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1.
Urologiia ; (5): 35-40, 2021 Nov.
Artigo em Russo | MEDLINE | ID: mdl-34743429

RESUMO

BACKGROUND: An overactive bladder and cognitive impairment are two medical and social problems, which have an outmost importance, affecting the quality of life. Both disorders are common in the practice of a urologist, neurologist, internist, and other physicians. Parkinsons disease and multiple sclerosis are the most common neurological diseases, which often manifest by pelvic dysfunction and cognitive dysfunction. The clinician needs to understand the pathogenesis of the underlying disease and the pharmacologic properties of drugs, which can be used both in neurology and urology, as well as in other related specialties. AIM: To evaluate cognitive functions in patients with neurogenic overactive bladder treated with trospium chloride. MATERIALS AND METHODS: A total of 45 patients with neurological disease (28 with Parkinsons disease [group 1] and 17 with multiple sclerosis [group 2]) were included in the study. All patients had symptoms of an overactive bladder. Trospium chloride was administered in an individually adjusted dose for 12 weeks. Cognitive functions were assessed using the international Montreal Cognitive Assessment (MoCA) before and after the therapy. A change of total scores over time was assessed using the paired Wilcoxon test. The level of significance of <0.05 was used (confidence level of 95%). RESULTS: A significant decrease in all studied parameters of an overactive bladder in both groups was seen. The baseline evaluation of the total score on the MoCA scale prior to the start of taking trospium chloride revealed the presence of moderate cognitive impairment (21.3+/-2.9 points) in patients of the group 1. After 12 weeks of therapy, no significant change in cognitive functions was observed (21.7+/-3.1 points; p>0.05). In group 2, moderate cognitive impairment (MoCA 22.5+/-3.7 points) was found at baseline. After taking trospium chloride, no significant changes were noted (MoCA 22.9+/-4.1 points) (p>0.05). No central nervous system side effects were reported in any group. CONCLUSION: Trospium chloride is an effective drug, which does not affect cognitive functions in patients with neurogenic overactive bladder. This drug is safe to use in both Parkinsons disease and multiple sclerosis, considering the low risk of cognitive impairment in polypharmacy.


Assuntos
Nortropanos , Bexiga Urinaria Neurogênica , Bexiga Urinária Hiperativa , Benzilatos , Cognição , Humanos , Qualidade de Vida , Bexiga Urinaria Neurogênica/tratamento farmacológico , Bexiga Urinária Hiperativa/tratamento farmacológico
2.
Auton Neurosci ; 233: 102813, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33894531

RESUMO

OBJECTIVES: Parkinson's disease (PD) is the most common degenerative cause of movement disorder, and autonomic dysfunction has been recognized in this disorder. PD patients' lower urinary tract (LUT) function is not established. We investigated LUT function in PD by single-photon emission computerized tomography (SPECT) imaging of the dopamine transporter with 123I-ioflupane and clinical-urodynamic observations. PATIENTS AND METHODS: We retrospectively analyzed the cases of 30 patients diagnosed with PD based on published criteria who completed a systematized lower urinary tract symptoms (LUTS) questionnaire and a urodynamics examination irrespective of the presence of LUTS. None of the patients were taking anti-parkinsonian medication during the study. RESULTS: The questionnaire revealed that all 30 patients had LUTS: night-time urinary frequency (in 70%), urinary incontinence (40%), and daytime urinary frequency (80%). A urodynamic study revealed a mean volume at the first sensation at 92.3 ml, bladder capacity at 200.9 ml, and detrusor overactivity in 50%. Sphincter electromyography revealed neurogenic change in 13.6% of those for whom the test was performed. The average SBR showed a significant correlation with bladder capacity (Spearman's correlation coefficient p = 0.0076) and Hoehn Yahr motor stage (Spearman's correlation coefficient p = 0.012). CONCLUSION: Our findings demonstrate that the striatum is relevant to the higher control of storage in micturition function in PD.


Assuntos
Doença de Parkinson , Preparações Farmacêuticas , Humanos , Nortropanos , Doença de Parkinson/diagnóstico por imagem , Cintilografia , Estudos Retrospectivos , Bexiga Urinária/diagnóstico por imagem , Urodinâmica
3.
Molecules ; 26(6)2021 Mar 23.
Artigo em Inglês | MEDLINE | ID: mdl-33807018

RESUMO

The aminocarbonylation of various alkenyl and (hetero)aryl iodides was carried out using tropane-based amines of biological importance, such as 8-azabicyclo[3.2.1]octan-3-one (nortropinone) and 3α-hydroxy-8-azabicyclo[3.2.1]octane (nortropine) as N-nucleophile. Using iodoalkenes, the two nucleophiles were selectively converted to the corresponding amide in the presence of Pd(OAc)2/2 PPh3 catalysts. In the presence of several iodo(hetero)arenes, the application of the bidentate Xantphos was necessary to produce the target compounds selectively. The new carboxamides of varied structure, formed in palladium-catalyzed aminocarbonylation reactions, were isolated and fully characterized. In this way, a novel synthetic method has been developed for the producing of N-acylnortropane derivatives of biological importance.


