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Medicine Dec 2022Restless leg syndrome (Restless legs syndrome, RLS) is a common neurological disorder. The pathogenesis of RLS remains unknown, and recent pathophysiological... (Review)
Review
Restless leg syndrome (Restless legs syndrome, RLS) is a common neurological disorder. The pathogenesis of RLS remains unknown, and recent pathophysiological developments have shown the contribution of various genetic markers, neurotransmitter dysfunction, and iron deficiency to the disease, as well as other unidentified contributing mechanisms, particularly chronic renal dysfunction. RLS enhancement syndrome is frequently observed in patients with RLS who have received long-term dopamine agonist therapy, manifesting as a worsening of RLS symptoms, usually associated with an increase in the dose of dopamine agonist. Some patients with RLS can adequately control their symptoms with non-pharmacological measures such as massage and warm baths. First-line treatment options include iron supplementation for those with evidence of reduced iron stores, or gabapentin or pregabalin, as well as dopamine agonists, such as pramipexole. Second-line therapies include opioids such as tramadol. RLS seriously affects the quality of life of patients, and because its pathogenesis is unclear, more biological evidence and treatment methods need to be explored.
Topics: Humans; Dopamine Agonists; Restless Legs Syndrome; Quality of Life; Gabapentin; Iron
PubMed: 36550837
DOI: 10.1097/MD.0000000000032324 -
Neuroendocrinology 2019Dopamine agonists are usually very effective in the treatment of prolactinomas. Nonetheless, a subset of individuals does not respond satisfactorily to these agents, and... (Review)
Review
Dopamine agonists are usually very effective in the treatment of prolactinomas. Nonetheless, a subset of individuals does not respond satisfactorily to these agents, and this resistance is characterized by failure to achieve normoprolactinemia and a 30% or more reduction in maximal tumor diameter (in the case of macroprolactinoma) under maximally tolerated doses. The overall prevalence of dopamine agonist resistance is 20-30% for bromocriptine (BRC) and around 10% for cabergoline (CAB). The 2 main predictive factors are male gender and tumor invasiveness. The management of drug-resistant prolactinomas includes several options. Any BRC-resistant patient should be switched to CAB which will normalize prolactin in 80% of patients. As long as adverse effects do not develop, dose escalation of CAB is reasonable, with the expectation that subsequent dose reduction will be possible. Echocardiographic monitoring is advised in such patients because of the potential association with cardiac valvular fibrosis. Also, maintaining maximal CAB doses at 3.5 mg/week may lead to progressive hormonal control in a significant proportion of patients. Complete resistance to CAB is infrequent. In a study of 122 patients with a macroprolactinoma, only 7 (6%) could not achieve control despite maximal CAB doses for > 12 months. A large resistant prolactinoma is also an indication for transsphenoidal neurosurgery, aiming at a debulking which may improve postoperative medical control. For patients who harbor aggressive prolactinomas, radiotherapy may be considered. However, normal prolactinemia will eventually occur in only one-third of patients after many years. Finally, temozolomide may be a therapeutic option in malignant/aggressive prolactinomas.
Topics: Bromocriptine; Cabergoline; Dopamine Agonists; Drug Resistance; Humans; Pituitary Neoplasms; Prolactinoma
PubMed: 30481756
DOI: 10.1159/000495775 -
Biomolecules May 2023Current pharmacotherapy has limited efficacy and/or intolerable side effects in late-stage Parkinson's disease (LsPD) patients whose daily life depends primarily on... (Randomized Controlled Trial)
Randomized Controlled Trial
Current pharmacotherapy has limited efficacy and/or intolerable side effects in late-stage Parkinson's disease (LsPD) patients whose daily life depends primarily on caregivers and palliative care. Clinical metrics inadequately gauge efficacy in LsPD patients. We explored if a D dopamine agonist would have efficacy in LsPD using a double-blind placebo-controlled crossover phase Ia/b study comparing the D agonist PF-06412562 to levodopa/carbidopa in six LsPD patients. Caregiver assessment was the primary efficacy measure because caregivers were with patients throughout the study, and standard clinical metrics inadequately gauge efficacy in LsPD. Assessments included standard quantitative scales of motor function (MDS-UPDRS-III), alertness (Glasgow Coma and Stanford Sleepiness Scales), and cognition (Severe Impairment and Frontal Assessment Batteries) at baseline (Day 1) and thrice daily during drug testing (Days 2-3). Clinicians and caregivers completed the clinical impression of change questionnaires, and caregivers participated in a qualitative exit interview. Blinded triangulation of quantitative and qualitative data was used to integrate findings. Neither traditional scales nor clinician impression of change detected consistent differences between treatments in the five participants who completed the study. Conversely, the overall caregiver data strongly favored PF-06412562 over levodopa in four of five patients. The most meaningful improvements converged on motor, alertness, and functional engagement. These data suggest for the first time that there can be useful pharmacological intervention in LsPD patients using D agonists and also that caregiver perspectives with mixed method analyses may overcome limitations using methods common in early-stage patients. The results encourage future clinical studies and understanding of the most efficacious signaling properties of a D agonist for this population.
