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1.
Sci Rep ; 12(1): 15172, 2022 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-36071140

RESUMO

Opioid agonists are powerful drugs for managing pain. However, their central side effects are limiting their use and drugs with similar potency, but a lower risk profile are needed. (±)-N-(3-fluoro-1-phenethylpiperidine-4-yl)-N-phenylpropionamide (NFEPP) is a novel opioid agonist that preferentially activates opioid receptors at acidic extracellular pH. NFEPP was designed to activate peripheral opioid receptors in injured tissue, therefore precluding side effects elicited at normal pH in brain or intestinal wall. Considering the common combination of opioids and nonsteroidal anti-inflammatory drugs (NSAIDs) in multimodal analgesia, we investigated the interaction between NFEPP and a widely prescribed prototypical NSAID, diclofenac (DCF), in a rat model of unilateral hindpaw inflammation induced by complete Freund's adjuvant. We evaluated the effects of systemically applied DCF on the paw tissue pH, on the expression of inflammatory mediators in immune cells from inflamed paws and on the expression of opioid receptors in dorsal root ganglia. Additionally, we investigated the antinociceptive efficacy of NFEPP injected into the inflamed paws after DCF treatment. We found that DCF reduced inflammation-induced nociceptive responses and tissue acidosis, but did not change the mRNA expression of IL-1ß, TNF-α, IL-6, IL-4, NGF, or of mu-, delta-, or kappa-opioid receptors. The treatment with DCF moderately reduced the antinociceptive efficacy of NFEPP, suggesting a correlation between an increase in local tissue pH and the decreased antinociceptive effect of this pH-sensitive opioid agonist.


Assuntos
Acidose , Analgésicos Opioides , Piperidinas , Acidose/induzido quimicamente , Acidose/tratamento farmacológico , Analgésicos/farmacologia , Analgésicos Opioides/efeitos adversos , Animais , Concentração de Íons de Hidrogênio , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Piperidinas/farmacologia , Ratos , Receptores Opioides/metabolismo
2.
Int J Mol Sci ; 23(17)2022 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-36077329

RESUMO

Aedes aegypti mosquitoes transmit several human pathogens that cause millions of deaths worldwide, mainly in Latin America. The indiscriminate use of insecticides has resulted in the development of species resistance to some such compounds. Piperidine, a natural alkaloid isolated from Piper nigrum, has been used as a hit compound due to its larvicidal activity against Aedes aegypti. In the present study, piperidine derivatives were studied through in silico methods: pharmacophoric evaluation (PharmaGist), pharmacophoric virtual screening (Pharmit), ADME/Tox prediction (Preadmet/Derek 10.0®), docking calculations (AutoDock 4.2) and molecular dynamics (MD) simulation on GROMACS-5.1.4. MP-416 and MP-073 molecules exhibiting ΔG binding (MMPBSA -265.95 ± 1.32 kJ/mol and -124.412 ± 1.08 kJ/mol, respectively) and comparable to holo (ΔG binding = -216.21 ± 0.97) and pyriproxyfen (a well-known larvicidal, ΔG binding= -435.95 ± 2.06 kJ/mol). Considering future in vivo assays, we elaborated the theoretical synthetic route and made predictions of the synthetic accessibility (SA) (SwissADME), lipophilicity and water solubility (SwissADME) of the promising compounds identified in the present study. Our in silico results show that MP-416 and MP-073 molecules could be potent insecticides against the Aedes aegypti mosquitoes.


Assuntos
Aedes , Inseticidas , Animais , Biologia Computacional , Humanos , Inseticidas/farmacologia , Hormônios Juvenis , Larva , Piperidinas/farmacologia , Extratos Vegetais/farmacologia
3.
Molecules ; 27(15)2022 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-35956796

