[Tremor-dominant form of Parkinson's disease]. / Tremor-dominantnaya forma bolezni Parkinsona.

The article is of a review nature and is devoted to tremor, one of the maladaptive and difficult-to-treat symptoms of Parkinson's disease (PD). Along with the classic rest tremor, patients with PD may experience tremor of other modalities: postural tremor, kinetic tremor, which reflects a multimodal mechanism of tremor formation involving multiple neurotransmitter systems. The unpredictable response to therapeutic options, the ambiguous response to levodopa, also reflects the role of multiple underlying pathophysiological processes. Among the drug methods of tremor correction, preference is given to dopamine receptor agonists - due to the spectrum of their pharmaceutical action, high efficiency in relation to all leading motor and a number of non-motor manifestations. The evidence for advanced neurosurgical, non-invasive modalities is mixed, and there are insufficient comparative studies to assess their efficacy in patients with tremor-dominant forms of PD.

[Postural stability and walking in Parkinson's disease]. / Postural'naya ustoichivost' i khod'ba pri bolezni Parkinsona.

The article is of an overview nature and is devoted to movement disorders in Parkinson's disease. The article discusses the existing problems according to the latest literature data, a review on the treatment and rehabilitation of postural instability. Special attention in the article is paid to dopamine receptor agonists - namely, piribedil, prescribed for the correction of these disorders.

L-DOPA-therapy in Parkinson's disease: some personal reflections on L-DOPA therapy from Vienna and Berlin.

Dopamine was initially considered as a mere intermediate in the noradrenaline synthesis but was then found to be a neurotransmitter. Its depletion resulted in characteristic symptoms in experimental studies and could be antagonized by DOPA (3,4-dihydroxyphenylalanin), suggesting a similarity to the human disorder Parkinson´s disease (PD) and a therapeutic potential which was successfully exploited from the 1970s on. This was due to the pioneering work of Arvid Carlsson and clinicians around the world who first worked on the breakthrough of L-DOPA therapy and then on its amendment and modification and on alternative therapies for PD patients. All these developments led to the establishment of PD therapy as we know it today. It is characterized by the availability of many different compounds which are mostly employed in combination and by different methods: orally, intravenously, transdermally, subcutaneously, or duodenally. Here, we present without claim of completeness some personal reflections about causal drug developments for PD patients and reflect on some personal interactions with leading clinicians and basic researchers who cooperated with us. Such interactions are crucial for the creation, sometimes serendipitously, of fresh ideas and to further develop existing concepts to make therapeutical progress.

[Dopaminergic potential of domestic 3-hydroxypyridine and succinic acid derivatives and prospects for their therapeutic «retargeting¼]. / Dofaminergicheskii potentsial otechestvennykh proizvodnykh 3-oksipiridina i yantarnoi kisloty i perspektivy ikh terapevticheskogo «perenatselivaniya¼.

The review is devoted to the assessment of the pharmacological effects of 3-hydroxypyridine and succinic acid derivatives (emoxipin, reamberin and mexidol) from the standpoint of their dopaminergic activity. A systematic analysis of the data has been performed, allowing us to consider emoxipin, reamberin and mexidol as «normalizers of dopaminergic neurotransmission¼, the dopaminergic action of which in its phenotype corresponds to the effects of partial dopamine receptor agonists. The position that the dopaminergic effect, antioxidant and antidepressant potential of drugs containing 2-ethyl-6-methyl-3-oxypyridine (emoxipine and mexidol) are associated with their inhibitory effect on monoamine oxidase-A (MAO-A) has been substantiated. A direct relationship between the stimulating effect of succinate-containing drugs (reamberin and mexidol) on MAO-B, their prooxidant activity, insulin-potentiating and antidepressant effects was analyzed. A hypothesis has been put forward on the general pathological significance of dopaminergic regulation disorders, the correction of which with the 3-hydroxypyridine and succinic acid derivatives can be considered as a promising strategy for improving the complex therapy of socially significant and common human diseases.

Adenosine A2A antagonists and Parkinson's disease.

