How resistant are levodopa-resistant axial symptoms? Response of freezing, posture, and voice to increasing levodopa intestinal infusion rates in Parkinson disease.

BACKGROUND AND PURPOSE: Treatment of freezing of gait (FoG) and other Parkinson disease (PD) axial symptoms is challenging. Systematic assessments of axial symptoms at progressively increasing levodopa doses are lacking. We sought to analyze the resistance to high levodopa doses of FoG, posture, speech, and altered gait features presenting in daily-ON therapeutic condition. METHODS: We performed a pre-/postinterventional study including patients treated with levodopa/carbidopa intestinal gel infusion (LCIG) with disabling FoG in daily-ON condition. Patients were evaluated at their usual LCIG infusion rate (T1), and 1 h after 1.5× (T2) and 2× (T3) increase of the LCIG infusion rate by quantitative outcome measures. The number of FoG episodes (primary outcome), posture, speech, and gait features were objectively quantified during a standardized test by a blinded rater. Changes in motor symptoms, dyskinesia, and plasma levodopa concentrations were also analyzed. RESULTS: We evaluated 16 patients with a mean age of 69 ± 9.4 years and treated with LCIG for a mean of 2.2 ± 2.1 years. FoG improved in 83.3% of patients by increasing the levodopa doses. The number of FoG episodes significantly decreased (mean = 2.3 at T1, 1.7 at T2, 1.2 at T3; p = 0.013). Posture and speech features did not show significant changes, whereas stride length (p = 0.049), turn duration (p = 0.001), and turn velocity (p = 0.024) significantly improved on doubling the levodopa infusion rate. CONCLUSIONS: In a short-term evaluation, the increase of LCIG dose can improve "dopa-resistant" FoG and gait issues in most advanced PD patients with overall good control of motor symptoms in the absence of clinically significant dyskinesia.

Screening for impulse control disorders in Parkinson's disease and dopamine agonist use: a study of pharmacokinetic and psychological risk factors.

INTRODUCTION: Dopamine agonist (DA) use is considered the main risk factor for impulse control disorder (ICD) development in Parkinson's disease (PD). Besides DAs, personality traits and cognitive features may represent risk factors for ICDs. The primary aim of this study was to investigate differences in DA plasma concentrations in PD patients with and without a positive screening for ICDs according to validated tools. The secondary aim was to compare the psychological profile between ICD positive and negative screened patients. METHODS: PD patients receiving chronic DA therapy were screened for ICDs according to the Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease (QUIP). Blood samples for measurement of DA (pramipexole, ropinirole, rotigotine) trough plasma concentrations were drawn in the morning, at mean 16-19 h from the last DA dose. Patients' psychological profile was investigated by Millon Clinical Multiaxal Inventory III and Barratt Impulsiveness Scale (BIS-11). RESULTS: One hundred and five PD patients were enrolled. Forty-one patients (39%) were QUIP positive, mainly for binge eating and hobbyism. Median plasma concentrations of pramipexole (n = 71, 66%), ropinirole (n = 21, 19%), and rotigotine (n = 16, 15%) were similar between QUIP positive and negative patients. QUIP positive patients showed higher motor impulsiveness (p = 0.04) and tended to higher total impulsiveness (p = 0.05). CONCLUSION: This is the first prospective study to evaluate the relationship between DA plasma concentrations and ICDs risk in PD patients. DA plasma levels were overlapping between QUIP positive and negative patients. BIS-11, particularly the motor impulsiveness subscale, might be a useful screening tool in PD patients eligible for DA therapy.

DNMT1 mutations leading to neurodegeneration paradoxically reflect on mitochondrial metabolism.

