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1.
Nat Commun ; 15(1): 1173, 2024 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-38332002

RESUMO

Respiratory syncytial virus (RSV) is a common cause of acute lower respiratory tract infection in infants, older adults and the immunocompromised. Effective directly acting antivirals are not yet available for clinical use. To address this, we screen the ReFRAME drug-repurposing library consisting of 12,000 small molecules against RSV. We identify 21 primary candidates including RSV F and N protein inhibitors, five HSP90 and four IMPDH inhibitors. We select lonafarnib, a licensed farnesyltransferase inhibitor, and phase III candidate for hepatitis delta virus (HDV) therapy, for further follow-up. Dose-response analyses and plaque assays confirm the antiviral activity (IC50: 10-118 nM). Passaging of RSV with lonafarnib selects for phenotypic resistance and fixation of mutations in the RSV fusion protein (T335I and T400A). Lentiviral pseudotypes programmed with variant RSV fusion proteins confirm that lonafarnib inhibits RSV cell entry and that these mutations confer lonafarnib resistance. Surface plasmon resonance reveals RSV fusion protein binding of lonafarnib and co-crystallography identifies the lonafarnib binding site within RSV F. Oral administration of lonafarnib dose-dependently reduces RSV virus load in a murine infection model using female mice. Collectively, this work provides an overview of RSV drug repurposing candidates and establishes lonafarnib as a bona fide fusion protein inhibitor.


Assuntos
Dibenzocicloeptenos , Piridinas , Infecções por Vírus Respiratório Sincicial , Animais , Feminino , Camundongos , Reposicionamento de Medicamentos , Piperidinas/farmacologia , Piperidinas/uso terapêutico , Infecções por Vírus Respiratório Sincicial/tratamento farmacológico , Proteínas Virais de Fusão/genética , Proteínas Virais de Fusão/química
2.
Biosensors (Basel) ; 14(2)2024 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-38392012

RESUMO

Neurodegenerative diseases and Alzheimer's disease (AD), as one of the most common causes of dementia, result in progressive losses of cholinergic neurons and a reduction in the presynaptic markers of the cholinergic system. These consequences can be compensated by the inhibition of acetylcholinesterase (AChE) followed by a decrease in the rate of acetylcholine hydrolysis. For this reason, anticholinesterase drugs with reversible inhibition effects are applied for the administration of neurodegenerative diseases. Their overdosage, variation in efficiency and recommendation of an individual daily dose require simple and reliable measurement devices capable of the assessment of the drug concentration in biological fluids and medications. In this review, the performance of electrochemical biosensors utilizing immobilized cholinesterases is considered to show their advantages and drawbacks in the determination of anticholinesterase drugs. In addition, common drugs applied in treating neurodegenerative diseases are briefly characterized. The immobilization of enzymes, nature of the signal recorded and its dependence on the transducer modification are considered and the analytical characteristics of appropriate biosensors are summarized for donepezil, huperzine A, rivastigmine, eserine and galantamine as common anti-dementia drugs. Finally, the prospects for the application of AChE-based biosensors in clinical practice are discussed.


Assuntos
Doença de Alzheimer , Humanos , Doença de Alzheimer/tratamento farmacológico , Inibidores da Colinesterase/uso terapêutico , Acetilcolinesterase , Preparações Farmacêuticas , Piperidinas/farmacologia , Indanos/farmacologia , Indanos/uso terapêutico
3.
BMC Anesthesiol ; 24(1): 28, 2024 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-38233786

RESUMO

BACKGROUND: During arthroscopic rotator cuff repair (ARCR), clear surgical field visibility (SFV) is the basis of successful surgery, but the choice of anesthesia maintenance drugs may have different effects on SFV. In this study, we aimed to compare the effects of propofol- and sevoflurane-based general anesthesia on SFV in patients undergoing ARCR. METHODS: Patients (n = 130) undergoing elective ARCR in the lateral decubitus position were randomized into either the propofol group or sevoflurane group (65 per group). The duration of surgery and increased pressure irrigation (IPI), Boezaart score, rocuronium consumption and usage of remifentanil were recorded. The time of both spontaneous respiration recovery and extubation and the incidences of postoperative nausea and vomiting and agitation were also recorded. RESULTS: The Boezaart score, duration of IPI and ratio of the duration of IPI to the duration of surgery (IPI/S ratio) were similar between the groups (P > 0.05). Rocuronium consumption, number of patients requiring remifentanil infusion and total remifentanil consumption were significantly lower in the sevoflurane group (P < 0.05). The spontaneous respiration recovery time was significantly longer in the propofol group (P < 0.05), but there were no differences in the extubation time between the groups(P > 0.05). CONCLUSIONS: Compared with propofol, sevoflurane provides equally clear SFV while improving the convenience of anesthesia maintenance in ARCR patients with interscalene plexus (ISB) combined with general anesthesia. TRIAL REGISTRATION: This single-center, prospective, RCT was retrospective registered at Chinese Clinical Trial Registry with the registration number ChiCTR2300072110 (02/06/2023).