Although there is no cure for Parkinson's disease (PD), there are several classes of medications with various mechanisms of action that can help improve the functionality of someone with PD. Dopamine derivatives are first line therapies for PD, hence dopamine receptor agonists (DAs) have been shown to improve functionality of symptoms in PD patients. The two main formulations of dopamine agonist medications in PD therapy are ergoline and non-ergoline derivatives. Additionally, it has been shown that PD can involve irregularities in other neurotransmitters, such as acetylcholine, norepinephrine, and serotonin, hence why non-dopaminergic medications are also vital in PD management. Examples include NMDA receptor antagonists, dopamine antagonists (i.e. neuroleptics), acetylcholine receptor antagonists, serotonin receptor 2A agonists, and adenosine A2 antagonists. In general, dopaminergic medications are the most effective in improving motor involvement with PD, whereas non-dopaminergic medications tend to focus on the non-motor involvement of PD. In this chapter, we will focus on the chemistry and medication background on dopaminergic vs non-dopaminergic therapy, with a focus of adenosine A2 antagonists at the end.

An update on the pharmacogenetic considerations when prescribing dopamine receptor agonists for Parkinson's disease.

INTRODUCTION: Parkinson's disease is a chronic neurodegenerative multisystemic disorder that affects approximately 2% of the population over 65 years old. This disorder is characterized by motor symptoms which are frequently accompanied by non-motor symptoms such as cognitive disorders. Current drug therapies aim to reduce the symptoms and increase the patient's life expectancy. Nevertheless, there is heterogeneity in therapy response in terms of efficacy and adverse effects. This wide range in response may be linked to genetic variability. Thus, it has been suggested that pharmacogenomics may help to tailor and personalize drug therapy for Parkinson's disease. AREAS COVERED: This review describes and updates the clinical impact of genetic factors associated with the efficacy and adverse drug reactions related to common medications used to treat Parkinson's disease. Additionally, we highlight current informative recommendations for the drug treatment of Parkinson's disease. EXPERT OPINION: The pharmacokinetic, pharmacodynamic, and safety profiles of Parkinson's disease drugs do not favor the development of pharmacogenetic tests with a high probability of success. The chances of obtaining ground-breaking pharmacogenetics biomarkers for Parkinson's disease therapy are limited. Nevertheless, additional information on the metabolism of certain drugs, and an analysis of the potential of pharmacogenetics in novel drugs could be of interest.

Switching antipsychotics to partial dopamine D2-agonists in individuals affected by schizophrenia: a narrative review.

OBJECTIVE: The aim of this review is to analyse the literature regarding studies centred on the clinical outcome of individuals affected by schizophrenia and treated with various antipsychotics, and then switched to orally administered partial D2-dopamine agonists (PD2A): Aripiprazole (ARI), brexpiprazole (BREX) or cariprazine (CARI). METHOD: A PubMed literature search was performed on 16 February 2021, and updated on Jan 26, 2022 for literature on antipsychotic switching in individuals affected by schizophrenia. Literature was included from 2002 onward. Six strategies were defined: Abrupt, gradual and cross-taper switch, and 3 hybrid strategies. The primary outcome was all-cause discontinuation rate per switch strategy per goal medication. RESULTS: In 10 reports on switching to ARI, 21 studies with different strategies were described, but there were only 4 reports and 5 strategies on switching to BREX. Only one study about CARI was included, but it was not designed as a switch study. The studies are difficult to compare due to differences in methodology, previous antipsychotic medication, doses of the introduced P2DA and study duration. CONCLUSION: This analysis did not reveal evidence for a preferable switching strategy. A protocol should be developed which defines optimal duration, instruments to be used, and the timing of the exams.KEY MESSAGESMost switch studies on partial D2-agonists focus on ARI, with only a few on BREX, while little is known about the clinical outcome of switching individuals to CARIThere is a wide variation of possible switch methods: Abrupt switch - gradual switch - cross-tapering switch - hybrid strategies including plateau switchThe protocols used differ considerably between the studies. A strict comparison between the studies is difficult, for which reason the present evidence does not support an unambiguous preference for a particular switch strategy.From a methodological point of view, a standardised clinical protocol should be developed to allow comparisons between studies regarding the clinical outcome of individuals switched from one antipsychotic drug to another.

Comparative efficacy and safety of six non-ergot dopamine-receptor agonists in early Parkinson's disease: a systematic review and network meta-analysis.