ADCA-DN and HSN-IE are rare neurodegenerative syndromes caused by dominant mutations in the replication foci targeting sequence (RFTS) of the DNA methyltransferase 1 (DNMT1) gene. Both phenotypes resemble mitochondrial disorders, and mitochondrial dysfunction was first observed in ADCA-DN. To explore mitochondrial involvement, we studied the effects of DNMT1 mutations in fibroblasts from four ADCA-DN and two HSN-IE patients. We documented impaired activity of purified DNMT1 mutant proteins, which in fibroblasts results in increased DNMT1 amount. We demonstrated that DNMT1 is not localized within mitochondria, but it is associated with the mitochondrial outer membrane. Concordantly, mitochondrial DNA failed to show meaningful CpG methylation. Strikingly, we found activated mitobiogenesis and OXPHOS with significant increase of H2O2, sharply contrasting with a reduced ATP content. Metabolomics profiling of mutant cells highlighted purine, arginine/urea cycle and glutamate metabolisms as the most consistently altered pathways, similar to primary mitochondrial diseases. The most severe mutations showed activation of energy shortage AMPK-dependent sensing, leading to mTORC1 inhibition. We propose that DNMT1 RFTS mutations deregulate metabolism lowering ATP levels, as a result of increased purine catabolism and urea cycle pathways. This is associated with a paradoxical mitochondrial hyper-function and increased oxidative stress, possibly resulting in neurodegeneration in non-dividing cells.

A Rapid and Simple UHPLC-MS/MS Method for Quantification of Plasma Globotriaosylsphingosine (lyso-Gb3).

Fabry disease (FD) is a rare X-linked lysosomal storage disorder caused by α-galactosidase A gene (GLA) mutations, resulting in loss of activity of the lysosomal hydrolase, α-galactosidase A (α-Gal A). As a result, the main glycosphingolipid substrates, globotriaosylceramide (Gb3) and globotriaosylsphingosine (lyso-Gb3), accumulate in plasma, urine, and tissues. Here, we propose a simple, fast, and sensitive method for plasma quantification of lyso-Gb3, the most promising secondary screening target for FD. Assisted protein precipitation with methanol using Phree cartridges was performed as sample pre-treatment and plasma concentrations were measured using UHPLC-MS/MS operating in MRM positive electrospray ionization. Method validation provided excellent results for the whole calibration range (0.25-100 ng/mL). Intra-assay and inter-assay accuracy and precision (CV%) were calculated as <10%. The method was successfully applied to 55 plasma samples obtained from 34 patients with FD, 5 individuals carrying non-relevant polymorphisms of the GLA gene, and 16 healthy controls. Plasma lyso-Gb3 concentrations were larger in both male and female FD groups compared to healthy subjects (p < 0.001). Normal levels of plasma lyso-Gb3 were observed for patients carrying non-relevant mutations of the GLA gene compared to the control group (p = 0.141). Dropping the lower limit of quantification (LLOQ) to 0.25 ng/mL allowed us to set the optimal plasma lyso-Gb3 cut-off value between FD patients and healthy controls at 0.6 ng/mL, with a sensitivity of 97.1%, specificity of 100%, and accuracy of 0.998 expressed by the area under the ROC curve (C.I. 0.992 to 1.000, p-value < 0.001). Based on the results obtained, this method can be a reliable tool for early phenotypic assignment, assessing diagnoses in patients with borderline GalA activity, and confirming non-relevant mutations of the GLA gene.

Development and Validation of an UHPLC-MS/MS Assay for the Therapeutic Monitoring of Brivaracetam Plasma Concentrations in Patients with Epilepsy.

