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1.
Talanta ; 251: 123767, 2023 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-35973252

RESUMO

The dynamic new psychoactive substances (NPS) market presents a great challenge for public health officers, law enforcement and analytical and forensic chemists. Wastewater analysis is a complementary tool in the ongoing surveillance of these compounds but the low doses, somewhat unknown metabolism and the different chemical classes have made analytical methods difficult to develop. The current study presents a direct injection method for the quantification of 32 NPS. These include a range of classes: phenethylamines (25C-NBOMe and 4-fluoroamphetamine), synthetic cathinones (3-methylmethcathinone, butylone, dibutylone, eutylone, methcathinone, N-ethylheptedrone, N-ethylhexedrone, N-ethylpentylone and pentylone), synthetic cannabinoid receptor agonists (5F-EMB-PICA, 5F-MDMB-PICA, 5F-MDMB-PINACA, AMB FUBINACA, MDMB-4en-PINACA, cumyl pegaclone and cumyl-5F-pegaclone), opioids (2-methyl AP-237, AP-238, brorphine, isotonitazene, metonitazene and protonitazene), benzodiazepines (clonazolam, etizolam, flualprazolam and flubromazolam), plant-based NPS (7-hydroxymitragynine and mitragynine) and dissociatives (2F-deschloroketamine, 2-oxo-PCE). The method was validated in terms of linearity, range, precision (interday and intraday), limit of detection and limit of quantification, while filtration losses and matrix effects were also examined. The method was applied to wastewater samples collected from New South Wales and Queensland over the 2021-22 New Year period, when recreational drug use was expected to increase. Three NPS were found: eutylone, clonazolam and etizolam, with eutylone having the highest mass loads.


Assuntos
Espectrometria de Massas em Tandem , Águas Residuárias , Analgésicos Opioides , Austrália , Benzodiazepinas , Agonistas de Receptores de Canabinoides , Canabinoides , Cromatografia Líquida/métodos , Imidazóis , Fenetilaminas , Piperidinas , Espectrometria de Massas em Tandem/métodos
2.
Molecules ; 27(21)2022 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-36364337

RESUMO

Monoacylglycerol lipase (MAGL) can regulate the endocannabinoid system and thus becomes a target of antidepressant drugs. In this paper, molecular docking and molecular dynamics simulations, combined with binding free energy calculation, were employed to investigate the inhibitory mechanism and binding modes of four aryl formyl piperidine derivative inhibitors with different 1-substituents to MAGL. The results showed that in the four systems, the main four regions where the enzyme bound to the inhibitor included around the head aromatic ring, the head carbonyl oxygen, the tail amide bond, and the tail benzene ring. The significant conformational changes in the more flexible lid domain of the enzyme were caused by 1-substituted group differences of inhibitors and resulted in different degrees of flipping in the tail of the inhibitor. The flipping led to a different direction of the tail amide bond and made a greater variation in its interaction with some of the charged residues in the enzyme, which further contributed to a different swing of the tail benzene ring. If the swing is large enough, it can weaken the binding strength of the head carbonyl oxygen to its nearby residues, and even the whole inhibitor with the enzyme so that the inhibition decreases.


Assuntos
Simulação de Dinâmica Molecular , Monoacilglicerol Lipases , Simulação de Acoplamento Molecular , Benzeno , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/química , Piperidinas/farmacologia , Piperidinas/química , Amidas , Oxigênio
4.
J Am Chem Soc ; 144(46): 21088-21095, 2022 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-36350999

RESUMO

The development of efficient and sustainable methods for the synthesis of nitrogen heterocycles is an important goal for the chemical industry. In particular, substituted chiral piperidines are prominent targets due to their prevalence in medicinally relevant compounds and their precursors. A potential biocatalytic approach to the synthesis of this privileged scaffold would be the asymmetric dearomatization of readily assembled activated pyridines. However, nature is yet to yield a suitable biocatalyst specifically for this reaction. Here, by combining chemical synthesis and biocatalysis, we present a general chemo-enzymatic approach for the asymmetric dearomatization of activated pyridines for the preparation of substituted piperidines with precise stereochemistry. The key step involves a stereoselective one-pot amine oxidase/ene imine reductase cascade to convert N-substituted tetrahydropyridines to stereo-defined 3- and 3,4-substituted piperidines. This chemo-enzymatic approach has proved useful for key transformations in the syntheses of antipsychotic drugs Preclamol and OSU-6162, as well as for the preparation of two important intermediates in synthetic routes of the ovarian cancer monotherapeutic Niraparib.


