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3.
Sci Rep ; 14(1): 7896, 2024 04 03.
Artigo em Inglês | MEDLINE | ID: mdl-38570571

RESUMO

Ornamental foliage plants that have a dense appearance are highly valued. One way to achieve this is by using plant growth regulators as a tool for plant growth management. In a greenhouse with a mist irrigation system, a study was conducted on dwarf schefflera, an ornamental foliage plant, which was exposed to foliar application of gibberellic acid and benzyladenine hormones. The hormones were sprayed on dwarf schefflera leaves at 0, 100, and 200 mg/l concentrations, at 15-day intervals in three stages. The experiment was conducted as a factorial based on a completely randomized design, with four replicates. The combination of gibberellic acid and benzyladenine at 200 mg/l concentration had a significant effect on leaf number, leaf area, and plant height. The treatment also resulted in the highest content of photosynthetic pigments. Furthermore, the highest soluble carbohydrate to reducing sugars ratio was observed in treatments of 100 and 200 mg/l benzyladenine, and 200 mg/l gibberellic acid + benzyladenine. Stepwise regression analysis showed that root volume was the first variable to enter the model, explaining 44% of variations. The next variable was root fresh weight, and the two-variable model explained 63% of variations in leaf number. The greatest positive effect on leaf number was related to root fresh weight (0.43), which had a positive correlation with leaf number (0.47). The results showed that 200 mg/l concentration of gibberellic acid and benzyladenine significantly improved morphological growth, chlorophyll and carotenoid synthesis, and reducing sugar and soluble carbohydrate contents in dwarf schefflera.


Assuntos
Benzilaminas , Giberelinas , Giberelinas/farmacologia , Benzilaminas/farmacologia , Plantas , Carboidratos/análise , Hormônios/farmacologia , Folhas de Planta/química
4.
Neurologia (Engl Ed) ; 39(4): 340-344, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38616061

RESUMO

BACKGROUND AND PURPOSE: The aim of this study was to assess the possible pharmacological interactions between safinamide and antidepressants, and in particular the appearance of serotonin syndrome with data from real life. METHODS: We conducted a retrospective observational study of patients with Parkinson's disease from our Movement Disorders Unit, who were under treatment with any antidepressant drug and safinamide. Specifically, symptoms suggestive of serotonin syndrome were screened for. Also, we collected time of simultaneous use, doses of levodopa and other antiparkinsonian drugs. RESULTS: Clinical records were reviewed for the study period of September 2018 to September 2019. Seventy-eight PD patients who were treated with safinamide of which 25 (32.05%) had a concomitant treatment with an antidepressant drug, being sertraline and escitalopram the most frequent. Mean age was 80 years±8.43 and H&Y stage was 3 [2-4]. Mean dose of levodopa used was 703.75mg±233.15. Median duration of concomitant treatment with safinamide and antidepressant drug was 6 months (IQR 20.5), and over eighteen months in 5 cases. No case of serotonin syndrome was recorded, neither was any of its typical manifestations combined or in isolation. CONCLUSIONS: Our real clinical practice study suggests that concomitant use of safinamide with antidepressant drugs in PD patients seemed to be safe and well tolerated, even in the long term. However, caution is warranted, individualizing treatment regimens and monitoring the potential appearance of adverse effects.


Assuntos
Alanina/análogos & derivados , Benzilaminas , Doença de Parkinson , Síndrome da Serotonina , Humanos , Idoso de 80 Anos ou mais , Levodopa/efeitos adversos , Antidepressivos/efeitos adversos , Doença de Parkinson/tratamento farmacológico
5.
J Am Heart Assoc ; 13(8): e030607, 2024 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-38591260

