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1.
Dev Med Child Neurol ; 62(3): 346-353, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31495925

RESUMO

AIM: To determine: the effectiveness of three anticholinergic medications in reducing drooling in children with developmental disabilities (such as cerebral palsy, intellectual disability, and autism spectrum disorder), the frequency and nature of side effects, and their impact on treatment discontinuation. METHOD: After prescription of benzhexol hydrochloride, glycopyrrolate, or scopolamine patches at a tertiary saliva control clinic, all carers of 110 consecutive, eligible patients were recruited over a 5-year period. They provided data for 52 weeks, or until drug discontinuation, on compliance, drooling, adverse effects, and reasons for cessation. We evaluated and compared best drooling response, side effects, and drug cessation rates using survival analysis, and the effect of baseline variables on the discontinuation rate using proportional hazards regression. RESULTS: Among 110 participants (71 males, 39 females; mean age 8y 5mo [SD 4y 3mo], range 1y 11mo-18y 11mo), benzhexol, glycopyrrolate, and scopolamine were prescribed 81, 62, and 17 times respectively, with respective response rates of 85%, 75%, and 65%. Poor head control and poor oromotor function were predictive of poor response. Side effects frequently prompted drug cessation in males more than females (hazard ratio 1.8 [95% confidence interval 1.0-3.2], p=0.048). Glycopyrrolate had the fewest side effects. INTERPRETATION: Benzhexol, glycopyrrolate, and scopolamine reduce drooling, but improvement is offset by adverse side effects. Overall, glycopyrrolate performs best. WHAT THIS PAPER ADDS: In drooling, glycopyrrolate produced the greatest improvement with fewer side effects compared with benzhexol and scopolamine. Poor head control and poor oromotor function were associated with poor response. Medication side effects were common and often led to treatment discontinuation. Behavioural issues instigated cessation of benzhexol more often in males than females.


Assuntos
Antagonistas Colinérgicos/uso terapêutico , Deficiências do Desenvolvimento/complicações , Sialorreia/tratamento farmacológico , Adolescente , Criança , Pré-Escolar , Feminino , Glicopirrolato/uso terapêutico , Humanos , Lactente , Masculino , Escopolamina/uso terapêutico , Sialorreia/etiologia , Resultado do Tratamento , Triexifenidil/uso terapêutico
2.
Int Clin Psychopharmacol ; 34(2): 101-107, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30614850

RESUMO

Clozapine is the only evidence-based antipsychotic for treatment-resistant schizophrenia. However, it has considerable side effects, limiting its usability and reducing patients' adherence. One of the most common and distressing side effects is hypersalivation, which can be debilitating, stigmatizing and potentially dangerous through its association with aspiration pneumonia. There is a paucity of evidence guiding possible treatment strategies for hypersalivation. This study aims to examine the efficacy of hyoscine (scopolamine) for clozapine-induced hypersalivation. Fourteen inpatients diagnosed with treatment-resistant schizophrenia, treated with clozapine and suffering from hypersalivation were randomized to receive hyoscine 0.3 mg and placebo daily for 4 weeks each in a randomized, double-blind, placebo-controlled cross-over trial. The primary outcome was improvement in the Toronto Nocturnal Hypersalivation Scale. The secondary outcomes were change in the mass of the pillowcase, anxiety, depression and quality of life. Hypersalivation improved significantly with hyoscine over placebo when measured by the Toronto Nocturnal Hypersalivation Scale (odds ratio=0.21, 95% confidence interval: 0.16-0.28, P<0.001). No significant difference was observed in any of the secondary outcomes. This study showed a beneficial effect of hyoscine over placebo for clozapine-induced hypersalivation.


Assuntos
Antipsicóticos/efeitos adversos , Clozapina/efeitos adversos , Antagonistas Muscarínicos/uso terapêutico , Esquizofrenia/tratamento farmacológico , Escopolamina/uso terapêutico , Sialorreia/induzido quimicamente , Sialorreia/tratamento farmacológico , Adulto , Estudos Cross-Over , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
3.
Int J Neuropsychopharmacol ; 22(1): 10-18, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30184133