Assuntos
Piperidinas , Piridinas , Piridinas/química , Estereoisomerismo , Catálise , Piperidinas/química , Iminas/química
5.
Medicine (Baltimore) ; 101(45): e31625, 2022 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-36397447

RESUMO

To examine the real-world effects of the cholinesterase inhibitors (AChEI) on all-cause mortality. A nationwide, retrospective cohort study. Participants were diagnosed with incident AD in Denmark from January 1, 2000 to December 31, 2011 with follow-up until December 31, 2012. A total of 36,513 participants were included in the current study with 22,063 deaths during 132,426 person-years of follow-up. At baseline, patients not treated with AChEI (n = 28,755 [9961 males (35%)]) had a mean age ±â€…standard deviation (SD) of 80.33 ±â€…7.98 years (78.97 ±â€…8.26 for males and 81.04 ±â€…7.98 for females), as compared to 79.95 ±â€…7.67 (78.87 ±â€…7.61 for males and 80.61 ±â€…7.63 for females) in the group exposed at baseline. Patients treated with AChEI had a beneficial hazard ratio (HR) of 0.69, 95% confidence interval (CI) (0.67-0.71) for all-cause mortality as compared to patients not treated, with donepezil (HR 0.80, 95% CI [0.77-0.82]) and galantamine (HR 0.93,95% CI [0.89-0.97]) having beneficial effects on mortality rate as compared to non-treatment, whereas rivastigmine (HR 0.99, 95% CI [0.95-1.03]) was associated with a mortality rate comparable to non-treatment with AChEI. Patients were primarily exposed to donepezil (65.8%) with rivastigmine (19.8%) and galantamine (14.4%) being used less often. These findings underscore the effect of AChEI on not only reducing speed of cognitive decline but also directly prolonging life, which could result in changes in treatment recommendation for when to stop treatment.


Assuntos
Doença de Alzheimer , Galantamina , Masculino , Feminino , Humanos , Rivastigmina/uso terapêutico , Donepezila/uso terapêutico , Galantamina/uso terapêutico , Galantamina/farmacologia , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/induzido quimicamente , Indanos/uso terapêutico , Indanos/farmacologia , Estudos Retrospectivos , Fenilcarbamatos/uso terapêutico , Piperidinas/efeitos adversos
6.
Biomed Res Int ; 2022: 3305696, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36389109

RESUMO

Objective: To compare the effects of propofol-dexmedetomidine versus propofol-remifentanil for endoscopic ultrasonography (EUS). Design, Setting, and Participants. A single-center, randomized trial from August 20, 2020 to August 20, 2021, in patients undergoing EUS. Interventions. Propofol-dexmedetomidine (PD) versus propofol-remifentanil (PR). Outcome Measures. The primary outcome was the endoscopist satisfaction level. The secondary outcomes included patient satisfaction, the incidence of adverse events, induction time, and time to achieve postanesthesia discharge score (PADS) ≥9. Methods: Total of 200 patients were enrolled and randomized into PD and PR groups. A bolus dose of 0.5 µg/kg dexmedetomidine was injected intravenously for 5 min. Subsequently, a continuous infusion of 0.5 µg/kg/h for the PD group. Remifentanil was continuously infused at 1.5 µg/kg/h for the PR group. A bolus dose of 1 mg/kg propofol was administered to both groups and then continuously infused. Results: The endoscopist satisfaction level was higher in the PR group than in the PD group (P = 0.009). Patient satisfaction was not significantly different between the groups (P = 0.738). No patients required mask ventilation or tracheal intubation in both groups. All patients were relatively hemodynamically stable. The incidence of body movements during the procedure in the PD group was higher than in the PR group (P = 0.035). The induction time and time taken to achieve PADS ≥9 in the PD group were longer than in the PR group (P < 0.05). Conclusions: PR sedation can increase the satisfaction level of the endoscopist by providing faster induction time and lower body movement and that of the patient by achieving faster PADS than PD sedation. Trial registration number: http://www.chictr.org.cn (ChiCTR2000034987).


