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Objective: This study aimed to understand the effect of time to remission of acromegaly on survival in people living with acromegaly. Design, Patients and Measurement: This cross‐sectional study used data from the UK Acromegaly Register. We considered remission of acromegaly growth hormone controlled at ≤2 μg/L following the diagnosis of acromegaly. We used the accelerated failure time model to assess the effect of time to remission on survival in acromegaly. Results: The study population comprises 3569 individuals with acromegaly, with a median age of diagnosis of 47.3 (36.5–57.8) years, 48% females and a majority white population (61%). The number of individuals with the first remission of acromegaly was 2472, and the median time to first remission was 1.92 (0.70–6.58) years. In this study, time to first remission in acromegaly was found to have a significant effect on survival (p <.001); for every 1‐year increase in time to first remission, there was a median 1% reduction in survival in acromegaly. In an analysis adjusted for covariates, the survival rate was 52% higher (p <.001) in those who underwent surgery as compared to those who did not have surgery, 18% higher (p =.01) in those who received treatment with somatostatin analogues (SMA) as compared to those with dopamine agonists and 21% lower (p <.001) in those who received conventional radiotherapy as compared to those who did not receive radiotherapy. Conclusion: In conclusion, this population‐based study conducted in patients with acromegaly revealed that faster remission time, surgical intervention and treatment with SMA are linked to improved survival outcomes. [ABSTRACT FROM AUTHOR]

Objective: Acromegaly is associated with increased morbidity and mortality if left untreated. The therapeutic options include surgery, medical treatment, and radiotherapy. Several guidelines and recommendations on treatment algorithms and follow‐up exist. However, not all recommendations are strictly evidence‐based. To evaluate consensus on the treatment and follow‐up of patients with acromegaly in the Nordic countries. Methods: A Delphi process was used to map the landscape of acromegaly management in Denmark, Sweden, Norway, Finland, and Iceland. An expert panel developed 37 statements on the treatment and follow‐up of patients with acromegaly. Dedicated endocrinologists (n = 47) from the Nordic countries were invited to rate their extent of agreement with the statements, using a Likert‐type scale (1−7). Consensus was defined as ≥80% of panelists rating their agreement as ≥5 or ≤3 on the Likert‐type scale. Results: Consensus was reached in 41% (15/37) of the statements. Panelists agreed that pituitary surgery remains first line treatment. There was general agreement to recommend first‐generation somatostatin analog (SSA) treatment after failed surgery and to consider repeat surgery. In addition, there was agreement to recommend combination therapy with first‐generation SSA and pegvisomant as second‐ or third‐line treatment. In more than 50% of the statements, consensus was not achieved. Considerable disagreement existed regarding pegvisomant monotherapy, and treatment with pasireotide and dopamine agonists. Conclusion: This consensus exploration study on the management of patients with acromegaly in the Nordic countries revealed a relatively large degree of disagreement among experts, which mirrors the complexity of the disease and the shortage of evidence‐based data. [ABSTRACT FROM AUTHOR]

Context Prolactinoma, the most common subtype of pituitary adenoma, is rare in children and adolescents. Clinical presentation and treatment outcomes of prolactinomas in this population have been evaluated insufficiently. Objective To summarize the clinical features, both medication and surgical outcomes of prolactinomas in children and adolescents in a large retrospective cohort from China. Methods A cohort of patients with prolactinomas aged ≤20 years at diagnosis between 2012 and 2021 in Peking Union Medical College Hospital were retrospectively analyzed. Results The cohort comprised 170 patients (115 females and 55 males, median age 16.6 years), with 20.0% (23/115) girls without menarche and 33.3% (18/54) boys in prepuberty. The median maximal diameter was 15.0 mm (61.2% macroadenomas and 4.6% giant adenomas), and the median baseline prolactin (PRL) level was 211.0 ng/mL. Larger sizes and higher PRL levels were observed in girls without menarche at diagnosis and in boys. Most girls presented with menstrual disturbance (86.7%), and boys were frequently bothered by headaches (42.6%), reduced height velocities (25.9%), and delayed puberty (18.2%). Dopamine agonists (DAs) were used as first-line treatment in 133 patients, and the resistance rate was 22.5% (25/111), independently associated with maximal tumor diameters (P =.035). Surgery was performed in 76 patients. Long-term surgical remission rates were 32.9% (25/76) overall, negatively associated with cavernous sinus invasion independently (P =.025), 59.4% (19/32) in noninvasive tumors (64.0% in 25 noninvasive macroadenomas), and 5.0% (1/20) in invasive tumors. Conclusion Pediatric prolactinomas exhibited more severe clinical characteristics in boys and in patients diagnosed during earlier stages of pubertal developments. Given the overall efficacy of PRL normalization by medication and considerable surgical remission rate in noninvasive tumors, DAs remain the first-line recommendation for prolactinomas in children and adolescents, while surgery might be viable for noninvasive tumors. [ABSTRACT FROM AUTHOR]

Introduction and purpose Cariprazine is an atypical antipsychotic drug approved for the treatment of schizophrenia, as well as manic and mixed episodes associated with bipolar disorder. It functions as a dopamine multifunctional agent, a partial agonist at dopamine and serotonin receptors. Unlike the majority of antipsychotics, which primarily target positive symptoms through dopaminergic antagonism, often neglecting negative, cognitive, and affective symptoms, the unique cariprazine's pharmacological profile, particularly potent blockade of D3 dopamine receptors, suggests the potential for numerous clinical applications. The aim of this study is to present current knowledge of cariprazine, focusing particularly on its mechanism of action, potential applications, adverse effects, and pharmacokinetic properties that could impact its clinical use. Methods and materials A review of the literature available in the PubMed database was performed using the key words: cariprazine; atypical antipsychotic drug; antipsychotic medication; schizophrenia treatment; bipolar disorder treatment; mania treatment; depression treatment, dopamine agonist. Conclusions Cariprazine demonstrates a unique pharmacological profile, offering potential benefits in managing a wide range of psychiatric disorders, including schizophrenia, bipolar disorder (mania, depression, mixed episodes), unipolar depression, and co-occurring substance use disorders. Clinical studies have shown efficacy in reducing symptoms and improving negative and cognitive function, with a favorable metabolic profile, minimal impact on cardiovascular system, and generally mild adverse effect profile. However, further research is necessary to explore its full therapeutic potential and optimize its clinical use in diverse patient populations. [ABSTRACT FROM AUTHOR]

Background Objectives Methods Results Conclusions There has been a long debate whether delaying treatment with levodopa prevents motor complications in Parkinson's disease (PD).We performed a meta‐analysis on randomized clinical trials (RCTs) that compared early‐ versus delayed‐start treatment with levodopa in PD.A systematic review was conducted in PubMed, EMBASE, and Web of Science databases from inception to July 1, 2023. Only RCTs that compared early and delayed levodopa treatment in PD were included. Non‐randomized comparisons from follow‐up studies were included as well. Our primary outcomes were occurrence of overall motor complications, motor fluctuations, and dyskinesias.Seven studies with a total of 1149 patients (636 in the early‐start group and 513 in the delayed‐start) were included in our analysis. There was no difference between groups regarding motor complications (OR 1.39; 95% CI: 0.68–1.72; P = 0.37) or dyskinesias (OR 1.52; 95% CI: 0.90–2.57; P = 0.11). Motor fluctuations occurred less frequently in the early‐start group (OR 0.70; 95% CI: 0.52–0.95; P = 0.02). Nonetheless, on subgroup analysis of dopamine agonists, rate of dyskinesias was smaller in the delayed‐start group (OR 1.82; 95% CI: 1.08–3.07; P = 0.03).Delaying treatment with levodopa does not seem to prevent levodopa‐related motor complications in PD. Adjunct treatment with dopamine agonists may reduce the need for higher doses of levodopa and thus reduce the risk for dyskinesias but this practice is often associated with a higher frequency of adverse effects related to dopamine agonists. [ABSTRACT FROM AUTHOR]

