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Bromocriptine and cocaine cue reactivity in cocaine-dependent patients.

Based on previous reports that bromocriptine, a postsynaptic dopamine agonist, reduced cocaine craving and prevented relapse in cocaine-dependent subjects, effects of the drug were evaluated in 20 cocaine-dependent males in an inpatient drug rehabilitation programme. The subjective and physiologic effects of exposure to both cocaine-associated and neutral stimuli, presented using videotapes, were measured at one-week intervals. Between laboratory sessions subjects received either bromocriptine (1.25 mg bid) or a matched placebo, administered in double-blind fashion. Compared with the neutral videotape, the cocaine videotape elicited both a greater desire to use cocaine and more symptoms associated with cocaine self-administration. These results support an appetitive conditioning model of cocaine effects. Bromocriptine, however, had no effect on the cocaine-cue-associated reactivity, which declined over the 1-week interval in both treatment groups. Methodological differences among studies that have examined the effects of bromocriptine in cocaine-dependent subjects may explain the variable findings observed.

Adolescent↗

A comparison of the ocular hypotensive effect of 0.025% bromocriptine and 0.25% timolol eye drops in normal human volunteers.

1. The ocular hypotensive effect of 0.025% bromocriptine and 0.25% timolol eye drops was compared in nine healthy human volunteers, using non-contact tonometry. 2. Considering all post-dosing measurements compared with placebo and including the baseline values as continuous independent variables, using multiple linear regression analysis, both bromocriptine and timolol had a significant ocular hypotensive effect (P less than 0.0001) in the treated eye with a significant but lesser effect in the contralateral eye. 3. In the concentrations used, timolol was more efficacious than bromocriptine in lowering intraocular pressure (P less than 0.025). 4. Using other forms of vehicles for bromocriptine to improve efficacy and studying the ocular hypotensive effect of topical application of other dopamine-2-receptor agonists such as pergolide and lisuride was suggested.

Adult↗

Pituitary function in normoprolactinaemic infertile men receiving bromocriptine.

A double blind trial of bromocriptine 7.5 mg daily versus placebo was carried out in ten infertile men. Pretreatment basal plasma prolactin, thyroid stimulating hormone (TSH) testosterone and luteinizing hormone (LH) concentrations were normal, but plasma follicle-stimulating-hormone (FSH) was raised in four individuals. After 4 months treatment with bromocriptine a significant fall in plasma prolactin was observed (P less than 0.01), both under basal conditions and following thyroid stimulating hormone releasing hormone (TRH). Basal plasma gonadotrophin, testosterone and thyroid stimulating hormone (TSH) concentrations did not alter. No change in sperm density, volume or motility was noted. However an apparent fall in the peak plasma LH (but not FSH) response to gonadotrophin releasing hormone (LHRH) was observed in patients receiving bromocriptine. This reduction in plasma LH responsiveness was significant when compared with the baseline response (P less than 0.05) but failed to reach significance when compared with the placebo response. It is concluded that prolonged bromocriptine therapy in normoprolactinaemic men does not suppress FSH secretion, and any reduction in plasma LH responsiveness to LHRH is not accompanied by a significant fall in plasma testosterone.

Adult↗

Changes in circulating somatomedin-C levels in bromocriptine-treated acromegaly.

To determine whether the improvement in clinical status of patients with active acromegaly correlates with a reduction of circulating somatomedin-C, serum immunoreactive somatomedin-C was measured in twenty-seven patients before and during bromocriptine therapy. The patients were assessed using a clinical and metabolic score which included both subjective criteria of improved sweating and facial features, and objective criteria of a reduction in ring circumference and the area under the glucose tolerance curve. Using this, together with the change in GH levels before and during bromocriptine therapy, the patients could be divided into three groups. In one group, there was no clinical improvement, a less than 30% decline in somatomedin-C, and in four of six patients no significant decline in GH. In both the other groups there was clinical improvement and a greater than 30% decrease in somatomedin-C. In one of these two groups, however GH did not decline, while in the other it was reduced significantly. The results suggest that during bromocriptine treatment of acromegaly, serum somatomedin-C concentrations correlate better with clinical status that does serum GH. Since some patients have no significant fall in GH but show both clinical improvement and a reduction in somatomedin-C, it seems likely that in some patients bromocriptine may improve acromegaly by a mechanism other than a simple decrease in total immunoreactive GH secretion.

