all patents , patent applications and literature references cited herein are incorporated by reference in their entirety as if their disclosures were physically present in the present specification . in case of conflict , however , the present disclosure controls . it has recently been discovered that the restenosis of blood vessels after non - bypass , invasive intervention can be partially or totally abrogated by administering to a mammalian subject ( including a human ) a dopamine - potentiating / prolactin - reducing compound daily at a predetermined time during a 24 - hour period designed to decrease the blood prolactin level and / or increase dopamine activity of said subject during at least a substantial portion of the daytime ( 07 : 00 - 22 : 00 ). this administration also serves to partially or totally abrogate chest pain typically suffered by humans as a result of the restenosis of blood vessels subsequent to non - bypass invasive procedures . non - bypass invasive intervention in blood vessels ( arteries ) such as ptca , atherectomy , or endarterectomy is a mechanical ablation or removal of arterial plaques . typically , the subjects undergoing such procedures suffer from metabolic abnormalities . healthy ( normal ) subjects , i . e ., lean young members of a species not suffering from metabolic abnormalities , have highly predictable daily prolactin release profiles , which in humans are characterized by a low and relatively constant prolactin level during the waking hours ( daytime : 07 : 00 - 22 : 00 ) followed by a sharp rise to a peak during night - time and subsequent more gradual tapering down to the waking hours level by morning ( 22 : 00 - 07 : 00 ). fig1 depicts the normal or healthy prolactin profile for humans ( curve a : males ; curve b : females ). subjects suffering from metabolic abnormalities have abnormal circadian rhythms of plasma prolactin . the majority of these abnormal profiles include abnormally high prolactin levels during daytime . abnormally high daytime levels are those higher than the normal level by at least 1 sem above the corresponding point of the normal profile , if a complete profile has been generated for the subject , and by at least 2 sem , if only 3 or 4 key prolactin levels have been measured . 1 sem is 1 - 2 ng / ml for males and 1 - 3 ng / ml for females during waking hours . instead of ( or in addition to ) abnormally high daytime prolactin levels , some subjects with metabolic abnormalities exhibit abnormally low night - time prolactin levels , i . e ., levels at least 1 sem below the corresponding levels of healthy subjects if a complete prolactin profile has been generated and at least 2 sem below the corresponding healthy levels if only one or two key night - time prolactin level ( s ) has ( have ) been measured . in human males , 1 sem for night - time prolactin levels is about 3 ng / ml ; in human females , 1 sem for night - time prolactin levels is between about 3 and 6 ng / ml . a prolactin profile of a subject is obtained by collecting blood samples from the subject at a plurality of time points during a 24 - hour time period ( preferably at 3 hour intervals ), assaying each blood sample for prolactin content , plotting the time of blood sampling against the quantity of prolactin present in each sample to generate a data point for each sample , and connecting the data points ( or fitting a curve through them ) to form the subject &# 39 ; s prolactin profile . generation of prolactin profiles has been described in detail in related applications ser . nos . 07 / 995 , 292 and 08 / 264 , 558 . a baseline prolactin profile is generated , preferably , before the invasive intervention . if this is not possible , a prolactin profile should be generated as soon after the intervention as practical , within 30 days , preferably within 10 days of the procedure . to prevent possible restenosis or chest pain in a subject who has undergone non - bypass invasive intervention , a dopamine potentiating / prolactin reducing compound ( e . g ., bromocriptine ) is administered following such intervention . therapy may , in fact , begin prior to the intervention if desired . therapy , in the latter case , may begin as early as the diagnosis leading to the intervention . &# 34 ; prolactin reducing compound &# 34 ; shall include substances which directly or indirectly inhibit prolactin secretion or accelerate prolactin depletion in a subject ( mammals including humans ). additionally , these compounds can increase dopamine activity . non - limiting examples of prolactin reducing compounds include dopamine potentiating compounds , dopamine agonists ( particularly d2 dopamine agonists ) such as dopamine and certain ergot - related prolactin - inhibiting compounds . non - limiting examples of d2 dopamine agonists are 2 - bromo - alpha - ergocriptine ; 6 - methyl - 8 - beta - carbobenzyloxy - aminoethyl - 10 - alpha - ergoline ; 8 - acylaminoergolines , 6 - methyl - 8 - alpha -( n - acyl ) amino - 9 - ergoline ; 6 - methyl - 8 - alpha -( n - phenyl - acetyl ) amino - 9 - ergoline ; ergocornine ; 9 , 10 - dihydroergocornine ; and d - 2 - halo - 6 - alkyl - 8 - substituted ergolines , e . g ., d - 2 - bromo - 6 - methyl - 8 - cyanomethylergoline . moreover , the non - toxic salts of the prolactin - inhibiting ergot - related compounds formed from pharmaceutically acceptable acids are also useful in the practice of this invention . bromocriptine , or 2 - bromo - alpha - ergocryptine , has been found particularly useful in the practice of this invention . if the subject who has undergone non - bypass invasive intervention has abnormally low night - time prolactin levels , a prolactin enhancer ( i . e ., a compound that increases circulating prolactin levels ) is administered . this therapy can be used on its own or as an adjunct to administration of a prolactin reducing compound if such combination is warranted , ( i . e ., if the subject as diagnosed has both abnormally high daytime prolactin levels and abnormally low night - time prolactin levels or if the subject &# 39 ; s treatment with a dopamine potentiating / prolactin reducing compound to decrease his / her daytime prolactin levels causes a decrease also in the night - time prolactin levels ). again , therapy should begin immediately following the intervention , but may begin as early as the diagnosis which leads to the non - bypass invasive intervention . &# 34 ; prolactin enhancer &# 34 ; shall include substances which directly or indirectly stimulate prolactin secretion or inhibit prolactin elimination . non - limiting examples of a prolactin enhancer include prolactin ; melatonin ; dopamine antagonists such as metoclopramide , haloperidol , pimozide , phenothiazine , domperidone , sulpiride and chlorpromazine ; serotonin agonists ( i . e ., mao inhibitors ), e . g ., pargyline , synthetic morphine analogs , methadone ; antiemetics , e . g ., metoclopramide ; estrogens ; and various other serotonin agonists , e . g ., tryptophan , 5 - hydroxytryptophan ( 5 - htp ), fluoxirane , and dexfenfluramine . moreover , the non - toxic salts of the foregoing prolactin enhancing compounds formed from pharmaceutically acceptable acids are also useful in the practice of this invention . metoclopramide has been found particularly useful in the practice of this invention . &# 34 ; prolactin modulator &# 34 ; shall refer to either prolactin enhancers , prolactin reducers , or both . in treating mammals , generally , dosages of the dopamine potentiating / prolactin reducing compound ( e . g ., bromocriptine ) and / or enhancer ( e . g ., metoclopramide ), respectively , are each given generally once a day . therapy should last at least until the tissue injured by the intervention heals , generally 6 to 24 months . the preferred dopamine potentiating / prolactin reducing compound ( bromocriptine ) is given daily at dosage levels ranging from about 3 micrograms to about 200 micrograms , preferably from about 10 micrograms to about 100 micrograms , per kg . of body weight , and the prolactin enhancer ( e . g ., metoclopramide ) is given daily at dosage levels ranging from about 5 micrograms to about 100 micrograms , preferably from about 10 micrograms to about 50 micrograms , per kg . of body weight per day to modify , or alter , the prolactin secretion profile and continued for a time sufficient to reset the circadian plasma prolactin rhythm . in treating humans , the dopamine potentiating / prolactin reducing compound ( e . g . bromocriptine ) is generally given at daily dosage levels ranging from about 3 micrograms to about 200 micrograms , preferably from about 10 micrograms to about 100 micrograms , per kg . of body weight . the prolactin enhancer metoclopramide is generally given at daily dosage levels ranging from about 5 micrograms to about 100 micrograms , preferably from about 10 micrograms to about 50 micrograms , per kg . of body weight per day . such treatment ( using one or both types of drugs ) is typically continued over a period of time ranging from about 10 days to usually about 180 days , but may be continued for longer periods such as several years . in the practice of this invention , a dopamine potentiating / prolactin reducing compound , and / or a prolactin enhancer are 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 more than one predetermined time or times to reduce daytime prolactin levels . the amount ( s ) and time ( s ) of prolactin modulator administration may be adjusted if needed based on subsequently measured prolactin profile ( or levels ) of the patient and the criteria and guidelines described in ser . no . 