Assuntos
Dexmedetomidina , Propofol , Humanos , Propofol/farmacologia , Propofol/uso terapêutico , Remifentanil , Dexmedetomidina/farmacologia , Dexmedetomidina/uso terapêutico , Endossonografia , Estudos Prospectivos , Hipnóticos e Sedativos/uso terapêutico , Piperidinas/uso terapêutico , Método Duplo-Cego
7.
Front Immunol ; 13: 981502, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36189238

RESUMO

Behçet's syndrome (BS) is a chronic form of relapsing multisystem vasculitis, characterized by recurrent oral and genital ulcers. Intestinal BS is a special type of BS. Volcano-shaped ulcers in the ileocecum are a typical finding of intestinal BS, and punched-out ulcers can be observed in the intestine or esophagus. At present, there is no recognized radical treatment for intestinal BS. Glucocorticoids and immunosuppressants are currently the main drugs used to improve the condition. Although it has been reported that monoclonal anti-TNF antibodies may be effective for some refractory intestinal BS, further randomized, prospective trials are necessary to confirm these findings. Some patients are restricted from using biological agents because of serious allergic reactions of drugs, inconvenient drug injections or the impact of the novel coronavirus epidemic. If endoscopic remission (endoscopic healing) is not achieved for a prolonged period of time, serious complications, such as perforation, fistula formation, and gastrointestinal bleeding can be induced. Therefore, it is necessary to develop new treatment methods for controlling disease progression. We reviewed the relevant literature, combined with the analysis of the correlation between the pathogenesis of BS and the mechanism of Janus kinase (JAK) inhibition, and considered that tofacitinib (TOF) may be effective for managing refractory intestinal BS. We report for the first time that four patients with severe refractory intestinal BS were successfully treated with TOF. We hope to provide valuable information on JAK inhibitors as potential therapeutic targets for the treatment of severe refractory intestinal BS.


Assuntos
Síndrome de Behçet , Inibidores de Janus Quinases , Piperidinas , Pirimidinas , Anticorpos Monoclonais/uso terapêutico , Síndrome de Behçet/tratamento farmacológico , Fatores Biológicos/uso terapêutico , COVID-19/epidemiologia , Humanos , Imunossupressores/uso terapêutico , Intestinos/patologia , Inibidores de Janus Quinases/uso terapêutico , Janus Quinases , Piperidinas/uso terapêutico , Estudos Prospectivos , Pirimidinas/uso terapêutico , Inibidores do Fator de Necrose Tumoral , Úlcera/tratamento farmacológico
8.
Parkinsonism Relat Disord ; 104: 21-25, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36198248

RESUMO

INTRODUCTION: The peripheral autonomic nervous system may be involved years before onset of motor symptoms in some patients with Parkinson's disease (PD). Specific imaging techniques to quantify the cholinergic nervous system in peripheral organs are an unmet need. We tested the hypothesis that patients with PD display decreased [18F]FEOBV uptake in peripheral organs - a sign of parasympathetic denervation. METHODS: We included 15 PD patients and 15 age- and sex matched healthy controls for a 70 min whole-body dynamic positron emission tomography (PET) acquisition. Compartmental modelling was used for tracer kinetic analyses of adrenal gland, pancreas, myocardium, spleen, renal cortex, muscle and colon. Standard uptake values (SUV) at 60-70 min post injection were also extracted for these organs. Additionally, SUVs were also determined in the total colon, prostate, parotid and submandibular glands. RESULTS: We found no statistically significant difference of [18F]FEOBV binding parameters in any organs between patients with PD and healthy controls, although trends were observed. The pancreas SUV showed a 14% reduction in patients (P = 0.021, not statistically significant after multiple comparison correction). We observed a trend towards lower SUVs in the pancreas, colon, adrenal gland, and myocardium of PD patients with versus without probable REM sleep behavior disorder. CONCLUSION: [18F]FEOBV PET may not be a sensitive marker for parasympathetic degeneration in patients with PD.


