Bromocriptine

Selective Agonism at D2 Dopamine Receptors

This compound is recognized as a potent agonist, particularly at the dopamine D2 receptor subtype. drugbank.comnih.govmedchemexpress.commuseonaturalistico.it This agonistic activity is considered a primary mechanism for its clinical effects, such as inhibiting prolactin secretion and improving motor function in Parkinson's disease. drugbank.comnih.govfda.gov Studies have shown that this compound binds to the D2 receptor with high affinity. medchemexpress.com It activates both isoforms of the D2 receptor, D2L and D2S, with varying potencies. rndsystems.comtocris.com

Interaction with D3 and D4 Receptors

This compound interacts with other dopamine receptor subtypes within the D2-like family, specifically D3 and D4 receptors. It is considered a selective D3 and D2 dopamine receptor agonist, with a higher affinity for D3 receptors compared to D4. museonaturalistico.itrndsystems.comtocris.com While its primary action is at D2 receptors, its activity at D3 and D4 receptors may also play a role in its therapeutic effects. museonaturalistico.it

Impact on Striatal Dopamine Activity

This compound significantly impacts dopaminergic activity in the striatum, a brain region crucial for motor control. drugbank.comnih.govmuseonaturalistico.it By directly stimulating striatal dopamine D2 receptors, this compound enhances dopaminergic signaling. nih.govmuseonaturalistico.itfda.gov This stimulation can lead to improvements in coordinated muscle activity, which is particularly relevant in conditions like Parkinson's disease characterized by a loss of dopaminergic neurons in the nigrostriatal pathway. drugbank.comnih.govfda.gov Studies in animal models have shown that this compound can restore locomotor activity. caymanchem.comfrontiersin.org The effect on striatal dopamine release can be complex and dose-dependent, with some studies suggesting that lower doses might increase dopamine release. frontiersin.org

Serotonin Receptor Modulations (e.g., 5-HT2B receptor partial agonism/antagonism)

This compound interacts with several serotonin receptor subtypes. It has been shown to have agonist activity at 5-HT1A, 5-HT1D, and 5-HT2A receptors. drugbank.comcaymanchem.com Its interaction with the 5-HT2B receptor has been a subject of research, with findings indicating it acts as a partial agonist at this receptor. drugbank.comwikipedia.orgendocrine-abstracts.orgnih.gov This partial agonism at 5-HT2B receptors is relevant due to the association of other ergot derivatives with cardiac valvulopathy mediated through this receptor. wikipedia.orgendocrine-abstracts.orgnih.gov this compound has also been reported to inhibit 5-HT2A receptors. nih.govdovepress.com

Adrenergic Receptor Interactions

This compound has been shown to interact with adrenergic receptors. Specifically, it exhibits antagonist activity at alpha-2A, alpha-2C, and alpha-2B adrenergic receptors. drugbank.com Additionally, some research indicates that this compound targets Alpha-1A, Alpha-1B, and Alpha-1D adrenergic receptors, although the precise nature of agonism or antagonism at these subtypes is not consistently specified across sources. drugbank.com The interaction with adrenergic receptors contributes to this compound's influence on sympathetic tone, particularly within the central nervous system.

Inhibition of Prolactin Exocytosis and Gene Expression in Anterior Pituitary Lactotrophic Cells

A well-established mechanism of this compound is its potent inhibition of prolactin release and synthesis in anterior pituitary lactotrophic cells. As a dopamine D2 receptor agonist, this compound binds to D2 receptors on these cells, which are coupled to Gi proteins. drugbank.commdpi.comnih.govfrontiersin.org This binding leads to the inhibition of adenylyl cyclase activity, resulting in decreased intracellular cyclic adenosine monophosphate (cAMP) levels. drugbank.comnih.gov Reduced cAMP contributes to the inhibition of prolactin gene expression. mdpi.comnih.govnih.gov Furthermore, D2 receptor activation by this compound modulates calcium signaling. It can block IP3-dependent release of Ca2+ from intracellular stores and inhibit calcium influx through voltage-gated calcium channels, leading to decreased intracellular calcium concentrations. drugbank.commdpi.comnih.gov These changes in calcium dynamics are crucial in inhibiting the exocytosis of prolactin-containing secretory granules. mdpi.comnih.gov Additionally, D2 receptor activation can block the phosphorylation of p42/p44 MAPK and decrease MAPK/ERK kinase phosphorylation, further contributing to the inhibition of prolactin synthesis and lactotroph proliferation. mdpi.comnih.gov

Modulation of Growth Hormone Release

This compound exhibits a complex and sometimes paradoxical effect on growth hormone (GH) release. In patients with acromegaly, a condition characterized by excessive GH secretion, this compound's dopaminergic effect can paradoxically suppress GH release through actions on tuberoinfundibular pathways. drugbank.comnih.gov This is in contrast to the typical stimulatory effect of dopamine on GH release in healthy individuals, which is mediated through D2 receptors. oup.comresearchgate.net Studies in obese premenopausal women have shown that short-term this compound treatment can enhance diurnal GH secretion, suggesting that its effect on GH release can vary depending on the physiological context, potentially by addressing impaired dopaminergic signaling associated with obesity. oup.comresearchgate.net

Influence on Hypothalamic Dopamine Levels and Sympathetic Tone

This compound influences hypothalamic dopamine levels and sympathetic outflow, particularly relevant in the context of metabolic regulation. It is believed to augment low hypothalamic dopamine levels and inhibit excessive sympathetic tone within the central nervous system. tandfonline.comnih.govdiabetesjournals.orgnih.govahajournals.orgkarger.com This action is thought to be mediated through effects on neuronal activities in hypothalamic nuclei, such as the ventromedial hypothalamus (VMH). diabetesjournals.orgkarger.comnih.gov Studies in animal models have demonstrated that this compound treatment can decrease abnormally elevated noradrenergic and serotonergic activity in the VMH, which are associated with insulin resistance and increased sympathetic drive. diabetesjournals.orgkarger.comnih.gov This modulation of hypothalamic activity and sympathetic tone is considered a key mechanism underlying this compound's metabolic benefits. nih.govdiabetesjournals.orgnih.gov

Research findings illustrating the effect on hypothalamic activity include studies in obese hamsters where this compound treatment promoted an immediate reduction of MHPG (a norepinephrine metabolite) release in the VMH. karger.com

Inhibition of Glutamate Release via GLT1 Glutamate Transporter Reversal

Beyond its dopaminergic effects, this compound has been found to inhibit the release of glutamate by reversing the operation of the glutamate transporter GLT1 (also known as EAAT2). jneurosci.orgnih.govbiologists.comnih.govwikipedia.org GLT1 is a primary transporter responsible for clearing extracellular glutamate from the synapse, thus preventing excitotoxicity. nih.gov Studies have shown that this compound dose-dependently inhibits d-[3H] aspartate release (used as a marker for glutamate release via transporter reversal) elicited by chemical anoxia or high KCl in cells expressing GLT1. nih.gov This inhibitory action on glutamate release through GLT1 reversal appears to be independent of dopamine D2 receptor antagonism. nih.gov

Effects on Metabolic Pathways (e.g., gluconeogenesis, lipogenesis)

This compound's influence on hypothalamic pathways and sympathetic tone translates into significant effects on peripheral metabolic pathways, including gluconeogenesis and lipogenesis. By reducing sympathetic outflow from the CNS, this compound can decrease hepatic glucose production (gluconeogenesis) and reduce adipose tissue lipolysis. tandfonline.comnih.govdiabetesjournals.orgnih.govkarger.comnih.govmdpi.com Animal studies have shown that this compound treatment reduces hepatic lipid levels and decreases the protein content of transcription factors and enzymes involved in lipogenesis and gluconeogenesis, such as SREBP1, mTORC, PPARγ, PGC1β, FOXO1, G6Pase, and PEPCK. tandfonline.comnih.govmdpi.com These effects contribute to improved insulin sensitivity and glucose homeostasis. tandfonline.comdiabetesjournals.orgnih.govmdpi.com

Data from animal models demonstrate reductions in key metabolic parameters following this compound treatment. For instance, studies in insulin-resistant animals have shown decreased basal and insulin-stimulated hepatic lipogenesis and hepatic triglyceride secretion. tandfonline.com

Table 1: Illustrative Metabolic Effects of this compound in Animal Models

These mechanistic insights highlight this compound's multifaceted actions, extending beyond its primary role as a dopamine D2 receptor agonist to include interactions with adrenergic systems and modulation of glutamate transport, collectively contributing to its diverse physiological effects.

Neuroprotective Mechanisms (e.g., modulation of oxidative stress, neuroinflammation, mitochondrial function)

Research indicates that this compound exerts neuroprotective effects through several converging mechanisms. These include the modulation of oxidative stress pathways, the attenuation of neuroinflammatory responses, and the preservation or enhancement of mitochondrial function.

