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Dopamine agonists (DA) have proven very successful in the treatment of Parkinson's disease for a good many years now. In the 1990's they experienced a high level of acceptance particularly in the European countries because their efficacy was in fact established, their tolerability was improved on and, in addition, several preparations were available with longer effect durations. But the discovery of cardiac fibroses led to a substantial setback and even rejection of therapy using ergoline DA. In recent years, impulse control disturbances have been observed increasingly with the result that higher doses have been reduced and the previously popular use of non-ergoline DA was discontinued. In addition, newer data on levodopa were published which clearly relativized the occurrence of late complications under levodopa and led to a differentiated use. Thus the importance of their use has waned over the years. But we should rather avoid repeating the mistakes of the past. DA serve us well and reliably so. The pendulum apparently thrives of the extremes but in the case of DA we should keep from falling back into the other extreme: We can and in fact must further make use of the DA, but with a clear view of specific goals and in a differentiated way. DA constitute the second-most important substance class after levodopa. Their optimized application can only be recommended for the good of our patients. [ABSTRACT FROM AUTHOR]

Background: Gender differences in the access to advanced therapies for Parkinson's disease (PD) are poorly investigated. Objective: The objective of this study was to investigate the presence of any gender disparity in the access to advanced therapies for PD. Design: Retrospective study. Methods: Data from patients with consistent access to the Parkinson's and Movement Disorder Center of L'Aquila over the last 10-year period were screened. Patients selected for advanced therapies were included. Results: Out of 1,252 patients, 200 (mean age ± SD 71.02 ± 9.70; 72% males; median Hoen Yahr level: 3, minimum 1 maximum 5) were selected for advanced therapies: 133 for Magnetic Resonance guided Focused Ultrasound (MRgFUS) thalamotomy (mean age ± SD 70.0 ± 8.9; 77% males), 49 for Levodopa/Carbidopa Intestinal Gel (LCIG) infusion (mean age ± SD 74.3 ± 11.4; 59% males), 12 for Deep Brain Stimulation (DBS) (mean age ± SD 71.2 ± 6.3; 75% males), and 7 for Continuous Subcutaneous Apomorphine Infusion (CSAI) (mean age ± SD 69.7 ± 5.5; 43% males). No sex differences were found in relation to age (MRgFUS group: males vs. females 70.2 ± 8.9 vs. 70.8 ± 8.9, p -value = 0.809; LCIG group: males vs. females 73.5 ± 13.0 vs. 75.5 ± 8.5, p -value = 0.557; DBS group: males vs. females 77.2 ± 8.1 vs. 67.3 ± 8.6, p -value = 0.843; CSAI group: males vs. females 73.3 ± 4.0 vs. 67.0 ± 5.2, p -value = 0.144) and disease duration (MRgFUS group: males vs. females 8.3 ± 4.4 vs. 9.6 ± 6.7, p -value = 0.419; LCIG group: males vs. females 14.5 ± 5.81 vs. 17.3 ± 5.5; p -value = 0.205; DBS group: males vs. females 15.0 ± 9.6 vs. 15.5 ± 7.7, p -value = 0.796; CSAI group: males vs. females 11.7 ± 3.7 vs. 10.3 ± 3.7, p -value = 0.505). Conclusion: The predominance of males is higher than that expected based on the higher prevalence of PD in men. Women are less confident in selecting advanced therapies during the natural progression of their disease. Factors accounting for this discrepancy deserve further investigation. [ABSTRACT FROM AUTHOR]

Infusion pump-based therapies are an effective treatment option for patients with advanced Parkinson´s disease. Achieving monotherapy with infusion-based therapies could simplify the treatment regimen, provide better medication adherence, reduce adverse events and drug interactions. This review presents the literature data on the efficacy, safety, and achievability of monotherapy with all available infusion-based therapies, including apomorphine, levodopa-carbidopa-intestinal gel (LCIG), levodopa-entacapone-carbidopa intestinal gel (LECIG), and foslevodopa-foscarbidopa (LDp/CDp). In summary, monotherapy is achievable and effective in most patients on intestinal levodopa infusion therapy and in some patients on apomorphine infusion. There is a need for further investigation of monotherapy compared to polytherapy, especially in new pump treatment options (LECIG and LDp/CDp). Future research should reveal which patients on infusion-based therapies could benefit from monotherapy, including identification of potential baseline predictors of achieving monotherapy in patients treated with specific infusion-based therapies. [ABSTRACT FROM AUTHOR]

