIONS BY »PREVENTING LFL STENOSIS ASSOCIATED WITH INTERVENTION AFTER INTERVENTIONS INVASIVE WITHOUT DERIVATION FIELD OF THE INVENTION The invention relates to methods for reducing, in an animal subject (including a human) in need of such treatment, the rate at which blood vessels are affected by restenosis after percutaneous transluminal coronary angioplasty (PTCR), aterectornia or endarterectornia . This invention also relates to methods for decreasing symptomatic chest pain (angina pectoris or amaurosis fugax) in humans, which occurs after restenosis of the blood vessel after invasive non-shunt procedures, i.e. percutaneous transluminal coronary angioplasty, aterectornía and endarterectornia.

BACKGROUND OF THE INVENTION Cardiovascular disease and invasive intervention without referral In the United States, myocardial infarction (MI) is a leading cause of death. Almost all myocardial infarctions are completely attributable to atherosclerosis. Atherosclerosis is a progressive len + amenté disease that begins in childhood but does not manifest until years later when it results in clinical symptoms associated with damage to susceptible organs, mainly the heart and brain. The aterosselerosis, I commonly knew, gives horn "Hardening of the arteries" results from the formation of known lesions such as fibroids or fibrous plaques on the internal arterial wall. The plaques are composed primarily of a center of lipid and cholesterol deposits surrounded by connective tissue and smooth muscle cells. Among the important risk factors for the development of atherosclerotic lesions are several metabolic disorders such as hyperlipidernia, hyperlipoprotememia, diabetes, obesity, hyperglyceria and hyperinsulmemia. 01 increasing the size of the lesions, they can restrict the flow of blood in the artery leading to a variety of clinical results. One of these results is coronary ischemia that can manifest clinically either as angina pectoris (chest pain) or myocardial infarction. Another result is cerebral ischemia that can lead to cerebral infarction (ie, attack) or ischemic encephalopathy. Significant stenosis of the coronary arteries can be treated by percutaneous transluminal coronary angioplasty (PTCA), also called balloon angioplasty, or by atherectomy. These treatments for coronary heart disease have become the main alternatives for coronary bypass surgery. Similarly, stenoses of the internal carotid arteries, which cause cerebral ischemia and can lead to seizures, are removed by endarterectomy, a technique similar to athereal surgery. In the United States alone, approximately 400,000 people submit to the PTCA each year. Unfortunately, 25-50% of those patients treated with PTCñ experience recurrent ischemia at 6 months, as a result of artery restenosis. Restenosis is due, in part, to the arterial endothelial lesion that occurs during angioplasty. This injury results in a focal increase in permeability to plasma constituents and allows platelets and monocytes to adhere to the endothelium or subendothelial connective tissue. Platelets and activated rhonocytes will secrete a variety of potent showcases (eg, platelet-derived growth factor (PDGF), epidermal growth factor (EGF), fibroblast growth factor + or (FGF), heterosterium). n-1 (IL-1) and tumor necrosis factor (TNF)) that result in the reestablishment of fibroblasts and smooth muscle cells in the area, and hyperproliferation of smooth muscle cells. Smooth muscle cells synthesize components of the extracellular matrix such as collagen, elastic fibers and proteoglycans. The rhonocytes also migrate to the intima of the blood vessels and become foam cells, which are activated macrophages that actively accumulate lipids and store them as micellular lipid droplets. Hyperlipidernia also seems to play a role, which is still not well defined, in the generation of post-treatment injuries. Res + enosis results in the recurrence of ischemia and its symptoms that include angina and abnormal electrocardiogram readings, and may result in myocardial infarction. Researchers have tried to prevent restenosis with a variety of pharmacological, biotechnological and mechanical approaches. To date, despite substantial efforts, a strategy that significantly reduces the rate of restenosis has not yet been developed. In fact, in recent years, more than 50 drugs have been used in attempts to prevent restenosis without success.

Previous work of the present inventors The present inventors and their collaborators have discovered that the administration of certain dopamine-enhancing and / or prolactin-reducing compounds (e.g., dopa agonists such as bromocriptine) and / or prolactum enhancers ( e.g., dopamine antagonists such as metoclopramide, agonists and serotonin precursors, such as 5-hydroxypropionate) and particularly the administration of said substances at predetermined times, reduce fat deposits in the body, obesity. , tngl cepdos and cholesterol in the plasma, and can prevent or alleviate atherosclerosis, as well as hypersensitivity and insulin resistance. (See U.S. Patents Nos. 4,659,715, 4,749,709, 4,783,459, 5,006,526, 5,344,832, and PCT Application US92 / 11166.

