Bromocriptine: Past and present : From the In Vitro … · Bromocriptine: Past and present : From...

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Bromocriptine: Past and present : From the In Vitroand In Vivo Experimental Studies to the ClinicalDataCorresponding Author:Prof. Maria S Venetikou,Professor of Pathophysiology and Nosology, School of Health and Caring Professions, Technological Institutte ofAthens, Aigaleo, Greece, 88, Agias Varvaras St, 15231 - Greece

Submitting Author:Prof. Maria S Venetikou,Professor of Pathophysiology and Nosology, School of Health and Caring Professions, Technological Institutte ofAthens, Aigaleo, Greece, 88, Agias Varvaras St, 15231 - Greece

Article ID: WMC004010

Article Type: Review articles

Submitted on:10-Feb-2013, 07:48:49 PM GMT Published on: 11-Feb-2013, 07:54:07 AM GMT

Article URL: http://www.webmedcentral.com/article_view/4010

Subject Categories:PHARMACOLOGY

Keywords:Bromocriptine, Hyperprolactinaemia, Tumour treatment, Side effects

How to cite the article:Venetikou MS. Bromocriptine: Past and present : From the In Vitro and In VivoExperimental Studies to the Clinical Data . WebmedCentral PHARMACOLOGY 2013;4(2):WMC004010

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Bromocriptine: Past and present : From the In Vitroand In Vivo Experimental Studies to the ClinicalDataAuthor(s): Venetikou MS

Abstract

Bromocrriptine is a drug introduced in the medicaltherapeutics in 1967, and since then it has beenwidely used in the treatment of hyperprolactinaemia. Inexperimental animals and in vitro experiments itinhibits prolactin secretion and the phasic secretion ofgonadotrophins, while it does not seem to have aneffect on growth hormone, or vasopressin secretion.Various central nervous effects, autonomic effects andcardiologic actions of bromocriptine have beenreported on experimental animals during the firststudies. After the initial evaluations, bromocriptine hasbeen used in preventing lactation and galactorroea, intreating infertility, especially when related tohyperprolactinaemia, in prolactinomas of various sizes,in acromegaly and in Parkinson’s disease. Throughthe years of its clinical use, various acute and chronicside effects has been reported and closely monitored.Due to its need for continuous use and frequentdosage, effort has been undertaken to develop newercompounds with longer action and similar or betterclinical effects. Although this has been achieved,bromocriptine due to its long clinical application andexperience remains the drug with whom the actions ofnewer compounds are still compared. Resistance toprolactin level suppression and tumour size reductionis also frequently estimated for all dopamine agonistsused in comparison with these seen afterbromocriptine treatment. We present here the mostimportant points of the numerous pharmaceuticalstudies on bromocriptine.

Introduction

First studies on the ergo-alkaloids andbromocriptine

Shelesnyak (1975), studying the mechanism of oocyteimplantation in the rat, was the first to notice that someergo-alkaloids decrease prolactin secretion (1). In1954, in his first observations, Shelesnyak concludedthat these drugs act either on the hypothalamus or thepituitary. Later Zeilmaker and Carlen (1962) (2)

showed that one of the ergoalkaloids, ergocorcin actsdirectly on the pituitary. Naturally then, there was aquestion of how much the action of these drugs in thepituitary was clinically applicable and with what way itwas connected with the other properties of thesedrugs. In the decade of the 60’s, a systematicresearch for the ergo-alkaloids and their derivativeshas started with the aim to produce a compound thatreduced the prolactin action. During these years theobstacle in such a research was the lack of a methodto estimate prolactin levels in the blood. Thus for theinitial evaluation of the action of these drugs severalbioassays were used (e.g. the inhibit ion ofleukocytosis in vaginal smears of rat withpseudocyesis, or the inhibition of oocyte implantationin fertilized rats). All these initial methods had thedisadvantage that they excluded the short acting drugs(3, 4). Also another method that was used in theevaluation of these drugs was the inhibition of lactationboth in humans and in mammals (5, 6). The results ofthese initial researchs of the decade of the 60’s led tothe production of the 2Br-a-methyl-ergocriptine(CB154-bromocriptine mesylate) (Parlodel, Providel) in1967 (illustration 1) (7, 8). Since then, many analogshave been used, but bromocriptine remains the mostwidely tried drug in hyperprolactinaemia.

Chemistry

The ergot alkaloids can all be considered derivativesof the tetracyclic ergoline skeleton and can be dividedinto two main groups based on their structuralcharacteristics (9). The first group includes all lysergicacid derivatives of the acid amide types, such asamine alkaloids (ergonovine) and the structurally morecomplex ergopeptines (ergotamine, ergocristine). Thesecond group includes the so-called “clavicle alkaloid”derivatives that contain either a methyl or ahydroxymethyl group at position 8 (9). The ergotalkaloids and their derivatives have a wide spectrum ofpharmacological actions that include central,neurohumoral and peripheral effects, mediated bynorepinephrine, serotonin, and dopamine receptors. The diversity of biological properties of ergotderivatives is likely to be due to diverse mechanismsof action at the cellular and molecular level (9).Because the ergot derivatives interact with different



receptor sites, it is not surprising that these drugs (aswell as the natural alkaloids) display a number of sideeffects (9).