RESUMO

BACKGROUND: The phase 2 PIONEER-HCM (Phase 2 Open-label Pilot Study Evaluating Mavacamten in Subjects With Symptomatic Hypertrophic Cardiomyopathy and Left Ventricular Outflow Tract Obstruction) study showed that mavacamten improved left ventricular outflow tract gradients, exercise capacity, and symptoms in patients with obstructive hypertrophic cardiomyopathy (HCM), but the results of longer-term treatment are less well described. We report interim results from the PIONEER-OLE (PIONEER Open-Label Extension) study, the longest-term study of mavacamten in patients with symptomatic obstructive HCM. METHODS AND RESULTS: Patients who previously completed PIONEER-HCM (n=20) were eligible to enroll in PIONEER-OLE. Patients received oral mavacamten, 5 mg once daily (starting dose), with individualized dose titration at week 6. Evaluations included serial monitoring of safety, echocardiography, Kansas City Cardiomyopathy Questionnaire-Overall Summary Score, and serum NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels. Thirteen patients enrolled and received mavacamten (median study duration at data cutoff, 201 weeks). Most patients (92.3%) received ß-blockers concomitantly. Treatment-emergent adverse events were predominantly mild/moderate. One patient had an isolated reduction in left ventricular ejection fraction to 47%, which recovered and remained normal with continued treatment at a reduced dose. At week 180, mavacamten was associated with New York Heart Association class improvements from baseline (class II to I, n=9; class III to II, n=1; and unchanged, n=2), sustained reductions in left ventricular outflow tract gradients (mean [SD] change from baseline: resting, -50 [55] mm Hg; Valsalva, -70 [41] mm Hg), and serum NT-proBNP levels (median [interquartile range] change from baseline: -498 [-2184 to -76] ng/L), and improved Kansas City Cardiomyopathy Questionnaire-Overall Summary Score (mean [SD] change from baseline: +17 [16]). CONCLUSIONS: This long-term analysis supports the continued safety and effectiveness of mavacamten for >3 years in obstructive HCM. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03496168.


Assuntos
Benzilaminas , Cardiomiopatia Hipertrófica , Uracila/análogos & derivados , Função Ventricular Esquerda , Humanos , Volume Sistólico , Projetos Piloto , Cardiomiopatia Hipertrófica/diagnóstico , Cardiomiopatia Hipertrófica/tratamento farmacológico , Cardiomiopatia Hipertrófica/complicações
6.
Ann Med ; 56(1): 2329140, 2024 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-38470973

RESUMO

AIM: The combination of granulocyte-colony stimulating factor (G-CSF) and plerixafor is one of the approaches for hematopoietic stem cell mobilization in patients with multiple myeloma (MM), non-Hodgkin's lymphoma (NHL), and Hodgkin's lymphoma (HL). This systematic review and meta-analysis aimed to determine the ability of G-CSF + plerixafor to mobilize peripheral blood (PB) CD34+ cells and examine its safety profile. METHODS: We performed a database search using the terms 'granulocyte colony stimulating factor', 'G-CSF', 'AMD3100', and 'plerixafor', published up to May 1, 2023. The methodology is described in further detail in the PROSPERO database (CRD42023425760). RESULTS: Twenty-three studies were included in this systematic review and meta-analysis. G-CSF + plerixafor resulted in more patients achieving the predetermined apheresis yield of CD34+ cells than G-CSF alone (OR, 5.33; 95%, 4.34-6.55). It was further discovered that G-CSF + plerixafor could mobilize more CD34+ cells into PB, which was beneficial for the next transplantation in both randomized controlled (MD, 18.30; 95%, 8.74-27.85) and single-arm (MD, 20.67; 95%, 14.34-27.00) trials. Furthermore, G-CSF + plerixafor did not cause more treatment emergent adverse events than G-CSF alone (OR, 1.25; 95%, 0.87-1.80). CONCLUSIONS: This study suggests that the combination of G-CSF and plerixafor, resulted in more patients with MM, NHL, and HL, achieving the predetermined apheresis yield of CD34+ cells, which is related to the more effective mobilization of CD34+ cells into PB.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Compostos Heterocíclicos , Linfoma não Hodgkin , Linfoma , Mieloma Múltiplo , Humanos , Mobilização de Células-Tronco Hematopoéticas/métodos , Mieloma Múltiplo/terapia , Fator Estimulador de Colônias de Granulócitos , Compostos Heterocíclicos/efeitos adversos , Linfoma/induzido quimicamente , Linfoma/terapia , Linfoma não Hodgkin/induzido quimicamente , Linfoma não Hodgkin/terapia , Células-Tronco Hematopoéticas , Transplante Autólogo , Benzilaminas , Transplante de Células-Tronco Hematopoéticas/métodos
7.
Dalton Trans ; 53(12): 5616-5623, 2024 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-38439632