Related Applications Co-pending patent application No. of Sene 07 / 919,685 discloses methods for regulating disorders in lipid metabolism by administering prolactin (or prolactin and a glucocorticosteroid ("GC") in the bloodstream of an animal or human in a target base regulated in a quantity and for a period of time sufficient to modify and reduce the oscillation of the neural phase of the daily prolactum rhythm.It was found that this modification increases the sensitivity to insulin.The injections of prolactin are regulated in time to create a peak in the daily secretion profile of prolactin (or prolactin and glucocorticosteroid) of the subject that coincides in time with peak prolactin secretion (or prolactin and GC peaks, respectively) of a thin, sensitive human insulin to increase insulin sensitivity and reduce body fat deposits. Serial No. 07 / 719,745 also describes and claims the additional administration of a thyroid hormone to subjects who are being treated with a dopamine agonist and a prolactone enhancer, especially those subjects who are chronically or temporarily hypothyroid. Co-pending applications Serial No. 07 / 995,292 and 08 / 264,558 describe methods for determining whether the daily profile of circulating prolactum in a subject is normal, and methods for normalizing prolactm profiles that are aberrant. In pertinent part, the method of treatment includes the administration of a prolactin reducing compound not after the time during which during the waking hours the level of prolactin in the subject to be treated is at its highest point, and may also include the administration of a regulated-time prolactin improver to cause a peak in the prolactin level to occur at night. The objective of this treatment is the alteration ("sculpted") of the prolactum profile of the subject to imitate or reach in phase and amplitude the profile of a thin and healthy human who does not suffer from any disorder. Co-pending patent application No. of sene 08 / 263,607 discloses methods for regulating lipid metabolism and glucose metabolism by the time-regulated administration of pirenzepma, methyl scopola ma or another receptor antagonist (preferably MI) uscarmeme alone or in combination with a prolactone reducing compound as a treatment for diabetes. This application further describes maintaining the therapy for a period of time sufficient to cause the reduction of the oscillators of the neural phase that control the daily prolactin rhythm, resulting in continuous metabolic improvement after the conclusion of the therapy. The co-pending patent application No. of sene 08 / 271,881 describes a method for adjusting the phase relationship between the circadian rhythms for prolactm and for one or more immune responses. The invention includes normalizing (or reducing) the circadian rhythm for prolactm to be that of a young and healthy subject. The invention also includes manipulating the circadian rhythm for prolactin and bringing it into such a phase-amplitude relationship with the immune-responsive nature of prolactin to exert an amplifying effect on a predetermined aspect of the immune response.

OBJECTS OF THE INVENTION It is an object of this invention to provide methods for totally or partially preventing restenosis and / or eliminating one or more clinical symptoms associated with restenosis, such as chest pain, thereby extending the benefit of PTCA, the aterectorma and / or endarterectonia. In particular, it is an object of this invention to provide a pharmacological method for the treatment of mammals, including humans, that typically develop recurrent coronary ischemia after six months of having undergone percutaneous transluminal coronary angioplasty or atherectomy. Another object of this invention is to provide a pharmacological method for the treatment of mammals, including humans, that develop recurrent cerebral ischemia after six months of having undergone endarterectomy. A more specific object of the invention is to provide a pharmacological method to reduce or prevent chest pain or amaurosis fleeting that may occur in a mammal in need of such treatment. Another more specific object of the invention is to provide a pharmacological method to reduce or prevent restenosis of the arteries that have been subjected to compression or removal of atherosclerotic lesions.