Assuntos
Anestésicos Inalatórios , Éteres Metílicos , Propofol , Humanos , Propofol/farmacologia , Sevoflurano , Remifentanil , Rocurônio , Estudos Prospectivos , Manguito Rotador/cirurgia , Estudos Retrospectivos , Éteres Metílicos/farmacologia , Piperidinas/farmacologia , Anestesia Geral , Anestésicos Intravenosos/farmacologia , Anestésicos Inalatórios/farmacologia
4.
Life Sci ; 338: 122406, 2024 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-38176583

RESUMO

AIMS: Curcumin is a natural compound and has good antitumor properties, but its clinical use is limited by its low bioavailability. We constructed the derivative CP41 (3,5-bis(2-chlorobenzylidene)-1-piperidin-4-one) by enhancing the bioavailability of curcumin while retaining its antitumor properties. MAIN METHODS: CCK-8 (Cell Counting Kit-8) was used to detect the effect of CP41 on cell proliferation; Western blotting, immunofluorescence, immunoprecipitation, quantitative PCR and enzyme-linked immunosorbent assay were used to evaluate the expression of subcutaneous tumor-related molecules in cells and mice. KEY FINDINGS: Our results showed that CP41 inhibited the proliferation of endometrial cancer cells by suppressing the proliferation of AN3CA and HEC-1-B cells. We found that CP41 significantly increased H3F3A and inhibited proteasome activity, which activated MAPK signaling and led to apoptosis. Further experiments showed that H3F3A is a potential target of CP41. Correlation analysis showed that H3F3A was positively correlated with the sensitivity to chemotherapeutic agents in endometrial cancer. CP41 significantly induced reactive oxygen species (ROS) levels and activated endoplasmic reticulum stress, which led to apoptosis. The safety profile of CP41 was also evaluated, and CP41 did not cause significant drug toxicity in mice. SIGNIFICANCE: CP41 showed stronger antitumor potency than curcumin, and its antitumor activity may be achieved by inducing ROS and activating H3F3A-mediated apoptosis.


Assuntos
Curcumina , Neoplasias do Endométrio , Animais , Feminino , Humanos , Camundongos , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células , Curcumina/análogos & derivados , Curcumina/farmacologia , Neoplasias do Endométrio/tratamento farmacológico , Estresse do Retículo Endoplasmático , Estresse Oxidativo/efeitos dos fármacos , Complexo de Endopeptidases do Proteassoma/efeitos dos fármacos , Complexo de Endopeptidases do Proteassoma/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Piperidinas/farmacologia , Proteínas Quinases Ativadas por Mitógeno/efeitos dos fármacos , Proteínas Quinases Ativadas por Mitógeno/metabolismo
5.
Pharmacol Biochem Behav ; 236: 173707, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38244864

RESUMO

Synthetic cannabinoids are associated with higher risk of dependence and more intense withdrawal symptoms than plant-derived Δ9-tetrahydrocannabinol (THC). Avoidance of withdrawal symptoms, including anxiogenic effects, can contribute to continued cannabinoid use. Adult male and female Long-Evans rats were given escalating doses of WIN 55,212-2 (WIN) via twice daily intrajugular infusions. Precipitated withdrawal was elicited with SR 141716 (rimonabant) 4 h after the final infusion. Global withdrawal scores (GWS) were compiled by summing z-scores of observed somatic behaviors over a 30-min period with locomotor activity simultaneously collected via beam breaks. Rimonabant precipitated withdrawal in female and male rats at 3 or 10 mg/kg, respectively, but the individual behaviors contributing to GWS were not identical. 3 mg/kg rimonabant did not impact locomotor behavior in females, but 10 mg/kg decreased locomotion in male controls. Spontaneous withdrawal observed between 6 and 96 h after the final infusion was quantifiable up to 24 h following WIN administration. Individual behaviors contributing to GWS varied by sex and time point. Males undergoing spontaneous withdrawal engaged in more locomotion than females undergoing withdrawal. Separate groups of rats were subjected to a battery of anxiety-like behavioral tests (elevated plus maze, open field test, and marble burying test) one or two weeks after WIN or vehicle infusions. At one week abstinence, sex-related effects were noted in marble burying and the open field test but were unrelated to drug treatment. At two weeks abstinence, females undergoing withdrawal spent more time grooming during marble burying and performed more marble manipulations than their male counterparts. WIN infusions did not impact estrous cycling, and GWS scores were not correlated with estrous at withdrawal. Collectively, these results show qualitative sex differences in behaviors contributing to the behavioral experience of cannabinoid withdrawal supporting clinical findings from THC.


