Motor fluctuations are a common and burdensome complication of Parkinson's disease (PD) when the disease progresses, largely driven by the short half-life and variable absorption of immediate-release (IR) levodopa. IPX203 is a next-generation modified-release levodopa/carbidopa formulation that delivers rapid onset and sustained plasma levodopa concentrations through IR granules and extended-release pellets. Clinical studies have shown that IPX203 increases Good ON time (ON time without dyskinesia plus ON time with non-troublesome dyskinesia, equivalent to ON time without troublesome dyskinesia), reduces OFF time and improves motor symptom control compared with IR levodopa/carbidopa. In anticipation of the introduction of IPX203 in Europe, nine PD specialists convened to develop consensus recommendations for its use in clinical practice. Through a structured process incorporating predefined statements, voting and moderated discussion, the group reached high levels of agreement (88.9% to 100%) across seven topics. These included defining motor symptoms control, identifying patients most likely to benefit from IPX203, positioning of IPX203 within the treatment pathway, practical considerations for switching to IPX203 from current regimens and recommendations for monitoring and follow-up. The experts emphasised that IPX203 should be considered for patients with motor fluctuations insufficiently controlled on optimised oral levodopa therapy, before introduction of device-aided therapies. They highlighted the need for flexible dose adjustments, comprehensive patient and neurologist education and practical tools to support conversion to IPX203. This consensus insight provides practical guidance for integrating IPX203 into routine care of PD patients with motor fluctuations, aiming to increase mobility and reduce treatment burden for patients with PD.

Hypertensive disorders of pregnancy (HDP) are associated with maternal and neonatal morbidity. Although delivery is the definitive treatment, antihypertensive agents are often prescribed to control blood pressure to facilitate safe prolongation of pregnancy. International guidelines vary in their treatment recommendations and preferences for methyldopa, labetalol and nifedipine. Within the field of HDP, randomised trials are often underpowered and observational studies are limited in causal inference due to confounding. Therefore, we propose a target trial emulation with hospital-based electronic health record (EHR) data to compare methyldopa, labetalol and nifedipine in pregnancies complicated by HDP, focusing on maternal and perinatal outcomes.

Long-term l-3,4-dihydroxyphenylalanine (l-DOPA) therapy for Parkinson's disease increases plasma concentrations of 3-O-methyldopa (3-OMD), a major metabolite of l-DOPA. This study aimed to investigate the role of 3-OMD in the central nervous system (CNS)-mediated behavioral effects associated with chronic l-DOPA treatment in rats. The effects of 3-OMD on CNS function were examined using two rat models: repeated oral co-administration of l-DOPA/benserazide and single or repeated intraperitoneal (i.p.) administration of 3-OMD. Behavioral assessments included spontaneous locomotor activity, spontaneous alternation behavior (SAB), spatial learning, and depression-like behavior. Plasma and brain concentrations of 3-OMD were also measured. Repeated oral administration of l-DOPA/benserazide maintained plasma 3-OMD concentrations at 1.57-3.50 μg/mL and brain concentrations at 1.68-3.23 μg/g. This treatment reduced SAB by up to 30% and showed a trend toward reduced spatial learning, whereas locomotor activity was unaffected. Repeated i.p. administration of 3-OMD produced comparable plasma and brain concentrations of 3-OMD, reduced SAB, and showed a trend toward reduced spatial learning, without affecting other behaviors. The reduction in SAB was reversed after a 7-d washout period. In contrast, a single administration of 3-OMD had no detectable behavioral effects. In conclusion, sustained, but not transient, exposure to 3-OMD may contribute to reduced working memory performance during chronic l-DOPA therapy.

