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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.
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Trastornos Disruptivos, del Control de Impulso y de la Conducta , Enfermedad de Parkinson , Humanos , Agonistas de Dopamina/efectos adversos , Enfermedad de Parkinson/complicaciones , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/psicología , Pramipexol/uso terapéutico , Estudios Prospectivos , Trastornos Disruptivos, del Control de Impulso y de la Conducta/diagnóstico , Factores de RiesgoRESUMEN
Young individuals constitute an intriguing population, as their drinking habits are notably shaped by their perception of their peers' alcohol consumption. Nonetheless, excessive alcohol intake can have detrimental effects on academic performance, interpersonal relationships, and the risk and severity of accidents. This study reported the first data involving students enrolled from three universities on a voluntary basis for alcohol consumption evaluation. Alcohol consumption was assessed through questionnaires and EtG quantification in hair (hEtG) carried out by liquid chromatography-mass spectrometry (LC-MS/MS) analysis after a solid-phase extraction (SPE) purification step. The results of our study demonstrated that 77.1% of samples tested negative for hEtG or displayed hEtG ≤ 5 pg/mg. Particularly, the student population was not characterized by samples with hEtG indicative of chronic excessive consumption (hEtG ≥ 30 pg/mg). No significant association was identified between biological sex, among the degree course/the year attended, nor in relation to BMI or smoking/coffee consumption. Among the obtained results, it was worth noting that the comparison of self-reporting abstinence from tobacco and coffee accounted for 65.3% and 16.7%, respectively, while only 2.8% of the total declared abstinence from alcohol. The current study has uncovered a significant level of interest among students in this analysis and its interpretation. This suggests that implementing public health promotion activities within a university setting could be beneficial.
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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.
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ADN (Citosina-5-)-Metiltransferasa 1/genética , Predisposición Genética a la Enfermedad , Neuropatías Hereditarias Sensoriales y Autónomas/genética , Degeneración Nerviosa/genética , Ataxias Espinocerebelosas/genética , Metilación de ADN/genética , Sordera/genética , Sordera/fisiopatología , Femenino , Fibroblastos/metabolismo , Neuropatías Hereditarias Sensoriales y Autónomas/fisiopatología , Humanos , Masculino , Mitocondrias/genética , Mitocondrias/metabolismo , Mutación/genética , Narcolepsia/genética , Narcolepsia/fisiopatología , Degeneración Nerviosa/fisiopatología , Fosforilación Oxidativa , Fenotipo , Procesamiento Proteico-Postraduccional/genética , Ataxias Espinocerebelosas/fisiopatologíaRESUMEN
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.
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Cromatografía Líquida de Alta Presión/métodos , Enfermedad de Fabry/sangre , Glucolípidos/sangre , Esfingolípidos/sangre , Espectrometría de Masas en Tándem/métodos , Adulto , Cromatografía Líquida de Alta Presión/economía , Humanos , Límite de Detección , Persona de Mediana Edad , Espectrometría de Masas en Tándem/economía , Factores de Tiempo , Trihexosilceramidas/sangreRESUMEN
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.
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Anticonvulsivantes/sangre , Cromatografía Líquida de Alta Presión/métodos , Monitoreo de Drogas/métodos , Epilepsia/tratamiento farmacológico , Pirrolidinonas/sangre , Espectrometría de Masas en Tándem/métodos , Anticonvulsivantes/uso terapéutico , Cromatografía Líquida de Alta Presión/normas , Monitoreo de Drogas/normas , Humanos , Pirrolidinonas/uso terapéutico , Reproducibilidad de los ResultadosRESUMEN
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 12â¯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¯14â¯years were enrolled in the study. The mean PMP dose was 6.7⯱â¯2.3â¯mg, drug treatment averaged 46⯱â¯34â¯weeks. The mean plasma concentration was 360⯱â¯268â¯ng/mL (range: 37-1213â¯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.
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Anticonvulsivantes , Piridonas , Adulto , Anticonvulsivantes/uso terapéutico , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Masculino , Persona de Mediana Edad , Nitrilos , Plasma , Estudios Prospectivos , Piridonas/uso terapéutico , Resultado del Tratamiento , Adulto JovenRESUMEN
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.
