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Journal of Parkinson's Disease 2018Continuous dopaminergic stimulation in Parkinson's disease (PD) has several advantages over pulsatile, non-continuous, stimulation. These therapies currently consist of... (Review)
Review
Continuous dopaminergic stimulation in Parkinson's disease (PD) has several advantages over pulsatile, non-continuous, stimulation. These therapies currently consist of pump-based and transcutaneous therapies and are based on a more constant delivery of the dopaminergic drug resulting in continuous dopaminergic stimulation and a more stable treatment effect. Several clinical and experimental observations have shown that continuous stimulation of dopaminergic receptors induces fewer complications, such as dyskinesia, compared to pulsatile stimulation. Currently available non-oral pharmacological continuous therapies in PD include the transdermal Rotigotine (RTG) patch, infusion therapies with Apomorphine and Intrajejunal Levodopa (IJLI) and the Rivastigmine patch. Here we aim to provide a concise review of these current therapies and discuss ongoing and future developments of continuous non-oral pharmacological dopaminergic therapies in PD.
Topics: Antiparkinson Agents; Dopamine Agonists; Drug Delivery Systems; Humans; Parkinson Disease
PubMed: 30584160
DOI: 10.3233/JPD-181476 -
British Journal of Clinical Pharmacology Apr 2023Dopamine agonists are a key tool in the therapeutic arsenal of endocrinologists worldwide. They exert their effects by binding to dopamine-2 (D2) receptors expressed by... (Review)
Review
Dopamine agonists are a key tool in the therapeutic arsenal of endocrinologists worldwide. They exert their effects by binding to dopamine-2 (D2) receptors expressed by pituitary tumour cells to modulate hormonal secretion and tumour size. They are the established first-line treatment for prolactinomas which express high levels of D2 receptors. Growing data support their use as an adjuvant treatment option for other pituitary tumours including growth hormone, adrenocorticotrophic hormones, thyroid hormone secreting adenomas and nonfunctional pituitary tumours, all of which have been shown to express D2 receptors as well, albeit to varying extents. For those pituitary tumours inadequately treated by dopamine agonist alone, combined agonism of D2 and somatostatin receptors represent a new frontier in clinical development. Here we review the development and role of dopamine agonist for the treatment of prolactinomas, the literature supporting their adjuvant use for the treatment of all other pituitary tumours, and recent progress in the development of the next generation of chimeric compounds that target D2 and other receptor subtypes highly expressed on pituitary tumour cells.
Topics: Humans; Adenoma; Dopamine Agonists; Pituitary Neoplasms; Prolactinoma; Somatostatin; Claviceps; Biological Products
PubMed: 36630197
DOI: 10.1111/bcp.15660 -
Current Opinion in Endocrinology,... Aug 2013Recently developed agents treat Cushing's disease by inhibiting ACTH secretion from corticotrope tumors or antagonizing cortisol action. (Review)
Review
PURPOSE OF REVIEW
Recently developed agents treat Cushing's disease by inhibiting ACTH secretion from corticotrope tumors or antagonizing cortisol action.
RECENT FINDINGS
The dopamine agonist cabergoline and the somatostatin agonist pasireotide target ACTH secretion. Each has low rates of normalization of urine-free cortisol (UFC), about 40% at doses of 1-7 mg weekly and 20% at doses of 600 or 900 μg twice daily, respectively. Cabergoline, an oral agent, has a relatively benign side-effect profile, primarily asthenia. Small trials suggest that combination therapy with ketoconazole increases effectiveness. Pasireotide, a parenteral agent, is associated with types and rates of adverse events similar to those seen with other somatostatin agonists (diarrhea, nausea, cholelithiasis), except for glucose intolerance, which occurs more frequently (∼75%). It may be most effective when UFC is less than two-fold normal. A few case reports suggest that pasireotide or cabergoline may control tumor size and ACTH secretion from macroadenomas. Retinoic acid must be evaluated further. The glucocorticoid antagonist mifepristone ameliorates glucose intolerance but may not normalize other Cushingoid features.
SUMMARY
These novel approaches provide options for treatment of patients in whom surgery has failed or is not possible, and those who decline adrenalectomy or radiation therapy.
