RESUMEN
In Alzheimer's disease (AD) clinical trials, disease-modifying therapies are expected to slow the rate of disease progression. Treatment effects are evaluated using a validated clinical scale as the difference between treatment and placebo in mean change from baseline to endpoint. Understanding the clinical relevance of this metric is not necessarily intuitive. Expressing active treatment-placebo difference as a time metric (i.e., months saved with treatment) has potential to provide a metric that is more easily and consistently interpreted. Using data from the TRAILBLAZER-ALZ study, time component tests (TCTs) were employed to determine the time saved with donanemab (an amyloid lowering drug) treatment. At study endpoint (Week 76), disease progression was delayed by 5.3 months and 5.2 months as measured by the Integrated Alzheimer's Disease Rating Scale (iADRS) and the Clinical Dementia Rating Sum of Boxes (CDR-SB), respectively.
Asunto(s)
Enfermedad de Alzheimer , Humanos , Enfermedad de Alzheimer/diagnóstico , Enfermedad de Alzheimer/tratamiento farmacológico , Resultado del Tratamiento , Anticuerpos Monoclonales/uso terapéutico , Pruebas de Estado Mental y Demencia , Progresión de la EnfermedadRESUMEN
Human Precision-cut intestinal slices (hPCIS) are used to study intestinal physiology, pathophysiology, drug efficacy, toxicology, kinetics, and metabolism. However, the use of this ex vivo model is restricted to approximately a 24 h timeframe because of declining viability of the hPCIS during traditional culture. We hypothesized that we could extend the hPCIS viability by using organoid medium. Therefore, we cultured hPCIS for up to 72 h in organoid media [expansion medium (Emed) and differentiation medium (Dmed)]. After incubation, we assessed culture-induced changes on viability markers, specific cell type markers and we assessed the metabolic activity of enterocytes by measuring midazolam metabolite formation. We show that the adenosine triphosphate (ATP)/protein ratio of Emed-cultured hPCIS and morphology of both Emed- and Dmed-cultured hPCIS was improved compared to WME-cultured hPCIS. Emed-cultured hPCIS showed an increased expression of proliferation and stem cell markers, whereas Dmed-cultured hPCIS showed an increased expression of proliferation and enterocyte markers, along with increased midazolam metabolism. Using the Emed, the viability of hPCIS could be extended for up to 72 h, and proliferating stem cells remained preserved. Using Dmed, hPCS also remained viable for up to 72 h, and specifically rescued the metabolizing enterocytes during culture. In conclusion, by using two different organoid culture media, we could extend the hPCIS viability for up to 72 h of incubation and specifically steer stem cells or enterocytes towards their original function, metabolism, and proliferation, potentially allowing pharmacokinetic and toxicology studies beyond the 24 h timeframe.
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Intestinos , Midazolam , Medios de Cultivo , Humanos , Inactivación Metabólica , Midazolam/farmacología , OrganoidesRESUMEN
BACKGROUND: Computerized cognitive assessments may improve Alzheimer's disease (AD) secondary prevention trial efficiency and accuracy. However, they require validation against standard outcomes and relevant biomarkers. OBJECTIVE: To assess the feasibility and validity of the tablet-based Computerized Cognitive Composite (C3). DESIGN: Cross-sectional analysis of cognitive screening data from the A4 study (Anti-Amyloid in Asymptomatic AD). SETTING: Multi-center international study. PARTICIPANTS: Clinically normal (CN) older adults (65-85; n=4486). MEASUREMENTS: Participants underwent florbetapir-Positron Emission Tomography for Aß+/- classification. They completed the C3 and standard paper and pencil measures included in the Preclinical Alzheimer's Cognitive Composite (PACC). The C3 combines memory measures sensitive to change over time (Cogstate Brief Battery-One Card Learning) and measures shown to be declining early in AD including pattern separation (Behavioral Pattern Separation Test- Object- Lure Discrimination Index) and associative memory (Face Name Associative Memory Exam- Face-Name Matching). C3 acceptability and completion rates were assessed using qualitative and quantitative methods. C3 performance was explored in relation to Aß+/- groups (n=1323/3163) and PACC. RESULTS: C3 was feasible for CN older adults to complete. Rates of incomplete or invalid administrations were extremely low, even in the bottom quartile of cognitive performers (PACC). C3 was moderately correlated with PACC (r=0.39). Aß+ performed worse on C3 compared with Aß- [unadjusted Cohen's d=-0.22 (95%CI: -0.31,-0.13) p<0.001] and at a magnitude comparable to the PACC [d=-0.32 (95%CI: -0.41,-0.23) p<0.001]. Better C3 performance was observed in younger, more educated, and female participants. CONCLUSIONS: These findings provide support for both the feasibility and validity of C3 and computerized cognitive outcomes more generally in AD secondary prevention trials.