Assuntos
Doença de Parkinson , Transtorno do Comportamento do Sono REM , Masculino , Humanos , Doença de Parkinson/diagnóstico por imagem , Piperidinas , Tomografia por Emissão de Pósitrons/métodos , Parassimpatectomia
9.
PLoS One ; 17(10): e0270291, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36201482

RESUMO

The objective of this study was to describe real-world health-related quality of life (HRQoL) and treatment satisfaction of ibrutinib-treated patients with CLL compared to a reference group. This study was completed in two parts. The first portion (Norming Study) was a US online survey conducted to serve as a reference population. The Norming Study included a total of 139 patients with CLL, excluding those treated with ibrutinib: 64 were treatment naive (Tx naive), 36 were 1st line (1L), and 38 were in or had completed ≥2 lines (2L+) patients with CLL. The second portion (CLL Ibrutinib Study) included 1L and 2L+ ibrutinib patients with CLL treated for ≥6 months in which 118 patients (1L n = 88 and 2L+ n = 30) completed the study. Respondents completed demographic and clinical information and the following HRQoL surveys: (Short Form-12v2® Health Survey [SF-12v2], Functional Assessment of Cancer Therapy-General [FACT-G], FACT-Leukemia [FACT-Leu] Functional Assessment of Chronic Illness Therapy [FACIT]-Fatigue, and Cancer Therapy Satisfaction Questionnaire [CTSQ]). Higher scores indicate better HRQoL/treatment satisfaction. Differences in effect sizes between the two samples at the group level were calculated using Hedges' g. Medium to large positive effects were seen in the CLL Ibrutinib group on several measures compared to the Reference Study groups. The FACT-G total score was 89.2±11.1 for CLL Ibrutinib Study patients compared to 75.8±22.6 CLL Norming Tx naïve patients, 61.3±21.8 in 1L, and 61.7±20.7 in 2L+. Similar trends were seen with FACT-Leu total score and FACIT-Fatigue. CLL Ibrutinib Study patients scored higher on all CTSQ domain scores compared to the CLL Norming patients treated with other CLL therapies. We found that Ibrutinib-treatment had better HRQoL and treatment satisfaction compared to patients receiving other therapies, irrespective of line of therapy.


Assuntos
Leucemia Linfocítica Crônica de Células B , Adenina/análogos & derivados , Estudos Transversais , Fadiga/tratamento farmacológico , Humanos , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Leucemia Linfocítica Crônica de Células B/epidemiologia , Satisfação do Paciente , Satisfação Pessoal , Piperidinas , Pirazóis , Pirimidinas , Qualidade de Vida
10.
Reumatol Clin (Engl Ed) ; 18(8): 493-494, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36210142

RESUMO

We describe a case of a 57-year-old white woman treated for rheumatoid arthritis (RA) with tofacitinib 10mg daily (started one year ago) and prednisolone 5mg daily. She presented to the emergency department with a tight squeezing chest pain and shortness of breath for 7h and the clinical evaluation revealed regional systolic dysfunction of the left ventricle, mimicking a myocardial infarction, in the absence of angiographic evidence of obstructive coronary artery disease or acute plaque rupture. All changes were transient and resolved completely within 4 days. The diagnosis of Takotsubo cardiomyopathy (TKM) was established. This is, as far as we know, the first report of a case of TKM in a RA patient taking tofacitinib. Although the association has not been previously described and the precise cause cannot be identified in this patient, the association with tofacitinib should be considered given the etiopathogenic rationale and the absence of any other identifiable cause.


Assuntos
Artrite Reumatoide , Cardiomiopatia de Takotsubo , Artrite Reumatoide/complicações , Artrite Reumatoide/tratamento farmacológico , Feminino , Humanos , Pessoa de Meia-Idade , Piperidinas/efeitos adversos , Prednisolona , Pirimidinas , Cardiomiopatia de Takotsubo/induzido quimicamente , Cardiomiopatia de Takotsubo/diagnóstico
11.
Front Public Health ; 10: 985834, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36211665