Modulation of Oxidative Stress

Oxidative stress, characterized by an imbalance between reactive oxygen species (ROS) production and the cellular antioxidant defense system, plays a significant role in neuronal damage and death in various neurological disorders. Studies have demonstrated that this compound possesses antioxidant properties. museonaturalistico.it It has been shown to scavenge free radicals and reduce oxidative damage in the brain. museonaturalistico.it

One key mechanism involves the upregulation of the nuclear factor-E2-related factor-2 (Nrf2) pathway. Nrf2 is a transcription factor that regulates the expression of numerous antioxidant enzymes. This compound has been found to increase the expression and nuclear translocation of Nrf2, leading to the upregulation of downstream antioxidant enzymes such as NAD(P)H quinone oxidoreductase 1 (NQO1). mdpi.comnih.gov This activation of the Nrf2-NQO1 pathway contributes to the protection of cells against oxidative damage induced by agents like hydrogen peroxide (H₂O₂). nih.gov

Furthermore, this compound treatment has been shown to attenuate oxidative stress induced by neurotoxins such as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). nih.gov In studies using MPTP models, this compound blocked the formation of hydroxyl radicals (.OH), a highly reactive form of ROS. nih.gov It also reduced the MPTP-induced increase in the activity of antioxidant enzymes like catalase and superoxide dismutase (SOD) in the substantia nigra, suggesting a reduction in the oxidative burden. nih.gov In a rodent model of focal brain trauma, acute this compound treatment was associated with reduced lipid peroxidation, a marker of oxidative damage, in brain regions including the striatum and substantia nigra. nih.gov

Modulation of Neuroinflammation

Neuroinflammation, mediated by activated glial cells such as microglia and astrocytes, contributes to neuronal injury and disease progression in neurodegenerative disorders. While the direct mechanisms by which this compound modulates neuroinflammation are less extensively detailed in the provided search results compared to oxidative stress, the literature suggests that dopamine D₂ receptor agonists, including this compound, can play a role in suppressing neuroinflammatory responses. consensus.appconsensus.app

Dopamine D₂ agonists have been reported to suppress neuroinflammation, potentially through mechanisms involving astrocytic D₂ receptors and the modulation of signaling pathways such as the CRYAB/STAT3 pathway, as observed in models of ischemic stroke. consensus.app Further research into the specific pathways and cellular targets involved in this compound's anti-inflammatory effects is ongoing and could lead to the development of more potent neuroprotective strategies. museonaturalistico.it

Modulation of Mitochondrial Function

Research using induced pluripotent stem cells (iPSCs) and Drosophila models related to Parkinson's disease, particularly those with genetic mutations affecting mitochondrial clearance pathways like PINK1, has shown that this compound can improve impaired mitochondrial clearance and reduce apoptosis. nih.gov In PINK1-deficient Drosophila larvae, this compound treatment stimulated ATP production, indicating an enhancement of mitochondrial energy metabolism. nih.gov Among several tested dopamine D₂ receptor agonists, this compound was found to be the most effective in improving mitochondrial clearance and suppressing cell death in certain neuronal models. nih.gov

General mechanisms attributed to dopamine D₂ agonists in the context of neuroprotection include the restoration of mitochondrial function by reducing ROS production, maintaining mitochondrial membrane potential, and preserving the activity of mitochondrial complexes. consensus.appconsensus.app These effects collectively help to protect neurons from mitochondrial-mediated cell death pathways.

Absorption and Bioavailability

Following oral administration, this compound is rapidly absorbed from the gastrointestinal tract. mims.com Peak plasma concentrations are typically reached within approximately 1 to 3 hours for the conventional formulation and around 45 to 60 minutes for the rapid-release formulation when administered under fasting conditions. mims.comnih.govdrugs.com

The absolute bioavailability of this compound varies depending on the formulation. The conventional formulation has an absolute bioavailability of approximately 28%. drugs.com Due to substantial first-pass metabolism, only about 6% of the oral dose of the conventional formulation reaches systemic circulation unchanged. drugbank.commims.com The rapid-release formulation (Cycloset) demonstrates higher bioavailability, ranging from 65% to 95%. drugs.com Food intake does not significantly affect the systemic exposure of this compound. nih.gov

Here is a summary of absorption characteristics:

Distribution and Protein Binding

This compound exhibits high plasma protein binding, typically ranging from 90% to 96%. mims.comnih.govdrugs.com It primarily binds to serum albumin. mims.comnih.govdrugs.com While it shows preferential distribution into tissues, apparent accumulation of drug-related material has not been observed in the body. nih.gov

Metabolism by Cytochrome P450 Enzymes (e.g., CYP3A4)

This compound undergoes extensive first-pass biotransformation in the liver. nih.govdrugs.com It is primarily metabolized by cytochrome P450 (CYP) enzymes, specifically CYP3A4. drugbank.compdr.net Hydrolysis of the amide bond is a primary metabolic pathway, producing inactive and non-toxic metabolites, such as lysergic acid and a peptide fragment. drugbank.commims.com this compound has a high affinity for CYP3A4 and acts as an inhibitor of this enzyme. nih.gov Consequently, inhibitors or potent substrates for CYP3A4 may inhibit this compound clearance, leading to increased plasma levels. nih.gov

Elimination Pathways and Half-Life

The parent drug and its metabolites are almost completely excreted via the liver, primarily through biliary secretion into the feces. drugbank.comnih.govmims.comnih.gov Approximately 82% to 95% of the administered dose is eliminated via feces. mims.comwikipedia.orgbccancer.bc.ca Only a small portion, approximately 2% to 6%, is excreted via the urine. drugbank.commims.comwikipedia.orgnih.gov

The elimination half-life of this compound is biphasic. The terminal half-life of the conventional formulation is approximately 15 hours, while the elimination half-life of the rapid-release formulation is approximately 6 hours. drugs.com Other sources report a half-life for the parent drug between 2 and 8 hours, with metabolites having a longer half-life of 50 to 70 hours. nih.govaapharma.ca

Here is a summary of elimination characteristics:

Here is a summary of half-life information:

Receptor Occupancy Studies and Correlation with Efficacy

This compound is a dopamine receptor agonist with selective agonist activity on D2 dopamine receptors. nih.gov It also acts as a partial antagonist for D1 dopamine receptors. nih.gov this compound binds directly to striatal dopamine D2 receptors, stimulating locomotion and attenuating bradykinetic symptoms in conditions like Parkinson's disease. nih.gov This agonistic effect on D2 receptors in anterior pituitary lactotrophic cells inhibits prolactin exocytosis and gene expression, thereby reducing circulating prolactin levels and the formation of the 16-kDa prolactin isoform. nih.gov In acromegaly, this compound's dopaminergic effect can paradoxically block growth hormone release through tuberoinfundibular pathways, decreasing circulating growth hormone concentrations. nih.gov

Studies have indicated a dose relationship between pharmacological effects, such as hypothermia in animal models, and plasma this compound concentrations. nih.gov The parent drug is considered the pharmacologically active entity. nih.gov The clinical efficacy of ergot derivatives, including this compound, is generally linked to their binding to the D2 receptor subtype. cambridge.org While this compound monotherapy for Parkinson's disease has shown less efficacy and a higher rate of adverse effects compared to levodopa monotherapy, it resulted in fewer dyskinesias and motor fluctuations. nsj.org.sa Early use of combined this compound and levodopa has been suggested to decrease the incidence of wearing-off and dyskinesias and allows for a reduction in the levodopa dose. nsj.org.sa These effects were observed with this compound doses above 15 mg/day. nsj.org.sa

Dose-Response Relationships in Preclinical Models

Preclinical studies have investigated the dose-response relationships of this compound across various models, revealing its effects on different physiological processes. In the proestrus rat, this compound blocks the natural increase in prolactin secretion (the prolactin surge) in a dose-dependent manner. hres.ca

Studies in mice have explored the effect of this compound on morphine-induced analgesia, tolerance, and dependence. Small doses of this compound (0.04 and 0.08 mg/kg) did not affect the baseline tail flick latency but dose-dependently potentiated morphine analgesia. journalagent.com Pretreatment with a D₂ antagonist, sulpiride, blocked the effect of this compound and also antagonized morphine analgesia, suggesting a dopamine D₂ receptor-mediated interaction. journalagent.com Daily combined treatment of this compound with morphine suppressed the development of tolerance to morphine analgesia in a dose-dependent manner in mice. journalagent.com

In the context of type 2 diabetes, animal studies suggest that timed this compound administration within a specific window relative to the wake cycle can impact glucose and lipid metabolism. diabetesjournals.org In high-fat-fed canine models, a daily subcutaneous injection of this compound at 15 µg/kg, administered within 30 minutes of the beginning of the light cycle, improved glucose tolerance and disposal. nih.gov This dose was based on pharmacodynamic studies and the effective dose for inhibiting plasma prolactin in dogs. nih.gov