Assuntos
Nortropanos/química , Nortropanos/síntese química , Paládio/química , Catálise , Estrutura Molecular
4.
N Engl J Med ; 384(8): 717-726, 2021 02 25.
Artigo em Inglês | MEDLINE | ID: mdl-33626254

RESUMO

BACKGROUND: The muscarinic receptor agonist xanomeline has antipsychotic properties and is devoid of dopamine receptor-blocking activity but causes cholinergic adverse events. Trospium is a peripherally restricted muscarinic receptor antagonist that reduces peripheral cholinergic effects of xanomeline. The efficacy and safety of combined xanomeline and trospium in patients with schizophrenia are unknown. METHODS: In this double-blind, phase 2 trial, we randomly assigned patients with schizophrenia in a 1:1 ratio to receive twice-daily xanomeline-trospium (increased to a maximum of 125 mg of xanomeline and 30 mg of trospium per dose) or placebo for 5 weeks. The primary end point was the change from baseline to week 5 in the total score on the Positive and Negative Syndrome Scale (PANSS; range, 30 to 210, with higher scores indicating more severe symptoms of schizophrenia). Secondary end points were the change in the PANSS positive symptom subscore, the score on the Clinical Global Impression-Severity (CGI-S) scale (range, 1 to 7, with higher scores indicating greater severity of illness), the change in the PANSS negative symptom subscore, the change in the PANSS Marder negative symptom subscore, and the percentage of patients with a response according to a CGI-S score of 1 or 2. RESULTS: A total of 182 patients were enrolled, with 90 assigned to receive xanomeline-trospium and 92 to receive placebo. The PANSS total score at baseline was 97.7 in the xanomeline-trospium group and 96.6 in the placebo group. The change from baseline to week 5 was -17.4 points with xanomeline-trospium and -5.9 points with placebo (least-squares mean difference, -11.6 points; 95% confidence interval, -16.1 to -7.1; P<0.001). The results for the secondary end points were significantly better in the xanomeline-trospium group than in the placebo group, with the exception of the percentage of patients with a CGI-S response. The most common adverse events in the xanomeline-trospium group were constipation, nausea, dry mouth, dyspepsia, and vomiting. The incidences of somnolence, weight gain, restlessness, and extrapyramidal symptoms were similar in the two groups. CONCLUSIONS: In a 5-week trial, xanomeline-trospium resulted in a greater decrease in the PANSS total score than placebo but was associated with cholinergic and anticholinergic adverse events. Larger and longer trials are required to determine the efficacy and safety of xanomeline-trospium in patients with schizophrenia. (Funded by Karuna Therapeutics and the Wellcome Trust; ClinicalTrials.gov number, NCT03697252.).


Assuntos
Antipsicóticos/uso terapêutico , Benzilatos/uso terapêutico , Antagonistas Colinérgicos/uso terapêutico , Agonistas Muscarínicos/uso terapêutico , Nortropanos/uso terapêutico , Piridinas/uso terapêutico , Esquizofrenia/tratamento farmacológico , Tiadiazóis/uso terapêutico , Administração Oral , Adulto , Antipsicóticos/efeitos adversos , Benzilatos/efeitos adversos , Antagonistas Colinérgicos/efeitos adversos , Método Duplo-Cego , Combinação de Medicamentos , Feminino , Humanos , Análise dos Mínimos Quadrados , Masculino , Pessoa de Meia-Idade , Agonistas Muscarínicos/efeitos adversos , Nortropanos/efeitos adversos , Piridinas/efeitos adversos , Tiadiazóis/efeitos adversos
5.
Ann Nucl Med ; 35(4): 504-513, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33630226

