Sex Is the Main Determinant of Levodopa Clinical Pharmacokinetics: Evidence from a Large Series of Levodopa Therapeutic Monitoring

Background: Different studies, mostly with limited cohorts, have suggested the effects of patients' characteristics on levodopa (LD) pharmacokinetics. Objective: We primarily aimed at investigating in a large population the relationship between patients' features and LD kinetic variables, to assess the main demographic and clinical predictors of LD clinical pharmacokinetics. Methods: The study was retrospective, based on data collected from subjects with parkinsonism on chronic LD undergoing LD therapeutic monitoring (TM). LD TM includes serial quantitative motor tests and blood samples to measure plasma drug concentrations after each subject's chronically taken first-morning LD dose intake. Results: Five hundred patients, 308 males (61.6%), mean (SD) age of 65 (10.1) years were included. Parkinsonian symptoms and LD therapy lasted 5.5 (4.5) and 3.4 (3.9) years, respectively. MDS-UPDRS part III "off" score was 28.8 (15.2). LD dose was 348.2 (187.1) mg/day. From multiple linear regression analysis, test dose, sex, type of LD decarboxylase inhibitor, weight and MDS-UPDRS part III score were linear predictors of both LD peak plasma concentration (Cmax) (R2 = 0.52) and area under the 3-h plasma concentration-time curve (AUC) (R2 = 0.71), while age was a further predictor only for AUC. Besides test dose, sex was the strongest independent contributing variable to LD AUC, which resulted 27% higher in females compared to males. Conclusion: This is the largest collection of data on the relationship between demographic and clinical-therapeutic variables and LD kinetics in patients with parkinsonian symptoms. As a main clinically practical finding, women might require a 25% reduced weight-normalized LD dose compared with men to achieve the same LD bioavailability

Cannabis-Based Products in a Neurological Setting: A Clinical and Pharmacokinetic Survey

Background and aim: Limited data are available in clinical settings on the pharmacokinetics of delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). We investigated the use of cannabis-based products in neurological practice, monitoring patients' steady-state cannabinoids (CBs) plasma concentrations matched with different preparations. Methods: This was a prospective, single-center, observational study. Patients underwent venous blood withdrawal before the CBs' morning dose and then 2.5 h post-dosing. Spasticity or pain were patient self-assessed by the Numeric Rating Scale (NRS) before the morning CB's administration and 2.5 h post-dosing. Results: Thirty-three patients were enrolled. Main indications for CBs were spasticity and chronic pain. Sixteen patients were treated with oromucosal spray formulation Sativex® and 17 with oil-based solutions. Both CBs trough plasma concentrations were ≤ limit of detection (0.1 ng/ml) in 45% of patients. Intrasubject CB's plasma levels significantly increased over baseline values in patients treated with Bediol® oil (p < 0.05) and Sativex® (p < 0.01). Post-dosing CB's bioavailability did not significantly differ between oral oil and oromucosal spray. NRS scores decreased (p < 0.01), matching the increase (p < 0.01) in CB's plasma concentrations. Conclusion: This is the first study investigating CB's plasma concentrations of oral and oromucosal preparations in real-world neurological practice. Findings of similar bioavailability for both CBD and THC after galenic oil compared with oromucosal spray dosing may be clinically relevant and deserve additional research in larger cohorts

Mathematical modeling and parameter estimation of levodopa motor response in patients with parkinson disease.

Parkinson disease (PD) is characterized by a clear beneficial motor response to levodopa (LD) treatment. However, with disease progression and longer LD exposure, drug-related motor fluctuations usually occur. Recognition of the individual relationship between LD concentration and its effect may be difficult, due to the complexity and variability of the mechanisms involved. This work proposes an innovative procedure for the automatic estimation of LD pharmacokinetics and pharmacodynamics parameters, by a biologically-inspired mathematical model. An original issue, compared with previous similar studies, is that the model comprises not only a compartmental description of LD pharmacokinetics in plasma and its effect on the striatal neurons, but also a neurocomputational model of basal ganglia action selection. Parameter estimation was achieved on 26 patients (13 with stable and 13 with fluctuating LD response) to mimic plasma LD concentration and alternate finger tapping frequency along four hours after LD administration, automatically minimizing a cost function of the difference between simulated and clinical data points. Results show that individual data can be satisfactorily simulated in all patients and that significant differences exist in the estimated parameters between the two groups. Specifically, the drug removal rate from the effect compartment, and the Hill coefficient of the concentration-effect relationship were significantly higher in the fluctuating than in the stable group. The model, with individualized parameters, may be used to reach a deeper comprehension of the PD mechanisms, mimic the effect of medication, and, based on the predicted neural responses, plan the correct management and design innovative therapeutic procedures

Dyskinesia detection and monitoring by a single sensor in patients with Parkinson's disease