Bromocriptine has initially been used in the treatmentof hyperprolactinaemia (8), but at the time of itsdiscovery, the type of action of the drug wasunknown. It was later that it was shown that it acts onthe dopaminergic receptors; what exactly happensfrom the moment that the drug is bound to the cellreceptors in order to exert its action still remainsunclear. In fact, till the 70’s, even the existence ofprolactin was not sure and then the growth hormonewas thought to be the human lactogen hormone. Thediscovery of bromocriptine and the isolation ofprolactin were almost simultaneous. Friesen and hisco – workers isolated prolactin in 1971 (10), and thisalso led to the development of a special and sensitiveradioimmunoassay for human prolactin (11).

With the use of the sensitive prolactin assays, thephysiology of prolactin secretion was studied andhyperprolactinaemia was established as thecommonest human hypophysial disorder (12, 13, 14).It is important to remember that it was established as aclinical entity, at the same time that the suitable drugwas ready for its effective treatment. With 2-3 clinicaltrials, it was shown that the drug acts stimulating thedopaminergic receptors (15,16). In the next few years,dopamine was established as the basic hypothalamicfactor in prolactin inhibition (17). Due to its properties,bromocriptine was also used in the treatment of bothacromegaly and Parkinson’s disease.

Endocrinological action of bromocriptine

Inhibition of prolactin secretion

Bromocriptine inhibits prolactin secretion in allmammals and fishes that have so far been examined(18), either under physiological conditions or duringthe phase that the hormone secretion is stimulatedwith physiological, pharmacological or surgical criteria.

Area of action

When bromocriptine is added to pituitary cell cultures,it inhibits prolactin secretion in vitro (19). Thus, thebelief that the drug acted directly on the lactotrophswas firmly eastablished. The experimental in vivoexperience also proved the direct effect ofbromocriptine on the pituitary. The drug inhibits theTRH – induced stimulation of prolactin (20), decreasesplasma prolactin in the presence of ectopic pituitary(21), and the increased prolactin levels in rats that

have been treated with reserpine and a-methyl-π-tyrosine (22).

Mechanism of bromocriptine action

Bromocriptine reduces prolactin secretion withoutinfluencing directly the hormonal synthesis but withreducing the out cellular events (23). After the drugingestion, initially an increase of pituitary prolactin isnoticed (24), while protracted use leads to a decreaseof the quantity and concentration of the hormone (25).

In rats, where oestrogens were given, simultaneoustreatment with bromocriptine decreases prolactinlevels, DNA synthesis and the mitotic activity of thepituitary (26, 27). It appears that the continuousinhibition of prolactin secretion leads to a decrease ofthe cell metabolism and the ability for mitotic division.

The bromocriptine-induced inhibition of prolactinsecret ion in the rats, is overpowered bychlorpromazine. As already known, chlorpromazine isan inhibitor of the dopamine receptors’ antagonists ina dose dependent degree (18).

Prolactin secretion in vitro is increased, when cAMP isincreased (28), this ability though is inhibited in thepresence of bromocriptine (29) or dopamine (30). Bothdopamine and bromocriptine reduce the basic actionof adeny lcyclase in rat pituitaries (31). Opposite viewsthough have been mentioned by other researchersand a few believe that both these substances have noeffect on the enzyme activity (32).

Since calcium is indispensable both for the action ofpotassium and TRH in the prolactin secretion andsince bromocriptine antagonizes these two stimulatoryinfluences (18, 20), it was concluded that the drugreduces the hormonal plasma levels by eitherdecreasing the intracellular quantity of calcium oraffecting the cell membrane receptors function.

Classically, dopamine receptors have been dividedinto D1 receptors, which stimulate adenyl cyclaseactivity, and D2 receptors, which inhibit this enzyme(33, 34, 35); three further discrete receptors subtypeshave been described (D3, D4 and D5) with lessactivity on prolactin secretion (34). Dopamine inhibitionof prolactin secretion is mediated by the D2 dopaminereceptors expressed by the normal and tumorouslactotrophs (33, 34, 35). D2 receptors belong to thefamily of G protein – coupled receptors, characterizedby a single polypeptide chain containing sevenhydrophobic transmembrane domains; besides theireffect on adenyl cyclase, they are able to inhibit



inositol phosphate production (36) with an effect thatinvolves G proteins sensitive to pertussis toxin (33, 34,35, 36). Additionally, dopamine inhibits arachidonicacid release from pituitary cells independently fromother mechanisms (37). Two isoforms generated byalternative spicing of the D2 receptors have beendescribed (38). These two isoforms differ by a 29 –amino ac id sequence located wi th in theintracytoplasmic domain that interacts with G proteins;dopamine inhibition of adenyl cyclase activity isobserved with both isoforms.

The inhibition of cAMP levels is a key step in theinhibition of prolactin release by dopamine (39). It islikely that the dopaminergic ergot derivatives sharesimilar mechanisms of action (40).

Dopamine agonists reduce the size of prolactinomasby causing a reduction in cell volume (via an earlyinhibition of the secretory mechanism, and a lateinhibition of gene transcription and prolactinsynthesis), as well as causing perivascular necrosisand partial cell necrosis (41). There may also be anantimitotic effect. Histologically there is a reduction insecretory activity and cell size, an increase inimmunoreactive prolactin cellular content andinhibition of exocytosis (42).

Effects on other pituitary hormones

Gonadotrophins

The bromocriptine effect on the gonadotrophinsecretion has also been evaluated. The drug effectmay or may not be identified with the dopaminergicact iv i ty. In fact, the neural control of thegonadotrophins has not been completely understoodand there is still difficulty in explaining the action ofthese substances in the receptors.

Secretion

Bromocriptine brings new oocytic cycles in rats withpseudocyesis, or pseudocyesis can be produced byectopic source of prolactin secretion (21), or afteringestion of drugs that have an effect on the neuralaminic functions (43). It appears that bromocriptinerestores the basic gonadotrophic secretion in severalspecies probably because it initially reduces theprolactin levels. Having in mind though that dopamineis involved in the control of the gonadotrophinsecretion (44), it is possible that bromocriptine has adirect action.