RESUMO

Objective: Six anaplastic lymphoma kinase-tyrosine kinase inhibitors (ALK-TKIs), including one domestic (ensartinib) and five imported ALK-TKIs (crizotinib, ceritinib, alectinib, brigatinib, and lorlatinib), have been recommended as first-line treatments for advanced ALK-positive NSCLC in China. This study sought to examine the cost-effectiveness of these six novel therapies in Chinese patients. Material and methods: We constructed a Markov model to compare the cost-effectiveness of the six ALK-TKIs as a first-line treatment for patients with advanced ALK-positive NSCLC from the perspective of the Chinese healthcare system. Transition probabilities were estimated by synthesizing data from the PROFILE 1,029 trial and a network meta-analysis. Health state utilities and costs were sourced from published literature, publicly available national databases, and local general hospitals. The robustness of model was assessed via deterministic sensitivity analyses and probabilistic sensitivity analyses. Results: Compared with crizotinib, ensartinib achieved additional 0.12 quality-adjusted life-year (QALY) with marginal costs of $3,249, resulting in an incremental cost-effectiveness ratio (ICER) of $27,553/ QALY. When compared with ceritinib and brigatinib, ensartinib achieved additional 0.06 and 0.03 QALYs with substantially reduced costs. When compared with lorlatinib and alectinib, ensartinib was associated with a lower QALY and decreased total costs; the ICERs for lorlatinib and alectinib were $934,101/ QALY and $164,888/ QALY, respectively. Conclusion: For Chinese patients with advanced ALK-positive NSCLC, ensartinib was a cost-effective option compared with crizotinib, and was a dominant alternative to ceritinib and brigatinib. Although lorlatinib and alectinib were associated with prolonged survival compared with ensartinib, they were less cost-effective than ensartinib due to the overwhelming total costs.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Aminopiridinas , Quinase do Linfoma Anaplásico/análise , Carbazóis , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Ensaios Clínicos como Assunto , Análise Custo-Benefício , Crizotinibe , Humanos , Lactamas , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Metanálise em Rede , Compostos Organofosforados , Piperazinas , Piperidinas , Inibidores de Proteínas Quinases/uso terapêutico , Pirazóis , Piridazinas , Pirimidinas , Sulfonas
12.
J Drugs Dermatol ; 21(10): 1133-1134, 2022 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-36219043

RESUMO

Dermatomyositis (DM) is an autoimmune myopathy with characteristic dermatologic features.1 Tofacitinib is an immunomodulator with proven efficacy against numerous immune-mediated disorders, including rheumatoid arthritis (RA) and psoriasis.2 Several reports have demonstrated oral tofacitinib’s ability to treat the cutaneous and extracutaneous manifestations of refractory dermatomyositis (DM).1,4,5 However, evidence for sustained improvement remains limited.2,3 The goal of this study is to investigate the long-term response of recalcitrant DM to oral and topical tofacitinib at varied dosing regimens.


Assuntos
Dermatomiosite , Dermatomiosite/diagnóstico , Dermatomiosite/tratamento farmacológico , Humanos , Fatores Imunológicos , Piperidinas/uso terapêutico , Pirimidinas , Pirróis/uso terapêutico , Estudos Retrospectivos , Resultado do Tratamento
13.
J Clin Pharm Ther ; 47(11): 1858-1866, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36196520

RESUMO

WHAT IS KNOWN AND OBJECTIVE: Significant individual differences have been observed in pain sensitivity and analgesic effect of opioids. Previous studies have shown that genetic factors contributed to analgesics requirement obviously. Therefore, we investigated the role of genetic polymorphisms in the sensitivity to the analgesic effect of remifentanil in this study. METHODS: One hundred thirty-seven patients undergoing gynaecological surgery were observed. Before procedures, we measured the basal pain threshold of each patient, including the pressure pain threshold and pressure pain tolerance threshold. Subsequently, patients received a continuous remifentanil infusion for 15 min at a constant rate of 0.2 µg/(kg min). The pain thresholds were measured again after the remifentanil infusion. Moreover, respiratory depression was estimated using oxygen saturation during infusion. DNA was extracted from peripheral venous blood and genotyped using SNaPshot technology. RESULTS AND DISCUSSION: Polymorphisms were found in genes associated with the individual variation in analgesia. Participants carrying OPRM1 rs9397685 AA, ADRB1 rs1801253 CC, and GCH1 rs8007267 CC polymorphisms showed higher sensitivity to analgesic effect induced by remifentanil, and the participants carrying the OPRD1 rs2234918 TT showed lower sensitivity to remifentanil-related respiratory depression. Moreover, individual susceptibility to remifentanil increases with age. WHAT IS NEW AND CONCLUSION: Gene variation in OPRM1 rs9397685 AA, ADRB1 rs1801253 CC, GCH1 rs8007267 CC, and OPRD1 rs2234918 TT were related to the conspicuous interindividual differences in the analgesia and respiratory depression of remifentanil, mainly by affecting the target protein receptors and relative metabolic enzymes.