RESUMO

Background: This randomized, placebo-controlled, crossover trial examined the antidepressant efficacy of the muscarinic antagonist scopolamine in major depressive disorder subjects with more severe and refractory forms of major depressive disorder relative to previous reports. Methods: Participants included 23 medication-free major depressive disorder subjects (12 F/11 M, 20-55 years) currently experiencing a major depressive episode. Subjects had scored ≥20 on the Montgomery-Asberg Depression Rating Scale. Following a single-blind, placebo lead-in, participants were randomized to receive 2 counterbalanced blocks of 3 i.v. infusions of scopolamine (4 µg/kg) and placebo in a double-blind manner. The primary and secondary outcomes were the Montgomery-Asberg Depression Rating Scale and the Hamilton Anxiety Rating Scale, respectively. Magnetoencephalography and plasma brain-derived neurotrophic factor concentrations were obtained prior to and after each treatment phase. Results: As assessed by both the Montgomery-Asberg Depression Rating Scale and Hamilton Anxiety Rating Scale, scopolamine had no significant antidepressant or anxiolytic effects relative to placebo. No significant drug vs placebo effects were seen in magnetoencephalography gamma power or brain-derived neurotrophic factor plasma concentrations, and brain-derived neurotrophic factor changes did not correlate with change in Montgomery-Asberg Depression Rating Scale score in response to scopolamine. Conclusions: These results do not support the efficacy of scopolamine for more severe or refractory forms of depression. No pre- to post-infusion changes in plasma brain-derived neurotrophic factor were detected, and magnetoencephalography gamma power changed only in the placebo lead-in, suggesting that these biomarker measures were not affected by scopolamine in this cohort. While difficult to interpret given the lack of antidepressant response, the findings suggest that the neurobiological effects of ketamine and scopolamine are at least partly distinct.


Assuntos
Antidepressivos/uso terapêutico , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Maior/fisiopatologia , Ketamina/uso terapêutico , Escopolamina/uso terapêutico , Adulto , Antidepressivos/efeitos adversos , Biomarcadores/sangue , Encéfalo/efeitos dos fármacos , Encéfalo/fisiopatologia , Fator Neurotrófico Derivado do Encéfalo/sangue , Estudos Cross-Over , Método Duplo-Cego , Feminino , Ritmo Gama/efeitos dos fármacos , Humanos , Ketamina/efeitos adversos , Masculino , Pessoa de Meia-Idade , Escalas de Graduação Psiquiátrica , Escopolamina/efeitos adversos , Método Simples-Cego , Resultado do Tratamento , Adulto Jovem
4.
Mol Psychiatry ; 24(5): 694-709, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30120418

RESUMO

Mood disorders are highly prevalent and are the leading cause of disability worldwide. The neurobiological mechanisms underlying depression remain poorly understood, although theories regarding dysfunction within various neurotransmitter systems have been postulated. Over 50 years ago, clinical studies suggested that increases in central acetylcholine could lead to depressed mood. Evidence has continued to accumulate suggesting that the cholinergic system has a important role in mood regulation. In particular, the finding that the antimuscarinic agent, scopolamine, exerts fast-onset and sustained antidepressant effects in depressed humans has led to a renewal of interest in the cholinergic system as an important player in the neurochemistry of major depression and bipolar disorder. Here, we synthesize current knowledge regarding the modulation of mood by the central cholinergic system, drawing upon studies from human postmortem brain, neuroimaging, and drug challenge investigations, as well as animal model studies. First, we describe an illustrative series of early discoveries which suggest a role for acetylcholine in the pathophysiology of mood disorders. Then, we discuss more recent studies conducted in humans and/or animals which have identified roles for both acetylcholinergic muscarinic and nicotinic receptors in different mood states, and as targets for novel therapies.


Assuntos
Colinérgicos/farmacologia , Colinérgicos/uso terapêutico , Transtornos do Humor/tratamento farmacológico , Acetilcolina/metabolismo , Afeto/efeitos dos fármacos , Afeto/fisiologia , Animais , Antidepressivos/farmacologia , Transtorno Bipolar/tratamento farmacológico , Encéfalo/fisiopatologia , Depressão/tratamento farmacológico , Transtorno Depressivo Maior/tratamento farmacológico , Humanos , Transtornos do Humor/fisiopatologia , Antagonistas Muscarínicos/farmacologia , Escopolamina/uso terapêutico
5.
Clin Oral Investig ; 23(5): 2339-2344, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30298452

RESUMO

OBJECTIVES: To investigate whether scopolamine, an anticholinergic agent which induces hyposalivation, represents a risk factor for the occurrence of dental caries. MATERIALS AND METHODS: A retrospective cohort study was carried out among sailors treated with scopolamine for seasickness. The study population included 370 young healthy male adults (18-30 years old) who served in the Israel Navy between 2012 and 2016. Of these, 66 subjects who were chronically treated with intermittent administration of scopolamine, either by the oral or transdermal route, were assigned to the study group. Documented subject characteristics included age, socioeconomic status, level of education, body mass index, smoking history, and dental hygiene. Follow-up lasted 1 to 3.5 years. RESULTS: Two- to 3.5-year follow-up revealed a higher risk of dental caries in 15 of 16 subjects (93.8%) treated with an average of 50.9 mg scopolamine, in contrast to only 71 of 108 control subjects (65.7%) (RR = 1.43, p = 0.02 [95% CI = 1.18-1.72]). Follow-up for 1-1.5 years revealed a lower occurrence of dental caries in both the study group (11/22, 50.0%) and the control group (46/104, 44.2%). Follow-up of 1.5-2 years also revealed less dental caries, in 16/28 subjects (57.1%) in the study group and 51/92 subjects (55.4%) in the control group. The differences were not statistically significant. CONCLUSIONS: In healthy young adults, prolonged intermittent use of scopolamine was found to be a risk factor for the development of dental caries. CLINICAL SIGNIFICANCE: Dental care and hygiene should be intensified when administering hyposalivatory anticholinergic agents.