Inhibition of the gonadotrophin secretion

Bromocriptine inhibits the phasic secretion ofgonadotrophins and the ovulation in young rats wherepremature cycle is induced after giving plasma ofpregnant mare (45). In such animals, when a givendose inhibits prolactin surge, simultaneously both LHsurge and ovulation is inhibited (45). In adult animalsbig doses are usually needed for both phasic secretionof the gonadotrophins and ovulation inhibition. Thedoses must be greater than those needed for theinhibition of prolactin increase before ovulation. Theseexperiments show that in young animals the neuralcontrol of the phasic gonadotrophic secretion isdifferent that this of the adult rats. Adult rats can takebromocriptine for a long time, without disruption oftheir cycle periodicity. But there is a time dependentaggregation of non active luteal bodies due to therepeated inhibition of the prolactin increase beforeovulation (46). Thus, dopamine is involved in thecontrol of LH secretion. The comparison ofdopaminergic compounds activity as far as ovulationinhibition and implantation inhibition lead to the initialconclusion that these two properties are different (4).

Growth hormone

Bromocriptine does not seem to affect the growthhormone in experimental animals (23). In adult rats,where oestrogens are given, bromocriptine does notaffect the growth hormone response (47). In rat cellcultured lines (GH3), bromocriptine has no effect in thebasal levels of growth hormone (48). In similarexperiments the drug has no effect in the potassium –mediated increase of this hormone (49), at least inconcentrations that reduce prolactin secretion. On thecontrary, bromocriptine has been found to reduce bothprolactin and growth hormone secretion inadenomatous tissue taken from acromegalic patients(50).

Adrenocorticotrophic hormone (ACTH)

There are no many studies in animals where ACTHwas estimated after the ingestion of bromocriptine. Indirectly, it appears that the drug has no intenseeffect on ACTH levels. In rats, long duration treatmentwith bromocriptine has not caused increase orreduction of the weight of the adrenals or a differencein the corticosterone plasma levels (51). In cowsduring lactation, doses of bromocriptine that reducedprolactin secretion, had no effect on the cortisol levels(52).

Effect of bromocriptine on the hormones of theposterior pituitary

Vasopressin (AVP)



In rat experiments, bromocriptine does not affect thewater excretion (18) and appears that the vasopressinsecretion is not affected by the drug. Of course withlong term use of bromocriptine, at least in rats, there isreduction of osmolarity (53) and the special weight (54)of urine, but it is not known if this phenomenon is dueto the direct effect of the drug in renal function, inprolactin reduction, or a mild inhibition of vasopressinsecretion.

Oxytocin

In rats, the oxytocin secretion that is observed as aresponse to nursing (milk ejection test) during lactationis reduced by many ergoalkaloids (55). Bromocriptinethough does not reduce the response to nursing(ejection) (22). There must be a inhibitorydopaminergic mechanism , that regulates the oxytocinsecretion in rats (in vitro studies) (56).

Effect on the peripheral endocrine system

Organs producing steroid hormones

Bromocriptine produces changes in stereoidogenesis.Initially they were thought as a result of changes inprolactin levels and not as a direct effect of the drug atthe peripheral endocrine organs. When a dose ofbromocriptine is injected the fifth day into the ratoocyte , an increase o f the 20a hydroxysteroido-dihydrogenase is noticed, which does nothappen the sixteen day of pregnancy. Prolactini n j e c t i o n a b o l i s h e s t h e 2 0 a h y d r o x y lsteroid-dihyrogenase (57). Long term ingestion ofbromocriptine in ,male rats causes decrease of thecirculating testosterone levels (58). The role ofprolactin in testicular function has been welldocumented in the past (59). It is also known thatprolactin plays some role in the stereoidogenesis thattakes place at least in the rat adrenals (60).

Other peripheral endocrine organs

Dopamine increases the cAMP production and theparathormone secretion in vitro (61). It appears thatdopamine in the parathyroid cells acts through the D1receptors (62). But the effect of bromocriptine in thecells of the parathyroid glands in not exactly known.

Renin secretion in dogs (63) and insulin and glucagonsecretion in humans (64) are both stimulated by thedopamine effect. Again there are no experimentaldata for the bromocriptine effect on these hormones

Effect on the central nervous system

Bromocriptine influences the extrapituitary areas of the

brain. Sometimes its action is obvious in doses similarto those they cause prolactin suppression, other timesthough there is need for higher doses

Autonomic functions

Bromocriptine shows strong emetic effect in dogs(ED50 7.5 µg/kg IV or 11.4 µg/kg SC). When it is givenIV, bromocriptine is three times less potent (as far asthe emetic behavior is concerned) from the a –ergocriptine and 2.5 times less from ergotamine. Thedrug reduces the body temperature of rats that havebeen exposed to cold environment, action that isabolished by the dopamine agonists, pimozide (65),haloperidol and sulpiride (66). It appears that thethermorythmisis is based in the dopaminergicbehaviour. When reserpine is given to the rats forhypothermia induction, bromocriptine increases thebody temperature, while the action is reversed byadministration of sulpiride (67). Haloperidol reversesthe hyperthermia induced by small bromocriptinedoses, but has no effect when big doses are given. Incontrast cyproheptadine suppresses the hyperthemicaction of both small and big bromcriptine doses (68).This phenomenon explains that dopamine has bothdopaminergic and serotoninergic action.

