Impaired pituitary response to bromocriptine suppression: reversal after bromocriptine plus tamoxifen.
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Adenoma, Chromophobe↗
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Bromocriptine in Parkinson disease.
Bromocriptine is an ergopeptine derivative and dopamine agonist that predominantly stimulates the striatal D2 non-adenyl cyclase-linked dopamine receptors. Bromocriptine, unlike other dopamine agonists, has mixed "agonist-antagonist" properties at these receptors. The striatal dopamine receptors exist in two different affinity states: a low and a high affinity state. Bromocriptine, unlike other dopamine agonists, does not differentiate between the low and the high affinity state of the D2 receptors, and bromocriptine does not induce a conformational change in these receptors. Bromocriptine, in low doses, is effective in patients with mild to moderate Parkinson's disease, while bromocriptine in higher doses is needed in patients with advanced disease. Both in low doses and in high doses, bromocriptine combined with levodopa is usually more effective than bromocriptine alone. The efficacy of low dose (5-30 mg/day) and high dose (31-100 mg/day) bromocriptine alone and with levodopa was examined in 27 studies encompassing 790 patients. Forty-six % of the studies were done in a double blind manner. In four studies of 79 patients, low dose bromocriptine (16 mg/day) without levodopa resulted in improvement in 58% of the patients. Only 9% of the patients experienced adverse effects. Most of the patients (63%) and mild or moderate Parkinson disease. In seven studies of 143 patients, high dose bromocriptine (56 mg/day) without levodopa resulted in improvement in 62% of patients, but with 27% having adverse effects. Most of these patients (77%) had mild or moderate disease. Diurnal oscillations in performance, the "wearing off" or "on-off" effect, were not seen during treatment with bromocriptine alone. In nine studies of 201 patients, low dose bromocriptine (23 mg/day) and levodopa resulted in improvement in 71% of patients with 26% having adverse effects. Most of these patients (66%) had advanced disease, and many had diurnal oscillations in performance. In seven studies of 367 patients, high dose bromocriptine (48 mg/day) and levodopa resulted in improvement in 58% with 37% having adverse effects. Most of these patients (85%) had advanced disease. The increased effectiveness of bromocriptine in combination with levodopa may be explained as follows. Bromocriptine by itself does not discriminate between the low and the high affinity states of the dopamine receptors.(ABSTRACT TRUNCATED AT 400 WORDS)
Aged↗
Low and high dose bromocriptine have different effects on striatal dopamine release: an in vivo study.
We wished to determine if low and high doses of bromocriptine produce distinct patterns of dopamine release and metabolism. Accordingly, we administered bromocriptine (0, 2.5, 5, and 10 mg/kg, IP) to rats and monitored extracellular concentrations of dopamine and dopamine metabolites in the corpus striatum with the technique of cerebral microdialysis. Extracellular dopamine levels increased following administration of 2.5 and 5 mg/kg bromocriptine. In contrast, dopamine levels decreased following 10 mg/kg bromocriptine. Dopamine metabolite levels decreased 45 minutes following all doses of bromocriptine. Bromocriptine administration had no effect on the levels of 5HIAA, the major serotonin metabolite. These findings with high dose bromocriptine fit the predicted profile of a dopamine D2 receptor agonist. The delayed decrease in dopamine metabolites at all bromocriptine doses is consistent with the known dopamine synthesis inhibiting action of bromocriptine. In contrast, the increased dopamine release observed following low and medium doses of bromocriptine is not readily explainable by current theories of bromocriptine action which predict decreased dopamine release and therefore decreased striatal extracellular dopamine levels with both high and low-doses of bromocriptine. Our findings indicate that bromocriptine has a complex pharmacological action that extends beyond simple agonism at dopamine D2 receptors.
3,4-Dihydroxyphenylacetic Acid↗
Distinct guanine nucleotide binding protein alpha-subunit receptor coupling in GH cell lines: effects of bromocriptine and hormones on effector enzyme modulation.