Assuntos
Benzoxazinas , Canabinoides , Morfolinas , Naftalenos , Síndrome de Abstinência a Substâncias , Ratos , Feminino , Animais , Masculino , Agonistas de Receptores de Canabinoides/farmacologia , Rimonabanto/farmacologia , Dronabinol/efeitos adversos , Piperidinas/farmacologia , Pirazóis , Ratos Long-Evans , Canabinoides/farmacologia , Ansiedade/induzido quimicamente , Carbonato de Cálcio
6.
J Cell Physiol ; 239(2): e31168, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38149794

RESUMO

Arthrofibrosis, which causes joint motion restrictions, is a common complication following total knee arthroplasty (TKA). Key features associated with arthrofibrosis include myofibroblast activation, knee stiffness, and excessive scar tissue formation. We previously demonstrated that adiponectin levels are suppressed within the knee tissues of patients affected by arthrofibrosis and showed that AdipoRon, an adiponectin receptor agonist, exhibited anti-fibrotic properties in human mesenchymal stem cells. In this study, the therapeutic potential of AdipoRon was evaluated on TGFß1-mediated myofibroblast differentiation of primary human knee fibroblasts and in a mouse model of knee stiffness. Picrosirius red staining revealed that AdipoRon reduced TGFß1-induced collagen deposition in primary knee fibroblasts derived from patients undergoing primary TKA and revision TKA for arthrofibrosis. AdipoRon also reduced mRNA and protein levels of ACTA2, a key myofibroblast marker. RNA-seq analysis corroborated the anti-myofibrogenic effects of AdipoRon. In our knee stiffness mouse model, 6 weeks of knee immobilization, to induce a knee contracture, in conjunction with daily vehicle (DMSO) or AdipoRon (1, 5, and 25 mg/kg) via intraperitoneal injections were well tolerated based on animal behavior and weight measurements. Biomechanical testing demonstrated that passive extension angles (PEAs) of experimental knees were similar between vehicle and AdipoRon treatment groups in mice evaluated immediately following immobilization. Interestingly, relative to vehicle-treated mice, 5 mg/kg AdipoRon therapy improved the PEA of the experimental knees in mice that underwent 4 weeks of knee remobilization following the immobilization and therapy. Together, these studies revealed that AdipoRon may be an effective therapeutic modality for arthrofibrosis.


Assuntos
Artroplastia do Joelho , Artropatias , Animais , Humanos , Camundongos , Colágeno/metabolismo , Artropatias/tratamento farmacológico , Artropatias/metabolismo , Articulação do Joelho/metabolismo , Piperidinas/farmacologia , Feminino , Camundongos Endogâmicos C57BL , Fator de Crescimento Transformador beta1/farmacologia
7.
J Med Chem ; 67(1): 709-727, 2024 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-38117239

RESUMO

Atypical dopamine transporter (DAT) inhibitors have shown therapeutic potential in the preclinical models of psychostimulant use disorders (PSUD). In rats, 1-(4-(2-((bis(4-fluorophenyl)methyl)sulfinyl)ethyl)-piperazin-1-yl)-propan-2-ol (JJC8-091, 3b) was effective in reducing the reinforcing effects of both cocaine and methamphetamine but did not exhibit psychostimulant behaviors itself. Improvements in DAT affinity and metabolic stability were desirable for discovering pipeline drug candidates. Thus, a series of 1-(4-(2-bis(4-fluorophenyl)methyl)sulfinyl)alkyl alicyclic amines were synthesized and evaluated for binding affinities at DAT and the serotonin transporter (SERT). Replacement of the piperazine with either a homopiperazine or a piperidine ring system was well tolerated at DAT (Ki range = 3-382 nM). However, only the piperidine analogues (20a-d) showed improved metabolic stability in rat liver microsomes as compared to the previously reported analogues. Compounds 12b and 20a appeared to retain an atypical DAT inhibitor profile, based on negligible locomotor activity in mice and molecular modeling that predicts binding to an inward-facing conformation of DAT.