BACKGROUND: Brivaracetam is an antiepileptic drug used as an add-on therapy for partial-onset seizures in subjects aged 4 years and older. Owing to potential drug interactions and intersubject variability in plasma concentrations, therapeutic monitoring for brivaracetam may be useful. The aim of this study was to develop a simplified method for measuring brivaracetam plasma concentrations applicable to therapeutic drug monitoring in epilepsy. METHODS: An ultra high-pressure liquid chromatography-tandem mass spectrometry method was developed and validated according to current guidelines for bioanalytical methods. Sample preparation (100 µL) involved only a simple precipitation step by acetonitrile. Brivaracetam-d7 was used as internal standard. The chromatographic analysis was performed by a Synergi Fusion column using 0.1% formic acid in water/acetonitrile as a binary gradient mobile phase, at a flow rate of 0.3 mL/min. Both brivaracetam and the internal standard eluted at 1.01 minutes. This method was applied to measure trough and 1-hour postmorning dose brivaracetam plasma concentrations of 11 patients with epilepsy. RESULTS: The method was validated over a concentration range of 0.10-10 mcg/mL. The mean recovery was 95%. Both intra- and inter-assay imprecision and inaccuracy were <15% for all quality control samples. The lower limit of quantitation and detection was 0.10 and 0.05 mcg/mL, respectively. No interferences or carry-over was observed. Median (25%-75% quartiles) trough and 1-hour postdosing brivaracetam plasma concentrations were 0.61 mcg/mL (0.47-0.83 mcg/mL) and 1.55 mcg/mL (1.24-2.12 mcg/mL), respectively, at a median dose of 80 mg/d (50-150 mg/d). Large, up to 8-fold, intrasubject fluctuations of brivaracetam concentrations between trough and 1-hour postdosing were observed. CONCLUSIONS: The present assay is faster and simpler than previously published analytical reports for brivaracetam in human plasma and is suitable for therapeutic drug monitoring.

Relationship between plasma concentrations and clinical effects of perampanel: A prospective observational study.

PURPOSE: The purpose of the study was to investigate the potential correlation between plasma concentration of the newer antiseizure medication (ASM) perampanel (PMP) and both tolerability and seizure control in patients with epilepsy. METHODS: The study design was multicenter, open, and prospective. Plasma samples were collected in the morning 12 h apart from once-a-day bedtime PMP dose. Perampanel tolerability was assessed on the day of drug monitoring by clinical examination and patients' interview. Response to PMP was defined as ≥50% reduction from baseline seizure frequency (pretreatment). The main outcomes were the comparisons of PMP plasma concentration-to-weight-adjusted dose ratio (C/D) [(µg/mL)/(mg/kg/day)] between patients with and without PMP-related adverse effects (AEs) and between responders and nonresponders. RESULTS: Ninety-seven patients (54% men), mean ±â€¯SD age 36 ±â€¯14 years were enrolled in the study. The mean PMP dose was 6.7 ±â€¯2.3 mg, drug treatment averaged 46 ±â€¯34 weeks. The mean plasma concentration was 360 ±â€¯268 ng/mL (range: 37-1213 ng/mL). Forty patients (41%) reported at least one AE, mainly dizziness and behavioral changes. No significant difference was found in median PMP C/Ds between patients with (2.94) and without (2.76) AEs, otherwise comparable for clinical variables. Forty-four patients (45%) were responders, at a median PMP C/D of 3.10, similar to the value of 2.76 found in nonresponders. These two groups also overlapped for clinical characteristics. CONCLUSION: This is the first prospective real-life study to evaluate the relationship between PMP plasma concentrations, seizure control, and AEs. In line with the few real-world available data, we did not find any significant correlation between PMP plasma concentrations and both tolerability and seizure control.

The Bologna motor and non-motor prospective study on parkinsonism at onset (BoProPark): study design and population.

OBJECTIVE: The Bologna motor and non-motor prospective study on parkinsonism at onset (BoProPark) was designed to prospectively characterize motor and non-motor features in patients with a progressive neurodegenerative disease starting with parkinsonism since early disease stage and to investigate their diagnostic and prognostic role in the differential diagnosis of Parkinson's disease from atypical parkinsonisms. The aim of this paper is to describe the method and population of the BoProPark study. METHODS: Patients referred to our Department with parkinsonism within 3 years from motor onset were recruited. Secondary causes of parkinsonism were excluded. Each patient underwent a comprehensive evaluation of motor and non-motor symptoms, assessed by means of quantitative, objective instrumental tests in addition to scales and questionnaires. The evaluations were performed at enrolment (T0), after 16 months (T1) and after 5 years (T2). Diagnoses were made according to consensus criteria. RESULTS: We recruited 150 patients, with mean age 61.5 ± 9.8 years and mean disease duration 20 ± 9 months. H&Y stage was 1 in 47.3% and 2 in 46.7% of cases. Mean UPDRS-III was 17.7 ± 9.2. Fifty-four patients were on dopaminergic treatment with median levodopa equivalent daily dose (LEDD) of 200 mg. CONCLUSIONS: We expect that the prospective nature of the BoProPark study as well as the comprehensive, instrumental evaluation of motor and non-motor symptoms in patients with parkinsonism will provide important new insights for both clinical practice and research. Our data could be used for comparison with other cohorts and shared with national and international collaborators to develop new innovative projects.