Assuntos
Antagonistas Colinérgicos/efeitos adversos , Cárie Dentária/induzido quimicamente , Escopolamina/efeitos adversos , Adolescente , Adulto , Antagonistas Colinérgicos/uso terapêutico , Humanos , Israel , Masculino , Militares , Higiene Bucal , Estudos Retrospectivos , Escopolamina/uso terapêutico , Adulto Jovem
6.
Transl Psychiatry ; 8(1): 280, 2018 12 14.
Artigo em Inglês | MEDLINE | ID: mdl-30552317

RESUMO

Growing evidence suggests that the glutamatergic modulator ketamine has rapid antidepressant effects in treatment-resistant depressed subjects. The anticholinergic agent scopolamine has also shown promise as a rapid-acting antidepressant. This study applied genome-wide markers to investigate the role of genetic variants in predicting acute antidepressant response to both agents. The ketamine-treated sample included 157 unrelated European subjects with major depressive disorder (MDD) or bipolar disorder (BD). The scopolamine-treated sample comprised 37 unrelated European subjects diagnosed with either MDD or BD who had a current Major Depressive Episode (MDE), and had failed at least two adequate treatment trials for depression. Change in Montgomery-Asberg Depression Rating Scale (MADRS) or the 17-item Hamilton Depression Rating Scale (HAM-D) scale scores at day 1 (24 h post-treatment) was considered the primary outcome. Here, we conduct pilot genome-wide association study (GWAS) analyses to identify potential markers of ketamine response and dissociative side effects. Polygenic risk score analysis of SNPs ranked by the strength of their association with ketamine response was then calculated in order to assess whether common genetic markers from the ketamine study could predict response to scopolamine. Findings require replication in larger samples in light of low power of analyses of these small samples. Neverthless, these data provide a promising illustration of our future potential to identify genetic variants underlying rapid treatment response in mood disorders and may ultimately guide individual patient treatment selection in the future.


Assuntos
Antidepressivos/uso terapêutico , Transtorno Bipolar/tratamento farmacológico , Transtorno Bipolar/genética , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Maior/genética , Ketamina/uso terapêutico , Testes Farmacogenômicos , Escopolamina/uso terapêutico , Adolescente , Adulto , Idoso , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Herança Multifatorial , Projetos Piloto , Polimorfismo de Nucleotídeo Único , Escalas de Graduação Psiquiátrica , Fatores de Risco , Resultado do Tratamento , Adulto Jovem
7.
Spec Care Dentist ; 38(6): 362-366, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30238487

RESUMO

Drooling is a condition that affects patients with difficulties in swallowing, being common in patients with mental, neurological or dysphagic deficiency. This condition is difficult to diagnose, as it is often confused with sialorrhea, and in many cases we have a hyposalivation scenario. Its diagnosis is subjective, which is why scales should be used for the standardization of the evaluation of the degree of drooling before and after the proposed treatment, as the Thomas-Stonell and Greenberg scale. It causes problems such as perioral infections, rashes, wet clothing, leading to social embarrassment, and may be a risk factor for respiratory infections caused by asymptomatic aspiration of saliva. It presents several treatments, among them the pharmacological one, that is dependent of the clinical picture of each patient that must be evaluated daily. This article refers to a series of reports of cases of children in mechanical ventilation by tracheostomy, hospitalized, with clinical diagnosis of drooling, and clinical improvement with the use of scopolamine by gastrostomy, without intercurrences during its use. The objective of this study is to show other professionals the importance of drooling management, and to expose the adopted behavior in the described cases, providing reduction of respiratory infections and improvement of the clinical and social complications resulting from drooling.