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Enfermedad de Alzheimer/diagnóstico , Ensayos Clínicos como Asunto , Pruebas de Estado Mental y Demencia , Anciano , Péptidos beta-Amiloides/metabolismo , Biomarcadores/metabolismo , Computadores , Estudios Transversales , Estudios de Factibilidad , Femenino , Humanos , Masculino , Investigación Cualitativa , Prevención SecundariaRESUMEN
The Integrated Alzheimer's Disease (AD) Rating Scale (iADRS) is a composite tool that combines scores from the AD Assessment Scale-Cognitive subscale (ADAS-Cog) and the AD Cooperative Study - instrumental Activities of Daily Living (ADCS-iADL). It demonstrates acceptable psychometric properties, and is effective in capturing both disease progression and separation of placebo and active drug effect. We assessed the performance of iADRS in the solanezumab EXPEDITION3 study, an 80-week, placebo-controlled study of individuals with mild AD dementia. A statistically significant difference between placebo and active drug was observed for iADRS score change from baseline at Week 28 (p=0.028) through Week 80 (p=0.015). Across the Phase 3 solanezumab trials, iADRS was the only tool that consistently differentiated between solanezumab and placebo groups. These findings suggest that the iADRS is a useful integrated measurement tool for treatment trials of individuals with mild AD dementia.
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Enfermedad de Alzheimer/diagnóstico , Enfermedad de Alzheimer/tratamiento farmacológico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Índice de Severidad de la Enfermedad , Progresión de la Enfermedad , Femenino , Humanos , Masculino , PsicometríaRESUMEN
Ertapenem is a carbapenem antibiotic with activity against Mycobacterium tuberculosis Dose simulations in a hollow-fiber infection model showed that 2,000 mg once daily is an appropriate dose to be tested in clinical studies. Before using this dose in a phase II study, the aim of this prospective pharmacokinetic study was to confirm the pharmacokinetics of 2,000 mg once daily in tuberculosis (TB) patients. Twelve TB patients received a single intravenous dose of 2,000 mg ertapenem as a 30-min infusion. Blood samples were collected at 0, 0.5, 1, 2, 3, 4, 8, 12, and 24 h postadministration. Drug concentrations were measured using a validated liquid chromatography-tandem mass spectrometry assay. A large interindividual variation in the pharmacokinetics of ertapenem was observed. The median (interquartile range) area under the plasma concentration-time curve to infinity (AUC0-∞) was 2,032 (1,751 to 2,346) mg · h/liter, the intercompartmental clearance (CL12) was 1.941 (0.979 to 2.817) liters/h, and the volume of distribution in the central compartment (V1) was 1.514 (1.064 to 2.210) liters. A more than dose-proportional increase in AUC was observed compared to results reported for 1,000 mg ertapenem in multidrug-resistant TB patients. Based on a MIC of 1.0 mg/liter, 11 out of 12 patients would have reached the target value of unbound drug exceeding the MIC over 40% of the time (f40% T>MIC). In conclusion, this study shows that 2,000 mg ertapenem once daily in TB patients reached the expected f40% T>MIC for most of the patients, and exploration in a phase 2 study can be advocated.