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Cromatografía Líquida de Alta Presión/métodos , Hidroxibutiratos/sangre , Espectrometría de Masas en Tándem/métodos , Recolección de Muestras de Sangre , Humanos , Hidroxibutiratos/farmacocinética , Hidroxibutiratos/uso terapéutico , Límite de Detección , Modelos Lineales , Narcolepsia/tratamiento farmacológico , Reproducibilidad de los ResultadosRESUMEN
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.
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Anticonvulsivantes/uso terapéutico , Epilepsia/tratamiento farmacológico , Piridonas/farmacocinética , Piridonas/uso terapéutico , Ácido Valproico/uso terapéutico , Adolescente , Adulto , Anciano , Anticonvulsivantes/efectos adversos , Anticonvulsivantes/clasificación , Niño , Inductores de las Enzimas del Citocromo P-450/efectos adversos , Inductores de las Enzimas del Citocromo P-450/uso terapéutico , Inhibidores Enzimáticos del Citocromo P-450/efectos adversos , Inhibidores Enzimáticos del Citocromo P-450/uso terapéutico , Interacciones Farmacológicas , Quimioterapia Combinada , Epilepsia/sangre , Femenino , Humanos , Masculino , Persona de Mediana Edad , Nitrilos , Estudios Prospectivos , Ácido Valproico/efectos adversos , Adulto JovenRESUMEN
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.
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Seudoobstrucción Intestinal/cirugía , Trasplante de Hígado/métodos , Encefalomiopatías Mitocondriales/cirugía , Adulto , Humanos , Masculino , Distrofia Muscular Oculofaríngea , Oftalmoplejía/congénitoRESUMEN
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 â 147.00 for rotigotine and 256.10 â 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.
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Cromatografía Líquida de Alta Presión/métodos , Agonistas de Dopamina/sangre , Enfermedad de Parkinson/tratamiento farmacológico , Espectrometría de Masas en Tándem/métodos , Tetrahidronaftalenos/sangre , Tiofenos/sangre , Agonistas de Dopamina/química , Agonistas de Dopamina/farmacocinética , Agonistas de Dopamina/uso terapéutico , Humanos , Límite de Detección , Modelos Lineales , Reproducibilidad de los Resultados , Tetrahidronaftalenos/química , Tetrahidronaftalenos/farmacocinética , Tetrahidronaftalenos/uso terapéutico , Tiofenos/química , Tiofenos/farmacocinética , Tiofenos/uso terapéuticoRESUMEN
INTRODUCTION: In the dynamic universe of new psychoactive substances (NPS), the identification of multiple and chemically diverse compounds remains a challenge for forensic laboratories. Since hair analysis represents a gold-standard to assess the prevalence of NPS, which are commonly detected together with classical drugs of abuse (DoA), our study aimed at developing a wide-screen method to detect and quantify 127 NPS and 15 DoA on hair. MATERIALS AND METHODS: A multi-analyte ultra-high performance liquid chromatography mass spectrometry method for the identification and quantification of 127 NPS (phenethylamines, arylcyclohexylamines, synthetic opioids, tryptamines, synthetic cannabinoids, synthetic cathinones, designer benzodiazepines) and 15 DoA in hair samples was developed. A full validation was performed according to the European medicines Agency (EMA) guidelines, by assessing selectivity, linearity, accuracy, precision, limit of quantification (LOQ), limit of detection (LOD), matrix effect and recovery. As a proof of the applicability, the method was applied to 22 authentic hair samples collected for forensic purposes. RESULTS: Successful validation was achieved, by meeting the required technical parameters, for 137 compounds (122 NPS and 15 DoA), with LOQ set at 4â¯pg/mg for 129 compounds, at 10â¯pg/mg for 6 and at 40â¯pg/mg for 2. The method was not considered validated for 5 NPS, as LLOQ resulted too high for a forensic analysis (80â¯pg/mg). Among authentic forensic samples, 17 tested positive for DoA, and 10 to NPS, most samples showing positivity for both. Detected NPS were ketamine and norketamine, 5-MMPA, ritalinic acid, methoxyacetyl fentanyl, methylone and RCS-4. CONCLUSION: The present methodology represents an easy, low cost, wide-panel method for the quantification of 122 NPS and 15 DoA, for a total of 137 analytes, in hair samples. The method can be profitably applied by forensic laboratories. Similar multi-analyte methods on the hair matrix might be useful in the future to study the prevalence of NPS and the co-occurrence of NPS-DoA abuse.