Assuntos
Antagonistas Muscarínicos/uso terapêutico , Escopolamina/uso terapêutico , Sialorreia/tratamento farmacológico , Adolescente , Criança , Feminino , Gastrostomia , Humanos , Masculino , Antagonistas Muscarínicos/administração & dosagem , Respiração Artificial , Escopolamina/administração & dosagem , Resultado do Tratamento
8.
Neuropharmacology ; 141: 214-222, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30145321

RESUMO

Scopolamine, a muscarinic cholinergic receptor antagonist, exerts fast and prolonged antidepressant effects in the clinic. In contrast, the current treatments for major depressive disorder (MDD) require long-term drug administration. On the other hand, the sole use of scopolamine might be related to the high risk of adverse effects. Therefore, it may be preferable to reduce its therapeutic dose. A new approach might include the co-administration of low-dose scopolamine with selected ligands of metabotropic glutamate (mGlu) receptors, which are known to possess antidepressant-like activity in several rodent tests and models of depression. The aim of the present study was to evaluate the potential antidepressant activity of low-dose scopolamine combined with an allosteric agonist of mGlu7 receptors, AMN082 in C57BL/6 mice. It was found that the combination of scopolamine (0.1 mg/kg) and AMN082 (1 mg/kg) exerted significant antidepressant-like effects in the tail suspension test (TST), but these effects were not observed in the mGlu7-/- mice. Furthermore, low-dose AMN082 co-administered with low-doses scopolamine (0.03 and 0.1 mg/kg) induced antidepressant-like activity in the forced swim test (FST) in mice. The tested compounds did not affect locomotor activity and did not impair spatial memory in the Morris water maze (MWM) test or motor coordination in the rotarod test. The results strongly indicated that there is an enhanced antidepressant-like action of scopolamine by AMN082. Co-administration of scopolamine with AMN082 might be a new strategy with better efficacy and a lower risk of adverse effects compared with the sole use of scopolamine or AMN082.


Assuntos
Antidepressivos/efeitos adversos , Antidepressivos/farmacologia , Compostos Benzidrílicos/administração & dosagem , Compostos Benzidrílicos/farmacologia , Receptores de Glutamato Metabotrópico/agonistas , Escopolamina/efeitos adversos , Escopolamina/farmacologia , Regulação Alostérica/efeitos dos fármacos , Animais , Antidepressivos/administração & dosagem , Antidepressivos/uso terapêutico , Compostos Benzidrílicos/efeitos adversos , Sinergismo Farmacológico , Agonistas de Aminoácidos Excitatórios/farmacologia , Resposta de Imobilidade Tônica/efeitos dos fármacos , Locomoção/efeitos dos fármacos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Camundongos Knockout , Receptores de Glutamato Metabotrópico/genética , Teste de Desempenho do Rota-Rod , Escopolamina/administração & dosagem , Escopolamina/uso terapêutico
9.
BMC Anesthesiol ; 18(1): 41, 2018 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-29661153

RESUMO

BACKGROUND: Enhanced Recovery After Surgery (ERAS) pathways have been shown in multiple surgical disciplines to improve outcomes, including reduced opioid consumption, length of stay, and post-operative nausea and vomiting (PONV). However, very few studies describe the application of ERAS to breast surgery and even fewer describe ERAS for outpatient surgery. We describe the implementation and efficacy of an Enhanced Recovery After Surgery (ERAS) pathway for total skin-sparing mastectomy with immediate reconstruction in an outpatient setting. METHODS: We implemented an evidence-based, multimodal ERAS pathway for all patients undergoing total skin-sparing mastectomy surgery with immediate reconstruction at a single 23-h stay surgery center. Highlights of the ERAS pathway included: preoperative acetaminophen, gabapentin, and scopolamine; regional anesthesia for the breast (Pectoral blocks type 1 and 2 or paravertebral block); and intraoperative dexamethasone and ondansetron. This retrospective study included all American Society of Anesthesiology (ASA) Class 1-3 patients undergoing total skin-sparing mastectomy surgery with immediate reconstruction between July 2013 and April 2016. We compared 96 patients who were in the ERAS pathway (ERAS group) to a retrospective cohort of 276 patients (Pre group). The primary outcome was total perioperative opioid consumption. Secondary outcomes were highest postoperative pain scores, incidence of PONV, and length of stay. RESULTS: Patients in the ERAS group had significantly lower total perioperative opioid consumption compared to the Pre group (mean (SD): 111.4 mg (46.0) vs. 163.8 mg (73.2) oral morphine equivalents, p < 0.001). Patients in the ERAS group also had a lower incidence of PONV (28% vs. 50%, p < 0.001). Patients in the ERAS group reported less pain in the recovery room, with a two-point decrease in highest pain score (median [interquartile range (IQR)]: 4 [2,6] in ERAS group vs. 6 [4,7] in Pre group, p < 0.001). There was no clinically significant difference in length of stay (median [IQR]: 1144 min [992, 1259] in ERAS group vs. 1188 [1058, 1344] in Pre group, p = 0.006). CONCLUSION: Implementation of an ERAS pathway for total skin-sparing mastectomy with reconstruction that incorporates regional anesthesia is feasible in a 23-h-stay hospital. Patients in the ERAS pathway had improved post-operative analgesia and reduced post-operative nausea and vomiting.