Movement activity

In small rodents, bromocriptine has a biphasic effect inmovement activity (69). The first hour, after thesubcutaneous injection of bromocriptine into the rats, adeduction in exploratory activity is observed. Similarbehavioral changes are observed after apomorphineand l-dopa, while amphetamine (which releases theendogenous catecholamines) increases theexploratory activity. After the initial reduction ofmovement activity, both bromocriptine and l-dopacause a stimulation of the moving behaviour whichlasts from the second till the fifth hour.

Stereotypies

Like apomorphine, d-amphetamine and l-dopa,bromocriptine cause stereotypic behaviour in rodents(69) which consists of repetitive biting or sneezing.Stereotypy is achieved through stimulation of thedopaminergic receptors and is inhibited by pimozide(69), selective antagonist of the dopaminergicreceptors (70). In hamsters, bromocriptine does notcause stereotypic behaviour, but the sensitivity ofthese animals increases with time or with thesimultaneous giving of d – amphetamine orapomorphine (71).

Cardiologic action of bromocriptine



IV injection of bromocriptine in continually increasingdoses up to 18.7 µg/kg in anaesthetized cats (18) hasshown that after a dose of more than 0.1 µg/kg, boththe cardiac rhythm and arterial blood pressure arereduced (18). While the IV injection (10 µg/kg) has noeffect, when it is given inside the ventricles, reducesthe blood pressure up to 30 mmHg. This action lastsapproximately for 2 hours. In parallel, there is alsobradycardia. Bromocriptine reduces blood pressure,when given to dogs, and its action is also proportionalto the dose and to the way of the drug is given. Theinitial effective dose is 6 µg/kg and usually the drugshould be given intravenously. In these experimentalanimals rarely bradycardia is encountered. The actionof the drug in the cardiac rhythm and pressure can besuppressed, when haloperidol, ergometrine ormethyl-ergometrine are previously given (72, 73, 74).All these initial studies have shown that thehypotensive properties of bromocriptine are due to theaction of this substance in three possible areas: 1)CNS, 2) endings of the sympathetic neurons 3)smooth muscles. In all three cases, bromocriptineaction is due to the stimulation of the dopaminergicreceptors.

Clinical relevance of bromocriptine (illustration 2)

Lactation

The normal lactation process can be suppressed bygiving 2.5 mg bromocriptine 2-3 times per day. If thisdose is given for three weeks, the milk productionstops and does not reappear. Comparing thebromocriptine suppressing effect on lactation to this ofoestrogens, bromocriptine is safer, since thethromboembolic risk is smaller. Furthermore, afterbromocriptine use, fertility reappears four weeks afterdelivery, in those women they nurse though threemonths are needed.

Galactorroea

Whatever the galactoroea cause, treatment withbromocriptine (5-10 mg per day) in divided dosesrestores both prolactin in normal levels and the milksuppression within a week. When galactorroea is dueto the use of neuroleptic drugs or to very high prolactinlevels, doses of bromocriptine up to 50 mg per daymay be needed.

Infertility

Infertility may be seen even when the prolactin levelsare slightly elevated. Treatment with bromocriptinerestores both prolactin levels and fertility. 4-12 weeksare enough to restore the menstrual cycle in women

with amenorrhoea and potency to males. In refractorycases, the treatment may be prolonged up to 6-12months, if needed. In women with polycystic ovarysyndrome (high dehydroepiadrosterone levels),commonly (20%) high prolactin levels are also noticed.Bromocriptine decreases both the increased levels ofdehydroepiandrosterone and prolactin. When there isno hyperprolactinaemia, it does not appear thatbromocriptine restores fertility. A similar phenomenonis seen in anorexia nervosa. Bromocriptine is effectiveonly if there is concomitant hyperprolactinaemia. Ininfertile women with short luteal phase, (5 days), andtemporary hyperprolactinaemia, or low progesteronevalues, bromocriptine restores the menstrual cycle.Thus, it is obvious that bromocriptine restores fertilitythat is related to hyperprolactinaemia.

Premenstrual tension syndrome

When bromocriptine is given at a dose of 2.5 mg 1-3times per day, 5-15 days before the menses appear, itseems that it causes reduction of the reportedsymptoms.

Breast cancer

Bromocriptine has not shown promising results inbreast cancer.

Parkinson’s disease

Bromocriptine has been tried in Parkinson’s disease. It appears that the dose should be high. In somecases, doses up to 200 mg per day have been used.Levodopa has been tried in Parkinson’s, but it showsmany side effects. Bromocriptine can in such casessubstitute levodopa, because although it has loweraction, its effect has longer duration.

Prolactinomas

These adenomas are relatively common cause ofinfertility. Usually bromocriptine (2.5-10 mg three tofour times daily) reduces hyperprolactinaemia andrestores fertility. Furthermore, it ameliorates visualfields and reduces the size of the adenomas (75).

Acromegaly

Most of the acromegalics, after treatment withbromocriptine (5-10 mg three times daily), showreduction of the growth hormone levels. The growthhormone levels though do not fall as easily asprolactin ones. Although the decline of growth



hormone is obvious within the first week, clinicalimprovement often needs 8 weeks of treatment. Bestresults are obtained with high doses (10-20 mg threetimes daily for 6 months). The clinical improvement isgreater than that expected in comparison with thereduction of the levels of growth hormone. Patientsthat show concomitant hyperprolactinaemia, show abetter response. In no case though can bromocriptinereplace the operation, when it is needed.