Background: Non-ergot dopamine agonists (NEDAs) have been used as monotherapy or as an adjunctive therapy to levodopa for many years. Novel long-acting formulations of NEDAs including pramipexole extended-release (ER), ropinirole prolonged-release (PR), and rotigotine transdermal patch have been developed. However, there is no strong evidence that a given NEDA is more potent than another. We performed a systematic review and network meta-analysis to evaluate the efficacy, tolerability and safety of six commonly used NEDAs in early Parkinson's disease (PD). Methods: Six NEDAs including piribedil, rotigotine transdermal patch, pramipexole immediate-release (IR)/ER, and ropinirole IR/PR were investigated. The efficacy outcomes including Unified Parkinson's Disease Rating Scale activities in daily life (UPDRS-II), motor function (UPDRS-III), and their subtotal (UPDRS-II + III), tolerability and safety outcomes were analyzed. Results: A total of 20 RCTs (5,355 patients) were included in the current study. The result indicated that compared with placebo, all six investigated drugs had statistically significant differences in the improvement of UPDRS-II, UPDRS-III, and UPDRS-II + III (except ropinirole PR in UPDRS-II). There were no statistically significant differences between six NEDAs for the UPDRS-II and UPDRS-III. For UPDRS-II + III, the improvement of ropinirole IR/PR and piribedil were higher than that of rotigotine transdermal patch, and piribedil was higher than that of pramipexole IR. The surface under the cumulative ranking curve (SUCRA) indicated that piribedil resulted in best improvement in UPDRS-II and UPDRS-III (0.717 and 0.861, respectively). For UPDRS-II + III, piribedil and ropinirole PR exhibited similar improvement and both had high rates (0.858 and 0.878, respectively). Furthermore, piribedil performed better as monotherapy, ranking first in the improvement of UPDRS-II, III, and II + III (0.922, 0.960, and 0.941, separately). With regard to tolerability, there was a significant increase in overall withdrawals with pramipexole ER (0.937). In addition, the incidence of adverse reaction of ropinirole IR was relatively high (nausea: 0.678; somnolence: 0.752; dizziness: 0.758; fatigue: 0.890). Conclusions: In this systematic review and network meta-analysis of six NEDAs, piribedil exhibited better efficacy, especially as monotherapy, and ropinirole IR was associated with a higher incidence of adverse events in patients with early PD.

Xanthine-Dopamine Hybrid Molecules as Multitarget Drugs with Potential for the Treatment of Neurodegenerative Diseases.

Multitarget drugs based on a hybrid dopamine-xanthine core were designed as potential drug candidates for the treatment of neurodegenerative diseases. Monoamine oxidase B (MAO-B) inhibitors with significant ancillary A2A adenosine receptor (A2AAR) antagonistic properties were further developed to exhibit additional phosphodiesterase-4 and -10 (PDE4/10) inhibition and/or dopamine D2 receptor (D2R) agonistic activity. While all of the designed compounds showed MAO-B inhibition in the nanomolar range mostly combined with submicromolar A2AAR affinity, significant enhancement of PDE-inhibitory and D2R-agonistic activity was additionally reached for some compounds through various structural modifications. The final multitarget drugs also showed promising antioxidant properties in vitro. In order to evaluate their potential neuroprotective effect, representative ligands were tested in a cellular model of toxin-induced neurotoxicity. As a result, protective effects against oxidative stress in neuroblastoma cells were observed, confirming the utility of the applied strategy. Further evaluation of the newly developed multitarget ligands in preclinical models of Alzheimer's and Parkinson's diseases is warranted.

Differential effects of dopamine receptor agonists ropinirole and quinpirole on locomotor and anxiolytic behaviors in larval zebrafish (Danio rerio): A role for the GABAergic and glutamate system?

