Article ID: WMC004010 ISSN 2046-1690

Bromocriptine: Past and present : From the In Vitro and In Vivo Experimental Studies to the Clinical Data

Corresponding Author: Prof. Maria S Venetikou, Professor of Pathophysiology and Nosology, School of Health and Caring Professions, Technological Institutte of Athens, 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 of Athens, 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 Vivo Experimental Studies to the Clinical Data . WebmedCentral PHARMACOLOGY 2013;4(2):WMC004010 Copyright: This is an open-access article distributed under the terms of the Creative Commons Attribution License(CC-BY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Source(s) of Funding: There was no funding

Competing Interests: There were no competing interests

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Bromocriptine: Past and present : From the In Vitro and In Vivo Experimental Studies to the Clinical Data

Author(s): Venetikou MS

Abstract showed that one of the ergoalkaloids, ergocorcin acts directly on the pituitary. Naturally then, there was a question of how much the action of these drugs in the pituitary was clinically applicable and with what way it Bromocrriptine is a drug introduced in the medical was connected with the other properties of these therapeutics in 1967, and since then it has been drugs. In the decade of the 60’s, a systematic widely used in the treatment of hyperprolactinaemia. In research for the ergo-alkaloids and their derivatives experimental animals and in vitro experiments it has started with the aim to produce a compound that inhibits prolactin secretion and the phasic secretion of reduced the prolactin action. During these years the gonadotrophins, while it does not seem to have an obstacle in such a research was the lack of a method effect on growth hormone, or vasopressin secretion. to estimate prolactin levels in the blood. Thus for the Various central nervous effects, autonomic effects and initial evaluation of the action of these drugs several cardiologic actions of bromocriptine have been bioassays were used (e.g. the inhibition of reported on experimental animals during the first leukocytosis in vaginal smears of rat with studies. After the initial evaluations, bromocriptine has pseudocyesis, or the inhibition of oocyte implantation been used in preventing lactation and galactorroea, in in fertilized rats). All these initial methods had the treating infertility, especially when related to disadvantage that they excluded the short acting drugs hyperprolactinaemia, in prolactinomas of various sizes, (3, 4). Also another method that was used in the in acromegaly and in Parkinson’s disease. Through evaluation of these drugs was the inhibition of lactation the years of its clinical use, various acute and chronic both in humans and in mammals (5, 6). The results of side effects has been reported and closely monitored. these initial researchs of the decade of the 60’s led to Due to its need for continuous use and frequent the production of the 2Br-a-methyl-ergocriptine dosage, effort has been undertaken to develop newer (CB154-bromocriptine mesylate) (Parlodel, Providel) in compounds with longer action and similar or better 1967 (illustration 1) (7, 8). Since then, many analogs clinical effects. Although this has been achieved, have been used, but bromocriptine remains the most bromocriptine due to its long clinical application and widely tried drug in hyperprolactinaemia. experience remains the drug with whom the actions of newer compounds are still compared. Resistance to Chemistry prolactin level suppression and tumour size reduction is also frequently estimated for all dopamine agonists The ergot alkaloids can all be considered derivatives used in comparison with these seen after of the tetracyclic ergoline skeleton and can be divided bromocriptine treatment. We present here the most into two main groups based on their structural important points of the numerous pharmaceutical characteristics (9). The first group includes all lysergic studies on bromocriptine. acid derivatives of the acid amide types, such as amine alkaloids (ergonovine) and the structurally more Introduction complex ergopeptines (ergotamine, ergocristine). The second group includes the so-called “clavicle alkaloid” derivatives that contain either a methyl or a First studies on the ergo-alkaloids and hydroxymethyl group at position 8 (9). The ergot bromocriptine alkaloids and their derivatives have a wide spectrum of pharmacological actions that include central, Shelesnyak (1975), studying the mechanism of oocyte neurohumoral and peripheral effects, mediated by implantation in the rat, was the first to notice that some norepinephrine, serotonin, and dopamine receptors. ergo-alkaloids decrease prolactin secretion (1). In The diversity of biological properties of ergot 1954, in his first observations, Shelesnyak concluded derivatives is likely to be due to diverse mechanisms that these drugs act either on the hypothalamus or the of action at the cellular and molecular level (9). pituitary. Later Zeilmaker and Carlen (1962) (2) Because the ergot derivatives interact with different

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receptor sites, it is not surprising that these drugs (as have been treated with reserpine and a-methyl-π well as the natural alkaloids) display a number of side -tyrosine (22). effects (9). Mechanism of bromocriptine action