BRIEF DESCRIPTION OF THE INVENTION A method for preventing or limiting restenosis in a mammal (including humans) that has undergone an invasive procedure without derivation selected from the group consisting of (i) percutaneous transluminal coronary angioplasty; (ii) atherectomy; and (iii) endarterectomy. The method comprises administering to the mammal a daily amount of a dopamine / prolactin reducing compound at a predetermined time, the time and amount being selected to reduce the level of prolactin in the blood and / or increase the activity of the dopamine in the blood. the subject during all or a portion of the hours of day 0700-2200; and continuing the administration for a period of time at least sufficient to allow the vascular lesion incident to the invasive procedure to heal. A method for reducing or eliminating chest pain in a human who has undergone an invasive procedure without derivation selected from the group consisting of (i) transcutaneous percutaneous coronary angioplasty is also described; (ii) atherectomy and (iii) endarterectornia. The method comprises administering to a human a daily amount of a dopamine / prolactin reducing compound at a predetermined time, the time and amount being selected to reduce the level of prolactin in the blood and / or increase the activity of dopamine. in the subject during all or a portion of the hours of day 0700-2200; and continuing the administration for a period of time at least enough to allow the vascular lesion incident to the invasive procedure to heal.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 illustrates normal or healthy prolactin profiles for humans. Curve "a" illustrates the profile of healthy men and curve "b" illustrates the profile of healthy women.

DETAILED DESCRIPTION OF THE INVENTION All patents, patent applications and literature references cited herein are incorporated by reference in their entirety as to whether their descriptions were physically present in the present disclosure. However, in case of conflict, however, the present description controls it. It has recently been discovered that restenosis of blood vessels after an invasive intervention without derivation can be partially or totally abrogated by administering daily a mammalian subject (including a human) a dopamine enhancer / prolactin reducing compound at a predetermined time during a a 24-hour period designed to decrease the level of prolactin in the blood and / or increase the dopamine activity of said subject during at least a substantial portion of the day (07: 00-22: 00). This administration also serves to partially or totally abrogate the chest pain typically suffered by humans as a result of restenosis of the blood vessels subsequent to invasive procedures without referral. Invasive intervention without bypass in blood vessels (arteries) such as PTCA, atherectomy or endarterectomy, a mechanical ablation or removal of arterial plaque. Typically, subjects who undergo these procedures suffer from metabolic abnormalities. Healthy (normal) subjects, ie the young, thin limbs of a species that does not suffer from metabolic abnormalities, have highly predictable daily prolactin release profiles, which in humans are characterized by a low and relatively constant level of prolactin during waking hours (day: 07: 00-22: 00) followed by a sharp increase to a peak during the night and a more gradual downward tilt down to the level of waking hours in the morning ( 22: 00-07: 00). Figure 1 illustrates the profile of normal or healthy prolactin for humans (curve a: male; curve b: female). Subjects suffering from metabolic abnormalities have abnormal circadian rhythms of prolactum in the plasma. Most of these abnormal profiles include abnormally high prolactum levels during the day. The abnormally high levels during the day are those higher than the normal level in at least 1 SEM over the corresponding point of the normal profile, if a complete profile has been generated for the subject, and in at least 2 SEM, if only 3 or 4 mleeves of prolactin clavee have been measured. 1 SEM is 1-2 ng / ml for men and 1-3 ng / rnl for women during waking hours. Instead of (or in addition to) having abnormally high levels of prolactin during the day, some subjects with metabolic abnormalities exhibit abnormally low levels of procyctin during the night, that is, levels of at least 1 SEM below the levels. corresponding subjects healthy if a complete prolactin profile has been generated, and at least 2 SEM below the corresponding healthy levels if only one or two level (s) of key key (s) during the key night has (n) been med? you). In male humans, 1 SEM for prolactum levels during the night is approximately 3 ng / ml; in female humans, 1 SEM for prolactum levels during the night is between approximately 3 and 6 ng / rnl. A prolactum profile of a subject is obtained by taking blood samples from it at a plurality of time points over a period of 24 hours (preferably at 3 hour intervals), testing each blood sample to verify the prolactin content, setting the time of the blood sampling against the amount of prolactom present in each sample to generate a data point for each sample, and connecting the data points (or adapting a curve through them) to form the prolactm profile of the subject . The generation of prolactin profiles has been described in detail in related applications Nos. 07 / 995,292 and 08 / 264,558. Preferably, a reference prolactum profile is generated before the invasive intervention. If this is not possible, a prolactum profile should be generated as soon as the intervention has been practiced, after 30 days, preferably after 10 days of the procedure. To prevent possible restinosis or chest pain in a subject who has undergone an invasive procedure without a bypass, a dopamine / prolactin-reducing compound (v.gr, brornocriptine) is administered after said intervention. In fact, therapy can begin-before the intervention if desired. The therapy, in the last case, can begin as soon as the diagnosis that leads to the intervention. The "prolactin-reducing compound" should include substances that directly or indirectly inhibit the secretion of prolactin or accelerate the depletion of prolactin in a subject (mammals including humans). Additionally, these compounds can increase the activity of dopamine. Non-limiting examples of prolactone reducing compounds include dopamine enhancer compounds, dopamine agonists (particularly dopamine d2 agonists), such as dopa ma and certain prolactin-inhibiting compounds related to ergotamma. Non-limiting examples of doparnin d2 agonists are 2-bromo-alpha-ergocr? Pt? Na; 6-met? L-8-beta-carbobenc? Lox? -am? Noet? L-10-alpha-ergol? Na; 8-ac? Lam? Noergolmas, 6-met? L-8-alfa- (N-ac? L) am? No-9-ergoline; 6-met? L-8-alpha- (N-phen? L-acetyl) am? No-9-ergolm; Ergocornin; 9,10-d? H? Drergocorn? Na and ergolinas D-2-halogeno-6-alquil-B-sust? Tu? Das, e.g., D-2-bromo-6-rnet? I-8- c anometiiergol? na. Moreover, non-toxic salts of ergotarnine-related prolactone inhibitor compounds formed from pharmaceutically acceptable acids are also useful in the practice of this invention. It has been found that brornocriptine or 2-bruno-alpha-ergocryptine is particularly useful in the practice of this invention. If the subject who has undergone an invasive procedure without a referral has abnormally low prolactin levels during the night, a prolactin enhancer (ie, a compound that increases circulating prolactin levels) is administered. This therapy can be used alone or as an adjunct to the administration of a prolactin-reducing compound if such a combination is warranted, (i.e., if the subject diagnosed has both abnormally high levels of prolactin during the day, and levels abnormally. Low prolactin during the night, or if treatment of the subject with a dopamine / prolactin-reducing compound decreases prolactin levels during the day also causes a decrease in prolactin levels during the night). Again, therapy should start immediately after the intervention, but it can begin as soon as the diagnosis has been made that leads to the invasive intervention without referral.