RESUMO

Alzheimer's disease (AD) is a chronic dysfunction of neurons in the brain leading to dementia. It is characterized by gradual mental failure, abnormal cognitive functioning, personality changes, diminished verbal fluency, and speech impairment. It is caused by neuronal injury in the cerebral cortex and hippocampal area of the brain. The number of individuals with AD is growing at a quick rate. The pathology behind AD is the progress of intraneuronal fibrillary tangles, accumulation of amyloid plaque, loss of cholinergic neurons, and decrease in choline acetyltransferase. Unfortunately, AD cannot be cured, but its progression can be delayed. Various FDA-approved inhibitors of cholinesterase enzyme such as rivastigmine, galantamine, donepezil, and NDMA receptor inhibitors (memantine), are available to manage the symptoms of AD. An exhaustive literature survey was carried out using SciFinder's reports from Alzheimer's Association, PubMed, and Clinical Trials.org. The literature was explored thoroughly to obtain information on the various available strategies to prevent AD. In the context of the present scenario, several strategies are being tried including the clinical trials for the treatment of AD. We have discussed pathophysiology, various targets, FDA-approved drugs, and various drugs in clinical trials against AD. The goal of this study is to shed light on current developments and treatment options, utilizing phytopharmaceuticals, nanomedicines, nutraceuticals, and gene therapy.


Assuntos
Doença de Alzheimer , Plantas Medicinais , Doença de Alzheimer/tratamento farmacológico , Inibidores da Colinesterase/uso terapêutico , Humanos , Indanos/farmacologia , Nanotecnologia , Piperidinas/farmacologia , Rivastigmina
4.
Cell Calcium ; 106: 102640, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-36030694

RESUMO

The transient receptor potential cation channel, subfamily M, members 6 and 7 (TRPM6 and TRPM7) are homologous membrane proteins encompassing cation channel units fused to cytosolic serine/threonine-protein kinase domains. Clinical studies and experiments with animal disease models suggested that selective inhibition of TRPM6 and TRPM7 currents might be beneficial for subjects with immune and cardiovascular disorders, tumours and other pathologies, but the suitable pharmacological toolkit remains underdeveloped. The present study identified small synthetic molecules acting specifically on the channel moieties of TRPM6 and TRPM7. Using electrophysiological analysis in conjunction with Ca2+ imaging, we show that iloperidone and ifenprodil inhibit the channel activity of recombinant TRPM6 with IC50 values of 0.73 and 3.33 µM, respectively, without an impact on the TRPM7 channel. We also found that VER155008 suppresses the TRPM7 channel with an IC50 value of 0.11 µM but does not affect TRPM6. Finally, the effects of iloperidone and VER155008 were found to be suitable for blocking native endogenous TRPM6 and TRPM7 in a collection of mouse and human cell models. Hence, the identification of iloperidone, ifenprodil, and VER155008 allows for the first time to selectively manipulate TRPM6 and TRPM7 currents.


Assuntos
Canais de Cátion TRPM , Animais , Humanos , Isoxazóis/farmacologia , Magnésio/metabolismo , Camundongos , Piperidinas/farmacologia , Proteínas Serina-Treonina Quinases , Nucleosídeos de Purina/farmacologia , Canais de Cátion TRPM/efeitos dos fármacos , Canais de Cátion TRPM/metabolismo , Canais de Potencial de Receptor Transitório/efeitos dos fármacos , Canais de Potencial de Receptor Transitório/metabolismo
5.
Neurourol Urodyn ; 41(7): 1528-1538, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35870169

RESUMO

OBJECTIVE: To examine the effects of the selective 5-HT1A receptor agonist, NLX-112, on urethral function in streptozotocin-induced diabetic rats. MATERIALS AND METHODS: Female Sprague-Dawley rats (n = 32) were divided into two groups: rats with type 1 diabetes mellitus (T1DM) and age-matched normal control rats (NC). T1DM was induced by intraperitoneal injection of streptozotocin (65 mg/kg). Isovolumetric cystometry and urethral perfusion pressure (UPP) were evaluated 10 weeks postinjection in rats (n = 9 per group). The selective 5-HT1A receptor antagonist, WAY-100635 maleate salt, was administered after NLX-112 hydrochloride dose-response curve was generated (intravenously). The remaining rats were used for immunofluorescence and Western blot assays. RESULTS: Compared to controls, type 1 diabetic rats (T1D rats) had lower maximal intravesical pressure (IP max) and UPP changes. In T1D rats, NLX-112 hydrochloride (0.003-1.0 mg/kg) induced dose-dependent decreases in UPP nadir, IP max, high-frequency oscillations (HFOs) rate; and increases in UPP change and HFOs amplitude. WAY-100635 maleate salt (0.3 mg/kg) partially or completely reversed the NLX-112-induced changes. Immunofluorescence revealed that 5-HT1A receptors were found in the L6-S1 spinal cord dorsolateral nucleus, but the expression was significantly higher in the T1D rats. Additionally, Western blot showed there were significantly more 5-HT1A receptors in the ventral L6-S1 spinal cord of T1D rats. CONCLUSIONS: Urethral dysfunction in T1D rats was improved by NLX-112. 5-HT1A receptors were upregulated in the dorsolateral nucleus of L6-S1 spinal cord in T1D rats. These findings suggest that NLX-112 may constitute a novel therapeutic strategy to treat diabetic urethral dysfunction.