Bromocriptine has initially been used in the treatment Bromocriptine reduces prolactin secretion without of hyperprolactinaemia (8), but at the time of its influencing directly the hormonal synthesis but with discovery, the type of action of the drug was reducing the out cellular events (23). After the drug unknown. It was later that it was shown that it acts on ingestion, initially an increase of pituitary prolactin is the dopaminergic receptors; what exactly happens noticed (24), while protracted use leads to a decrease from the moment that the drug is bound to the cell of the quantity and concentration of the hormone (25). receptors in order to exert its action still remains unclear. In fact, till the 70’s, even the existence of In rats, where oestrogens were given, simultaneous prolactin was not sure and then the growth hormone treatment with bromocriptine decreases prolactin was thought to be the human lactogen hormone. The levels, DNA synthesis and the mitotic activity of the discovery of bromocriptine and the isolation of pituitary (26, 27). It appears that the continuous prolactin were almost simultaneous. Friesen and his inhibition of prolactin secretion leads to a decrease of co – workers isolated prolactin in 1971 (10), and this the cell metabolism and the ability for mitotic division. also led to the development of a special and sensitive radioimmunoassay for human prolactin (11). The bromocriptine-induced inhibition of prolactin secretion in the rats, is overpowered by With the use of the sensitive prolactin assays, the chlorpromazine. As already known, chlorpromazine is physiology of prolactin secretion was studied and an inhibitor of the dopamine receptors’ antagonists in hyperprolactinaemia was established as the a dose dependent degree (18). commonest human hypophysial disorder (12, 13, 14). It is important to remember that it was established as a Prolactin secretion in vitro is increased, when cAMP is clinical entity, at the same time that the suitable drug increased (28), this ability though is inhibited in the was ready for its effective treatment. With 2-3 clinical presence of bromocriptine (29) or dopamine (30). Both trials, it was shown that the drug acts stimulating the dopamine and bromocriptine reduce the basic action dopaminergic receptors (15,16). In the next few years, of adeny lcyclase in rat pituitaries (31). Opposite views dopamine was established as the basic hypothalamic though have been mentioned by other researchers factor in prolactin inhibition (17). Due to its properties, and a few believe that both these substances have no bromocriptine was also used in the treatment of both effect on the enzyme activity (32). acromegaly and Parkinson’s disease. Endocrinological action of bromocriptine Since calcium is indispensable both for the action of potassium and TRH in the prolactin secretion and Inhibition of prolactin secretion since bromocriptine antagonizes these two stimulatory influences (18, 20), it was concluded that the drug Bromocriptine inhibits prolactin secretion in all reduces the hormonal plasma levels by either mammals and fishes that have so far been examined decreasing the intracellular quantity of calcium or (18), either under physiological conditions or during affecting the cell membrane receptors function. the phase that the hormone secretion is stimulated with physiological, pharmacological or surgical criteria. Classically, dopamine receptors have been divided Area of action into D1 receptors, which stimulate adenyl cyclase activity, and D2 receptors, which inhibit this enzyme When bromocriptine is added to pituitary cell cultures, (33, 34, 35); three further discrete receptors subtypes it inhibits prolactin secretion in vitro (19). Thus, the have been described (D3, D4 and D5) with less belief that the drug acted directly on the lactotrophs activity on prolactin secretion (34). Dopamine inhibition was firmly eastablished. The experimental in vivo of prolactin secretion is mediated by the D2 dopamine experience also proved the direct effect of receptors expressed by the normal and tumorous bromocriptine on the pituitary. The drug inhibits the lactotrophs (33, 34, 35). D2 receptors belong to the TRH – induced stimulation of prolactin (20), decreases family of G protein – coupled receptors, characterized plasma prolactin in the presence of ectopic pituitary by a single polypeptide chain containing seven (21), and the increased prolactin levels in rats that hydrophobic transmembrane domains; besides their effect on adenyl cyclase, they are able to inhibit

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inositol phosphate production (36) with an effect that Bromocriptine inhibits the phasic secretion of involves G proteins sensitive to pertussis toxin (33, 34, gonadotrophins and the ovulation in young rats where 35, 36). Additionally, dopamine inhibits arachidonic premature cycle is induced after giving plasma of acid release from pituitary cells independently from pregnant mare (45). In such animals, when a given other mechanisms (37). Two isoforms generated by dose inhibits prolactin surge, simultaneously both LH alternative spicing of the D2 receptors have been surge and ovulation is inhibited (45). In adult animals described (38). These two isoforms differ by a 29 – big doses are usually needed for both phasic secretion amino acid sequence located within the of the gonadotrophins and ovulation inhibition. The intracytoplasmic domain that interacts with G proteins; doses must be greater than those needed for the dopamine inhibition of adenyl cyclase activity is inhibition of prolactin increase before ovulation. These observed with both isoforms. experiments show that in young animals the neural control of the phasic gonadotrophic secretion is The inhibition of cAMP levels is a key step in the different that this of the adult rats. Adult rats can take inhibition of prolactin release by dopamine (39). It is bromocriptine for a long time, without disruption of likely that the dopaminergic ergot derivatives share their cycle periodicity. But there is a time dependent similar mechanisms of action (40). aggregation of non active luteal bodies due to the repeated inhibition of the prolactin increase before Dopamine agonists reduce the size of prolactinomas ovulation (46). Thus, dopamine is involved in the by causing a reduction in cell volume (via an early control of LH secretion. The comparison of inhibition of the secretory mechanism, and a late dopaminergic compounds activity as far as ovulation inhibition of gene transcription and prolactin inhibition and implantation inhibition lead to the initial synthesis), as well as causing perivascular necrosis conclusion that these two properties are different (4). and partial cell necrosis (41). There may also be an Growth hormone antimitotic effect. Histologically there is a reduction in secretory activity and cell size, an increase in Bromocriptine does not seem to affect the growth immunoreactive prolactin cellular content and hormone in experimental animals (23). In adult rats, inhibition of exocytosis (42). where oestrogens are given, bromocriptine does not Effects on other pituitary hormones affect the growth hormone response (47). In rat cell cultured lines (GH3), bromocriptine has no effect in the Gonadotrophins basal levels of growth hormone (48). In similar experiments the drug has no effect in the potassium – The bromocriptine effect on the gonadotrophin mediated increase of this hormone (49), at least in secretion has also been evaluated. The drug effect concentrations that reduce prolactin secretion. On the may or may not be identified with the dopaminergic contrary, bromocriptine has been found to reduce both activity. In fact, the neural control of the prolactin and growth hormone secretion in gonadotrophins has not been completely understood adenomatous tissue taken from acromegalic patients and there is still difficulty in explaining the action of (50). these substances in the receptors. Adrenocorticotrophic hormone (ACTH) Secretion There are no many studies in animals where ACTH Bromocriptine brings new oocytic cycles in rats with was estimated after the ingestion of bromocriptine. pseudocyesis, or pseudocyesis can be produced by Indirectly, it appears that the drug has no intense ectopic source of prolactin secretion (21), or after effect on ACTH levels. In rats, long duration treatment ingestion of drugs that have an effect on the neural with bromocriptine has not caused increase or aminic functions (43). It appears that bromocriptine reduction of the weight of the adrenals or a difference restores the basic gonadotrophic secretion in several in the corticosterone plasma levels (51). In cows species probably because it initially reduces the during lactation, doses of bromocriptine that reduced prolactin levels. Having in mind though that dopamine prolactin secretion, had no effect on the cortisol levels is involved in the control of the gonadotrophin (52). secretion (44), it is possible that bromocriptine has a Effect of bromocriptine on the hormones of the direct action. posterior pituitary Inhibition of the gonadotrophin secretion Vasopressin (AVP)