Introduction. In Poland, not all forms of device-aided therapies for advanced Parkinson's Disease (APD) are currently available. Material and methods. We aimed to produce a consensus recommendation from Polish movement disorders experts after discussing gaps in the APD care pathway in Poland. Results. Rescue therapy with apomorphine (APO) PEN injection and levodopa-entacapone-carbidopa intestinal gel infusion are not included in Poland's Specialist Therapeutic Programme, and are thus not reimbursed. For APO infusion, only the medication is reimbursed but not the device. Conclusions. Consensus expert opinion is that APD patients in Poland would benefit from additional reimbursement access to these treatment options to improve APD patient care. [ABSTRACT FROM AUTHOR]

Metabolic dysfunction-associated steatohepatitis (MASH), characterized by progressive inflammation and fibrosis, evolves from metabolic dysfunction-associated steatotic liver disease and significantly heightens the risk of cirrhosis and hepatocellular carcinoma. Understanding metabolic pathways that influence MASH progression is crucial for developing targeted therapies. Non-targeted metabolomics offer a comprehensive view of metabolic alterations, enabling identification of novel biomarkers and pathways without preconceived ideas. Conversely, targeted metabolomics deliver precise and reproducible measurements, focusing on predefined metabolites to accurately quantify established pathways. This study utilized hepatocyte-specific PTEN knockout mice as a model to explore metabolic shifts associated with MASH. By integrating non-targeted metabolomics and targeted metabolomics, we analyzed liver samples from three groups: normal, pathological (MASH-affected), and MASH-affected, but treated with apomorphine, an antioxidant and recently reported ferroptosis inhibitor with potential therapeutic effects. Metabolic profiling identified lysophospholipids (LPLs) as significantly altered metabolites, with elevated levels in the MASH model and a notable reduction after apomorphine treatment. This suggests that LPLs are central to the etiology of MASH and may serve as targets for therapeutic intervention. Our findings underscore the effectiveness of apomorphine in modulating disease-specific metabolic disruptions, offering insights into its potential as a treatment for human MASH. [ABSTRACT FROM AUTHOR]

Dopamine (DA) and norepinephrine (NE) have been repeatedly implicated in neuropsychiatric vulnerability, in part via their roles in mediating the decision-making processes. Although two neuromodulators share a synthesis pathway and are coactivated under states of arousal, they engage in distinct circuits and modulatory roles. However, the specific role of each neuromodulator in decision-making, in particular the exploration–exploitation tradeoff, remains unclear. Revealing how each neuromodulator contributes to exploration– exploitation tradeoff is important in guiding mechanistic hypotheses emerging from computational psychiatric approaches. To under- stand the differences and overlaps of the roles of these two catecholamine systems in regulating exploration, a direct comparison using the same dynamic decision-making task is needed. Here, we ran male and female mice in a restless two-armed bandit task, which encourages both exploration and exploitation. We systemically administered a nonselective DA antagonist (flupenthixol), a nonselective DA agonist (apomorphine), a NE beta-receptor antagonist (propranolol), and a NE beta-receptor agonist (isoproterenol) and examined changes in exploration within subjects across sessions. We found a bidirectional modulatory effect of dopamine on exploration. Increasing dopamine activity decreased exploration and decreasing dopamine activity increased exploration. The modulatory effect of beta-noradrenergic receptor activity on exploration was mediated by sex. Reinforcement learning model parameters suggested that dopamine modulation affected exploration via decision noise and norepinephrine modulation affected exploration via sensitivity to outcome. Together, these findings suggested that the mechanisms that govern the exploration–exploitation transition are sensitive to changes in both catechol- amine functions and revealed differential roles for NE and DA in mediating exploration. [ABSTRACT FROM AUTHOR]

Advanced Parkinson´s disease (PD) is often complicated by fluctuations of disability depending on plasma levels of levodopa. For most patients OFF phases with worsening of tremor and immobility, but also pain, depression, autonomic symptoms are troublesome. While adjustments of levodopa administrations can relief such fluctuations for some time, "on demand" therapies become more and more important. These "on demand" therapies should provide fast and efficacious relief. During the past years, new options for on demand therapies in PD-associated OFF episodes have been developed, including new formulations of levodopa and apomorphine to provide fast and readily accessible on demand treatment. In this narrative review, the challenges of the treatment of PD-associated fluctuations and OFF states are addressed, with a special focus on sublingual apomorphine (SL-APO) including the results from recent clinical trials. [ABSTRACT FROM AUTHOR]