Development and validation of volumetric absorptive microsampling coupled with UHPLC-MS/MS for the analysis of gamma-hydroxybutyric acid in human blood.

A volumetric microsampling (VAMS) device (20 µl) was evaluated and validated for the analysis of γ-hydroxybutyric acid (GHB) in venous blood using a simple ultra-high-pressure liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method. GHB was extracted from VAMS device by acetonitrile, after a re-hydration step in a temperature-controlled ultrasonic bath at 60°C for 10 min. Chromatographic analysis was carried out on a Kinetex C18 column using 0.1% formic acid in water and acetonitrile as binary gradient mobile phase (from 5 to 95% of acetonitrile from 1 to 2.5 min) at a flow rate of 0.3 ml/min. The VAMS method was fully validated according to current guidelines with satisfactory results in terms of linearity, selectivity, precision, absolute recovery, matrix effect and stability. The linearity was determined from 0.5 to 200 µg/ml and the lower limit of quantitation was 0.5 µg/ml. The novel VAMS-UHPLC-MS/MS method was successfully compared with plasma-based method in a GHB-treated patient as a proof of concept.

Effect of valproic acid on perampanel pharmacokinetics in patients with epilepsy.

We prospectively examined the effect of antiepileptic (AED) cotherapy on steady state plasma concentrations of perampanel (PMP) in epileptic patients. We classified AEDs as strong enzyme inducers (carbamazepine, phenobarbital, phenytoin, oxcarbazepine), not strong enzyme inducers/not inhibitors (levetiracetam, lamotrigine, topiramate, rufinamide, lacosamide, zonisamide, clobazam), and enzyme inhibitors (valproic acid [VPA]). The main outcome was the comparison of PMP plasma concentration to weight-adjusted dose ratio (C/D; [µg/mL]/mg kg-1  d-1 ) among comedication subgroups. From 79 patients (42 females, 37 males) aged (mean ± standard deviation) 33 ± 13 years (range = 12-66 years), 114 plasma samples were collected. Twenty-eight patients (44 samples) were cotreated with enzyme inducers (group A), 21 (27 samples) with not strong enzyme inducers/not inhibitors (group B), 21 (31 samples) with not strong enzyme inducers/not inhibitors + VPA (group C), and 9 (12 samples) with enzyme inducers + VPA (group D). PMP C/D was reduced (-56%, P < .001) in group A (1.79 ± 0.80) versus group B (4.05 ± 2.16) and increased (P < .001) in group C (6.72 ± 4.04) compared with groups A (+275%), B (+66%), and D (2.76 ± 2.00, +143%). Our study documents the unpublished higher PMP C/D in patients cotreated with VPA. These findings have both theoretical relevance, suggesting better characterization of PMP metabolic pathways with ad hoc studies, and clinical usefulness in managing patients on AED polytherapy.

Liver transplantation for mitochondrial neurogastrointestinal encephalomyopathy.

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a fatal, recessive disease caused by mutations in the gene encoding thymidine phosphorylase, leading to reduced enzymatic activity, toxic nucleoside accumulation, and secondary mitochondrial DNA damage. Thymidine phosphorylase replacement has been achieved by allogeneic hematopoietic stem cell transplantation, a procedure hampered by high mortality. Based on high thymidine phosphorylase expression in the liver, a 25-year-old severely affected patient underwent liver transplantation. Serum levels of toxic nucleosides rapidly normalized. At 400 days of follow-up, the patient's clinical conditions are stable. We propose liver transplantation as a new therapy for MNGIE. Ann Neurol 2016;80:448-455.