Acromegaly↗

The effects of prolonged bromocriptine administration on PRL secretion GH and glycaemic control in stable insulin-dependent diabetes mellitus.

Plasma glucose, PRL and GH concentrations were measured at hourly intervals over a 24-h period before and after oral bromocriptine administration in a dosage of 7.5 mg/day for 6 weeks in nine stable insulin-dependent diabetic men. The pattern of PRL secretion was noted to be normal in stable diabetes (with a mean concentration of 205 mu/l +/- 23 SEM) and was effectively suppressed by bromocriptine (to a mean concentration of 51 mu/l +/- 2 SEM). This suppression of PRL secretion caused no major alteration in glycaemic control, mean plasma glucose for the group was 10.6 mmol/l +/- 3.4 SD before and 9.6 mmol/l +/- 3.1 SD after bromocriptine administration. Bromocriptine produced no change in plasma glucose or GH profiles. It is concluded that PRL secretion is not a major influence on carbohydrate metabolism in stable diabetics.

Adult↗

Dramatic and rapid shrinkage of a massive invasive prolactinoma with bromocriptine: a case report.

Shrinkage of a massive, highly invasive, longstanding (probably 40 years) prolactin-secreting pituitary tumour is described in which tumour volume was reduced by 40% 8 d after beginning bromocriptine treatment. After 4 months of treatment the tumour was only 11% of the pretreatment volume and by 8 months it was further reduced in size being confined to the pituitary fossa, which was partially empty. Reduction in tumour volume was accompanied by a gradual reduction in serum prolactin concentrations to normal values at 4 months. Between 4 and 18 months serum prolactin has remained normal on 5 mg of bromocriptine daily. Visual function improved within 48 h of starting bromocriptine and was almost normal by 6 d. CSF rhinorrhoea developed as the tumour shrank and was successfully managed with the relatively minor procedure of a diversionary lumbo-peritoneal shunt. Bromocriptine should be considered as the initial treatment of choice for massive invasive prolactinomas because of the significant risk of morbidity from neurosurgical treatment.

Bromocriptine↗

Bromocriptine treatment of women with clomiphene-resistant polycystic ovary syndrome.

Twenty-three patients with polycystic ovary syndrome and anovulatory infertility have been treated with bromocriptine. All had previously failed to respond to clomiphene. Twenty had normal serum prolactin concentrations and, of these, four (20%) developed regular ovulatory cycles. All three women with moderate hyperprolactinaemia ovulated regularly on bromocriptine so that, overall, seven of 23(30%) responded, which was a significantly higher proportion than that observed during a control period of no treatment. A further eight women ovulated at least once during the study period but these occasional ovulations were no more common during bromocriptine than with either clomiphene or no treatment. No suppression of LH was noted except during the luteal phase of ovulatory cycles and there was no change in the pattern of pulsatile release of LH. Testosterone and androstenedione concentrations remained elevated and unchanged. We conclude that bromocriptine may be expected to induce ovulation in hyperprolactinaemic women with polycystic ovary syndrome but that there is no clear indication for its use in clomiphene-resistant patients with normal serum prolactin concentrations.

Adult↗

Factors in the outcome of transsphenoidal surgery for prolactinoma and non-functioning pituitary tumour, including pre-operative bromocriptine therapy.