RESUMO

The chemokine receptor CXCR4 is implicated in multiple diseases including inflammatory disorders, cancer growth and metastasis, and HIV/AIDS. CXCR4 targeting has been evaluated in treating cancer metastasis and therapy resistance. Cyclam derivatives, most notably AMD3100 (Plerixafor™), are a common motif in small molecule CXCR4 antagonists. However, AMD3100 has not been shown to be effective in cancer treatment as an individual agent. Configurational restriction and transition metal complex formation increases receptor binding affinity and residence time. In the present study, we have synthesized novel trans-IV locked cyclam-based CXCR4 inhibitors, a previously unexploited configuration, and demonstrated their higher affinity for CXCR4 binding and CXCL12-mediated signaling inhibition compared to AMD3100. These results pave the way for even more potent CXCR4 inhibitors that may provide significant efficacy in cancer therapy.


Assuntos
Complexos de Coordenação , Ciclamos , Compostos Heterocíclicos , Benzilaminas , Complexos de Coordenação/farmacologia , Compostos Heterocíclicos/farmacologia , Compostos Heterocíclicos/química , Receptores CXCR4/antagonistas & inibidores
8.
Org Biomol Chem ; 22(15): 3059-3067, 2024 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-38545887

RESUMO

This article presents the controlled synthesis of a rare example of C,C'-linked bis-cyclam architecture in mild conditions through the "bis-aminal" route previously used for the advantageous synthesis of cyclam, N- and C-functional cyclams and N,N'-bis-cyclams. Two synthetic pathways were explored with the smart design of α,ß-unsaturated ketones or alkyl halides bis-cyclizing agents. The first led to the isolation of a key intermediate for the future design of N-functionalized bis-cyclams, whereas the second allowed the preparation of the targeted C,C'-xylylene-bis-cyclam under mild conditions with decent yield. This compound was then studied as a CXCR4 receptor inhibitor, one of the main applications known for bis-macrocyclic compounds, in particular in the context of HIV (human immunodeficiency virus) infection. Although results demonstrated that its potency is lower (i.e. 137-fold higher IC50) than the gold standard AMD3100 against HIV infection, clear evidence of CXCR4 inhibition is presented, confirming the potential of this novel architecture and related compounds in this research field.


Assuntos
Infecções por HIV , Compostos Heterocíclicos , Humanos , Receptores CXCR4/metabolismo , Compostos Heterocíclicos/farmacologia , Transdução de Sinais , Benzilaminas/farmacologia
9.
Signal Transduct Target Ther ; 9(1): 63, 2024 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-38453934

RESUMO

Neurotransmitter-initiated signaling pathway were reported to play an important role in regulating the malignant phenotype of tumor cells. Cancer cells could exhibit a "neural addiction" property and build up local nerve networks to achieve an enhanced neurotransmitter-initiated signaling through nerve growth factor-mediated axonogenesis. Targeting the dysregulated nervous systems might represent a novel strategy for cancer treatment. However, whether intrahepatic cholangiocarcinoma (ICC) could build its own nerve networks and the role of neurotransmitters in the progression ICC remains largely unknown. Immunofluorescence staining and Enzyme-linked immunosorbent assay suggested that ICC cells and the infiltrated nerves could generate a tumor microenvironment rich in acetylcholine that promotes ICC metastasis by inducing epithelial-mesenchymal transition (EMT). Acetylcholine promoted ICC metastasis through interacting with its receptor, alpha 5 nicotine acetylcholine receptor subunits (CHRNA5). Furthermore, acetylcholine/CHRNA5 axis activated GSK3ß/ß-catenin signaling pathway partially through the influx of Ca2+-mediated activation of Ca/calmodulin-dependent protein kinases (CAMKII). In addition, acetylcholine signaling activation also expanded nerve infiltration through increasing the expression of Brain-Derived Neurotrophic Factor (BDNF), which formed a feedforward acetylcholine-BDNF axis to promote ICC progression. KN93, a small-molecule inhibitor of CAMKII, significantly inhibited the migration and enhanced the sensitivity to gemcitabine of ICC cells. Above all, Acetylcholine/CHRNA5 axis increased the expression of ß-catenin to promote the metastasis and resistance to gemcitabine of ICC via CAMKII/GSK3ß signaling, and the CAMKII inhibitor KN93 may be an effective therapeutic strategy for combating ICC metastasis.