RESUMO

OBJECTIVE: Dopamine transporter single-photon emission computed tomography (DAT SPECT) has been widely used to diagnose Parkinson syndrome. Using the standardized uptake value (SUV) of DAT SPECT, we propose "functional dopamine transporter volume (f-DTV)" as a new quantitative index to evaluate the three-dimensional volume of functional dopamine transporters and assess its diagnostic ability in differentiating dopaminergic neurodegenerative diseases (dNDD) from non-dNDD. METHODS: Seventy-nine patients were enrolled (42 dNDD, 37 non-dNDD; 38 men; age 24-88 years). We analyzed seven quantitative indices. The specific binding ratio (SBR) was calculated using a program specialized for DAT SPECT (SBR_Bolt). The SUVmax, SUVpeak, and SUVmean were calculated using a quantification program for bone SPECT. SBR_SUV was calculated by dividing striatal SUVmean by the average of background SUVmean. The cutoff value of the active dopamine transporter level was examined using three methods (threshold of 40% of SUVmax, SUV 2, and SUV 3) to calculate the active dopamine transporter volume (ADV). The f-DTV was calculated by multiplying ADV and SUVmean. We assessed the correlations between SBR_Bolt and SBR_SUV, and compared the mean value of each index between the dNDD and non-dNDD groups. The abilities of SBR_Bolt, SBR_SUV, SUVmax, SUVpeak, SUVmean, ADV, and f-DTV in differentiating dNDD from non-dNDD were determined by the area under the receiver operating curve (AUC) generated by the receiver operating characteristics analysis. RESULTS: The SBR_Bolt and SBR_SUV highly correlated with each other (r = 0.71). The cutoff value of the active dopamine transporter level was determined as SUV 3. All seven quantitative indices showed lower values in the dNDD group than in the non-dNDD group, and the difference between the two groups was statistically significant (p < 0.05). Sensitivity, specificity, and AUC of f-DTV were slightly lower than those of SBR_Bolt (71%, 79%, and 0.81, respectively, for f-DTV, and 81%, 84%, 0.88, respectively, for SBR_Bolt). The difference in AUC between f-DTV and SBR_Bolt was not statistically significant. CONCLUSIONS: This study demonstrates the utility of f-DTV as a novel quantitative index for evaluating the three-dimensional volume of functional dopamine transporters, and that f-DTV has almost the same diagnostic ability to differentiate dNDD from non-dNDD using DAT SPECT.


Assuntos
Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Radioisótopos do Iodo/química , Nortropanos/química , Doença de Parkinson/diagnóstico por imagem , Tomografia Computadorizada de Emissão de Fóton Único/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Transporte Biológico , Diagnóstico Diferencial , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/classificação , Imagens de Fantasmas , Curva ROC , Estudos Retrospectivos
6.
Neuroimage ; 224: 117399, 2021 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-32971267

RESUMO

In the last two decades, it has been shown that anatomically-guided PET reconstruction can lead to improved bias-noise characteristics in brain PET imaging. However, despite promising results in simulations and first studies, anatomically-guided PET reconstructions are not yet available for use in routine clinical because of several reasons. In light of this, we investigate whether the improvements of anatomically-guided PET reconstruction methods can be achieved entirely in the image domain with a convolutional neural network (CNN). An entirely image-based CNN post-reconstruction approach has the advantage that no access to PET raw data is needed and, moreover, that the prediction times of trained CNNs are extremely fast on state of the art GPUs which will substantially facilitate the evaluation, fine-tuning and application of anatomically-guided PET reconstruction in real-world clinical settings. In this work, we demonstrate that anatomically-guided PET reconstruction using the asymmetric Bowsher prior can be well-approximated by a purely shift-invariant convolutional neural network in image space allowing the generation of anatomically-guided PET images in almost real-time. We show that by applying dedicated data augmentation techniques in the training phase, in which 16 [18F]FDG and 10 [18F]PE2I data sets were used, lead to a CNN that is robust against the used PET tracer, the noise level of the input PET images and the input MRI contrast. A detailed analysis of our CNN in 36 [18F]FDG, 18 [18F]PE2I, and 7 [18F]FET test data sets demonstrates that the image quality of our trained CNN is very close to the one of the target reconstructions in terms of regional mean recovery and regional structural similarity.


Assuntos
Encéfalo/diagnóstico por imagem , Processamento de Imagem Assistida por Computador/métodos , Redes Neurais de Computação , Tomografia por Emissão de Pósitrons , Fluordesoxiglucose F18 , Humanos , Imageamento por Ressonância Magnética , Nortropanos , Compostos Radiofarmacêuticos , Tirosina/análogos & derivados
7.
Clin Toxicol (Phila) ; 59(3): 235-245, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32762574