Summary This study aimed to investigate sex‐related differences in the response to ropinirole and pramipexole in patients with restless legs syndrome (RLS). By analysing clinical parameters and polysomnographic (PSG) findings, we sought to elucidate the potential factors related to sex disparities modulating treatment responses and sleep quality in RLS. A total of 41 drug‐free patients with RLS, aged ≥18 years, underwent two consecutive nocturnal PSG recordings, without medication at baseline; before the second night, 26 patients received an oral dose of 0.25 mg pramipexole whereas 15 received 0.5 mg ropinirole. After each PSG recording, patients self‐evaluated the severity of their previous night symptoms by means of an ad hoc visual analogue scale (VAS). At baseline, sleep efficiency and percentage of Stage N2 tended to be higher in females while wakefulness after sleep onset was significantly higher in males. After treatment, total leg movements during sleep (LMS), periodic LMS (PLMS), and periodicity indexes were significantly lower in females than in males. The VAS score was lower after treatment in all patients, without differences between the two sexes. This study demonstrates a higher acute responsiveness of PLMS to dopamine agonists (pramipexole and ropinirole) in females than in males with RLS. These findings might be explained by differential sex‐related expression of dopamine receptors, especially D3, within the central nervous system. In addition, our findings provide translational hints toward a better tailored and sex‐specific approach to the treatment of RLS associated with PLMS, with dopamine agonist possibly associated with a better outcome in females than in males. [ABSTRACT FROM AUTHOR]

In patients with Parkinson's disease (PD), dopamine replacement therapy with dopamine D2/D3 receptor agonists induces impairments in decision-making, including pathological gambling. The neurobiological mechanisms underlying these adverse effects remain elusive. Here, in a mouse model of PD, we investigated the effects of the dopamine D3 receptor (D3R)-preferring agonist pramipexole (PPX) on decision-making. PD model mice were generated using a bilateral injection of the toxin 6-hydroxydopamine into the dorsolateral striatum. Subsequent treatment with PPX increased disadvantageous choices characterized by a high-risk/high-reward in the touchscreen-based Iowa Gambling Task. This effect was blocked by treatment with the selective D3R antagonist PG-01037. In model mice treated with PPX, the number of c-Fos-positive cells was increased in the external globus pallidus (GPe), indicating dysregulation of the indirect pathway in the corticothalamic-basal ganglia circuitry. In accordance, chemogenetic inhibition of the GPe restored normal c-Fos activation and rescued PPX-induced disadvantageous choices. These findings demonstrate that the hyperactivation of GPe neurons in the indirect pathway impairs decision-making in PD model mice. The results provide a candidate mechanism and therapeutic target for pathological gambling observed during D2/D3 receptor pharmacotherapy in PD patients. [ABSTRACT FROM AUTHOR]

Background: Emotionally unstable personality disorder (EUPD) is debilitating psychiatric disorder, particularly common in female and forensic populations. However, appropriate pharmacological treatment to effectively manage symptoms of EUPD remains an unmet clinical need. Dopamine receptor partial agonists (DRPAs), such as aripiprazole, have a favourable tolerability profile and have demonstrated some benefits in targeting symptoms of emotional dysregulation, although, evidence regarding the effects of novel D2/D3 DRPA cariprazine in EUPD patients has been limited. Objectives: To evaluate the efficacy and tolerability of cariprazine for EUPD in a case series of female forensic inpatients where the diagnosis is more prevalent. Methods: Demographic and clinical information of the patients were collected from patient electronic records during their admission in a specialized NHS forensic service. Treatment response was measured using the Positive and Negative Syndrome Scale (PANSS) at baseline, 3 and 6 months and Global Clinical Impression Scale (CGI-scores) at baseline and 6 months. Tolerability and BMI, ECG QTc interval and prolactin levels were recorded prior to initiation and at 6 months. Results: Eight female patients with EUPD (mean age 29.8 years, SD 5.3) were treated with cariprazine (range 3-6mg). Total CGI-scores modestly improved from 5.6 baseline to 5.0 at 6 months. There was a reduction in mean total PANSS scores from baseline to 6 months (92.5, SD 8.1 to 72.4, SD 15.8), general psychopathology (56.1 SD 6.7 to 42.5, SD9.7), positive (21.9 SD 4.6 to 17.1, SD4.8) and negative PANSS scores (14.5 SD 6.3 to 12.8, SD4.6), corresponding to a 21%, 23%, 20% and 3% mean score reduction, respectively. Cariprazine demonstrated a favourable metabolic and hormonal side effect profile with no treatment discontinuation at 6 months follow up. Conclusion: This is the first case series to evaluate the effectiveness of cariprazine in EUPD. Its efficacy in improving PANSS and CGI-S scores was overall modest and highly variable, reflective of an inherently heterogenous and comorbid patient sample but the benefits on treatment perseverance and tolerability were considerable. Cariprazine may be of particular benefit in EUPD where psychotic symptoms are co-morbid, as an augmentation strategy to clozapine, or where previous antipsychotics have caused metabolic or hormonal side effects. [ABSTRACT FROM AUTHOR]

Reports suggest possible risks of adverse cardiovascular reactions, including heart failure, associated with non-ergot dopamine agonist (DA) use in Parkinson's disease (PD). The objectives of our review were to evaluate the risk of heart failure and other adverse cardiovascular reactions in PD patients who received a non-ergot DA compared with other anti-PD pharmacological interventions, placebo, or no intervention. Studies were identified via searches of six bibliographic databases. Randomized controlled trials (RCTs) and non-randomized studies (NRS) were eligible for study inclusion. Random-effect meta-analyses were performed to estimate adverse cardiovascular reaction risks. Quality of evidence was assessed using GRADE. In total, forty-four studies (thirty-six RCTs and eight NRS) satisfied our inclusion criteria. A single RCT found no significant difference in the risk of heart failure with ropinirole compared with bromocriptine (odds ratio (OR) 0.39, 95% confidence interval (CI) 0.07 to 2.04; low certainty). Conversely, three case–control studies reported a risk of heart failure with non-ergot DA treatment. The quality of evidence for the risk of heart failure was judged as low or very low. Findings suggest that non-ergot DA use may be associated with adverse cardiovascular outcomes, including heart failure. Studies are needed to better understand cardiovascular risks associated with PD treatment. [ABSTRACT FROM AUTHOR]

Introduction: Parkinson's disease (PD) patients harboring recessive gene variants exhibit a distinct clinical phenotype with an early disease onset and relatively mild symptoms. Data concerning individualized therapy for autosomal recessive PD forms are still scarce. Methods: Demographic and treatment data of a cohort of PD carriers of recessive genes (nine homozygous or compound heterozygous PRKN carriers, four heterozygous PRKN carriers, and three biallelic PINK1 carriers) were evaluated. Results: The average levodopa equivalent daily dose (LEDD) was 806.8 ± 453.5 (range 152–1810) in PRKN carriers and 765 ± 96.6 (range 660–850) in PINK1 carriers. The majority responded to low/moderate doses of levodopa. The response to dopamine agonists (DAs) was often favorable both as initial and longitudinal therapy. In total, 8/13 PRKN and 1/3 PINK1 carriers were treated with amantadine successfully, and this also applied to patients who could not tolerate levodopa or DAs. Conclusions: In the era of personalized treatment, the therapeutic approach in recessive PD gene carriers might differ as compared to idiopathic PD. Lower LEDD doses were efficient even in patients with a very long disease duration, while a few patients were doing well without any levodopa treatment decades after disease initiation. DAs or amantadine could be used as a first and main line treatment regimen if well tolerated. Literature data on therapeutic strategies in carriers of pathogenic mutations in recessive PD genes, including device-aided treatments, will be further discussed. [ABSTRACT FROM AUTHOR]