Assuntos
60532 , Benzilaminas , Neoplasias dos Ductos Biliares , Colangiocarcinoma , Humanos , beta Catenina/metabolismo , Fator Neurotrófico Derivado do Encéfalo/genética , Nicotina , Acetilcolina , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/genética , Gencitabina , Glicogênio Sintase Quinase 3 beta , Linhagem Celular Tumoral , Colangiocarcinoma/tratamento farmacológico , Colangiocarcinoma/genética , Ductos Biliares Intra-Hepáticos/metabolismo , Ductos Biliares Intra-Hepáticos/patologia , Neoplasias dos Ductos Biliares/tratamento farmacológico , Neoplasias dos Ductos Biliares/genética , Neoplasias dos Ductos Biliares/metabolismo , Neurotransmissores , Receptores Colinérgicos , Microambiente Tumoral
11.
Exp Lung Res ; 50(1): 53-64, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38509754

RESUMO

OBJECTIVE: The aim of this study is to assess the impact of Liver X receptors (LXRs) on airway inflammation, airway remodeling, and lipid deposition induced by cigarette smoke and lipopolysaccharide (LPS) exposure in the lung. METHODS: Wild mice and LXR-deficient mice were exposed to cigarette smoke and LPS to induce airway inflammation and remodeling. In addition, some wild mice received intraperitoneal treatment with the LXR agonist GW3965 before exposure to cigarette smoke and LPS. Lung tissue and bronchoalveolar lavage fluid were collected to evaluate airway inflammation, airway remodeling and lipid deposition. RESULTS: Exposure to cigarette smoke and LPS resulted in airway inflammation, emphysema and lipid accumulation in wild mice. These mice also exhibited downregulated LXRα and ABCA1 in the lung. Treatment with GW3965 mitigated inflammation, remodeling and lipid deposition, while the deletion of LXRs exacerbated these effects. Furthermore, GW3965 treatment following exposure to cigarette smoke and LPS increased LXRα and ABCA1 expression and attenuated MyD88 expression in wild mice. CONCLUSION: LXRs demonstrate the potential to mitigate cigarette smoke and LPS- induced airway inflammation, emphysema and lipid disposition in mice.


Assuntos
Benzoatos , Benzilaminas , Fumar Cigarros , Enfisema , Enfisema Pulmonar , Animais , Camundongos , Remodelação das Vias Aéreas , Líquido da Lavagem Broncoalveolar , Fumar Cigarros/efeitos adversos , Enfisema/metabolismo , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Lipopolissacarídeos/farmacologia , Receptores X do Fígado/metabolismo , Pulmão/metabolismo , Camundongos Endogâmicos C57BL
12.
Cells ; 13(6)2024 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-38534327

RESUMO

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia, yet the cellular and molecular mechanisms underlying the AF substrate remain unclear. Isolevuglandins (IsoLGs) are highly reactive lipid dicarbonyl products that mediate oxidative stress-related injury. In murine hypertension, the lipid dicarbonyl scavenger 2-hydroxybenzylamine (2-HOBA) reduced IsoLGs and AF susceptibility. We hypothesized that IsoLGs mediate detrimental pathophysiologic effects in atrial cardiomyocytes that promote the AF substrate. Using Seahorse XFp extracellular flux analysis and a luminescence assay, IsoLG exposure suppressed intracellular ATP production in atrial HL-1 cardiomyocytes. IsoLGs caused mitochondrial dysfunction, with reduced mitochondrial membrane potential, increased mitochondrial reactive oxygen species (ROS) with protein carbonylation, and mitochondrial DNA damage. Moreover, they generated cytosolic preamyloid oligomers previously shown to cause similar detrimental effects in atrial cells. In mouse atrial and HL-1 cells, patch clamp experiments demonstrated that IsoLGs rapidly altered action potentials (AP), implying a direct effect independent of oligomer formation by reducing the maximum Phase 0 upstroke slope and shortening AP duration due to ionic current modifications. IsoLG-mediated mitochondrial and electrophysiologic abnormalities were blunted or totally prevented by 2-HOBA. These findings identify IsoLGs as novel mediators of oxidative stress-dependent atrial pathophysiology and support the investigation of dicarbonyl scavengers as a novel therapeutic approach to prevent AF.