Assuntos
Analgesia/métodos , Cuidados Intraoperatórios/métodos , Mastectomia Simples , Manejo da Dor/métodos , Náusea e Vômito Pós-Operatórios/prevenção & controle , Cuidados Pré-Operatórios/métodos , Acetaminofen/uso terapêutico , Analgésicos/uso terapêutico , Analgésicos não Entorpecentes/uso terapêutico , Anestesia por Condução/métodos , Antieméticos/uso terapêutico , Dexametasona/uso terapêutico , Feminino , Gabapentina/uso terapêutico , Humanos , Tempo de Internação/estatística & dados numéricos , Pessoa de Meia-Idade , Ondansetron/uso terapêutico , Estudos Retrospectivos , Escopolamina/uso terapêutico
10.
J Clin Neurosci ; 51: 12-17, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29475576

RESUMO

Sialorrhea is a common distress associated with certain neurological disorders. The aim of this study is to compare the pharmacological agents used for treating sialorrhea by network meta-analysis. Electronic databases were searched for randomized clinical trials comparing active drugs with either placebo or other active drugs. Total drooling scores was the primary outcome measure. Inverse variance heterogeneity model was used for both direct and mixed treatment comparison analysis. Twenty one studies were included in the systematic review and 15 in the meta-analysis. Compared to placebo, benztropine, botulinum toxins A and B are associated with a significant reduction in the frequency and severity of drooling both in the overall neurological disorders as well as for children with cerebral palsy. Only botulinum toxin A and B were associated with significant therapeutic effects in Parkinson's disease. Benztropine and botulinum toxins A and B were observed to be effective in reducing sialorrhea associated with neurological disorders.


Assuntos
Doenças do Sistema Nervoso/complicações , Doenças do Sistema Nervoso/tratamento farmacológico , Sialorreia/tratamento farmacológico , Sialorreia/etiologia , Benzotropina/uso terapêutico , Toxinas Botulínicas Tipo A/uso terapêutico , Criança , Pré-Escolar , Feminino , Glicopirrolato/uso terapêutico , Humanos , Antagonistas Muscarínicos/uso terapêutico , Metanálise em Rede , Ensaios Clínicos Controlados Aleatórios como Assunto , Escopolamina/uso terapêutico
11.
Br J Oral Maxillofac Surg ; 56(3): 212-215, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29402551

RESUMO

Our aim was to investigate whether perioperative transdermal application of scopolamine could help to prevent fistulas after parotidectomy, and to this end we retrospectively studied the records of all patients (n=645) who had benign parotid tumours treated by partial parotidectomy between 2011 and 2016. We found that scopolamine led to a significant decrease in the incidence of salivary fistulas from 54/371(15%) in the group not given it to 10/274 (4%) in the group given it (p<0.0001). The "number needed to treat" was 9.17. There was a relatively low incidence of all adverse effects after scopolamine. Our results are encouraging. Thorough consideration of the contraindications and a knowledge of the potential adverse effects are crucial for its successful implementation.


Assuntos
Antagonistas Colinérgicos/uso terapêutico , Glândula Parótida/cirurgia , Fístula das Glândulas Salivares/prevenção & controle , Escopolamina/uso terapêutico , Antagonistas Colinérgicos/administração & dosagem , Feminino , Humanos , Masculino , Neoplasias Parotídeas/cirurgia , Estudos Retrospectivos , Fístula das Glândulas Salivares/etiologia , Escopolamina/administração & dosagem , Adesivo Transdérmico
12.
Neuropharmacology ; 131: 209-222, 2018 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-29274366

RESUMO

Emerging data have identified certain drugs such as scopolamine as rapidly acting antidepressants for major depressive disorder (MDD) that increase glutamate release and induce neurotrophic factors through α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) activation in rodent models. However, little research has addressed the direct mechanisms of scopolamine on AMPAR activation or vesicular glutamate transporter 1 (VGLUT1)-mediated glutamate release in the prefrontal cortex (PFC) of mice. Herein, using a chronic unpredictable stress (CUS) paradigm, acute treatment with scopolamine rapidly reversed stress-induced depression-like behaviors in mice. Our results showed that CUS-induced depression-like behaviors, accompanied by a decrease in membrane AMPAR subunit 1 (GluA1), phosphorylated GluA1 Ser845 (pGluA1 Ser845), brain-derived neurotrophic factor (BDNF) and VGF (non-acronymic) and an increase in bicaudal C homolog 1 gene (BICC1) in the PFC of mice, and these biochemical and behavioral abnormalities were ameliorated by acute scopolamine treatments. However, pharmacological block of AMPAR by NBQX infusion into the PFC significantly abolished these effects of scopolamine. In addition, knock down of VGLUT1 by lentiviral-mediated RNA interference in the PFC of mice was sufficient to induce depression-like phenotype, to decrease extracellular glutamate accumulation and to cause similar molecular changes with CUS in mice. Remarkably, VGLUT1 knockdown alleviated the rapid antidepressant-like actions of scopolamine and the effects of scopolamine on membrane GluA1-mediated BDNF, VGF and BICC1 changes. Altogether, our findings suggest that VGLUT1-mediated glutamate release and membrane GluA1 activation may play a critical role in the rapid-acting antidepressant-like effects of scopolamine in mice.