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Antituberculosos/farmacocinética , Antituberculosos/uso terapéutico , Ertapenem/farmacocinética , Tuberculosis/tratamiento farmacológico , Adulto , Antituberculosos/administración & dosificación , Ertapenem/administración & dosificación , Ertapenem/uso terapéutico , Femenino , Humanos , Masculino , Pruebas de Sensibilidad Microbiana , Estudios ProspectivosRESUMEN
The Alzheimer's Disease Assessment Scale's cognitive subscale (ADAS-Cog) has been widely used as an outcome measure in Alzheimer's Disease (AD) clinical trials. In its original form (ADAS-Cog11), the scale has been used successfully in mild-to-moderate AD dementia populations, but its use is more limited in the study of earlier disease (mild cognitive impairment [MCI] or mild dementia due to AD) owing to lack of appropriate sensitivity of some items. With recent focus on earlier treatment, efforts have focused on the development of more sensitive tools, including the Clinical Dementia Rating-Sum of Boxes (CDR-SB), a global assessment tool to evaluate both cognition and function. The ability of the ADAS-Cog and CDR-SB to detect treatment group differences in the clinical trial environment has not been systematically studied. The aim of this analysis was to compare the utility of these tools in detecting treatment group differences, by reviewing study findings identified through advanced searches of clinicaltrials.gov and Ovid, and press releases and scientific presentations. Findings from placebo-controlled studies of ≥ 6m duration and enrolling >100 participants were included; reporting of both the ADAS-Cog and CDR-SB at endpoint was also a requirement. Of the >300 records identified, 34 studies fulfilled the criteria. There were significant placebo versus active drug group differences based on findings from at least one measure for 14 studies. The ADAS-Cog detected treatment differences more frequently than the CDR-SB. Based on these and previously published findings, the ADAS-Cog appears more useful than the CDR-SB in detecting treatment group differences.
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Enfermedad de Alzheimer/diagnóstico , Enfermedad de Alzheimer/terapia , Pruebas de Estado Mental y Demencia/normas , Ensayos Clínicos Fase II como Asunto , Ensayos Clínicos Fase III como Asunto , Disfunción Cognitiva/diagnóstico , Humanos , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Resultado del TratamientoRESUMEN
Several ongoing clinical development programs are investigating potential disease-modifying treatments for Alzheimer's disease (AD), including lanabecestat (AZD3293/LY3314814). Lanabecestat is a brain-permeable oral inhibitor of human beta-site amyloid (Aß) precursor protein-cleaving enzyme 1 (BACE1) that reduces Aß production. As a potent BACE1 inhibitor, lanabecestat significantly reduced soluble Aß species and soluble amyloid precursor proteins (sAPPß) in mouse, guinea pig, and dog in a time- and dose-dependent manner. Significant reductions in plasma and cerebrospinal fluid (CSF) Aß1-40 and Aß1-42 were observed in Phase 1 studies of healthy subjects and AD patients treated with lanabecestat. Three lanabecestat trials are ongoing and intended to support registration in Early AD: (1) Phase 2/3 study in patients with mild cognitive impairment (MCI) due to AD and mild AD dementia (AMARANTH, NCT02245737); (2) Delayed-start extension study (AMARANTH-EXTENSION, NCT02972658) for patients who have completed treatment in the AMARANTH Study; and (3) Phase 3 study in mild AD dementia (DAYBREAK-ALZ, NCT02783573). This review will discuss the development of lanabecestat, results from the completed nonclinical and clinical studies, as well as describe the ongoing Phase 3 clinical trials.