PDE10A inhibition represents a potential mechanism for treating schizophrenia. PDE10A inhibitors increase cyclic nucleotides in striatal neurons, thereby mimicking the effects of dopamine receptor D2 antagonists and D1 agonists. We evaluated the PDE10A inhibitor MK-8189 for treating schizophrenia. Randomized, double-blind, placebo and active-controlled, phase 2a, multicenter, inpatient trial in adults experiencing an acute episode of schizophrenia. Participants were randomized 2:2:1 to once-daily MK-8189 12 mg, placebo, or risperidone 6 mg (active control) for 4-weeks. The primary outcome was change-from-baseline in total score on the Positive and Negative Syndrome Scale (PANSS) at 4 weeks. The number of treated participants was 90 for MK-8189, 89 for placebo, and 45 for risperidone. MK-8189 demonstrated a trend towards improvement versus placebo for change-from-baseline in PANSS total score after 4 weeks (difference = −4.7 [95 % CI: −9.8,0.5], P = 0.074). The active control risperidone was superior to placebo on PANNS total score (difference = −7.3 [95 % CI: −14.0,−0.6], P = 0.033), demonstrating assay sensitivity, while MK-8189 and risperidone did not significantly differ (difference = 2.6 [95 % CI: −4.0,9.2], P = 0.440). MK-8189 had a nominally significant effect on PANSS positive subscale score compared to placebo (difference = −2.2 [95 % CI: −3.8,−0.5], P = 0.011). Discontinuation of MK-8189 treatment due to an adverse event was low (<10 %). Extrapyramidal symptoms occurred with MK-8189 but were mostly mild and transient. Compared with placebo, MK-8189 reduced body weight while risperidone increased weight. These findings suggest that PDE10A inhibition may produce antipsychotic effects and associated weight loss and that further trials with PDE10A inhibitors are warranted. Clinicaltrials.gov identifier: NCT03055338 [ABSTRACT FROM AUTHOR]

Impulse control disorders and their consequences display variability among individuals, indicating potential involvement of environmental and genetic factors. In this retrospective study, we analyzed a cohort of Parkinson's disease patients treated with dopamine agonists and investigated the influence of the dopamine D4 receptor gene polymorphism, DRD4 7R+, which is linked to psychiatric disorders, impulsive traits, and addictive behaviors. We found that DRD4 7R+ is a significant genetic risk factor associated with the severity of ICD. [ABSTRACT FROM AUTHOR]

Rationale: Internally perceived stimuli evoked by morphine administration can form Pavlovian associations such that they can function as occasion setters (OSs) for externally perceived reward cues in rats, coming to modulate reward-seeking behaviour. Though much research has investigated mechanisms underlying opioid-related reinforcement and analgesia, neurotransmitter systems involved in the functioning of opioids as Pavlovian interoceptive discriminative stimuli remain to be disentangled despite documented differences in the development of tolerance to analgesic versus discriminative stimulus effects. Objectives: Dopamine has been implicated in many opioid-related behaviours, so we aimed to investigate the role of this neurotransmitter in expression of morphine occasion setting. Methods: Male and female rats were assigned to positive- (FP) or negative-feature (FN) groups and received an injection of morphine or saline before each training session. A 15-s white noise conditioned stimulus (CS) was presented 8 times during every training session; offset of this stimulus was followed by 4-s access to liquid sucrose on morphine, but not saline, sessions for FP rats. FN rats learned the reverse contingency. Following stable discrimination, rats began generalization testing for expression of morphine-guided sucrose seeking after systemic pretreatment with different doses of the non-selective dopamine receptor antagonist, flupenthixol, and the non-selective dopamine receptor agonist, apomorphine, combined with training doses of morphine or saline in a Latin-square design. Results: The morphine discrimination was acquired under both FP and FN contingencies by males and females. Neither flupenthixol nor apomorphine at any dose substituted for morphine, but both apomorphine and flupenthixol disrupted expression of the morphine OS. This inhibition was specific to sucrose seeking during CS presentations rather than during the period before CS onset and, in the case of apomorphine more so than flupenthixol, to trials on which access to sucrose was anticipated. Conclusions: Our findings lend support to a mechanism of occasion setting involving gating of CS-induced dopamine release rather than by direct dopaminergic modulation by the morphine stimulus. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD), affecting about ten million people globally, presents a significant health challenge. Rotigotine (RTG), a dopamine agonist, is currently administered as a transdermal patch (Neupro®) for PD treatment, but the daily application can be burdensome and cause skin irritation. This study introduces a combinatorial approach of dissolving microarray patch (MAP) and nanosuspension (NS) for the transdermal delivery of RTG, offering an alternative to Neupro®. The RTG-NS was formulated using a miniaturized media milling method, resulting in a nano-formulation with a mean particle size of 274.09 ± 7.43 nm, a PDI of 0.17 ± 0.04 and a zeta potential of −15.24 ± 2.86 mV. The in vitro dissolution study revealed an enhanced dissolution rate of the RTG-NS in comparison to the coarse RTG powder, under sink condition. The RTG-NS MAPs, containing a drug layer and a 'drug-free' supporting baseplate, have a drug content of 3.06 ± 0.15 mg/0.5 cm2 and demonstrated greater amount of drug delivered per unit area (∼0.52 mg/0.5 cm2) than Neupro® (∼0.20 mg/1 cm2) in an ex vivo Franz cell study using full-thickness neonatal porcine skin. The in vivo pharmacokinetic studies demonstrated that RTG-NS MAPs, though smaller (2 cm2 for dissolving MAPs and 6 cm2 for Neupro®), delivered drug levels comparable to Neupro®, indicating higher efficiency per unit area. This could potentially avoid unnecessarily high plasma levels after the next dose at 24 h, highlighting the benefits of dissolving MAPs over conventional transdermal patches in PD treatment. [Display omitted] • An alternative approach to deliver rotigotine via microarray patch was introduced. • Dose per unit area can be improved by using such approach in comparison to Neupro®. • A single 24 h application can provide therapeutic rotigotine levels to at least 2 days. • Unnecessarily high rotigotine plasma level may be avoided by using such approach. [ABSTRACT FROM AUTHOR]

Neuromodulation in the retina is crucial for effective processing of retinal signal at different levels of illuminance. Intrinsically photosensitive retinal ganglion cells (ipRGCs), the neurons that drive nonimage-forming visual functions, express a variety of neuromodulatory receptors that tune intrinsic excitability as well as synaptic inputs. Past research has examined actions of neuromodulators on light responsiveness of ipRGCs, but less is known about how neuromodulation affects synaptic currents in ipRGCs. To better understand how neuromodulators affect synaptic processing in ipRGC, we examine actions of opioid and dopamine agonists have on inhibitory synaptic currents in ipRGCs. Although µ-opioid receptor (MOR) activation had no effect on γ-aminobutyric acid (GABA) currents, dopamine [via the D1-type dopamine receptor (D1R)]) amplified GABAergic currents in a subset of ipRGCs. Furthermore, this D1R-mediated facilitation of the GABA conductance in ipRGCs was mediated by a cAMP/PKA-dependent mechanism. Taken together, these findings reinforce the idea that dopamine's modulatory role in retinal adaptation affects both nonimage-forming and image-forming visual functions. NEW & NOTEWORTHY: Neuromodulators such as dopamine are important regulators of retinal function. Here, we demonstrate that dopamine increases inhibitory inputs to intrinsically photosensitive retinal ganglion cells (ipRGCs), in addition to its previously established effect on intrinsic light responsiveness. This indicates that dopamine, in addition to its ability to intrinsically modulate ipRGC activity, can also affect synaptic inputs to ipRGCs, thereby tuning retina circuits involved in nonimage-forming visual functions. [ABSTRACT FROM AUTHOR]

Purpose: To estimate incidence rates of suicidal ideation and behavior following treatment initiation with gabapentinoids or dopamine agonists (DAs) in patients with newly diagnosed early‐onset idiopathic restless legs syndrome (RLS) and to examine suicidal behavior risk, comparing between those receiving gabapentinoids and DAs. Methods: A new user retrospective cohort study using MarketScan claims data from 2012 to 2019 was conducted. Exposures were monotherapy gabapentinoids or DAs initiated within 60 days of new RLS diagnosis. Three varying outcome measures of suicidality were examined and incidence rates were calculated for each. A log‐binomial regression model the estimated relative risk (RR) of the outcomes with gabapentinoids. Propensity score weighting adjusted for baseline covariates, including age, substance use disorders, hyperlipidemia, antipsychotic use, hypnotic/sedative use, and mood stabilizer use, which were most imbalanced before weighting. Results: The cohort included 6672 patients, with 4986 (74.7%) initiating a DA and 1686 (25.3%) initiating a gabapentinoid. Incidence rates for all outcome measures were higher in the gabapentinoid group (suicidality: 21.6 vs. 10.7 per 1000 person‐years; suicidality with self‐harm: 23.0 vs. 11.1 per 1000 person‐years; overdose‐ and suicide‐related events: 30.0 vs. 15.5 person‐years). Associated risk of suicidality (adjusted RR, 1.27 [95% CI, 0.86–1.88]); suicidality with self‐harm (adjusted RR, 1.30 [95% CI, 0.89–1.90]); or overdose‐ and suicide‐related events (adjusted RR, 1.30 [95% CI, 0.93–1.80]) was not significant with gabapentinoids. Conclusions: Incidence rates for suicidal ideation and behavior were higher among the gabapentinoid group, although increased risk was not detected after adjustment. A possible signal cannot be ruled out given limitations of the data and rarity of the outcome. [ABSTRACT FROM AUTHOR]