RESUMO

CONTEXT: Investigate whether 123I-ioflupane SPECT (DaT SPECT) has the potential as a marker of basal ganglia damage in acute methanol poisoning. METHODS: Prospective, single-centre, cohort study of patients with confirmed methanol poisoning was conducted. DaT SPECT was performed twice with semi-quantification using DaTQUANTTM and MRI-based volumetry was calculated. Specific binding ratios (SBR) of striatum, caudate nucleus, and putamen were correlated with laboratory parameters of outcome, volumetric data, and retinal nerve fibres layer (RNFL) thickness measurements. RESULTS: Forty-two patients (mean age 46.3 ± 4.2 years; 8 females), including 15 with MRI-detected putamen lesions (group I) and 27 patients with intact putamen (group II), underwent DaT SPECT. Volumetry was calculated in 35 of the patients assessed. SBR values for the left putamen correlated with putamen volume (r = 0.665; p < 0.001). Decreased bilateral SBR values were determined for the striatum and the putamen, but not for the nucleus caudate, in group I (p < 0.05). Significant correlation was observed between the SBR of the posterior putamen and arterial blood pH (r = 0.574; p < 0.001) and other toxicological parameters of severity of poisoning/outcome including serum lactate, glucose, and creatinine concentrations (p < 0.05). The SBR of the posterior putamen positively correlated with the global RNFL thickness (p < 0.05). ROC analysis demonstrated a significant discriminatory ability of SBR of the posterior putamen with AUC = 0.753 (95%CI 0.604-0.902; p = 0.007). The multivariate regression model demonstrated that arterial blood pH, age, and gender were the most significant factors associated with SBR of the posterior putamen. CONCLUSION: DaT SPECT demonstrates significant potential for the diagnosis of methanol-induced basal ganglia damage.


Assuntos
Doenças dos Gânglios da Base/induzido quimicamente , Gânglios da Base/efeitos dos fármacos , Metanol/envenenamento , Adulto , Gânglios da Base/diagnóstico por imagem , Doenças dos Gânglios da Base/diagnóstico por imagem , Feminino , Humanos , Radioisótopos do Iodo , Estudos Longitudinais , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Neuroimagem , Nortropanos , Estudos Prospectivos , Putamen/diagnóstico por imagem , Putamen/efeitos dos fármacos , Compostos Radiofarmacêuticos , Tomografia Computadorizada de Emissão de Fóton Único/métodos
8.
J Cereb Blood Flow Metab ; 41(6): 1291-1300, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-32955955

RESUMO

Quantification of dopamine transporter (DAT) availability with [18F]FE-PE2I PET enables the detection of presynaptic dopamine deficiency and provides a potential progression marker for Parkinson`s disease (PD). Simplified quantification is feasible, but the time window of short acquisition protocols may have a substantial impact on the reliability of striatal binding estimates. Dynamic [18F]FE-PE2I PET data of cross-sectional (33 PD patients, 24 controls), test-retest (9 patients), and longitudinal (12 patients) cohorts were used to assess the variability and reliability of specific binding ratios (SBR) measured during early peak and late pseudo-equilibrium. Receiver operating characteristics area under the curve (PD vs. controls) was high for early (0.996) and late (0.991) SBR. Early SBR provided more favourable effect size, absolute variability, and standard error of measurement than late SBR (caudate: 1.29 vs. 1.23; 6.9% vs. 9.8%; 0.09 vs. 0.20; putamen: 1.75 vs. 1.67; 7.7% vs. 14.0%; 0.08 vs. 0.17). The annual percentage change was comparable for both time windows (-7.2%-8.5%), but decline was significant only for early SBR. Whereas early and late [18F]FE-PE2I PET acquisitions have similar discriminative power to separate PD patients and controls, the early peak equilibrium acquisition can be recommended if [18F]FE-PE2I is used to measure longitudinal changes of DAT availability.


Assuntos
Neuroimagem/métodos , Nortropanos , Doença de Parkinson/diagnóstico por imagem , Tomografia por Emissão de Pósitrons/métodos , Compostos Radiofarmacêuticos , Idoso , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes
9.
Eur J Neurol ; 28(4): 1392-1395, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33175431

RESUMO

BACKGROUND AND PURPOSE: Anti-IgLON5 disease is a rare disorder characterized by a heterogeneous myriad of symptoms that may include sleep disorders, bulbar dysfunction, gait problems, movement disorders, cognitive impairment, oculomotor abnormalities, and nervous system hyperexcitability. Its physiopathology remains unknown, with a combination of both autoimmune and neurodegenerative findings. METHODS: We describe clinical, cerebrospinal fluid (CSF), and ioflupane single-photon emission computed tomography (SPECT) findings of a positive case of anti-IgLON5 disease mimicking probable progressive supranuclear palsy (PSP). We performed a literature review of previous publications reporting on anti-IgLON5 disease and ioflupane SPECT. RESULTS: We report the case of a 66-year-old male who met clinical criteria for probable PSP, in whom ioflupane SPECT showed an alteration of the left presynaptic dopaminergic pathway. However, the presence of atypical neurological symptoms for PSP led to further complementary tests, and IgLON5 antibodies were detected in CSF. According to our literature review, ioflupane SPECT findings have been previously described in only three other patients with anti-IgLON5 disease, with a reduced uptake in the striatum in two of them. CONCLUSIONS: Ioflupane SPECT abnormalities, though scarcely described, are not uncommon in anti-IgLON5 disease. They could be related to nigrostriatal dopaminergic degeneration in the context of the tauopathy component of the disease, but further case descriptions are necessary.