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Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Inhibidores Enzimáticos/farmacología , Imidazoles/farmacología , Compuestos de Espiro/farmacología , Enfermedad de Alzheimer/sangre , Enfermedad de Alzheimer/líquido cefalorraquídeo , Enfermedad de Alzheimer/tratamiento farmacológico , Precursor de Proteína beta-Amiloide/metabolismo , Animales , Ensayos Clínicos como Asunto , Disfunción Cognitiva/sangre , Disfunción Cognitiva/líquido cefalorraquídeo , Disfunción Cognitiva/tratamiento farmacológico , Inhibidores Enzimáticos/farmacocinética , Inhibidores Enzimáticos/uso terapéutico , Humanos , Imidazoles/farmacocinética , Imidazoles/uso terapéutico , Compuestos de Espiro/farmacocinética , Compuestos de Espiro/uso terapéuticoRESUMEN
It is generally recognized that more sensitive instruments for the earliest stages of Alzheimer's disease (AD) are needed. The integrated Alzheimer's Disease Rating Scale (iADRS) combines scores from 2 widely accepted measures, the Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog) and the Alzheimer's Disease Cooperative Study - instrumental Activities of Daily Living (ADCS-iADL). Disease progression and treatment differences as measured by the iADRS were analyzed using data from solanezumab EXPEDITION, EXPEDITION2, and EXPEDITION-EXT Studies; semagacestat IDENTITY Study; and donepezil ADCS - mild cognitive impairment (ADCS-MCI) Study. Psychometric properties of the iADRS were established through principal component analysis (PCA) and estimation of contributions of subscores and individual item scores to the iADRS total score. The iADRS performed better than most composites and scales in detecting disease progression and comparably or better than individual scales in detecting treatment differences. PCA demonstrated the iADRS can be divided into two principal components primarily representing cognitive items and instrumental ADLs. Dynamic ranges of the subscales were similar across all studies, reflecting approximately equal contributions from both subscales to the iADRS total score. In item analyses, every item contributed to the total score, with varying strength of contributions by item and across data sets. The iADRS demonstrated acceptable psychometric properties and was effective in capturing disease progression from MCI through moderate AD and treatment effects across the early disease spectrum. These findings suggest the iADRS can be used in studies of mixed populations, ensuring sensitivity to treatment effects as subjects progress during studies of putative disease-modifying agents.
RESUMEN
Ertapenem, a carbapenem, relies on time-dependent killing. Therapeutic drug monitoring (TDM) should be considered, when ertapenem is used in specific populations, to achieve optimal bactericidal activity and optimize drug-dosing regimens. No validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method has been reported using deuterated ertapenem as the internal standard. A new simple and robust LC-MS/MS method using a quadrupole mass spectrometer was developed for analysis of ertapenem in human plasma, using deuterated ertapenem as the internal standard. The calibration curve was linear over a range of 0.1 (lower limit of quantification [LLOQ]) to 125 mg/liter. The calculated accuracy ranged from -2.4% to 10.3%. Within-run coefficients of variation (CV) ranged from 2.7% to 11.8%, and between-run CV ranged from 0% to 8.4%. Freeze-thaw stability had a bias of -3.3% and 0.1%. Storage of QC samples for 96 h at 4°C had a bias of -4.3 to 5.6%, storage at room temperature for 24 h had a bias of -10.7% to -14.8%, and storage in the autosampler had a bias between -2.9% and -10.0%. A simple LC-MS/MS method to quantify ertapenem in human plasma using deuterated ertapenem as the internal standard has been validated. This method can be used in pharmacokinetic studies and in clinical studies by performing TDM.