Purpose: Erectile dysfunction (ED) is frequently underreported in men suffering from prolactinomas and can be challenging to manage. Both dopamine agonists (DAs) and transsphenoidal surgery (TSS) correct hyperprolactinemia and restore gonadal function. However, there is scarce data regarding their effectiveness in correcting ED over the long term. Methods: This study is a retrospective single-center comparative cohort study analyzing men diagnosed with prolactinomas, both with and without confirmed erectile dysfunction (ED) at diagnosis. Independent risk factors for persistent ED over the long term were examined using multivariate logistic regression. Results: Among the 39 men with lactotroph adenomas, ED was one of the presenting symptoms in 22 (56%). The mean age at diagnosis was 45 ± 12 years. Surgery was the primary treatment in 6 (27%) ED patients and 8 (47%) non-ED patients. After a mean follow-up of 74 ± 48 months, remission from hyperprolactinemia was achieved in the majority (76%) of men: 71% in the non-ED cohort and 81% in the ED group (p = 0.70), regardless of the primary treatment strategy (surgical 84% versus medical 72%, p = 0.46). Long-term remission of ED was noted in 16 (73%) patients. Interestingly, high baseline BMI levels emerged as potential risk factors for persistent ED over the long term (OR 1.4, 95%CI 1.0–1.9; p = 0.04), while neither the initial adenoma size nor the primary treatment strategy (i.e., TSS vs. DAs) reached statistical significance. Conclusions: Correcting hyperprolactinemia and its associated hypogonadism significantly improves ED in the majority of men with prolactinomas over the long term, regardless of the primary treatment strategy employed. In addition to addressing endocrine deficiencies, the early initiation of weight control programs may be considered for men with lactotroph adenomas and ED. Although our study suggests an association between BMI and the risk of persistent ED, further research is needed to establish any causal relationships. [ABSTRACT FROM AUTHOR]

• Age-related cognitive decline was detected through rodent temporal order recognition. • Poor temporal order memory is rescued by D 1 dopamine agonists. • Optimal effective doses vary markedly among individual rats of different age groups. • Population effectiveness may be influenced by agonist functional selectivity. Dopamine D 1 receptor agonists improve spatial working memory, but their effects on temporal order memory, particularly prone to the effects of aging, have not been studied. Two D 1 agonists, PF6256142 (PF) and 2-methyldihydrexidine (2MDHX), were examined for their effects in a rodent temporal order recognition task. Our results are consistent with the hypothesis that there is an age-related decline in rodent temporal order memory. The data also show that either agonist rescues the poor memory performance with a large effective size. Interestingly, the optimal effective dose varied among individual rats of different age groups. PF showed greater potency for older rats, whereas 2MDHX showed better overall population effectiveness. Both PF and 2MDHX have high intrinsic activity at rodent D 1 -mediated cAMP synthesis. Conversely, at D 1 -mediated β-arrestin recruitment, PF has essentially no intrinsic activity, whereas 2MDHX is a super-agonist. These findings suggest that D 1 agonists have potential to treat age-related cognitive decline, and the pattern of functional selectivity may be useful for developing drugs with an improved therapeutic index. [ABSTRACT FROM AUTHOR]

Ischemic stroke is a leading cause of disability worldwide. While much of post-stroke recovery is focused on physical rehabilitation, post-stroke dementia (PSD) is also a significant contributor to poor functional outcomes. Predictive tools to identify stroke survivors at risk for the development of PSD are limited to brief screening cognitive tests. Emerging biochemical, genetic, and neuroimaging biomarkers are being investigated in an effort to unveil better indicators of PSD. Additionally, acetylcholinesterase inhibitors, NMDA receptor antagonists, dopamine receptor agonists, antidepressants, and cognitive rehabilitation are current therapeutic options for PSD. Focusing on the chronic sequelae of stroke that impair neuroplasticity highlights the need for continued investigative trials to better assess functional outcomes in treatments targeted for PSD. [ABSTRACT FROM AUTHOR]

This document provides information on the synthesis of the dopamine agonist Rotigotine, which is used to treat Parkinson's disease and restless leg syndrome. The authors discuss different synthetic approaches and successfully synthesized Rotigotine using reductive amination with a high yield. The document also includes information on the synthesis and characterization of three compounds related to Rotigotine, along with their spectral data. Additionally, it provides details on the synthesis and chiral separation of (±)-Rotigotine, including its chemical structure, physical properties, and analytical data. The authors acknowledge Chemveda Life Sciences for their assistance in the separation process. [Extracted from the article]

Pituitary adenomas are very common representing 18.1% of all brain tumors and are the second most common brain pathology. Transsphenoidal surgery is the mainstay of treatment for all pituitary adenomas except for prolactinomas which are primarily treated medically with dopamine agonists. A thorough endocrine evaluation of pituitary adenoma preoperatively is crucial to identify hormonal compromise caused by the large sellar mass, identifying prolactin‐producing tumors and comorbidities associated with Cushing and acromegaly to improve patient care and outcome. Transsphenoidal surgery is relatively safe in the hands of experienced surgeons, but still carries a substantial risk of causing hypopituitarism that required close follow‐up in the immediate postoperative period to decrease mortality. A multidisciplinary team approach with endocrinologists, ophthalmologists, and neurosurgeons is the cornerstone in the perioperative management of pituitary adenomas. [ABSTRACT FROM AUTHOR]

A pharmacokinetic (PK) bridging approach was successfully employed to support the dosing regimen and approval of brexpiprazole in pediatric patients aged 13‐17 years with schizophrenia. Brexpiprazole was approved in 2015 for the treatment of schizophrenia and the adjunctive treatment of major depressive disorder in adults based on efficacy and safety data from clinical trials. On January 13, 2020, the US Food and Drug Administration issued a general advice letter to sponsors highlighting the acceptance of efficacy extrapolation of certain atypical antipsychotics from adult patients to pediatric patients considering the similarity in disease and exposure–response relationships. Brexpiprazole is the first atypical antipsychotic approved in pediatrics using this approach. The PK data available from pediatric patients aged 13‐17 years have shown high variability due to the limited number of PK evaluable subjects, which limits a robust estimation of differences between adult and pediatric patients. The PK model‐based approach was thus utilized to evaluate the appropriateness of the dosing regimen by comparing PK exposures in pediatric patients aged 13‐17 years with exposures achieved in adults at the approved doses. In addition to exposure matching, safety data from a long‐term open‐label clinical study in pediatric patients informed the safety profile in pediatric patients. This report illustrates the potential of leveraging previously collected efficacy, safety, and PK data in adult patients to make a regulatory decision in pediatric patients for the indication of schizophrenia. [ABSTRACT FROM AUTHOR]