The "prolactin improver" should include-substances that directly or indirectly stimulate prolactin secretion or inhibit the elimination of prolactin. Non-limiting examples of a prolactm enhancer include prolactm; rnelatonin; doparnin antagonists such as rnetocloprarnide, halogenopenol, pyrnozide, phenothamma, dompepdone, sulpipda and chlorprornazm; serotonin agonists (ie, MfiO inhibitors), e.g., pargyline, synthetic morphine analogs, rhetadone; antiemetics, v.gr. rnetocloprarnide; estrogens; and various other serotonin agonists, e.g., tryptophan, 5-hydrox-tpptofan (5-HTP), fluoxitan and dexfenflurarnma. Moreover, the non-toxic salts of the above prolactin-enhancing compounds formed from pharmaceutically acceptable acids are also useful in the practice of this invention. It has been discovered that rnetocloprannide is particularly useful in the practice of this invention. "Prolactm modulator" should refer to either prolactm breeders, prolactm reducers or both. For treating mammals, generally, doses of the doparnin enhancer compound / prolactin redoubt (e.g., bromocriptine) and / or enhancer (e.g., metoclopramide), respectively, are each generally administered once a day. The therapy should last at least until the tissue injured by the intervention heals, usually from 6 to 24 months. The preferred doparnin / prolactin reducer compound (bromocriptine) is administered daily at dosage levels ranging from about 3 micro-grams to about 200 micrograms, preferably from about 10 nicrograms to about 100 micrograms, per kilogram. of body weight, and the prolactone enhancer (e.g., metocloprarnide) is administered daily at dosage levels ranging from about 5 micrograms to about 100 micrograms, preferably from about 10 micrograms to about 50 micrograms per kilogram. of body weight per day to modify or alter the profile of prolactin secretion and continue for a sufficient time to reduce the circadian rhythm of prolactin in the plasma. For treating humans, the prolactin-reducing dopamine-reducing compound (e.g., bromocriptine) is generally administered at daily dosage levels ranging from approximately 3 micro-grams to approximately 200 micro-grams, preferably from approximately 10 micro-grams to approximately 100 micro-grams, per kg. of body weight. The prolactin enhancer metoclopramide is generally administered at daily dosage levels ranging from about 5 micrograms to about 100 micrograms, preferably from about 10 micrograms to about 50 micrograms per day, per kilogram. of body weight.