Assuntos
Piperidinas , Insuficiência Respiratória , Humanos , Feminino , Remifentanil , Piperidinas/farmacologia , Analgésicos Opioides/farmacologia , Dor , China
14.
J Clin Psychopharmacol ; 42(6): 544-551, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36190440

RESUMO

PURPOSE/BACKGROUND: Pimavanserin is a selective serotonin 5-HT 2A receptor inverse agonist/antagonist being investigated in patients with negative symptoms of schizophrenia. This analysis aimed to characterize exposure-response relationships of pimavanserin in this population. METHODS/PROCEDURES: Exposure-response models were developed using data from ADVANCE. Patients with negative symptoms of schizophrenia receiving background antipsychotics were randomized to pimavanserin 20 mg (adjusted to 34 or 10 mg between weeks 2-8 based on efficacy or tolerability) or placebo for 26 weeks. Time-varying pimavanserin exposure measures were predicted for each patient using a population pharmacokinetic model and individual empiric Bayesian parameter estimates. Response measures were the Negative Symptom Assessment 16 (NSA-16, primary end point), Personal and Social Performance scale, negative symptoms component of the Clinical Global Impression of Schizophrenia-Severity Scale, and adverse events. FINDINGS/RESULTS: A higher pimavanserin exposure was associated with greater improvement in NSA-16 score. For a median area under the pimavanserin plasma concentration-time curve from time 0 to 24 hours of 1465 ng × h/mL for the 34-mg dose, the model predicted a 10.5-point reduction in NSA-16 score. This exposure-response relationship with NSA-16 scores was not influenced by covariates. Similar results were observed with Personal and Social Performance and Clinical Global Impression of Schizophrenia-Severity, but not to the extent as NSA-16. There was no significant exposure-response relationship with anxiety, headache, insomnia, or somnolence. IMPLICATIONS/CONCLUSIONS: Increasing pimavanserin plasma concentration was associated with improved NSA-16 scores (primary end point) in patients with negative symptoms of schizophrenia. No exposure-response relationship with select adverse events was observed.


Assuntos
Antipsicóticos , Esquizofrenia , Humanos , Esquizofrenia/tratamento farmacológico , Teorema de Bayes , Antipsicóticos/efeitos adversos , Piperidinas/efeitos adversos
15.
J Psychopharmacol ; 36(11): 1273-1279, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36205074

RESUMO

BACKGROUND: There is an urgent need to understand and reverse cognitive impairment. The lack of appropriate animal models combined with the limited knowledge of pathophysiological mechanisms makes the development of new cognition-enhancing drugs complex. Scopolamine is a pharmacologic agent which impairs cognition and functional imaging in a wide range of animal species, similarly to what is seen in cognitive impairment in humans. METHODS: In this study, using a functional ultrasound (fUS) neuroimaging technique, we monitored the impact of donepezil (DPZ), a potent acetylcholinesterase inhibitor and first-line treatment in patients with mild to moderate Alzheimer's disease, in a scopolamine-induced mouse model. RESULTS: We demonstrated that despite its low impact on the cerebral blood volume (CBV) signal, scopolamine injection produced an overall decrease in functional connectivity between various brain areas. In addition, we revealed that DPZ induced a strong decrease in CBV signal without causing a difference in functional connectivity. CONCLUSION: Finally, our work highlighted that DPZ counteracted the impact of scopolamine on functional connectivity changes and confirmed the interest of using pharmaco-fUS imaging on cognitive disorders, both in frequent and rare neurological disorders.


Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Animais , Camundongos , Humanos , Indanos/farmacologia , Acetilcolinesterase/uso terapêutico , Piperidinas/farmacologia , Donepezila/farmacologia , Donepezila/uso terapêutico , Disfunção Cognitiva/induzido quimicamente , Disfunção Cognitiva/tratamento farmacológico , Escopolamina/farmacologia , Doença de Alzheimer/tratamento farmacológico , Proteína FUS de Ligação a RNA
16.
J Mol Model ; 28(11): 355, 2022 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-36222928