Assuntos
Encefalite , Nortropanos , Paralisia Supranuclear Progressiva , Idoso , Moléculas de Adesão Celular Neuronais , Humanos , Masculino , Paralisia Supranuclear Progressiva/diagnóstico por imagem , Tomografia Computadorizada de Emissão de Fóton Único
10.
Neurobiol Aging ; 97: 120-128, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33212336

RESUMO

Striatal dopamine transporter (DAT) uptake assessment through I123-Ioflupane Single-Pphoton Emission Computed Tomography (SPECT) provides valuable information about the dopaminergic denervation occurring in Parkinson's disease (PD). However, little is known about the clinical or biological relevance of extrastriatal DAT uptake in PD. Here, from the Parkinson's Progression Markers Initiative, we studied 623 participants (431 PD and 192 healthy controls) with available SPECT data. Even though striatal denervation was undoubtedly the imaging hallmark of PD, extrastriatal DAT uptake was also reduced in patients with PD. Topographically, widespread frontal but also temporal and posterior cortical regions showed lower DAT uptake in PD patients with respect to healthy controls. Importantly, a longitudinal voxelwise analysis confirmed an active one-year loss of extrastriatal DAT uptake within the PD group. Extrastriatal DAT uptake also correlated with the severity of motor symptoms, cognitive performance, and cerebrospinal fluid α-synuclein levels. In addition, we found an association between the Catechol-O-methyltransferase val158met genotype and extrastriatal DAT uptake. These results highlight the clinical and biological relevance of extrastriatal SPECT-DAT uptake in PD.


Assuntos
Corpo Estriado/diagnóstico por imagem , Corpo Estriado/metabolismo , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Doença de Parkinson/diagnóstico por imagem , Doença de Parkinson/metabolismo , Tomografia Computadorizada de Emissão de Fóton Único/métodos , Idoso , Catecol O-Metiltransferase/genética , Dopamina/metabolismo , Feminino , Genótipo , Humanos , Radioisótopos do Iodo , Masculino , Pessoa de Meia-Idade , Nortropanos , Doença de Parkinson/genética , Compostos Radiofarmacêuticos , Índice de Gravidade de Doença
11.
J Nucl Med Technol ; 49(2): 114-119, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33361183

RESUMO

The aim of the current article is to describe how to improve the quality of imaging with 123I-ioflupane SPECT and to serve as a teaching tool on this topic. The radiopharmaceutical 123I-ioflupane is used to visualize the nigrostriatal pathway. Parkinson disease and parkinsonian syndromes are movement disorders that exhibit nigrostriatal degeneration, with a decreased dopamine transporter level in the pathway and thus a decreased 123I-ioflupane distribution. Other nonparkinsonian movement disorders, such as essential tremor, will have intact dopaminergic neurons and exhibit a normal distribution of the radiopharmaceutical throughout the striata. Parkinsonian disorders are usually diagnosed clinically. However, 123I-ioflupane SPECT can be a valuable tool when the clinical features are not sufficiently clear. 123I-ioflupane SPECT image interpretation is not always straightforward. Many pitfalls, including biologic factors, technical factors, medications, and factors such as age, race, ethnicity, and body habitus, can make the interpretation challenging. The technologist and nuclear radiologist must identify the expected imaging findings to avoid the most common mistakes related to artifacts. This article reviews the usual pitfalls and artifacts of 123I-ioflupane SPECT that can compromise an accurate diagnosis and lead to misinterpretation of image findings.


Assuntos
Artefatos , Transtornos Parkinsonianos , Humanos , Radioisótopos do Iodo , Nortropanos , Transtornos Parkinsonianos/diagnóstico por imagem , Melhoria de Qualidade , Tomografia Computadorizada de Emissão de Fóton Único
12.
Int J Mol Sci ; 22(1)2020 Dec 22.
Artigo em Inglês | MEDLINE | ID: mdl-33375004

RESUMO

BACKGROUND: The muscarinic receptor antagonist trospium chloride (TCl) is used for pharmacotherapy of the overactive bladder syndrome. TCl is a hydrophilic positively charged drug. Therefore, it has low permeability through biomembranes and requires drug transporters for distribution and excretion. In humans, the organic cation transporters OCT1 and OCT2 and the multidrug and toxin extrusion MATE1 and MATE2-K carriers showed TCl transport. However, their individual role for distribution and excretion of TCl is unclear. Knockout mouse models lacking mOct1/mOct2 or mMate1 might help to clarify their role for the overall pharmacokinetics of TCl. METHOD: In preparation of such experiments, TCl transport was analyzed in HEK293 cells stably transfected with the mouse carriers mOct1, mOct2, mMate1, and mMate2, respectively. RESULTS: Mouse mOct1, mOct2, and mMate1 showed significant TCl transport with Km values of 58.7, 78.5, and 29.3 µM, respectively. In contrast, mMate2 did not transport TCl but showed MPP+ transport with Km of 60.0 µM that was inhibited by the drugs topotecan, acyclovir, and levofloxacin. CONCLUSION: TCl transport behavior as well as expression pattern were quite similar for the mouse carriers mOct1, mOct2, and mMate1 compared to their human counterparts.