Growing evidence indicates that activation of cannabinoid type 2 (CB2) receptors protects dopamine neurons in the pathogenesis of Parkinson's disease (PD). However, the mechanisms underlying neuroprotection mediated by CB2 receptors are still elusive. In this study, we investigated the effects of CB2 receptor activation on 6-hydroxydopamine (6-OHDA)-induced dopamine neuron degeneration and iron accumulation in the substantia nigra (SN) of rats. We found that treatment with JWH133, a selective CB2 receptor agonist, significantly improved the apomorphine (APO)-induced rotational behavior in 6-OHDA-treated rats. The decreased numbers of tyrosine hydroxylase (TH)-positive neurons and reduced TH protein expression in the lesioned SN of rats were effectively restored by JWH133. Moreover, we found that JWH133 inhibited the increase of iron-staining cells in the lesioned SN of rats. To explore the protective mechanisms of activation of CB2 receptors on dopamine neurons, we further observed the effect of JWH133 on 1-methyl-4-phenylpyridinium (MPP+)-treated primary cultured ventral mesencephalon (VM) neurons from rats. We found that JWH133 significantly inhibited the increase of intracellular reactive oxygen species (ROS), the activation of Caspase-3, the decrease of mitochondrial transmembrane potential (ΔΨm), and the decrease of Bcl-2/Bax protein expression caused by MPP+ treatment. JWH133 also inhibited the MPP+-induced upregulation of divalent metal transporter-1 (DMT1) and downregulation of ferroportin 1 (FPN1). Furthermore, JWH133 also suppressed the MPP+-accelerated iron influx in the VM neurons. These results suggest that activation of CB2 receptor suppresses MPP+-induced cellular iron accumulation and prevents neurodegeneration. NEW & NOTEWORTHY: Expression of cannabinoid type 2 receptors (CB2Rs) was discovered on dopamine neurons in recent years. The role of CB2R expressed on dopamine neurons in the pathogenesis of Parkinson's disease (PD) has not been fully elucidated. The content of iron accumulation in the brain is closely related to the progress of PD. We verified the inhibitory effect of CB2R on iron deposition in dopamine neurons through experiments, which provided a new idea for the treatment of PD. [ABSTRACT FROM AUTHOR]

Background: Diabetes mellitus‐induced erectile dysfunction (DMED) has become a common disease in adult men that can seriously reduce the quality of life of patients, and new therapies are urgently needed. miRNA‐100 has many targets and can induce autophagy and reduce fibrosis by inhibiting the mTOR pathway and the TGF‐β pathway. However, no research has been conducted with miR‐100 in the field of DMED, and the specific mechanism of action is still unclear. Objectives: To ascertain the effects of miR‐100 on corpus cavernosum tissue of DMED rats and vascular endothelial cells in a high glucose environment and to elucidate the relevant mechanisms in autophagy, fibrosis and inflammation to find a new approach for the DMED therapy. Methods: Thirty rats were divided into three groups: the control group, the DMED group, and the DMED + miR‐100 group. Using intraperitoneal injections of streptozotocin, all rats except the control group were modeled with diabetes mellitus, which was verified using the apomorphine (APO) test. For rats in the DMED + miR‐100 group, rno‐miR‐100‐5p agomir (50 nmol/kg, every 2 days, 6 times in total) was injected via the tail vein. After 13 weeks, the erectile function of each rat was assessed using cavernous manometry, and the corpus cavernosum tissue was harvested for subsequent experiments. For cellular experiments, human coronary microartery endothelial cells (HCMEC) were divided into four groups: the control group, the high‐glucose (HG, 40 mM) group, the HG + mimic group, and the HG + inhibitor group. The cells were cultured for 6 days and collected for subsequent experiments 2 days after transfection. Results: Diabetic modeling impaired the erectile function in rats, and miR‐100 reversed this effect. By measuring autophagy‐related proteins such as mTOR/Raptor/Beclin1/p62/LC3B, we found that miR‐100 could suppress the expression of mTOR and induce autophagy. The analysis of the eNOS/NO/cGMP axis function indicated that impaired endothelial function was improved by miR‐100. By evaluating the TGF‐β1/CTGF/Smad2/3 and NF‐κB/TNF‐α pathways, we found that miR‐100 could lower the level of inflammation and fibrosis, which contributed to the improvement of the erectile function. Cellular experiments can be used as supporting evidence for these findings. Conclusion: MiR‐100 can improve the erectile function by inhibiting mTOR and thus inducing autophagy, improving the endothelial function through the eNOS/NO/cGMP axis, and exerting antifibrotic and anti‐inflammatory effects, which may provide new ideas and directions for the treatment of DMED. [ABSTRACT FROM AUTHOR]