Side effects of bromocriptine (illustration 3)

There is no doubt that bromocriptine has been a usefuldrug. Despite this, the drug administration often leadsto side effects, although there has never beenmentioned a permanent lesion after bromocriptine use.There are though some patients that they are moresensitive than others. Some side effects are only seenwhen very big doses are used. Finally, some sideeffects are observed especially in some patients suchas psychiatric and parkinsonian ones. Thebromocriptine side effects are divided in acute (onsetof therapy) and chronic (after long term administrationof the drug). The side effects of bromocriptineresemble very much those of l-dopa. They all stemfrom the diffuse stimulation of the central andperipheral dopaminergic receptors. Vasospasm,erythromelalgia, lack of tolerance of alcohol and pepticbleeding are side effects that characterize exclusivelybromocriptine.

Acute side effects

Usually, nausea, emesis and orthostatic hypotension.The appearance of these side effects vary dependingon the disease for which the patient is treated. Youngnormal subjects who took the drug experimentallytaking part in clinical studies are more prone todevelop acute side effects. The hyperprolactinaemicsubjects are also prone to develop acute side effects,while acromegalics are more resistant. It is rare tonotice these symptoms in women who takebromocriptine , either after parturition or for lactationsuppression. The intensity of these side effects can bereduced when the drug is given concomitantly withsmall quantities of food just before sleep. When thepatient is lying down these side effects are usuallyavoided. In patients that developed these side effectsit is usually preferable to increase the dose moreslowly than usual. Rarely hyperprolactinaemic patientsneed doses more than 7.5 mg per day , while on thecontrary parkinsonians and acromegalics may need10-80 mg per day. Usually with the small doses ofbromocriptine, only few side effects are seen in thebeginning of therapy.

Chronic side effects

When small doses of bromocriptine are used, rarelythere are such side effects that demand thediscontinuation of therapy. Acromegalics, althoughthey usually take big bromocriptine doses, rarely showsuch side effects that the treatment should bediscontinued. Parkinsonians, on the contrary, manytimes show intense side effects that the drug mayneed to be discontinued.

Headaches

Mild headaches are observed often in the beginning oftreatment with bromocriptine. They are rarely seriousand usually are temporary.

Gastrointestinal side effects

Symptoms from the gastrointestinal system are rare.After the administration of big doses, mild dyspepsiamay be noticed. Usually these symptoms resemblethose of gastrooesophageal feedback and they arerelieved when the patient lies down. Gastrointestinalbleeding after the administration of bromocriptine hasbeen observed (76), but there is no evidence about itsfrequency.

Vasospam

It has been noticed initially in patients taking big dosesof bromocriptine. It has been seen in up to 30% of theacromegalics (77, 76) and in parkinsonians (78). It isnot an ergotism phenomenon, because it is notfollowed by pain or finger ischaemia and because it isrelieved as soon as the dose of the drug is reduced.

Alcohol non tolerance

In a 10% of patients, immediately after the beginningof treatment with bromocriptine, non tolerance ofalcohol develops especially for quantities they used toconsumed in the past. With the continuation of therapythis side effect usually disappears.

Side effects seen in Parkinson’s disease

Dyskinesia

Choreoathetoid movements of the limbs and the headand neck muscles are a characteristic side effect ofl-dopa, when it is administered in big doses for thetreatment of parkinsonism. The movements canmimick any movement disorder such as dystonia andmyoclonus. The precise mechanism that leads to



these side effects is unclear, although it has alreadybeen said that this disease leads to denervation andhypersensitivity of the dopamine receptors, thus l-dopacauses diskinesia due to a toxic mechanism.

In patients who showed dyskinesia after administrationof l-dopa, administration of bromocriptine can produceexactly the same phenomena even if they continuetaking l-dopa or not. Despite this, the dyskinesia that isproduced by bromocriptine seems to be less dramatic.

Psychiatric disturbances

Parkinson’s disease, if left without treatment, showsmental disturbances, such as depression, dementia,hallucinations or illusions (79). But also anyantiparkinsonic treatment can cause or worsen similarpsychomental disturbances. At least 20% of theparkinsonians that take anticholinergic drugs reportpsychiatric disturbances. The same symptoms arealso seen in patients who take l-dopa. With theadministration of l-dopa, hallucinations of paranoidtype may be seen. With the use of bromocriptine, thedanger for such side effects is even greater. In theinitial stages of toxicity, with either l-dopa orbromocriptine, the patients complain for frequent andintense dreams that quickly lead to nocturnalhallucinations. Slowly a complicated system ofhallucinations is organized that is characterized byvisual hallucinations and paranoid ideation. Theseside effects of bromocriptine are seen exclusively inpatients with Parkinson’s disease. Their severityparallels the existing neurological disorder.Discontinuation of the drug leads to amelioration of themental condition, although for full improvement a fewweeks are usually needed. The decision for stoppingthe drug is a dilemma, because in some patients theneurological disorder is so much worsen that they facethe danger of aspiration, vein thrombosis or infectionof the urogenital tract. The clinician then findshim/herself in a difficult position to choose between adestructive parkinsonism and a dramatic psychoticcondition.

Rarerly, in patients with Parkinson’s disease treatedwith very high doses of bromocriptine, pulmonaryinfiltrates, fibrosis, pleural effusions, pleural thickeningand retroperitoneal fibrosis have been described (80,81, 82). These adverse effects appear to bedose-ependent and they are not usually seen whenusing small dose for the treatment of prolactinomas.