Assuntos
Antidepressivos/uso terapêutico , Antagonistas Colinérgicos/uso terapêutico , Depressão/tratamento farmacológico , Receptores de AMPA/metabolismo , Escopolamina/uso terapêutico , Proteína Vesicular 1 de Transporte de Glutamato/metabolismo , Animais , Antidepressivos/farmacologia , Antagonistas Colinérgicos/farmacologia , Depressão/etiologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Jejum/efeitos adversos , Comportamento Alimentar/efeitos dos fármacos , Preferências Alimentares/efeitos dos fármacos , Ácido Glutâmico/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Locomoção/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Sacarina/administração & dosagem , Escopolamina/farmacologia , Comportamento Social , Estresse Psicológico/complicações , Natação/psicologia , Privação de Água
13.
Mol Med Rep ; 17(1): 1625-1632, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29257227

RESUMO

Neurofilaments (NFs) including neurofilament­200 kDa (NF­H), neurofilament­165 kDa (NF­M) and neurofilament­68 kDa (NF­L) are major protein constituents of the brain, and serve important roles in the regulation of axonal transport. NF alteration is a key feature in the pathogenesis of neurological disorders involving cognitive dysfunction. In the present study, cognitive impairments were investigated, via assessments using the Morris water maze and passive avoidance tests, in mice following chronic systemic treatment with 1 mg/kg scopolamine (SCO) for 4 weeks. SCO­induced cognitive impairments were significantly observed 1 week following the SCO treatment, and these cognitive deficits were maintained for 4 weeks. However, the NF immunoreactivities and levels were altered differently according to the hippocampal subregion following SCO treatment. NF­H immunoreactivity and levels were markedly altered in all hippocampal subregions, and were significantly increased 1 week following the SCO treatment; thereafter, the immunoreactivity and levels significantly decreased with time. NF­M immunoreactivity and levels gradually decreased in the hippocampus and were significantly decreased 4 weeks following SCO treatment. NF­L immunoreactivity and levels gradually decreased in the hippocampus, and were significantly decreased 2 and 4 weeks following SCO treatment. In conclusion, the results of the present study demonstrated that chronic systemic treatment with SCO induced cognitive impairment from 1 week following SCO treatment, and NF expression was diversely altered according to the hippocampal subregion from 1 week following SCO treatment. These results suggest that SCO­induced changes in NF expression may be associated with cognitive impairment.


Assuntos
Disfunção Cognitiva/tratamento farmacológico , Hipocampo/efeitos dos fármacos , Filamentos Intermediários/patologia , Antagonistas Muscarínicos/uso terapêutico , Proteínas de Neurofilamentos/análise , Escopolamina/uso terapêutico , Animais , Disfunção Cognitiva/patologia , Hipocampo/patologia , Masculino , Camundongos , Camundongos Endogâmicos ICR
14.
J Affect Disord ; 227: 633-642, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29174736

RESUMO

BACKGROUND: Clinical reports have shown that scopolamine produces a rapid (3-4 d) and potent anti-depressive response without severe adverse effects. Animal experiments have proven that scopolamine induces mTOR pathway activation in an AMPAR dependent manner. The present study aimed to determine the role of PKA in scopolamine-induced potentiation of AMPAR, as well as in mTOR pathway activation and rapid antidepressant effects. METHODS: We utilized electrophysiological recording, Western blotting, and behavior tests to examine the effects of scopolamine, the selective M2 cholinergic receptor antagonist methoctramine, and H89, a PKA specific inhibitor on AMPAR potentiation, mTOR pathway activation, and behavioral responses in a rat depression model of learned helplessness. RESULTS: Scopolamine (1µM) rapidly increased AMPAR-fEPSP amplitudes and membrane GluA1 expression in CA1 region of hippocampal slices, both of which were abolished by H89. Moreover, scopolamine promoted AMPAR phosphorylation on GluA1 ser845, a PKA site involved in GluA1 membrane insertion. H89 disrupted both GluA1 ser845 phosphorylation and mTOR activation, as well as the antidepressant effects of scopolamine as determined via forced swim test. Additionally, methoctramine mimicked the effects of scopolamine on phosphorylation and counter-depressive action in a PKA-dependent manner. LIMITATIONS: Only one test was used to evaluate depressive behavior, and gene knock-out rats were not yet utilized to refine our hypotheses. CONCLUSION: Our findings revealed that PKA pathway is necessary for scopolamine-induced synaptic plasticity and mTOR pathway activation, and indicated that a potential M2-PKA mechanism underlies scopolamine's antidepressant effects. Such findings suggest that GluA1 ser845 phosphorylation may be a trigger event for scopolamine's actions, and that PKA may represent a novel target for the treatment of depressive symptoms.