In current clinical practice, assessment of levodopa-induced dyskinesias (LIDs) in Parkinson's disease (PD) is based on semiquantitative scales or patients' diaries. We aimed to assess the feasibility, clinical validity, and usability of a waist-worn inertial sensor for discriminating between LIDs and physiological sway in both supervised and unsupervised settings

Multimodal Cues for Gait Rehabilitation With Smart Glasses in Persons With Parkinson’s Disease (PD): A Methodology for the Selection of Effective Design Solutions

Introduction: Persons with PD are affected by motor impairments that compromise their autonomy. Recent advances in wearable systems showed that sensory biofeedback (BF) can improve gait in PD. Through verbal BF, an existing smartphone-based gait rehabilitation system (CuPiD-system) makes PD subjects better aware of their gait performance. Thanks to Smart Glasses (SG), real-time visual and haptic cues are also feasible: this study describes strategies to design an innovative mHealth system obtained by integrating the smartphone-based CuPiD-system with SG. The aim is to rehabilitate postural and transient gait disturbances and to provide gait training at home for persons with PD. Methods: We performed a pilot trial on five subjects not belonging to a particular category of users, following a Human-Centered design research approach. We proposed sensory BF suggesting a rhythm to be followed: auditory by wireless earphones, visual and haptic by the SG. We analyzed the subjects’ qualitative and quantitative responses through an interview and a specific gait analysis protocol. Results: This testing phase investigated how sensory BF influences the user’s gait, the most efficient cues to improve user’s performance, and acceptance of the mHealth system. We applied an ad-hoc redesigned version of the Quality-Function-Deployment (QFD) design tool to manage the complexity of the collected data, Figure 33. Discussion: While visual BF improves spatial gait parameters, auditory and somatosensory BF improve temporal gait features (cadence). QFD’s results confirm the role of sensory BF on gait rehabilitation: auditory and haptic BF reach a higher efficacy than the visual one. Some critical aspects emerged: the gap between the user’s cadence and the target one; the subjects’ sensory preferences. In the next phase on PD subjects, the target cadence will be subject-specific, and questionnaires should be used to evaluate subjects’ sensory preferences and integrate them into the QFD matrix

User-Centered Design Methodologies for the Prototype Development of a Smart Harness and Related System to Provide Haptic Cues to Persons with Parkinson’s Disease

This paper describes the second part of the PASSO (Parkinson smart sensory cues for older users) project, which designs and tests an innovative haptic biofeedback system based on a wireless body sensor network using a smartphone and different smartwatches specifically designed to rehabilitate postural disturbances in persons with Parkinson’s disease. According to the scientific literature on the use of smart devices to transmit sensory cues, vibrotactile feedback (particularly on the trunk) seems promising for improving people’s gait and posture performance; they have been used in different environments and are well accepted by users. In the PASSO project, we designed and developed a wearable device and a related system to transmit vibrations to a person’s body to improve posture and combat impairments like Pisa syndrome and camptocormia. Specifically, this paper describes the methodologies and strategies used to design, develop, and test wearable prototypes and the mHealth system. The results allowed a multidisciplinary comparison among the solutions, which led to prototypes with a high degree of usability, wearability, accessibility, and effectiveness. This mHealth system is now being used in pilot trials with subjects with Parkinson’s disease to verify its feasibility among patients

Mucuna pruriens in Parkinson Disease: A Kinetic-Dynamic Comparison With Levodopa Standard Formulations

Objectives: We compared levodopa (LD) kinetic-dynamic profile of a dose of LD/aromatic amino acid decarboxylase peripheral inhibitors versus a nominally equivalent dose of a commercial Mucuna pruriens (Mucuna) seeds extract in 2 patients with Parkinson disease chronically taking LD standard combined with self-prescribed Mucuna. Methods: Patients were challenged with a fasting morning dose of 100 mg LD/25 mg carbidopa (patient 1) or benserazide (patient 2) versus 100 mg LD from Mucuna capsules in 2 different sessions, after a 12-hour standard LD formulations\u2019 washout. They underwent kinetic-dynamic LD monitoring based on LD dose intake and simultaneous serial assessments of plasma drug concentrations and motor test performances. Quantitative analysis of LD in Mucuna capsules was also performed. Results: Levodopa bioavailability was markedly lower after Mucuna administration compared with LD standard formulations: in patient 1, peak plasma LD concentration (Cmax) decreased from 2.0 to 1.0 mg/L and the area under the plasma concentration time curve from 137 to 33.6 mg/L per minute; in patient 2, Cmax was 0.7 mg/L after LD/benserazide and nearly undetectable afterMucuna. In patient 1, impaired LD bioavailability from Mucuna resulted in reduced duration and overall extent of drug response compared with LD/carbidopa. In patient 2, no significant subacute LD motor response was observed in either condition. Quantitative analysis of Mucuna formulation confirmed the 100 mg LD content for the utilized capsules. Conclusions: Our results show an impaired LD bioavailability from Mucuna preparation, as expected by the lacking aromatic amino acid decarboxylase inhibitors coadministration,whichmight explain the suggested lower dyskinetic potential of Mucuna compared with standard LD formulations