Asunto(s)
Antibacterianos/sangre , Cromatografía Líquida de Alta Presión/métodos , Monitoreo de Drogas/métodos , Espectrometría de Masas en Tándem/métodos , beta-Lactamas/sangre , Antibacterianos/química , Antibacterianos/farmacocinética , Calibración , Estabilidad de Medicamentos , Ertapenem , Humanos , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , beta-Lactamas/química , beta-Lactamas/farmacocinéticaRESUMEN
Clarithromycin and rifampicin are used for the treatment of Mycobacteria. Pharmacokinetic drug interaction is possibly due to the influence of the two drugs on the liver enzymes. Using a Hypurity Aquastar C18 column (50mm×2.1mm×5µm) for liquid chromatography including a polar end-capped phase for the determination of clarithromycin, rifampicin and their metabolites together in plasma using LC-MS/MS resulted in a substantial carry-over. As a consequence, the throughput of the method is not assured. Using a step-by-step troubleshooting procedure, such carry-over was found originating from column memory effect. With the use of another type of C18 column, the carry-over is eliminated. Due to the absence of carry-over, the analytical concentration ranges are extended and are therefore more appropriate for the analysis of patient samples. The method was re-validated for linearity, reproducibility and dilution integrity.
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Cromatografía Liquida/métodos , Claritromicina/sangre , Rifampin/sangre , Espectrometría de Masas en Tándem/métodos , Claritromicina/análogos & derivados , Claritromicina/química , Claritromicina/metabolismo , Humanos , Modelos Lineales , Reproducibilidad de los Resultados , Rifampin/análogos & derivados , Rifampin/química , Rifampin/metabolismo , Sensibilidad y EspecificidadAsunto(s)
Examen de Aptitud para la Conducción de Vehículos/legislación & jurisprudencia , Conducción de Automóvil/legislación & jurisprudencia , Trastornos Mentales/complicaciones , Anciano , Envejecimiento/psicología , Examen de Aptitud para la Conducción de Vehículos/psicología , Conducción de Automóvil/psicología , Humanos , Trastornos Mentales/psicologíaRESUMEN
In a randomized controlled trial in Ghana, treatment of Mycobacterium ulcerans infection with streptomycin (SM)-rifampin (RIF) for 8 weeks was compared with treatment with SM-RIF for 4 weeks followed by treatment with RIF-clarithromycin (CLA) for 4 weeks. The extent of the interaction of RIF and CLA combined on the pharmacokinetics of the two compounds is unknown in this population and was therefore studied in a subset of patients. Patients received CLA at a dose of 7.5 mg/kg of body weight once daily, rounded to the nearest 125 mg. RIF was administered at a dose of 10 mg/kg, rounded to the nearest 150 mg. SM was given at a dose of 15 mg/kg once daily as an intramuscular injection. Plasma samples were drawn at steady state and analyzed by liquid chromatography-tandem mass spectroscopy. Pharmacokinetic parameters were calculated with the MW/Pharm (version 3.60) program. Comedication with CLA resulted in a 60% statistically nonsignificant increase in the area under the plasma concentration-time curve (AUC) for RIF of 25.8 mg x h/liter (interquartile ratio [IQR], 21.7 to 31.5 mg x h/liter), whereas the AUC of RIF was 15.2 mg x h/liter (IQR, 15.0 to 17.5 mg x h/liter) in patients comedicated with SM (P = 0.09). The median AUCs of CLA and 14-hydroxyclarithromycin (14OH-CLA) were 2.9 mg x h/liter (IQR, 1.5 to 3.8 mg x h/liter) and 8.0 mg x h/liter (IQR, 6.7 to 8.6 mg x h/liter), respectively. The median concentration of CLA was above the MIC of M. ulcerans, but that of 14OH-CLA was not. In further clinical studies, a dose of CLA of 7.5 mg/kg twice daily should be used (or with an extended-release formulation, 15 mg/kg should be used) to ensure higher levels of exposure to CLA and an increase in the time above the MIC compared to those achieved with the currently used dose of 7.5 mg/kg once daily.