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In rat experiments, bromocriptine does not affect the brain. Sometimes its action is obvious in doses similar water excretion (18) and appears that the vasopressin to those they cause prolactin suppression, other times secretion is not affected by the drug. Of course with though there is need for higher doses long term use of bromocriptine, at least in rats, there is Autonomic functions reduction of osmolarity (53) and the special weight (54) of urine, but it is not known if this phenomenon is due Bromocriptine shows strong emetic effect in dogs to the direct effect of the drug in renal function, in (ED50 7.5 µg/kg IV or 11.4 µg/kg SC). When it is given prolactin reduction, or a mild inhibition of vasopressin IV, bromocriptine is three times less potent (as far as secretion. the emetic behavior is concerned) from the a – Oxytocin ergocriptine and 2.5 times less from ergotamine. The drug reduces the body temperature of rats that have In rats, the oxytocin secretion that is observed as a been exposed to cold environment, action that is response to nursing (milk ejection test) during lactation abolished by the dopamine agonists, pimozide (65), is reduced by many ergoalkaloids (55). Bromocriptine haloperidol and sulpiride (66). It appears that the though does not reduce the response to nursing thermorythmisis is based in the dopaminergic (ejection) (22). There must be a inhibitory behaviour. When reserpine is given to the rats for dopaminergic mechanism , that regulates the oxytocin hypothermia induction, bromocriptine increases the secretion in rats (in vitro studies) (56). body temperature, while the action is reversed by Effect on the peripheral endocrine system administration of sulpiride (67). Haloperidol reverses the hyperthermia induced by small bromocriptine Organs producing steroid hormones doses, but has no effect when big doses are given. In contrast cyproheptadine suppresses the hyperthemic Bromocriptine produces changes in stereoidogenesis. action of both small and big bromcriptine doses (68). Initially they were thought as a result of changes in This phenomenon explains that dopamine has both prolactin levels and not as a direct effect of the drug at dopaminergic and serotoninergic action. the peripheral endocrine organs. When a dose of bromocriptine is injected the fifth day into the rat Movement activity oocyte, an increase of the 20a hydroxy steroido-dihydrogenase is noticed, which does not In small rodents, bromocriptine has a biphasic effect in happen the sixteen day of pregnancy. Prolactin movement activity (69). The first hour, after the injection abolishes the 20a hydroxyl subcutaneous injection of bromocriptine into the rats, a steroid-dihyrogenase (57). Long term ingestion of deduction in exploratory activity is observed. Similar bromocriptine in ,male rats causes decrease of the behavioral changes are observed after apomorphine circulating testosterone levels (58). The role of and l-dopa, while amphetamine (which releases the prolactin in testicular function has been well endogenous catecholamines) increases the documented in the past (59). It is also known that exploratory activity. After the initial reduction of prolactin plays some role in the stereoidogenesis that movement activity, both bromocriptine and l-dopa takes place at least in the rat adrenals (60). cause a stimulation of the moving behaviour which lasts from the second till the fifth hour. Other peripheral endocrine organs Stereotypies Dopamine increases the cAMP production and the parathormone secretion in vitro (61). It appears that Like apomorphine, d-amphetamine and l-dopa, dopamine in the parathyroid cells acts through the D1 bromocriptine cause stereotypic behaviour in rodents receptors (62). But the effect of bromocriptine in the (69) which consists of repetitive biting or sneezing. cells of the parathyroid glands in not exactly known. Stereotypy is achieved through stimulation of the dopaminergic receptors and is inhibited by pimozide Renin secretion in dogs (63) and insulin and glucagon (69), selective antagonist of the dopaminergic secretion in humans (64) are both stimulated by the receptors (70). In hamsters, bromocriptine does not dopamine effect. Again there are no experimental cause stereotypic behaviour, but the sensitivity of data for the bromocriptine effect on these hormones these animals increases with time or with the simultaneous giving of d – amphetamine or Effect on the central nervous system apomorphine (71).