The purpose of the present study was to elucidate how the dopamine agonist bromocriptine affected receptor-effector systems in GH cells by measuring adenylate cyclase (AC) and phospholipase C (PL-C) modulation in cell membrane preparations. To perturb the interaction between the receptor and G-protein, polyclonal antibodies reacting with the predicted C-terminal amino acid sequence of G-protein alpha-subunits were used. The effect of bromocriptine on secretagogue elicited prolactin (PRL) secretion from whole cells was also monitored. Bromocriptine inhibited the basal secretion of PRL in a dose dependent manner, and completely abolished both the thyroliberin (TRH) and the vasoactive intestinal peptide (VIP) stimulated PRL secretion in GH(3) cells. Maximal inhibitory effect on PRL egress elicited by both hormones was obtained at 10-50 microM of bromocriptine. Messenger RNAs for both the short and long form of the D(2) receptor (D(2)R) were demonstrated in all three GH cell lines using the RT-PCR technique, advocating that D(2)Rs are coupled to distinct G-proteins and, thus, probably being responsible for the observed effects of bromocriptine in these cell lines. Basal AC activity, as measured in membrane preparations of GH(3) cells, remained unaffected by bromocriptine treatment (10 microM), while TRH and VIP stimulated AC activities (175% and 350% of control values, respectively) were partially inhibited (by some 50%). This inhibitory effect of bromocriptine was completely and specifically abolished in the presence of an antiserum against G(i2)alpha. Basal PL-C activity was also unaffected by bromocriptine, while TRH stimulated PL-C activity (350% of control value) was inhibited by bromocriptine (10 microM) by approximately 50%. Immunoblocking of G(q/11)alpha, however, reduced the stimulatory effect of TRH on PL-C activation by some 65%, while an antiserum against G(o)alpha partly counteracted the inhibitory effect of bromocriptine (10 microM) on TRH stimulated PL-C activity. Thus, TRH dependent AC stimulation was counteracted by bromocriptine via G(i2). TRH activation of PL-C occurs via G(q/11), while inhibition by bromocriptine appears to involve G(o). These mechanisms probably account for the major part of the actions of bromocriptine, however, other not yet recognised intermediates may be involved.
Adenylyl Cyclases↗
[Long-acting and repeatable dose bromocriptine in the prolonged treatment of prolactinoma].
BACKGROUND: The presentations of intravenous or depot bromocriptine (bromocriptine LA or long acting, Pariodel LA and bromocriptine LAR or long acting repeatable, Pariodel LAR) have improved the efficacy and the tolerance of oral bromocriptine. In contrast to bromocriptine LA, bromocriptine LAR may be repeatedly administered intramuscularly. METHODS: Five patients with macroprolactinoma and 4 with microprolactinoma were included in the study. A 50 mg bottle of bromocriptine LAR was administered intramuscularly every month, over a minimum period of 6 months. PRL was determined prior to the study, 1, 3, 7, 14, and 28 days following the initial dose of bromocriptine and thereafter with monthly periodicity. RESULTS: The PRL values decreased in those patients with macroprolactinomas following the administration of bromocriptine LAR; in 2 patients the monthly doses of bromocriptine LAR was increased to 100 mg since the month after the initial dose PRL remained greater than 200 ng/ml with serum RPL normalizing in most of the patients at 6 months of treatment. In two of the three patients who presented visual changes a clear improvement was observed and in all the cases a reduction in the size of the macroprolactinoma was found upon CAT control at 6 months. The PRL values also decreased in the patients with microprolactinomas following administration of bromocriptine LAR, although the response was not as homogeneous as in the patients with macroprolactinomas due to that at 6 months 2 patients continued to have slightly elevated serum PRL levels. The microadenoma persisted in the control CAT at 6 months except in one case. Local and general tolerance to bromocriptine LAR was very good. CONCLUSIONS: This study indicates good tolerance to bromocriptine LAR, being a therapeutic option in the treatment of macroprolactinomas.
Adult↗
Association of the antidiabetic effects of bromocriptine with a shift in the daily rhythm of monoamine metabolism within the suprachiasmatic nuclei of the Syrian hamster.