Radical transsphenoidal surgery in 58 patients with large non-functioning pituitary tumours relieved pressure symptoms and disconnection hyperprolactinaemia without loss of pituitary function, and verified the diagnosis. Pre-operative bromocriptine did not cause any shrinkage of non-functioning tumours (n = 8), even up to 48 weeks. Thirty-two patients not given postoperative radiotherapy are being followed-up, and although two show minor CT scan evidence of tumour regrowth, for the others the delay in radiotherapy is enabling reproduction where required. In 20 patients with non-invasive macroprolactinomas radical surgery caused no loss of pituitary function but cured eight, of whom one has relapsed; none of eight invasive prolactinomas was cured by surgery. Pre-operative bromocriptine caused marked size reduction in seven of seven macroprolactinomas, but if continued beyond 6 weeks induced tumour fibrosis and uneven shrinkage which made surgery dangerous and unproductive. Selective transsphenoidal surgery relieved hyperprolactinaemia in 70% of patients with meso- (n = 15) or microprolactinoma (n = 24) usually without loss of pituitary function: the relapse rate was 1 per 88 patient years of follow-up. Invasive prolactinomas, and macroprolactinomas showing uneven shrinkage with a short (up to 4 weeks) course of bromocriptine should have radiotherapy rather than surgery, while the patients most suited to surgery are those with mesoprolactinomas, or some macroprolactinomas with compact intrasellar shrinkage after short-term bromocriptine. Microprolactinomas generally did not benefit from surgery as compared to conservative therapy. In none of the tumour groups were the surgical findings an accurate predictor of postoperative pituitary function.

Adenoma↗

Effect of CV 205-502 in hyperprolactinaemic patients intolerant of bromocriptine.

CV 205-502 (Sandoz), an octahydrobenzol [g]quinoline, is a long-acting dopamine agonist which inhibits prolactin secretion. We conducted a phase 2 clinical study in 10 hyperprolactinaemic women (nine of whom were previously intolerant of bromocriptine) in order to determine (1) the dose at which CV 205-502 exerted its prolactin-lowering effect; (2) the nature of adverse reactions associated with long-term therapy; and (3) whether patients who were intolerant of bromocriptine could tolerate CV 205-502. At first patients were randomized to take initial doses of either 0.02 or 0.05 mg daily at bedtime. Thereafter these doses of medication were gradually increased either to the point of normalizing serum prolactin (to 0.70 IU/l or 20 ng/ml) or to a maximum dose of 0.14 mg daily. The lower initial dose was ineffective and had to be increased in all patients. The higher initial dose (0.05 mg) normalized prolactin in three of five women within 24 h. During chronic administration of the final dose of CV 205-502 (mean 0.09 mg a day), serum prolactin decreased from a mean level of 9.19 +/- 4.9 (SEM) IU/l to a mean level of 1.55 +/- 0.49 IU/l (n = 10 patients). Prolactin was normalized in five patients. Two patients, one of whom had been previously unresponsive to bromocriptine, and another unresponsive to pergolide with regard to prolactin inhibition, were also unresponsive to CV 205-502. Nausea, the side-effect responsible for these patients' previous intolerance of bromocriptine, occurred in six of 10 patients taking CV 205-502 but was much less disabling and did not cause any of the patients to stop this medication. Only one patient taking CV 205-502 discontinued treatment because of adverse effects (light-headedness).

Adult↗

Efficacy of a new long-acting injectable form of bromocriptine in hyperprolactinaemic patients.

OBJECTIVE: The objective of this study was to assess the relationship of different doses of a long-acting bromocriptine preparation (Parlodel LAR) to the degree and duration of PRL suppression. We also measured circulating bromocriptine levels and altered tolerability of the drug. DESIGN: A double-blind randomized study of three different doses 25, 50 and 100 mg of Parlodel LAR. PATIENTS: Twenty-one female patients (seven patients/dose) with both tumoral and non-tumoral hyperprolactinaemia. MEASUREMENTS: After a single injection of Parlodel LAR 25, 50 or 100 mg, serum PRL and plasma bromocriptine levels were assessed during a follow-up of 60 days together with changes in clinical symptoms and signs of hyperprolactinaemia. RESULTS: Serum PRL levels normalized in 19 of 21 patients. The suppression of PRL secretion lasted 28 days in four of seven patients treated with either 25 or 50 mg Parlodel LAR and in five of seven patients who received Parlodel LAR 100 mg. In five of seven patients treated with the 100 mg dose, serum PRL levels were still within the normal range on day 60. Plasma bromocriptine levels remained therapeutically active for 28 days in all three groups. On day 60 they were within the therapeutic range only in the 100 mg group. Clinical data show a rapid disappearance of symptoms and signs of hyperprolactinaemia. Adverse events were mostly mild and transient. CONCLUSIONS: These data support the excellent efficacy and good tolerability of Parlodel LAR in patients with hyperprolactinaemia.