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Úlcera de Buruli/tratamiento farmacológico , Claritromicina/uso terapéutico , Rifampin/uso terapéutico , Antibióticos Antituberculosos/uso terapéutico , Cromatografía Liquida , Claritromicina/sangre , Claritromicina/farmacocinética , Humanos , Pruebas de Sensibilidad Microbiana , Rifampin/sangre , Rifampin/farmacocinética , Espectrometría de Masas en TándemRESUMEN
Fungal infections occur in immunocompromised patients. Azole antifungal agents are used for the prophylaxis and treatment of these infections. The interest in therapeutic drug monitoring azole agents has increased over the last few years. Inter- and intra-patient variability of pharmacokinetics, drug-drug interactions, serum concentration related toxicity and success of therapy has stressed the need of frequently therapeutic drug monitoring of the drugs, belonging to the group of azoles. Therefore a simple, rapid and flexible method of analysis is required. This method is based on the precipitation of proteins in human serum with LC/MS/MS detection. Validation was performed according to the guidelines for bioanalytical method validation of the food and drug administration agency. The four most used azole drugs can be detected in human serum within the clinical relevant serum levels with good accuracy and reproducibility at the limit of quantification. Intra- and inter-day validation demonstrated good accuracy and reproducibility. A rapid, sensitive and flexible LC/MS/MS method has been developed and validated to measure voriconazole (VRZ), fluconazole (FLZ), itraconazole (ITZ) and posaconazole (PSZ) in human serum. This new method is suitable for clinical pharmacokinetic studies and routine monitoring in daily practice.
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Antifúngicos/sangre , Cromatografía Liquida/métodos , Monitoreo de Drogas/métodos , Espectrometría de Masas en Tándem/métodos , Triazoles/sangre , Análisis de Varianza , Estabilidad de Medicamentos , Humanos , Reproducibilidad de los Resultados , Sensibilidad y EspecificidadAsunto(s)
Encéfalo/patología , Diabetes Mellitus Tipo 1/patología , Envejecimiento , Femenino , Humanos , MasculinoRESUMEN
AIMS/HYPOTHESIS: Cognitive performance in type 1 diabetes may be compromised as a result of chronic hyperglycaemia. The aim of this study was to investigate the cognitive functioning of patients with type 1 diabetes (including a subgroup with a microvascular complication) and nondiabetic controls, and to assess the relationship between cognition and cerebral grey and white matter volumes. MATERIALS AND METHODS: Twenty-five patients with type 1 diabetes (of whom ten had proliferative retinopathy) and nine nondiabetic controls (matched in terms of sex, age and education) underwent a neuropsychological examination and magnetic resonance imaging of the brain. Fractional brain tissue volumes (tissue volume relative to total intracranial volume) were obtained from each participant. RESULTS: Compared with nondiabetic controls, patients with diabetes performed worse on tests measuring speed of information processing and visuoconstruction; patients with microvascular disease performed worse on the former cognitive domain (p = 0.03), whereas patients without complications performed worse on the latter domain (p = 0.01). Patients with a microvascular complication had a significantly smaller white matter volume than nondiabetic controls (p = 0.04), and smaller white matter volume was associated with worse performance on the domains of speed of information processing and attention and executive function. CONCLUSIONS/INTERPRETATION: Patients with diabetes demonstrated several subtle neuropsychological deficits, which were found to be related to white matter volume. Since patients with diabetic retinopathy had a smaller white matter volume, this suggests that cognitive decline is at least partly mediated by microvascular disease. This needs to be addressed in future studies.