Preclinical evidence also suggests that this compound may have activity against chemoresistant prostate cancer (PCa). As a monotherapy, this compound treatment at 15 mg/kg, three times per week, via the intraperitoneal route significantly inhibited the skeletal growth of chemoresistant C4-2B-TaxR xenografts in athymic nude mice. researchgate.netnih.gov Previous studies indicated that this compound as a single agent showed weak to moderate cytotoxicities in various experimental cancer models, with IC₅₀ values typically ranging from 10 to > 60 µM. researchgate.net

The variability in dose response in humans can be partly attributed to the extreme variability in gastrointestinal tract absorption and extensive and individually variable first-pass metabolism of this compound. hres.ca

A summary of dose-response findings in selected preclinical models is presented in the table below:

Temporal Dynamics of Pharmacological Effects

The temporal dynamics of this compound's pharmacological effects have been examined in both preclinical and clinical settings, providing insights into its onset and duration of action. Following oral administration in humans, this compound is rapidly absorbed, with peak plasma concentrations typically reached within 1 to 3 hours. mims.commedicines.org.uk Some sources indicate peak plasma levels within 1-1.5 hours drugbank.com, while others suggest approximately 2.5 ± 2 hours nih.gov. The absorption half-life is approximately 0.3 hours. hres.cahres.ca

The onset of the prolactin-lowering effect typically occurs within 1 to 2 hours after oral ingestion, reaching its maximum effect within about 5 hours and lasting for 8 to 12 hours. medicines.org.ukdrugbank.com In studies involving oral administration of 5 mg this compound in humans, plasma levels of prolactin decreased rapidly, with maximal effect observed at 4 hours, and substantial inhibition still present at 24 hours after administration. ird.fr

In patients with acromegaly, a single oral dose of 2.5 mg of this compound can reduce growth hormone concentrations within 1 to 2 hours, and these decreased levels can persist for at least 4 to 5 hours. drugbank.com

The elimination of the parent drug from plasma is biphasic, with a terminal half-life reported to be around 15 hours mims.commedicines.org.uk or approximately 4.85 hours nih.gov. Other sources indicate an elimination half-life between 2 to 8 hours for the parent drug and 50 to 70 hours for metabolites after single oral doses. hres.cahres.ca this compound is extensively metabolized by the liver, with metabolites primarily excreted via the bile. hres.canih.govdrugbank.com Only a small percentage (approximately 2% to 6%) is eliminated via the kidney. nih.govhres.cahres.ca

Preclinical pharmacokinetic studies in wild-type CD1 mice administered 10 mg/kg this compound intravenously showed that most unmodified this compound was cleared from both brain (92.9% decrease) and plasma (88.2% decrease) by 60 minutes post-administration. biorxiv.org

The temporal profile of this compound's effects is closely linked to its pharmacokinetic properties, including absorption rate, metabolism, and elimination half-life. The rapid absorption contributes to a relatively quick onset of effects, while the elimination half-life dictates the duration of action.

Cellular Proliferation and Apoptosis Modulation in Disease Models

This compound has demonstrated the ability to modulate cellular proliferation and induce apoptosis in various disease models in vitro. For instance, studies on prostate cancer cells have shown that this compound can suppress cell proliferation at concentrations as low as 20 μmol/L. aacrjournals.orgnih.gov This effect is associated with the induction of cell cycle arrest, primarily at the G1/S checkpoint and, to a lesser extent, the G2/M checkpoint. nih.gov this compound treatment has been observed to alter the expression of key cell cycle regulators, including a decrease in c-Myc, E2F-1, and Skp2, and an increase in p53, p21, and p27. aacrjournals.orgnih.gov Furthermore, this compound treatment resulted in a rapid reduction of survivin, an antiapoptotic protein, and decreased protein expression of PARP1 and caspase-3 at 72 hours in prostate cancer cells. aacrjournals.org

In the context of adenomyosis, this compound significantly inhibited the proliferative and migratory abilities of endometrial stromal cells derived from women with the condition in vitro. nih.govnih.gov This antiproliferative effect was dose-dependent, with 113.3 µM identified as an optimal dosage for inhibitory effects in vitro. nih.gov

This compound has also shown anti-leukemia activity in acute myeloid leukemia (AML) cell lines, reducing cell viability, increasing apoptosis, and inducing myeloid differentiation with minimal effects on normal cells. researchgate.net A synergistic effect on inducing apoptosis was observed when AML cells were treated with a combination of cytarabine and this compound in vitro. researchgate.netanticancer360.com

Neurotransmitter Release and Receptor Binding Assays

This compound is known to be a dopamine D2 receptor agonist. wikipedia.orgmims.comguidetopharmacology.orgfishersci.ptscienceopen.com Radioligand binding studies have been conducted to determine its binding affinity to dopamine receptors. For example, this compound mesylate is a selective D3 and D2 dopamine receptor agonist with Ki values of approximately 5 nM and 8 nM, respectively. fishersci.pt It activates both isoforms of the D2 receptor (D2L and D2S) with EC50 values of 0.10-0.12 nM and 4.4 nM, respectively. fishersci.pt

In pancreatic beta-cells, this compound reduces glucose-stimulated insulin secretion by acting on both D2 receptors and alpha-2A adrenergic receptors (α2A-AR). nih.gov Competition binding assays in INS-1E cell-derived membranes indicated that this compound displaces the selective α2-adrenergic receptor antagonist [3H]-RX821002 with a high nanomolar affinity (Ki = 161.8 nM). nih.gov

Studies have also investigated the binding of this compound to other receptors. For instance, in vitro direct binding affinity of this compound at the human cannabinoid CB1 receptor was found to be negligible (IC50 > 100 μM). ucl.ac.be

Signaling Pathway Analysis in Target Cells

Analysis of signaling pathways in target cells has revealed several pathways influenced by this compound. In prostate cancer cells, this compound treatment inhibited the expression of total CREB and p-CREB, suggesting an inhibition of cAMP synthesis. aacrjournals.orgnih.gov It also significantly increased the phosphorylation of ERK1/2 kinases. aacrjournals.orgnih.gov These findings suggest that this compound may act as a DRD2 agonist by inhibiting cAMP signaling and activating the ERK1/2 pathway in these cells. aacrjournals.orgnih.gov Additionally, this compound significantly inhibited the phosphorylation of Stat3. aacrjournals.orgnih.gov The effects on p-CREB, p-ERK1/2, and p-Stat3 were reversed by the presence of sulpiride, a D2 receptor antagonist. aacrjournals.orgnih.gov this compound may also rescue p53 from degradation in an MDM2-dependent manner, as it decreased the phosphorylated form of MDM2. aacrjournals.org

In adenomyosis, small RNA sequencing and KEGG pathway analysis on targeted genes of differentially expressed miRNAs after this compound treatment showed enrichment in several signaling pathways associated with cell proliferation and apoptosis. nih.govnih.govfrontiersin.org

In this compound-resistant prolactinoma cells, the combination of pimozide and this compound led to a reduction in phosphoSTAT5, cyclin D1, and BclxL expression levels, suggesting involvement of the STAT5/BclxL and STAT5/cyclin D1 signaling pathways. ingentaconnect.com

In Alzheimer's disease models, this compound, via activating DRD2, promoted the recruitment of PP2A and JNK by scaffold protein β-arrestin 2, which repressed JNK-mediated transcription of proinflammatory cytokines and activation of NLRP3 inflammasome in microglia. nih.gov

In pancreatic beta-cells, D2 receptor activation by this compound recruits G proteins and β-arrestin2, while α2A-AR activation recruits an ensemble of G proteins but not β-arrestin2, demonstrating receptor-specific signaling. nih.gov

This compound has also been shown to inhibit NF-κB activity in a dose-dependent manner in NF-κB reporter cells. scienceopen.com Molecular docking studies suggested that this compound binds strongly to NF-κB pathway proteins and interacts more strongly with DNA-bound NF-κB than free NF-κB, potentially inhibiting DNA binding. scienceopen.com

Parkinson's Disease Models (e.g., 6-OHDA lesioned rats)

The 6-hydroxydopamine (6-OHDA) lesioned rat model is a widely used animal model for studying Parkinson's disease (PD). researchgate.netfrontiersin.org Unilateral injection of 6-OHDA into the medial forebrain bundle selectively destroys dopamine neurons, mimicking the dopamine depletion seen in PD. researchgate.netfrontiersin.org

Studies in 6-OHDA lesioned rats have investigated the effects of this compound on motor function and dopamine receptors. Chronic administration of this compound (2 mg/kg i.p.) in 6-OHDA lesioned rats reversed the denervation supersensitivity in striatal dopamine receptors. nih.gov This reversal was analyzed by Scatchard plot using 3H-spiroperidol as a ligand. nih.gov Neither the lesion nor chronic this compound treatment significantly changed the affinity (KD) for 3H-spiroperidol or the maximal number of binding sites (Bmax) when administered alone. nih.gov