Bromocriptine, a dopamine D2 agonist, inhibits seasonal fattening and improves seasonal insulin resistance in Syrian hamsters. Alterations in daily rhythms of neuroendocrine activities are involved in the regulation of seasonal metabolic changes. Changes in circadian neuroendocrine activities that regulate metabolism are believed to be modulated by central circadian oscillators within the hypothalamic suprachiasmatic nuclei (SCN) of seasonal animals. We examined the association of metabolic responses to bromocriptine with its effects on the daily rhythms of metabolic hormones and daily monoamine profiles within the SCN, a primary circadian pacemaker known to regulate metabolism, in Syrian hamsters. Obese glucose-intolerant male Syrian hamsters (body weight [BW] 185 +/- 10 g) held on 14h daily photoperiods were treated at light onset with bromocriptine (800 microg/animal/day, ip) or vehicle for 2 weeks. Animals were then subjected to a glucose tolerance test (GTT) (3 g/kg BW, ip). Different subsets of animals (n = 6) from each treatment group were sacrificed at 0h/24h, 5h, 10h, 15h, or 20h after light onset for analyses of SCN monoamines, plasma insulin, prolactin, cortisol, thyroxin (T4), triiodothyronine (T3), glucose, and free fatty acids (FFAs). Compared with control values, bromocriptine treatment significantly reduced weight gain (14.9 vs. -2.9 g, p < .01) and the areas under the GTT glucose and insulin curves by 29% and 48%, respectively (p < .05). Basal plasma insulin concentration was markedly reduced throughout the day in bromocriptine-treated animals without influencing plasma glucose levels. Bromocriptine reduced the daily peak in FFA by 26% during the late light span (p < .05). Bromocriptine significantly shifted the daily plasma cortisol peak from the early dark to the light period of the day, reduced the plasma prolactin (mean 1.8 vs. 39.4 ng/dL) and T4 throughout the day (mean 1.6 vs. 3.8 microg/dL), and selectively reduced T3 during the dark period of the day (p < .01). Concurrently, bromocriptine treatment significantly reduced SCN dopamine turnover during the light period and shifted daily peaks of SCN serotonin and 5-hydroxy-indoleacetic acid (5-HIAA) content by 12h from the light to the dark period of the day (p < .05). This was confirmed by a further in vivo microdialysis study in which bromocriptine increased SCN extracellular 5-HIAA of glucose-intolerant hamsters during the dark phase (47% increase, p < .05) toward levels observed in normal glucose-tolerant hamsters. Thus, bromocriptine-induced resetting of daily patterns of SCN neurotransmitter metabolism is associated with the effects of bromocriptine on attenuation of the obese insulin-resistant and glucose-intolerant condition. A large body of corroborating evidence suggests that such bromocriptine-induced changes in SCN monoamine metabolism may be functional in its effects on metabolism.
Animals↗
A comparison of octreotide, bromocriptine, or a combination of both drugs in acromegaly.
We investigated the pharmacokinetics of bromocriptine and octreotide, both individually and in combination, in 12 patients with active acromegaly. The pharmacodynamics of the drugs were assessed by 12-h profiles of GH secretion and insulin-like growth factor-I (IGF-I) measurements. During the 42-day study period, bromocriptine was administered for 28 days (from day 8; 5 mg, orally, twice daily) and octreotide (200 micrograms, sc, twice daily) from days 15-42. IGF-I levels, 12-h GH, and plasma bromocriptine and octreotide profiles were obtained on days 0, 14, 28, and 42. During bromocriptine treatment, both the area under the GH day curves (AUC) and mean IGF-I decreased to 64% (95% confidence limits, 43-72% and 48-82%, respectively) of initial values. During octreotide treatment, the respective values were 23% (18-30%) and 32% (21-36%), which were greater decreases than those during bromocriptine treatment [36% (95% confidence limits, 32-54%) for AUC for GH and 50% (95% confidence limits, 34-58%) for IGF-I]. With combined treatment, the AUC for GH was reduced to 16% (12-21%) and that of IGF-I to 25% (16-27%) of initial values. This combination was more effective than bromocriptine [25% (95% confidence limits, 22-37%) for AUC for GH and 39% (95% confidence limits, 25-43%) for IGF-I] and octreotide alone [78% (95% confidence limits, 53-89%) for AUC for GH and 78% (95% confidence limits, 57-98%) for IGF-I]. The pharmacokinetic parameters of octreotide were unchanged by the coadministration of bromocriptine. The bioavailability of bromocriptine increased by approximately 40% when bromocriptine was administered together with octreotide compared with administration alone (P < 0.01). Bromocriptine disposition parameters were unaltered. In conclusion, treatment of acromegalics with a combination of octreotide and bromocriptine increases the bioavailability of bromocriptine and reduces both GH and IGF-I levels more effectively than treatment with either drug alone. This presents the possibility of less frequent drug administrations, lower doses of octreotide, and, consequently, lower treatment costs.
