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Neurotherapeutics : the Journal of the... Jan 2021Restless legs syndrome (RLS) is characterized by an uncomfortable urge to move the legs while at rest, relief upon movement or getting up to walk, and worsened symptom... (Review)
Review
Restless legs syndrome (RLS) is characterized by an uncomfortable urge to move the legs while at rest, relief upon movement or getting up to walk, and worsened symptom severity at night. RLS may be primary (idiopathic) or secondary to pregnancy or a variety of systemic disorders, especially iron deficiency, and chronic renal insufficiency. Genetic predisposition with a family history is common. The pathogenesis of RLS remains unclear but is likely to involve central nervous system dopaminergic dysfunction, as well as other, undefined contributing mechanisms. Evaluation begins with a thorough history and examination, and iron measures, including ferritin and transferrin saturation, should be checked at presentation and with worsened symptoms, especially when augmentation develops. Augmentation is characterized by more intense symptom severity, earlier symptom occurrence, and often, symptom spread from the legs to the arms or other body regions. Some people with RLS have adequate symptom control with non-pharmacological measures such as massage or temperate baths. First-line management options include iron-replacement therapy in those with evidence for reduced body-iron stores or, alternatively, with prescribed gabapentin or pregabalin, and dopamine agonists such as pramipexole, ropinirole, and rotigotine. Second-line therapies include intravenous iron infusion in those who are intolerant of oral iron and/or those having augmentation with intense, severe RLS symptoms, and opioids including tramadol, oxycodone, and methadone. RLS significantly impacts patients' quality of life and remains a therapeutic area sorely in need of innovation and a further pipeline of new, biologically informed therapies.
Topics: Dopamine Agonists; Humans; Quality of Life; Restless Legs Syndrome
PubMed: 33880737
DOI: 10.1007/s13311-021-01019-4 -
Science Advances Oct 2019Cocaine use continues to be a serious worldwide public health problem. Cocaine abuse is associated with substantial morbidity and mortality. Cocaine overdose deaths are... (Review)
Review
Cocaine use continues to be a serious worldwide public health problem. Cocaine abuse is associated with substantial morbidity and mortality. Cocaine overdose deaths are increasing in the United States and, in certain populations, outnumber heroin and opiate overdose deaths. Psychosocial treatments remain the treatments of choice for cocaine use disorder (CUD), with standard approaches including contingency management and cognitive behavioral therapy. However, the effect sizes of these treatments are not large, and they are not effective for most patients. Consequently, investigators have sought to develop pharmacological agents to augment the efficacy of psychosocial treatments. Despite these efforts, no medications have yet been proven to be safe and effective for the treatment of CUD. The most promising pharmacological strategies for CUD treatment thus far include the use of dopamine agonists, such as long-acting amphetamine and modafinil or glutamatergic and GABAergic agents such as topiramate. Combination drugs may be especially promising.
Topics: Animals; Cocaine; Cocaine-Related Disorders; Dopamine Agonists; Humans; United States
PubMed: 31663022
DOI: 10.1126/sciadv.aax1532 -
Medicina (Kaunas, Lithuania) Aug 2022Prolactinomas are the commonest form of pituitary neuroendocrine tumor (PitNET), representing approximately half of such tumors. Dopamine agonists (DAs) have... (Review)
Review
Prolactinomas are the commonest form of pituitary neuroendocrine tumor (PitNET), representing approximately half of such tumors. Dopamine agonists (DAs) have traditionally been the primary treatment for the majority of prolactinomas, with surgery considered the second line. The aim of this review is to examine the historical and modern management of prolactinomas, including medical therapy with DAs, transsphenoidal surgery, and multimodality therapy for the treatment of aggressive prolactinomas and metastatic PitNETs, with an emphasis on the efficacy, safety, and future directions of current therapeutic modalities. DAs have been the mainstay of prolactinoma management since the 1970s, initially with bromocriptine and more recently with cabergoline. Cabergoline normalizes prolactin in up to 85% of patients and causes tumor shrinkage in up to 80%. Primary surgical resection of microprolactinomas and enclosed macroprolactinomas performed by experienced pituitary neurosurgeons have similar remission rates to cabergoline. Aggressive prolactinomas and metastatic PitNETS should receive multimodality therapy including high dose cabergoline, surgery, radiation therapy (preferably using stereotactic radiosurgery where suitable), and temozolomide. DAs remain a reliable mode of therapy for most prolactinomas but results from transsphenoidal surgery in expert hands have improved considerably over the last one to two decades. Surgery should be strongly considered as primary therapy, particularly in the setting of microprolactinomas, non-invasive macroprolactinomas, or prior to attempting pregnancy, and has an important role in the management of DA resistant and aggressive prolactinomas.