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Encéfalo/patología , Cognición/fisiología , Diabetes Mellitus Tipo 1/patología , Adulto , Análisis de Varianza , Diabetes Mellitus Tipo 1/fisiopatología , Diabetes Mellitus Tipo 1/psicología , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Pruebas NeuropsicológicasRESUMEN
AIMS: Mild cognitive deficits have been determined in both types of diabetes using neurocognitive tests. Little is known about the degree to which patients complain about their cognitive functioning. This study set out to investigate the magnitude and correlates of self-reported cognitive failure in adult out-patients with Type 1 and Type 2 diabetes. METHODS: Subjective cognitive functioning was measured in 187 diabetic patients using the Cognitive Failures Questionnaire (CFQ). Demographic and clinical characteristics were retrieved from the medical records. The Patient Health Questionnaire 9 items (PHQ-9) was self-administered along with the CFQ to correct for the confounding effect of depression. RESULTS: Analyses were based on 55 patients with Type 1 diabetes and 100 patients with Type 2 diabetes. No difference in mean CFQ score was observed between Type 1 and Type 2 diabetic patients or between Type 1 diabetic patients and healthy control subjects. Female patients with Type 2 diabetes reported significantly fewer cognitive complaints compared with female healthy control subjects. None of the demographic variables and diabetes-related complications was associated with subjective cognitive complaints. A strong positive association was found between depression symptomatology and frequency of self-reported cognitive failure. CONCLUSIONS: Our study could not confirm elevated subjective cognitive complaints in a group of Type 1 and Type 2 diabetes patients, as might be expected given the observed elevated rates of mild cognitive dysfunction in patients with diabetes. Self-reported cognitive failure appears largely determined by depressive symptomatology. Therefore, affective status should be included in any cognitive assessment procedure.
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Trastornos del Conocimiento/etiología , Trastorno Depresivo/psicología , Diabetes Mellitus Tipo 1/complicaciones , Diabetes Mellitus Tipo 2/complicaciones , Adulto , Anciano , Trastornos del Conocimiento/psicología , Estudios Transversales , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pruebas Neuropsicológicas , Autoevaluación (Psicología) , Encuestas y CuestionariosRESUMEN
An unexpectedly high number of initially suspected cocaine-intoxicated patients was presented to a general hospital in Lelystad, The Netherlands. Based on the unusual toxidram rate of not fitting cocaine intoxication, the suspicion of co-presence of an anticholinergic agent was raised. A newly developed HPLC-MS/MS analytical method revealed the presence of 10% atropine in a cocaine sample retrieved and subsequently in the sera of 6 intoxicated patients.
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Atropina/sangre , Atropina/envenenamiento , Antagonistas Colinérgicos/sangre , Antagonistas Colinérgicos/envenenamiento , Trastornos Relacionados con Cocaína/sangre , Adulto , Cromatografía Líquida de Alta Presión , Femenino , Humanos , Masculino , Espectrometría de Masas , Persona de Mediana Edad , Países BajosRESUMEN
AIMS/HYPOTHESIS: In addition to nephropathy, retinopathy and peripheral neuropathy, a microvascular complication of type 1 diabetes that may be tentatively referred to as 'diabetic encephalopathy' has gained increasing attention. There is growing evidence that lowered cognitive performance in patients with type 1 diabetes is related to chronic hyperglycaemia rather than recurrent episodes of severe hypoglycaemia, as previously speculated. The aim of our study was to use magnetic resonance imaging (MRI) to establish whether long-term hyperglycaemia, resulting in advanced retinopathy, contributes to structural changes in the brain (reduced grey matter). SUBJECTS, MATERIALS AND METHODS: We applied voxel-based morphometry on magnetic resonance images to compare grey matter density (GMD) between three groups of participants. GMD is used as a marker of cortical atrophy. We compared 13 type 1 diabetic patients with a microvascular complication (i.e. proliferative retinopathy) with 18 type 1 diabetic patients who did not have retinopathy in order to assess the effects of microvascular changes on GMD. Both patient groups were compared with 21 healthy control subjects to assess the effect of diabetes in itself. RESULTS: Patients with diabetic retinopathy showed reduced GMD in the right inferior frontal gyrus and right occipital lobe compared both with patients without retinopathy and with healthy controls (p<0.05). CONCLUSIONS/INTERPRETATION: Our data show that patients with type 1 diabetes, who, as a consequence of chronic hyperglycaemia, had developed advanced retinopathy, also showed increased focal cortical atrophy on brain MRI.