Acromegaly↗
Effect of bromocriptine on lipid plasma levels in rats.
Results show that bromocriptine induced marked alterations in plasma levels of cholesterol and lipids in response to acute and chronic administrations in rats. Two hours after an I.P. dose of 10 mg/kg, bromocriptine mesylate caused significant reductions in plasma levels of total high density lipoprotein (HDL) and high density lipoprotein cholesterol (HDL cholesterol). At a dose of 20 mg/kg, bromocriptine mesylate induced significant elevations in plasma levels of total cholesterol, total HDL, HDL cholesterol, total low density lipoproteins (LDL), and low density lipoprotein cholesterol (LDL cholesterol). Injected at a dose of 4 or 10 mg/kg daily for 14 consecutive days, bromocriptine mesylate caused significant increases in plasma levels of total cholesterol, LDL cholesterol and total LDL whereas the levels of HDL cholesterol, total HDL triglycerides (TG) were reduced. At a dose of 20 mg/kg all parameters were significantly increased. Marked hyperglycaemia was noticed in response to doses of 10, 15 and 20 mg/kg injected daily for 14 consecutive days or 2 hrs after a single administration of 15 mg/kg. Plasma insulin activity was reduced 2 hours after injection of bromocriptine at a dose of 15 mg/kg Likewise, a significant reduction in plasma insulin activity was observed in response to daily I.P. injections of bromocriptine at a dose of 15 mg/kg. Hyperglycaemic and hypoinsulinaemic effects of bromocriptine (acute and chronic) were markedly decreased when sulpiride, a dopaminergic D2 antagonist, was injected at an I.P. dose of 10 mg/kg before bromocriptine. Plasma ACTH activity was significantly increased in response to bromocriptine (15 mg/kg I.P.) in acute and chronic experiments. This effect was markedly diminished when sulpiride was injected prior to bromocriptine. In conclusion, bromocriptine induced marked elevations in plasma levels of total cholesterol and lipids which are likely to be related to hyperglycaemic and hypoinsulinaemic effects.
Adrenocorticotropic Hormone↗
Plasma growth hormone suppressive effect of bromocriptine in acromegaly. Evaluation by plasma GH day profiles and plasma GH concentrations during oral glucose tolerance tests.
In most studies reporting favourable results of chronic bromocriptine treatment in acromegaly, plasma GH levels are measured at fixed intervals during the day. Negative results are reported in one major study measuring plasma GH levels during oral glucose tolerance tests (Lindholm et al., 1981). This study does not mention the time interval between the last dose of bromocriptine and the performance of an OGTT, but due to the short duration of action of bromocriptine this may be critical. Therefore, in the present report the plasma GH suppressive effect of bromocriptine in acromegaly is studied using plasma GH day-profiles as well as OGTT's during continued bromocriptine administration and OGTT's at two different time intervals after the last dose of bromocriptine. Twelve patients with clinically active acromegaly were treated with 10-20 mg bromocriptine for 6-9 months. After 6-9 months during continued bromocriptine administration the plasma GH suppressive effect of bromocriptine was evaluated by the mean of four plasma GH determinations during the day and by the mean of seven plasma determinations during oral glucose tolerance tests (OGTT's) performed 1 h, 10 h and 34 h after the last dose. The percentage decrease of the mean plasma GH level during the day induced by chronic bromocriptine treatment showed a good correlation (r = 0.86, P less than 0.001) with the percentage decrease of the mean plasma GH level during OGTT, if the post-treatment test was carried out one hour after the last dose of bromocriptine.(ABSTRACT TRUNCATED AT 250 WORDS)
Acromegaly↗
Double blind randomized study using oral or injectable bromocriptine in patients with hyperprolactinaemia.