Topics: Humans; Parkinson Disease; Levodopa; Dopamine Agonists; Antiparkinson Agents; Dopamine
PubMed: 37238699
DOI: 10.3390/biom13050829 -
Sleep Medicine May 2016A Task Force was established by the International Restless Legs Syndrome Study Group (IRLSSG) in conjunction with the European Restless Legs Syndrome Study Group...
Guidelines for the first-line treatment of restless legs syndrome/Willis-Ekbom disease, prevention and treatment of dopaminergic augmentation: a combined task force of the IRLSSG, EURLSSG, and the RLS-foundation.
A Task Force was established by the International Restless Legs Syndrome Study Group (IRLSSG) in conjunction with the European Restless Legs Syndrome Study Group (EURLSSG) and the RLS Foundation (RLS-F) to develop evidence-based and consensus-based recommendations for the prevention and treatment of long-term pharmacologic treatment of dopaminergic-induced augmentation in restless legs syndrome/Willis-Ekbom disease (RLS/WED). The Task Force made the following prevention and treatment recommendations: As a means to prevent augmentation, medications such as α2δ ligands may be considered for initial RLS/WED treatment; these drugs are effective and have little risk of augmentation. Alternatively, if dopaminergic drugs are elected as initial treatment, then the daily dose should be as low as possible and not exceed that recommended for RLS/WED treatment. However, the physician should be aware that even low dose dopaminergics can cause augmentation. Patients with low iron stores should be given appropriate iron supplementation. Daily treatment by either medication should start only when symptoms have a significant impact on quality of life in terms of frequency and severity; intermittent treatment might be considered in intermediate cases. Treatment of existing augmentation should be initiated, where possible, with the elimination/correction of extrinsic exacerbating factors (iron levels, antidepressants, antihistamines, etc.). In cases of mild augmentation, dopamine agonist therapy can be continued by dividing or advancing the dose, or increasing the dose if there are breakthrough night-time symptoms. Alternatively, the patient can be switched to an α2δ ligand or rotigotine. For severe augmentation the patient can be switched either to an α2δ ligand or rotigotine, noting that rotigotine may also produce augmentation at higher doses with long-term use. In more severe cases of augmentation an opioid may be considered, bypassing α2δ ligands and rotigotine.
Topics: Consensus; Dopamine Agonists; Drug Synergism; Evidence-Based Medicine; Humans; Practice Guidelines as Topic; Restless Legs Syndrome
PubMed: 27448465
DOI: 10.1016/j.sleep.2016.01.017 -
CNS Drug Reviews 2004The functional role of dopamine D(1) receptors is still controversial. One reason for this controversy is that for a long time the only available agonists for in vivo... (Review)
Review
The functional role of dopamine D(1) receptors is still controversial. One reason for this controversy is that for a long time the only available agonists for in vivo characterization of dopamine D(1) receptors were benzazepines. Among them was the prototype dopamine D(1) receptor partial agonist, SKF 38393. The lack of a selective and fully efficacious dopamine D(1) receptor agonist hampered basic research on dopamine D(1) receptors and left the potential clinical utility of dopamine D(1) receptor agonists elusive. The research situation improved when the first potent full dopamine D(1) receptor agonist dihydrexidine, a phenanthridine, was introduced in the late 1980s. In contrast to SKF 38393, dihydrexidine was shown to stimulate cyclic AMP synthesis just as well or better than dopamine, and potently displaced [(3)H]SCH 23390 from rat and monkey striatal membranes. Also, dihydrexidine was the first dopamine D(1) receptor agonist that had potent antiparkinsonian activity in a primate model of Parkinson's disease. This finding suggested clinical utility for dopamine D(1) receptor agonists in Parkinson's disease and that this utility might be critically dependent on the intrinsic efficacy of the drug. Clinical utility for dopamine D(1) receptor agonists in other central nervous disorders might also be dependent on the intrinsic efficacy of the drug. However, even though studies with dihydrexidine as a pharmacological tool have pointed to the clinical use for dopamine D(1) receptor agonists, dihydrexidine's unfavorable pharmacokinetic profile and various adverse effects are likely to restrict or even preclude its use in humans. This review article provides an updated overview of the pharmacology of dihydrexidine and discusses possible clinical utility of dopamine D(1) receptor agonists in various central nervous system disorders.