Pramipexole, a D2/D3 dopamine receptor agonist, is used to treat the motor symptoms of Parkinson's disease, caused by degeneration of the dopaminergic nigrostriatal pathway. There are three paradoxes associated with its mode of action. Firstly, stimulation of D2/D3 receptors leads to neuronal inhibition, although pramipexole does not inhibit but promotes some dopamine-modulated functions, such as locomotion and reinforcement. Secondly, another dopamine-modulated function, arousal, is not promoted but inhibited by pramipexole, leading to sedation. Thirdly, pramipexole-evoked sedation is associated with an increase in pupil diameter, although sedation is expected to cause pupil constriction. To resolve these paradoxes, the path from stimulation of D2/D3 receptors to the modification of dopamine-modulated functions has been tracked. The functions considered are modulated by midbrain dopaminergic nuclei: locomotion – substantia nigra pars compacta (SNc), reinforcement/motivation – ventral tegmental area (VTA), sympathetic activity (as reflected in pupil function) – VTA; arousal – ventral periaqueductal grey (vPAG), with contributions from VTA and SNc. The application of genetics-based molecular techniques (optogenetics and chemogenetics) has enabled tracing the chains of neurones from the dopaminergic nuclei to their final targets executing the functions. The functional neuronal circuits linked to the D2/D3 receptors in the dorsal and ventral striata, stimulated by inputs from SNc and VTA, respectively, may explain how neuronal inhibition induced by pramipexole is translated into the promotion of locomotion, reinforcement/motivation and sympathetic activity. As the vPAG may increase arousal mainly by stimulating cortical D1 dopamine receptors, pramipexole would stimulate only presynaptic D2/D3 receptors on vPAG neurones, curtailing their activity and leading to sedation. [ABSTRACT FROM AUTHOR]

Introduction Cariprazine is an atypical dopamine receptor partial agonist antipsychotic available in the form of capsules. Although capsules are one of the most desirable routes of administration, there are certain situations (e. g., in an acute psychiatric setting, or when swallowing difficulties, or liquid shortages are present) when they cannot be administered. Therefore, alternative solutions like orodispersible tablets are needed. This study aimed to investigate the bioequivalence of a newly developed orodispersible tablet to the commercially available hard gelatine capsule of cariprazine 1.5 mg. Methods This was a phase I, open-label, randomized, single-dose bioequivalence study. It had a 2-period, 2-sequence, cross-over design, where each subject received one test and one reference product in a randomized sequence, separated by a wash-out period of 55 days. Blood sampling was performed over 72 h after dosing. Cariprazine concentrations were analyzed by a validated HPLC-MS/MS method. Standard bioequivalence statistics was applied to PK parameters calculated by non-compartmental analysis. Safety measures were analyzed descriptively. Result Pharmacokinetic data of 43 healthy volunteers and safety data of 54 subjects was analyzed. Cariprazine AUC0–72h and Cmax geometric mean ratios were 117.76% and 100.88%, respectively. The 90% confidence intervals were within the pre-defined bioequivalence acceptance limits of 80.00% – 125.00%. Safety data was in line with the Summary of Product Characteristics of Cariprazine. Discussion The result of this clinical trial proved the bioequivalence of the new orodispersible tablet formulation when compared to hard gelatine capsules, enabling an alternative option for treatment of those suffering from schizophrenia. [ABSTRACT FROM AUTHOR]

Background: Levodopa‐induced dyskinesias (LID) are frequent in Parkinson's disease (PD). Objective: To analyze the change in the frequency of LID over time, identify LID related factors, and characterize how LID impact on patients' quality of life (QoL). Patients and Methods: PD patients from the 5‐year follow‐up COPPADIS cohort were included. LID were defined as a non‐zero score in the item "Time spent with dyskinesia" of the Unified Parkinson's Disease Rating Scale—part IV (UPDRS‐IV). The UPDRS‐IV was applied at baseline (V0) and annually for 5 years. The 39‐item Parkinson's disease Questionnaire Summary Index (PQ‐39SI) was used to asses QoL. Results: The frequency of LID at V0 in 672 PD patients (62.4 ± 8.9 years old; 60.1% males) with a mean disease duration of 5.5 ± 4.3 years was 18.9% (127/672) and increased progressively to 42.6% (185/434) at 5‐year follow‐up (V5). The frequency of disabling LID, painful LID, and morning dystonia increased from 6.9%, 3.3%, and 10.6% at V0 to 17.3%, 5.5%, and 24% at V5, respectively. Significant independent factors associated with LID (P < 0.05) were a longer disease duration and time under levodopa treatment, a higher dose of levodopa, a lower weight and dose of dopamine agonist, pain severity and the presence of motor fluctuations. LID at V0 (β = 0.073; P = 0.027; R2 = 0.62) and to develop disabling LID at V5 (β = 0.088; P = 0.009; R2 = 0.73) were independently associated with a higher score on the PDQ‐39SI. Conclusion: LID are frequent in PD patients. A higher dose of levodopa and lower weight were factors associated to LID. LID significantly impact QoL. [ABSTRACT FROM AUTHOR]

Background: Subthalamic deep brain stimulation (STN‐DBS) reduces antiparkinsonian medications in Parkinson's disease (PD) compared with the preoperative state. Longitudinal and comparative studies on this effect are lacking. Objective: To compare longitudinal trajectories of antiparkinsonian medication in STN‐DBS treated patients to non‐surgically treated control patients. Methods: We collected retrospective information on antiparkinsonian medication from PD patients that underwent subthalamic DBS between 1999 and 2010 and control PD patients similar in age at onset and baseline, sex‐distribution, and comorbidities. Results: In 74 DBS patients levodopa‐equivalent daily dose (LEDD) were reduced by 33.9–56.0% in relation to the preoperative baseline over the 14‐year observational period. In 61 control patients LEDDs increased over approximately 10 years, causing a significant divergence between groups. The largest difference amongst single drug‐classes was observed for dopamine agonists. Conclusion: In PD patients, chronic STN‐DBS was associated with a lower LEDD compared with control patients over 14 years. [ABSTRACT FROM AUTHOR]

Dopamine agonists (DAs) constitute the standard therapeutic scheme for restless leg syndrome (RLS) because they have been proven to be effective. However, DAs may change sleep parameters, thus having adverse effects on patient condition. This meta-analysis clarified the effects of DAs used in RLS treatment on the sleep architecture. PubMed, Embase, and Cochrane Central databases were searched for randomized control trials (RCT) (up to October 2023) that discussed the effects of DAs on sleep architecture in patients with RLS. A meta-analysis employing a random-effects model was conducted. The patients were divided into subgroups according to individual DAs and treatment duration (1 day or ≥4 weeks). Thirteen eligible randomized placebo-controlled trials were included in the assessment. The effects of three DAs (i.e., pramipexole, ropinirole, and rotigotine) on rapid eye movement (REM) sleep, slow-wave sleep (SWS), and sleep efficiency (SE) were analyzed. Overall, pramipexole significantly improved SE but decreased the percentage of REM sleep among treated patients. Ropinirole also enhanced SE compared with the placebo group. Rotigotine did not affect SE and REM sleep. Subgroup analysis found that pramipexole used for 1 day and ≥4 weeks significantly diminished the percentage of REM sleep. Ropinirole used for 1 day showed similar REM sleep patterns. Finally, none of the three DAs affected SWS. This meta-analysis demonstrated that DAs significantly affect sleep parameters. • A meta-analysis examined the effects of pramipexole, ropinirole, and rotigotine on sleep structure. • Pramipexole improved sleep efficiency (SE) but decreased the percentage of rapid eye movement (REM) sleep. • Ropinirole enhanced sleep efficiency. • None of the three DAs had any effect on slow-wave sleep (SWS). [ABSTRACT FROM AUTHOR]

Motivation allows us to energise actions when we expect reward and is reduced in depression. This effect, termed motivational vigour, has been proposed to rely on central dopamine, with dopaminergic agents showing promise in the treatment of depression. This suggests that dopaminergic agents might act to reduce depression by increasing the effects of reward or by helping energise actions. The aim of the current study was to investigate whether the dopamine agonist pramipexole enhanced motivational vigour during a rewarded saccade task. In addition, we asked whether the effects of pramipexole on vigour differ between reward contingent on performance and guaranteed reward. Healthy adult participants were randomised to receive either pramipexole (n = 19) or placebo (controls n = 18) for 18 days. The vigour of saccades was measured twice, once before the administration of study medication (Time 1) and after taking it for 12–15 days (Time 2). To separate motivation by contingency vs. reward, saccadic vigour was separately measured when (1) rewards were contingent on performance (2) delivered randomly with matched frequency, (3) when reward was guaranteed, (4) when reward was not present at all. Motivation increased response vigour, as expected. Relative to placebo, pramipexole also increased response vigour. However, there was no interaction, meaning that the effects of reward were not modulated by drug, and there was no differential drug effect on contingent vs. guaranteed rewards. The effect of pramipexole on vigour could not be explained by a speed/accuracy trade-off, nor by autonomic arousal as indexed by pupillary dilation. Chronic D2 stimulation increases general vigour, energising movements in healthy adults irrespective of extrinsic reward. [ABSTRACT FROM AUTHOR]

