Bromocriptine mesylate

Bromocriptine mesylate is a potent dopamine D2/D3 receptor agonist, which binds D2 dopamine receptor with pKi of 8.05±0.2.

In Vitro:Bromocriptine stimulates [35S]-GTPγS binding at D2 dopamine receptor expressed in CHO cells with pEC50 of 8.15±0.05[1]. Bromocriptine also is a strong inhibitor of brain nitric oxide synthase. The ergot alkaloid Bromocriptine (BKT) is found to act as a strong inhibitor of purified neuronal nitric oxide synthase (NOS) (IC50=10±2 μM) whereas it is poorly active towards inducible macrophage NOS (IC50>100 μM) [2]. Bromocriptine is found to inhibit the activity of at least one human cytochrome P450 enzyme. Bromocriptine is a potent inhibitor of CYP3A4 with a calculated IC50 value for the interaction of 1.69 μM[3].

In Vivo:Bromocriptine mesylate (2 mg/kg, i.p.) is administered for 7 days in groups of mice in forced swimming test (FST) and tail suspension test (TST). Bromocriptine group shows significant anti-immobility action as compared to control. When Bromocriptine administered 30 min after the last dose of 7 days MPE treatment and subjected to FST, this dopaminergic agonist produces significant and dose dependent potentiation of anti-immobility action of MPE (200 mg/kg, p.o.) as compared to MPE treatment alone. Bromocriptine treatment group shows a significant reduction of immobility time as compared to control. Bromocriptine administration after 7 days pretreatment with MPE (100 and 200 mg/kg, p.o.) shows significant and dose dependent potentiation of anti-immobility action of MPE as compared to MPE treatment alone[4]. Intracisternal administration of Bromocriptine decreases significantly the static mechanical allodynia (SMA) score compared to that of sham (saline-injected rats) and its effect lasted for 30 min. Intraperitoneal administration of Bromocriptine induces a significant, dose dependent (0.1 mg and 1 mg/kg) decrease in pain scores in CCI-IoN group when compared to sham and its effect lasted for 6 h. The highest dose induces the highest score decrease (P<0.01). Bromocriptine effect lasts for 20 min. Intraperitoneal administration of Bromocriptine induces a significant dose dependent decrease in SMA score in CCI-IoN+6-OHDA lesioned group compared to that of sham. Its effect lasts for 6 h[5].

References:
[1]. Gardner B, et al. Agonist action at D2(long) dopamine receptors: ligand binding and functional assays. Br J Pharmacol. 1998 Jul;124(5):978-84. [2]. Renodon A, et al. Bromocriptine is a strong inhibitor of brain nitric oxide synthase: possible consequences for the origin of its therapeutic effects.FEBS Lett. 1997 Apr 7;406(1-2):33-6. [3]. Wynalda MA, et al. Assessment of potential interactions between dopamine receptor agonists and various human cytochrome P450 enzymes using a simple in vitro inhibition screen. Drug Metab Dispos. 1997 Oct;25(10):1211-4. [4]. Rana DG, et al. Dopamine mediated antidepressant effect of Mucuna pruriens seeds in various experimental models of depression. Ayu. 2014 Jan;35(1):90-7. [5]. Dieb W, et al. Nigrostriatal dopaminergic depletion increases static orofacial allodynia. J Headache Pain. 2016;17:11.

Effects of bromocriptine mesylate on homocysteine and high-sensitivity C-reactive protein levels in patients with type-2 diabetes mellitus.[Pubmed:27069561]

J Cardiovasc Thorac Res. 2016;8(1):8-12.

INTRODUCTION: Quick release bromocriptine (BROM-QR), currently approved for glycemic control, reduces the risk of cardiovascular events in adults with type-2 diabetes mellitus (T2DM). This study evaluates the effect of BROM-QR on homocysteine (HOMC) and high sensitive C-reactive protein (hs-CRP), the biochemical markers of coronary atherosclerosis/inflammation, in patients with uncontrolled T2DM. METHODS: In this non-randomized, before-and-after clinical trial, patients with uncontrolled T2DM on stable doses of two oral hypoglycemic agents received BROM-QR for 6 months. The change in serum concentrations of HOMC was the primary endpoint. Anthropometric measurements such as body mass index (BMI) and waist circumference were measured at the baseline and at the completion of treatment along with fasting plasma glucose (FPG), HbA1c, total cholesterol, triglyceride, creatinine and hs-CRP. Multivariate regression analysis was performed to identify factors associated with changes in the levels of HOMC. RESULTS: In 64 patients (46 completed 6 months of treatment), age was 55+/-7 years and the duration of T2DM was 8.0 +/- 4.4 years. On enrollment, mean HbA1c, FPG, hs-CRP and HOMC levels were 9.0+/- 1.3 percent, 184 +/- 42 mg/dL, 3.8+/- 3.4 mg/dl and 10.8 +/- 6.2 micromole/L; respectively. Mean decrease of 0.7 +/- 1.1 percent for HbA1c (P = 0.001) and 22 +/- 44 mg/dL for FPG was observed (P = 0.002). HOMC levels decreased to 8.5 +/- 5.2 micromole/L (P = 0.011) while hs-CRP levels remained unchanged at 3.7 +/- 2.9 mg/dL (P = 0.835). CONCLUSION: While HOMC and HbA1c levels decreased significantly after 6 months of treatment with BROM-QR in patients with T2DM, serum levels of hs-CRP, total cholesterol and triglyceride did not significantly change.

