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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 -
Neurology Nov 2021To review the current evidence on the options available for initiating dopaminergic treatment of motor symptoms in early-stage Parkinson disease and provide... (Review)
Review
BACKGROUND AND OBJECTIVES
To review the current evidence on the options available for initiating dopaminergic treatment of motor symptoms in early-stage Parkinson disease and provide recommendations to clinicians.
METHODS
A multidisciplinary panel developed practice recommendations, integrating findings from a systematic review and following an Institute of Medicine-compliant process to ensure transparency and patient engagement. Recommendations were supported by structured rationales, integrating evidence from the systematic review, related evidence, principles of care, and inferences from evidence.
RESULTS
Initial treatment with levodopa provides superior motor benefit compared to treatment with dopamine agonists, whereas levodopa is more likely than dopamine agonists to cause dyskinesia. The comparison of different formulations of dopamine agonists yielded little evidence that any one formulation or method of administration is superior. Long-acting forms of levodopa and levodopa with entacapone do not appear to differ in efficacy from immediate-release levodopa for motor symptoms in early disease. There is a higher risk of impulse control disorders associated with the use of dopamine agonists than levodopa. Recommendations on initial therapy for motor symptoms are provided to assist the clinician and patient in choosing between treatment options and to guide counseling, prescribing, and monitoring of efficacy and safety.
Topics: Dopamine Agents; Dopamine Agonists; Dyskinesia, Drug-Induced; Humans; Levodopa; Motor Activity; Parkinson Disease; Practice Guidelines as Topic
PubMed: 34782410
DOI: 10.1212/WNL.0000000000012868 -
Pituitary Jun 2023A small subset of lactotroph adenomas is resistant to dopamine agonists (DA) and can also demonstrate aggressive or even malignant behavior. The implicated mechanisms... (Review)
Review
A small subset of lactotroph adenomas is resistant to dopamine agonists (DA) and can also demonstrate aggressive or even malignant behavior. The implicated mechanisms are not clearly defined. Management can be challenging and requires a multidisciplinary approach. In DA resistant prolactinomas, switching to another DA could be the first option to consider. Further strategies include surgery and radiotherapy used alone or in combination. In cases of aggressive or malignant prolactinomas, temozolomide could be offered. Immune checkpoint inhibitors have been also recently proposed as an alternative approach. The place of other treatments (e.g., metformin, selective estrogen modulators, somatostatin analogues, tyrosine kinase inhibitors, inhibitors of mammalian target of rapamycin and peptide radio-receptor therapy) remains to be carefully assessed.
Topics: Humans; Prolactinoma; Pituitary Neoplasms; Dopamine Agonists; Temozolomide; Somatostatin
PubMed: 36928728
DOI: 10.1007/s11102-023-01305-8 -
CNS & Neurological Disorders Drug... 2024Currently, available therapeutics for the treatment of Parkinson's disease (PD) fail to provide sustained and predictable relief from motor symptoms without significant... (Review)
Review
Currently, available therapeutics for the treatment of Parkinson's disease (PD) fail to provide sustained and predictable relief from motor symptoms without significant risk of adverse events (AEs). While dopaminergic agents, particularly levodopa, may initially provide strong motor control, this efficacy can vary with disease progression. Patients may suffer from motor fluctuations, including sudden and unpredictable drop-offs in efficacy. Dopamine agonists (DAs) are often prescribed during early-stage PD with the expectation they will delay the development of levodopa-associated complications, but currently available DAs are less effective than levodopa for the treatment of motor symptoms. Furthermore, both levodopa and DAs are associated with a significant risk of AEs, many of which can be linked to strong, repeated stimulation of D2/D3 dopamine receptors. Targeting D1/D5 dopamine receptors has been hypothesized to produce strong motor benefits with a reduced risk of D2/D3-related AEs, but the development of D1-selective agonists has been previously hindered by intolerable cardiovascular AEs and poor pharmacokinetic properties. There is therefore an unmet need in PD treatment for therapeutics that provide sustained and predictable efficacy, with strong relief from motor symptoms and reduced risk of AEs. Partial agonism at D1/D5 has shown promise for providing relief from motor symptoms, potentially without the AEs associated with D2/D3-selective DAs and full D1/D5-selective DAs. Tavapadon is a novel oral partial agonist that is highly selective at D1/D5 receptors and could meet these criteria. This review summarizes currently available evidence of tavapadon's therapeutic potential for the treatment of early through advanced PD.
Topics: Humans; Dopamine Agonists; Parkinson Disease; Levodopa; Dopamine Agents; Receptors, Dopamine D2; Receptors, Dopamine D1; Antiparkinson Agents
PubMed: 36999711
DOI: 10.2174/1871527322666230331121028 -
Endocrine, Metabolic & Immune Disorders... 2023This guideline (GL) is aimed at providing a reference for the management of prolactin (PRL)-secreting pituitary adenoma in adults. However, pregnancy is not considered.