Zebrafish are frequently used as a vertebrate model to elucidate toxicological and pharmacological mechanisms of action in the central nervous system. Pharmacological studies demonstrate that dopamine, signaling via several receptor subtypes, regulates zebrafish larval behavior. Quinpirole is a selective dopamine receptor agonist for D2 and D3 subtypes while ropinirole exhibits selectivity toward D2, D3, and D4 receptors. The main objective of this study was to determine the short-term actions of quinpirole and ropinirole on the locomotor activity and anxiolytic/anti-anxiolytic behaviors of zebrafish. Furthermore, dopamine signaling can cross talk with other neurotransmitter systems, including the GABAergic and glutamatergic system. As such, we measured transcriptional responses in these systems to determine whether dopamine receptor activation modulated GABAergic and glutaminergic systems. Ropinirole reduced locomotor activity of larval fish at concentrations of 1 µM and greater but quinpirole did not affect locomotor activity at all concentrations tested. Anxiolytic-related behaviors were also compared between the two pharmaceuticals. Noteworthy was that both dopamine receptor agonists at 1 µM increased the activity of zebrafish in the light phase of a light-dark preference test, which may be related to the activation of D2 and/or D3 receptors. In terms of interactions with other neurotransmitter systems, ropinirole up-regulated transcripts in larvae zebrafish related to both the GABAergic and glutamatergic systems (abat, gabra1, gabrb1, gad1b, gabra5, gabrg3, and grin1b). Conversely, quinpirole did not alter the abundance of any transcript measured, suggesting that dopamine-GABA interaction may involve D4-receptors, which has been noted in mammalian models. This study demonstrates pleiotropic actions of dopamine agonism on the GABA and glutamate system in larval zebrafish. This study has relevance for characterizing toxicants that act via dopamine receptors and for elucidating mechanisms of neurological disorders that involve motor circuits and multiple neurotransmitter systems, like Parkinson's disease.

[Motor and autonomic disorders influence on pain syndrome of patients with Parkinson's disease of the I-III H&Y stages]. / Vliyanie motornykh i vegetativnykh narushenii na vyrazhennost' bolevogo sindroma u patsientov s I­III stadiyami bolezni Parkinsona.

OBJECTIVE: To evaluate the influence of motor and autonomic disorders on the pain of patients with PD of the I-III H&Y stages and possibility of correcting the pain with dopamine receptor agonists (ADR). MATERIAL AND METHODS: 252 patients (128 women and 124 men, 42-80 years old) with PD of I-III Hoehn and Yahr stages (H&Y) were examined using the following scales: UPDRS, daily activity Sch&En, quality of life PDQ-39, MMSE, BDI, PFS-16, NMSQuest, GSRS, AUA; 53 patients were piribedil treated during 6 months. RESULTS: Our results indicated a wide prevalence of pain syndrome in PD patients (58.6%), starting from the early stages (50% for the Ist stage). The most stable pain associations were found with the PD stage, levodopa doses, severity of motor symptoms (postural disorders and hypokinesia manifestations) and motor complications («off-periods¼ and dyskinesias), as well as non-motor PD manifestations depression and autonomic dysfunctions (constipation, swallowing disorders, and frequent urination). The regression analysis showed, that the severity of motor complications and depression were the predictors of pain occurrence. The pain syndrome in patients with PD of I-III stages underwent significant regression (by 51% and 62%, after 1.5 and 6 months of therapy, respectively) after ADR (piribedil) addition to their therapy; it's probably due to improving the motor component and decreasing depressive disorders. CONCLUSIONS: The piribedil inclusion contributes to the reduction of pain syndrome, regardless is it used in monotherapy or in conjunction with levodopa preparations.

Dopamine receptor agonists mechanism of actions on glucose lowering and their connections with prolactin actions.

Robust experiment evidence suggests that prolactin can enhance beta-cell proliferation and increase insulin secretion and sensitivity. Apart from acting as an endocrine hormone, it also function as an adipokine and act on adipocytes to modulate adipogenesis, lipid metabolism and inflammation. Several cross-sectional epidemiologic studies consistently showed that circulating prolactin levels positive correlated with increased insulin sensitivity, lower glucose and lipid levels, and lower prevalence of T2D and metabolic syndrome. Bromocriptine, a dopamine receptor agonist used to treat prolactinoma, is approved by Food and Drug Administration for treatment in type 2 diabetes mellitus since 2009. Prolactin lowering suppress insulin secretion and decrease insulin sensitivity, therefore dopamine receptor agonists which act at the pituitary to lower serum prolactin levels are expected to impair glucose tolerance. Making it more complicating, studies exploring the glucose-lowering mechanism of bromocriptine and cabergoline have resulted in contradictory results; while some demonstrated actions independently on prolactin status, others showed glucose lowering partly explained by prolactin level. Previous studies showed that a moderate increase in central intraventricular prolactin levels stimulates hypothalamic dopamine with a decreased serum prolactin level and improved glucose metabolism. Additionally, sharp wave-ripples from the hippocampus modulates peripheral glucose level within 10 minutes, providing evidence for a mechanistic link between hypothalamus and blood glucose control. Central insulin in the mesolimbic system have been shown to suppress dopamine levels thus comprising a feedback control loop. Central dopamine and prolactin levels plays a key role in the glucose homeostasis control, and their dysregulation could lead to the pathognomonic central insulin resistance depicted in the "ominous octet". This review aims to provide an in-depth discussion on the glucose-lowering mechanism of dopamine receptor agonists and on the diverse prolactin and dopamine actions on metabolism targets.