RESUMO

Recently, the non-covalent Bruton tyrosine kinase (BTK) inhibitor fenebrutinib was presented as a therapeutic option with strong inhibitory efficacy against a single (C481S) and double (T474S/C481S) BTK variant in the treatment of Waldenström macroglobulinemia (WM). However, the molecular events surrounding its inhibition mechanism towards this variant remain unresolved. Herein, we employed in silico methods such as molecular dynamic simulation coupled with binding free energy estimations to explore the mechanistic activity of the fenebrutinib on (C481S) and (T474S/C481S) BTK variant, at a molecular level. Our investigations reveal that amino acid arginine contributed immensely to the total binding energy, this establishing the cruciality of amino acid residues, Arg132 and Arg156 in (C481S) and Arg99, Arg137, and Arg132 in (T474S/C481S) in the binding of fenebrutinib towards both BTK variants. The structural orientations of fenebrutinib within the respective hydrophobic pockets allowed favorable interactions with binding site residues, accounting for its superior binding affinity by 24.5% and relative high hydrogen bond formation towards (T474S/C481S) when compared with (C481S) BTK variants. Structurally, fenebrutinib impacted the stability, flexibility, and solvent accessible surface area of both BTK variants, characterized by various alterations observed in the bound and unbound structures, which proved enough to disrupt their biological function. Findings from this study, therefore, provide insights into the inhibitory mechanism of fenebrutinib at the atomistic level and reveal its high selectivity towards BTK variants. These insights could be key in designing and developing BTK mutants' inhibitors to treat Waldenström macroglobulinemia (WM).


Assuntos
Macroglobulinemia de Waldenstrom , Adenina , Tirosina Quinase da Agamaglobulinemia/genética , Aminoácidos/genética , Arginina/genética , Arginina/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Humanos , Mutação , Piperazinas , Piperidinas , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Pirazóis/farmacologia , Piridonas , Pirimidinas/química , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Solventes , Macroglobulinemia de Waldenstrom/tratamento farmacológico , Macroglobulinemia de Waldenstrom/genética , Macroglobulinemia de Waldenstrom/metabolismo
17.
Drug Alcohol Depend ; 240: 109646, 2022 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-36191533

RESUMO

Evidence suggests the existence of a functional interaction between endogenous cannabinoid (CB) and opioid systems. Thus, targeting CB1 receptors might be a viable approach to develop new medications for opioid use disorders (OUD). The present studies were undertaken to evaluate the effects of the neutral CB1 antagonist AM4113 and the CB1 antagonist/inverse agonist rimonabant in male rats trained to discriminate 0.032 mg/kg fentanyl from saline under a 10-response fixed-ratio (FR-10) schedule of food reinforcement. Results show that the µ-opioid agonists (fentanyl, oxycodone, and morphine) substituted fully and dose-dependently for fentanyl, whereas pretreatment with the µ-opioid antagonist naltrexone antagonized fentanyl's discriminative-stimulus effects. In interaction studies, AM4113 (0.32 or 1.0 mg/kg) was more effective in blocking fentanyl discrimination at 10-fold lower doses that did not modify rates of food-maintained responding, whereas rimonabant (1.0-10 mg/kg) produced some attenuation of fentanyl's discriminative-stimulus effects at the highest dose tested which also significantly decreased response rates. These results extend our recent work showing that AM4113 can effectively block the behavioral effects of heroin without producing rimonabant-like adverse effects. Taken together, these data suggests that CB1 neutral antagonists effectively block the behavioral effects of structurally distinct morphinan (heroin) and phenylpiperidine-based (fentanyl) opioids and may provide a novel therapeutic option for the treatment of OUD.


Assuntos
Antagonistas de Receptores de Canabinoides , Canabinoides , Ratos , Masculino , Animais , Antagonistas de Receptores de Canabinoides/farmacologia , Rimonabanto/efeitos adversos , Heroína , Antagonistas de Entorpecentes/farmacologia , Fentanila/farmacologia , Naltrexona , Analgésicos Opioides , Oxicodona , Piperidinas/farmacologia , Canabinoides/farmacologia
18.
Int J Mol Sci ; 23(19)2022 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-36232744