Topics: Bromocriptine; Cabergoline; Dopamine Agonists; Female; Humans; Pituitary Neoplasms; Pregnancy; Prolactinoma; Treatment Outcome
PubMed: 36013562
DOI: 10.3390/medicina58081095 -
Pharmacotherapy Jan 2009Use of antipsychotic agents has been associated with hyperprolactinemia, or elevated prolactin levels; this hormonal abnormality can interfere with the functioning of... (Review)
Review
Use of antipsychotic agents has been associated with hyperprolactinemia, or elevated prolactin levels; this hormonal abnormality can interfere with the functioning of reproductive, endocrine, and metabolic systems. As antipsychotic agents are increasingly used for both United States Food and Drug Administration-approved and nonapproved indications, many individuals are at risk for developing antipsychotic-induced hyperprolactinemia. First-generation antipsychotics pose the greatest risk of causing this adverse effect; however, second-generation antipsychotics, particularly risperidone and paliperidone, also often increase prolactin secretion. Hyperprolactinemia has short- and long-term consequences that can seriously affect quality of life: menstrual disturbances, galactorrhea, sexual dysfunction, gynecomastia, infertility, decreased bone mineral density, and breast cancer. Although many of these are definitively connected to elevated prolactin levels, some, such as breast cancer, require further study. Both clinicians and patients should be aware of hyperprolactinemia-associated effects. To prevent or alleviate the condition, tailoring an antipsychotic drug regimen to each individual patient is essential. In addition, the risk of hyperprolactinemia can be minimized by using the lowest effective dose of the antipsychotic agent. If the effects of prolactin are evident, the drug can be changed to another agent that is less likely to affect prolactin levels; alternatively, a dopamine agonist may be added, although this may compromise antipsychotic efficacy. Additional research is needed to clarify the appropriate level of monitoring, the long-term effects, and the optimal treatment of antipsychotic-induced hyperprolactinemia.
Topics: Antipsychotic Agents; Bone Density; Breast Neoplasms; Dopamine Agonists; Female; Humans; Hyperprolactinemia; Menstrual Cycle; Meta-Analysis as Topic; Pituitary Neoplasms; Prolactin; Randomized Controlled Trials as Topic; Sexual Dysfunction, Physiological
PubMed: 19113797
DOI: 10.1592/phco.29.1.64 -
European Journal of Clinical... Dec 2020To investigate the comparative effectiveness of dopamine agonists and monoamine oxidase type-B (MAO-B) inhibitors available for treatment of Parkinson's disease. (Comparative Study)
Comparative Study Meta-Analysis
PURPOSE
To investigate the comparative effectiveness of dopamine agonists and monoamine oxidase type-B (MAO-B) inhibitors available for treatment of Parkinson's disease.
METHODS
We performed a systematic literature search identifying randomized controlled trials investigating 4 dopamine agonists (cabergoline, pramipexole, ropinirole, rotigotine) and 3 MAO-B inhibitors (selegiline, rasagiline, safinamide) for Parkinson's disease. We extracted and pooled data from included clinical trials in a joint model allowing both direct and indirect comparison of the seven drugs. We considered dopamine agonists and MAO-B inhibitors given as monotherapy or in combination with levodopa. Selected endpoints were change in the Unified Parkinson's Disease Rating Scale (UPDRS) score, serious adverse events and withdrawals. We estimated the relative effectiveness of each dopamine agonist and MAO-B inhibitor versus comparator drug.
RESULTS
Altogether, 79 publications were included in the analysis. We found all the investigated drugs to be effective compared with placebo when given as monotherapy except safinamide. When considering combination treatment, the estimated relative effects of selegiline, pramipexole, ropinirole, rotigotine, cabergoline, rasagiline and safinamide were 2.316 (1.819, 2.951), 2.091 (1.889, 2.317), 2.037 (1.804, 2.294), 1.912 (1.716, 2.129), 1.664 (1.113, 2.418), 1.584 (1.379, 1.820) and 1.179 (1.031, 1.352), respectively, compared with joint placebo and levodopa treatment.
CONCLUSIONS
Dopamine agonists were found to be effective as treatment for Parkinson's disease, both when given as monotherapy and in combination with levodopa. Selegiline and rasagiline were also found to be effective for treating Parkinson's disease, and selegiline was the best option in combination with levodopa among all the drugs investigated.