Bromocriptine influences the extrapituitary areas of the Cardiologic action of bromocriptine

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IV injection of bromocriptine in continually increasing with amenorrhoea and potency to males. In refractory doses up to 18.7 µg/kg in anaesthetized cats (18) has cases, the treatment may be prolonged up to 6-12 shown that after a dose of more than 0.1 µg/kg, both months, if needed. In women with polycystic ovary the cardiac rhythm and arterial blood pressure are syndrome (high dehydroepiadrosterone levels), reduced (18). While the IV injection (10 µg/kg) has no commonly (20%) high prolactin levels are also noticed. effect, when it is given inside the ventricles, reduces Bromocriptine decreases both the increased levels of the blood pressure up to 30 mmHg. This action lasts dehydroepiandrosterone and prolactin. When there is approximately for 2 hours. In parallel, there is also no hyperprolactinaemia, it does not appear that bradycardia. Bromocriptine reduces blood pressure, bromocriptine restores fertility. A similar phenomenon when given to dogs, and its action is also proportional is seen in anorexia nervosa. Bromocriptine is effective to the dose and to the way of the drug is given. The only if there is concomitant hyperprolactinaemia. In initial effective dose is 6 µg/kg and usually the drug infertile women with short luteal phase, (5 days), and should be given intravenously. In these experimental temporary hyperprolactinaemia, or low progesterone animals rarely bradycardia is encountered. The action values, bromocriptine restores the menstrual cycle. of the drug in the cardiac rhythm and pressure can be Thus, it is obvious that bromocriptine restores fertility suppressed, when haloperidol, ergometrine or that is related to hyperprolactinaemia. methyl-ergometrine are previously given (72, 73, 74). All these initial studies have shown that the Premenstrual tension syndrome hypotensive properties of bromocriptine are due to the action of this substance in three possible areas: 1) When bromocriptine is given at a dose of 2.5 mg 1-3 CNS, 2) endings of the sympathetic neurons 3) times per day, 5-15 days before the menses appear, it smooth muscles. In all three cases, bromocriptine seems that it causes reduction of the reported action is due to the stimulation of the dopaminergic symptoms. receptors. Clinical relevance of bromocriptine (illustration 2) Breast cancer

Lactation Bromocriptine has not shown promising results in breast cancer. The normal lactation process can be suppressed by giving 2.5 mg bromocriptine 2-3 times per day. If this Parkinson’s disease dose is given for three weeks, the milk production stops and does not reappear. Comparing the Bromocriptine has been tried in Parkinson’s disease. bromocriptine suppressing effect on lactation to this of It appears that the dose should be high. In some oestrogens, bromocriptine is safer, since the cases, doses up to 200 mg per day have been used. thromboembolic risk is smaller. Furthermore, after Levodopa has been tried in Parkinson’s, but it shows bromocriptine use, fertility reappears four weeks after many side effects. Bromocriptine can in such cases delivery, in those women they nurse though three substitute levodopa, because although it has lower months are needed. action, its effect has longer duration. Galactorroea Prolactinomas

Whatever the galactoroea cause, treatment with These adenomas are relatively common cause of bromocriptine (5-10 mg per day) in divided doses infertility. Usually bromocriptine (2.5-10 mg three to restores both prolactin in normal levels and the milk four times daily) reduces hyperprolactinaemia and suppression within a week. When galactorroea is due restores fertility. Furthermore, it ameliorates visual to the use of neuroleptic drugs or to very high prolactin fields and reduces the size of the adenomas (75). levels, doses of bromocriptine up to 50 mg per day may be needed. Acromegaly Infertility Most of the acromegalics, after treatment with Infertility may be seen even when the prolactin levels bromocriptine (5-10 mg three times daily), show are slightly elevated. Treatment with bromocriptine reduction of the growth hormone levels. The growth restores both prolactin levels and fertility. 4-12 weeks hormone levels though do not fall as easily as are enough to restore the menstrual cycle in women prolactin ones. Although the decline of growth