OBJECTIVE: A new long-acting injectable form of bromocriptine has become available for long-term treatment of hyperprolactinaemic patients. The objective of this study was to compare efficacy and tolerability of injectable and oral forms of bromocriptine. DESIGN: A double-blind randomized study. All patients received either one injection of bromocriptine 50 mg intramuscularly and placebo tablets for 28 days (Group A) or one placebo injection and oral bromocriptine 7.5 mg daily for 28 days (Group B). PATIENTS: Twenty-three (12 patients for Group A and 11 patients for Group B) hyperprolactinaemia patients with (19 patients) or without (4 patients) CT/MRI evidence of tumour were studied. MEASUREMENTS: Plasma PRL levels and serum bromocriptine levels were assessed during a follow-up of 42 days. MRI and/or CT were evaluated before and 28 days after the beginning of the study. RESULTS: All patients had significant reductions of PRL levels from 1000 h and 1100 h of day 1 to 2000 h of day 35. Normoprolactinaemia was shown in eight patients of Group A and six of Group B on days 1-28. Normal PRL levels were still present in five patients of Group A and in one patient of Group B on day 35; only three patients of Group A had normoprolactinaemia on day 42. A significantly greater decrease in Group A in comparison with Group B was shown at 1200 h on day 1 and at all times as a percentage decrease from basal levels. Significantly higher levels of bromocriptine were shown in Group A at all timepoints studied. No difference was shown in tolerability and incidence of side-effects. CONCLUSION: Our data show that injectable bromocriptine more frequently induced a prolonged normoprolactinaemia than did the oral drug. Moreover, bromocriptine levels released during injectable bromocriptine were significantly higher than during oral bromocriptine. On the other hand no difference was shown in the tolerability of bromocriptine according to the route of administration.
Administration, Oral↗
Nationwide multicenter prospective study on the long-term effects of bromocriptine for Parkinson's disease. Final report of a ten-year follow-up.
A 10-year nationwide multicenter prospective study on the long-term efficacy of bromocriptine for Parkinson's disease is reported. Six patients remained on bromocriptine monotherapy for 10 years, while 22 patients achieved good disease control with bromocriptine plus levodopa (added during the course of the study). In the 6 patients on bromocriptine alone, the disease remained in Hoehn and Yahr stage I or II for 10 years. In the other 22 patients on bromocriptine plus levodopa therapy, disease progression was very slow for 7-8 years. None of the 6 patients remaining on bromocriptine monotherapy experienced adverse reactions like the wearing-off phenomenon, dyskinesia, or the on-off phenomenon. Among the 22 patients who started levodopa therapy during the course of the study, these adverse reactions to levodopa were infrequent (10, 3, and 3 patients, respectively). Thus, early introduction and long continuation of bromocriptine therapy with restricted concomitant use of levodopa may have led to very slow disease progression and the suppression of adverse reactions. Although the patients who could be maintained long-term on bromocriptine monotherapy might represent a population who have very slowly progressive disease, their adequate disease control and the low incidence of adverse reactions in the patients who later started concomitant levodopa suggest that the unwanted effects of levodopa may be reduced by early and sustained treatment with bromocriptine. Introduction of bromocriptine monotherapy at an early stage of Parkinson's disease or with restricted use of additional levodopa therapy to bromocriptine when necessary may be a useful strategy for achieving adequate and sustained disease control.
Aged↗
Suppression of basal and stimulated noradrenergic activities by the dopamine agonist bromocriptine in man.
This study was designed to determine the effects of dopaminergic receptor stimulation on basal and stimulated catecholamine release in man. Five normal white male volunteer subjects were studied in metabolic balance at constant 150-meq sodium, 60-meq potassium intake and then daily for 8 days on an isocaloric constant diet of 10 meq sodium and 60 meq potassium/day in each of two separate protocols. In one protocol, the subjects received the dopamine agonist bromocriptine for 14 days before and during the study; in the other protocol, placebo was substituted for bromocriptine. During normal sodium intake, bromocriptine suppressed supine plasma norepinephrine concentrations from 193 +/- 10 to 159 +/- 9 pg/ml (P = 0.01). Dietary sodium depletion increased supine plasma norepinephrine concentrations in subjects taking placebo from 193 +/- 10 to 229 +/- 10 pg/ml (P less than 0.001). Bromocriptine prevented the supine plasma norepinephrine response to sodium depletion. After discontinuation of bromocriptine treatment, supine plasma norepinephrine concentrations returned to placebo control values. Upright posture stimulated an increase in plasma norepinephrine concentrations from 193 +/- 10 to 419 +/- 30 pg/ml (P = 0.0001) during normal sodium intake, and bromocriptine suppressed this response from 419 +/- 30 to 286 +/- 29 pg/ml (P = 0.004). Dietary sodium depletion enhanced the plasma norepinephrine response to upright posture, and bromocriptine markedly suppressed this enhancement. After discontinuation of bromocriptine treatment, supine and upright plasma norepinephrine concentrations returned to placebo control values. Bromocriptine induced a parallel downward shift in the inverse hyperbolic relationship between the plasma norepinephrine concentration and urinary sodium excretion in erect subjects, and decreased overnight urinary norepinephrine excretion in supine subjects from 1.1 +/- 0.1 to 0.6 +/- 0.1 ng/h (P = 0.0002). No consistent effects of bromocriptine on plasma epinephrine or dopamine concentrations were observed. The results of this study strongly suggest an inhibitory action of dopamine receptor stimulation by bromocriptine on basal and stimulated norepinephrine output at noradrenergic nerve terminals in the central nervous system and/or the periphery.