This compound has also been evaluated for its ability to ameliorate impairments in more complex operant tasks in 6-OHDA lesioned rats, which assess both motor and nonmotor deficits. researchgate.netnih.gov In one study, this compound (1.25 mg/kg) induced a transient improvement in motor function and a persistent improvement in the accuracy of performance in a lateralized choice reaction time task. researchgate.netnih.gov This improvement in response initiation and selection persisted even in the absence of this compound and was not reversed by a D2 antagonist. researchgate.netnih.gov

Another study comparing this compound with other dopamine agonists in unilaterally 6-OHDA lesioned rats found that this compound induced circling behavior, a common measure in this model. neurology.org Pergolide was found to be more potent than this compound in inducing circling. neurology.org

Hyperprolactinemia Models

Animal models of hyperprolactinemia have been developed to study the effects of this compound on prolactin secretion and pituitary function. Estrogen-induced hyperprolactinemia in ovariectomized rats is one such model. ufrgs.brscielo.brnih.gov

In estradiol-treated ovariectomized Wistar rats, administration of this compound (0.2 or 0.6 mg/rat/day) decreased serum prolactin levels. ufrgs.brscielo.brnih.gov In rats treated with a higher dose of estradiol (300 µ g/rat/week ), which resulted in a significant increase in the number of prolactin cells, this compound treatment also led to a significant decrease in pituitary weight and the number of immunoreactive prolactin cells compared to the group treated with estradiol alone. ufrgs.brscielo.brnih.gov These antiprolactinemic and antiproliferative pituitary effects validate the experimental model of estrogen-induced hyperprolactinemic rats for studying the interaction between estrogen and dopamine in controlling prolactin secretion and lactotroph proliferation. ufrgs.brscielo.brnih.gov

Another model of hyperprolactinemia involves inducing the condition with metoclopramide in rats. ajol.info In this model, this compound treatment (0.6 mg/kg) significantly attenuated the increased serum prolactin levels observed in model rats. ajol.info This was associated with an increase in hypothalamus dopamine D2 receptor protein expression and a reduction in hypothalamus cAMP and PKA levels. ajol.info

Animal models of systemic lupus erythematosus (SLE), where hyperprolactinemia can be a factor, have also been used to study this compound. In estrogen-treated lupus-prone mice, this compound treatment (400 μ g daily) led to reduced titers of anti-DNA antibodies and diminished IgG deposition in kidneys compared to estrogen treatment alone. nih.govjci.org This suggests that some of the effects of estrogen on naive autoreactive B cells in this model may require the presence of prolactin, and this compound can abrogate the estrogen-induced breakdown in B-cell tolerance by inducing anergy in high-affinity DNA-reactive B cells. nih.govjci.org

Metabolic Disorder Models (e.g., type 2 diabetes, insulin resistance)

Preclinical studies utilizing animal models of obesity and diabetes have demonstrated that this compound administration can lead to improvements in glucose intolerance and reductions in elevated serum insulin and lipid levels. conicet.gov.ar These effects are suggested to be partly linked to this compound's ability to modify the circadian rhythm of hypothalamic dopamine. conicet.gov.ar Studies in rodents have indicated that the timing of this compound administration is critical for achieving optimal results in glucose homeostasis. conicet.gov.ar

Specifically, intraperitoneal or intracerebroventricular administration of this compound to animals with seasonal insulin resistance has been shown to reverse insulin resistance or glucose intolerance. conicet.gov.ar Such treatment has also been observed to reduce both hepatic glucose and lipid production and secretion. conicet.gov.ar Research in various animal models of insulin resistance syndrome, including seasonal insulin-resistant hamsters, genetically leptin-deficient ob/ob mice, and spontaneously hypertensive rats (SHRs), has shown that circadian-timed this compound administration, aimed at reinstating the normal circadian peak in central nervous system (CNS) dopaminergic activity, can normalize elevated hypothalamic activities that contribute to insulin resistance. tandfonline.com

Timed daily administration of this compound to increase diminished circadian peak dopaminergic hypothalamic activity in a variety of animal models of metabolic syndrome and type 2 diabetes mellitus (T2DM) has resulted in improvements in the obese, insulin-resistant, glucose-intolerant condition. This is achieved by improving hypothalamic fuel sensing and reducing insulin resistance, elevated sympathetic tone, and leptin resistance. tandfonline.com

This compound-induced decreases in body fat stores in obese, insulin-resistant animals were not associated with changes in food consumption but were coupled with substantial increases in whole-body protein turnover rate and whole-body protein content. tandfonline.com These findings suggest that this compound treatment in these models shifts metabolism from a state of lipid accretion, glucose production, and insulin resistance to one of protein accretion and insulin sensitivity. tandfonline.com

Timed this compound treatment of insulin-resistant animals has also been demonstrated to reset towards normal the circadian rhythm of cortisol secretion and the circadian expression of the circadian clock gene, per1, in the suprachiasmatic nucleus (SCN), indicating its ability to reset circadian clock systems. tandfonline.com These effects are consistent with a mechanism involving circadian-dependent timed dopaminergic activity at the clock to reset clock regulation of metabolism. tandfonline.com

Preclinical studies also suggest that this compound-QR, a quick-release formulation, improves insulin sensitivity and dysglycemia by correcting hypothalamic activity aberrations that potentiate insulin resistance and loss of appropriate fuel sensing mechanisms. nih.gov

The following table summarizes some preclinical findings in metabolic disorder models:

Cancer Models (e.g., prostate cancer chemoresistance)

Preclinical research has explored the potential of this compound in cancer models, particularly focusing on overcoming chemoresistance in prostate cancer. Studies have demonstrated that the dopamine D2 receptor (DRD2) agonist this compound effectively enhances the efficacy of docetaxel and suppresses the skeletal growth of prostate cancer in preclinical models. nih.govaacrjournals.org DRD2 is expressed in prostate cancer cell lines and its expression is significantly reduced in prostate cancer tissues with high Gleason scores. aacrjournals.org

This compound has shown weak to moderate cytotoxicity in prostate cancer cells but effectively induces cell-cycle arrest. aacrjournals.org At the molecular level, this compound has been found to inhibit the expression of proteins such as c-Myc, E2F-1, and survivin, while increasing the expression of p53, p21, and p27. aacrjournals.org Notably, this compound has also been observed to markedly reduce androgen receptor levels, partly through Hsp90-mediated protein degradation. aacrjournals.org

The combination of this compound and docetaxel has demonstrated enhanced in vitro cytotoxicity in prostate cancer cells and significantly retarded the skeletal growth of C4-2-Luc tumors in mice. aacrjournals.org These findings provide preclinical evidence for repurposing this compound as an adjunct therapy to enhance docetaxel efficacy in prostate cancer. aacrjournals.org

As a monotherapy, this compound treatment at 15 mg/kg, three times per week, administered intraperitoneally, significantly inhibited the skeletal growth of chemoresistant C4-2B-TaxR xenografts in athymic nude mice. nih.govnih.gov These results provided preclinical evidence that this compound can be a selective and effective inhibitor of chemoresistant prostate cancer. nih.govnih.gov

RNA-seq analyses have revealed that this compound affects a subset of genes implicated in the regulation of the cell cycle, DNA repair, and cell death. nih.gov this compound effectively induced cell cycle arrest and activated apoptosis in chemoresistant prostate cancer cells but not in chemoresponsive cells. nih.gov Approximately one-third of the differentially expressed genes affected by this compound overlapped with known p53-p21-retinoblastoma protein (RB) target genes. nih.gov At the protein level, this compound increased the expression of DRD2 and affected several classical and non-classical dopamine receptor signaling pathways in chemoresistant prostate cancer cells, including AMPK, p38 MAPK, NF-κB, EZH2, and survivin. nih.gov

Preclinical studies have also shown that the combination of docetaxel and this compound effectively reduced tumor growth and bone metastasis in prostate cancer xenograft models. exonpublications.com

The following table summarizes some preclinical findings in cancer models:

Peripartum Cardiomyopathy Models

Preclinical models have been instrumental in understanding the potential role of this compound in peripartum cardiomyopathy (PPCM). A key finding from animal models is the implication of a toxic 16-kDa prolactin fragment in the pathogenesis of PPCM. nih.govcfrjournal.com This fragment is generated by oxidative stress-mediated cleavage of the nursing hormone prolactin. nih.govcfrjournal.comjacc.org The 16-kDa prolactin fragment has been shown to possess vasculotoxic and pro-apoptotic properties, leading to vascular and myocardial dysfunction in a STAT3 knockout mouse model. jacc.org

In this STAT3 knockout mouse model of pregnancy-associated cardiomyopathy, treatment with this compound, a suppressor of prolactin secretion, resulted in a complete reversal of the cardiomyopathy. jacc.org This finding provided initial preclinical evidence for the potential therapeutic benefit of inhibiting prolactin in PPCM. nih.gov

Another vascular-hormonal mouse model of PPCM, developed by cardiac-specific genetic deletion of proliferator-activated receptor-gamma coactivator-1a (PGC-1a), also showed vasculotoxicity mediated by the activation of the 16-kDa prolactin fragment. jacc.org In this model, the cardiomyopathy could only be partly reversed with this compound, requiring the addition of vascular endothelial growth factor (VEGF) for complete recovery. jacc.org This suggests that while prolactin inhibition is beneficial, other factors, such as impaired angiogenesis, may also play a role in some cases of PPCM.