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hormone is obvious within the first week, clinical Chronic side effects improvement often needs 8 weeks of treatment. Best results are obtained with high doses (10-20 mg three When small doses of bromocriptine are used, rarely times daily for 6 months). The clinical improvement is there are such side effects that demand the greater than that expected in comparison with the discontinuation of therapy. Acromegalics, although reduction of the levels of growth hormone. Patients they usually take big bromocriptine doses, rarely show that show concomitant hyperprolactinaemia, show a such side effects that the treatment should be better response. In no case though can bromocriptine discontinued. Parkinsonians, on the contrary, many replace the operation, when it is needed. times show intense side effects that the drug may Side effects of bromocriptine (illustration 3) need to be discontinued. Headaches There is no doubt that bromocriptine has been a useful drug. Despite this, the drug administration often leads Mild headaches are observed often in the beginning of to side effects, although there has never been treatment with bromocriptine. They are rarely serious mentioned a permanent lesion after bromocriptine use. and usually are temporary. There are though some patients that they are more sensitive than others. Some side effects are only seen Gastrointestinal side effects when very big doses are used. Finally, some side effects are observed especially in some patients such Symptoms from the gastrointestinal system are rare. as psychiatric and parkinsonian ones. The After the administration of big doses, mild dyspepsia bromocriptine side effects are divided in acute (onset may be noticed. Usually these symptoms resemble of therapy) and chronic (after long term administration those of gastrooesophageal feedback and they are of the drug). The side effects of bromocriptine relieved when the patient lies down. Gastrointestinal resemble very much those of l-dopa. They all stem bleeding after the administration of bromocriptine has from the diffuse stimulation of the central and been observed (76), but there is no evidence about its peripheral dopaminergic receptors. Vasospasm, frequency. erythromelalgia, lack of tolerance of alcohol and peptic bleeding are side effects that characterize exclusively Vasospam bromocriptine. It has been noticed initially in patients taking big doses Acute side effects of bromocriptine. It has been seen in up to 30% of the acromegalics (77, 76) and in parkinsonians (78). It is Usually, nausea, emesis and orthostatic hypotension. not an ergotism phenomenon, because it is not The appearance of these side effects vary depending followed by pain or finger ischaemia and because it is on the disease for which the patient is treated. Young relieved as soon as the dose of the drug is reduced. normal subjects who took the drug experimentally Alcohol non tolerance taking part in clinical studies are more prone to develop acute side effects. The hyperprolactinaemic In a 10% of patients, immediately after the beginning subjects are also prone to develop acute side effects, of treatment with bromocriptine, non tolerance of while acromegalics are more resistant. It is rare to alcohol develops especially for quantities they used to notice these symptoms in women who take consumed in the past. With the continuation of therapy bromocriptine , either after parturition or for lactation this side effect usually disappears. suppression. The intensity of these side effects can be reduced when the drug is given concomitantly with Side effects seen in Parkinson’s disease small quantities of food just before sleep. When the patient is lying down these side effects are usually Dyskinesia avoided. In patients that developed these side effects it is usually preferable to increase the dose more Choreoathetoid movements of the limbs and the head slowly than usual. Rarely hyperprolactinaemic patients and neck muscles are a characteristic side effect of need doses more than 7.5 mg per day , while on the l-dopa, when it is administered in big doses for the contrary parkinsonians and acromegalics may need treatment of parkinsonism. The movements can 10-80 mg per day. Usually with the small doses of mimick any movement disorder such as dystonia and bromocriptine, only few side effects are seen in the myoclonus. The precise mechanism that leads to beginning of therapy.

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these side effects is unclear, although it has already that is characterized by red, sensitive and oedematous been said that this disease leads to denervation and limbs, that is followed by a sense of local heat and hypersensitivity of the dopamine receptors, thus l-dopa dysphoria. The symptoms usually affect the lower causes diskinesia due to a toxic mechanism. limbs, but they may affect the upper limbs or even the knees. The whole clinical picture is followed by In patients who showed dyskinesia after administration polyarthralgia and increased sedimentation rate. This of l-dopa, administration of bromocriptine can produce clinical picture is also exclusively seen in parkinsonic exactly the same phenomena even if they continue patients who take big doses of bromocriptine for a long taking l-dopa or not. Despite this, the dyskinesia that is time. Of these patients, only a 10% show produced by bromocriptine seems to be less dramatic. erytromelalgia. After discontinuation of bromocriptine, this syndrome virtually disappears within 3 – 4 days. Psychiatric disturbances On the whole, the adverse effects of bromocriptine Parkinson’s disease, if left without treatment, shows may be grouped into three categories: gastrointestinal, mental disturbances, such as depression, dementia, cardiovascular, and neurological (83). Symptoms as hallucinations or illusions (79). But also any already said tend to occur after the initial dose and antiparkinsonic treatment can cause or worsen similar with dosage increases, but can be minimized by psychomental disturbances. At least 20% of the introducing the drug at a low dosage (0.625 or 1.25 parkinsonians that take anticholinergic drugs report mg/day) at bedtime, by taking it with food, and by very psychiatric disturbances. The same symptoms are gradual dose escalation (40). Sometimes, tolerance to also seen in patients who take l-dopa. With the the adverse effects develops, but occasionally, administration of l-dopa, hallucinations of paranoid therapy withdrawal or dose reduction followed by a type may be seen. With the use of bromocriptine, the more gradual reintroduction is required. Up to 12% of danger for such side effects is even greater. In the patients are unable to tolerate therapeutic doses of initial stages of toxicity, with either l-dopa or bromocriptine (84). Usually though the initial side bromocriptine, the patients complain for frequent and effects mentioned above can be avoided by taking the intense dreams that quickly lead to nocturnal drug at bedtime or while recumbent, but tolerance hallucinations. Slowly a complicated system of usually develops rapidly making this precaution hallucinations is organized that is characterized by unecsssary after the first few days. From the visual hallucinations and paranoid ideation. These symptoms they have not been mentioned so far, some side effects of bromocriptine are seen exclusively in infrequent psychiatric side effects need to be patients with Parkinson’s disease. Their severity considered. Bromocriptine, even in low doses has parallels the existing neurological disorder. been associated with mania in postpartum patients (83, Discontinuation of the drug leads to amelioration of the 84, 85) and signs and symptoms of psychosis or mental condition, although for full improvement a few exacerbations of preexisting psychosis have been weeks are usually needed. The decision for stopping associated with the use of bromocriptine (86, 87, 88). the drug is a dilemma, because in some patients the Turner et al., observed de novo psychotic reactions in neurological disorder is so much worsen that they face 8 of 600 patients treated with bromocriptine or lisuride the danger of aspiration, vein thrombosis or infection (88). The symptoms which included auditory of the urogenital tract. The clinician then finds hallucinations, delusional ideas, and mood alterations, him/herself in a difficult position to choose between a entirely remitted when the drug was reduced in dose destructive parkinsonism and a dramatic psychotic or discontinued (89). The safety of the drug in the condition. psychiatric population subjects remains to be established, although in a short-term trial in which Rarerly, in patients with Parkinson’s disease treated bromocriptine was given to 16 individuals with with very high doses of bromocriptine, pulmonary psychiatric disorders who were previously stabilized infiltrates, fibrosis, pleural effusions, pleural thickening on neuroleptic agents, exacerbations of psychosis was and retroperitoneal fibrosis have been described (80, not observed (89). Some other psychiatric symptoms 81, 82). These adverse effects appear to be associated with higher doses of bromocriptine, include dose-ependent and they are not usually seen when anxiety, depression, confusion, auditory hallucinations, using small dose for the treatment of prolactinomas. hyperactivity, disinhibition, insomnia, day-time Erythromelalgia somnolence, and paranoia (84, 88, 90). Other rarer side effects include paraesthesia, nightmares, blurred Patients taking bromocriptine may show a syndrome vision, diplopia (high doses) and reversible ototoxicity