Bromocriptine Mesylate Attenuates Amyotrophic Lateral Sclerosis: A Phase 2a, Randomized, Double-Blind, Placebo-Controlled Research in Japanese Patients.[Pubmed:26910108]

PLoS One. 2016 Feb 24;11(2):e0149509.

OBJECTIVE: Bromocriptine mesylate (BRC), a dopamine D2 receptor agonist has been shown to confer neuroprotection, sustained motor function and slowed disease progression in mouse models of amyotrophic lateral sclerosis (ALS) Here we report a first in human trial in ALS. DESIGN: A multicenter, Riluzole add-on, randomized, double-blind, placebo controlled 102-week extension BRC clinical trial. METHODS: The trial was conducted between January 2009 and March 2012 on 36 Japanese ALS patients. A 12-week treatment with Riluzole observational period was followed by combined treatment (Riluzole + BRC; n = 29 or Riluzole + placebo; n = 7). The dosing commenced at 1.25 mg/day increasing in steps at two weeks intervals to a maximum of 15 mg/day. The efficacy of BRC was evaluated by comparing BRC and placebo groups upon completion of stepwise dosing at 14 weeks 2 points (1st endpoint) and upon completion or discontinuation of the study (2nd endpoint) of the dosing. RESULTS: Statistics analyses revealed a marginal BRC treatment efficacy with P<==20%to placebo by 1st and 2nd endpoint analysis. In the 1st endpoint analysis, BRC group was significantly effective on the scores of ALSAQ40-communicaton (P = 1.2%), eating and drinking (P = 2.2%), ALSFRS-R total (P = 17.6%), grip strength (P = 19.8%) compared to the placebo group. In the 2nd endpoint analysis, differences between the scores of Limb Norris Scale (P = 18.3%), ALSAQ40-communication (P = 11.9%), eating and drinking (P = 13.6%), and neck forward-bent test (P = 15.4%) of BRC group were detected between the two groups. There was no significant difference between the treatment groups for adverse events or serious drug reactions incidence. CONCLUSIONS: BRC sustains motoneuronal function at least in part through BRC treatment. Further analysis involving a Phase 2b or 3 clinical trial is required but BRC currently shows promise for ALS treatment. TRIAL REGISTRATION: UMIN Clinical Trials UMIN000008527.

Dopamine receptor pharmacology.[Pubmed:7940991]

Trends Pharmacol Sci. 1994 Jul;15(7):264-70.

Dopamine receptors are the primary targets in the treatment of schizophrenia, Parkinson's disease, and Huntington's chorea, and are discussed in this review by Philip Seeman and Hubert Van Tol. Improved therapy may be obtained by drugs that selectively target a particular subtype of dopamine receptor. Most antipsychotic drugs block D2 receptors in direct correlation to clinical potency, except clozapine, which prefers D4 receptors. D1 and D2 receptors can enhance each other's actions, possibly through subunits of the G proteins. In schizophrenia, the D2 and D3 receptor density is elevated by 10%, while the D4 receptor density is elevated by 600%. Therefore, D4 receptors may be a target for future antipsychotic drugs. While antipsychotics originally helped to discover dopamine receptors, the five cloned dopamine receptors are now facilitating the discovery of selective antipsychotic and antiparkinson drugs.

Bromocriptine produces decreases in cocaine self-administration in the rat.[Pubmed:2317262]

Neuropsychopharmacology. 1990 Apr;3(2):101-8.

The effect of bromocriptine pretreatment was investigated in rats trained to self-administer intravenous cocaine on a fixed-ratio (FR) 5 schedule of reinforcement. Bromocriptine, a dopamine agonist, produced dose-dependent decreases in cocaine self-administration at doses of 4.0, 8.0, 16.0, and 32.0 mg/kg. In a separate group of rats trained on a DRL 20-second schedule of food reinforcement used to produce the same overall rate of responding for food as for cocaine on the FR 5 schedule, bromocriptine did not produce a significant effect on overall response rate, number of reinforced responses, or percent of responses that were reinforced. Given that bromocriptine produced a specific effect on cocaine-maintained responding, the present results suggest that bromocriptine is interacting with the neurochemical substrate mediating the reinforcing effects of cocaine. The potential effectiveness of bromocriptine as a pharmacotherapy for cocaine dependence is discussed.

Bromocriptine in Parkinson disease.[Pubmed:3901046]

Pharmacol Rev. 1985 Jun;37(2):217-27.

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)

The effects of chronic bromocriptine treatment on behaviour and dopamine receptor binding in the rat striatum.[Pubmed:3936723]

Eur J Pharmacol. 1985 Nov 26;118(1-2):147-54.

Agonist-induced rotation and striatal binding of [3H]spiperone ([3H]SPIP) were assessed in rats with unilateral lesions of the substantia nigra during and after a period of chronic bromocriptine administration. Agonist-induced rotation significantly increased over a three week period of daily administration of bromocriptine (10 mg/kg i.p.); control animals were tested for agonist-induced rotation at one week intervals, which remained constant. Rotation was increased by chronic bromocriptine administration in response to either of two DA agonists, apomorphine (APO) and bromocriptine, suggesting that increased agonist sensitivity did not reflect a reduction in the metabolism of bromocriptine. Striatal binding of the dopamine D2 radioligand, [3H]SPIP, was significantly increased in the denervated striata of nigra-lesioned rats. Chronic bromocriptine administration decreased binding in denervated striata to levels not significantly different from control values. [3H]SPIP binding in intact striata was significantly reduced by bromocriptine to below control values. Differences in receptor levels reflected changes in the maximum density of binding sites with no change in affinities. Paradoxical behavioural hypersensitivity developing during chronic bromocriptine levels is not apparently mediated by changes in striatal D2 binding sites.