Oxidative stress from generation of increased reactive oxygen species or has been reported to play an important role in dementia. Oxidative stress due to free radicals of oxygen or reactive oxygen species could be precipitating factors in the etiology of dementia. Apomorphine has been reported to have neuroprotective effects. To monitor memory enhancing and neuroprotective effects of apomorphine, we determined the antioxidant enzymes activities, lipid peroxidation, acetylcholine esterase (AChE) activity in brain and plasma, following repetitive administration of apomorphine in rat model of dementia. Biogenic amine levels were also monitored in hippocampus. Repeated administration of scopolamine was taken as an animal model of dementia. Decreased glutathione peroxidase, superoxide dismutase and catalase activities were observed in these animal models of dementia. While increased lipid peroxidation was also observed in the brain and plasma samples. The results showed significant effects of apomorphine. The activities of antioxidant enzymes displayed increased activities in both brain and plasma. Glutathione peroxidase and catalase activities were found to be significantly higher in brain and plasma of apomorphine treated rats. Superoxide dismutase (SOD) was significantly decreased in plasma of scopolamine injected rats; and a decreased tendency (non-significant) of SOD in brain was also observed. AChE activity in brain and plasma was significantly decreased in scopolamine treated rats. Learning and memory of rats in the present study was assessed by Morris Water Maze (MWM). Short-term memory and long-term memory was impaired significantly in scopolamine treated rats, which was prevented by apomorphine. Moreover, a marked decrease in biogenic amines was also found in the brain of scopolamine treated rats and was reverted in apomorphine treated rats. Results showed that scopolamine-treatment induced memory impairment and induced oxidative stress in rats as compared to saline-treated controls. These impairments were significantly restored by apomorphine administration. In conclusion, our data suggests that apomorphine at the dose of 1 mg/kg could be a potential therapeutic agent to treat dementia and related disorders. [ABSTRACT FROM AUTHOR]

Background: Spermidine is a natural biologically active substance that has widespread influences on the body. Objective: This study aims to enhance our understanding of the potential effect of spermidine on long non‐coding RNA MALAT1 and explore the underlying mechanism in the rotenone‐induced rat model of Parkinson's disease. Methods: Rats were sacrificed after locomotor behavioral testing. Striatal tissues were used to assess the expression of MALAT1, oxidative stress markers, and autophagy markers. Results: Our study found that treatment with spermidine for 2 weeks during the induction of the model significantly improved behavioral assessment, dopamine levels, and attenuated the histopathological changes that occurred in PD in comparison to the non‐treated group. Conclusion: Our preliminary study supports the protective effect of spermidine on the activation of autophagy and its antioxidant properties. Part of the antioxidant activity is due to the inhibition of MALAT1. However, MALAT1 does not correlate with the spermidine‐induced autophagy pathway. [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]

The objective of this study was to compare the effectiveness of subcutaneous (SC) and sublingual (SL) formulations of apomorphine for the treatment of motor fluctuations in Parkinson's disease using a pharmacokinetics (PK)/pharmacodynamics (PD) modeling approach. The PK of SC and SL apomorphine are best described by a one-compartment model with first-order absorption and a two-compartment model with delayed absorption, respectively. The PK/PD model relating apomorphine plasma concentrations to the Unified Parkinson's Disease Rating Scale (UPDRS) motor scores was described by a sigmoidal Emax model assuming effective concentration = drug concentration in an effect compartment. Apomorphine concentrations and UPDRS motor scores were simulated from the PK/PD models using 500 hypothetical subjects. UPDRS motor score change from baseline was evaluated using time to clinically relevant response, response duration, area under the curve, maximal response, and time to maximal response. Higher doses of each apomorphine formulation were associated with shorter time to response, longer response duration, and greater maximal response. Although the mean maximal responses to SC and SL apomorphine were comparable, the time to response was four times shorter (7 vs. 31 min) and time to maximal response was two times shorter (27 vs. 61 min) for 4 mg SC vs. 50 mg SL. Thus, faster onset of action was observed for the SC formulation compared to SL. These data may be useful for physicians when selecting "on demand" therapy for patients with Parkinson's disease experiencing motor fluctuations. [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]

Background: Parkinson's disease (PD) is characterized by striatal dopamine deficiency. Since dopamine cannot cross the digestive and blood-brain barriers, its precursor, levodopa (L-DOPA), remains the mainstay of treatment. However, the significant pharmacokinetic (Pk) and pharmacodynamic (Pd) limitations of L-DOPA, combined with the severity of PD, may trigger motor and non-motor complications, for which continuous dopaminergic delivery therapies have been developed. Objective: The aim of this study was to review the literature on the Pk/Pd limitations of L-DOPA and how current treatments of continuous dopaminergic administration ameliorate these problems, in order to identify the need for new therapeutic avenues. Methods: A comprehensive literature search was carried out using PubMed and 75 articles were initially extracted. Following independent screening by two reviewers and consideration of eligibility, 10 articles were chosen for further analysis. Information concerning the Pk/Pd of L-DOPA was classified for each article. Results: Pk/Pd problems notably include: (i) restricted digestive and cerebral absorption; (ii) unnecessary peripheral distribution; (iii) short half-life; (iv) age- and PD-induced decline of central aromatic L-amino acid decarboxylase; (v) misdistribution in many cells; and (vii) pulsatile stimulation of dopaminergic receptors. Current treatments only slightly ameliorate some of these problems. Conclusions: Many Pk/Pd constraints are not resolved by existing continuous dopaminergic delivery therapies. This highlights the significant gap between these treatments and the ideal of continuous dopaminergic stimulation. [ABSTRACT FROM AUTHOR]