Efficacy and safety of non-ergot dopamine-receptor agonists as an adjunct to levodopa in advanced Parkinson's disease: A network meta-analysis.

BACKGROUND AND PURPOSE: Non-ergot dopamine agonists (NEDAs) have been used as an adjunct therapy to levodopa in advanced Parkinson's disease (PD) for many years. However, there is no strong evidence that a given NEDA is more potent than another. To compare and rank the efficacy, tolerability, and safety of six commonly used NEDAs as an adjunct to levodopa in advanced PD, which includes long-acting and standard formulations, a network meta-analysis was performed. METHODS: The MEDLINE, Embase, Cochrane Central Register of Controlled Trials, China National Knowledge Infrastructure, and Wanfang databases were searched from January 1996 to June 2022 for eligible randomized controlled trials (RCTs). Six NEDAs, including rotigotine transdermal patch, ropinirole immediate-release (IR)/prolonged-release (PR), pramipexole IR/extended-release (ER), and piribedil, were investigated. RESULTS: A total of 34 RCTs (7868 patients) were included in the current study. The surface under the cumulative ranking curve indicated that ropinirole PR was associated with the best improvement in Unified Parkinson's Disease Rating Scale (UPDRS)-II, UPDRS-III, and UPDRS-II + III (0.811, 0.742, and 0.827). For OFF time reduction, pramipexole IR ranked first (0.979), and ropinirole PR ranked first in OFF time responder rate (0.927). Pramipexole ER ranked first in overall withdrawals, and rotigotine transdermal patch ranked first in the incidence of adverse events (≥1 AEs). CONCLUSIONS: This network meta-analysis suggests six commonly used NEDAs are effective as an adjunct to levodopa in advanced PD. In comprehensive consideration of better symptomatic management, ropinirole PR may be a better choice than other NEDAs in advanced PD. Six NEDAs showed different profiles of AEs.

Current and Perspective Approaches to the Treatment of Prolactinomas.

Background: Along with the presence of the 2011 Endocrine Society Clinical Practice Guidelines and numerous large-scale studies on the treatment of hyperprolactinemia of different origin, there are some unresolved questions, ambiguous and sometimes contradictory points of view regarding the management of patients with prolactinomas. This overview is devoted to the analysis of the results of modern clinical studies and the approaches towards the management of hyperprolactinemia caused by prolactinoma. Materials and methods: A systematic research of the literature for the appropriate keywords published mainly for the last 10 years was done; also, a reference list of each selected article was analysed. We included to our review the articles reporting controversial issues or new data on the treatment of hyperprolactinemia. Results: The review describes various problems arising during the treatment of prolactinoma. The presence of primary and secondary dopamine agonist resistance in each case requires an individual approach, and sometimes may include the use of the antineoplastic agent t emozolomide. The side effects of dopamine agonists are discussed, with quite rare ones, including valvulopathy, pathological psychological conditions and cerebrospinal rhinorrhea. The controversial issue of the duration and doses of the drug used to achieve a lasting effect in the treatment of prolactinomas is considered. There are some points connected with the frequency of relapses. Thus, recurrence is correlated to the duration of treatment with dopamine agonists, prolactin levels at diagnosis, and the initial tumor size. Metformin, somatostatin analogues, selective estrogen receptor modulators, tyrosine kinase inhibitors, inhibitors of the mammalian target of rapamycin, epidermal growth factor receptor antagonists are investigated nowadays as potential alternative methods of drug treatment of prolactinomas. Conclusion: Drug therapy with dopamine agonists makes it possible to achieve the desired results in the vast majority of patients. However, despite the proven safety of this group of medicines, the risk of side effects should still be taken into account. The therapy regimen should be determined by the clinical course of prolactinoma and the patient's response to treatment. Other options of treatment should be considered in patients intolerant to medical therapy, with contraindication or resistance to dopamine agonists, in the case of a malignant tumor. The presence of refractory to any of the applied methods of treatment and aggressive prolactinomas leads to the search for new drugs.