Erythromelalgia

Patients taking bromocriptine may show a syndrome

that is characterized by red, sensitive and oedematouslimbs, that is followed by a sense of local heat anddysphoria. The symptoms usually affect the lowerlimbs, but they may affect the upper limbs or even theknees. The whole clinical picture is followed bypolyarthralgia and increased sedimentation rate. Thisclinical picture is also exclusively seen in parkinsonicpatients who take big doses of bromocriptine for a longt ime. Of these pat ients, only a 10% showerytromelalgia. After discontinuation of bromocriptine,this syndrome virtually disappears within 3 – 4 days.

On the whole, the adverse effects of bromocriptinemay be grouped into three categories: gastrointestinal,cardiovascular, and neurological (83). Symptoms asalready said tend to occur after the initial dose andwith dosage increases, but can be minimized byintroducing the drug at a low dosage (0.625 or 1.25mg/day) at bedtime, by taking it with food, and by verygradual dose escalation (40). Sometimes, tolerance tothe adverse effects develops, but occasionally,therapy withdrawal or dose reduction followed by amore gradual reintroduction is required. Up to 12% ofpatients are unable to tolerate therapeutic doses ofbromocriptine (84). Usually though the initial sideeffects mentioned above can be avoided by taking thedrug at bedtime or while recumbent, but toleranceusually develops rapidly making this precautionunecsssary after the first few days. From thesymptoms they have not been mentioned so far, someinfrequent psychiatric side effects need to beconsidered. Bromocriptine, even in low doses hasbeen associated with mania in postpartum patients (83,84, 85) and signs and symptoms of psychosis orexacerbations of preexisting psychosis have beenassociated with the use of bromocriptine (86, 87, 88).Turner et al., observed de novo psychotic reactions in8 of 600 patients treated with bromocriptine or lisuride(88). The symptoms which included auditoryhallucinations, delusional ideas, and mood alterations,entirely remitted when the drug was reduced in doseor discontinued (89). The safety of the drug in thepsychiatric population subjects remains to beestablished, although in a short-term trial in whichbromocriptine was given to 16 individuals withpsychiatric disorders who were previously stabilizedon neuroleptic agents, exacerbations of psychosis wasnot observed (89). Some other psychiatric symptomsassociated with higher doses of bromocriptine, includeanxiety, depression, confusion, auditory hallucinations,hyperactivity, disinhibition, insomnia, day-timesomnolence, and paranoia (84, 88, 90). Other rarerside effects include paraesthesia, nightmares, blurredvision, diplopia (high doses) and reversible ototoxicity



(in patients with chronic liver disease) (83, 84). CSFrhinorrhoea has been reported during treatment withbromocriptine, not only post surgically, but also in theabsence of prior radiotherapy or surgical interventiondue to tumour shrinkage, when the tumour previouslyserved as an obstacle for the tumour – induced skullbase defect (91,92, 93, 94, 95, 96). Reports from postpartum women have suggested a causal associationbetween the use of bromocriptine and hypertension,thromboembolic events, severe leucopenia,hyponatriaemia and oedema (97, 98, 99, 100,101).Although, the causative association is not proven,in the United States, the FDA has determined thatbromocriptine should not be used to treat postpartumlactation.

In a small group of patients at low doses ofbromocriptine (5-10 mg/daily), transient asymptomaticincreases in serum alkaline phosphatase and/ortransaminases have been reported (83,84 ).Hyponatriaemia has been associated with the use ofbromocriptine in patients with cirrhosis and hepaticencephalopathy (101).

The use of bromocriptine, when is taken for only thefirst few weeks of gestation, has not been associatedwith an increase in the rates of spontaneous abortions,ectopic pregnancies, trophoblastic disease, multiplepregnancies, or congenital malformations in a verylarge number of pregnancies (102, 103). In a studywhich undertook a long term follow up of 64 children,between the ages of 6 months and 9 years, who wereborn to mothers who took bromocriptine for a limitedduration in early pregnancy, have shown no adverseeffects on childhood development (104). Data oninfant outcomes of approximately 100 women whoused bromocriptine throughout pregnancy revealedabnormalities in 2 infants, one newborn with anundescended testicle and one with a talipes deformity(105). So far from all the available data on dopamineagonists and pregnancy, bromocriptine has the largestsafety database and has a proven safety record forpregnancy. The incidence of malformation in theoffspring is not greater than that in the generalpopulation. In case during pregnancy, reinstitution of adopamine agonist is needed to control tumour growth,bromocriptine is favoured to other dopamine agonistsdue to greater experience with the drug in this settingthroughout the years.

Current clinical considerations

Up to recent years, the basic drug used clinically in thetreatment of hyperprolactinaemia was bromocriptine(Parlodel, Sandoz). The drug gave good results in

controlling high prolactin levels in most of the patients.But there have been disadvantages in bromocriptineaction.

The fact that the drug usually is given at a dose of 2.5mg three times daily, means that the patient dependsabsolutely from this frequent administration. Indiseases such as acromegaly and parkinsonism, thedoses had to be greater, the intervals of administrationare many times per day. Taking tablets many timesper day has been very problematic for many patientsand this eventually led to patients’ reduced tolerance.

The initiation of bromocriptine treatment has beenfollowed by side effects as presented above (eg,nausea, emesis, and arterial hypotension). These firstside effects have made through the years manypatients to be hesitant in the continuation of thetreatment.

Discontinuation of bromocriptine administration isfollowed by the re – increase of prolactin levels to theinitial high values. In the case the drug has causeddecrease of the tumour growth, its discontinuationoften is followed from its re-increase (106).

Although, the bromocriptine value is undisputable, thefact that i t may given for l i fe, and that i tsdiscontinuation may lead in the recurrence of thedisease, is definitely a disadvantage. For years theresearchers have tried to overcome the disadvantagesof bromocriptine and discover substances with greatereffectiveness, longer action and the lack of diseaserecurrence after their discontinuation.