OBJECTIVE To evaluate the effect of abdominal thrusts as a synergistic procedure to IV apomorphine administration on the occurrence and rate of onset of successful induction of emesis in dogs, ANIMALS 31 client-owned dogs. METHODS Dogs in which induction of emesis via IV apomorphine was prescribed by the attending clinician were prospectively randomized to either receive abdominal thrusts performed by a nurse or clinician or to have no physical interventions performed following IV apomorphine administration. Data collected included signalment, weight, reason for emesis, time from suspected ingestion to presentation, time from the dog's last meal to presentation, dose of apomorphine administered in milligrams, and time from apomorphine administration to emesis. RESULTS Emesis induction was successful in 14 of 14 (100%) of the dogs in the abdominal thrust group and 13 of 17 (76.5%) in the control group (P = .02). In dogs with successful emesis, median time to emesis was 90.5 seconds (range, 36 to 348 seconds) in the abdominal thrust group and 106 seconds (range, 37 to 360 seconds) in the control group (P = .29). CLINICAL RELEVANCE Abdominal thrusts were associated with an increased frequency of successful emesis in dogs following IV apomorphine, but did not shorten the rate of onset of emesis in dogs that vomited. Application of abdominal thrusts may be beneficial in dogs in which emesis is indicated and that do not have a clear contraindication. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is a debilitating condition that affects 1.8% of people 65 years of age and older. Patients with PD often require hospitalization and are frequently admitted through the emergency department (ED). Notably, their hospital durations tend to be lengthier compared with patients without PD. The primary outcome of this research was to compare the length of stay (LOS) of patients who received carbidopa-levodopa (CL) in the ED with those who did not. Secondary outcomes included 30-day-readmission rates and administration of injectable for agitation. In addition, the percentage of patients receiving CL before and after an information management technology (IMT) alert implementation was compared in a sub-analysis. Patients that received CL during their inpatient stay were identified by a database report in this retrospective study. Patients were excluded if they were not admitted through the ED, younger than 65 years of age, or admitted to the intensive care unit after the ED. There was a total of 266 in the control group and 217 patients in the intervention group. The intervention group had a significantly shorter LOS than the control group (3.29 vs 5.37 days; P = 0.002), significantly less frequent 30-day readmissions (P = 0.032), and used fewer injectables for agitation (P = 0.035). The sub-analysis of the IMT alert revealed that prior to the alert's implementation, 28.5% of patients received CL in the ED; whereas post-alert, this percentage increased to 91.4% (P < 0.001). The results of this study found that the group of PD patients who received CL in the ED had shorter LOS, lower 30-day readmissions, and used less injectables for agitation compared with the group that did not receive CL in the ED. This improvement is possibly due to continuity of CL supply considering its short half-life and clinical importance for PD. [ABSTRACT FROM AUTHOR]