[Upper gastrointestinal tract dysfunction and its correction by dopamine agonists for patients with Parkinson's disease of I-III stage]. / Disfunktsiya verkhnikh otdelov zheludochno-kishechnogo trakta u patsientov na I­III stadiyakh bolezni Parkinsona i ee korrektsiya agonistami dofaminovykh retseptorov.

OBJECTIVE: To evaluate the main symptoms of the upper gastrointestinal dysfunction (salivation and swallowing disorders) and to determine their impact on the quality of life for patients with PD of stages I-III, as well as the possibility of their correction by dopamine receptor agonists. MATERIAL AND METHODS: 252 patients (128 women and 124 men, 42-80 years old) with PD of stages I-III were examined using: UPDRS items «salivation¼, «swallowing¼ and «anorexia¼, scale of daily activity (Schwab and England ADL scale), questionnaire quality of life (PDQ-39), measurement of saliva amount, BMI, MMSE scale; 53 patients were treated with piribedil during 6 months. RESULTS: The upper gastrointestinal tract dysfunction of mild to moderate severity was detected in 51.2% of patients. The prevalence of sialorrhea was 38.9, 42.9 and 46.2%, and that of dysphagia was 22.2, 24.3 and 17.3% at stages I-III, respectively. According to the results of the correlation analysis dysphagia is associated with a long history of PD, low BMI, high doses of levodopa and low Sch & En score; and sialorrhea is also associated with low BMI and with old age. For the early stages of PD we can tell, that the quality of patients' life deteriorates, and this to a large extent is due to impaired salivation and swallowing, which manifest themselves in daily activity and communication difficulties. CONCLUSIONS: The inclusion of piribedil (150-250 mg/day) in the 6-months therapy reduces the dysfunction of the upper gastrointestinal tract (by 61 and 74% of the initial level of dysphagia and sialorrhea, respectively) regardless the drug use in monotherapy or in complex therapy with levodopa.

Metopimazine is primarily metabolized by a liver amidase in humans.

Metopimazine (MPZ) is a peripherally restricted, dopamine D2 receptor antagonist used for four decades to treat acute nausea and vomiting. MPZ is currently under clinical investigation for the treatment of gastroparesis (GP). MPZ undergoes high first-pass metabolism that produces metopimazine acid (MPZA), the major circulating metabolite in humans. Despite a long history of use, the enzymes involved in the metabolism of MPZ have not been identified. Here we report a series of studies designed to identify potential MPZ metabolites in vitro, determine their clinical relevance in humans, and elucidate the enzymes responsible for their formation. The findings demonstrated that the formation of MPZA was primarily catalyzed by human liver microsomal amidase. Additionally, human liver cytosolic aldehyde oxidase (AO) catalyzes the formation of MPZA, in vitro, although to a much lesser extent. Neither cytochrome P450 enzymes nor flavin-monooxygenases (FMO) were involved in the formation MPZA, although two minor oxidative pathways were catalyzed by CYP3A4 and CYP2D6 in vitro. Analysis of plasma samples from subjects dosed 60 mg of MPZ verified that these oxidative pathways are very minor and that CYP enzyme involvement was negligible compared to microsomal amidase/hydrolase in overall MPZ metabolism in humans. The metabolism by liver amidase, an enzyme family not well defined in small molecule drug metabolism, with minimal metabolism by CYPs, differentiates this drug from current D2 antagonists used or in development for the treatment of GP.

Dopamine agonist responsive burning mouth syndrome: Report of eight cases.

BACKGROUND: Burning mouth syndrome (BMS) is characterized by burning sensation of the oral mucosa. There is a lack of effective treatment. In recent years, a special subtype of BMS has been reported, in which oral burning sensation is alleviated after chewing, speaking, or dopaminergic drug delivery. Currently, there are few reports about the subtype of BMS in China. This study was a retrospective analysis of the clinical data of BMS patients sensitive to dopamine agonist at our hospital, aiming to improve the recognition on this disease. CASE SUMMARY: Eight patients diagnosed with dopamine agonist responsive BMS at the Liaocheng People's Hospital from January 1, 2017 to June 30, 2020 were recruited. The clinical manifestations, treatment, and prognosis were retrospectively analyzed. There were three male and five females in the eight patients. The median age was 56 years (range, 46-65 years). All the eight patients showed burning pain in the mouth. The symptoms were mild in the morning and severe in the evening, and alleviated after chewing, talking, and other oral activities. Four patients were accompanied by restless legs syndrome (RLS). Family history of RLS was positive in two patients. All patients were treated with pramipexol, and symptoms were basically relieved after 2-8 wk. CONCLUSION: Dopamine agonist responsive BMS is a special subtype of BMS, which is alleviated after oral activities. Dopamine receptor agonist is an effective treatment.