Assuntos
Fibrilação Atrial , Benzilaminas , Doenças Mitocondriais , Animais , Camundongos , Miócitos Cardíacos/metabolismo , Lipídeos/química , Espécies Reativas de Oxigênio/metabolismo
13.
Hua Xi Kou Qiang Yi Xue Za Zhi ; 42(1): 37-45, 2024 Feb 01.
Artigo em Inglês, Chinês | MEDLINE | ID: mdl-38475949

RESUMO

OBJECTIVES: This study aimed to investigate the effects of sitagliptin on the proliferation, apoptosis, inflammation, and osteogenic differentiation of human periodontal ligament stem cells (hPDLSCs) in lipopolysaccharide (LPS)-induced inflammatory microenvironment and its molecular mechanism. METHODS: hPDLSCs were cultured in vitro and treated with different concentrations of sitagliptin to detect cell viability and subsequently determine the experimental concentration of sitagliptin. An hPDLSCs inflammation model was established after 24 h of stimulation with 1 µg/mL LPS and divided into blank, control, low-concentration sitagliptin (0.5 µmol/L), medium-concentration sitagliptin (1 µmol/L), and high-concentration sitagliptin (2 µmol/L), high-concentrationsitagliptin+stromal cell derived factor-1 (SDF-1)/CXC chemokine receptor 4 (CXCR4) pathway inhibitor (AMD3100) (2 µmol/L+10 µg/mL) groups. A cell-counting kit-8 was used to detect the proliferation activity of hPDLSCs after 24, 48, and 72 h culture. The apoptosis of hPDLSCs cultured for 72 h was detected by flow cytometry. After inducing osteogenic differentiation for 21 days, alizarin red staining was used to detect the osteogenic differentiation ability of hPDLSCs. The alkaline phosphatase (ALP) activity in hPDLSCs was determined using a kit. The levels of inflammatory factors [tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, and IL-6] in the supernatant of hPDLSCs culture were detected by enzyme-linked immunosorbent assay. The mRNA expressions of osteogenic differentiation genes [Runt-associated transcription factor 2 (RUNX2), osteocalcin (OCN), osteopontin (OPN)], SDF-1 and CXCR4 in hPDLSCs were detected by real-time fluorescence quantitative polymerase chain reaction (RT-qPCR). Western blot analysis was used to determine SDF-1 and CXCR4 protein expression in hPDLSCs. RESULTS: Compared with the blank group, the proliferative activity, number of mineralized nodules, staining intensity, ALP activity, and RUNX2, OCN, OPN mRNA, SDF-1, and CXCR4 mRNA and protein expression levels of hPDLSCs in the control group significantly decreased. The apoptosis rate and levels of TNF-α, IL-1ß, and IL-6 significantly increased (P<0.05). Compared with the control group, the proliferative activity, number of mineralized nodule, staining intensity, ALP activity, and RUNX2, OCN, OPN mRNA, SDF-1, and CXCR4 mRNA and protein expression levels of hPDLSCs in low-, medium-, and high-concentration sitagliptin groups increased. The apoptosis rate and levels of TNF-α, IL-1ß, and IL-6 decreased (P<0.05). AMD3100 partially reversed the effect of high-concentration sitagliptin on LPS-induced hPDLSCs (P<0.05). CONCLUSIONS: Sitagliptin may promote the proliferation and osteogenic differentiation of hPDLSCs in LPS-induced inflammatory microenvironment by activating the SDF-1/CXCR4 signaling pathway. Furthermore, it inhibited the apoptosis and inflammatory response of hPDLSCs.