Assuntos
Antidepressivos/farmacologia , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Depressão/metabolismo , Escopolamina/farmacologia , Serina-Treonina Quinases TOR/metabolismo , Animais , Antidepressivos/uso terapêutico , Comportamento Animal/efeitos dos fármacos , Depressão/tratamento farmacológico , Modelos Animais de Doenças , Eletrofisiologia , Hipocampo/metabolismo , Masculino , Plasticidade Neuronal/efeitos dos fármacos , Fosforilação , Ratos , Ratos Sprague-Dawley , Receptores de AMPA/metabolismo , Escopolamina/uso terapêutico , Transdução de Sinais/fisiologia
15.
Arch Dis Child ; 103(4): 371-376, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29192000

RESUMO

OBJECTIVE: Investigate whether hyoscine patch or glycopyrronium liquid is more effective and acceptable to treat drooling in children with neurodisability. DESIGN: Multicentre, single-blind, randomised controlled trial. SETTING: Recruitment through neurodisability teams; treatment by parents. PARTICIPANTS: Ninety children with neurodisability who had never received medication for drooling (55 boys, 35 girls; median age 4 years). EXCLUSION CRITERIA: medication contraindicated; in a trial that could affect drooling or management. INTERVENTION: Children were randomised to receive a hyoscine skin patch or glycopyrronium liquid. Dose was increased over 4 weeks to achieve optimum symptom control with minimal side-effects; steady dose then continued to 12 weeks. PRIMARY AND SECONDARY OUTCOMES: Primary outcome: Drooling Impact Scale (DIS) score at week-4. SECONDARY OUTCOMES: change in DIS scores over 12 weeks, Drooling Severity and Frequency Scale and Treatment Satisfaction Questionnaire for Medication; adverse events; children's perception about treatment. RESULTS: Both medications yielded clinically and statistically significant reductions in mean DIS at week-4 (25.0 (SD 22.2) for hyoscine and 26.6 (SD 16) for glycopyrronium). There was no significant difference in change in DIS scores between treatment groups. By week-12, 26/47 (55%) children starting treatment were receiving hyoscine compared with 31/38 (82%) on glycopyrronium. There was a 42% increased chance of being on treatment at week-12 for children randomised to glycopyrronium relative to hyoscine (1.42, 95% CI 1.04 to 1.95). CONCLUSIONS: Hyoscine and glycopyrronium are clinically effective in treating drooling in children with neurodisability. Hyoscine produced more problematic side effects leading to a greater chance of treatment cessation. TRIAL REGISTRATION NUMBERS: ISRCTN 75287237; EUDRACT: 2013-000863-94; Medicines and Healthcare Products Regulatory Agency: 17136/0264/001-0003.


Assuntos
Antagonistas Colinérgicos/uso terapêutico , Glicopirrolato/uso terapêutico , Doenças do Sistema Nervoso/complicações , Escopolamina/uso terapêutico , Sialorreia/tratamento farmacológico , Administração Oral , Adolescente , Criança , Pré-Escolar , Esquema de Medicação , Feminino , Seguimentos , Humanos , Masculino , Estudos Prospectivos , Sialorreia/etiologia , Método Simples-Cego , Adesivo Transdérmico , Resultado do Tratamento
18.
Mil Med ; 182(11): e1846-e1850, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-29087851

RESUMO

INTRODUCTION: Sea sickness may greatly impact the readiness of Service personnel deployed aboard naval vessels. Medications used in the treatment of sea sickness may have adverse effects, limiting their use as flight crew. Although the prevalence of sea sickness in flight crews remains unclear, individual susceptibility and high sea states are established risk factors. Literature review can guide optimized management strategies for this population. MATERIALS AND METHODS: The first author conducted a PubMed search using the terms "sea sickness" "flight crew" "scopolamine," "hyoscine," and "cinnarizine," identifying 15 articles of 350 matches, which addressed potential impact to flight performance. Analysis also included two historic reports about motion sickness maintained within the U.K. Army Aviation Centre's aeromedical archives in Middle Wallop, Hampshire. Both authors reviewed aeromedical policy for the International Civil Aviation Organization, U.K. Civil Aviation Authority, U.S. Federal Aviation Authority, the National Aeronautics Space Administration, U.S. Army, U.S. Navy, and U.S. Air Force. RESULTS: Scopolamine, also known as hyoscine, has fewer operationally relevant side effects than cinnarizine or first-generation antihistamines. Although no aeromedical authorities endorse the unsupervised use of scopolamine, many will consider authorizing its temporary use following an initial assessment on the ground. Evidence supports the concomitant use of stimulant medication for augmenting antinausea effects and countering the potential sedative effects of scopolamine. CONCLUSIONS: Scopolamine should be considered as a first-line medication for flight crews at risk of sea sickness but such use must be guided by the appropriate aeromedical authority, ideally in conjunction with a ground trial to evaluate individual response. The limited evidence to support concurrent use of stimulants must be weighed against the challenges of maintaining accountability of controlled substances in the operational environment.