User-Centered Design of Cues with Smart Glasses for Gait Rehabilitation in People with Parkinson’s Disease: A Methodology for the Analysis of Human Requirements and Cues Effectiveness

none6noAs an alternative to the technical industrial mindset, User-Centered Design has proven to be an effective tool to realize products and services for the Healthcare sector. In this scenario, this project aims to develop an innovative wearable gait rehabilitation solution obtained by integrating the Smart Glasses Vuzix Blade into the smartphone-based CuPiD-system. The specific aims of the testing phase described in this paper were to observe how submitted visual, auditory, and vibratory cues influence the user’s gait; and which were the most impacting and efficient typologies of cues. To achieve these results, we analyze the users’ qualitative and quantitative feedback, respectively obtained from an interview and a specific gait analysis protocol.noneImbesi, Silvia; Corzani, Mattia; Petrocchi, Filippo; Lopane, Giovanna; Chiari, Lorenzo; Mincolelli, GiuseppeImbesi, Silvia; Corzani, Mattia; Petrocchi, Filippo; Lopane, Giovanna; Chiari, Lorenzo; Mincolelli, Giusepp

Pharmacodynamics of a low subacute levodopa dose helps distinguish between multiple system atrophy with predominant Parkinsonism and Parkinson\u2019s disease

The differential diagnosis between multiple system atrophy with predominant parkinsonism (MSA-P) and Parkinson's disease (PD) may be challenging at disease onset. Levodopa responsiveness helps distinguish the two groups, but studies evaluating this issue using objective standardized tests are scanty. We retrospectively examined the extent of levodopa response by an objective kinetic-dynamic test in a series of patients prospectively followed up for a parkinsonian syndrome and eventually diagnosed as MSA-P or PD. Sixteen MSA-P and 31 PD patients under chronic levodopa therapy received a first morning fasting dose of levodopa/benserazide (100/25 mg) or levodopa/carbidopa (125/12.5 or 100/25 mg) and underwent simultaneous serial assessments of plasma levodopa concentration and alternate finger tapping frequency up to 3 h post dosing. The main levodopa pharmacodynamic variables were the maximum percentage increase in tapping frequency over baseline values (\u394Tapmax %) and the area under the tapping effect-time curve (AUCTap). Levodopa pharmacokinetics did not show significant differences between MSA-P and PD, whereas both the magnitude and overall extent of levodopa tapping effect were markedly reduced in the MSA-P group (p < 0.001). The combined use of specific cut-off values for both the main pharmacodynamic variables, \u394Tapmax % <20 % and AUCTap <1900 [(tapping/min)\ub7min], correctly discriminated 15 out of 16 MSA-P patients from PD patients. A combined estimation of these pharmacodynamic variables after a subacute low levodopa dose may be a simple and practical clinical tool to aid the differential diagnosis between MSA-P and PD

Clinical pharmacokinetics of pramipexole, ropinirole and rotigotine in patients with Parkinson's disease

Introduction: Pramipexole (PRA), ropinirole (ROP) and rotigotine (ROT) are non-ergoline dopaminergic agonists (DAs) used to treat Parkinson's disease (PD). Clinical pharmacokinetics of DAs is poorly characterized in PD. The main purpose of our study was to investigate the effect of dose, age and sex on steady-state plasma concentrations of DAs in real life PD patients on chronic DAs therapy. Methods: The study was single center, open and prospective. Blood samples for measurement of DAs plasma concentrations were drawn in the morning, at a median 18-h distance from the last DA dose. Results: Ninety-one patients treated with PRA, 50 with ROP and 37 with ROT were enrolled in the study. Plasma concentration of DAs significantly correlated with weight-adjusted daily dose in all subgroups, although at a given dose, matched plasma concentrations highly varied among patients. Median PRA plasma concentration-to-daily dose ratio (C/D) [(ng/mL)/(mg/kg/d)] was 68% higher in patients &gt;65 years than 6465 years (158 vs 94, p &lt; 0.001), while was not affected by age in ROP and ROT subgroups. No sex-mediated differences in C/D ratios were observed in any group. Conclusion: These are the first observations on DAs pharmacokinetics in PD patients\u2019 everyday clinical practice. Of relevance, patients over 65yrs may require about one third of PRA dose compared to under 65yrs to achieve the same plasma concentration. Due to the high intersubject variability in plasma concentrations at the same dosage, we speculate that monitoring of plasma DAs might be helpful in the individualization of treatment in selected patients