Assuntos
Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 1 , Piperidinas , Piridinas , Antagonistas do Receptor 5-HT1 de Serotonina , Uretra , Animais , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Tipo 1/induzido quimicamente , Diabetes Mellitus Tipo 1/complicações , Feminino , Maleatos , Piperidinas/farmacologia , Piridinas/farmacologia , Ratos , Ratos Sprague-Dawley , Receptor 5-HT1A de Serotonina , Serotonina , Antagonistas do Receptor 5-HT1 de Serotonina/farmacologia , Estreptozocina , Uretra/fisiopatologia
6.
Parasitol Res ; 121(9): 2673-2681, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35821144

RESUMO

The use of repellents is considered an alternative against biting insects, including Lutzomyia longipalpis (Diptera: Psychodidae), the main vector of the protozoan Leishmania infantum, visceral leishmaniasis's (VL) etiologic agent in the Americas. This study aimed to evaluate the repellent efficacy of icaridin nanostructured solution applied on cotton knitting fabric against L. longipalpis. Arm-in-cage tests were performed in eight volunteers at different concentrations (5%, 10%, 25%, and 50%), using L. longipalpis (n = 30). The bioassay was performed in 1, 24, 48, 72, 96, 120, and 144 h after impregnation and one test after washing the fabrics with icaridin. The total repellency rate (%R) > 95% was used as a reference to define a minimum effective concentration (MEC). The results revealed that the insects' landing mean decreased significantly in different icaridin concentrations, compared with the control tests (p < 0.05) and the 25% and 50% concentrations compared to lower concentration (5%) (p < 0.05). The higher concentrations (25% and 50%) provided longer complete protection times (CPTs) with 120 and 144 h of protection, respectively and the %R of 100% for 72 and 96 h after impregnation, respectively. The 25% was the MEC (%R Total = 98.18%). Our results indicate, for the first time, that icaridin nanostructured solution applied on cotton knitting fabric proved to be an efficient repellent against L. longipalpis with the presence of repellent action even after washing. The concentration of 25% showed better efficiency and may become an efficient method for L. longipalpis biting control.


Assuntos
Repelentes de Insetos , Leishmania infantum , Leishmaniose Visceral , Psychodidae , Animais , Brasil , Humanos , Repelentes de Insetos/farmacologia , Insetos Vetores , Piperidinas/farmacologia
7.
Eur J Med Chem ; 240: 114612, 2022 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-35863274

RESUMO

Cholesterol 24-hydroxylase (CH24H, CYP46A1) is a cytochrome P450 family enzyme that maintains the homeostasis of brain cholesterol. Soticlestat, a potent and selective CH24H inhibitor, is in development as a therapeutic agent for Dravet syndrome and Lennox-Gastaut syndrome. Herein, we report the discovery of aryl-piperidine derivatives as potent and selective CH24H positron emission tomography (PET) tracers which can be used for dose guidance of a clinical CH24H inhibitor and as a diagnostic tool for CH24H-related pathology. Starting from compound 1 (IC50 = 16 nM, logD = 1.7), which was reported as a CH24H inhibitor with lower lipophilicity, a18F-labeling site (3-fluoroazetidine) was incorporated by structure-based drug design (SBDD) utilizing the co-crystal structure of a compound 1 analog. Subsequent optimization to adjust key parameters for PET tracers, such as potency, lipophilicity, brain penetration, and unbound plasma protein binding, enabled compounds 3f (IC50 = 8.8 nM) and 3g (IC50 = 8.7 nM) as PET imaging candidates. Selectivity of these compounds for CH24H was validated by a brain distribution study using CH24H-WT and KO mice. In non-human primate PET imaging, [18F]3f and [18F]3g showed similar regional uptake in the brain, indicating that these tracers were specific to the CH24H-expressed regions and validated the expression of CH24H in the living brain by different tracers.