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Cannabinoides , Drogas Ilícitas , Trastornos Relacionados con Sustancias , Humanos , Detección de Abuso de Sustancias/métodos , Drogas Ilícitas/análisis , Analgésicos Opioides/análisis , Cannabinoides/análisis , Cabello/químicaRESUMEN
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.
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Epilepsia , Espectrometría de Masas en Tándem , Humanos , Adulto , Persona de Mediana Edad , Espectrometría de Masas en Tándem/métodos , Monitoreo de Drogas/métodos , Reproducibilidad de los Resultados , Estudios de Factibilidad , Recolección de Muestras de Sangre/métodos , Pruebas con Sangre Seca/métodos , Epilepsia/tratamiento farmacológicoRESUMEN
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.
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Acetamidas/sangre , Anticonvulsivantes/sangre , Cromatografía Líquida de Alta Presión/métodos , Epilepsia/tratamiento farmacológico , Acetamidas/administración & dosificación , Acetamidas/uso terapéutico , Adulto , Anticonvulsivantes/administración & dosificación , Anticonvulsivantes/uso terapéutico , Estudios de Cohortes , Relación Dosis-Respuesta a Droga , Monitoreo de Drogas/métodos , Quimioterapia Combinada , Femenino , Humanos , Lacosamida , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Espectrofotometría/métodos , Adulto JovenRESUMEN
European pharmaceutical companies have a legal requirement to provide non-promotional medical information (MI) services to support healthcare professionals (HCPs) using their medicinal products. While we are seeing an increased HCP preference and expectation towards digital channels, the lack of a compliance framework relating to the provision of non-promotional MI services is a key factor complicating and compromising the ability for companies to meet this need. Meanwhile, the internet is dominated by a large volume of unregulated, easy access, and potentially low-quality information from diverse sources. The Medical Information Leaders in Europe (MILE) association is therefore proposing a framework of principles to support pharmaceutical companies with the digital provision of MI services; these relate to digital access to non-promotional, medicinal product information to support clinical decision making and patient care. The three established European national MI associations have already considered the framework and expressed their endorsement. MILE continues to invite stakeholders, including pharmaceutical companies, regulators, national industry associations and healthcare professional bodies to engage and help refine and implement this framework. This publication does not constitute legal advice; decision making and accountability remains with each pharmaceutical company.
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Industria Farmacéutica , Personal de Salud , Humanos , Europa (Continente) , Preparaciones Farmacéuticas , Atención a la SaludRESUMEN
External contamination of hair by cannabis smoking requires a careful evaluation in forensic toxicology. Medical and recreational cannabis are increasingly consumed by e-cigarettes, which give rise to side-stream vapor. Moreover, products containing low Δ9-tetrahydrocannabinol (Δ9-THC) and rich in cannabidiol (CBD) started spreading legally. The goal of the present study was to assess whether hair analysis could allow to distinguish the type of delivered product, with low or high Δ9-THC, and the delivering mode, by smoking or vaping. Contamination of blank hair was mimicked by in vitro exposure to low- (0.4%) and high-Δ9-THC (9.7%) products delivered by smoking and vaping within a small confined system. Cannabis vaping extracts were prepared to deliver identical target Δ9-THC doses. Eighty samples were analyzed by ultrahigh-performance liquid chromatography mass spectrometry and quantified for Δ9-THC and CBD. After contamination by cannabis smoking, THC levels were in line with past in vitro and in vivo studies. Samples exposed to cannabis (169.30 ng/mg) showed significantly higher Δ9-THC than hair exposed to "light cannabis" (35.54 ng/mg), and the opposite was seen for the CBD/Δ9-THC ratio. Hair contaminated by vaping or smoking did not show a statistically different Δ9-THC content. Under our in vitro conditions, hair analysis might allow to discriminate whether external contamination is determined by products containing low or high Δ9-THC, but not the delivering mode. More research is needed in real-life conditions, to see whether the same also applies to the interpretation of forensic casework.