Adult↗
Resistance to bromocriptine in prolactinomas.
Bromocriptine therapy normalizes PRL secretion in most, but not all, patients with prolactinomas. This study was undertaken to determine the mechanism(s) responsible for bromocriptine resistance in patients with a PRL-secreting macroadenomas (n = 5) or microadenomas (n = 3). Their mean basal plasma PRL value was 807 +/- 220 (+/- SE) micrograms/L before treatment, and their nadir mean value was 354 +/- 129 micrograms/L during chronic therapy with 15-30 mg bromocriptine daily; four of the eight patients had an increase in tumor size during therapy. In cultures of prolactinoma cells from patients normally responsive to bromocriptine therapy (n = 10), considered as controls, 10(-9) mol/L bromocriptine inhibited PRL release by 71 +/- 6% (+/- SE), and the half-inhibitory dose was 7 x 10(-11) mol/L. In contrast, in cultures of prolactinoma cells from five patients resistant to bromocriptine, PRL release was inhibited by only 3-42% at 10(-9) mol/L bromocriptine. This partial inhibition was reversed by a 100-fold excess of haloperidol. In contrast, the effects of other inhibitors of PRL release (10(-8) mol/L T3 and 10(-8) mol/L somatostatin) or of a stimulator (10(-8) mol/L angiotensin-II) on cells from resistant and normally responsive patients were similar. In cell membranes from five bromocriptine-responsive adenomas the density of dopaminergic binding sites, labeled by [3H] spiroperidol was 243 +/- 65 (+/- SE) fmol/mg protein. In adenomas from the eight patients resistant to bromocriptine therapy the density of [3H]spiroperidol-binding sites lower (145 +/- 31 fmol/mg protein). In adenomas from five resistant patients whose tumor had grown during therapy the density of binding sites was 25 +/- 3 fmol/mg protein, 10% of that in normally responsive patients. The effects of dopamine on adenylate cyclase activity also were different in the three groups of adenomas. Dopamine inhibited adenylate cyclase activity by 28.8 +/- 5.6% in five bromocriptine-responsive tumors and by 16.5 +/- 4.3% in adenomas from eight resistant patients. In contrast, in the five patients whose tumors grew during therapy dopamine paradoxically stimulated adenylate cyclase activity (+26.4 +/- 9.8%). There was a very good correlation between the density of dopaminergic binding sites and maximal inhibition of adenylate cyclase activity in bromocriptine-responsive prolactinoma patients (r = 0.90) and resistant patients who had no tumor growth during therapy (r = 0.94).(ABSTRACT TRUNCATED AT 400 WORDS)
17-Hydroxycorticosteroids↗
Bromocriptine: a novel approach to the treatment of type 2 diabetes.