A recent Pituitary Society consensus statement provided clinical recommendations for diagnosing and managing prolactin-secreting pituitary adenomas, known as prolactinomas. Prolactinomas are rare, usually benign tumours of the anterior pituitary gland that result in excessive prolactin production, or hyperprolactinemia. Despite being non-life- -threatening, patients often prompt medical attention due to symptoms stemming from elevated prolactin levels, such as reproductive and sexual dysfunction, e.g. menstrual irregularities, galactorrhoea, infertility, or from mass effects like headaches, cranial nerve palsies, and vision problems. Laboratory testing showing hyperprolactinemia and low sex hormone levels is used for diagnosis. Unlike other pituitary tumours, the primary treatment for prolactinomas is typically pharmacological therapy with dopamine agonists. However, for patients with smaller tumours (microprolactinomas) or well-circumscribed larger tumours (macroprolactinomas), surgery may be considered the first-line option. It is a surprising shift in the therapeutic strategy. For patients resistant to dopamine agonists, alternative strategies include switching medications, increasing dosages, or pursuing neurosurgery or radiotherapy. The key treatment goals are to normalize prolactin levels, restore reproductive and sexual function, and reduce tumour size. This review aimed to provide clinicians with an up-to-date overview of diagnostics and treatment options for patients with prolactin- -secreting pituitary adenomas, as well as highlight the potential diagnostic challenges and complexity of treatment. [ABSTRACT FROM AUTHOR]

This review addresses tremor, which is among the maladaptive and difficult-to-treat symptoms of Parkinson's disease (PD). Along with classical resting tremor, patients with PD may experience postural and kinetic types of tremor, reflecting the multimodal mechanism of its formation, which involves multiple neurotransmitter systems. Unpredictable therapeutic responses and mixed responses to levodopa also reflect the roles of multiple underlying pathophysiological processes. Among medication-based methods for tremor correction, preference is given to dopamine receptor agonists because of their wide range of pharmaceutical effects and high efficacy in relation to the major motor and various non-motor manifestations. Evidence of the efficacy of advanced neurosurgical and non-invasive treatment methods is not always convincing; there have been no large-scale comparative studies assessing their efficacy in patients with tremor-dominant forms of PD. [ABSTRACT FROM AUTHOR]

While all reversible receptor-targeting radioligands for positron emission tomography (PET) can be displaced by competition with an antagonist at the receptor, many radiotracers show limited occupancies using agonists even at high doses. [11C]Raclopride, a D2/D3 receptor radiotracer with rapid kinetics, can identify the direction of changes in the neurotransmitter dopamine, but quantitative interpretation of the relationship between dopamine levels and radiotracer binding has proven elusive. Agonist-induced receptor desensitization and internalization, a homeostatic mechanism to downregulate neurotransmitter-mediated function, can shift radioligand-receptor binding affinity and confound PET interpretations of receptor occupancy. In this study, we compared occupancies induced by amphetamine (AMP) in drug-naive wild-type (WT) and internalization-compromised β-arrestin-2 knockout (KO) mice using a within-scan drug infusion to modulate the kinetics of [11C]raclopride. We additionally performed studies at 3 h following AMP pretreatment, with the hypothesis that receptor internalization should markedly attenuate occupancy on the second challenge, because dopamine cannot access internalized receptors. Without prior AMP treatment, WT mice exhibited somewhat larger binding potential than KO mice but similar AMP-induced occupancy. At 3 h after AMP treatment, WT mice exhibited binding potentials that were 15 % lower than KO mice. At this time point, occupancy was preserved in KO mice but suppressed by 60 % in WT animals, consistent with a model in which most receptors contributing to binding potential in WT animals were not functional. These results demonstrate that arrestin-mediated receptor desensitization and internalization produce large effects in PET [11C]raclopride occupancy studies using agonist challenges.

BackgroundSecond-generation antipsychotics (SGAs) are frontline treatments for serious mental illness. Often, individual patients benefit only from some SGAs and not others. The mechanisms underlying this unpredictability in treatment efficacy remain unclear. All SGAs bind the dopamine D3 receptor (D3R) and are traditionally considered antagonists for dopamine receptor signaling.MethodsHere, we used a combination of two-photon calcium imaging, in vitro signaling assays, and mouse behavior to assess signaling by SGAs at D3R.ResultsWe report that some clinically important SGAs function as arrestin-3 agonists at D3R, resulting in modulation of calcium channels localized to the site of action potential initiation in prefrontal cortex pyramidal neurons. We further show that chronic treatment with an arrestin-3 agonist SGA, but not an antagonist SGA, abolishes D3R function through postendocytic receptor degradation by GASP1 (G protein-coupled receptor-associated sorting protein-1).ConclusionsThese results implicate D3R-arrestin-3 signaling as a source of SGA variability, highlighting the importance of including arrestin-3 signaling in characterizations of drug action. Furthermore, they suggest that postendocytic receptor trafficking that occurs during chronic SGA treatment may contribute to treatment efficacy.

Hyperprolactinemia has multiple etiologies and is the most common endocrine manifestation of pathology of the hypo­thalamic-pituitary axis. Hyperprolactinemic hypogonadism is of great scientific interest due to the prevalence of endocrine pathology in the reproductive period and its effect on metabolic processes. Hyperprolactinemia is one of the serious obstacles to the implementation of reproductive function in both women and men. The article discusses current issues of diagnosis and management tactics for patients with hyperprolactinemia of various etiologies within the framework of preconception preparation.

Introduction: Parkinson’s disease (PD) patients harboring recessive gene variants exhibit a distinct clinical phenotype with an early disease onset and relatively mild symptoms. Data concerning individualized therapy for autosomal recessive PD forms are still scarce. Methods: Demographic and treatment data of a cohort of PD carriers of recessive genes (nine homozygous or compound heterozygous PRKN carriers, four heterozygous PRKN carriers, and three biallelic PINK1 carriers) were evaluated. Results: The average levodopa equivalent daily dose (LEDD) was 806.8 ± 453.5 (range 152–1810) in PRKN carriers and 765 ± 96.6 (range 660–850) in PINK1 carriers. The majority responded to low/moderate doses of levodopa. The response to dopamine agonists (DAs) was often favorable both as initial and longitudinal therapy. In total, 8/13 PRKN and 1/3 PINK1 carriers were treated with amantadine successfully, and this also applied to patients who could not tolerate levodopa or DAs. Conclusions: In the era of personalized treatment, the therapeutic approach in recessive PD gene carriers might differ as compared to idiopathic PD. Lower LEDD doses were efficient even in patients with a very long disease duration, while a few patients were doing well without any levodopa treatment decades after disease initiation. DAs or amantadine could be used as a first and main line treatment regimen if well tolerated. Literature data on therapeutic strategies in carriers of pathogenic mutations in recessive PD genes, including device-aided treatments, will be further discussed.