Preclinical studies using PPCM mouse models have shown that this compound can efficiently prevent the onset of the condition. nih.govcfrjournal.com this compound has also been shown to suppress apoptosis in cardiomyocytes in control peripartum mice. researchgate.net

The following table summarizes some preclinical findings in peripartum cardiomyopathy models:

Hyperprolactinemia and Prolactin-Secreting Adenomas

Hyperprolactinemia, a condition characterized by elevated levels of prolactin in the blood, is frequently caused by prolactin-secreting pituitary adenomas (prolactinomas) or other factors interfering with dopamine pathways. usk.ac.idoup.com this compound is a first-line treatment for this condition. unair.ac.idwho.int

This compound effectively inhibits prolactin secretion from the pituitary gland by stimulating D2 receptors on lactotroph cells. researchgate.net This inhibition leads to a reduction in circulating prolactin levels. Furthermore, this compound is known to cause a reduction in the size of prolactin-secreting adenomas. unair.ac.idnih.govacpjournals.orgspandidos-publications.com Studies have shown that this compound can rapidly inhibit prolactin secretion and lead to significant reductions in tumor volume. researchgate.netnih.govspandidos-publications.com The tumor shrinkage is thought to be a result of reduced tumor cell volumes, with cytoplasmic components like the rough endoplasmic reticulum and Golgi apparatus being particularly affected, rather than a reduction in tumor cell number. researchgate.net In some cases of non-functional pituitary macroadenomas, this compound has shown a stabilizing effect on tumor growth. unair.ac.id

Data from clinical studies illustrate the impact of this compound on prolactin levels and tumor size:

Hyperprolactinemia can lead to various symptoms related to hypogonadism due to the suppression of gonadotropin secretion. usk.ac.idoup.com These symptoms include amenorrhea (absence of menstruation), galactorrhea (abnormal milk production), infertility, and hypogonadism (impaired function of the gonads). usk.ac.idoup.comnih.govadvancedfertility.com this compound treatment, by normalizing prolactin levels, can effectively resolve these associated symptoms. nih.govadvancedfertility.com Studies have shown that this compound can lead to the cessation of galactorrhea, resumption of menstrual periods, and restoration of fertility in women with hyperprolactinemia. nih.gov In men, it can help restore potency and address hypogonadism. nih.gov

Clinical outcomes on associated symptoms with this compound treatment:

While this compound has been a cornerstone in treating hyperprolactinemia, other dopamine agonists, particularly cabergoline, are also used. Comparisons between this compound and cabergoline have been conducted to assess their relative efficacy. Research suggests that cabergoline may offer advantages over this compound in terms of efficacy and tolerability. who.intnih.govresearchgate.netnih.govmedwave.cl

Studies indicate that cabergoline is significantly more effective than this compound in normalizing prolactin levels and achieving a greater reduction in tumor volume in patients with hyperprolactinemia. who.intnih.govresearchgate.net A meta-analysis found that cabergoline was significantly more effective in normalizing prolactin levels, resolving persistent amenorrhea, normalizing menses, and restoring normal ovulatory cycles. nih.govmedwave.cl

Comparative efficacy data:

Despite cabergoline's higher efficacy in some aspects, this compound remains a valuable treatment option, particularly where cost is a significant factor. who.int

Impact on Associated Symptoms (e.g., amenorrhea, galactorrhea, infertility, hypogonadism)

Acromegaly

Acromegaly is an endocrine disorder characterized by the overproduction of growth hormone (GH) by the pituitary gland, often due to a GH-secreting adenoma. This compound has been investigated for its effects on GH levels in patients with acromegaly.

This compound can suppress circulating GH levels in a subset of patients with acromegaly by stimulating D2 receptors, which are often expressed in GH-secreting adenomas. nih.govresearchgate.netbmj.comscielo.brscilit.com Studies have shown that this compound can lead to a reduction in GH values, with some patients achieving normalization or a significant decrease in levels. nih.govscilit.com In one long-term review of 35 acromegalic patients treated with this compound, GH values fell to 5 µg/l or less in 16 patients and less than 10 µg/l in a further 6 patients. nih.gov In 33 patients, GH values fell to 50% of the basal value or less. nih.gov

However, the response to this compound in acromegaly is variable, and it is generally considered less effective in controlling GH secretion and tumor growth compared to somatostatin analogs, which are now often the first-line pharmacological treatment for acromegaly. scielo.br Despite this, this compound can lead to considerable clinical improvement in responsive acromegalic patients, including the abolition of excessive sweating, reduction in soft-tissue thickening, and improvement in facial features. bmj.com

Data on this compound's effect on GH levels in acromegaly:

It is important to note that in rare instances, this compound administration has been associated with an increase in GH secretion in a patient with acromegaly, highlighting the complexity of its effects and the need for careful monitoring. researchgate.net

Adjuvant Therapy to Radiotherapy and Surgery

This compound has been explored as an adjuvant therapy in certain conditions treated with radiotherapy and/or surgery, particularly in the context of pituitary tumors. While radiotherapy and surgery have been standard treatments for acromegaly, this compound can be a useful adjuvant therapy. nih.gov In the context of breast cancer, a pilot study investigated perioperative this compound as adjuvant treatment for operable breast cancer. The rationale was that elevated prolactin levels post-mastectomy, potentially due to surgical stress, might stimulate micrometastatic cells. The study found that this compound treatment significantly reduced prolactin levels and the S-phase fraction of tumor cells within the primary carcinoma. nih.gov This suggests a potential role in preventing metastasis by inhibiting the proliferative effect of prolactin. nih.gov

Type 2 Diabetes Mellitus

Quick-release this compound mesylate (this compound-QR) is approved for the treatment of type 2 diabetes mellitus (T2DM). mdpi.comnih.gov Its utility in T2DM is based on its activity in modulating central glucose and energy metabolism pathways, specifically by targeting circadian neuronal activities in the hypothalamus. nih.govdovepress.comresearchgate.net

Glycemic Control and Insulin Sensitivity

Clinical studies with this compound-QR have indicated its ability to improve glycemic control in patients with T2DM. nih.govtandfonline.com It has been shown to reduce postprandial glucose levels without increasing plasma insulin. tandfonline.comiomcworld.com This suggests an enhancement of tissue sensitivity to insulin. iomcworld.com Across various T2DM populations, this compound-QR has demonstrated a reduction in HbA1c levels, ranging from -0.4% to -1.7% in different studies. nih.govtandfonline.comresearchgate.net

One pilot study involving T2DM subjects poorly controlled on high-dose insulin demonstrated that this compound-QR therapy improved glycemic control and meal tolerance while reducing insulin requirements. In this study, average HbA1c decreased by 1.76% (from 9.74% to 7.98%), and average total daily insulin dose decreased by 27% over a 24-week treatment period. nih.gov

Several clinical trials have investigated the effects of quick-release this compound on glycemic parameters. A summary of findings regarding HbA1c reduction is presented in the table below:

This compound's mechanism in improving insulin sensitivity is thought to involve restoring a diminished circadian peak of dopaminergic activity, which in turn ameliorates aberrations in hypothalamic activities that contribute to insulin resistance. nih.gov

Impact on Cardiovascular Risk Factors and Events

This compound-QR therapy has shown a significant impact on cardiovascular outcomes in patients with T2DM. In a large randomized trial, circadian-timed administration of this compound-QR significantly reduced cardiovascular events by 40-55% over a single year in T2DM subjects, the majority of whom did not have pre-existing cardiovascular disease. mdpi.com Another large placebo-controlled clinical study assessed the impact of adding this compound-QR to existing metformin therapy in T2DM subjects. This study, derived from the Cycloset Safety Trial, found a 55% reduction in the composite cardiovascular endpoint (myocardial infarction, stroke, coronary revascularization, or hospitalization for unstable angina/congestive heart failure) in the this compound-QR group compared to placebo over 12 months. nih.gov

A systematic review summarizing available data on this compound in T2DM management noted that studies demonstrated significantly reduced blood glucose and BMI in patients treated with this compound, with BMI being a main cardiovascular risk factor in T2DM. nih.gov The review also highlighted that this compound-QR was associated with a 42% hazard ratio reduction of a pre-specified adverse cardiovascular endpoint, including myocardial infarction, stroke, hospitalization for congestive heart failure, and revascularization surgery. nih.gov