Novel UHPLC-MS/MS method for the determination of rotigotine in the plasma of patients with Parkinson's disease.

A novel ultra-high-pressure liquid chromatography-tandem mass spectrometry method was developed and validated for the determination of the dopamine receptor agonist rotigotine in human plasma. Following liquid-liquid extraction with tert-butyl methyl ether from 500 µL plasma, the chromatographic analysis was performed on a Gemini NX3 column using 5 mm pH 5.0 ammonium acetate-5 mm ammonium acetate in methanol as binary gradient mobile phase, at a flow rate of 0.3 mL/min. The MS/MS ion transitions were 316.00 → 147.00 for rotigotine and 256.10 → 211.00 for the internal standard (lamotrigine). The lower limit of quantitation was 50 pg/mL and the linearity was determined from 50 to 2500 pg/mL. The mean recovery was 96.9%. Both intra- and interassay imprecision and inaccuracy were ≤15% at all quality control concentrations. The method was successfully applied to measure morning trough plasma rotigotine concentrations in a series of patients with Parkinson's disease on chronic treatment. The present study describes the first fully validated method for rotigotine determination in human plasma.

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

OBJECTIVE: 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. METHODS: Forty-six PD patients on L-dopa therapy, 18 de novo PD patients, and 18 healthy controls were enrolled. Patients underwent clinical assessment of motor signs and dyskinesias and kinetic-dynamic L-dopa monitoring, tracked by serial measurements of plasma drug concentrations and motor and postural tests. RESULTS: A subset of features was selected, which showed excellent reliability. Sensitivity and specificity of the selected features for dyskinesia recognition were assessed in both supervised and unsupervised settings with an accuracy of 95% and 86%, respectively. CONCLUSIONS: Our preliminary findings suggest that it is feasible to design a reliable sensor-based application for dyskinesia monitoring at home.

Fingerprick volumetric absorptive microsampling for therapeutic drug monitoring of antiseizure medications: Reliability and real-life feasibility in epilepsy patients.

Volumetric absorptive microsampling (VAMS) is increasingly proposed as a clinically reliable therapeutic drug monitoring (TDM) sampling methodology. The study aimed to establish the reliability and real-life feasibility of patient self-collected capillary VAMS for TDM of antiseizure medication (ASMs), using plasma ASMs concentrations from venous blood as a reference standard. Nurses collected venous and capillary blood samples using VAMS. Afterward, persons with epilepsy (PWE) performed VAMS sampling by themselves. All samples were analyzed by UHPLC-MS/MS. We performed a cross-validation study, comparing ASMs concentrations obtained by VAMS nurses and patients' self-collected versus plasma through Bland-Altman analysis and Passing-Bablok regression. We enrolled 301 PWE (M: F 42.5%:57.5%; mean age 44±16 years), treated with 13 ASMs, providing a total of 464 measurements. Statistical analysis comparing VAMS self-collected versus plasma ASMs concentrations showed a bias close to zero and slope and intercept values indicating a good agreement for CBZ, LCS, LEV, LTG, OXC, PB, and PHT, while a systematic difference between the two methods was found for VPA, PMP, TPM and ZNS. This is the first study showing the reliability and feasibility of the real-world application of PWE self-collected VAMS for most of the ASMs considered, giving a promising basis for at-home VAMS applications.

Lacosamide therapeutic monitoring in patients with epilepsy: effect of concomitant antiepileptic drugs.