Assuntos
Benzilatos/metabolismo , Proteínas da Membrana Plasmática de Transporte de Catecolaminas/metabolismo , Nortropanos/metabolismo , Proteínas de Transporte de Cátions Orgânicos/metabolismo , Transportador 2 de Cátion Orgânico/metabolismo , Animais , Benzilatos/farmacocinética , Transporte Biológico , Proteínas da Membrana Plasmática de Transporte de Catecolaminas/genética , Células HEK293 , Humanos , Cinética , Camundongos Endogâmicos C57BL , Camundongos Knockout , Antagonistas Muscarínicos/metabolismo , Antagonistas Muscarínicos/farmacocinética , Nortropanos/farmacocinética , Proteínas de Transporte de Cátions Orgânicos/genética , Transportador 2 de Cátion Orgânico/genética
13.
Toxicon ; 188: 134-141, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33091389

RESUMO

The prolonged consumption of Ipomoea carnea produces neurologic symptoms in animals and a typical histological lesion, cytoplasmic vacuolization, especially in neurons. The toxic principles of I. carnea are the alkaloids swainsonine and calystegines B1, B2, B3 and C1. In this study, primary brain cultures from newborn mouse containing mixed glial cells were utilized. These cells were exposed to Ipomoea extracts containing between 0 and 250 µM swainsonine for 48 h. Morphological changes were investigated through Phase Contrast microscopy and Rosenfeld's staining. The extract induced cytoplasmic vacuolization in astrocytes and microglia in a dose dependent manner, being more evident when cultures were exposed to 250 µM of swainsonine. In addition, acridine orange staining evidenced an increase in the number of lysosomes in both microglia and astrocytes cells. Consistent with this, scanning electron microscopy also showed that both types of cells presented morphological characteristics of cell activation. Ultrastructurally, cells showed vacuoles filled with amorphous material and surrounded by a single membrane and also multilayer membranes. Taken together, these findings suggest that swainsonine along with calystegines, are probably responsible for the activation of glial cells due to a possible lysosomal dysfunction and therefore intracellular storage. Our results demonstrate that this in vitro glial cell model is a very good alternative to in vivo studies that require several weeks of animal intoxication to observe similar neurotoxic effects.


Assuntos
Ipomoea , Extratos Vegetais/toxicidade , Alcaloides , Animais , Cabras , Lisossomos , Camundongos , Microscopia Eletrônica de Varredura , Neuroglia , Nortropanos , Alcaloides de Solanáceas , Swainsonina , Tropanos
14.
Sci Rep ; 10(1): 15761, 2020 09 25.
Artigo em Inglês | MEDLINE | ID: mdl-32978422

RESUMO

Motor symptoms of Parkinson's disease (PD) occur unilaterally and progress with asymmetry, while progressive supranuclear palsy (PSP) and multiple system atrophy of the parkinsonism subtype (MSA-P) lack this tendency. We assessed the laterality of specific binding ratios (SBRs) on dopamine transporter single-photon emission computed tomography (DAT-SPECT) for the differential diagnosis of these diseases in 311 PD, 33 PSP, 20 MSA-P, and 137 control patients. The average SBR in PD was higher than that in PSP (P = 0.035). Compared with Hoehn-Yahr (HY) stages, the average SBR in PD with HY stage I was only higher than that in PSP (P < 0.001). SBR laterality in PD with HY stage I was significantly higher than that in PSP (P = 0.001). This difference was not observed in PD with HY stage II. The average and laterality of SBRs in MSA-P were similar to those in PD and PSP. The asymmetry indices were similar among PD, PSP, and MSA-P. These data suggest that PSP shows a pattern of SBRs different from that in PD, attributed to HY stage I in PD. The limited usefulness of DAT-SPECT may be explained by the low discrimination between PD with bilateral motor symptoms and PSP.