Some of the drugs that have been used are lergotrile,pergolide and lisuride. All three act by binding thedopamine receptors of the lactotrophs and showedthat they are capable of reducing prolactin secretion invitro. Clinically pergolide was the strongest drug withthe longest duration of action (107, 108). In a study of47 patients (all had hypersecretion of growth hormone(109)), pergolide was given once daily and the resultswere validated after three months. 35 of these patientsshowed normal prolactin levels after 3 months andonly 2 of them had levels a bit higher than the normalrange, while another 2 had a 38-58% reduction only.The clinical trial for pergolide has shown its potency toreduce tu mour size as shown previously forbromocriptine. A 30 months’study at Baylor hascompared the results of both action of bromocriptineand pergolide. 40 patients (28 women and 12 men)have been studied randomly. Others tookbromocriptine and othrers pergolide. Before the study,



i t h a s b e e n e s t i m a t e d t h e d e g r e e o fhyperprolactinaemia based at the hour fluctuations ofprolactin during a 24 hour period and the size of thetumour with computerized tomography. Both drugsproved to be effective to reduce the prolactin valuesand the size of the tumour. These patients that did notresponded to pergolide, eventually responded tobromocriptine (108). Thus it has been proved that thepatients that do not respond to one dopamine agonistmay respond to another. In the past a study at StBartholomews, compared the in vitro effect of fourergoalkaloids on prolactin secretion using the principleof a perifusion system (110). The action of lisuride (5nmol/l), lergotrile (5nmol/l) and pergolide (50 nmol/l)was compared to this of bromocriptine (5 nmol/l). Inthese doses, bromocriptine and lisuride had at least 3hour duration of action after their removal from thesystem, while lergotrile and pergolide had a shorterduration of action. Thus these initial studies showedthat in comparison with dopamine, lergotrile was 2.5more potent, bromocriptine 13, lisuride 15 andpergolide 23. This was the initial study that hasproved that lisuride and bromocriptine were longacting drugs in vitro.

We also proved the action of the newer tobromocriptine compounds, CV 205-501 (currentlyquinagolide) and CQP 201-403, both produced bySandoz Pharmaceutical Ltd) and comparing theirefeects we noticed that they both were effective in lowdoses (0.1 nM) and that their duration of action waslong; a hundred times bigger dose of bromocriptinehad an effect that did not last as long as these twocompounds on suppressing prolactin secretion (111,112). After this initial study on newer to bromocriptinecompounds, many followed both in vitro and in vivo sonew compounds evolved in the market currently usedin parallel with bromocriptine and due to their longeraction are given either once daily or once weeklymaking the regime more tolerable for long periods oftime. Due to the wide experience with bromocriptine,various studies are currently taking place to comparethem with the effect of bromocriptine.

Dopamine agonist/bromocriptine resistance

Although dopamine agonists are successful innormalizing plasma prolactin levels, alleviatingsymptoms of hyperprolactinaemia and reducingtumour size, some patients with prolactinomas do notshow a satisfactory response to these drugs (113).This phenomenon means that prolactinomas show avariable response to dopamine agonists, and mayrespond completely at one end or at the other end ofthe spectrum they may show a total resistance.

Resistance is not related to drug non tolerance, sincethe second phenomenon means that the drug sideeffects prevent the clinician to achieve an effectiveresponse.

Why some prolactinomas do not respond to dopamineagonists is not fully understood. There is no doubt thatthe substantial genetic heterogeneity of these tumourscomplicates our ability to find out the factorsresponsible for drug resistance. There is experimentalevidence that some dopamine agonist-resistantprolactinomas have a reduced density of D2 receptors(114, 115, 116) The lactotroph dopamine D2 receptoris most probably involved in the pathogenesis ofdopamine agonist resistance. Limited studies ofprolactinomas have not revealed mutations of the D2receptor. There is though evidence that somedopamine agonist resistant prolactinomas have lowerdensity of D2 receptors (114). Pellegrini et al., in cellcultures of prolactinomas reported a 50% reduction ofD2 dopamine receptors in drug resistantprolactinomas compared to sensitive ones (114).Some of these tumours actually showed only 10% ofthe binding D2 receptor sites compared with thoseseen in responsive prolactinomas (116). Caccavelli etal., (117) found a 4-fold lower level of D2 receptormRNA and a 5-fold lower number of D2 binding sitesamong bromocriptine-resistant compared withbromocriptine-sensitive prolactinomas, but Kovacs etal. (118), demonstrated preservation of both D2receptor mRNA and protein expression in theirprolactinoma resistant to dopamine agonist therapy(118). Thus, the absence of D2 receptor expression isnot a universal finding among prolactinomas resistantto dopamine agonist therapy. There is also apossibility of differences in the proportion of short(D2S) and long (D2L) dopamine receptor variants indrug resistant prolactinomas, since in sensitiveprolactinomas, the short and long receptor isoformsare found in equivalent proportions (117). By contrast,the proportion of mRNA corresponding to the D2S wasfound to be lower in resistant prolactinomas comparedto sensitive ones (119). Abnormal coupling of the D2receptor to Gai2 proteins and a reduction in Gaicontent cannot be excluded (120, 121). A role ofautocrine pathways of inhibitory growth signaling in thedevelopment of dopamine agonist resistance in humanprolactinomas cannot also be excluded.