The Cycloset Safety Trial, a 52-week, randomized, double-blind, multicenter trial, specifically evaluated the cardiovascular safety of this compound-QR. Fewer patients in the this compound-QR group experienced a cardiovascular endpoint (1.8%) compared to the placebo group (3.2%), resulting in a hazard ratio of 0.60. diabetesjournals.org

This compound-QR therapy may reduce adverse cardiovascular events in T2DM subjects potentially through the attenuation of an underlying chronic pro-oxidative/pro-inflammatory state, which is linked to elevated sympathetic nervous system activity and central hypodopaminergic function in these patients. mdpi.com

Role in Circadian Rhythm Resetting and Metabolic Regulation

This compound is thought to influence metabolic regulation in T2DM by acting on hypothalamic circadian neuronal activities. nih.govresearchgate.net The hypothesis is that it helps reset an abnormally elevated hypothalamic drive that contributes to increased plasma glucose, free fatty acids, and triglycerides in insulin-resistant individuals. nih.govresearchgate.net

Animal studies suggest that diminished circadian peak dopaminergic activity in the hypothalamus facilitates the onset of insulin resistance and glucose intolerance. Systemic circadian-timed administration of this compound, a dopamine D2 receptor agonist, is proposed to increase this diminished activity, leading to improvements in insulin resistance and glucose intolerance by improving hypothalamic fuel sensing and reducing elevated sympathetic tone. tandfonline.com

Timed this compound treatment in insulin-resistant animals has been shown to normalize the circadian rhythm of cortisol secretion and the circadian expression of the clock gene per1 in the suprachiasmatic nucleus (SCN), supporting its ability to reset circadian clock systems. tandfonline.com This resetting effect is consistent with a mechanism involving circadian-dependent timed dopaminergic activity at the clock to regulate metabolism. tandfonline.com Quick-release this compound, administered in the morning, is designed to provide a brief daily increase in circulating this compound to mimic the natural early morning peak of central dopaminergic activity, which is often diminished in insulin-resistant states. tandfonline.comnih.gov

While the circadian mechanism is a prominent hypothesis, some preclinical studies in obese mouse models suggest that this compound's effect on glucose tolerance may not be dependent on circadian rhythms. nih.gov However, the prevailing understanding in the context of its T2DM approval and clinical use emphasizes the circadian timing aspect.

Parkinson's Disease

This compound has demonstrated efficacy in the treatment of Parkinson's disease, a neurological disorder characterized by motor symptoms resulting from dopamine deficiency. nih.govcambridge.org As a dopamine receptor agonist, this compound stimulates dopamine receptors to help alleviate these symptoms. nih.gov

Clinical trials have investigated the use of this compound both as monotherapy and in combination with levodopa, the current best treatment for Parkinson's disease. nih.govcochrane.org In patients not on other treatments, this compound has shown a slight therapeutic effect, and it can provide an additional effect in patients already receiving levodopa. nih.gov A double-blind controlled trial comparing this compound with placebo in Parkinson's disease patients demonstrated a significant reduction in total disability and akinesia scores with active treatment. nih.govresearchgate.net Patients with less severe disability tended to show a greater response. nih.govresearchgate.net

Studies have also explored the use of slow-release formulations of this compound in Parkinson's disease. A multi-center, double-blind trial comparing a slow-release formulation with standard this compound found comparable clinical efficacy for symptoms like tremor, rigidity, akinesia, and gait disturbance. neurology.org

In the treatment of early Parkinson's disease, this compound may be beneficial in delaying the onset of motor complications and dyskinesias associated with long-term levodopa therapy, particularly in patients who can tolerate the drug. cochrane.org While some studies suggest modest, transient beneficial effects when used alone or with levodopa, they also indicate significantly less fluctuation of disability and fewer dyskinesias compared to levodopa alone. cambridge.org The transient nature of benefits on progressive disability suggests that both pre- and post-synaptic defects are involved in Parkinson's disease progression. cambridge.org

This compound's role in Parkinson's disease continues to be evaluated, particularly in strategies aimed at managing symptoms and potentially delaying complications.

Mechanism in Attenuating Bradykinetic Symptoms and Stimulating Locomotion

In Parkinson's disease, this compound directly binds to striatal dopamine D2 receptors. nih.gov This agonistic effect on D2 receptors is believed to stimulate locomotion and help attenuate the bradykinetic symptoms caused by the degeneration of dopaminergic nigrostriatal neurons. nih.gov By activating dopamine receptors, this compound mimics the action of dopamine, compensating for the reduced dopaminergic activity in the brain and improving motor function. patsnap.commuseonaturalistico.it this compound is a partial agonist of the dopamine D2 receptor and also interacts with other dopamine, serotonin, and adrenergic receptors. wikipedia.org

Monotherapy and Adjunctive Therapy with Levodopa

This compound can be used as initial monotherapy in patients with newly diagnosed Parkinson's disease, potentially providing symptomatic benefit comparable to levodopa initially. ccjm.org However, over time, levodopa is typically required for an adequate antiparkinsonian effect. ccjm.org

This compound is also clinically useful as an adjunct to levodopa therapy, often with a decarboxylase inhibitor, in the symptomatic management of selected patients with Parkinson's disease. cambridge.org When used as an adjuvant, this compound can result in clinical improvement and may permit a decreased levodopa requirement. ccjm.orgresearchgate.net Studies have demonstrated that early combination therapy using partial substitution of levodopa by this compound can influence the development of motor fluctuations and/or dyskinesia as complications of long-term levodopa treatment. neurology.org

A 7-year study involving this compound monotherapy and combination therapy with levodopa in Parkinson's disease reported that patients on this compound monotherapy for 7 years showed improvement or remained in the same Hoehn and Yahr stages, with no observed wearing-off phenomenon or dyskinesia. karger.com In contrast, patients who started on this compound alone but later received combination therapy with levodopa showed faster disease progression, with wearing-off phenomenon and dyskinesia occurring after the initiation of levodopa. karger.com

A 9-year follow-up study comparing this compound monotherapy and combination therapy with levodopa showed that some patients on monotherapy remained in the same stages, while others improved or deteriorated. karger.com In the combination therapy group, a larger proportion of patients reached more advanced stages. karger.com

Research suggests that substituting more than 25% of the levodopa dose with this compound may be required to lower the incidence of motor complications. neurology.org

Impact on Motor Complications

Adjunctive this compound therapy has been introduced to ameliorate motor complications associated with levodopa use in Parkinson's disease. nih.gov Some trials have reported a lower occurrence of dyskinesias in patients initially treated with this compound compared to levodopa alone, although this difference was not always statistically significant, particularly for moderate-to-severe dyskinesias. neurology.orgnih.govacpjournals.org There has also been a trend for wearing-off and on-off fluctuations to occur less frequently in the this compound group in some studies. nih.gov

However, a 14-year follow-up of a trial comparing initial treatments in Parkinson's disease found that while the this compound arm initially showed fewer motor complications, this difference was not sustained over the long term, and moderate and severe forms were equally common. neurology.org

Neuroleptic Malignant Syndrome

Neuroleptic Malignant Syndrome (NMS) is a rare, life-threatening reaction often associated with antipsychotic medications, characterized by symptoms like high fever, rigid muscles, confusion, and autonomic dysfunction. emcrit.orgwikipedia.org The underlying mechanism is believed to involve a deficiency of signaling via D2 dopamine receptors in the brain, leading to symptoms similar to Parkinsonism due to dopamine deficiency in the striatal pathways. emcrit.org

This compound, as a dopamine agonist, is used off-label in the management of NMS. nih.govmedscape.com It is thought to work by overcoming neuroleptic-induced dopaminergic blockade and enhancing dopamine signaling, which is a rational strategy to improve the underlying pathophysiology. emcrit.orgmedscape.com While there is no high-quality evidence from randomized controlled trials for any therapy in NMS, the use of dopamine agonists like this compound is supported by case reports and systematic literature reviews suggesting they might reduce mortality in severe cases when compared to purely symptomatic therapy. emcrit.org

Idiopathic Intracranial Hypertension (IIH)

Idiopathic Intracranial Hypertension (IIH) is a disorder characterized by elevated intracranial pressure without an identifiable cause, commonly affecting young obese women. researchgate.netnih.gov this compound, a dopamine D2 receptor agonist, has emerged as a potential novel therapy for IIH, possibly due to its metabolic effects. researchgate.netnih.gov

A retrospective cohort study evaluating the use of this compound in IIH management demonstrated significant improvement in papilledema and headache severity over 24 months, with early effects observed at one month. nih.govx-mol.net The study also reported a marked reduction in refractory IIH and reduced dependency on acetazolamide. nih.govx-mol.net These findings suggest that this compound shows promise as an effective therapeutic option for IIH, providing sustained improvement in clinical parameters and reducing reliance on conventional treatment. nih.govx-mol.net

Peripartum Cardiomyopathy (Off-label use)