Assuntos
Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Transtornos Parkinsonianos/diagnóstico por imagem , Transtornos Parkinsonianos/metabolismo , Tomografia Computadorizada de Emissão de Fóton Único , Idoso , Idoso de 80 Anos ou mais , Diagnóstico Diferencial , Feminino , Humanos , Masculino , Nortropanos/metabolismo , Ligação Proteica , Especificidade por Substrato
15.
Mol Nutr Food Res ; 64(20): e2000515, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32918337

RESUMO

SCOPE: Metabolites derived from specific foods present in urine samples can provide objective biomarkers of food intake (BFIs). This study investigated the possibility that calystegines (a class of iminosugars) may provide BIFs for potato (Solanum tuberosum L.) product exposure. METHODS AND RESULTS: Calystegine content is examined in published data covering a wide range of potato cultivars. Rapid methods are developed for the quantification of calystegines in cooked potato products and human urine using triple quadrupole mass spectrometry. The potential of calystegines as BFIs for potato consumption is assessed in a controlled food intervention study in the United Kingdom and validated in an epidemiological study in Portugal. Calystegine concentrations are reproducibly above the quantification limit in first morning void urines the day after potato consumption, showing a good dose-response relationship, particularly for calystegine A3 . The design of the controlled intervention mimicks exposure to a typical UK diet and showed that neither differences in preparation/cooking method or influence of other foods in the diet has significant impact on biomarker performance. Calystegine biomarkers also perform well in the independent validation study. CONCLUSION: It is concluded that calystegines have many of the characteristics needed to be considered as specific BFIs for potato product intake.


Assuntos
Biomarcadores/urina , Solanum tuberosum/química , Tropanos/urina , Adulto , Cromatografia Líquida/métodos , Feminino , Análise de Alimentos/métodos , Humanos , Isomerismo , Masculino , Pessoa de Meia-Idade , Nortropanos/urina , Inquéritos Nutricionais , Sensibilidade e Especificidade , Alcaloides de Solanáceas/urina , Solanum tuberosum/genética , Espectrometria de Massas em Tandem/métodos , Tropanos/análise , Adulto Jovem
16.
Clin Interv Aging ; 15: 1493-1503, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32921995

RESUMO

Overactive bladder syndrome (OAB) is defined as urinary urgency, usually accompanied by frequency and nocturia, with or without urgency incontinence, in the absence of urinary tract infection or other obvious pathology. The mainstay of treatment of OAB is anticholinergic/antimuscarinic medication. These drugs block muscarinic receptors throughout the body, not only the bladder, including in the brain, which may lead to cognitive side effects. Anticholinergic load or burden is the cumulative effect of taking drugs that are capable of producing anticholinergic adverse effects. The elderly are more susceptible to these effects, especially as there is increased permeability of the blood brain barrier. The anticholinergic drugs for OAB are able to enter the central nervous system and lead to central side effects. There is increasing evidence that a high anticholinergic load is linked to the development of cognitive impairment and even dementia. Some studies have found an increased risk of mortality. In view of this, care is needed when treating OAB in the elderly. Trospium chloride is a quaternary amine anticholinergic, which has a molecular structure, which theoretically means it is less likely to cross the blood brain barrier and exert central side effects. Alternatively, mirabegron can be used, which is a beta-3 adrenoceptor agonist, which does not add to the anticholinergic load or exert central nervous system side effects. Conservative therapy can be used as an alternative to pharmacological treatment in the form of behavioral modification, fluid management and bladder retraining. Neuromodulation or the use of botox can also be alternatives, but success may be less in the older adult and will require increased hospital attendances.


Assuntos
Antagonistas Colinérgicos/efeitos adversos , Disfunção Cognitiva/induzido quimicamente , Bexiga Urinária Hiperativa/tratamento farmacológico , Acetanilidas/efeitos adversos , Idoso , Terapia Comportamental , Benzilatos/efeitos adversos , Barreira Hematoencefálica/efeitos dos fármacos , Disfunção Cognitiva/prevenção & controle , Feminino , Humanos , Antagonistas Muscarínicos/uso terapêutico , Nortropanos/efeitos adversos , Tiazóis/efeitos adversos , Bexiga Urinária Hiperativa/psicologia
17.
Sci Rep ; 10(1): 14181, 2020 08 25.
Artigo em Inglês | MEDLINE | ID: mdl-32843670

RESUMO

Glial fibrillary acidic protein expressing (GFAP+) glia modulate nociceptive neuronal activity in both the peripheral nervous system (PNS) and the central nervous system (CNS). Resident GFAP+ glia in dorsal root ganglia (DRG) known as satellite glial cells (SGCs) potentiate neuronal activity by releasing pro-inflammatory cytokines and neuroactive compounds. In this study, we tested the hypothesis that SGC Gq-coupled receptor (Gq-GPCR) signaling modulates pain sensitivity in vivo using Gfap-hM3Dq mice. Complete Freund's adjuvant (CFA) was used to induce inflammatory pain, and mechanical sensitivity and thermal sensitivity were used to assess the neuromodulatory effect of glial Gq-GPCR activation in awake mice. Pharmacogenetic activation of Gq-GPCR signaling in sensory SGCs decreased heat-induced nociceptive responses and reversed inflammation-induced mechanical allodynia via peripheral adenosine A1 receptor activation. These data reveal a previously unexplored role of sensory SGCs in decreasing afferent excitability. The identified molecular mechanism underlying the analgesic role of SGCs offers new approaches for reversing peripheral nociceptive sensitization.