Background: Oral levodopa remains the mainstay of treatment for Parkinson's disease (PD). However, as PD progresses, response to treatment may fluctuate. Managing fluctuations can be demanding for clinicians and patients. There is a paucity of real-world studies reporting on PD management in patients with fluctuations in treatment response, especially in patients with advanced stages of PD. The multicentre, observational Parkinson's Disease Fluctuations treatment PAthway (PD-FPA) study describes the real-life management of response fluctuations in Italian patients with advanced PD. Patients and Methods: PD-FPA had a retrospective and prospective phase; herein, retrospective results are presented. Ten Italian centres enrolled patients with a PD diagnosis from 10-15 years prior to study entry (T0) and who had ≥2-year history of fluctuations. Data on patient demographics, medical history, PD stage, fluctuation characteristics, symptoms, and prescribed treatments were collected at T0 and retrospectively (2 years prior to T0) via patient chart review/interview. Results: Overall, 296 patients (60% male, mean age 68 years, 84% with Hoehn and Yahr scores 2-3) were enrolled. At T0, most patients (99.3%) were on oral levodopa therapy. All patients used dopaminergic medications; adjunctive medications included dopamine agonists (56%) and monoamine oxidase B (60%) and catechol-O-methyltransferase enzyme inhibitors (41%). At T0, 51% of patients had changed therapy, with response fluctuations being the most common reason (74%); wearing-off was the most common fluctuation (83%). Conclusion: This interim analysis of PD-FPA suggests that adequate levodopa dosing and adjunctive medications can stabilize advanced PD and provide patients with a good quality of life. [ABSTRACT FROM AUTHOR]

Abstract Context Acromegaly is a rare disease caused by excessive growth hormone (GH) secretion, mostly induced by pituitary adenomas. The care of pregnant women with acromegaly is challenging, in part due to existing clinical data being limited and not entirely consistent with regard to potential risks for mother and child. Objective To retrospectively examine data on pregnancy and maternal as well as neonatal outcomes in patients with acromegaly. Design & methods Retrospective data analysis from 47 pregnancies of 31 women treated in centers of the German Acromegaly Registry. Results 87.1% of the studied women underwent transsphenoidal surgery before pregnancy. In 51.1% a combination of dopamine agonists and somatostatin analogs were used before pregnancy. Three women did not receive any therapy for acromegaly. During pregnancy only 6.4% received either somatostatin analogs or dopamine agonists. In total, 70.2% of all documented pregnancies emerged spontaneously. Gestational diabetes was diagnosed in 10.6% and gravid hypertension in 6.4%. Overall, no preterm birth was detected. Indeed, 87% of acromegalic women experienced a delivery without complications. Conclusion Pregnancies in women with acromegaly are possible and the course of pregnancy is in general safe for mother and child both with and without specific treatment for acromegaly. The prevalence of concomitant metabolic diseases such as gestational diabetes is comparable to the prevalence in healthy pregnant women. Nevertheless, larger studies with more data in pregnant patients with acromegaly are needed to provide safe and effective care for pregnant women with this condition.

Purpose: An increase of IGF-1 has been reported during therapy with dopamine agonists (DA) for prolactinomas; in such cases a correct diagnosis is pivotal to avoid an unnecessary reduction or withdrawal of DA, which are needed to maintain normal prolactin levels. This study was aimed to measure IGF-1 levels, at baseline and during follow-up, in a cohort of patients with prolactinoma, treated with cabergoline, stratified by body mass index. Methods: We retrospectively enrolled 35 patients (15 F/20 M; age m ± SD, years: 43.4 ± 13.7) with prolactinoma (21 microadenomas and 14 macroadenomas) who were followed-up at the Endocrinology Unit, in Siena, and with available pituitary hormone assessment at baseline and during follow-up (m ± SD, years: 2.74 ± 0.55). Results: IGF-1 increased in the whole cohort, but remaining within normal range, except two patients, in whom acromegaly was ruled out with oral glucose tolerance test. After dividing patients by weight, this trend was confirmed only in subjects with overweight and obesity (OV/OB) (p = 0.04). Interestingly, the reduction of prolactin levels was significantly greater in the OV/OB compared to normal-weight patients (median decrease of 97.5% versus 88.2%, p = 0.04). Conclusions: Since DA and normalization of prolactin are known to improve insulin sensitivity, we speculated they have favored the increase of IGF-1 in OV/OB. Our results should be confirmed and the hypothesis proven by further studies. [ABSTRACT FROM AUTHOR]

Background Objectives Methods Results Conclusion Dopaminergic responsiveness is a defining feature of Parkinson's disease (PD). However, there is limited information on how this evolves over time.To examine serial dopaminergic responses, if there are distinct patterns, and which factors predict these.We analyzed data from the Parkinson's Progression Markers Initiative on repeated dopaminergic challenge tests (≥24.5% defined as a definite response). Growth‐mixture modeling evaluated for different response patterns and multinomial logistic regression tested for predictors of these clusters.1525 dopaminergic challenge tests were performed in 336 patients. At enrolment, mean age was 61.2 years (SD 9.6), 66.4% were male and disease duration was 0.5 years (SD 0.5). 1 to 2 years after diagnosis, 48.0% of tests showed a definite response, but this proportion increased with longer disease duration (51.1–74.3%). We identified 3 response groups: “Striking” (n = 29, 8.7%); “Excellent” (n = 110; 32.7%) and “Modest” (n = 197, 58.6%). Significant differences were as follows: striking responders commenced treatment earlier (P = 0.02), were less likely to be on dopamine agonist monotherapy (P = 0.01), and had better cognition (P < 0.01) and activities of daily living (P = 0.01). Excellent responders had higher challenge doses (P = 0.03) and were more likely to be on combination therapy (P < 0.01).Three distinct patterns of the dopaminergic response were observed. As the proportion of PD cases with definite dopa responsiveness increased over time, the initial treatment response may be an unreliable diagnostic aid. [ABSTRACT FROM AUTHOR]

Introduction: Impulse control disorders (ICDs) are defined as excessive and repetitive behaviors that may affect Parkinson's disease (PD) patients exposed to dopamine agonists. Current data on ICDs in patients with early-onset Parkinson's disease (EOPD) is lacking. In this study we aim to assess the frequency of use of dopamine agonists, the prevalence of ICDs, and to explore potential factors associated with their development in patients with EOPD. Methods: We used the Mayo Clinic Data Explorer system to investigate a population-based cohort of EOPD patients between 1990 and 2022 at Mayo Clinic, Rochester, MN. We used ICD coding for parkinsonism; then, we reviewed all the clinical records and included only those patients with a clinical diagnosis of PD with symptoms onset at or before the age of 50, and who developed ICDs after using therapeutic doses of dopamine agonists. Results: A total of 831 (513 males and 318 females) patients with EOPD were included with a median age at symptom onset of 42 years of age (CI: 37-46). Dopamine agonists were used in 49.7% of all patients; of these, only 14.5% developed symptoms of one or more ICDs. Hypersexuality was the most commonly observed ICD (38.3%), and the only one having a statistically significant male predominance (p = 0.011). Conclusion: ICDs are common in EOPD, particularly when associated with the use of dopamine agonists. [ABSTRACT FROM AUTHOR]

Dendritic cells (DCs) are known as antigen‐presenting cells that are capable of regulating immune responses. DCs and T cells can interact mutually to induce antigen‐specific T‐cell responses. Cabergoline, which is a dopamine (DA) receptor agonist, seems to implement anti‐inflammatory properties in the immune system, and therefore in the present study the impact of a DA receptor agonist cabergoline on the monocyte‐derived DCs (moDCs) was assessed. Immature moDCs were treated with lipopolysaccharide to produce mature DCs (mDCs). The expression of DCs' related surface markers namely: CD11c, HLA‐DR, and CD86 was measured by utilizing of flow cytometry. Real‐time PCR was the technique of choice to determine the levels at which diverse inflammatory and anti‐inflammatory factors in cabergoline‐treated and control mDC groups were expressed. DCs treated with cabergoline displayed a significant decrease in CD86 and HLA‐DR expression, markers linked to maturation and antigen presentation, respectively. In addition, the cabergoline‐mDC group showed a considerable decline in terms of the levels at which IL‐10, TGF‐β, and IDO genes were expressed, and an increase in the expression of TNF‐α and IL‐12 in comparison to the mDC control group. Our findings revealed that cabergoline as an immunomodulatory agent can relatively shift DCs into an immunogenic state, and there is a requirement for further investigations to evaluate the effects of cabergoline‐treated DCs on the T cell responses in vitro, and also in various diseases including cancer in animal models. Significance statement: Cabergoline‐mediated dopamine receptor provoking in the monocyte‐derived dendritic cells (DCs) significantly decreased CD86 and HLA‐DR expression, markers linked to maturation and antigen presentation, respectively. Furthermore, it could downregulate the expression of IL‐10, TGF‐β, and IDO genes, and upregulate the expression of TNF‐α and IL‐12 genes. Our findings revealed that cabergoline as an immunomodulatory agent can shift DCs into a partially immunogenic state. [ABSTRACT FROM AUTHOR]