Topics: Cabergoline; Dopamine Agonists; Drug Therapy, Combination; Ergolines; Humans; Hydrocortisone; Pituitary ACTH Hypersecretion; Somatostatin
PubMed: 23807605
DOI: 10.1097/MED.0b013e3283631809 -
Neuropsychopharmacology Reports Jun 2021Otsuka Pharmaceutical Co., Ltd. successfully developed the first dopamine D receptor partial agonist approved for schizophrenia, the antipsychotic aripiprazole (Abilify... (Review)
Review
Otsuka Pharmaceutical Co., Ltd. successfully developed the first dopamine D receptor partial agonist approved for schizophrenia, the antipsychotic aripiprazole (Abilify ). The drug was approved for this indication in the United States in 2002 and has received approval in the United States, Europe, Japan, and many other countries for several indications including schizophrenia, acute mania, adjunctive treatment of major depressive disorder (MDD), irritability associated with autistic disorder, and Tourette's disorder. Otsuka next developed brexpiprazole (Rexulti ), another D receptor partial agonist, which was granted marketing approval in the United States in 2015 as adjunctive therapy in major depressive disorder and for the treatment of schizophrenia. In Japan, brexpiprazole also received approval as a treatment for schizophrenia in 2018. In this review, we describe Otsuka's research history and achievements over the preceding 40 years in the area of antipsychotic drug discovery for dopamine D receptor partial agonists.
Topics: Aripiprazole; Depressive Disorder, Major; Dopamine; Dopamine Agonists; Humans; Quinolones; Research; Thiophenes; United States
PubMed: 33960741
DOI: 10.1002/npr2.12180 -
Neurotherapeutics : the Journal of the... Oct 2012Restless legs syndrome (RLS) is a common neurological disorder of unknown etiology that is managed by therapy directed at relieving its symptoms. Treatment of patients... (Review)
Review
Restless legs syndrome (RLS) is a common neurological disorder of unknown etiology that is managed by therapy directed at relieving its symptoms. Treatment of patients with milder symptoms that occur intermittently may be treated with nonpharmacological therapy but when not successful, drug therapy should be chosen based on the timing of the symptoms and the needs of the patient. Patients with moderate to severe RLS typically require daily medication to control their symptoms. Although the dopamine agonists, ropinirole and pramipexole have been the drugs of choice for patients with moderate to severe RLS, drug emergent problems like augmentation may limit their use for long term therapy. Keeping the dopamine agonist dose as low as possible, using longer acting dopamine agonists such as the rotigotine patch and maintaining a high serum ferritin level may help prevent the development of augmentation. The α2δ anticonvulsants may now also be considered as drugs of choice for moderate to severe RLS patients. Opioids should be considered for RLS patients, especially for those who have failed other therapies since they are very effective for severe cases. When monitored appropriately, they can be very safe and durable for long term therapy. They should also be strongly considered for treating patients with augmentation as they are very effective for relieving the worsening symptoms that occur when decreasing or eliminating dopamine agonists.
Topics: Analgesics, Opioid; Anticonvulsants; Dopamine Agonists; Humans; Restless Legs Syndrome
PubMed: 22923001
DOI: 10.1007/s13311-012-0139-4 -
BMC Endocrine Disorders May 2020Surgical resection of prolactinomas resistant to dopamine agonists is frequently incomplete due to fibrotic changes of the tumour under pharmacological therapy. In order...
BACKGROUND
Surgical resection of prolactinomas resistant to dopamine agonists is frequently incomplete due to fibrotic changes of the tumour under pharmacological therapy. In order to identify a subgroup of patients who may benefit from early surgery, we thought to investigate possible predictive factors of pharmacological resistance of prolactinomas to dopamine agonists.
METHODS
We retrospectively analyzed a database of a Belgian tertiary reference center for patients with pituitary tumours from 2014 to 2016. The groups of interest were patients with dopamine agonist responsive and resistant prolactinomas. The possible predictive factors, including MRI findings, endocrinological parameters, response of tumour and patient factors for dopamine agonist resistance were investigated.
RESULTS
We included 69 patients of whom 52 were women (75,4%) and 17 were men (24,6%). Rate of dopamine agonist resistance was 15.9%. We identified four significant predictors of dopamine agonist resistance: male gender, a large tumour volume, prolonged time to prolactin normalization and presence of a cystic, hemorrhagic and/or necrotic component. In addition, symptoms due to mass effect, high baseline prolactin level and a high contrast capture on MRI are factors that can be taken into consideration.
CONCLUSION
We identified predictive factors for pharmacological resistance and developed a scoring system for patient specific prediction of resistance to dopamine agonists. This scoring system may have impact on the timing and decision of surgery in prolactinoma patients after further prospective evaluation.