Peripartum cardiomyopathy (PPCM) is a rare disorder characterized by left ventricular systolic dysfunction and heart failure symptoms occurring in the last month of pregnancy or within the first five months postpartum. researchgate.net this compound is used off-label for PPCM in conjunction with standard heart failure pharmacotherapy. nih.gov

The introduction of this compound as a treatment for PPCM is based on the theory of prolactin-mediated endothelial dysfunction. bmj.com Recent data suggest that oxidative stress can lead to the activation of an enzyme that cleaves prolactin, resulting in a 16 kDa prolactin fragment with angiostatic and proapoptotic properties that may adversely impact the endothelium and cardiomyocytes. researchgate.net this compound, by reducing prolactin production through its dopamine agonist actions, may improve outcomes in PPCM patients by eliminating this cleaved form of prolactin. researchgate.net

Limited case reports and proof-of-concept studies have shown that the use of this compound in the early stages of PPCM may improve outcomes. researchgate.net A meta-analysis indicated that adjunctive this compound therapy, added to standard treatment, significantly improved left ventricular ejection fraction and increased the likelihood of left ventricular recovery, although it did not result in a statistically significant reduction in all-cause mortality. nih.gov An open-label study showed greater recovery of LV ejection fraction in the group treated with this compound plus standard therapy compared to standard therapy alone. oup.com

This compound has also been shown to lower plasma norepinephrine levels and induce vasodilation via dopaminergic receptors in the vessel wall, suggesting potential mechanisms independent of its effect on prolactin levels. bmj.com

Here is a summary of some research findings:

Premenstrual Syndrome and Cyclical Mastalgia

This compound has been investigated for its effects on premenstrual syndrome (PMS) and cyclical mastalgia, conditions that have been linked to hormonal fluctuations, including elevated prolactin levels. Studies utilizing this compound have provided indirect evidence supporting the involvement of prolactin in PMS symptoms. wikipedia.orgmims.com Clinical trials have assessed the efficacy of this compound in alleviating the diverse symptoms associated with PMS. A double-blind, randomized, cross-over trial involving women with PMS demonstrated a statistically significant improvement in somatic symptoms such as abdominal tension, edema, weight gain, and breast tenderness with this compound administration. wikipedia.org While self-rating scores in this study indicated an improvement in psychological symptoms like depression and irritability during this compound treatment, physician assessments did not show a similar difference compared to placebo. wikipedia.org

In the context of cyclical mastalgia, this compound appears to be a more consistently supported therapeutic option, particularly for premenstrual mastodynia. wikipedia.org A European multicenter randomized trial involving patients with cyclical mastalgia reported significantly greater reductions in breast pain, heaviness, and tenderness in the group treated with this compound compared to the placebo group. wikipedia.orgmims.commims.com This improvement in symptoms was correlated with a significant reduction in serum prolactin levels, even in individuals with prolactin levels within the normal range. mims.com Comparative studies on mastalgia treatments have also indicated that this compound is effective, although its response rate and side effect profile may differ from other agents such as danazol or topical non-steroidal anti-inflammatory drugs. wikidata.orgwikidoc.org

Luteal Phase Insufficiency

Luteal phase insufficiency (LPI), characterized by inadequate progesterone production by the corpus luteum, has been a focus of research involving this compound, particularly in cases associated with hyperprolactinemia. As a dopamine agonist, this compound inhibits the secretion of prolactin, which can interfere with normal luteal function. nih.gov Studies have explored the impact of this compound on hormonal profiles and pregnancy rates in women with LPI and infertility. In one study, continuous treatment with this compound in women diagnosed with LPI and a history of infertility resulted in depressed plasma prolactin levels. fishersci.ca While there was no significant improvement in the levels of progesterone, 17 alpha-hydroxy-progesterone, or estradiol over the treatment period, two subjects became pregnant during the study. fishersci.ca Another study focusing on hyperprolactinemic luteal insufficiency treated with this compound reported that insufficient luteal function completely reverted to normal during treatment in patients with persistent hyperprolactinemia. mims.comcfspharmacy.pharmacy Additionally, five out of ten normoprolactinemic patients in this study achieved normal luteal function with this compound therapy, and one patient later conceived while on treatment. mims.comcfspharmacy.pharmacy Research indicates that this compound treatment in women with LPD and hyperprolactinemia effectively suppresses serum prolactin levels. nih.gov

Portal-Systemic Encephalopathy

This compound has been investigated as a potential treatment for portal-systemic encephalopathy (PSE), a neurological complication of liver dysfunction. The rationale for its use is partly based on the observation of parkinsonian or extrapyramidal symptoms in hepatic encephalopathy and the potential for dopamine agonists to influence neurotransmission. fishersci.ca Early anecdotal reports and small studies suggested that treatment with this compound might lead to improvements in clinical status and electroencephalographic findings in patients with hepatic encephalopathy. fishersci.ca Some research has proposed that this compound can exert a direct effect on the brain by influencing GABA-ergic pathways. mims.com One study suggested this compound as a useful treatment for chronic hepatic encephalopathy in cases unresponsive to conventional therapy, observing significant clinical improvement and favorable changes in cerebral blood flow and glucose consumption in a small group of patients. atamanchemicals.com However, the efficacy of this compound for PSE is not consistently supported by controlled trials. A randomized double-blind study comparing this compound to placebo in cirrhotic patients with chronic PSE who were already stabilized on standard treatment (neomycin and cathartics) found that this compound was not significantly superior to placebo and was consistently inferior to the standard therapy. wikidata.org Similarly, a study evaluating higher doses of this compound in patients with severe chronic PSE found that it was not more effective than standard treatment. wikipedia.org The lack of well-designed prospective controlled trials remains a limitation in definitively establishing the efficacy of this compound for portal-systemic encephalopathy. fishersci.ca

Cocaine Withdrawal (Off-label use)

This compound has been used off-label in attempts to mitigate the symptoms of cocaine withdrawal, based on the hypothesis that cocaine use may lead to dopamine depletion in the brain. nih.govctdbase.orguni.lu Early investigations suggested that this compound, as a dopaminergic agonist, might be effective in alleviating some withdrawal symptoms. ctdbase.org However, more recent and controlled studies have not provided substantial evidence to support the efficacy of this compound for reducing cocaine use or craving. ctdbase.orgwikipedia.org A randomized, double-blind, placebo-controlled trial in methadone-maintained male patients with cocaine dependence found no significant difference between the this compound and placebo groups in self-reported cocaine use, positive urine toxicology samples, cocaine craving, resistance to cocaine use, or mood symptoms. ctdbase.org Furthermore, a Cochrane review that included multiple studies on dopamine agonists for cocaine use disorder concluded that there was no difference between these agents (including this compound) and placebo in any clinically relevant outcome, such as abstinence from cocaine use or treatment retention. wikipedia.org

Galactorrhea Precipitated by Dopamine Antagonists

This compound has demonstrated effectiveness in managing galactorrhea, particularly when it is precipitated by the use of dopamine-antagonizing medications. Dopamine agonists are considered first-line therapy for hyperprolactinemia, a common underlying cause of galactorrhea. fishersci.atguidetopharmacology.org this compound has been successfully employed in cases of galactorrhea induced by dopamine antagonists, such as risperidone. nih.gov While cabergoline is often favored over this compound due to its greater efficacy in lowering prolactin levels and reducing tumor size, as well as its more favorable tolerability profile, this compound remains a viable alternative for the treatment of hyperprolactinemia and associated galactorrhea. fishersci.atguidetopharmacology.orgnih.govnih.gov Dopamine agonists are effective in normalizing elevated prolactin levels, which in turn can resolve galactorrhea. guidetopharmacology.orgnih.gov

Cancer Therapy (e.g., prostate cancer, breast cancer)

Research has explored the potential of this compound in cancer therapy, particularly in prostate and breast cancers, often focusing on its ability to reduce prolactin levels and its direct effects on cancer cells. Hyperprolactinemia is frequently observed in metastatic breast and prostate cancers and has been linked to a poorer prognosis and reduced efficacy of anticancer therapies. researchgate.net

Studies have investigated this compound's effects on prolactin levels in patients with metastatic breast and prostate cancer. A study involving 10 women with metastatic breast cancer and 10 men with metastatic prostate cancer who had persistent hyperprolactinemia showed that a low dose of this compound (2.5 mg orally) was sufficient to acutely normalize prolactin secretion in both groups within 24 hours. researchgate.net Mean prolactin levels remained significantly lower than baseline throughout the 24-hour period. researchgate.net This suggests that this compound could be a valuable adjunct to standard antitumor therapies in patients with cancer-related hyperprolactinemia to potentially improve treatment efficacy. researchgate.net