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(in patients with chronic liver disease) (83, 84). CSF controlling high prolactin levels in most of the patients. rhinorrhoea has been reported during treatment with But there have been disadvantages in bromocriptine bromocriptine, not only post surgically, but also in the action. absence of prior radiotherapy or surgical intervention due to tumour shrinkage, when the tumour previously The fact that the drug usually is given at a dose of 2.5 served as an obstacle for the tumour – induced skull mg three times daily, means that the patient depends base defect (91,92, 93, 94, 95, 96). Reports from post absolutely from this frequent administration. In partum women have suggested a causal association diseases such as acromegaly and parkinsonism, the between the use of bromocriptine and hypertension, doses had to be greater, the intervals of administration thromboembolic events, severe leucopenia, are many times per day. Taking tablets many times hyponatriaemia and oedema (97, 98, 99, 100, per day has been very problematic for many patients 101).Although, the causative association is not proven, and this eventually led to patients’ reduced tolerance. in the United States, the FDA has determined that bromocriptine should not be used to treat postpartum The initiation of bromocriptine treatment has been lactation. followed by side effects as presented above (eg, nausea, emesis, and arterial hypotension). These first In a small group of patients at low doses of side effects have made through the years many bromocriptine (5-10 mg/daily), transient asymptomatic patients to be hesitant in the continuation of the increases in serum alkaline phosphatase and/or treatment. transaminases have been reported (83,84 ). Hyponatriaemia has been associated with the use of Discontinuation of bromocriptine administration is bromocriptine in patients with cirrhosis and hepatic followed by the re – increase of prolactin levels to the encephalopathy (101). initial high values. In the case the drug has caused decrease of the tumour growth, its discontinuation The use of bromocriptine, when is taken for only the often is followed from its re-increase (106). first few weeks of gestation, has not been associated with an increase in the rates of spontaneous abortions, Although, the bromocriptine value is undisputable, the ectopic pregnancies, trophoblastic disease, multiple fact that it may given for life, and that its pregnancies, or congenital malformations in a very discontinuation may lead in the recurrence of the large number of pregnancies (102, 103). In a study disease, is definitely a disadvantage. For years the which undertook a long term follow up of 64 children, researchers have tried to overcome the disadvantages between the ages of 6 months and 9 years, who were of bromocriptine and discover substances with greater born to mothers who took bromocriptine for a limited effectiveness, longer action and the lack of disease duration in early pregnancy, have shown no adverse recurrence after their discontinuation. effects on childhood development (104). Data on infant outcomes of approximately 100 women who Some of the drugs that have been used are lergotrile, used bromocriptine throughout pregnancy revealed pergolide and lisuride. All three act by binding the abnormalities in 2 infants, one newborn with an dopamine receptors of the lactotrophs and showed undescended testicle and one with a talipes deformity that they are capable of reducing prolactin secretion in (105). So far from all the available data on dopamine vitro. Clinically pergolide was the strongest drug with agonists and pregnancy, bromocriptine has the largest the longest duration of action (107, 108). In a study of safety database and has a proven safety record for 47 patients (all had hypersecretion of growth hormone pregnancy. The incidence of malformation in the (109)), pergolide was given once daily and the results offspring is not greater than that in the general were validated after three months. 35 of these patients population. In case during pregnancy, reinstitution of a showed normal prolactin levels after 3 months and dopamine agonist is needed to control tumour growth, only 2 of them had levels a bit higher than the normal bromocriptine is favoured to other dopamine agonists range, while another 2 had a 38-58% reduction only. due to greater experience with the drug in this setting The clinical trial for pergolide has shown its potency to throughout the years. reduce tu mour size as shown previously for Current clinical considerations bromocriptine. A 30 months’study at Baylor has compared the results of both action of bromocriptine Up to recent years, the basic drug used clinically in the and pergolide. 40 patients (28 women and 12 men) treatment of hyperprolactinaemia was bromocriptine have been studied randomly. Others took (Parlodel, Sandoz). The drug gave good results in bromocriptine and othrers pergolide. Before the study,

