BackgroundLevodopa (LD) is the most effective drug in the treatment of Parkinson’s disease (PD). Unfortunately, prolonged use of LD leads to complications, mainly motor/non-motor fluctuations (MNMF) and dyskinesias (DYS). Women seem more prone to develop such LD-related complications. Nonetheless, there is a paucity of prospective studies examining gender-related predictors of MNMF and DYS. Among several factors, which concur with a very complex scenario, changes in LD pharmacokinetics influence the drug’s effectiveness. The present study aimed to assess gender-related differences in LD pharmacokinetics in patients with PD at their first-ever intake of LD.Materials and MethodsThis is a multicentric study enrolling patients with PD, who were LD-naïve and received a single dose of LD/benserazide (100/25 mg) formulation. All participants gave their written informed consent, and the study was approved by the local Ethics Committees. To measure plasma LD concentrations and pharmacokinetic parameters (AUC, Cmax, Tmax, t1/2), fasting blood samples were collected before drug intake and then at 8-time points until 260 min. LD concentrations were measured by ultra-high-performance liquid chromatography coupled with mass spectrometry (UHPLC-MS). Multiple linear regression analyses were performed to identify the predictors of the parameters.ResultsThirty-five patients (16 women and 19 men) were consecutively enrolled. Area under curve (AUC) and maximum plasma concentration (Cmax) were significantly higher in women than men (p = 0.0006 and p = 0.0014, respectively). No statistically significant difference was found regarding Tmax and t1/2. Multiple linear regression analyses revealed that female sex (β = 1.559116, 95% CI 0.8314479 2.286785; p < 0.0001) and body mass index (BMI) (β = −0.0970631, 95% CI −0.1733004 −0.0208258; p = 0.014) significantly predicted AUC. Only female sex significantly predicted Cmax (β = 1,582.499, 95% CI 731.581 2,433.417; p = 0.001). Moreover, only BMI significantly predicted t1/2 (β = 0.0756267, 95% CI 0.0143407 0.1369126; p = 0.017). Stratifying by gender, BMI was confirmed to significantly predict t1/2 in women (β = 0.1300486, 95% CI 0.0172322 0.242865; p = 0.027), but not in men.ConclusionThis study provides novel insights on gender differences in LD pharmacokinetics, possibly contributing to the later development of motor complications and dyskinesia in PD.
Parkinson's disease (PD) and Multiple System Atrophy (MSA) are progressive neurodegenerative diseases with overlap of symptoms in early stages of disease. No reliable biomarker exists and the diagnosis is mainly based on clinical features. Several studies suggest that miRNAs are involved in PD and MSA pathogenesis. Our goal was to study two serum circulating microRNAs (miR-96-5p and miR-339-5p) as novel biomarkers for the differential diagnosis between PD and MSA. Serum samples were obtained from 51 PD patients, 52 MSA patients and 56 healthy controls (HC). We measured levels of miRNAs using quantitative PCR and compared the levels of miR-96-5p and miR-339-5p among PD, MSA and HC groups using a one-way analysis of variance. Correlations between miRNA expression and clinical data were calculated using Pearson's rho test. We used the miRTarBase to detect miRNA targets and STRING to evaluate co-expression relationship among target genes. MiR-96-5p was significantly increased in MSA patients compared with HC (Fold change (fc): 3.6; p = 0.0001) while it was decreased in PD patients compared with HC (Fold change: 4; p = 0.0002). Higher miR-96-5P levels were directly related to longer disease duration in MSA patients. We observed a significant increase of miR-339-5p in MSA patients compared with PD patients (fc: 2.5; p = 0.00013). miR-339-5p was increased in MSA patients compared with HC (fc: 2.4; p = 0.002). We identified 32 target genes of miR-96-5p and miR-339-5p, some of which are involved in neurodegenerative diseases. The study of those miRNAs could be useful to identify non-invasive biomarkers for early differential diagnosis between PD and MSA.
Gender is an important factor influencing epidemiological and clinical features of Parkinson’s disease (PD). We aimed to evaluate gender differences in the expression of a panel of miRNAs (miR-34a-5p, miR-146a, miR-155, miR-29a, miR-106a) possibly involved in the pathophysiology or progression of disease. Serum samples were obtained from 104 PD patients (58 men and 46 women) never treated with levodopa. We measured levels of miRNAs using quantitative PCR. Correlations between miRNA expression and clinical data were assessed using the Spearman’s correlation test. We used STRING to evaluate co-expression relationship among target genes. MiR-34a-5p was significantly upregulated in PD male patients compared to PD female patients (fc: 1.62; p < 0.0001). No correlation was found with age, BMI, and disease severity, assessed by UPDRS III scale, in male and female patients. MiR-146a-5p was significantly upregulated in female as compared to male patients (fc: 3.44; p < 0.0001) and a significant correlation was also observed between disease duration and mir-146a-5p. No differences were found in the expression of miR-29a, miR-106a-5p and miR-155 between genders. Predicted target genes for miR-34a-5p and miR-146-5p and protein interactions in biological processes were reported. Our study supports the hypothesis that there are gender-specific differences in serum miRNAs expression in PD patients. Follow-up of this cohort is needed to understand if these differences may affect disease progression and response to treatment.
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