Said treatment (using one or both types of drugs) is typically continued for a period of time ranging from about 10 days to normally about 180 days, but may be continued for longer periods such as several years. In the practice of this invention, a dopamine / prolactin reducing compound, and / or a prolactin enhancer is preferably administered daily to a subject, preferably orally, or by subcutaneous, intravenous or intramuscular injection. Each prolactin modulator is administered in one or multiple dosages at a predetermined time or at a predetermined time or times to reduce prolactin levels during the day. The amount (s) and time (s) of administration of the prolactin modulator can be adjusted if needed, based on a profile (or levels) of prolactin from the patient subsequently measured, and the criteria and linearities are described in 08 / 264,558. For example, if the prolactin enhancer causes prolactin levels to remain high during the day, the amount or time of administration, or both, will be adjusted to avoid this. The goal is to reduce abnormally high prolactin levels during the day and / or increase abnormally low levels of overnight to mimic or reach the corresponding normal levels. The determination of the effectiveness of the treatment can be done by subtracting a "key" prolactin level from the subject of the corresponding normal level (or vice versa) and determining if the difference exceeds two normal errors of the mean. If a complete prolactum profile is generated, this determination can be made by subtracting the difference between any point in the patient's profile from the corresponding point in the normal prolactin curve, and determining if the difference exceeds in SEM; alternatively, the determination can be made by comparing the difference in the area ba or the curve between the patient profile and the normal profile. Prolactin profiles or additional key levels are measured periodically during therapy to determine the efficacy of the modulator or modulators administered to adjust prolactum levels. Preferably, said measurements are made or said profile is generated every 4 weeks during the first 3 months of therapy, and then every 24 weeks. The following examples illustrate the present invention without limiting its scope: EXAMPLE 1 Direct effect of bromocript ina on smooth muscle cell proliferation An in vitro preparation of rat smooth muscle cells (5 x 103) was cultured in DMEM plus fetal calf serum (2%), and either prolactm, PDGF or prolactin plus PDGF. Each of these medium preparations were incubated with or without brornocpptine. Bromocriptma (10-7 to 10-5 M) was added to each culture and the cells were incubated at 37 ° C for 24 hours. The proliferation of smooth muscle cells was determined by the incorporation of 3H-t? M? Dma and compared with the controls (to which brornocriptine was not added). The results were as follows: Brornocriptine at a dose of 10 -7 M inhibited the proliferation of stimulated smooth muscle cells in fetal calf serum, and at a dose of 10-5 M inhibited between 30-50% the proliferation of smooth muscle cells stimulated with prolactm, PDGF, and prolactin plus PDGF. This experiment demonstrates that bromocript na has a direct inhibitory effect on the proliferation of arterial wall smooth muscle cells. Although not limiting to the theory, the inventors believe that bromocriptine works at a cellular level (ie, directly on the smooth muscle cells) by blocking the entry of Ca ++ and inhibiting the activity of protein kinase C, possibly in part, linking to receptor D2 on the surface of the cell. This direct effect is in addition to, and independent of, the ability of brocryptine to lower prolactin levels, and is thought to be a contributory factor to the ability of bromocriptine to prevent restenosis.

EXAMPLE 2 Study of a human case of prevention of restenosis and abrogation of chest pain Patient SC (42 years, 67 kilos) suffered an acute inferior myocardial infarction diagnosed on the basis of symptoms and electrocardiogram. He was treated with TPA and eight days later he underwent an angiogram that showed moderate to severe atheroeclerosis with stenosis of 99% in the left circumflex artery and 50% of stenosis in the left coronary artery. Two days later the PTCA was performed, which reopened the lumen of the circumflex artery to approximately 80% of the original transvereal area of the circumflex artery (ie, 20% post-PTCA etenosis), as determined by angiography. One week after poet-PTCA angiography, a thallium re-titration test was performed which confirmed the blood flow to the damaged area but resulted in abnormalities in the ECG approximately 9 minutes after the test. Abnormalities were associated with the area of the damaged heart distal to the infarct. Plasma lipid analysis showed elevated triglyceride levels (approximately 400 ng / dl) and total cholesterol levels (approximately 250 ng / dl). The subject was medicated with Cardizam 30 mg / day, Mevacor (40 mg / day) and aepirin (325 mg / day).