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We report a rapid and sensitive LC-MS/MS method that allows the simultaneous detection of 68 commonly prescribed antidepressants, benzodiazepines, neuroleptics, and metabolites in whole blood with a small sample volume after a rapid protein precipitation. The method was also tested on post-mortem blood from 85 forensic autopsies. Three sets of commercial serum calibrators containing a mix of prescription drugs of increasing concentration were spiked with red blood cells (RBC) to obtain 6 calibrators (3 "serum calibrators" and 3 "blood calibrators"). Curves obtained from serum calibrators and from blood calibrators were compared using a Spearman correlation test and by analyzing slopes and intercepts, to assess if the points from six calibrators could be plotted together in a single calibration model. The validation plan included interference studies, calibration model, carry-over, bias, within-run and between-run precision, limit of detection (LOD), limit of quantification (LOQ), matrix effect and dilution integrity. Four deuterated Internal Standards (Nordiazepam-D5, Citalopram-D6, Ketamine-D4 and Amphetamine-D5) and two different dilutions were assessed. Analyses were performed using an Acquity UPLC® System coupled with triple quadrupole detector Xevo TQD®. The degree of agreement with a previously validated method was calculated on whole blood samples of 85 post-mortem cases, by performing a Spearman correlation test with a Bland-Altman plot. Percentage error between the two methods was evaluated. Slopes and intercepts of curves obtained from serum calibrators and from blood calibrators showed a good correlation, and the calibration model was built plotting all points together. No interferences were found. The calibration curve appeared to provide a better fit of the data using an unweighted linear model. Negligible carry-over was observed, and very good linearity, precision, bias, matrix effect and dilution integrity were achieved. The LOD and the LOQ were at the lower limits of the therapeutic range for the tested drugs. In a series of 85 forensic cases, 11 antidepressants, 11 benzodiazepines and 8 neuroleptics were detected. For all analytes, a very good agreement between the new method and the validated method was demonstrated. The innovation of our method consists in the use of commercial calibrators, readily available to most forensic toxicology laboratories, for the validation of a fast, inexpensive, wide-panel LC-MS/MS method that can be used as a reliable and accurate screening for psychotropic drug in postmortem samples. As observed in the implementation on real cases, this method could be profitably applied in forensic cases.
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Antipsicóticos , Espectrometría de Masas en Tándem , Cromatografía Liquida/métodos , Espectrometría de Masas en Tándem/métodos , Autopsia , Psicotrópicos , Límite de Detección , Antidepresivos , Anfetamina , Benzodiazepinas , Toxicología Forense/métodosRESUMEN
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.
RESUMEN
European pharmaceutical companies have a legal requirement to provide non-promotional Medical Information (MI) services to support healthcare professionals (HCPs) who are using their medicinal products. While the industry has self-regulating bodies with established Codes of Practice, these mainly focus on promotional messaging and commercial activities. In the absence of similar frameworks for MI, such services struggle to understand how to meet HCP digital expectations, often in fear of breaching the promotional codes. This is limiting access to the wealth of non-promotional patient-focussed information held within the industry. Meanwhile, a large volume of unregulated, low-quality information can be readily found on the internet. To understand the current status, the Medical Information Leaders in Europe (MILE) industry association performed a benchmarking survey which explored the online MI service provision of 13 mid-large pharmaceutical companies across Europe. This highlighted a great diversity in approach in terms of geographical coverage and content. Visibility and access for HCPs is complex, compromising online engagement and website utilisation. This MILE position paper highlights the critical need to establish a clear governance model, which empowers pharmaceutical company MI functions to provide unbranded, non-promotional, medicinal product information sources to support HCP online information needs. It is essential to build confidence, transparency and trust by establishing a practical quality framework with principles and standards for online MI services for HCPs.
Asunto(s)
Personal de Salud , Servicios de Información , Benchmarking , Humanos , Encuestas y Cuestionarios , ConfianzaRESUMEN
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 (100/25âmg) and underwent simultaneous serial assessments of plasma LD concentration and alternate finger tapping frequency up to 3âh. The main outcome was the extent of LD motor response, calculated by the area under the 3âh 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 (pâ<â0.001). 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), pâ<â0.0001. CONCLUSION: The estimation of 3âh 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.
Asunto(s)
Trastornos Parkinsonianos , Antiparkinsonianos , Diagnóstico Diferencial , Humanos , Levodopa , Trastornos Parkinsonianos/diagnóstico , Estudios ProspectivosRESUMEN
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.