RESUMO

Diet-induced obesity (DIO) reduces fatty acid oxidation in skeletal muscle and decreases circulating levels of adiponectin. Endocannabinoid signaling is overactive in obesity, with some effects abated by antagonism of cannabinoid receptor 1 (CB1). This research aimed to determine if treatment with the global CB1 antagonist/inverse agonist, AM251, in high-fat diet (HFD) fed rats influenced adiponectin signaling in skeletal muscle and a "browning" of white adipose tissue (WAT) defined by UCP1 expression levels. Male Sprague Dawley rats consumed an HFD (21% fat) for 9 weeks before receiving daily intraperitoneal injections with vehicle or AM251 (3 mg/kg) for 6 weeks. mRNA expression of genes involved in metabolic functions were measured in skeletal muscle and adipose tissue, and blood was harvested for the measurement of hormones and cytokines. Muscle citrate synthase activity was also measured. AM251 treatment decreased fat pad weight (epididymal, peri-renal, brown), and plasma levels of leptin, glucagon, ghrelin, and GLP-1, and increased PAI-1 along with a range of pro-inflammatory and anti-inflammatory cytokines; however, AM251 did not alter plasma adiponectin levels, skeletal muscle citrate synthase activity or mRNA expression of the genes measured in muscle. AM251 treatment had no effect on white fat UCP1 expression levels. AM251 decreased fat pad mass, altered plasma hormone levels, but did not induce browning of WAT defined by UCP1 mRNA levels or alter gene expression in muscle treated acutely with adiponectin, demonstrating the complexity of the endocannabinoid system and metabolism. The CB1 ligand AM251 increased systemic inflammation suggesting limitations on its use in metabolic disorders.


Assuntos
Grelina , Leptina , Adiponectina/metabolismo , Tecido Adiposo/metabolismo , Animais , Citrato (si)-Sintase/metabolismo , Citocinas/metabolismo , Dieta Hiperlipídica/efeitos adversos , Endocanabinoides/metabolismo , Grelina/metabolismo , Glucagon/metabolismo , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Inflamação/metabolismo , Leptina/metabolismo , Ligantes , Masculino , Obesidade/etiologia , Obesidade/metabolismo , Piperidinas , Inibidor 1 de Ativador de Plasminogênio/metabolismo , Pirazóis , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Receptor CB1 de Canabinoide/genética , Receptor CB1 de Canabinoide/metabolismo , Receptores de Canabinoides/metabolismo , Redução de Peso
19.
Int J Mol Sci ; 23(19)2022 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-36232878

RESUMO

Starting from a screening hit, a set of analogs was synthesized based on a 4-(2-aminoethyl)piperidine core not associated previously with trace amine-associated receptor 1 (TAAR1) modulation in the literature. Several structure-activity relationship generalizations have been drawn from the observed data, some of which were corroborated by molecular modeling against the crystal structure of TAAR1. The four most active compounds (EC50 for TAAR1 agonistic activity ranging from 0.033 to 0.112 µM) were nominated for evaluation in vivo. The dopamine transporter knockout (DAT-KO) rat model of dopamine-dependent hyperlocomotion was used to evaluate compounds' efficacy in vivo. Out of four compounds, only one compound (AP163) displayed a statistically significant and dose-dependent reduction in hyperlocomotion in DAT-KO rats. As such, compound AP163 represents a viable lead for further preclinical characterization as a potential novel treatment option for disorders associated with increased dopaminergic function, such as schizophrenia.


Assuntos
Proteínas da Membrana Plasmática de Transporte de Dopamina , Transtornos Psicóticos , Animais , Dopamina , Piperidinas/farmacologia , Piperidinas/uso terapêutico , Ratos , Receptores Acoplados a Proteínas G/metabolismo
20.
Int J Mol Sci ; 23(19)2022 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-36233094

RESUMO

Hybrid nanoarchitectures such as magnetic polymeric micelles (MPMs) are among the most promising nanotechnology-enabled materials for biomedical applications combining the benefits of polymeric micelles and magnetic nanoparticles within a single bioinstructive system. MPMs are formed by the self-assembly of polymer amphiphiles above the critical micelle concentration, generating a colloidal structure with a hydrophobic core and a hydrophilic shell incorporating magnetic particles (MNPs) in one of the segments. MPMs have been investigated most prominently as contrast agents for magnetic resonance imaging (MRI), as heat generators in hyperthermia treatments, and as magnetic-susceptible nanocarriers for the delivery and release of therapeutic agents. The versatility of MPMs constitutes a powerful route to ultrasensitive, precise, and multifunctional diagnostic and therapeutic vehicles for the treatment of a wide range of pathologies. Although MPMs have been significantly explored for MRI and cancer therapy, MPMs are multipurpose functional units, widening their applicability into less expected fields of research such as bioengineering and regenerative medicine. Herein, we aim to review published reports of the last five years about MPMs concerning their structure and fabrication methods as well as their current and foreseen expectations for advanced biomedical applications.


Assuntos
Hipertermia Induzida , Micelas , Meios de Contraste , Sistemas de Liberação de Medicamentos/métodos , Mesilatos , Piperidinas , Polímeros/química , Medicina de Precisão
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