Six weeks after the start of the medication there were no significant changes in triglyceride and cholesterol levels, but the subject began to experience chest pain induced by mild exercise (walk of 925 meters). The chest pain increased in the following two weeks and due to this the exercise was discontinued. Cold weather also induced severe chest pain. Bro scrippsin was then administered to the subject (1.25 mg / day at 08:00) and rnetoclopramide (5 rng / day at 23:00) after a prolactin profile demonstrated elevated prolactin levels during the period of 08: 00-21. : 00 hours Chest pain decreased rapidly after the start of prolactin modulation therapy. The dose of bromocriptine was increased to 2.5 rng / day after 4 weeks. After an additional six months, the total cholesterol was reduced by 60% and the triglycerides were not altered. The levels of prolactin during the day were also reduced by 50%. A thallium resistance test and the ECG carried out at that time showed that there was no decrease in blood flow compared to the ECG after the PTCA and the period of time before the abnormalities in the ECG were apparent increased slightly (from 9 to 11.5 minutes ). No chest pain was experienced at all during the resistance test. Chest pain induced by cold weather also disappeared. The subject has continued with the prolactin modulator therapy for 2.5 years without changes in his condition.

This case study indicates that prolactin modulators have a beneficial effect in reducing or eliminating chest pain and preventing restenosis.

Claims (13)

NOVELTY OF THE INVENTION CLAIMS

1. - The use of a dopamine / prolactin reducing compound to prepare compositions for preventing or limiting restenosis in a mammal that has undergone an invasive procedure without selected derivation a? Ar + -ir from the group consisting of (i) angioplasty percutaneous transluninal coronary artery; di) atherectomy and (iii) endarterectorní, sicha composition being useful to (a) administer to said mammal a daily amount of the doparnin enhancing compound / prolactum reducer at a predetermined first time, said time being selected to reduce the level of prolactin in the blood of said subject during all or a portion of the hours of the day 07:00 - 22:00; and for (b) continuing said administration for a period of time at least sufficient to allow the vascular lesion incident to said invasive procedure to emanate.

2. The use according to claim 1, wherein said administration continues for a period in excess of about one year.

3. The use according to claim 1, wherein said composition containing the dopami a / prolactone reducing compound is administered as a single agent. doeie

4. The use according to claim 1, wherein said composition containing the dopamine / prolactone reducing compound is administered as multiple doses.

5. The use according to claim 1, wherein said dopa enhancer / prolactin reducer compound is brornocript na.

6. The use according to claim 5, wherein said daily amount of bro ocpptina is on the scale of about 0.8 to 8.0 rng.

7. The use according to claim 1, wherein said dopamine enhancer / prolactin reducing compound is brornocriptine and said daily amount is from about 0.2 to 15 mg.

8. The use of a prolactin-enhancing compound in the preparation of a composition for raising the level of prolactin during the night in the prevention or limitation of reetenoeis in a mammal, by administering a composition of a dopamine-enhancing compound / reducing agent. prolactin

9. The use according to claim 8, wherein said prolactin enhancing compound is metoclopramide.

10. The use according to claim 9, wherein the prepared composition is administered in an amount such that said daily amount of metoclopramide is on the scale of about 0.5 to 2.0 mg.

11. The use according to claim 8, wherein said prolactin enhancing compound is rnetocloprarnide and the prepared composition is administered in an amount such that the target amount of rnetocloprannide is about 0.5 to 5.0 rng.

12. The use according to claim 1, wherein said invasive procedure without derivation is percutaneous translummal coronary angioplasty.

13. The use of a prolactin dopamine / eductor enhancer compound to prepare compositions to reduce or eliminate angina pectoris or amaurosis fugax in a mammal that has undergone an invasive procedure without derivation selected from the group consisting of (i) percutaneous transluminal coronary angioplasty; (ii) atherectomy and (iii) endarterectomy, said compositions being useful for (a) administering to said mammal a daily amount of a dopamine / prolactone reducing compound at a predetermined time, said time being selected to reduce the level of prolactin in the blood of said subject during all or a portion of the hours of the day 07:00 - 22:00; and for (b) continuing said administration for a period of time at least sufficient to allow the vascular lesion incident to said invasive procedure to heal.