Assuntos
Tomografia por Emissão de Pósitrons , Piridinas , Animais , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Colesterol 24-Hidroxilase/metabolismo , Camundongos , Piperidinas/metabolismo , Piperidinas/farmacologia , Tomografia por Emissão de Pósitrons/métodos , Piridinas/metabolismo
9.
Comput Math Methods Med ; 2022: 7083022, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35872930

RESUMO

Objective: Ischemia-reperfusion is an ongoing clinical challenge that can lead to a series of pathological changes including oxidative stress. The inhibition of soluble epoxide hydrolase inhibitor (sEH) by 1-(1-propanoylpiperidin-4-yl)-3-[4-(trifluoromethoxy)phenyl]urea (TPPU) results in an anti-inflammatory, cardioprotective, and blood vessel growth-promoting effects. Therefore, this study focused on the protective effect of TPPU on a rat pheochromocytoma (PC-12) cell oxidative stress model induced by H2O2. Methods: CCK-8 and Hoechst 33342 were used to evaluate cell apoptosis and western blot to detect the apoptotic proteins and brain-derived neurotrophic factor (BDNF) expression. Result: The incubation with 100 µM, 50 µM, and 25 µM TPPU significantly increased PC-12 cell viability. Epoxyeicosatrienoic acid (EET) pretreatment also protected PC-12 cells from oxidative stress. In addition, TPPU reduced caspase-3 and Bax expression and induced Bcl-2 expression, and EETs exerted the same effect on caspase-3 expression as TPPU. A positive relationship was found between TPPU or EET incubation and BDNF expression. Conclusion: These results revealed that TPPU reduced PC-12 cell oxidative stress injury induced by H2O2 and promoted BDNF expression.


Assuntos
Fator Neurotrófico Derivado do Encéfalo , Epóxido Hidrolases , Animais , Fator Neurotrófico Derivado do Encéfalo/genética , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Caspase 3/metabolismo , Inibidores Enzimáticos/farmacologia , Epóxido Hidrolases/genética , Epóxido Hidrolases/metabolismo , Peróxido de Hidrogênio/toxicidade , Estresse Oxidativo , Compostos de Fenilureia/farmacologia , Compostos de Fenilureia/uso terapêutico , Piperidinas/farmacologia , Piperidinas/uso terapêutico , Ratos
10.
Acta Anaesthesiol Scand ; 66(9): 1070-1076, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35908167

RESUMO

BACKGROUND: The effects of glucocorticoids may include both genomic and rapid nongenomic effects. The potential rapid analgesic effect during surgery has not previously been investigated. We aimed to explore the effect of dexamethasone on intraoperative infusion rate of remifentanil in patients undergoing total knee arthroplasty (TKA) surgery under general anaesthesia. METHODS: In this post hoc subgroup analysis, we included patients randomised in the DEX-2-TKA trial, who were operated under total intravenous anaesthesia with remifentanil and propofol. Trial medication, intravenous dexamethasone 24 mg or placebo, was administered immediately after anaesthesia onset. The primary outcome was the median weight-corrected infusion rate of remifentanil during surgery. Secondary outcomes included median weight-corrected infusion rate of propofol, median intraoperative bispectral index and time spent in the post-anaesthesia care unit. RESULTS: Eighty-seven patients were included in the analysis of the primary outcome. A significantly higher remifentanil infusion rate was observed in the dexamethasone group compared with the placebo group, p = .02. None of the secondary outcomes resulted in statistically significant differences between groups. CONCLUSION: This explorative post hoc analysis of the randomised DEX-2-TKA trail showed that patients undergoing TKA surgery under general anaesthesia and who received dexamethasone seemed to have a higher remifentanil infusion rate compared with patients who received placebo. The clinical implications of the potentially increased remifentanil infusion rate need to be validated and explored further. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05002361 (12 August 2021).