Assuntos
Benzilaminas , Ciclamos , Lipopolissacarídeos , Ligamento Periodontal , Humanos , Ligamento Periodontal/metabolismo , Lipopolissacarídeos/metabolismo , Lipopolissacarídeos/farmacologia , Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo , Receptores CXCR4/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Interleucina-6/metabolismo , Interleucina-6/farmacologia , Osteogênese , Transdução de Sinais , Inflamação/metabolismo , Células-Tronco , RNA Mensageiro/metabolismo , Apoptose , Proliferação de Células , Células Estromais/metabolismo , Diferenciação Celular , Células Cultivadas
14.
J Mass Spectrom ; 59(3): e5007, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38445805

RESUMO

The present study aimed to separate, identify, and characterise the degradation products formed when mavacamten is exposed to stress degradation as well as the stability of the drug in various environments and also to understand its degradation chemistry. Prediction of in silico toxicity and mutagenicity was aimed at the observed degradation products. Stress degradation along with stability studies and degradation kinetics were performed on mavacamten, and separation of degradation products was carried out by high-performance liquid chromatography. Tandem mass spectrometry studies were executed to characterise the structures of degradation products using product ion fragments. Orthogonally, nuclear magnetic resonance experiments were conducted to elucidate the structures having ambiguity in characterising them. Deductive Estimation of Risk from Existing Knowledge and Structure Activity Relationship Analysis using Hypotheses software were used to establish in silico toxicity and mutagenic profiles of mavacamten and its degradation products. Two degradation products of mavacamten found in acidic hydrolytic stress conditions were separated, identified, characterised, and proposed as 1-isopropylpyrimidine-2,4,6(1H,3H,5H)-trione and 1-phenylethanamine. Mavacamten was found to be stable under different pH and gastrointestinal conditions. The degradation kinetics of mavacamten under 1 N acidic condition followed zero-order kinetics, and it was degraded completely within 6 h. In silico toxicity and mutagenicity studies revealed that 1-phenylethanamine can be a skin sensitiser. A high-performance liquid chromatography method was developed for the separation of degradation products of mavacamten and characterised by liquid chromatography-tandem mass spectrometry and nuclear magnetic resonance. During the manufacturing and storage of drug product, precautions need to be taken when dealing with acidic solutions as the drug is prone to hydrolysis in acidic conditions. The formation of 1-phenylethanamine under these conditions is to be monitored as it is a skin sensitiser.


Assuntos
Benzilaminas , 60705 , Mutagênicos , Fenetilaminas , Uracila/análogos & derivados , Mutagênicos/toxicidade , Espectroscopia de Ressonância Magnética
15.
J Coll Physicians Surg Pak ; 34(3): 351-354, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38462874

RESUMO

OBJECTIVE: To assess the impact of vitamin B12 levels in the failure of the dapoxetine used in premature ejaculation (PE) treatment. STUDY DESIGN: Experimental study. Place and Duration of the Study: Andrology Clinic, between May and December 2020. METHODOLOGY: Patients with premature ejaculation complaints completed the Premature Ejaculation Diagnostic Tool (PEDT) questionnaire. Patients were also asked to fill in the Premature Ejaculation Profile (PEP) surveys. Intravaginal ejaculation latency time (IELT) were recorded based on the estimates of patients. Serum vitamin B12 levels were evaluated based on blood samples. All patients were advised to use dapoxetine 30 mg, 1-3 hours prior to intercourse. After four weeks, patients were asked to complete the PEP questionnaire again. IELT times were recorded. RESULTS: A total of 62 patients were included in the study. A total of 39 patients (62.90%) were satisfied with the treatment of the dapoxetine. In comparison to patients who benefited from dapoxetine treatment and those who did not, vitamin B12 levels of patients who did not benefit from dapoxetine were found to be significantly lower (p=0.005). CONCLUSION: Vitamin B12 deficiency can reduce the effectiveness of dapoxetine treatment in patients with PE. It is important to evaluate serum vitamin B12 levels for the evaluation of patients with PE. KEY WORDS: Premature ejaculation, Dapoxetine, Vitamin B12, Serotonin, Treatment.