Assuntos
Gerenciamento Clínico , Militares , Enjoo devido ao Movimento/tratamento farmacológico , Pilotos , Medicina Aeroespacial , Cinarizina/uso terapêutico , Antagonistas dos Receptores Histamínicos/uso terapêutico , Humanos , Enjoo devido ao Movimento/fisiopatologia , Fatores de Risco , Escopolamina/uso terapêutico
19.
J Emerg Med ; 53(4): 520-523, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28756934

RESUMO

BACKGROUND: Scopolamine is a potent anticholinergic compound used commonly for the prevention of postoperative nausea and vomiting. Scopolamine can cause atypical anticholinergic syndromes due to its prominent central antimuscarinic effects. CASE REPORT: A 47-year-old female presented to the emergency department (ED) 20 h after hospital discharge for a right-knee meniscectomy, with altered mental status (AMS) and dystonic extremity movements that began 12 h after her procedure. Her vital signs were normal and physical examination revealed mydriasis, visual hallucinations, hyperreflexia, and dystonic movements. Laboratory data, lumbar puncture, and computed tomography were unrevealing. The sustained AMS prompted a re-evaluation that revealed urinary overflow with 500 mL of retained urine discovered on ultrasound and a scopolamine patch hidden behind her ear. Her mental status improved shortly after patch removal and physostigmine, with complete resolution after 24 h with discharge diagnosis of scopolamine-induced anticholinergic toxicity. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Although therapeutically dosed scopolamine transdermal patches rarely cause complications, incomplete toxidromes can be insidiously common in polypharmacy settings. Providers should thoroughly evaluate the skin of intoxicated patients for additional adherent medications that may result in a delay in ED diagnosis and curative therapies. Our case, as well as rare case reports of therapeutic scopolamine-induced anticholinergic toxicity, demonstrates that peripheral anticholinergic effects, such as tachycardia, dry mucous membranes, and hyperpyrexia are often not present, and incremental doses of physostigmine may be required to reverse scopolamine's long duration of action. This further complicates identification of the anticholinergic toxidrome and diagnosis.


Assuntos
Síndrome Anticolinérgica/diagnóstico , Antagonistas Colinérgicos/envenenamento , Síndrome Anticolinérgica/etiologia , Antagonistas Colinérgicos/uso terapêutico , Distonia/etiologia , Serviço Hospitalar de Emergência/organização & administração , Feminino , Alucinações/etiologia , Humanos , Meniscectomia/efeitos adversos , Meniscectomia/normas , Pessoa de Meia-Idade , Midríase/etiologia , Período Pós-Operatório , Escopolamina/envenenamento , Escopolamina/uso terapêutico , Adesivo Transdérmico
20.
Sci Rep ; 7(1): 5775, 2017 07 18.
Artigo em Inglês | MEDLINE | ID: mdl-28720796

RESUMO

Monitoring effects of disease or therapeutic intervention on brain function is increasingly important for clinical trials, albeit hampered by inter-individual variability and subtle effects. Here, we apply complementary biomarker algorithms to electroencephalography (EEG) recordings to capture the brain's multi-faceted signature of disease or pharmacological intervention and use machine learning to improve classification performance. Using data from healthy subjects receiving scopolamine we developed an index of the muscarinic acetylcholine receptor antagonist (mAChR) consisting of 14 EEG biomarkers. This mAChR index yielded higher classification performance than any single EEG biomarker with cross-validated accuracy, sensitivity, specificity and precision ranging from 88-92%. The mAChR index also discriminated healthy elderly from patients with Alzheimer's disease (AD); however, an index optimized for AD pathophysiology provided a better classification. We conclude that integrating multiple EEG biomarkers can enhance the accuracy of identifying disease or drug interventions, which is essential for clinical trials.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Colinérgicos/uso terapêutico , Eletroencefalografia/efeitos dos fármacos , Aprendizado de Máquina , Idoso , Idoso de 80 Anos ou mais , Algoritmos , Doença de Alzheimer/fisiopatologia , Biomarcadores/análise , Encéfalo/efeitos dos fármacos , Encéfalo/fisiopatologia , Eletroencefalografia/métodos , Feminino , Humanos , Modelos Logísticos , Masculino , Escopolamina/uso terapêutico
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