Assuntos
Artroplastia do Joelho , Propofol , Analgésicos , Anestesia Geral/métodos , Anestésicos Intravenosos/farmacologia , Dexametasona , Humanos , Piperidinas/farmacologia , Piperidinas/uso terapêutico , Remifentanil
11.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 30(3): 965-969, 2022 Jun.
Artigo em Chinês | MEDLINE | ID: mdl-35680835

RESUMO

Zanubrutinib is a highly selective second-generation BTK inhibitor developed in China and first approved by the U.S. Food and Drug Administration (FDA) as a novel antineoplastic drug. In recent years, with the birth of molecularly targeted drugs, the treatment of B-cell lymphoma have entered the era of targeted therapy, and immunotherapy has been widely accepted. Especially in some relapsed and refractory lymphomas, zanubrutinib has shown deep and sustained remissions and a favorable safety, which lays a foundation for precision therapy. In this review the clinical application and new progress for zanubrutinib in B-cell lymphoma was summarized briefly.


Assuntos
Linfoma de Células B , Pirimidinas , Humanos , Linfoma de Células B/tratamento farmacológico , Piperidinas/farmacologia , Piperidinas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Pirazóis/farmacologia , Pirazóis/uso terapêutico , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico
12.
Chem Biol Interact ; 362: 109999, 2022 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-35654123

RESUMO

Pulmonary fibrosis is a highly aggressive and lethal disease that currently lacks effective targeting therapies. Herein, we established a mouse model of pulmonary fibrosis induced by intratracheal instillation of bleomycin (BLM) in wild-type (WT) and 8-oxoguanine DNA glycosylase-1 (OGG1) knockout (Ogg1-/-) mice. TH5487, a specific small-molecule inhibitor of OGG1, was found to ameliorate BLM-induced pulmonary fibrosis in WT mice. Concomitantly, TH5487 treatment markedly suppressed the BLM-mediated alveolar epithelial-mesenchymal transition (EMT) and increase in OGG1 protein level in the lungs of WT mice. However, administration of TH5487 did not further improve this fibrotic transformation in Ogg1-/- mice. More importantly, adeno-associated virus-mediated lung-specific OGG1 overexpression accelerated alveolar EMT and the resultant fibrosis progression antagonized by TH5487 in the fibrotic lungs of WT mice, suggesting that the down-regulation of OGG1 protein level could be essential for TH5487 to exert its anti-fibrogenic function. Mechanism study in alveolar epithelial cells demonstrated that TH5487 treatment canceled TGF-ß1-mediated suppression of NEDD4-like E3 ubiquitin ligase (NEDD4L), which ubiquitinated OGG1 and targeted it for proteasomal degradation. Furthermore, TH5487-mediated suppression of alveolar EMT and the fibrotic processes was counteracted by silencing NEDD4L in TGF-ß1-induced alveolar epithelial cells. Collectively, these data underline the potential of TH5487 as an effective anti-fibrotic agent for pulmonary fibrosis.


Assuntos
Benzimidazóis , DNA Glicosilases , Piperidinas , Fibrose Pulmonar , Animais , Benzimidazóis/farmacologia , Bleomicina/farmacologia , DNA Glicosilases/antagonistas & inibidores , DNA Glicosilases/metabolismo , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Camundongos , Ubiquitina-Proteína Ligases Nedd4 , Piperidinas/farmacologia , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/tratamento farmacológico , Fibrose Pulmonar/metabolismo , Fator de Crescimento Transformador beta1/metabolismo
13.
Nat Commun ; 13(1): 3140, 2022 06 06.
Artigo em Inglês | MEDLINE | ID: mdl-35668129

RESUMO

Sarcoidosis is an idiopathic inflammatory disorder that is commonly treated with glucocorticoids. An imprecise understanding of the immunologic changes underlying sarcoidosis has limited therapeutic progress. Here in this open-label trial (NCT03910543), 10 patients with cutaneous sarcoidosis are treated with tofacitinib, a Janus kinase inhibitor. The primary outcome is the change in the cutaneous sarcoidosis activity and morphology instrument (CSAMI) activity score after 6 months of treatment. Secondary outcomes included change in internal organ involvement, molecular parameters, and safety. All patients experience improvement in their skin with 6 patients showing a complete response. Improvement in internal organ involvement is also observed. CD4+ T cell-derived IFN-γ is identified as a central cytokine mediator of macrophage activation in sarcoidosis. Additional type 1 cytokines produced by distinct cell types, including IL-6, IL-12, IL-15 and GM-CSF, also associate with pathogenesis. Suppression of the activity of these cytokines, especially IFN-γ, correlates with clinical improvement. Our results thus show that tofacitinib treatment is associated with improved sarcoidosis symptoms, and predominantly acts by inhibiting type 1 immunity.