Assuntos
Benzilaminas , Naftalenos , Ejaculação Precoce , Masculino , Humanos , Ejaculação Precoce/tratamento farmacológico , Resultado do Tratamento , Ejaculação , Vitamina B 12/uso terapêutico
16.
J Biomed Mater Res B Appl Biomater ; 112(2): e35378, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38356051

RESUMO

Globally, peripheral nerve injury (PNI) is a common clinical issue. Successfully repairing severe PNIs has posed a major challenge for clinicians. GW3965 is a highly selective LXR agonist, and previous studies have demonstrated its positive protective effects in both central and peripheral nerve diseases. In this work, we examined the potential reparative effects of GW3965-loaded polylactic acid co-glycolic acid microspheres in conjunction with a chitosan nerve conduit for peripheral nerve damage. The experiment revealed that GW3965 promoted Schwann cell proliferation and neurotrophic factor release in vitro. In vivo experiments conducted on rats showed that GW3965 facilitated the restoration of motor function, promoted axon and myelin regeneration in the sciatic nerve, and enhanced the microenvironment of nerve regeneration. These results offer a novel therapeutic approach for the healing of nerve damage. Overall, this work provides valuable insights and presents a promising therapeutic strategy for addressing PNI.


Assuntos
Benzoatos , Benzilaminas , Quitosana , Traumatismos dos Nervos Periféricos , Ratos , Animais , Quitosana/farmacologia , Receptores X do Fígado/uso terapêutico , Microesferas , Células de Schwann , Nervo Isquiático/lesões , Traumatismos dos Nervos Periféricos/tratamento farmacológico , Regeneração Nervosa
17.
Rev Med Liege ; 79(2): 120-128, 2024 Feb.
Artigo em Francês | MEDLINE | ID: mdl-38356430

RESUMO

Mavacamten (Camzyos®) is a myosin modulator which reduces the interactions between myosin and actin. These are overly activated in hypertrophic cardiomyopathy (HCM), a source of exaggerated ventricular contractility, energy loss, and impairment of diastolic function (relaxation). The Food and Drug Administration (FDA) and the European Medication Agency (EMA) approved mavacamten for the treatment of symptomatic obstructive HCM (NYHA class II or III) in adult patients in 2022 and 2023, respectively. The medication is not yet reimbursed in Belgium. As seen in its clinical development studies, mavacamten reduces the intraventricular gradient, improves functional capacity and reduces symptoms. It also seems to be an innovative alternative to septal reduction. Mavacamten is usually very well tolerated knowing that, through its mechanism of action, it causes a dose-dependent and reversible reduction in left ventricular ejection fraction, which must therefore be closely monitored. The good tolerance and the effectiveness of mavacamten seem to be maintained over time. Consequently, the recent European Society of Cardiology Updated Guidelines on cardiomyopathy (ESC 09/2023) already recommend mavacamten in the pharmacological management of obstructive HCM.


Le mavacamten (Camzyos®) est un modulateur de la myosine qui diminue les interactions entre la myosine et l'actine. En effet, celles-ci sont trop activées dans la cardiomyopathie hypertrophique (CMH), source de contractilité ventriculaire exagérée, de déperdition énergétique et de troubles de la fonction diastolique (relaxation). Le mavacamten est approuvé par la Food and Drug Administration (FDA 2022) et l'European Medication Agency (EMA 2023) pour le traitement de la CMH obstructive (CMHO) symptomatique (classe NYHA II ou III) chez les patients adultes. Il n'est pas encore remboursé en Belgique. Les études pivots de son développement clinique ont montré que le mavacamten réduit le gradient intraventriculaire, améliore la capacité fonctionnelle et diminue les symptômes. Il semble aussi représenter une alternative innovante à la réduction septale. Le mavacamten est généralement très bien toléré, sachant que, par son mécanisme d'action, il entraîne une diminution dose-dépendante et réversible de la fraction d'éjection ventriculaire gauche, qui devra donc être surveillée étroitement. Sa bonne tolérance et son efficacité semblent se maintenir au cours du temps. En conséquence, les récentes recommandations de la Société Européenne de Cardiologie (ESC 2023) à propos des cardiomyopathies recommandent déjà le mavacamten dans l'arsenal pharmacologique de la prise en charge des CMHO.