Topics: Animals; Behavior, Animal; Biochemical Phenomena; Biochemistry; Brain Diseases; Clinical Trials as Topic; Dopamine Agonists; Drug Interactions; Electrophysiology; Humans; Mental Disorders; Phenanthridines; Receptors, Dopamine D1
PubMed: 15492773
DOI: 10.1111/j.1527-3458.2004.tb00024.x -
The Journal of Pharmacology and... Apr 2018Although dystonia is often associated with abnormal dopamine neurotransmission, dopaminergic drugs are not currently used to treat dystonia because there is a general...
Although dystonia is often associated with abnormal dopamine neurotransmission, dopaminergic drugs are not currently used to treat dystonia because there is a general view that dopaminergic drugs are ineffective. However, there is little conclusive evidence to support or refute this assumption. Therefore, to assess the therapeutic potential of these compounds, we analyzed results from multiple trials of dopamine receptor agonists in patients with idiopathic dystonias and also tested the efficacy of dopamine receptor agonists in a mouse model of generalized dystonia. Our results suggest that dopamine receptor agonists were effective in some, but not all, patients tested. Further, the mixed D1/D2 dopamine receptor agonist apomorphine was apparently more effective than subtype selective D2 dopamine receptor agonists. However, rigorously controlled trials are still needed. In a mouse model of dystonia, a selective D1 dopamine receptor agonist was not effective while a selective D2 dopamine receptor had modest efficacy. However, when combined, these receptor-selective agonists acted synergistically to ameliorate the dystonia. Coactivation of D1 and D2 dopamine receptors using apomorphine or by increasing extracellular concentrations of dopamine was also effective. Thus, results from both clinical trials and tests in mice suggest that coactivation of D1 and D2 dopamine receptors may be an effective therapeutic strategy in some patients. These results support a reconsideration of dopamine receptors as targets for the treatment of dystonia, particularly because recent genetic and diagnostic advances may facilitate the identification of the subtypes of dystonia patients who respond and those who do not.
Topics: Animals; Biogenic Monoamines; Dopamine Agonists; Dystonia; Female; Humans; Male; Mice; Receptors, Dopamine D1; Receptors, Dopamine D2
PubMed: 29348266
DOI: 10.1124/jpet.117.246348 -
Expert Review of Endocrinology &... May 2019Prolactinomas represent the most common pituitary adenomas encountered in the clinic. While a majority of these tumors will be successfully treated by dopamine agonist... (Review)
Review
INTRODUCTION
Prolactinomas represent the most common pituitary adenomas encountered in the clinic. While a majority of these tumors will be successfully treated by dopamine agonist (DA) such as cabergoline, their management becomes problematic since a resistance to DA can occur and/or if the tumor displays features of aggressiveness, two conditions that are closely related.
AREAS COVERED
Epidemiology and medical treatment of prolactinomas; resistance to DA and molecular basis of DA-resistance; therapeutical alternatives in case of DA-resistant Prolactinomas and therapies in development; summarizing conclusions.
EXPERT OPINION
The management of DA-resistant prolactinomas requires a multidisciplinary approach by an expert team. Along with discussions about surgery with or without gamma knife radiosurgery, genetic screening for multiple endocrine neoplasia type 1 (MEN1) syndrome is actively discussed in a case-by-case approach. In case of surgery, a careful analysis of the tumor sample can provide information about its aggressivity potential according to recent criteria. Ultimately, temozolomide can be indicated if the tumor is rapidly growing and/or threatening for the patient.