Assuntos
Pirimidinas , Sarcoidose , Citocinas/metabolismo , Humanos , Piperidinas/farmacologia , Piperidinas/uso terapêutico , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Sarcoidose/tratamento farmacológico , Sarcoidose/patologia
14.
Int Immunopharmacol ; 108: 108888, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35729829

RESUMO

This study aimed to investigate the differential effects of remifentanil and sufentanil anesthesia on post-operative pain and recovery of cognitive functions following surgical resection of human colon cancer orthotopically transplanted in rats. Human colon cancer cells HT-29 were used to establish a rat model of orthotopically transplanted colon cancer on to the cecal wall of rats. The transplanted tumors were then surgically removed after 5 weeks, using different doses of remifentanil and sufentanil anesthesia. At 24 h after the surgery, von Frey test, hot plate test and voluntary wheel running test were used to evaluated post-operative pain in the rats. Morris water maze test and fear conditioning test were employed to assess cognitive functions. Serum and colon tissues of the rats were also subjected to ELISA to measure levels of stress response factors, while colon tissues were analyzed by RT-PCR and Western blot to measure expression of inflammation response factors and NF-κB pathway-related factors. Sufentanil showed better effect in reducing post-operative pain, while remifentanil showed better recovery of cognitive functions after surgery. In addition, remifentanil resulted in less stress and inflammation response, caused milder activation of NF-κB pathway-related factors after surgery. Remifentanil and sufentanil exhibited differential effects on post-operative pain and recovery of cognitive function. Specifically, remifentanil caused lower stress and inflammation response, associated with dampened activation of the NF-κB pathway. Our results could provide theoretical basis for adopting appropriate analgesic strategy and agents according to the characteristics of individual patients.


Assuntos
Anestesia , Neoplasias do Colo , Analgésicos Opioides/uso terapêutico , Animais , Cognição , Humanos , Inflamação , Atividade Motora , NF-kappa B , Dor Pós-Operatória/tratamento farmacológico , Piperidinas/farmacologia , Piperidinas/uso terapêutico , Ratos , Remifentanil , Sufentanil/uso terapêutico
15.
BMC Anesthesiol ; 22(1): 197, 2022 06 24.
Artigo em Inglês | MEDLINE | ID: mdl-35751029

RESUMO

BACKGROUND: Laryngeal mask airways have been widely used in clinical practice. The aim of this study was to investigate whether the remifentanil requirement for facilitation of i-gel insertion in Parkinson's disease (PD) patients undergoing deep brain stimulation (DBS) surgery was different from that in non-PD (NPD) patients undergoing intracranial surgery. STUDY DESIGN: An up-and-down sequential allocation trial. METHODS: Male patients aged between 40 and 64 years old were enrolled. The first patient in each group (PD and NPD) group received an effect-site concentration (Ce) of remifentanil (Minto pharmacokinetic model) of 4.0 ng.ml-1 during a target-controlled infusion (TCI) of 3.5 µg.ml-1 propofol (Marsh pharmacokinetic model). The next dose of remifentanil was determined by the response of the previous patient. The Ce of remifentanil required for i-gel insertion in 50% of patients (EC50) was estimated by the modified Dixon's up-and-down method and by probit analysis. RESULTS: The PD group included 24 patients and the NPD group included 23. The EC50 of remifentanil for i-gel insertion during a TCI of 3.5 µg.ml-1 propofol estimated by the modified Dixon's up-and-down method in PD patients (2.38 ± 0.65 ng.ml-1) was significantly lower than in NPD patients (3.21 ± 0.49 ng.ml-1) (P = 0.03). From the probit analysis, the EC50 and EC95 (effective Ce in 95% of patients) of remifentanil were 1.95 (95% CI 1.52-2.36) ng.ml-1 and 3.12 (95% CI 2.53-5.84) ng.ml-1 in PD patients and 2.85 (95% CI 2.26-3.41) ng.ml-1 and 4.57 (95% CI 3.72-8.54) ng.ml-1 in NPD patients, respectively. CONCLUSIONS: The remifentanil requirement for successful i-gel insertion is reduced in male PD patients undergoing DBS implantation during propofol TCI induction. Clinicians should closely monitor the remifentanil requirement in patients with PD. TRIAL REGISTRATION: Registered at http://www.chictr.org.cn ( ChiCTR1900021760 ).