Topics: Dopamine Agonists; Drug Therapy, Combination; Humans; Indans; Levodopa; Monoamine Oxidase Inhibitors; Parkinson Disease; Randomized Controlled Trials as Topic; Selegiline; Treatment Outcome
PubMed: 32710141
DOI: 10.1007/s00228-020-02961-6 -
Psychogeriatrics : the Official Journal... Sep 2013Dopaminergic dysfunction is implicated in the pathophysiology of treatment-resistant depression. In this review, we describe the putative role of dopamine in depression,... (Review)
Review
Dopaminergic dysfunction is implicated in the pathophysiology of treatment-resistant depression. In this review, we describe the putative role of dopamine in depression, summarize the evidence for the efficacy of dopamine receptor agonists in the treatment of treatment-resistant depression, and discuss the underlying mechanisms by which these medications work. Both preclinical and clinical data suggest that adjunctive dopamine agonists could be a promising option for the treatment of such a condition, indicating that there is a dopamine agonist-responsive subgroup of depression. Future clinical studies are warranted to clarify unresolved issues regarding dopamine agonists such as long-term efficacy, efficacy as a monotherapy, and efficacy for juvenile and senile depression. Further basic research is also necessary to fully understand how dopamine acts in the brain of depressed patients.
Topics: Depressive Disorder; Dopamine; Dopamine Agonists; Humans
PubMed: 25913769
DOI: 10.1111/psyg.12014 -
Neuroendocrinology 2022Dopamine agonists (DAs) are preferred for the treatment of prolactinomas and are usually very effective. Nonetheless, 20-30% of bromocriptine- and approximately 10% of... (Review)
Review
Dopamine agonists (DAs) are preferred for the treatment of prolactinomas and are usually very effective. Nonetheless, 20-30% of bromocriptine- and approximately 10% of cabergoline-treated individuals exhibit resistance to DAs. In addition, the mechanism underlying this phenomenon remains elusive. In this study, we summarize the major findings regarding the role of microRNAs (miRNAs) in the pathogenesis of DA-resistant prolactinoma (DARP). Currently available evidence suggests that miRNAs are usually dysregulated in DARP and that, although controversial, the dysregulated miRNAs target the transforming growth factor (TGF)-β, dopamine 2 receptor (D2R), or estradiol (E2)/estrogen receptor (ER) signaling pathways to mediate the therapeutic effect of DAs. These findings provide new incentives for research on innovative strategies for predicting patients' responsiveness to dopamine therapies and for developing treatment approaches. Unfortunately, recent studies tended to focus exclusively on the differential miRNA expression profiles between DARP and dopamine-sensitive prolactinoma, and no definitive consensus has been reached regarding the role of these miRNAs in the modulation mechanism. Therefore, current and future efforts should be directed toward the exploration of the mechanism underlying the dysregulation of miRNAs as well as of the target proteins that are affected by the dysregulated miRNAs. Furthermore, the modulation of the expression of dysregulated miRNAs, which target the D2R, TGF-β, or E2/ER signaling pathways, might be a promising alternative to treat patients with DARP and improve their prognosis.
Topics: Dopamine; Dopamine Agonists; Drug Resistance, Neoplasm; Humans; MicroRNAs; Pituitary Neoplasms; Prolactinoma
PubMed: 34034260
DOI: 10.1159/000517356 -
JAMA Neurology Feb 2022Many people with Parkinson disease (PD) develop motor complications that are uncontrolled by levodopa dose adjustment. Among these patients, it is uncertain which drug... (Randomized Controlled Trial)
Randomized Controlled Trial
Long-term Effectiveness of Adjuvant Treatment With Catechol-O-Methyltransferase or Monoamine Oxidase B Inhibitors Compared With Dopamine Agonists Among Patients With Parkinson Disease Uncontrolled by Levodopa Therapy: The PD MED Randomized Clinical Trial.
IMPORTANCE
Many people with Parkinson disease (PD) develop motor complications that are uncontrolled by levodopa dose adjustment. Among these patients, it is uncertain which drug class is more effective as adjuvant therapy.
OBJECTIVE
To compare the long-term effects on patient-rated quality of life of adding a dopamine agonist vs a dopamine reuptake inhibitor (DRI), either a monoamine oxidase type B (MAO-B) inhibitor or a catechol-O-methyltransferase (COMT) inhibitor, to levodopa therapy for the treatment of patients with motor complications of PD.
DESIGN, SETTING, AND PARTICIPANTS
This pragmatic semifactorial (2 × 1) randomized clinical trial recruited from 64 neurology and geriatric clinics (62 in the United Kingdom, 1 in the Czech Republic, and 1 in Russia) between February 23, 2001, and December 15, 2009. A total of 500 patients with idiopathic PD who developed uncontrolled motor complications and did not have dementia were randomly assigned on a 1:1:1 basis using a computerized minimization program. Data were analyzed between 2017 and 2020.
INTERVENTIONS
Open-label dopamine agonist, MAO-B inhibitor, or COMT inhibitor.
MAIN OUTCOMES AND MEASURES
Primary outcomes were scores on the 39-item Parkinson's Disease Questionnaire (PDQ-39) mobility domain and cost-effectiveness. Outcomes were assessed before study entry, at 6 and 12 months after randomization, and annually thereafter. Repeated-measures and log rank analyses were used in an intention-to-treat approach.
