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ABSTRACTBackground:Lactoferrin (bLF) is an iron-binding multifunctional protein that is abundant in milk. In mice, it inhibits catechol-O-methyltransferase (COMT) activity and increases blood levodopa levels. However, the clinical effects are unknown.Objective:The objective of this study was to determine the effect of bLF on the kinetics of levodopa in blood.Design:The effects of the concomitant administration of a combined formulation of levodopa and an aromatic amino acid decarboxylase inhibitor and bLF on the concentration of levodopa in blood and its metabolism were assessed in eight healthy subjects. In addition, we analyzed the association with clinical factors and evaluated whether clinical factors affected the COMT inhibitory activity of bLF in vitro.Results:Although not statistically significant, the peak plasma concentration (Cmax) of levodopa increased by 18.5%. From the results of the stratified analysis of total cholesterol, a relationship with ΔCmaxwas predicted. Therefore, bLF was reacted with cholesterol in the presence of lecithin and sodium deoxycholate in vitroto evaluate COMT inhibitory activity, and an increase in inhibitory activity was observed. By contrast, the ester compound cholesteryl oleate had no effect. The inhibitory activity of free fatty acids, which are known to interact with bLF, was also enhanced.Conclusion:The COMT inhibitory activity of bLF is not effective in elevating blood levodopa levels. However, in humans with high lipid levels, such as cholesterol, interactions may enhance the inhibitory effect, resulting in the enhanced absorption of levodopa.Trial registration: ID, UMIN000026787, registered 30 March 2017; URL, https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000030749Trial registration:UMIN Japan identifier: UMIN000026787

Treatment with dopaminergic agents result excessive daytime sleepiness (EDS) and some studies have shown the benefit of using modafinil for treating excessive daytime sleepiness of Parkinson's disease (PD) patient. We investigated whether modafinil have ameliorative properties against levodopa induced excessive nighttime sleepiness (ENS) in MPTP-treated murine nocturnal PD model. Our EEG analyses of whole day recordings revealed that modafinil reduce ENS of this nocturnal PD models with levodopa medications. Therefore, we investigated whether, modafinil post-treatment followed by MPTP shows any effect on monoamine contents of brain and found to robustly increased noradrenaline (NA) concentration of MPTP treated mice. Modafinil post-treatment, in neurorestorative context (5 days post-lesion) led to increased striatal dopamine (DA) concentrations of MPTP-treated mice. Here, we first confirmed that modafinil ameliorates levodopa induced excessive sleepiness and restores monoaminergic systems. The arousal and anti-parkinsonian effects displayed by modafinil indicate that in combination with dopaminergic agents, modafinil co-administration may be worthwhile in trying to suppress the excessive daytime sleepiness and progressive dopaminergic neuron loss in PD.

Some patients with Parkinson disease improved their symptoms on treatment with nicotine patch or gum. Nicotine has also been studied for its antidyskinetic effect on levodopa-induced dyskinesia. We determined the effects of nicotine on levodopa pharmacokinetics and gastric emptying in healthy subjects and on levodopa transport in Caco-2 monolayers in vitro.

The effect of zonisamide, an antiepileptic agent with anti-parkinsonian effects, was studied on dopamine neurons of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated C57 mice and common marmosets. Groups of mice (n = 8 – 9) were treated with: MPTP (15 mg/kg every 2 h ×4); MPTP plus zonisamide (40 mg/kg administered 1 h before each MPTP dose); MPTP plus selegiline (2 mg/kg administered 1 h before the first MPTP dose); zonisamide (40 mg/kg ×4); and saline controls. Groups of common marmosets (n = 4 – 6) were treated with: MPTP (2.5 mg/kg every 24 h ×3); MPTP plus zonisamide (40 mg/kg administered 1 h before each MPTP dose); MPTP plus selegiline (2 mg/kg administered 1 h before the first MPTP dose); and saline controls. Brain dopamine and its metabolites were determined by HPLC. Dopamine content decreased in the striatum of MPTP-treated mice and monkeys. Co-administration of selegiline inhibited the effect of MPTP and dopamine contents were similar to those of the controls. Co-administration of zonisamide did not inhibit the effect of MPTP on dopamine content, but increased striatal dopamine turnover of animals treated with MPTP plus zonisamide more than in those treated with MPTP alone. MPTP treatment caused a compensatory increase of dopamine turnover in the striatum by remaining neurons. Zonisamide may help dopaminergic neurons by increasing striatal dopamine turnover following MPTP treatment.