Current Therapies in Clinical Trials of Parkinson's Disease: A 2021 Update.

Parkinson's disease (PD) is a progressive neurodegenerative disorder that currently has no cure, but treatments are available to improve PD symptoms and maintain quality of life. In 2020, about 10 million people worldwide were living with PD. In 1970, the United States Food and Drug Administration approved the drug levodopa as a dopamine replacement to manage PD motor symptoms; levodopa-carbidopa combination became commercialized in 1975. After over 50 years of use, levodopa is still the gold standard for PD treatment. Unfortunately, levodopa therapy-induced dyskinesia and OFF symptoms remain unresolved. Therefore, we urgently need to analyze each current clinical trial's status and therapeutic strategy to discover new therapeutic approaches for PD treatment. We surveyed 293 registered clinical trials on ClinicalTrials.gov from 2008 to 16 June 2021. After excluded levodopa/carbidopa derivative add-on therapies, we identified 47 trials as PD treatment drugs or therapies. Among them, 19 trials are in phase I (41%), 25 trials are in phase II (53%), and 3 trials are in phase III (6%). The three phase-III trials use embryonic dopamine cell implant, 5-HT1A receptor agonist (sarizotan), and adenosine A2A receptor antagonist (caffeine). The therapeutic strategy of each trial shows 29, 5, 1, 5, 5, and 2 trials use small molecules, monoclonal antibodies, plasma therapy, cell therapy, gene therapy, and herbal extract, respectively. Additionally, we discuss the most potent drug or therapy among these trials. By systematically updating the current trial status and analyzing the therapeutic strategies, we hope this review can provide new ideas and insights for PD therapy development.

Dopamine receptor agonists ameliorate bleomycin-induced pulmonary fibrosis by repressing fibroblast differentiation and proliferation.

Idiopathic pulmonary fibrosis (IPF) is the most common fatal interstitial lung disease, with limited therapeutic options. The abnormal and uncontrolled differentiation and proliferation of fibroblasts have been confirmed to play a crucial role in driving the pathogenesis of IPF. Therefore, effective and well-tolerated antifibrotic agents that interfere with fibroblasts would be an ideal treatment, but no such treatments are available. Remarkably, we found that dopamine (DA) receptor D1 (D1R) and DA receptor D2 (D2R) were both upregulated in myofibroblasts in lungs of IPF patients and a bleomycin (BLM)-induced mouse model. Then, we explored the safety and efficacy of DA, fenoldopam (FNP, a selective D1R agonist) and sumanirole (SMR, a selective D2R agonist) in reversing BLM-induced pulmonary fibrosis. Further data showed that DA receptor agonists exerted potent antifibrotic effects in BLM-induced pulmonary fibrosis by attenuating the differentiation and proliferation of fibroblasts. Detailed pathway analysis revealed that DA receptor agonists decreased the phosphorylation of Smad2 induced by TGF-ß1 in primary human lung fibroblasts (PHLFs) and IMR-90 cells. Overall, DA receptor agonists protected mice from BLM-induced pulmonary fibrosis and may be therapeutically beneficial for IPF patients in a clinical setting.

Blood pressure and its association with antiparkinsonian medications in patients with Parkinson′s disease / 中华神经科杂志

Parkinson′s disease (PD) is the second most common neurodegenerative disease following Alzheimer′s disease. The non-motor symptoms of PD have attracted increasing attention. The occurrence of abnormal blood pressure is related to many factors, including aging, PD related autonomic nerve dysfunction, and drugs for PD treatment,including levodopa, dopamine receptor agonists. Abnormal blood pressure severely limits the clinical use of anti-PD drugs. In order to better understand the relationship between anti-PD drugs and blood pressure in patients with PD. This article summarizes the manifestations of abnormal blood pressure, and analyzes the correlation between anti-PD drugs and blood pressure, summarizes the possible mechanisms of how anti-PD drugs affects the blood pressure in PD.