Assuntos
Cardiomiopatia Hipertrófica , Uracila/análogos & derivados , Função Ventricular Esquerda , Estados Unidos , Adulto , Humanos , Volume Sistólico , Cardiomiopatia Hipertrófica/tratamento farmacológico , Benzilaminas/efeitos adversos , Miosinas
18.
Environ Sci Pollut Res Int ; 31(11): 16437-16452, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38319423

RESUMO

Halonitromethanes (HNMs), a representative nitrogen-containing disinfection byproduct, have gained significant concerns due to their higher cytotoxicity and genotoxicity. UV/chlorination is considered a promising alternative disinfection technology for chlorination. This study aimed to investigate the HNMs formation from benzylamine (BZA) during UV/chlorination. The experimental results revealed that the yields of HNMs initially raised to a peak then dropped over time. Higher chlorine dosage and BZA concentration promoted the formation of HNMs, whereas alkaline pH inhibited their formation. The presence of bromine ion (Br-) not only converted chlorinated-HNMs (Cl-HNMs) to brominated (chlorinated)-HNMs Br (Cl)-HNMs) and brominated-HNMs (Br-HNMs) but also enhanced the total concentration of HNMs. Besides, the calculated cytotoxicity index (CTI) and genotoxicity index (GTI) of HNMs were elevated by 68.97% and 60.66% as Br- concentration raised from 2 to 6 µM. The possible formation pathways of HNMs from BZA were proposed based on the intermediates identified by a gas chromatography/mass spectrometry (GC/MS). In addition, the formation rules of HNMs in actual water verified the results in deionized water during UV/chlorination. The results of this study provide basic data and a theoretical basis for the formation and control of HNMs, which is conducive to applying UV/chlorination.


Assuntos
Desinfetantes , Poluentes Químicos da Água , Purificação da Água , Halogenação , Desinfetantes/química , Desinfecção/métodos , Cloro/química , Água , Benzilaminas/análise , Poluentes Químicos da Água/análise
19.
Clin Oral Investig ; 28(2): 148, 2024 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-38353803

RESUMO

OBJECTIVES: The present study aimed to determine in silico toxicity predictions of test compounds from hydraulic calcium silicate-based sealers (HCSBS) and AH Plus and computationally simulate the interaction between these substances and mediators of periapical inflammation via molecular docking. MATERIALS AND METHODS: All chemical information of the test compounds was obtained from the PubChem site. Predictions for bioavailability and toxicity analyses were determined by the Molinspiration Cheminformatics, pkCSM, ProTox-II and OSIRIS Property Explorer platforms. Molecular docking was performed using the Autodock4 AMDock v.1.5.2 program to analyse interactions between proteins (IL-1ß, IL-6, IL-8, IL-10 and TNF-α) and ligands (calcium silicate hydrate, zirconium oxide, bisphenol-A epoxy resin, dibenzylamine, iron oxide and calcium tungstate) to establish the affinity and bonding mode between systems. RESULTS: Bisphenol-A epoxy resin had the lowest maximum dose tolerated in humans and was the test compound with the largest number of toxicological properties (hepatotoxicity, carcinogenicity and irritant). All systems had favourable molecular docking. However, the ligands bisphenol-A epoxy resin and dibenzylamine had the greatest affinity with the cytokines tested. CONCLUSION: In silico predictions and molecular docking pointed the higher toxicity and greater interaction with mediators of periapical inflammation of the main test compounds from AH Plus compared to those from HCSBS. CLINICAL RELEVANCE: This is the first in silico study involving endodontic materials and may serve as the basis for further research that can generate more data, producing knowledge on the interference of each chemical compound in the composition of different root canal sealers.


Assuntos
Compostos Benzidrílicos , Benzilaminas , Compostos de Cálcio , Resinas Epóxi , Fenóis , Materiais Restauradores do Canal Radicular , Silicatos , Humanos , Resinas Epóxi/toxicidade , Simulação de Acoplamento Molecular , Inflamação , Materiais Restauradores do Canal Radicular/toxicidade
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