Beyond its prolactin-lowering effects, this compound has demonstrated direct anticancer activity in preclinical models. It has shown cytotoxic effects against both drug-sensitive and multidrug-resistant leukemic cells, as well as wild-type and multidrug-resistant breast cancer cell lines. researchgate.netanticancer360.com Studies have indicated that this compound can inhibit drug-resistant tumor cells with different resistance mechanisms in a hormone-independent manner, suggesting its potential for repurposing in cancer therapy, particularly for refractory and drug-resistant tumors which pose a significant challenge to chemotherapy. frontiersin.org

In prostate cancer, this compound has been identified as a potent and selective inhibitor of chemoresistant prostate cancer cells in preclinical models. anticancer360.comnih.gov It effectively induced cell cycle arrest and activated apoptosis in these resistant cells, while not affecting chemoresponsive cells. nih.gov this compound's mechanism in prostate cancer cells may involve acting as a "biased agonist" of the dopamine D2 receptor (DRD2), inhibiting the CREB and Stat3 pathways while activating ERK1/2 signaling. aacrjournals.orgnih.gov Both CREB and Stat3 pathways have been implicated in prostate cancer progression. nih.gov Preclinical studies have also shown that this compound can inhibit the skeletal growth of chemoresistant prostate cancer xenografts. nih.gov

Early, small-scale trials conducted between the 1970s and 2000s explored the benefits of this compound in prostate and breast cancer patients. While this compound as a monotherapy did not consistently elicit significant clinical responses, its combination with docetaxel in metastatic breast cancer patients pretreated with anthracyclines resulted in increased rates of partial response and stable disease compared to docetaxel alone. nih.gov

The potential anticancer effects of this compound are also linked to targeting angiogenesis, the process tumors rely on for growth. anticancer360.com Research indicates that this compound can inhibit the production of vascular endothelial growth factor (VEGF), a key protein in angiogenesis. anticancer360.com By blocking VEGF, this compound may limit the blood supply to tumors. anticancer360.com Dopamine agonists like this compound have been shown to downregulate proangiogenic factors and upregulate antiangiogenic factors, potentially reducing tumor size and vascular density. anticancer360.com

Data from a study on the effect of this compound on prolactin levels in patients with metastatic breast and prostate cancer is summarized below:

Note: Data derived from search result researchgate.net. Prolactin levels are approximate values extracted from the text.

Other Emerging Indications

Beyond its established uses and potential in cancer therapy, this compound is being investigated for other emerging indications, particularly in metabolic disorders like type 2 diabetes mellitus (T2DM). nih.govnih.govviamedica.pl

A quick-release formulation of this compound mesylate (this compound-QR) has been approved in the USA for the treatment of T2DM. nih.govviamedica.pldovepress.com This formulation is administered in the morning to align with the natural circadian rhythm of dopamine activity, which is believed to be disturbed in individuals with insulin resistance and T2DM. nih.govdovepress.com By increasing central dopaminergic tone during this period, this compound-QR appears to improve insulin sensitivity and glucose metabolism. nih.govdovepress.comresearchgate.net

Clinical trials have investigated the efficacy of this compound-QR in lowering glycated hemoglobin (HbA1c) levels in patients with T2DM. Phase II and III studies have shown that this compound-QR can lower HbA1c by 0.6-1.2% as monotherapy or in combination with other antidiabetes medications. nih.gov Other studies suggest a reduction of 0.4-0.8%. viamedica.plresearchgate.net

Clinical trials have also suggested that this compound may improve insulin sensitivity and could be a beneficial add-on therapy to metformin, although it might be less effective than other agents like teneligliptin. nih.gov The American Diabetes Association (ADA) 2024 guidelines recognize this compound as a therapeutic option for T2DM. nih.gov

This compound's effect on metabolic parameters in T2DM is thought to involve reversing the elevated hypothalamic drive for increased plasma glucose, triglycerides, and free fatty acid levels observed in insulin-resistant patients. viamedica.pl

Data on the effect of quick-release this compound (this compound-QR) on glycated hemoglobin (HbA1c) in patients with type 2 diabetes from randomized controlled trials is summarized below:

Dopamine Receptor Antagonists (e.g., neuroleptics, metoclopramide)

Dopamine receptor antagonists, particularly those with dopamine D₂ receptor blocking properties, can reduce the effectiveness of bromocriptine. nih.govrxlist.com This is due to their opposing effects on dopamine receptors; this compound acts as an agonist, while these agents act as antagonists. hres.cadrugbank.com Concomitant use with neuroleptic agents (such as phenothiazines, haloperidol, clozapine, olanzapine, and ziprasidone) or metoclopramide is generally not recommended as it can lead to a decrease in the therapeutic effects of this compound and potentially exacerbate symptoms in conditions like Parkinson's disease. nih.govrxlist.compdr.netfda.govebsco.combccancer.bc.ca Conversely, this compound may also theoretically diminish the effectiveness of central dopamine antagonists. pdr.net

Other Dopamine Receptor Agonists

Concomitant use of this compound with other dopamine receptor agonists is generally not recommended. rxlist.com While combining dopamine agonists may be therapeutically beneficial in some patients with Parkinsonism, the effectiveness and safety of combining this compound with other dopamine receptor agonists for other indications are not well-established. rxlist.commedscape.com There is a potential for increased dopaminergic effects and associated adverse reactions when combining these agents. pdr.net

Ergot Alkaloids with Vasoconstrictor Activity

This compound is an ergot derivative, and concomitant use with other ergot alkaloids, particularly those with vasoconstrictor activity (such as ergotamine and dihydroergotamine), is not recommended. hres.canih.govpdr.netfda.govmedscape.com This combination can potentially lead to additive vasoconstrictive effects and increase the risk of ergot toxicity, which may manifest as vasospasm, peripheral ischemia, and other serious cardiovascular events. nih.govpdr.netfda.govmedscape.comdrugs.com It is recommended that this compound and ergot-related medications not be administered within 6 hours of each other. nih.gov

Antihypertensive Medications

Caution should be exercised when administering this compound concomitantly with antihypertensive medications. nih.govaapharma.ca this compound can cause hypotension, particularly orthostatic hypotension, especially during the initiation of therapy and dose escalation. nih.govmedscape.com Concomitant use with antihypertensive agents may increase the risk of symptomatic hypotension. aapharma.ca Monitoring of blood pressure, particularly during the initial period of treatment, is advisable. nih.govaapharma.ca Some antihypertensive medications may have their activity decreased by this compound. drugbank.com

CYP3A4 Inhibitors and Inducers

This compound is extensively metabolized in the liver, with CYP3A4 being the major metabolic enzyme involved. ijnrd.orgnih.govfda.gov Therefore, drugs that inhibit CYP3A4 can decrease the metabolism of this compound, leading to increased plasma concentrations and potentially an increased risk of adverse effects. ijnrd.orgnih.govpdr.netmedscape.comfda.gov Strong CYP3A4 inhibitors, such as azole antimycotics (e.g., itraconazole, ketoconazole) and HIV protease inhibitors (e.g., ritonavir, indinavir), should generally be avoided or used with caution, potentially requiring dosage adjustments of this compound, especially when used for certain indications like type 2 diabetes mellitus. nih.govrxlist.compdr.netmedscape.comfda.govsiloamhospitals.com Moderate CYP3A4 inhibitors (e.g., erythromycin, clarithromycin, diltiazem, verapamil, fluvoxamine) can also increase this compound levels, and dosage limitations may be necessary when used concomitantly. rxlist.compdr.netfda.govmedscape.comfda.govsiloamhospitals.com

Conversely, drugs that induce CYP3A4 can increase the metabolism of this compound, leading to decreased plasma concentrations and potentially reduced therapeutic effectiveness. ijnrd.orgnih.govpdr.net Potent CYP3A4 inducers, such as apalutamide, carbamazepine, and phenytoin, may decrease the serum levels of this compound. pdr.netmedscape.com Caution and close monitoring are advised if these drugs are used together. pdr.net

Impact on Metabolism of Other Drugs (e.g., Atorvastatin)

This compound is primarily metabolized in the liver, extensively undergoing biotransformation via the cytochrome P450 (CYP) enzyme system, specifically CYP3A4. In vitro studies have shown this compound to be a potent inhibitor of CYP3A4. drugsporphyria.netmedchemexpress.com However, given the typically low therapeutic concentrations of this compound in patients, a significant alteration of the metabolism of a second drug primarily cleared by CYP3A4 is not generally expected. fda.gov

Despite this, the metabolism of certain drugs that are substrates for CYP3A4 can theoretically be decreased when combined with this compound. drugbank.com Atorvastatin, a statin commonly used to lower cholesterol, is metabolized by CYP3A4. nih.govconsensus.app While some sources suggest the metabolism of atorvastatin can be decreased when combined with this compound, the clinical significance of this specific interaction may depend on individual patient factors and the extent of CYP3A4 inhibition at therapeutic this compound concentrations. drugbank.comconsensus.app Statins like simvastatin, lovastatin, and to a lesser extent atorvastatin are more affected by CYP3A4 inhibition compared to others like rosuvastatin or pravastatin. nih.govconsensus.app