Assuntos
Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP/fisiologia , Hiperalgesia/prevenção & controle , Inflamação/fisiopatologia , Neuroglia/enzimologia , Nociceptividade/fisiologia , Receptor A1 de Adenosina/fisiologia , Receptor Muscarínico M3/fisiologia , Animais , Benzilatos/farmacologia , Clozapina/análogos & derivados , Clozapina/farmacologia , Adjuvante de Freund/toxicidade , Genes Sintéticos , Temperatura Alta , Hiperalgesia/fisiopatologia , Inflamação/induzido quimicamente , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Agonistas Muscarínicos/farmacologia , Neuroglia/fisiologia , Nortropanos/farmacologia , Regiões Promotoras Genéticas , Agonistas do Receptor Purinérgico P1/farmacologia , Antagonistas de Receptores Purinérgicos P1/farmacologia , Receptor A1 de Adenosina/efeitos dos fármacos , Receptor Muscarínico M3/efeitos dos fármacos , Receptor Muscarínico M3/genética , Receptores Acoplados a Proteínas G , Proteínas Recombinantes de Fusão/efeitos dos fármacos , Proteínas Recombinantes de Fusão/metabolismo , Teofilina/análogos & derivados , Teofilina/farmacologia , Tato , Xantinas/farmacologia
18.
Nucl Med Commun ; 41(11): 1117-1127, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32826621

RESUMO

OBJECTIVE: The aim of our study was to ascertain relationships between DaTSCAN, olfactory loss, behavioural and subjective measurements of impulsivity and emotional responsiveness in patients with clinically suspected Parkinsonian syndrome (PS). METHODS: A prospective study of 20 drug-naive patients with parkinsonism, underwent the University of Pennsylvania Smell Identification Test, impulsivity measurements and mood-state-questionnaires before visual and semi-quantitative DaTQUANT analyses. There were two subgroups: nine patients with scans without evidence of dopaminergic deficit (SWEDD - controls) and 11 patients with PS. RESULTS: The PS group reported lower non-planning impulsivity than the SWEDD group (P = 0.039). A positive correlation was found between the non-planning impulsivity ratings and right anterior putamen/background (bck) ratio in PS group (r = 0.598, P = 0.068). Higher ratings of anger (r = 0.575, P = 0.016), fatigue (r = 0.746, P = 0.001), confusion (r = 0.561, P = 0.019) and depression were positively correlated with putamen/caudate ratios (R > L) on DaTSCAN. Higher self-reported arousal was associated with lower right putamen/caudate ratio (P = -0.581, P = 0.014). Only fatigue was positively correlated with putamen/bck (r = 0.564, P = 0.018). The degree of smell deficit correlated negatively with performance on reflection impulsivity tasks (r = -0.470, P = 0.049). CONCLUSION: DaTSCAN appearances correlated with emotional dysfunction and self-reported impulsivity in patients with PS. Olfactory impairment was associated with increased reflection impulsivity and the age of patients. Higher DaTSCAN putamen/caudate ratios were associated with higher emotional responsiveness and higher non-planning impulsivity in PS patients. These preliminary findings may be relevant in clinical practice in differentiating PS from SWEDD and identifying susceptibility to impulse control disorder although larger studies are warranted.


Assuntos
Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Emoções , Comportamento Impulsivo , Imagem Molecular , Nortropanos , Percepção Olfatória , Transtornos Parkinsonianos/diagnóstico por imagem , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Transtornos Parkinsonianos/metabolismo , Transtornos Parkinsonianos/fisiopatologia , Transtornos Parkinsonianos/psicologia
20.
Ann Pharm Fr ; 78(5): 408-414, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32681902

RESUMO

Two simple, accurate, sensitive and precise conductometric methods were developed for determination of trospium chloride in pure form and in pharmaceutical formulations. It is based on using two precipitating reagents; Phosphomolybdic acid (PMA) and Silver nitrate (AgNO3). The mean recovery for Silver nitrate is in the range (98-100.95%) and for Phosphomolybdic acid in the range (98-101.69%). A molar ratio has been determined conductometrically for the two reagents, revealed (1/1) for (drug/reagent). The proposed methods were validated and successfully applied for the determination of the studied drug in pure form and in its pharmaceutical preparation. The results of the proposed methods were compared to the results of reported method with no significant difference between them.


Assuntos
Benzilatos/análise , Molibdênio/química , Nortropanos/análise , Ácidos Fosfóricos/química , Nitrato de Prata/química , Condutometria , Indicadores e Reagentes , Reprodutibilidade dos Testes , Comprimidos/análise
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