A nerve growth factor (NGF)-mediated autocrine loopthat controls proliferation and differentiation in pituitarylactotrophs has been identified (122). Dopaminesensitive prolactinomas secrete high levels of NGFand express the NGF receptors (123). From various



in vitro studies, it appears that NGF regulates D2receptor express ion ( induc ing p75NGFreceptor-mediated nuclear translocation and activationof nuclear factor-kB) (124, 125). NGF also promotes aconformational change in the tumour suppressor p53that permits its nuclear translocation and reconstitutesits DNA binding activity (126). Thus, although, someresistant to dopamine agonists prolactinomas areassociated with a reduction in D2 density, they do notseem to show alterations in receptors’ binding activity. Also some agonist resistant prolactinomas may exhibitdisruptions in the autocrine growth factor signalingpathway mediated by NGF, and this may contribute totumour progression.

Resistance to dopamine agonists has been estimatedto be in 24, 13, and 11% of patients for bromocriptine,pergolide and cabergoline, respectively. Resistance toother dopamine agonists such as quinagolide isdifficult to estimate, since there are no large publishedseries. Most of the clinical data regarding dopamineagonist resistance involve studies investigatingwhether another dopamine agonist may be effective inpatients resistant to bromocriptine. Of all the dopamineagonists, cabergoline has been shown to be mosteffective in normalizing prolactin levels in patientsresistant to bromocriptine. Approximately 80% ofbromocriptine resistant patients normalize theirprolactin on cabergoline. Approximately 85% of 20patients resistant to both bromocriptine andquinagolide, responded with prolactin normalization,and 70% responde with some change in tumour size(127). In a larger study, 70% of 58 patientsunresponsive to bromocriptine were controlled oncabergoline, although higher than average doses wererequired. It is possible that cabergoline can beeffective in patients resistant to bromocriptine due toits higher affinity for dopamine binding sites, its greateroccupancy of the receptor, and slower elimination ratefrom the pituitary (128).

Resistance to tumour reduction

Comparison among dopamine agonists for theirrelative ability for tumour size reduction has beenattempted in several studies. In one series of study,with 27 patients, bromocriptine normalized increasedprolactin levels in 66% of patients (12 months’assessment), and caused a 50% reduction of tumoursize in 64% of patients (129). Cabergoline (24 months’assessment), in 26 patients normalized increasedprolactin levels in 100% of patients and caused a 50%tumour size reduction in 96% (130). Another study inthe same series involved the effect of pergolide (27months’ assessment) where 22 patients were studied:

Plasma increased prolactin levels normalized in 68%of patients and in 86% of patients a 50% tumourreduction size was estimated (131). Since the tumourreduction in size may continue up to one year in thesestudies it is possible that the effect of bromocriptine ontumour mass effects is underestimated. Thus, inconcluding from these studies, with respect to lack ofnormalization of prolactin levels, resistance isexpected in 25 – 50% of patients taking bromocriptine,in 10 – 30% in those taking pergolide, and in 5 – 18%of those taking cabergoline. With respect to failure toachieve at least a 50% decrease in tumour size,resistance can be expected in about one third of thosetaking bromocriptine, about 15% of those takingpergolide, and 5 – 10% of those taking cabergoline.

Dopamine agonist/bromocriptine withdrawal

Dopamine agonist treatment of prolactinomas givesexcellent results, as far as normalizing prolactin levels,restoring gonadal function and reducing tumour size,particularly in view of the reported recurrence ofhyperprolactinaemia after surgery (132, 133, 134,135). The principal disadvantage of dopamine agonisttreatment has been to its supposed lifelongrequirement. In the first study on results onbromocriptine withdrawal, it was reported that althoughprolactin levels remained significantly lower than thosebefore treatment, they remained within the normalrange in only 2 of the 37 treated patients. Afterwithdrawal of bromocriptine, remission rates havebeen reported from as low as 0-9% (136, 137, 138,139) to as high as 20-44% (140, 141, 142, 143, 144,145). In patients though with only macroprolactinomasvan’t Verlaat and Croughs (146) reported a remissionrate in 8% of 12 patients after 12 months. Afterbromocriptine discontinuation, an increase in tumoursize (clear-cut reexpansion) has been found in lessthan 10% of cases (147, 148, 149).

Conclusion

Bromocriptine has been valuable in treating variousdisorders especially hyperprolactinaemia of variableaetiology. Due to its effectiveness and also to itslong-term use in clinical practice, new drugs are beingcompared both in their duration of action, but also intheir effectiveness in prolactin reduction levels andalso tumour reduction with bromocriptine in order todraw conclusive data (150). Practically though it stillconstitutes one of the valid first line treatments forhyperprolactinaemia.



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Illustrations

Illustration 1

Bromocriptine Chemistry



Illustration 2 : Clinical relevance of bromocriptine

1. Lactation suppression2. Galactorroea suppression3. Infertility treatment (hyperprolactinaemia (prolactinoma), polycystic ovary

syndrome, anorexia nervosa, short luteal phase defect)4. Premenstrual tension syndrome relieve5. Treatment of Parkinson’s disease

Acromegaly treatment

Illustration 2

Clinical relevance of bromocriptine



Illustration 3 : Side Effects of bromocriptine

Side effects at the beginning of treatment1. nausea2. emesis3. postural hypotension

Side effects during chronic treatmentA. In all patients1. headaches2. gastrointestinal side effects3. vasospasm4. alcohol non tolerance

B. In patients with Parkinson’s disease1. dyskinesia2. psychiatric disturbances

erytrhromelalgia

Illustration 3

Side Effects of bromocriptine



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Bromocriptine: Past and present : From the In Vitro … · Bromocriptine: Past and present : From...

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