Adult↗

DNA synthesis by pituitary tumours, with reference to plasma hormone levels and to effects of bromocriptine.

BACKGROUND AND OBJECTIVE: In parathyroid adenomas and experimentally in the normal rat pituitary gland, cell replication and secretory activity were previously shown to be correlated. A similar relationship has now been investigated in human pituitary tumours, since this could have relevance to their growth and aetiology. The effect of bromocriptine on the two variables was examined. PATIENTS: Data were derived from 50 patients undergoing operation for pituitary tumour, including 15 with acromegaly and 11 with prolactinoma. MEASUREMENTS: Preoperative plasma levels of GH, PRL and gonadotrophins were measured by radioimmunoassay. DNA synthesis, an index of cell replication, was measured in vitro in freshly removed tumour tissue. Nuclear diameter of tumour cells was measured in histological sections and immunostaining for relevant hormones was carried out on tumour tissue. RESULTS: DNA synthesis was correlated (P < 0.05) with plasma hormone levels in cases of prolactinoma, both treated and not treated with bromocriptine, and in a group of putative FSH secreting tumours from male patients. The correlation was not significant in cases of acromegaly. Comparisons of mean values between groups treated and not treated with bromocriptine showed significantly lower DNA synthesis and mean nuclear diameter in prolactinomas under treatment but not in GH secreting tumours. CONCLUSIONS: The findings in prolactinomas suggest a close relationship between secretion and tumour cell replication dependent on still undefined agents, but including dopamine, affecting both variables, and isoforms of PRL, which may stimulate or inhibit replication of PRL secreting cells. The basis of the relationship in FSH secreting tumours is unknown. The relationship was absent in the non-homogeneous group of GH secreting tumours. When secretion and growth are correlated, the secretory process may be the site of the primary abnormality in the tumour cell. Evidence that bromocriptine inhibits tumour cell replication was obtained for prolactinomas but not for GH secreting tumours.

Acromegaly↗

Bioactive GH-like immunoglobulins G in active acromegaly: response to long-term treatment with bromocriptine.

In acromegaly, certain forms of circulating immunoreactive hGH are not true GH but IgGs which possess GH biological activity (bioactive GH-like IgGs). In this study, we tested the effect of bromocriptine on circulating bioactive GH-like IgGs in an acromegalic woman. Increasing doses of oral bromocriptine (2.5, 5.0 and 7.5 mg/day) were administered (for 2, 8 and 6 months respectively). TRH tests were performed before treatment and at the end of treatment with each dose. The patient was without detectable pituitary or extra-pituitary tumour by magnetic resonance imaging. Her serum contained bioactive GH-like IgGs equivalent to 240 mU/l of hGH and elevated insulin-like growth factor I (IGF-I; 9500 U/l). Basal hGH was 12.8 mU/l and increased to 220 mU/l 15 min after TRH (200 micrograms, i.v.). In addition, in the basal samples of each test we measured total IgGs (radial immunodiffusion), bioactive GH-like IgGs (isolated by Sephadex and protein A affinity chromatography and assayed using the Nb2 cell assay) and IGF-I(RIA). Bromocriptine treatment gradually reduced serum levels of bioactive GH-like IgGs and IGF-I, with significant falls observed first at 10 months of treatment. Bioactive GH-like IgGs were 240, 240, 36.0 and < 0.124 mU/l and IGF-I levels were 9500, 8700, 4000 and 3100 U/l at 0, 2, 10 and 16 months of treatment, respectively. In contrast, IR-hGH response to TRH decreased after 2 months of treatment to 89 mU/l and to 49.2 mU/l at the end of the study while basal IR-hGH remained between 13 and 8.4 mU/l. Basal PRL fell to almost undetectable levels. Bromocriptine treatment decreased the GH response to TRH and the serum concentration of bioactive GH-like IgGs and IGF-I. The striking similarity between the pattern of decrease of serum bioactive GH-like IgGs and IGF-I supports the presence of an immuno component in our patient's acromegaly.