INTRODUCTION
This guideline (GL) is aimed at providing a reference for the management of prolactin (PRL)-secreting pituitary adenoma in adults. However, pregnancy is not considered.
METHODS
This GL has been developed following the methods described in the Manual of the Italian National Guideline System. For each question, the panel appointed by Associazione Medici Endocrinologi (AME) has identified potentially relevant outcomes, which have then been rated for their impact on therapeutic choices. Only outcomes classified as "critical" and "important" have been considered in the systematic review of evidence and only those classified as "critical" have been considered in the formulation of recommendations.
RESULTS
The present GL provides recommendations regarding the role of pharmacological and neurosurgical treatment in the management of prolactinomas. We recommend cabergoline (Cab) vs. bromocriptine (Br) as the firstchoice pharmacological treatment to be employed at the minimal effective dose capable of achieving the regression of the clinical picture. We suggest that medication and surgery are offered as suitable alternative first-line treatments to patients with non-invasive PRL-secreting adenoma, regardless of size. We suggest Br as an alternative drug in patients who are intolerant to Cab and are not candidates for surgery. We recommend pituitary tumor resection in patients 1) without any significant neuro-ophthalmologic improvement within two weeks from the start of Cab, 2) who are resistant or do not tolerate Cab or other dopamine-agonist drugs (DA), 3) who escape from previous efficacy of DA, and 4) who are unwilling to undergo a chronic DA treatment. We recommend that patients with progressive disease notwithstanding previous tumor resection and ongoing DA should be managed by a multidisciplinary team with specific expertise in pituitary diseases using a multimodal approach that includes repeated surgery, radiotherapy, DA, and possibly, the use of temozolomide.
CONCLUSION
The present GL is directed to endocrinologists, neurosurgeons, and gynecologists working in hospitals, in territorial services or private practice, and to general practitioners and patients.
Topics: Adult; Humans; Bromocriptine; Cabergoline; Dopamine Agonists; Ergolines; Pituitary Neoplasms; Prolactin; Prolactinoma
PubMed: 37171003
DOI: 10.2174/1871530323666230511104045 -
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 -
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 -
Journal of Neuroinflammation Oct 2022Major depressive disorder (MDD) is a prevalent and devastating psychiatric illness. Unfortunately, the current therapeutic practice, generally depending on the...
BACKGROUND
Major depressive disorder (MDD) is a prevalent and devastating psychiatric illness. Unfortunately, the current therapeutic practice, generally depending on the serotonergic system for drug treatment is unsatisfactory and shows intractable side effects. Multiple evidence suggests that dopamine (DA) and dopaminergic signals associated with neuroinflammation are highly involved in the pathophysiology of depression as well as in the mechanism of antidepressant drugs, which is still in the early stage of study and well worthy of investigation.
METHODS
We established two chronic stress models, including chronic unpredictable mild stress (CUMS), and chronic social defeat stress (CSDS), to complementarily recapitulate depression-like behaviors. Then, hippocampal tissues were used to detect inflammation-related molecules and signaling pathways. Pathological changes in depressive mouse hippocampal astrocytes were examined by RNA sequencing. After confirming the dopamine receptor 2 (Drd2)/β-arrestin2 signaling changes in the depressive mice brain, we then established the depressive mouse model using the β-arrestin2 knockout mice or administrating the β-arrestin2-biased Drd2 agonist to investigate the roles. Label-free mass spectrometry was used to identify the β-arrestin2-binding proteins as the underlying mechanisms. We modeled neuroinflammation with interleukin-6 (IL-6) and corticosterone treatment and characterized astrocytes using multiple methods including cell viability assay, flow cytometry, and confocal immunofluorescence.
RESULTS
Drd2-biased β-arrestin2 pathway is significantly changed in the progression of depression, and genetic deletion of β-arrestin2 aggravates neuroinflammation and depressive-like phenotypes. Mechanistically, astrocytic β-arrestin2 retains STAT3 in the cytoplasm by structural combination with STAT3, therefore, inhibiting the JAK-STAT3 pathway-mediated inflammatory activation. Furtherly, pharmacological activation of Drd2/β-arrestin2 pathway by UNC9995 abolishes the inflammation-induced loss of astrocytes and ameliorates depressive-like behaviors in mouse model for depression.
CONCLUSIONS
Drd2/β-arrestin2 pathway is a potential therapeutic target for depression and β-arrestin2-biased Drd2 agonist UNC9995 is identified as a potential anti-depressant strategy for preventing astrocytic dysfunctions and relieving neuropathological manifestations in mouse model for depression, which provides insights for the therapy of depression.
Topics: Animals; Astrocytes; Corticosterone; Depression; Depressive Disorder, Major; Disease Models, Animal; Dopamine; Dopamine Agonists; Hippocampus; Inflammation; Interleukin-6; Mice; Mice, Knockout; Receptors, Dopamine D2; Stress, Psychological; beta-Arrestin 1; beta-Arrestin 2
PubMed: 36183107
DOI: 10.1186/s12974-022-02597-6