Topics: Adult; Aged; Belgium; Cabergoline; Dopamine Agonists; Drug Resistance; Female; Humans; Male; Middle Aged; Pituitary Neoplasms; Predictive Value of Tests; Prolactin; Prolactinoma; Retrospective Studies; Tertiary Care Centers; Young Adult
PubMed: 32429916
DOI: 10.1186/s12902-020-0543-4 -
Clinical Therapeutics Mar 2014Restless legs syndrome (RLS) is a common chronic neurologic disorder. Symptoms are most prevalent during the evening and at night, although daytime symptoms may emerge... (Review)
Review
BACKGROUND
Restless legs syndrome (RLS) is a common chronic neurologic disorder. Symptoms are most prevalent during the evening and at night, although daytime symptoms may emerge as the disease progresses. Dopamine agonists are currently considered first-line therapy for moderate to severe idiopathic RLS. Most dopamine agonists have short half-lives and are administered in the evening, shortly before the onset of RLS symptoms. Rotigotine is a non-ergot dopamine receptor agonist that has been specifically developed as a transdermal patch to provide continuous drug delivery over a 24-hour period.
OBJECTIVE
This review details the development of rotigotine, from the preclinical studies that established its pharmacokinetic profile to large-scale clinical trials in patients with RLS. Placebo-controlled trials that demonstrated the efficacy and tolerability of rotigotine are discussed, in addition to open-label studies that investigated long-term therapy.
METHODS
Studies were identified by a PubMed search using the key word rotigotine in conjunction with restless legs syndrome and by reviewing reference lists of retrieved publications. All clinical trials of rotigotine in RLS published before September 2013 were included.
RESULTS
Preclinical studies have established activity of rotigotine as a dopamine receptor agonist, and pharmacokinetic data have shown that transdermal delivery maintains stable plasma levels over 24 hours. Rotigotine has demonstrated efficacy in improving moderate to severe RLS symptoms in randomized, placebo-controlled trials, based on scores on the International RLS Study Group rating scale, the RLS-6 scale, and the Clinical Global Impression-Severity subscale. Results of an open-label extension study suggest that efficacy may be maintained for up to 5 years. A polysomnographic study demonstrated an improvement in periodic limb movement index with rotigotine, and subjective assessments have suggested beneficial effects in terms of amelioration of sleep disturbances. Premature discontinuations from rotigotine treatment have ranged from 8% to 38% in studies of 6 weeks to 12 months in duration; 57% of patients discontinued prematurely during a 5-year study. In each trial, adverse events were typical of dopaminergic stimulation and use of a transdermal patch. The most common adverse events were application-site reactions, with a reported prevalence ranging from 17% (1-month sleep laboratory trial) to 58% (5-year open-label extension study). Clinically significant augmentation was recorded in 39 of 295 patients (13%) receiving rotigotine during the 5-year study, of whom 15 (5%) were receiving a dose within the US Food and Drug Administration-approved range of 1 to 3 mg/24 h.
CONCLUSIONS
Findings from clinical studies have suggested that rotigotine is efficacious in improving RLS symptoms and is generally well-tolerated. The risk of developing clinically significant augmentation appears to be low. As such, rotigotine represents an important addition for RLS treatment.
Topics: Administration, Cutaneous; Dopamine Agonists; Drug Delivery Systems; Humans; PubMed; Restless Legs Syndrome; Sleep; Tetrahydronaphthalenes; Thiophenes; Transdermal Patch; United States; United States Food and Drug Administration
PubMed: 24636821
DOI: 10.1016/j.clinthera.2014.01.021 -
Biomedicine & Pharmacotherapy =... Jan 2022Dopamine (DA) is a crucial neurotransmitter that plays an important role in maintaining physiological function in human body. In the past, most studies focused on the... (Review)
Review
Dopamine (DA) is a crucial neurotransmitter that plays an important role in maintaining physiological function in human body. In the past, most studies focused on the relationship between the dopaminergic system and neurological-related diseases. However, it has been found recently that DA is an immunomodulatory mediator and many immune cells express dopamine receptors (DRs). Some immune cells can synthesize and secrete DA and then participate in regulating immune function. DRs agonists or antagonists can improve the dysfunction of immune system through classical G protein signaling pathways or other non-receptor-dependent pathways. This article will discuss the relationship between the dopaminergic system and the immune system. It will also review the use of DRs agonists or antagonists to treat chronic and acute inflammatory diseases and corresponding immunomodulatory mechanisms.