BACKGROUND: Lacosamide (LCM) is one of the newer antiepileptic drugs (AEDs) licensed as add-on treatment for partial epilepsy. Data on LCM pharmacokinetics and interactions are limited and partly contradictory. The purpose of this study was to assess the effect of concomitant AED therapy on steady state plasma concentrations of LCM in a population of patients with epilepsy. METHODS: Steady state plasma concentrations of LCM were assessed in a cohort of 75 consecutive patients with epilepsy referred to the Laboratory of Clinical Neuropharmacology for AED therapeutic monitoring over 16 months. Plasma LCM concentrations were measured by high-performance liquid chromatography with spectrophotometric detection. RESULTS: Median morning trough plasma concentration-to-weight-adjusted dose ratio of LCM [(mg/L)/(mg/kg/d)] was significantly reduced (0.94 versus 1.35, P < 0.001) in patients treated with LCM plus AED strong inducers of cytochrome P450 metabolism, namely, carbamazepine, phenobarbital, and phenytoin (group A, n = 33), compared with a pool of patients not comedicated with AED strong inducers, predominantly including oxcarbazepine, levetiracetam, lamotrigine, and valproic acid (group B, n = 42). The 2 groups were comparable for age, gender, weight, LCM daily dose, and dosing frequency. LCM plasma concentrations were linearly related to daily drug doses, regardless of concomitant AED therapy, over a dose range from 75 to 600 mg/d, although, at a given drug dose, a large interpatient variability was observed in matched, plasma drug concentration. CONCLUSIONS: Our findings confirm, in a real-patient clinical setting, preliminary evidence from randomized, clinical trials showing that carbamazepine, phenobarbital, or phenytoin significantly reduces the overall systemic exposure to LCM. From a practical point of view, patients on concomitant AED strong inducers may require a 30% higher dose of LCM compared with patients not receiving strongly inducing AED cotherapy, to achieve the same plasma drug concentration.

Multiple system atrophy with prolonged survival: is late onset of dysautonomia the clue?

Multiple system atrophy (MSA) is a neurodegenerative disease characterised by cardiovascular autonomic failure and/or urinary dysfunctions, associated with parkinsonism, cerebellar and/or corticospinal signs, usually leading to death after an average of 7 years. We describe the disease course of five patients diagnosed with probable MSA (4 with predominant parkinsonism and 1 with predominant cerebellar ataxia) who survived for more than 15 years and were followed throughout the disease course at our department. Cardiovascular autonomic dysfunction of any severity occurred late (mean latency from disease onset 9.4 ± 5 years) in this subgroup of MSA patients. The time of involvement of the urogenital system was more variable (from 0 to 14 years after disease onset) and manifested with symptoms of storage disorders (urinary urgency, frequency and incontinence) and erectile dysfunction in men. Conversely complains suggestive of urinary voiding dysfunction (incomplete bladder emptying and urinary retention) were not recorded and patients required catheterization only late in the disease course. In conclusion, our study showed that late onset of both cardiovascular autonomic failure and urinary voiding disorders may be positive prognostic factors in MSA irrespective of the MSA subtype.

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.

Cannabidiol in Pharmacoresistant Epilepsy: Clinical Pharmacokinetic Data From an Expanded Access Program.

Background and Aim: Data on the clinical pharmacokinetics of cannabidiol (CBD) are scanty. We explored the effect of demographic and clinical variables on plasma concentrations of purified CBD in patients with Dravet (DS) and Lennox-Gastaut syndrome (LGS). Methods: The study design was an open, prospective, multicenter expanded access program (EAP). Venous blood samples were drawn from patients between 8 and 9 am, before the CBD morning dose, 12 h apart from the last evening dose, and then 2.5 h after their usual morning dose. Results: We collected 127 plasma samples (67-morning pre-dosing and 60 post-dosing) from 43 patients (24 females, 19 males), 27 with LGS and 16 with DS. Mean ± standard deviation age was 26 ± 15 years. Duration of CBD treatment averaged 4.2 ± 2.9 months at 13.2 ± 4.6 mg/kg/day. CBD median trough plasma concentration was 91 ng/ml; it doubled to 190 ng/ml 2.5 h post-dosing (p < 0.001). Cannabidiol trough plasma concentrations were linearly related to daily doses (r = 0.564, p < 0.001). Median trough CBD plasma concentration-to-weight-adjusted dose ratio (C/D) was 32% higher (p < 0.02) in plasma samples from subjects aged 18 and over than in those under 18. Sex and concomitant antiseizure medications (ASMs) were not associated with significant variations in CBD C/D, but caution is required due to the potential influence of confounders. Conclusion: These are the first data on CBD pharmacokinetics in children and adults with LGS or DS in a real-world setting. The most relevant finding was the higher CBD C/D in adults. In practice, reduced weight-normalized doses might be required with aging to achieve the same CBD plasma levels.