Topics: Disease Management; Dopamine Agonists; Drug Resistance, Neoplasm; Humans; Pituitary Neoplasms; Prolactinoma; Signal Transduction; Treatment Outcome
PubMed: 30913932
DOI: 10.1080/17446651.2019.1596024 -
Psychiatry and Clinical Neurosciences Mar 2023Impulse control disorders (e.g. pathological gambling, hypersexuality) may develop as adverse reactions to drugs. Pathogenetic hypotheses have mainly focused on...
INTRODUCTION
Impulse control disorders (e.g. pathological gambling, hypersexuality) may develop as adverse reactions to drugs. Pathogenetic hypotheses have mainly focused on D3-receptor agonism, and switching to alternatives with different pharmacologic mechanisms represents a common management strategy. Nonetheless, treatment failure is common and gaining pathophysiological insights is needed.
AIM
We aimed to identify targets potentially contributing to pathologic impulsivity.
METHOD
We performed a pharmacovigilance-pharmacodynamic study on dopamine agonists and antipsychotics using the Food and Drug Administration Adverse Event Reporting System (January 2004-December 2021). We estimated disproportionate reporting using the Bayesian information component. Using online public databases (IUPHAR, ChEMBL, PDSP, DrugBank), we calculated drug occupancies. To identify the targets potentially contributing to impulsivity, we fitted univariate regression models interpolating information components and occupancies within dopamine agonists and antipsychotics. Sensitivity analyses were performed to check for the robustness of the results.
RESULTS
Among 19 887 reports of impulsivity, 5898 recorded an antipsychotic, and 3100 a dopamine agonist. The more robust signals concerned aripiprazole (N = 3091; median information component [95% confidence interval] = 4.51[4.45-4.55]) and brexpiprazole (229; 4.00[3.78-4.16]) for antipsychotics, pergolide (105; 5.82[5.50-6.06]) and pramipexole (2009; 5.43[5.36-5.48]) for dopamine agonists. Robust, significant positive associations between drug occupancy and impulsivity reporting were found for D3 within dopamine agonists (beta = 1.52; P-value = 0.047) and 5-HT1a within antipsychotics (1.92, 0.029).
CONCLUSION
Our results supported the role of D3-receptor agonism in inducing impulsivity in dopamine receptor agonists and identified a potential role of 5-HT1a receptor agonism in antipsychotics. Investigating these receptors may drive towards a better management of drug-induced impulsivity.
Topics: Humans; Dopamine Agonists; Antipsychotic Agents; Pharmacovigilance; Bayes Theorem; Disruptive, Impulse Control, and Conduct Disorders
PubMed: 36436204
DOI: 10.1111/pcn.13511 -
BMJ Case Reports Feb 2019A 47-year-old Caucasian man was referred to our clinic with a severe clinical and biochemical phenotype of endogenous hypercortisolism for further evaluation and...
A 47-year-old Caucasian man was referred to our clinic with a severe clinical and biochemical phenotype of endogenous hypercortisolism for further evaluation and treatment. In addition to confirming adrenocorticotropic hormone (ACTH)-dependent Cushing's syndrome, we found left temporal hemianopsia, massively increased prolactin, increased growth hormone/insulin-like growth factor 1 values, hypogonadotropic hypogonadism and central hypothyroidism. As the cause of these abnormalities we revealed an invasive macroadenoma of the pituitary secreting ACTH, prolactin and growth hormone, resulting not only in a clinically predominant picture of Cushing's syndrome but also causing hypogonadotropic hypogonadism and central hypothyroidism. The patient responded surprisingly well to dopamine agonist treatment leading not only to normalisation of prolactin levels but also to clinical and biochemical remission of Cushing's syndrome. Tumour size decreased successively in follow-up MRI scans. Despite lacking immunohistochemical analysis of tumour tissue, we assume plurihormonal secretion of ACTH, prolactin and growth hormone from pituitary macroadenoma, which fortunately responded well to dopamine agonist treatment.
Topics: Adenoma; Adult; Dopamine Agonists; Humans; Male; Pituitary ACTH Hypersecretion; Pituitary Neoplasms; Prolactin; Treatment Outcome
PubMed: 30765454
DOI: 10.1136/bcr-2018-228045 -
Clinical Medicine (London, England) Apr 2008
Topics: Dopamine Agonists; Female; Humans; Hyperprolactinemia; Magnetic Resonance Imaging; Male; Pregnancy
PubMed: 18478876
DOI: 10.7861/clinmedicine.8-2-216