ObjectiveIPX203 is a newly approved oral carbidopa-levodopa formulation designed to prolong the therapeutic effect and reduce complications associated with the standard immediate-release formulation. Immediate-release carbidopa-levodopa remains the current standard of care but has a short duration of action. This study aimed to evaluate the efficacy and safety of IPX203 compared with immediate-release carbidopa-levodopa in patients with advanced Parkinson's disease.MethodsThis systematic review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and was registered in the International Prospective Register of Systematic Reviews (registration number: CRD42024623230). A comprehensive search of PubMed/MEDLINE, Cochrane Central Register of Controlled Trials, Web of Science, ScienceDirect, Scopus, and Embase identified randomized controlled trials comparing IPX203 with immediate-release carbidopa-levodopa. The primary outcomes were changes from baseline in "Good On-time" (periods of effective symptom control with minimal dyskinesia) and "Off-time" (periods when medication effects wear off and symptoms return). Secondary outcomes included scores on Part III of the Movement Disorder Society-Unified Parkinson's Disease Rating Scale and adverse events.ResultsA total of 466 records were screened, resulting in the inclusion of three randomized controlled trials involving 560 participants. Compared with immediate-release carbidopa-levodopa, IPX203 increased total "Good On-time" and reduced "Off-time." Scores on Part III of the Movement Disorder Society-Unified Parkinson's Disease Rating Scale demonstrated greater improvement in motor function with IPX203. The incidence of adverse events was comparable between the two groups, although treatment-emergent adverse events and treatment discontinuations were more frequent in the IPX203 group.ConclusionCompared with immediate-release carbidopa-levodopa, IPX203 increased "Good On-time," reduced "Off-time," improved motor function as measured by Part III of the Movement Disorder Society-Unified Parkinson's Disease Rating Scale, and demonstrated a comparable safety profile.

Bile acids (BAs) are steroidal molecules with endocrine and exocrine functions, eliminated primarily via bile. Intrahepatic cholestasis of pregnancy (ICP) features elevated maternal BA concentrations linked to adverse perinatal outcomes. Hypertensive disorders of pregnancy, often managed with methyldopa, co-occur with BA dysregulation, yet the impact of methyldopa on BA homeostasis is unclear. We examined methyldopa in a murine model of estrogen-induced cholestasis. Female C57BL/6J mice received ethinylestradiol (10 mg/kg, s.c.) with or without methyldopa (250 mg/kg, p.o.) for 7 days. BA profiles were quantified by LC-MS across plasma, bile, liver, urine, intestine, and feces. Hepatic, ileal, and renal expression of BA-related enzymes/transporters was assessed by RT-qPCR and Western blotting. In estrogen-challenged mice, methyldopa selectively reduced total BA concentrations in plasma and liver without increasing fecal or urinary BA excretion. The lowering coincided with induction of CAR-responsive detoxification/export markers, particularly Cyp2b10 and Abcc3/Mrp3, together with partial restoration of nuclear CAR and reduced p-ERK1/2 normalized to total ERK1/2. Methyldopa also reduced hepatic free cholesterol in cholestatic mice, accompanied by reduced Hmgcr abundance and increased Acat2 expression, indicating altered cholesterol handling that may limit substrate availability for BA synthesis. In conclusion, methyldopa lowered BA plasma concentrations under estrogenic stress consistent with reduced substrate availability for BA synthesis and enhanced detoxification/export. In the context of pregnancy-related BA dysregulation, these findings suggest that methyldopa, when used for hypertensive disorders of pregnancy, does not exacerbate BA accumulation and may selectively attenuate it; this hypothesis warrants clinical evaluation.

The present study investigated the therapeutic potential of quercetin nanoparticles (QNPs), administered alone or in combination with levodopa/carbidopa (L/C), against reserpine-induced neurochemical alterations and motor dysfunction in a rat model of Parkinson's disease (PD). Animals were randomly assigned to five experimental groups: a control group, a reserpine-induced PD group, and PD groups treated with QNPs, L/C, or their combination. Motor performance was assessed using the open-field and grid traction tests. Reserpine administration induced marked motor impairments accompanied by significant reductions in dopamine (DA), serotonin (5-HT), and norepinephrine (NE) levels in both the striatum and midbrain. These neurochemical deficits were associated with elevated monoamine oxidase (MAO) activity, increased lipid peroxidation (malondialdehyde, MDA), enhanced acetylcholinesterase (AChE) activity, and increased nitric oxide (NO) levels in both brain regions. Additionally, reduced glutathione (GSH) levels were decreased in the midbrain but elevated in the striatum. Treatment with QNPs significantly restored monoamine levels and normalized MAO and AChE activities. Moreover, QNPs markedly attenuated oxidative stress and improved motor performance in reserpine-treated rats. Similarly, L/C administration effectively reversed monoamine depletion, normalized enzymatic activities, and mitigated oxidative stress. Notably, combined treatment with QNPs and L/C produced effects comparable to those observed with either treatment alone, suggesting a lack of additive or synergistic interaction. These findings demonstrate that QNPs exert a significant neuroprotective effect against reserpine-induced motor dysfunction and neurochemical disturbances, supporting their potential as a therapeutic strategy for Parkinsonian pathology.