Topics: Central Nervous System; Dopamine; Dopamine Agonists; Dopamine Antagonists; Humans; Immune System; Immunologic Factors; Neurotransmitter Agents; Signal Transduction
PubMed: 34847478
DOI: 10.1016/j.biopha.2021.112458 -
Molecular Pharmaceutics Apr 2022The [F]fluoroethoxybenzovesamicol ([F]FEOBV) positron emission tomography (PET) ligand targets the vesicular acetylcholine transporter. Recent [F]FEOBV PET rodent...
The [F]fluoroethoxybenzovesamicol ([F]FEOBV) positron emission tomography (PET) ligand targets the vesicular acetylcholine transporter. Recent [F]FEOBV PET rodent studies suggest that regional brain [F]FEOBV binding may be modulated by dopamine D2-like receptor agents. We examined associations of regional brain [F]FEOBV PET binding in Parkinson's disease (PD) subjects without versus with dopamine D2-like receptor agonist drug treatment. PD subjects ( = 108; 84 males, 24 females; mean age 68.0 ± 7.6 [SD] years), mean disease duration of 6.0 ± 4.0 years, and mean Movement Disorder Society-revised Unified PD Rating Scale III 35.5 ± 14.2 completed [F]FEOBV brain PET imaging. Thirty-eight subjects were taking dopamine D2-like agonists. Vesicular monoamine transporter type 2 [C]dihydrotetrabenazine (DTBZ) PET was available in a subset of 54 patients. Subjects on dopamine D2-like agonists were younger, had a longer duration of disease, and were taking a higher levodopa equivalent dose (LED) compared to subjects not taking dopamine agonists. A group comparison between subjects with versus without dopamine D2-like agonist use did not yield significant differences in cortical, striatal, thalamic, or cerebellar gray matter [F]FEOBV binding. Confounder analysis using age, duration of disease, LED, and striatal [C]DTBZ binding also failed to show significant regional [F]FEOBV binding differences between these two groups. Chronic D2-like dopamine agonist use in PD subjects is not associated with significant alterations of regional brain [F]FEOBV binding.
Topics: Aged; Brain; Dopamine Agonists; Female; Humans; Male; Middle Aged; Parkinson Disease; Positron-Emission Tomography; Vesicular Acetylcholine Transport Proteins
PubMed: 35289620
DOI: 10.1021/acs.molpharmaceut.1c00961 -
Investigative Ophthalmology & Visual... Jun 2020The purpose of this study was to explore the role and mechanism of D2 receptor (D2R) involvement in myopia development and the effects of the full D2R agonist quinpirole...
PURPOSE
The purpose of this study was to explore the role and mechanism of D2 receptor (D2R) involvement in myopia development and the effects of the full D2R agonist quinpirole and partial D2R agonist aripiprazole on postnatal refractive development and form-deprivation myopia (FDM).
METHODS
C57BL/6 ("B6") mice, raised either in a visually normal or unilateral form-deprivation environment, were divided into three subgroups, including an intraperitoneally injected (IP) vehicle group and two quinpirole (1 and 10 µg/g body weight) treatment groups. The effects of quinpirole on FDM were further verified in D2R-knockout (KO) mice and corresponding wild-type littermates. Then, the modulation of normal vision development and FDM by aripiprazole (1 and 10 µg/g body weight, IP) was assessed in C57BL/6 mice. All biometric parameters were measured before and after treatments, and retinal cyclic adenosine phosphate (cAMP) and phosphorylated ERK (pERK) levels were analyzed to assess D2R-mediated signal transduction.
RESULTS
Neither quinpirole nor aripiprazole affected normal refractive development. FDM development was inhibited by quinpirole at low dose but enhanced at high dose, and these bidirectional effects were validated by D2R-specificity. FDM development was attenuated by the partial D2R agonist aripiprazole, at high dose but not at low dose. Quinpirole caused a dose-dependent reduction in cAMP levels, but had no effect on pERK. Aripiprazole reduced cAMP levels at both doses, but caused a dose-dependent increase of pERK in the form-deprived eyes.
CONCLUSIONS
Reduction of D2R-mediated signaling contributes to myopia development, which can be selectively attenuated by partial D2R agonists that activate D2Rs under the low dopamine levels that occur with FDM.
Topics: Animals; Disease Models, Animal; Dopamine Agonists; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Myopia; Quinpirole; Receptors, Dopamine D2; Signal Transduction
PubMed: 32572456
DOI: 10.1167/iovs.61.6.47