OBJECTIVE: In vertebrates, body fat stores and insulin action are controlled by the temporal interaction of circadian neuroendocrine oscillations. Bromocriptine modulates neurotransmitter action in the brain and has been shown to improve glucose tolerance and insulin resistance in animal models of obesity and diabetes. We studied the effect of a quick-release bromocriptine formulation on glucose homeostasis and insulin sensitivity in obese type 2 diabetic subjects. RESEARCH DESIGN AND METHODS: There were 22 obese subjects with type 2 diabetes randomized to receive a quick-release formulation of bromocriptine (n = 15) or placebo (n = 7) in a 16-week double-blind study. Subjects were prescribed a weight-maintaining diet to exclude any effect of changes in body weight on the primary outcome measurements. Fasting plasma glucose concentration and HbA(1c) were measured at 2- to 4-week intervals during treatment. Body composition (underwater weighing), body fat distribution (magnetic resonance imaging), oral glucose tolerance (oral glucose tolerance test [OGTT]), insulin-mediated glucose disposal, and endogenous glucose production (2-step euglycemic insulin clamp, 40 and 160 mU x min(-1) x m(-2)) were measured before and after treatment. RESULTS: No changes in body weight or body composition occurred during the study in either placebo- or bromocriptine-treated subjects. Bromocriptine significantly reduced HbA(1c) (from 8.7 to 8.1%, P = 0.009) and fasting plasma glucose (from 190 to 172 mg/dl, P = 0.02) levels, whereas these variables increased during placebo treatment (from 8.5 to 9.1%, NS, and from 187 to 223 mg/dl, P = 0.02, respectively). The differences in HbA(1c) (delta = 1.2%, P = 0.01) and fasting glucose (delta = 54 mg/dl, P < 0.001) levels between the bromocriptine and placebo group at 16 weeks were highly significant. The mean plasma glucose concentration during OGTT was significantly reduced by bromocriptine (from 294 to 272 mg/dl, P = 0.005), whereas it increased in the placebo group. No change in glucose disposal occurred during the first step of the insulin clamp in either the bromocriptine- or placebo-treated group. During the second insulin clamp step, bromocriptine improved total glucose disposal from 6.8 to 8.4 mg x min(-1) kg(-1) fat-free mass (FFM) (P = 0.01) and nonoxidative glucose disposal from 3.3 to 4.3 mg min(-1) x kg(-1) FFM (P < 0.05), whereas both of these variables deteriorated significantly (P < or = 0.02) in the placebo group. CONCLUSIONS: Bromocriptine improves glycemic control and glucose tolerance in obese type 2 diabetic patients. Both reductions in fasting and postprandial plasma glucose levels appear to contribute to the improvement in glucose tolerance. The bromocriptine-induced improvement in glycemic control is associated with enhanced maximally stimulated insulin-mediated glucose disposal.
Abdomen↗
Bromocriptine for idiopathic oligo/asthenospermia.
BACKGROUND: Oligo-astheno-teratospermia (sperm of low concentration, reduced motility and increased abnormal morphology)of unknown cause is common and the need for treatment is felt by patients and doctors alike. As a result, a variety of empirical, non-specific treatments have been used in an attempt to improve semen characteristics and fertility. Whilst bromocriptine treatment for reducing prolactin levels in hyperprolactinaemic males (as in females), and, in the treatment of hypogonadotropic hypogonadism with hyperprolactinaemia, is beneficial, it has also been used for oligospermic men in the absence of any endocrinopathy. Prolactin may play a direct role in spermatogenesis and hormone production. It has also been claimed that in oligospermic men with normal gonadotrophins mean prolactin levels are higher and that hyperprolactinaemia is more common compared to fertile men. It has been proposed that the administration of bromocriptine under these circumstances might counteract a prolactin-induced block on the action of gonadotrophins on the testicles and, subsequently, that the reduction in prolactin levels might lead to an improvement in semen parameters and fertility. Although it is not licensed for use in male infertility, bromocriptine has been used for normogonadotrophic individuals with oligospermia and normal or sligthly elevated prolactin levels. This review considers the available evidence of the effect of bromocriptine therapy for normoprolactinaemic males with idiopathic oligo and/or asthenospermia. OBJECTIVES: The objective of this review was to assess the effects of bromocriptine on pregnancy rates among couples where subfertility has been attributed to idiopathic oligo- and/or asthenospermia. SEARCH STRATEGY: The Cochrane Subfertility Review Group specialised register of controlled trials was searched". SELECTION CRITERIA: Randomised trials of oral bromocriptine versus placebo or no treatment for couples with subfertility attributed to male factor. DATA COLLECTION AND ANALYSIS: Data were extracted by one reviewer and any disagreements were resolved by discussion with other reviewers. MAIN RESULTS: Four studies were included. The method of randomisation was not specified in any of the trials, which were all of crossover design. Compared with placebo, bromocriptine was associated with a significant reduction in serum prolactin levels (weighted mean difference -195.3 micro international units per litre, 95% confidence interval -276.5 to -114). No effects on sperm parameters were seen. There was also no effect on pregnancy rates observed between bromocriptine and placebo (0.70 odds ratio, 95% confidence interval 0.15 to 3.24). REVIEWER'S CONCLUSIONS: Bromocriptine appears to reduce prolactin levels in subfertile men with normal gonadotrophic function. There is not enough evidence to show that bromocriptine is helpful in improving fertility.