Acromegaly↗

The value of plasma prolactin levels in the prediction of the responsiveness of growth hormone secretion to bromocriptine and TRH in acromegaly.

UNLABELLED: The mechanism of the inhibition of growth hormone secretion in response to bromocriptine and the ability of thyrotropin releasing hormone to stimulate growth secretion in acromegaly is unknown. In the present study the relationship between the plasma prolactin concentration of untreated acromegalic patients and the reaction of growth hormone to thyrotropin releasing hormone and bromocriptine was investigated. Plasma prolactin levels were elevated in thirty-three (42%) of seventy-nine untreated acromegalic patients. Seventeen patients had mildly elevated prolactin levels, but in sixteen the plasma prolactin concentration was higher than 30 ng/ml. Bromocriptine (2.5 mg) inhibited growth hormone secretion by more than 50% in 22% of the normoprolactinaemic, in 53% of the mild hyperprolactinaemic and in 88% of the patients with a prolactin level above 30 ng/ml (P less than 0.01 v. normoprolactinaemic; P less than 0.01 v. mildly elevated prolactin levels). An increase of growth hormone secretion by more than 100% of the basal value in response to thyrotropin releasing hormone was observed in 44% of the normoprolactinaemic, in 59% of the mildly hyperprolactinaemic and in 75% of the clearly hyperprolactinaemic patients; (P less than 0.01 v. normo- and mildly hyperprolactinaemic patients). CONCLUSION: An increased plasma prolactin concentration in patients with acromegaly is accompanied in most patients by a higher sensitivity of growth hormone secretion to bromocriptine.

Acromegaly↗

High affinity of ergopeptides for cytochromes P450 3A. Importance of their peptide moiety for P450 recognition and hydroxylation of bromocriptine.

The interaction between rat and human liver cytochromes P450 with a series of lysergic acid derivatives and ergopeptide alkaloids was studied by difference visible spectroscopy. Ergopeptides, like bromocriptine, ergocryptine and dihydroergotamine, strongly interacted with rat liver microsomes with the appearance of a difference spectrum which is characteristic of their binding to a protein site close to the heme. The intensity of this spectrum was clearly dependent on the amounts of P450s 3A in the microsomes and was at its maximum in dexamethasone-treated rat microsomes. All the ergopeptides studied exhibited a high affinity for rat P450s 3A (Ks around 1 microM), although lysergic acid derivatives not bearing the tripeptide moiety failed to give significant interactions with these P450s. A cyclic azatripeptide exhibiting a structure very similar to that of the tripeptide moiety of ergopeptides also interacted with P450s 3A with appearance of an intense type I difference spectrum. Very similar results were observed with two allelic forms of human liver P450 3A4, P450 NF25 and P450 hPCN1, produced in yeast. In both cases all the ergopeptides studied showed high affinities for the P450s (Ks 0.6-2.2 microM) and an intense shift from the low-spin to the high-spin state upon substrate binding (60-100% spin shift). Lysergic acid derivatives not bearing the tripeptide group of ergopeptides also completely failed to interact with P450s 3A4. Liver microsomes from rats pretreated with dexamethasone, a specific inducer of P450 3A, were found to be particularly active for the hydroxylation of bromocriptine, which occurs at the level of its tripeptide moiety. Human liver microsomes as well as P450 NF25 and P450 hPCN1 also exhibited a high activity for bromocriptine hydroxylation at this level. These results show that ergopeptides exhibit a particularly high affinity for P450s of the 3A subfamily. The tripeptide moiety of ergopeptides is essential for their recognition by P450s 3A and binds at a site close to P450 heme, producing type-I difference spectra. Accordingly, at least one of the studied ergopeptides, bromocriptine, is hydroxylated by P450s 3A at the proline ring of the cyclopeptide moiety. As cyclosporine is known to be a good substrate of P450s 3A, these results suggest that P450s 3A may be especially prone in a general manner to recognize and oxidize peptides or pseudopeptides.