Impulsive conditions in Parkinson's disease: A pharmacosurveillance-supported list.

BACKGROUND: "Impulse Control Disorders" are behavioral conditions (e.g., gambling, hypersexuality), which are increasingly reported as reactions to dopamine agonists in Parkinson's disease. The Questionnaire for Impulsive-Compulsive Disorders in Parkinson's disease focuses only on 6 behaviors. Nonetheless, impulsivity could affect the entire range of human practices. Because of their heterogeneity and undefined boundaries, it is not clear what conditions should be considered as Impulse Control Disorders. This results in poorly standardized scientific literature and underdiagnosis. OBJECTIVE: We aimed to create a comprehensive list of possible manifestations of drug-induced Impulse Control Disorders in Parkinson's disease and test it on pharmacosurveillance data. METHODS: PubMed was used to identify reviews in English about Impulse Control Disorders in Parkinson's disease. Mentioned conditions were charted and translated to the lexicon of MedDRA, ICD-11, and DSM-5. The relevant MedDRA terms were used to test potential association with dopamine agonists on the FDA Adverse Event Reporting System. RESULTS: 50 reviews published between 2001 and 2020 were identified. 66 conditions were collected as possible Impulse Control Disorders. Pathological gambling, shopping, eating and sexuality, dopamine dysregulation syndrome, hobbyism and punding were the most frequently mentioned, together with leisure activities, body-focused compulsivity, disruptive, impulse control and conduct disorders, and substance abuse. All these conditions were disproportionately reported with dopamine agonists, except for substance abuse. CONCLUSIONS: We defined a potential extended list of ICDs, which, along with its conversion to international taxonomies, can support the identification of drug-induced conditions in pharmacovigilance archives, as well as monitoring processes in clinical practice.

Quantitative Assessment of Motor Response to a Low Subacute Levodopa Dose in the Differential Diagnosis of Parkinsonisms at Disease Onset: Data from the BoProPark Cohort.

BACKGROUND: Differential diagnosis between Parkinson's disease (PD) and atypical parkinsonisms (APs) may be difficult at disease onset. The response to levodopa (LD) is a key supportive feature but its definition is largely empirical. Studies evaluating this issue by quantitative tests are scanty. OBJECTIVE: We aimed to assess the utility of a subacute low LD dose kinetic-dynamic test in the differential diagnosis between PD and APs. It was applied at the baseline of a prospective follow-up in patients with parkinsonian signs within three years of disease motor onset ("BoProPark" cohort) and eventually diagnosed as PD or APs according to consensus criteria. METHODS: Patients under at least 3-month LD therapy received a first morning fasting dose of LD/benserazide or carbidopa (100/25 mg) and underwent simultaneous serial assessments of plasma LD concentration and alternate finger tapping frequency up to 3 h. The main outcome was the extent of LD motor response, calculated by the area under the 3 h tapping effect-time curve (AUC_ETap). A receiver operating characteristic (ROC) curve analysis was performed to establish the optimal AUC_ETap cut-off to differentiate PD and APs. RESULTS: The first 100 consecutive "BoProPark" patients were analyzed. Forty-seven patients were classified as possible, 37 as probable PD and 16 as APs. AUC_ETap medians were similar in the PD subgroups but reduced to a third in APs (p < 0.001). The optimal AUC_ETap cut-off value was >2186 [(tap/min) x min], with a sensitivity of 92% and a specificity of 75%. Accuracy of the test was 0.85 (95% CI 0.74-0.95), p < 0.0001. CONCLUSION: The estimation of 3 h AUC_ETap after a subacute low LD dose proved a reliable, objective tool to assess LD motor response in our cohort of patients. AUC_ETap value rounded to ≥2200 supports PD diagnosis, while lower values may alert to AP diagnoses.