Bromocriptine↗
MK-801 disrupts the expression but not the development of bromocriptine sensitization: a state-dependency interpretation.
Repeated administration of the D2-type agonist bromocriptine (5.0 mg/kg, IP) caused progressive increases in the locomotor-stimulating effects of the drug in rats. Similar progressive increases in locomotor activity were observed in rats that received repeated coadministration of the NMDA receptor antagonist MK-801 (0.25 mg/kg, IP) plus bromocriptine. However, when rats previously treated with the combination of drugs received either bromocriptine or MK-801 alone, their levels of activity were comparable to those of rats having no prior experience with either drug. A second group of rats was sensitized to the effects of bromocriptine alone; no evidence of bromocriptine sensitization was seen when MK-801 was subsequently coadministered with bromocriptine. Thus, either the presence or the absence of MK-801 could--depending upon the conditions of previous drug treatment--block the expression of bromocriptine sensitization. When a third group of rats was sensitized to the combination of MK-801 plus bromocriptine and subsequently tested following 2 or 6 drug-free weeks, evidence of sensitized responses was still present. Thus, at the very least, blockade of NMDA receptors with MK-801 fails to compromise the cellular changes associated with sensitization to the repeated combination of MK-801 plus bromocriptine. Bromocriptine sensitization may prove to be unique in this regard, but the present findings suggest a control condition that should be carefully explored in studies of the effects of MK-801 on sensitization involving other stimulant drugs.
Animals↗
The determination of additive effect and intraocular pressure lowering effects of 0.05% bromocriptine and 0.25% timolol.
It has been confirmed that topically applied bromocriptine has a satisfactory intraocular pressure (IOP) lowering effect without serious ocular or systemic side effects. We compared the IOP lowering effects of 0.05% bromocriptine and 0.25% timolol and determined whether they have an additive effect in lowering IOP in normal volunteers. In a double-blind, randomised, prospective, single-dose study, we measured IOP in 24 ocular normotensive subjects before (baseline) and 2, 4 and 6 hours after topical instillation of the following drugs: timolol and bromocriptine alone (n: 14), timolol+bromocriptine, timolol+placebo, bromocriptine+placebo (n: 10). Both bromocriptine and timolol have a significant IOP lowering effect (p < 0.01) compared with the baseline value during the study period. There were no significant differences in IOP lowering effect between timolol and bromocriptine at 2 and 4 hours (p > 0.05), but timolol was more efficacious than bromocriptine at 6 hours (p < 0.05). An additive effect in lowering IOP was not found. Although timolol and bromocriptine have no additive effect in lowering IOP, topically applied bromocriptine may be used in the treatment of glaucoma.
Administration, Topical↗
Bromocriptine-induced locomotor stimulation in mice is modulated by dopamine D-1 receptors.
Mice were pretreated with reserpine plus alpha-methyl-p-tyrosine (10 mg/kg plus 200 mg/kg). One hour later they were administered the selective dopamine D-2 agonist bromocriptine or vehicle. Three hours after the bromocriptine, mice were challenged with the selective D-1 agonist SKF 38393, and locomotor activity was measured each 5 min for three hours. Neither bromocriptine nor SKF 38393 produced significant stimulation. The combination, however, produced a dose-dependent and coordinated increase in activity. If the bromocriptine was given only one hour before the SKF 38393 challenge (i.e., three hours after the reserpine plus alpha-methyl-p-tyrosine), no interaction was seen. In naive mice, when SKF 38393 and bromocriptine were administered together, the locomotor response to bromocriptine was quantitatively and qualitatively altered. The initial depressant response to bromocriptine was shortened, producing a more rapid onset of the stimulant response. In one experiment, the maximal activity induced by bromocriptine was increased by SKF 38393. The ability of SKF 38393 to alter the locomotor stimulant effect of bromocriptine in naive mice was blocked by their pretreatment with the selective D-1 antagonist, SCH 23390. The data indicate that the locomotor stimulant effects of bromocriptine are modulated by D1 receptors.
2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