The role of ferroptosis in steatohepatitis development is largely unknown. We investigated (1) whether hepatocyte ferroptosis occurs in a gene-modified steatohepatitis model without modifying dietary components, (2) whether ferroptosis occurs at an early stage of steatohepatitis, and (3) whether apomorphine, recently reported as a ferroptosis inhibitor, can ameliorate steatohepatitis. Hepatocyte-specific PTEN KO mice were used. Huh 7 and primary cultured hepatocytes isolated from the mice were used in this study. The number of dead cells increased in 10-week-old PTEN KO mice. This cell death was suppressed by the administration of ferroptosis inhibitor ferrostatin-1 for 2 weeks. Apomorphine also ameliorated the severity of steatohepatitis. Treatment with ferroptosis inhibitors, including apomorphine, decreases the level of lipid peroxidase. Apomorphine suppressed cell death induced by RSL-3 (a ferroptosis inducer), which was not suppressed by apoptosis or necroptosis inhibitors. Apomorphine showed a radical trapping capacity with much more potent activity than ferrostatin-1 and Trolox, a soluble form of vitamin E. In addition, apomorphine activated nrf2 and its downstream genes, including HO-1 and xCT. In conclusion, ferroptosis occurs in steatohepatitis from an early stage in PTEN KO mice. In addition, apomorphine ameliorates the severity of steatohepatitis by inhibiting ferroptosis. [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: Apomorphine sublingual film (SL-APO) is an on-demand treatment for OFF episodes in patients with Parkinson's disease (PD). Objective: To assess the long-term (≥ 3 years) safety/tolerability and efficacy of SL-APO. Methods: Study CTH-301 (http://www.clinicaltrials.gov NCT02542696; registered 2015-09-03) was a phase 3, multicentre, open-label study of SL-APO in PD patients with motor fluctuations, comprised of a dose-titration and long-term safety phase. All participants received SL-APO. The primary endpoint was safety/tolerability (treatment-emergent adverse events [TEAEs]) during the long-term safety phase. Efficacy assessments included the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part III (motor examination), assessed at weeks 24, 36 and 48 during the first year of the long-term safety phase. Results: 496 patients were included and 120 (24.2%) completed the long-term safety phase. Mean duration of SL-APO exposure was 294.3 days. TEAEs related to study drug were experienced by 65.3% of patients (most common: nausea [6.0%], stomatitis [1.8%], lip swelling [1.8%], dizziness [1.6%], oral mucosal erythema [1.6%], mouth ulceration [1.6%]). TEAEs leading to study drug withdrawal were experienced by 34.0% of patients (most common: nausea [5.4%], lip swelling [4.5%], mouth ulceration [2.6%], stomatitis [2.3%]). A clinically meaningful reduction in MDS-UPDRS part III score was observed as soon as 15 min following administration of SL-APO, with peak effects observed approximately 30 min post-dose and sustained up to 90 min post-dose; results were consistent over 48 weeks. Conclusions: SL-APO was generally well tolerated and efficacious over the long term as an on-demand treatment for OFF episodes in patients with PD. [ABSTRACT FROM AUTHOR]

Neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease, are characterised by the progressive loss of specific neuronal cell populations due to multifactorial factors, including neurochemical and immunological disturbances. Consequently, patients can develop cognitive, motor and behavioural dysfunctions, which lead to impairments in their quality of life. Over the years, studies have reported on the neuroprotective properties inherent in phenolic compounds. Therefore, this review highlights the most recent scientific findings regarding phenolic compounds as promising neuroprotective molecules against neurodegenerative diseases. [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]

In the area of drug research, several computational drug repurposing studies have highlighted candidate repurposed drugs, as well as clinical trial studies that have tested/are testing drugs in different phases. To the best of our knowledge, the aggregation of the proposed lists of drugs by previous studies has not been extensively exploited towards generating a dynamic reference matrix with enhanced resolution. To fill this knowledge gap, we performed weight-modulated majority voting of the modes of action, initial indications and targeted pathways of the drugs in a well-known repository, namely the Drug Repurposing Hub. Our method, DReAmocracy, exploits this pile of information and creates frequency tables and, finally, a disease suitability score for each drug from the selected library. As a testbed, we applied this method to a group of neurodegenerative diseases (Alzheimer's, Parkinson's, Huntington's disease and Multiple Sclerosis). A super-reference table with drug suitability scores has been created for all four neurodegenerative diseases and can be queried for any drug candidate against them. Top-scored drugs for Alzheimer's Disease include agomelatine, mirtazapine and vortioxetine; for Parkinson's Disease, they include apomorphine, pramipexole and lisuride; for Huntington's, they include chlorpromazine, fluphenazine and perphenazine; and for Multiple Sclerosis, they include zonisamide, disopyramide and priralfimide. Overall, DReAmocracy is a methodology that focuses on leveraging the existing drug-related experimental and/or computational knowledge rather than a predictive model for drug repurposing, offering a quantified aggregation of existing drug discovery results to (1) reveal trends in selected tracks of drug discovery research with increased resolution that includes modes of action, targeted pathways and initial indications for the investigated drugs and (2) score new candidate drugs for repurposing against a selected disease. [ABSTRACT FROM AUTHOR]