Impulse control disorders in Parkinson's disease are relatively common drug-induced addictive behaviours that are usually triggered by the dopamine agonists pramipexole, ropinirole and rotigotine. This narrative review aimed to provide a comprehensive overview of the current knowledge of impulse control disorders in Parkinson's disease. We summarised the prevalence, clinical features, risk factors and potential underlying mechanisms of impulse control disorders in Parkinson's disease. Moreover, recent advances in behavioural and imaging characteristics and management strategies are discussed. Early detection as well as a tailored multidisciplinary approach, which typically includes careful adjustment of the dopaminergic therapy and the treatment of associated neuropsychiatric symptoms, are necessary. In some cases, a continuous delivery of levodopa via a pump or the dopamine D1 receptor agonist, apomorphine, can be considered. In selected patients without cognitive or speech impairment, deep brain stimulation of the subthalamic nucleus can also improve addictions. Finding the right balance of tapering dopaminergic dose (usually dopamine agonists) without worsening motor symptoms is essential for a beneficial long-term outcome. [ABSTRACT FROM AUTHOR]

Background: Sleep disorders negatively impact quality of life in Parkinson's disease (PD), yet the role of antiparkinsonian drugs on sleep quality is still unclear. We aimed to explore the correlation between sleep dysfunction and dopaminergic therapy in a large cohort of advanced PD patients. Methods: Patients consecutively evaluated for device-aided therapies eligibility were evaluated by means of the PD Sleep Scale (PDSS-2; score ≥ 18 indicates poor sleep quality), and the Epworth Sleepiness Scale (ESS score ≥ 10 indicates excessive daytime sleepiness—EDS). Binary logistic regression analysis, adjusting for age, sex, disease duration, motor impairment, and sleep drugs, was employed to evaluate the association between dopaminergic therapy and PDSS-2 and ESS scores. Analysis of covariance assessed differences in PDSS-2 and ESS scores between patients without DA, and between patients treated with low or high doses of DA (cut-off: DA-LEDD = 180 mg). Results: In a cohort of 281 patients, 66.2% reported poor sleep quality, and 34.5% reported EDS. DA treatment demonstrated twofold lower odds of reporting relevant sleep disturbances (OR 0.498; p = 0.035), while DA-LEDD, levodopa-LEDD, total LEDD, and extended-release levodopa were not associated with disturbed sleep. EDS was not influenced by dopaminergic therapy. Patients with DA intake reported significant lower PDSS-2 total score (p = 0.027) and "motor symptoms at night" domain score (p = 0.044). Patients with higher doses of DA showed lower PDSS-2 total score (p = 0.043). Conclusion: Our study highlights the positive influence of DA add-on treatment on sleep quality in this group of advanced fluctuating PD patients. [ABSTRACT FROM AUTHOR]

Context: Functioning pituitary adenomas (FPAs) include most frequently prolactinomas, somatotroph or corticotroph adenomas, while thyrotroph and gonadotroph adenomas are very rare. Despite their benign histological nature (aggressive tumors are rare and malignant ones exceptional), FPAs could cause significant morbidity and increased mortality due to complications associated with hormonal excess syndromes and/or mass effect leading to compression of adjacent structures. This mini review will focus on the increasing role of medical therapy in the multimodal treatment, which also includes transsphenoidal surgery (TSS) and radiotherapy. Evidence synthesis: Most patients with prolactinomas are treated only with medications, but surgery could be considered for some patients in a specialized pituitary center, if higher chances of cure. Dopamine agonists, especially cabergoline, are efficient in reducing tumor size and normalizing prolactin. TSS is the first-line treatment for all other FPAs, but most patients require complex adjuvant treatment, including a combination of therapeutic approaches. Medical therapy is the cornerstone of treatment in all patients after unsuccessful surgery or when surgery cannot be offered and includes somatostatin receptor ligands and dopamine agonists (almost all FPAs), growth hormone receptor antagonists (acromegaly), adrenal steroidogenesis inhibitors and glucocorticoid receptor blockers (Cushing's disease). Novel medical treatments, especially for acromegaly and Cushing's disease are under research. Conclusions: An enlarged panel of effective drugs available with increased knowledge of predictive factors for response and/or adverse effects will enhance the possibility to offer a more individualized treatment. This would not only improve disease control and prognosis, but also quality of life. [ABSTRACT FROM AUTHOR]

Objective To review experience regarding the treatment of prolactinomas by endoscopic endonasal surgery focusing on the association between presurgical dopamine agonist (DA) treatment and perioperative outcomes, surgical morbidities, endocrine outcomes, and pathological characteristics. Methods A single-center series of 290 cases was analyzed retrospectively and clinical data were collected. Intratumoral collagen content was assessed by Masson trichrome staining. Results Tenacious tumor consistency (27.8% vs 9.8%, P <.001) was more common in DA-pretreated patients compared with patients who underwent initial surgery. Moreover, DA-pretreated macroadenomas presented more intraoperative blood loss (200 [100-400] mL vs 175 [100-300] mL; P =.014), longer surgical duration (177 ± 95 minutes vs 154 ± 57 minutes; P =.043), and more surgical morbidities (19.4% vs 8.9%; P =.034). Additionally, DA-pretreated macroadenomas presented a higher collagen volume fraction than that of the initial surgery group (23.6 ± 2.2% vs 13.2 ± 2.1%; P =.001). Correlation analysis revealed a close correlation between collagen volume fraction and the cumulative dose of bromocriptine (BRC) in macroadenomas (r = 0.438, P <.001). Regarding endocrine outcomes, DA-pretreated microadenomas showed a lower proportion of initial remission compared with patients who underwent initial surgery (86.7% vs 100%, P =.047). Conclusion This study described increased surgical difficulty and inferior endocrine outcomes associated with tumor fibrosis secondary to presurgical BRC treatment in prolactinomas. Neurosurgeons should note that presurgical BRC treatment may render subsequent surgery more challenging. [ABSTRACT FROM AUTHOR]

Mitochondrial diseases are mainly caused by dysfunction of mitochondrial respiratory chain complexes and have a variety of genetic variants or phenotypes. There are only a few approved treatments, and fundamental therapies are yet to be developed. Leigh syndrome (LS) is the most severe type of progressive encephalopathy. We previously reported that apomorphine, an anti- "off" agent for Parkinson's disease, has cell-protective activity in patient-derived skin fibroblasts in addition to strong dopamine agonist effect. We obtained 26 apomorphine analogs, synthesized 20 apomorphine derivatives, and determined their anti-cell death effect, dopamine agonist activity, and effects on the mitochondrial function. We found three novel apomorphine derivatives with an active hydroxy group at position 11 of the aporphine framework, with a high anti-cell death effect without emetic dopamine agonist activity. These synthetic aporphine alkaloids are potent therapeutics for mitochondrial diseases without emetic side effects and have the potential to overcome the low bioavailability of apomorphine. Moreover, they have high anti-ferroptotic activity and therefore have potential as a therapeutic agent for diseases related to ferroptosis. [ABSTRACT FROM AUTHOR]

There are currently no disease-modifying therapies for Parkinson's disease (PD), a progressive neurodegenerative disorder associated with dopaminergic neuronal loss. There is increasing evidence that endogenous dopamine (DA) can be a pathological factor in neurodegeneration in PD. Tyrosine hydroxylase (TH) is the key rate-limiting enzyme for DA generation. Drugs that inhibit TH, such as alpha-methyltyrosine (α-MT), have recently been shown to protect against neurodegeneration in various PD models. DA receptor agonists can activate post-synaptic DA receptors to alleviate DA-deficiency-induced PD symptoms. However, DA receptor agonists have no therapeutic effects against neurodegeneration. Thus, a combination therapy with DA receptor agonists plus TH inhibitors may be an attractive therapeutic approach. TH inhibitors can protect and promote the survival of remaining dopaminergic neurons in PD patients' brains, whereas DA receptor agonists activate post-synaptic DA receptors to alleviate PD symptoms. Additionally, other PD drugs, such as N-acetylcysteine (NAC) and anticholinergic drugs, may be used as adjunctive medications to improve therapeutic effects. This multi-drug cocktail may represent a novel strategy to protect against progressive dopaminergic neurodegeneration and alleviate PD disease progression. [ABSTRACT FROM AUTHOR]