Animals↗

Effects of prolactin and bromocriptine on physiological status of testis of the musk shrew (Suncus murinus L.).

This investigation was undertaken to study the effects of prolactin and bromocriptine on the testis of the musk shrew. None of these treatments had any effect on the weight of testis or on the accessory sex organs. Treatment of prolactin or bromocriptine failed to induce any change in esterified and free cholesterol content of the testis. No significant alterations were also recorded in the levels of macromolecules and in the levels of enzymes of the testis and the prostate gland. On the other hand, bromocriptine treatment resulted in an increase in the activity of Mg2+-ATPase and phospholipid:DNA ratio of the testis with a concomitant decrease in its DNA content. The absence of any change in the content of fructose in the ampullary gland, in the activity of beta-glucuronidase of the kidney, in cholesterol content of the testis, in diameters of seminiferous tubule and Leydig cell nucleus, in activities of acid phosphatase and beta-glucuronidase of the testis and in the weight of accessory sex organs of prolactin and bromocriptine treated musk shrews suggests that prolactin does not play a significant role in regulating the testicular function of the musk shrew.

Acid Phosphatase↗

Management of extra-sellar pituitary tumours with bromocriptine: comparison of prolactin secreting and non-functioning tumours using half-field visual evoked potentials and computerised tomography.

To determine whether prolactin secreting and non-functioning pituitary tumours respond differently in terms of shrinkage to bromocriptine, we prospectively studied ten consecutive patients (five with prolactinomas and five with non-functioning tumours) complicated by extra-sellar extensions. No patient had received prior radiotherapy or bromocriptine and the mean dose and duration of bromocriptine treatment were identical in the two groups of patients. Objective evidence of tumour shrinkage was provided by serial half-field visual evoked potentials (VEPs) and computerised tomography (CT). All five prolactinomas were shown to shrink as assessed by improvement in VEP and four of the five as assessed by CT. In contrast, only one of the five patients with non-functioning tumours showed any improvement in VEP or CT. Macroprolactinomas frequently shrink rapidly when treated with bromocriptine, whereas non-functioning tumours seldom show such a dramatic response.

Adult↗

Agentic extraversion modulates the cardiovascular effects of the dopamine D2 agonist bromocriptine.

A recent psychobiological theory postulates a dopaminergic basis for the agency facet of extraversion, leading to the prediction that this personality trait modulates the psychophysiological effects of dopaminergic drugs. A single dose of the dopamine D2 receptor agonist bromocriptine reduces blood pressure in healthy volunteers. However, it is currently unknown whether this hypotensive effect of bromocriptine is modulated by agentic extraversion. Therefore, we measured resting cardiovascular activation in groups of healthy male volunteers either high or low in agentic extraversion, either under bromocriptine (1.25 mg) or placebo. Focusing the analyses on activation components derived from 18 cardiovascular variables, we found that bromocriptine reduces alpha-adrenergic activation in the sample as a whole, whereas the effects on beta-adrenergic and cholinergic activation are modulated by agentic extraversion.

Adolescent↗

Effect of bromocriptine on the premenstrual syndrome. A double-blind clinical trial.

Twenty-one patients suffering from the premenstrual syndrome were each studied during three menstrual cycles. After a control cycle, bromocriptine and placebo were given during the luteal phase of the cycle in a random double-blind cross-over manner, each patient serving as her own control. The dosage of bromocriptine was 2-5 mg twice daily. Serum prolactin levels were found to equal during the follicular and luteal phases, except when reduced by bromocriptine. Serum progesterone and oestradiol-17-beta were within normal ranges, and did not change during treatment. Medication considerably improved all the premenstrual symptoms, but mastodynia was the only one where bromocriptine was significantly better than the placebo.

Adolescent↗