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it has been estimated the degree of Resistance is not related to drug non tolerance, since hyperprolactinaemia based at the hour fluctuations of the second phenomenon means that the drug side prolactin during a 24 hour period and the size of the effects prevent the clinician to achieve an effective tumour with computerized tomography. Both drugs response. proved to be effective to reduce the prolactin values and the size of the tumour. These patients that did not Why some prolactinomas do not respond to dopamine responded to pergolide, eventually responded to agonists is not fully understood. There is no doubt that bromocriptine (108). Thus it has been proved that the the substantial genetic heterogeneity of these tumours patients that do not respond to one dopamine agonist complicates our ability to find out the factors may respond to another. In the past a study at St responsible for drug resistance. There is experimental Bartholomews, compared the in vitro effect of four evidence that some dopamine agonist-resistant ergoalkaloids on prolactin secretion using the principle prolactinomas have a reduced density of D2 receptors of a perifusion system (110). The action of lisuride (5 (114, 115, 116) The lactotroph dopamine D2 receptor nmol/l), lergotrile (5nmol/l) and pergolide (50 nmol/l) is most probably involved in the pathogenesis of was compared to this of bromocriptine (5 nmol/l). In dopamine agonist resistance. Limited studies of these doses, bromocriptine and lisuride had at least 3 prolactinomas have not revealed mutations of the D2 hour duration of action after their removal from the receptor. There is though evidence that some system, while lergotrile and pergolide had a shorter dopamine agonist resistant prolactinomas have lower duration of action. Thus these initial studies showed density of D2 receptors (114). Pellegrini et al., in cell that in comparison with dopamine, lergotrile was 2.5 cultures of prolactinomas reported a 50% reduction of more potent, bromocriptine 13, lisuride 15 and D2 dopamine receptors in drug resistant pergolide 23. This was the initial study that has prolactinomas compared to sensitive ones (114). proved that lisuride and bromocriptine were long Some of these tumours actually showed only 10% of acting drugs in vitro. the binding D2 receptor sites compared with those seen in responsive prolactinomas (116). Caccavelli et We also proved the action of the newer to al., (117) found a 4-fold lower level of D2 receptor bromocriptine compounds, CV 205-501 (currently mRNA and a 5-fold lower number of D2 binding sites quinagolide) and CQP 201-403, both produced by among bromocriptine-resistant compared with Sandoz Pharmaceutical Ltd) and comparing their bromocriptine-sensitive prolactinomas, but Kovacs et efeects we noticed that they both were effective in low al. (118), demonstrated preservation of both D2 doses (0.1 nM) and that their duration of action was receptor mRNA and protein expression in their long; a hundred times bigger dose of bromocriptine prolactinoma resistant to dopamine agonist therapy had an effect that did not last as long as these two (118). Thus, the absence of D2 receptor expression is compounds on suppressing prolactin secretion (111, not a universal finding among prolactinomas resistant 112). After this initial study on newer to bromocriptine to dopamine agonist therapy. There is also a compounds, many followed both in vitro and in vivo so possibility of differences in the proportion of short new compounds evolved in the market currently used (D2S) and long (D2L) dopamine receptor variants in in parallel with bromocriptine and due to their longer drug resistant prolactinomas, since in sensitive action are given either once daily or once weekly prolactinomas, the short and long receptor isoforms making the regime more tolerable for long periods of are found in equivalent proportions (117). By contrast, time. Due to the wide experience with bromocriptine, the proportion of mRNA corresponding to the D2S was various studies are currently taking place to compare found to be lower in resistant prolactinomas compared them with the effect of bromocriptine. to sensitive ones (119). Abnormal coupling of the D2 Dopamine agonist/bromocriptine resistance receptor to Gai2 proteins and a reduction in Gai content cannot be excluded (120, 121). A role of Although dopamine agonists are successful in autocrine pathways of inhibitory growth signaling in the normalizing plasma prolactin levels, alleviating development of dopamine agonist resistance in human symptoms of hyperprolactinaemia and reducing prolactinomas cannot also be excluded. tumour size, some patients with prolactinomas do not show a satisfactory response to these drugs (113). A nerve growth factor (NGF)-mediated autocrine loop This phenomenon means that prolactinomas show a that controls proliferation and differentiation in pituitary variable response to dopamine agonists, and may lactotrophs has been identified (122). Dopamine respond completely at one end or at the other end of sensitive prolactinomas secrete high levels of NGF the spectrum they may show a total resistance. and express the NGF receptors (123). From various

