Levodopa and benserazide tablets (LBTs) are a combined preparation of levodopa (L-DP), a dopamine precursor, and benserazide (BZ), a peripheral dopa decarboxylase inhibitor, used for the treatment of Parkinson's disease, which predominantly affects middle-aged and elderly individuals. This study employed a single-center, randomized, open-label, two-formulation, three-period, three-sequence, partially replicated (reference formulation only) clinical study design to evaluate the pharmacokinetics and bioequivalence of the test and reference formulations of LBT administered orally to 96 healthy Chinese subjects under fasting or fed conditions. After fasting for at least 10 h and abstaining from water for 1 h, subjects received one tablet of either the test or reference formulation with 240 mL of warm water on Days 1, 8, and 15 of the study, either in the fasting state or 30 min after starting a high-fat meal. Plasma drug concentrations were determined using an ultra-high performance liquid chromatography-tandem mass spectrometry method. The 90% confidence intervals of the geometric mean ratios for the pharmacokinetic parameters Cmax, AUC0-t, and AUC0-∞ met the bioequivalence criteria, indicating that the test formulation is bioequivalent to the reference formulation in healthy Chinese adult subjects. No serious adverse events were reported.

Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder worldwide. It is associated with the ongoing degeneration of dopaminergic neurons in the substantia nigra and the formation of Lewy bodies that contain α-synuclein. These pathological changes lead to abnormalities of motor symptoms (tremor, rigidity, bradykinesia) and non-motor symptoms (cognitive decline, sleep abnormalities, psychiatric abnormalities). The pathogenesis of PD is complex and multifactorial, involving interconnected mechanisms such as oxidative stress, mitochondrial dysfunction, neuroinflammation, impaired autophagy, ferroptosis, and genetic factors. To develop effective therapeutic interventions, these pathways need to be understood. Current treatments, such as levodopa and deep-brain stimulation (DBS), are symptom-based and do not break disease progression. Thus, considerable research efforts have been geared towards finding disease-modifying therapeutic strategies. Natural bioactive compounds, gene-based therapies, stem cell-based therapies, and nanotechnology-assisted drug delivery systems are promising alternatives as suggested by recent advances. Antioxidant compounds like curcumin, resveratrol, and epigallocatechin gallate (EGCG) show promising antioxidant and neuroprotective effects, and nanomedicine provides boosted delivery to the brain and targeted drug distribution. In future clinical applications, these new strategies could help to more effectively and permanently manage PD.

Changes in the temporal parameters of EEG microstates are observed in various psychiatric illnesses, including psychotic disorders. These changes have also been observed in individuals with a clinical or genetic high risk for psychosis. It is unclear whether dopamine abnormalities, distinctive of psychotic disorders, contribute to microstate alterations. Fifty-eight healthy participants (M: F = 32:26) took part in a single-dose drug challenge study. Using a randomized, double-blind, cross-over, and placebo-controlled design, participants received the dopamine precursor L-DOPA (100 mg), the dopamine antagonist haloperidol (2 mg), and a placebo. Resting-state (10 min, eyes-closed) 64-channel EEG was recorded at peak drug effects. We calculated temporal parameters (coverage, duration, and occurrence) of 5 microstate classes (A-E) and compared them between drug conditions using linear mixed-effect models. Significant group x class interactions were observed for all parameters. Compared to placebo, parameters of microstate B were decreased under L-DOPA (duration and occurrence) and haloperidol (coverage, duration, and occurrence). Coverage and occurrence of microstate C were reduced under L-DOPA compared to haloperidol and placebo. Parameters of microstate E were reduced under L-DOPA compared to haloperidol (coverage and occurrence) and placebo (coverage, duration, and occurrence). Both haloperidol and L-DOPA increased all parameters of microstate D, compared to placebo. Our results show that resting-state EEG microstates are modulated by dopaminergic drugs. However, extrapolations from healthy controls to patients with psychotic disorders are complicated by various factors. Further studies should investigate the (long-term) effects of haloperidol and other antipsychotics on EEG microstates in patients with psychotic disorders.

Maximizing clinical benefits of therapeutics while minimizing adverse effects is a central challenge in drug development. For Parkinson's disease (PD), l-3,4-dihydroxyphenylalanine (l-dopa) is the most effective treatment available, but chronic use is associated with periods of reduced efficacy (motor fluctuations) and the debilitating on-target side effect of l-dopa-induced dyskinesia. To disentangle the molecular mechanisms underlying l-dopa's antiparkinsonian effects versus its dyskinetic effects, we analyzed transcriptomic data from the striata of mice exposed to different l-dopa doses, identifying distinct gene expression signatures associated with l-dopa's effect on parkinsonian motor symptoms and dyskinesia. By comparing these gene expression signatures with a large dataset of in vitro gene expression profiles of drug perturbations, we identified SB-0107, a positive allosteric modulator of protein kinase A type II with previous clinical experience that boosts l-dopa's benefits while reducing dyskinesia in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned macaque model of PD. Deuterated analogs, including SB-0110, were developed that improved both pharmacokinetics and pharmacological effects. This dual effect, established safety profile of the parent compound, and improved properties of the deuterated analog support further development of this compound as an adjunct treatment to l-dopa therapy for PD.