08 / 264 , 558 . for example , if the prolactin enhancer causes prolactin levels to stay high into the daytime , the amount or the time of administration or both will be adjusted to avoid this . the objective is to reduce abnormally daytime high prolactin levels and / or to increase abnormally low night - time levels to mimic or approach the corresponding normal levels . assessment of the effectiveness of the treatment can be made by subtracting a &# 34 ; key &# 34 ; prolactin level of the subject from the corresponding normal level ( or vice versa ) and determining whether the difference exceeds two standard errors of the mean . if a complete prolactin profile is generated , this assessment can be made by subtracting the difference between any point on the patient &# 39 ; s profile from the corresponding point on the normal prolactin curve and determining whether the difference exceeds on sem ; alternatively , the assessment can be made by comparing the difference in the area under the curve between the patient &# 39 ; s profile and the normal profile . additional prolactin profiles or key levels are measured periodically during therapy to assess the efficacy of the administered modulator ( s ) in adjusting prolactin levels . preferably , such measurements are taken or such profile is generated every 4 weeks during the first 3 months of therapy , and then every 24 weeks thereafter . the following examples illustrate the present invention without limiting its scope : an in vitro preparation of rat smooth muscle cells ( 5 × 10 3 ) was cultured in dmem plus fetal calf serum ( 2 %), and either prolactin , pdgf , or prolactin plus pdgf . each of these media preparations was incubated with or without bromocriptine . bromocriptine ( 10 - 7 to 10 - 5 m ) was added to each culture and the cells were incubated at 37 ° c . for 24 hours . proliferation of smooth muscle cells was assessed by 3 h - thymidine incorporation and compared to controls ( to which no bromocriptine was added ). bromocriptine at a dose of 10 - 7 m inhibited fetal calf serum stimulated smooth muscle cell proliferation and at a dose of 10 - 5 m inhibited prolactin , pdgf , and prolactin plus pdgf stimulated smooth muscle cell proliferation by 30 - 50 %. this experiment demonstrates that bromocriptine has a direct inhibitory effect on arterial wall smooth muscle cell proliferation . although not to be bound by theory , the inventors believe that bromocriptine works at a cellular level ( i . e ., directly on the smooth muscle cells ) by blocking ca ++ influx and inhibiting protein kinase c activity , possibly , in part , by binding to d 2 receptors on the cell surface . this direct effect is in addition to and independent of the ability of bromocriptine to decrease prolactin levels , and is believed to be a contributing factor to the ability of bromocriptine to prevent restenosis . patent sc ( 42 years , 180 lbs .) suffered an acute inferior myocardial infarction diagnosed based on symptoms and electro - cardiogram . he was treated with tpa and , eight days later , an angiogram was conducted which showed moderate to severe atherosclerosis with 99 % stenosis in the left circumflex artery and 50 % stenosis in the left coronary artery . two days thereafter ptca was performed which re - opened the lumen of the circumflex artery to about 80 % of the original cross - sectional area of the circumflex artery ( i . e ., 20 % post - ptca stenosis ), as determined by angiography . one week after the post - ptca angiography , a thallium stress test was performed which confirmed blood flow to the damaged area but resulted in ecg abnormalities about 9 minutes into the test . the abnormalities were associated with the damaged heart area distal to the infarct . plasma lipid analysis showed elevated triglyceride ( about 400 ng / dl ) and total cholesterol ( about 250 ng / dl ) levels . the subject was medicated with cardizam 30 mg / day , mevacor ( 40 mg / day ) and aspirin ( 325 mg / day ). six weeks following the initiation of medication there were no significant changes to triglyceride and cholesterol levels but the subject began experiencing chest pain induced by mild exercise ( 1 / 2 mile walk ). chest pain increased in the following two weeks and because of this exercise was discontinued . cold weather also induced severe chest pain . the subject was then administered bromocriptine ( 1 . 25 mg / day at 08 : 00 ) and metoclopramide ( 5 mg / day at 23 : 00 ) after a prolactin profile demonstrated elevated prolactin levels during the period 08 : 00 - 21 : 00 hours . the chest pain quickly subsided after the initiation of prolactin modulation therapy . bromocriptine dose was increased to 2 . 5 mg / day after 4 weeks . after an additional six months , total cholesterol was reduced by 60 % and triglycerides were unaltered . daytime prolactin levels were also reduced by 50 %. a thallium stress test and ecg performed at this time showed no decrease in blood flow compared with the ecg following ptca and the time period before ecg abnormalities were apparent slightly increased ( from 9 to 11 . 5 minutes ). chest pain was not experienced during the stress test at all . cold weather - induced chest pain also disappeared . the subject has continued on the prolactin modulator therapy for 2 . 5 years with no changes in his condition . this case study indicates that prolactin modulators have a beneficial effect in reducing or eliminating chest pain and in preventing restenosis .
the present invention relates to methods for reducing stenosis after non - bypass invasive intervention and for ameloriating symptomatic chest pains following non - bypass invasive intervention comprising administering a daily amount of a dopamine - potentiating / prolactin - reducing compound at a predetermined time and continuing administration for a period of time at least sufficient to permit the vascular injury to heal .