Background: Atorvastatin is a commonly prescribed medication for the prevention of cardiovascular diseases. Recent observational studies have suggested a potential association between atorvastatin use and the occurrence of Erectile Dysfunction (ED). In this study, we aimed to explore the relationship between atorvastatin and ED using real-world data from the FAERS database and employed Mendelian randomization to assess causality. Methods: To evaluate the disproportionality of atorvastatin in relation to ED, we conducted several pharmacovigilance analyses, including odds ratio (ROR), proportional reporting ratio (PRR), Bayesian Confidence propagation neural network (BCPNN), and gamma-Poisson contractile apparatus (GPS). Additionally, we employed Mendelian randomization to investigate the causal relationship between atorvastatin and ED. Results: Pharmacovigilance disproportionality analysis revealed a significant association between atorvastatin and ED, as indicated by the following results: ROR [3.707078559, 95% CI (3.33250349, 4.123756054)], PRR [3.702969038, χ² (669.2853829)], IC [1.870490139, IC025 (1.702813857)], and EBGM [3.656567867, EBGM05 (3.28709656)]. Furthermore, the two-sample Mendelian randomization analysis provided evidence supporting a causal relationship between atorvastatin use and ED, with an inverse variance weighted estimate of β = 3.17 (OR = 23.91, p = 0.02 < 0.05). Conclusion: Based on comprehensive analyses incorporating pharmacovigilance and Mendelian randomization, our findings suggest that atorvastatin use is associated with an increased risk of ED and indicate a causal relationship. These results emphasize the importance of considering potential adverse effects, such as ED, when prescribing atorvastatin for cardiovascular disease prevention. Further research and clinical monitoring are warranted to better understand the underlying mechanisms and develop appropriate strategies to mitigate this side effect. [ABSTRACT FROM AUTHOR]

Background: The simultaneous occurrence of Parkinson's disease (PD)--a progressive neurodegenerative disorder marked by the loss of monoaminergic neurons in the substantia nigra--and Myasthenia gravis (MG)--a neuromuscular junction disease--is exceptionally rare. Although these conditions have different pathophysiological foundations, literature reports at least 29 cases of individuals diagnosed with both disorders. Case Report: We present the case of a 66-year-old patient treated for Parkinson's disease for four years before being diagnosed with MG, following the onset of dysphagia and bilateral ptosis. Apomorphine infusion, an advanced treatment option, was safely initiated. Conclusion: This case highlights the coexistence of PD and MG and illustrates the potential benefits of apomorphine infusion therapy. Apomorphine was effective in reducing symptoms, improving motor function, and enhancing the patient's quality of life. [ABSTRACT FROM AUTHOR]

Purpose: A majority of advanced Parkinson's disease (PD) patients on oral levodopa experience motor fluctuations, including sudden OFF and delayed ON periods. Fast-acting rescue medications are a vital part of the clinician's armamentarium in the treatment of motor fluctuations. Sublingual apomorphine is the first sublingual rescue medication on the market for the treatment of OFF times in PD.Materials and Methods: Here, we review the development and pharmacology of apomorphine in the treatment of PD as well as the safety and efficacy of sublingual apomorphine established in clinical trials. Finally, we compare sublingual apomorphine to the other rescue medications available and provide our opinion on the use of sublingual apomorphine in clinical practice.Results: Clinical trials have demonstrated that sublingual apomorphine is a safe and effective option in the treatment of motor fluctuations in PD. In a Phase II trial, 100% of patients who achieved a full ON response did so within 30 min and 40% did so within 15 min. The mean duration of effect was 50 min. In a Phase III trial, 77.3% of patients achieved a full ON response. Side effects such as nausea, dizziness and somnolence were common but were generally mild. No patients experienced worsening dyskinesia.Conclusions: Sublingual apomorphine will provide patients with motor fluctuations due to advanced PD another safe and effective option for the treatment of OFF times. [ABSTRACT FROM AUTHOR]

OBJECTIVE The primary goal was to compare the efficacy of administration of apomorphine (APO) administered by intranasal (IN), transconjunctival (TC), SC and IV routes with ropinirole eye drops for induction of emesis in dogs with a secondary goal to evaluate the time of emesis as well as difficulty in administration. ANIMALS 125 client-owned dogs. METHODS Dogs were randomly enrolled between October 1, 2021, and March 30,2022, into groups of 25: IV APO, IN APO, TC APO, SC APO, and ropinirole eye drops. The IV, SC, and TC groups were dosed at 0.03 mg/kg, the IN group was dosed at 0.06 mg/kg, and the ropinirole group was dosed according to manufacturer guidelines. Data collected included success rate of emesis within 600 seconds, time to emesis, time to administer, and difficulty score. Results were compared to IV with P values and Cls being adjusted for multiple comparisons. RESULTS Emesis was successful within 600 seconds using IV APO in 22 of 25 dogs. By comparison, IN APO induced emesis in 18 of 25 dogs (P = .63). Ropinirole (14/25), SC APO (6/25), and TC APO (4/25) were significantly less successful (P = .047, P=< .001, and P< 0.001, respectively). When emesis was successful, it occurred most rapidly with TC APO, followed by IN APO and then ropinirole. It was most difficult to administer IV APO and TC APO. CLINICAL RELEVANCE Similar to IV APO, IN APO was a rapid, easy, and effective method of inducing emesis in dogs and should be considered when IV administration is not possible. Ropinirole was easy to administer but successfully induced emesis less reliably within a 10-minute timeframe. APO administered TC using the commercially compounded injectable formulation was ineffective. [ABSTRACT FROM AUTHOR]