RESULTS
Among 500 participants, the mean (SD) age was 73.0 (8.2) years; 314 participants (62.8%) were men. Over a median of 4.5 years (range, 0-13.3 years) of follow-up, the participants in the dopamine agonist group had a mean PDQ-39 mobility score that was 2.4 points (95% CI, -1.3 to 6.0 points) better than that of the combined MAO-B and COMT groups; however, this difference was not significant (P=.20). With regard to DRIs, participants in the MAO-B group had mean PDQ-39 mobility scores that were 4.2 points (95% CI, 0.4-7.9 points; P=.03) better than those of the COMT group and EuroQol 5-dimension 3-level (EQ-5D-3L) utility scores that were 0.05 points (95% CI, 0.003-0.09 points; P=.04) better than the COMT group. Nonsignificant improvements were found in the PDQ-39 summary index (mean difference, 2.2 points; 95% CI, -0.2 to 4.5 points; P=.07) along with nonsignificant reductions in dementia (rate ratio [RR], 0.70; 95% CI, 0.47-1.03; P = .07) and mortality (RR, 0.76; 95% CI, 0.56-1.03; P=.07). When dopamine agonists were compared with MAO-B inhibitors only, the outcomes were similar.
CONCLUSIONS AND RELEVANCE
In this study, patient-rated quality of life was inferior when COMT inhibitors were used as adjuvant treatment compared with MAO-B inhibitors or dopamine agonists among people with PD who experienced motor complications that were uncontrolled by levodopa therapy. The MAO-B inhibitors produced equivalent disease control, suggesting that these agents may be underused as adjuvant therapy.
TRIAL REGISTRATION
isrctn.org Identifier: ISRCTN69812316; EU Clinical Trials Register Identifier: 2005-001813-16.
Topics: Aged; Aged, 80 and over; Antiparkinson Agents; Catechol O-Methyltransferase; Catechol O-Methyltransferase Inhibitors; Chemotherapy, Adjuvant; Dopamine Agonists; Enzyme Inhibitors; Female; Humans; Levodopa; Male; Middle Aged; Monoamine Oxidase Inhibitors; Movement Disorders; Parkinson Disease; Quality of Life; Treatment Outcome
PubMed: 34962574
DOI: 10.1001/jamaneurol.2021.4736 -
Dopamine Agonist Cotreatment Alters Neuroplasticity and Pharmacology of Levodopa-Induced Dyskinesia.Movement Disorders : Official Journal... Mar 2023Current models of levodopa (L-dopa)-induced dyskinesia (LID) are obtained by treating dopamine-depleted animals with L-dopa. However, patients with LID receive...
BACKGROUND
Current models of levodopa (L-dopa)-induced dyskinesia (LID) are obtained by treating dopamine-depleted animals with L-dopa. However, patients with LID receive combination therapies that often include dopamine agonists.
OBJECTIVE
Using 6-hydroxydopamine-lesioned rats as a model, we aimed to establish whether an adjunct treatment with the D2/3 agonist ropinirole impacts on patterns of LID-related neuroplasticity and drug responses.
METHODS
Different regimens of L-dopa monotreatment and L-dopa-ropinirole cotreatment were compared using measures of hypokinesia and dyskinesia. Striatal expression of ∆FosB and angiogenesis markers were studied immunohistochemically. Antidyskinetic effects of different drug categories were investigated in parallel groups of rats receiving either L-dopa monotreatment or L-dopa combined with ropinirole.
RESULTS
We defined chronic regimens of L-dopa monotreatment and L-dopa-ropinirole cotreatment inducing overall similar abnormal involuntary movement scores. Compared with the monotreatment group, animals receiving the L-dopa-ropinirole combination exhibited an overall lower striatal expression of ∆FosB with a distinctive compartmental distribution. The expression of angiogenesis markers and blood-brain barrier hyperpermeability was markedly reduced after L-dopa-ropinirole cotreatment compared with L-dopa monotreatment. Moreover, significant group differences were detected upon examining the response to candidate antidyskinetic drugs. In particular, compounds modulating D1 receptor signaling had a stronger effect in the L-dopa-only group, whereas both amantadine and the selective NMDA antagonist MK801 produced a markedly larger antidyskinetic effect in L-dopa-ropinirole cotreated animals.
CONCLUSIONS
Cotreatment with ropinirole altered LID-related neuroplasticity and pharmacological response profiles. The impact of adjuvant dopamine agonist treatment should be taken into consideration when investigating LID mechanisms and candidate interventions in both clinical and experimental settings. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Topics: Rats; Animals; Levodopa; Dopamine Agonists; Antiparkinson Agents; Rats, Sprague-Dawley; Dyskinesia, Drug-Induced; Oxidopamine; Disease Models, Animal
PubMed: 36656044
DOI: 10.1002/mds.29301 -
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