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in vitro studies, it appears that NGF regulates D2 Plasma increased prolactin levels normalized in 68% receptor expression (inducing p75NGF of patients and in 86% of patients a 50% tumour receptor-mediated nuclear translocation and activation reduction size was estimated (131). Since the tumour of nuclear factor-kB) (124, 125). NGF also promotes a reduction in size may continue up to one year in these conformational change in the tumour suppressor p53 studies it is possible that the effect of bromocriptine on that permits its nuclear translocation and reconstitutes tumour mass effects is underestimated. Thus, in its DNA binding activity (126). Thus, although, some concluding from these studies, with respect to lack of resistant to dopamine agonists prolactinomas are normalization of prolactin levels, resistance is associated with a reduction in D2 density, they do not expected in 25 – 50% of patients taking bromocriptine, seem to show alterations in receptors’ binding activity. in 10 – 30% in those taking pergolide, and in 5 – 18% Also some agonist resistant prolactinomas may exhibit of those taking cabergoline. With respect to failure to disruptions in the autocrine growth factor signaling achieve at least a 50% decrease in tumour size, pathway mediated by NGF, and this may contribute to resistance can be expected in about one third of those tumour progression. taking bromocriptine, about 15% of those taking pergolide, and 5 – 10% of those taking cabergoline. Resistance to dopamine agonists has been estimated Dopamine agonist/bromocriptine withdrawal to be in 24, 13, and 11% of patients for bromocriptine, pergolide and cabergoline, respectively. Resistance to Dopamine agonist treatment of prolactinomas gives other dopamine agonists such as quinagolide is excellent results, as far as normalizing prolactin levels, difficult to estimate, since there are no large published restoring gonadal function and reducing tumour size, series. Most of the clinical data regarding dopamine particularly in view of the reported recurrence of agonist resistance involve studies investigating hyperprolactinaemia after surgery (132, 133, 134, whether another dopamine agonist may be effective in 135). The principal disadvantage of dopamine agonist patients resistant to bromocriptine. Of all the dopamine treatment has been to its supposed lifelong agonists, cabergoline has been shown to be most requirement. In the first study on results on effective in normalizing prolactin levels in patients bromocriptine withdrawal, it was reported that although resistant to bromocriptine. Approximately 80% of prolactin levels remained significantly lower than those bromocriptine resistant patients normalize their before treatment, they remained within the normal prolactin on cabergoline. Approximately 85% of 20 range in only 2 of the 37 treated patients. After patients resistant to both bromocriptine and withdrawal of bromocriptine, remission rates have quinagolide, responded with prolactin normalization, been reported from as low as 0-9% (136, 137, 138, and 70% responde with some change in tumour size 139) to as high as 20-44% (140, 141, 142, 143, 144, (127). In a larger study, 70% of 58 patients 145). In patients though with only macroprolactinomas unresponsive to bromocriptine were controlled on van’t Verlaat and Croughs (146) reported a remission cabergoline, although higher than average doses were rate in 8% of 12 patients after 12 months. After required. It is possible that cabergoline can be bromocriptine discontinuation, an increase in tumour effective in patients resistant to bromocriptine due to size (clear-cut reexpansion) has been found in less its higher affinity for dopamine binding sites, its greater than 10% of cases (147, 148, 149). occupancy of the receptor, and slower elimination rate from the pituitary (128). Conclusion Resistance to tumour reduction

Comparison among dopamine agonists for their Bromocriptine has been valuable in treating various relative ability for tumour size reduction has been disorders especially hyperprolactinaemia of variable attempted in several studies. In one series of study, aetiology. Due to its effectiveness and also to its with 27 patients, bromocriptine normalized increased long-term use in clinical practice, new drugs are being prolactin levels in 66% of patients (12 months’ compared both in their duration of action, but also in assessment), and caused a 50% reduction of tumour their effectiveness in prolactin reduction levels and size in 64% of patients (129). Cabergoline (24 months’ also tumour reduction with bromocriptine in order to assessment), in 26 patients normalized increased draw conclusive data (150). Practically though it still prolactin levels in 100% of patients and caused a 50% constitutes one of the valid first line treatments for tumour size reduction in 96% (130). Another study in hyperprolactinaemia. the same series involved the effect of pergolide (27 months’ assessment) where 22 patients were studied:

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Illustrations

Illustration 1

Bromocriptine Chemistry

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Illustration 2

Clinical relevance of bromocriptine

Illustration 2 : Clinical relevance of bromocriptine

1. Lactation suppression 2. Galactorroea suppression 3. Infertility treatment (hyperprolactinaemia (prolactinoma), polycystic ovary syndrome, anorexia nervosa, short luteal phase defect) 4. Premenstrual tension syndrome relieve 5. Treatment of Parkinson’s disease Acromegaly treatment

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Illustration 3

Side Effects of bromocriptine

Illustration 3 : Side Effects of bromocriptine

Side effects at the beginning of treatment 1. nausea 2. emesis 3. postural hypotension

Side effects during chronic treatment A. In all patients 1. headaches 2. gastrointestinal side effects 3. vasospasm 4. alcohol non tolerance

B. In patients with Parkinson’s disease 1. dyskinesia 2. psychiatric disturbances erytrhromelalgia

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