Apomorphine, used to treat OFF episodes in patients with Parkinson's disease (PD), is typically administered via subcutaneous injections. Administration of an oromucosal solution could offer a non‐invasive and user‐friendly alternative. This two‐part clinical study evaluated the safety, tolerability, pharmacokinetics (PK), and dose proportionality of a novel apomorphine hydrochloride oromucosal solution, as well as its relative bioavailability to subcutaneous apomorphine injection and apomorphine sublingual film. In part A of the study, 12 patients with PD received 2 mg oromucosal apomorphine (4% weight/volume) and 2 mg subcutaneous apomorphine in a randomized order, followed by 4 and 8 mg oromucosal apomorphine. In part B of the study, 13 patients with PD received 7 mg oromucosal apomorphine (7% weight/volume) and 30 mg sublingual apomorphine in a randomized order, followed by 14 mg oromucosal apomorphine. Washout between dose administrations in both study parts was at least 2 days. Safety, tolerability, and PK were assessed pre‐ and post‐dose. Both study parts showed that oromucosal apomorphine was generally well‐tolerated. Observed side effects were typical for apomorphine administration and included asymptomatic orthostatic hypotension, yawning, fatigue, and somnolence. Oromucosal apomorphine exposure increased with dose, although less than dose proportional. The mean (SD) maximum exposure reached with 14 mg oromucosal apomorphine was 753.0 (298.6) ng*min/mL (area under the plasma concentration–time curve from zero to infinity) and 8.0 (3.3) ng/mL (maximum plasma concentration). This was comparable to exposure reached after 2 mg subcutaneous apomorphine and approximately half of the exposure observed with 30 mg sublingual apomorphine. In summary, clinically relevant plasma concentrations could be reached in PD patients without tolerability issues. [ABSTRACT FROM AUTHOR]

Osteoporosis is the most common metabolic bone disorder and is characterized by decreased bone density, which has a relationship with the quality of life among the aging population. Previous research has found that activation of the dopamine D1 receptor can improve bone mass formation. SKF38393 is an agonist of dopamine D1 receptors. However, as a small-molecule drug, SKF38393 is unstable and releases quickly. The aim of this study was to prototype polylactic-co-glycolic acid (PLGA)/SKF38393 microspheres and assess their potential osteogenic effects compared to those under the free administration of SKF38393. The cytocompatibility of PLGA/SKF38393 was determined via CCK-8 and live/dead cell staining; the osteogenic effects in vitro were determined with ALP and alizarin red staining, qRT-PCR, and Western blotting; and the in vivo effects were assessed using 25 Balb/c mice. We also used a PCR array to explore the possible signaling pathway changes after employing PLGA/SKF38393. Our experiments demonstrated that the osteogenic effect of D1Rs activated by the PLGA/SKF38393 microsphere was better than that under free administration, both in vitro and in vivo. According to the PCR array, this result might be associated with six signaling pathways (graphical abstract). Ultimately, in this study, we prototyped PLGA/SKF38393, demonstrated its effectiveness, and preliminarily analyzed its mechanism of action. [ABSTRACT FROM AUTHOR]

Abnormal phosphorylation of the microtubule-binding protein tau in the brain is a key pathological marker for Alzheimer's disease and additional neurodegenerative tauopathies. However, how hyperphosphorylated tau causes cellular dysfunction or death that underlies neurodegeneration remains an unsolved question critical for the understanding of disease mechanism and the design of efficacious drugs. Using a recombinant hyperphosphorylated tau protein (p-tau) synthesized by the PIMAX approach, we examined how cells responded to the cytotoxic tau and explored means to enhance cellular resistance to tau attack. Upon p-tau uptake, the intracellular calcium levels rose promptly. Gene expression analyses revealed that p-tau potently triggered endoplasmic reticulum (ER) stress, unfolded protein response (UPR), ER stress-associated apoptosis, and pro-inflammation in cells. Proteomics studies showed that p-tau diminished heme oxygenase-1 (HO-1), an ER stress-associated anti-inflammation and anti-oxidative stress regulator, while stimulated the accumulation of MIOS and other proteins. p-Tau-induced ER stress-associated apoptosis and pro-inflammation are ameliorated by apomorphine, a brain-permeable prescription drug widely used to treat Parkinson's disease symptoms, and by overexpression of HO-1. Our results reveal probable cellular functions targeted by hyperphosphorylated tau. Some of these dysfunctions and stress responses have been linked to neurodegeneration in Alzheimer's disease. The observations that the ill effects of p-tau can be mitigated by a small compound and by overexpressing HO-1 that is otherwise diminished in the treated cells inform new directions of Alzheimer's disease drug discovery. [ABSTRACT FROM AUTHOR]