Assuntos
Doença de Parkinson , Propofol , Adulto , Anestésicos Intravenosos/farmacologia , Encéfalo , Humanos , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/terapia , Piperidinas/farmacologia , Propofol/farmacocinética , Remifentanil
16.
Nat Commun ; 13(1): 3760, 2022 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-35768468

RESUMO

The KCNQ1 ion channel plays critical physiological roles in electrical excitability and K+ recycling in organs including the heart, brain, and gut. Loss of function is relatively common and can cause sudden arrhythmic death, sudden infant death, epilepsy and deafness. Here, we report cryogenic electron microscopic (cryo-EM) structures of Xenopus KCNQ1 bound to Ca2+/Calmodulin, with and without the KCNQ1 channel activator, ML277. A single binding site for ML277 was identified, localized to a pocket lined by the S4-S5 linker, S5 and S6 helices of two separate subunits. Several pocket residues are not conserved in other KCNQ isoforms, explaining specificity. MD simulations and point mutations support this binding location for ML277 in open and closed channels and reveal that prevention of inactivation is an important component of the activator effect. Our work provides direction for therapeutic intervention targeting KCNQ1 loss of function pathologies including long QT interval syndrome and seizures.


Assuntos
Canal de Potássio KCNQ1 , Síndrome do QT Longo , Piperidinas , Tiazóis , Compostos de Tosil , Animais , Canal de Potássio KCNQ1/metabolismo , Síndrome do QT Longo/tratamento farmacológico , Síndrome do QT Longo/genética , Síndrome do QT Longo/metabolismo , Mutação , Piperidinas/farmacologia , Tiazóis/farmacologia , Compostos de Tosil/farmacologia , Xenopus
17.
Eur J Med Chem ; 239: 114504, 2022 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-35724566

RESUMO

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal diseases for which chemotherapy has not been very successful yet. FK866 ((E)-N-(4-(1-benzoylpiperidin-4-yl)butyl)-3-(pyridin-3-yl)acrylamide) is a well-known NAMPT (nicotinamide phosphoribosyltransferase) inhibitor with anti-cancer activities, but it failed in phase II clinical trials. We found that FK866 shows anti-proliferative activity in three PDAC cell lines, as well as in Jurkat T-cell leukemia cells. More than 50 FK866 analogues were synthesized that introduce substituents on the phenyl ring of the piperidine benzamide group of FK866 and exchange its buta-1,4-diyl tether for 1-oxyprop-3-yl, (E)-but-2-en-1,4-diyl and 2- and 3-carbon tethers. The pyridin-3-yl moiety of FK866 was exchanged for chlorinated and fluorinated analogues and for pyrazin-2-yl and pyridazin-4-yl groups. Several compounds showed low nanomolar or sub-nanomolar cell growth inhibitory activity. Our best cell anti-proliferative compounds were the 2,4,6-trimethoxybenzamide analogue of FK866 ((E)-N-(4-(1-(2,4,6-trimethoxybenzoyl)piperidin-4-yl)butyl)-3-(pyridin-3-yl)acrylamide) (9), the 2,6-dimethoxybenzamide (8) and 2-methoxybenzamide (4), which exhibited an IC50 of 0.16 nM, 0.004 nM and 0.08 nM toward PDAC cells, respectively.


Assuntos
Acrilamidas , Antineoplásicos , Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Piperidinas , Acrilamidas/química , Acrilamidas/farmacologia , Antineoplásicos/farmacologia , Carcinoma Ductal Pancreático/tratamento farmacológico , Citocinas , Humanos , Neoplasias Pancreáticas/tratamento farmacológico , Piperidinas/química , Piperidinas/farmacologia
18.
Bone ; 162: 116456, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35688363

RESUMO

Osteoporosis is common in patients undergoing spine surgery, and carries a considerable risk of adverse outcomes. New methods to positively influence bone regeneration and spine fusion under osteoporotic conditions would be impactful. Neutralizing anti-Dickkopf-1 (DKK1) antibodies has been used as a bone anabolic agent, and recently reported by our group to aid in stem cell-mediated appendicular bone regeneration. Here, a small molecule designed as a DKK1 inhibitor, WAY-262611, was used to induce posterolateral spine fusion in an ovariectomized rat model. In vitro, pharmacological inhibition of DKK1 enhanced osteogenesis and Wnt signaling activity among rat bone marrow-derived stem/stromal cells (BMSCs). In vivo, systemic treatment with WAY-262611 promoted both chondrogenesis and osteogenesis within the spinal fusion site, and ultimately led to significant improvements in lumbar fusion as assessed by XR, µCT, histology and manual palpation assessments. No significant effect on osteoclast numbers or fusion site angiogenesis was detected, suggesting a primary direct effect on mesenchymal cells of the implantation site. Finally, evidence from human stem/stromal cells further demonstrated that pharmacologic inhibition of DKK1 promoted osteogenic differentiation in vitro. Taken together, our results suggest that targeting DKK1 promotes local bone formation and suggests potential clinical value for osteoporotic bone repair.


Assuntos
Células-Tronco Mesenquimais , Naftalenos , Osteoporose , Piperidinas , Pirimidinas , Animais , Diferenciação Celular , Feminino , Humanos , Peptídeos e Proteínas de Sinalização Intercelular , Naftalenos/farmacologia , Osteogênese , Osteoporose/tratamento farmacológico , Ovariectomia , Piperidinas/farmacologia , Pirimidinas/farmacologia , Ratos , Via de Sinalização Wnt
19.
Bioorg Med Chem Lett ; 69: 128783, 2022 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-35569686

RESUMO

In this manuscript, we report a series of benzodioxine methyl piperidine derivatives as highly potent and selective α2C antagonists by ligand design to improve the pharmacokinetics of a previous candidate molecule.


Assuntos
Dioxinas , Receptores Adrenérgicos alfa 2 , Piperidinas/farmacologia
20.
Sci Signal ; 15(736): eabg5216, 2022 05 31.
Artigo em Inglês | MEDLINE | ID: mdl-35639855

RESUMO

The Bruton's tyrosine kinase (BTK) inhibitor ibrutinib irreversibly binds BTK at Cys481, inhibiting its kinase activity and thus blocking transduction of B cell receptor (BCR) signaling. Although ibrutinib is durably effective in patients with B cell malignancies, many patients still develop ibrutinib-resistant disease. Resistance can arise because of mutations at the ibrutinib-binding site in BTK. Here, we characterized the mechanism by which two BTK mutations, C481F and C481Y, may lead to ibrutinib resistance. Both mutants lacked detectable kinase activity in in vitro kinase assays. Structural modeling suggested that bulky Phe and Tyr side chains at position 481 sterically hinder access to the ATP-binding pocket in BTK, contributing to loss of kinase activity. Nonetheless, BCR signaling still propagated through BTK C481F and C481Y mutants to downstream effectors, the phospholipase PLCγ2 and the transcription factor NF-κB. This maintenance of BCR signaling was partially achieved through the physical recruitment and kinase-independent activation of hematopoietic cell kinase (HCK). Upon BCR activation, BTK C481F or C481Y was phosphorylated by Src family kinases at Tyr551, which then bound to the SH2 domain of HCK. Modeling suggested that this binding disrupted an intramolecular autoinhibitory interaction in HCK. Activated HCK subsequently phosphorylated PLCγ2, which propagated BCR signaling and promoted clonogenic cell proliferation. This kinase-independent mechanism could inform therapeutic approaches to CLL bearing either the C481F or C481Y BTK mutants.


Assuntos
Leucemia Linfocítica Crônica de Células B , Piperidinas , Proteínas Proto-Oncogênicas c-hck , Adenina/análogos & derivados , Tirosina Quinase da Agamaglobulinemia , Resistencia a Medicamentos Antineoplásicos , Humanos , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Leucemia Linfocítica Crônica de Células B/genética , Fosfolipase C gama/genética , Piperidinas/farmacologia , Proteínas Proto-Oncogênicas c-hck/metabolismo
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