Assuntos
Estimulantes do Sistema Nervoso Central , Cocaína , Ratos , Camundongos , Animais , Proteínas da Membrana Plasmática de Transporte de Dopamina , Aminas/farmacologia , Relação Estrutura-Atividade , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Estimulantes do Sistema Nervoso Central/farmacologia , Piperidinas/farmacologia
8.
J Am Chem Soc ; 145(48): 26202-26212, 2023 Dec 06.
Artigo em Inglês | MEDLINE | ID: mdl-37987622

RESUMO

The covalent inhibition of a target protein has gained widespread attention in the field of drug discovery. Most of the current covalent drugs utilize the high reactivity of cysteines toward modest electrophiles. However, there is a growing need for warheads that can target lysine residues to expand the range of covalently druggable proteins and to deal with emerging proteins with mutations resistant to cysteine-targeted covalent drugs. We have recently developed an N-acyl-N-alkyl sulfonamide (NASA) as a lysine-targeted electrophile. Despite its successful application, this NASA warhead suffered from instability in physiological environments, such as serum-containing medium, because of its high intrinsic reactivity. In this study, we sought to modify the structure of the NASA warhead and found that N-acyl-N-aryl sulfonamides (ArNASAs) are promising electrophiles for use in a lysine-targeted covalent inhibition strategy. We prepared a focused library of ArNASA derivatives with diverse structures and reactivity and identified several warhead candidates with suppressed hydrolysis-mediated inactivation and reduced nonspecific reactions with off-target proteins, without sacrificing the reactivity toward the target. These reaction properties enabled the improved covalent inhibition of intracellular heat shock protein 90 (HSP90) in the presence of serum and the development of the first irreversible inhibitor for ibrutinib-resistant Bruton's tyrosine kinase (BTK) bearing the C481S mutation. This study clearly demonstrated the use of a set of ArNASA warheads to create highly potent covalent drugs and highlighted the importance of enriching the current arsenal of lysine-reactive warheads.


Assuntos
Lisina , Piperidinas , Lisina/química , Tirosina Quinase da Agamaglobulinemia/metabolismo , Piperidinas/farmacologia , Cisteína/química , Sulfanilamida , Sulfonamidas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/química
9.
J Cell Biochem ; 124(11): 1734-1748, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37796142

RESUMO

The pathogenic complexity of Alzheimer's disease (AD) demands the development of multitarget-directed agents aiming at improving actual pharmacotherapy. Based on the cholinergic hypothesis and considering the well-established role of butyrylcholinesterase (BuChE) in advanced stages of AD, the chemical structure of the acetylcholinesterase (AChE) inhibitor drug donepezil (1) was rationally modified for the design of new N-benzyl-piperidine derivatives (4a-d) as potential multitarget-direct AChE and BuChE inhibitors. The designed analogues were further studied through the integration of in silico and in vitro methods. ADMET predictions showed that 4a-d are anticipated to be orally bioavailable, able to cross the blood-brain barrier and be retained in the brain, and to have low toxicity. Computational docking and molecular dynamics indicated the formation of favorable complexes between 4a-d and both cholinesterases. Derivative 4a presented the lowest binding free energy estimation due to interaction with key residues from both target enzymes (-36.69 ± 4.47 and -32.23 ± 3.99 kcal/mol with AChE and BuChE, respectively). The in vitro enzymatic assay demonstrated that 4a was the most potent inhibitor of AChE (IC50 2.08 ± 0.16 µM) and BuChE (IC50 7.41 ± 0.44 µM), corroborating the in silico results and highlighting 4a as a novel multitarget-directed AChE/BuChE inhibitor.


Assuntos
Doença de Alzheimer , Butirilcolinesterase , Humanos , Butirilcolinesterase/metabolismo , Butirilcolinesterase/uso terapêutico , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/química , Inibidores da Colinesterase/uso terapêutico , Acetilcolinesterase/metabolismo , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Piperidinas/farmacologia , Piperidinas/uso terapêutico , Relação Estrutura-Atividade , Simulação de Acoplamento Molecular
10.
Target Oncol ; 18(6): 869-883, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37847485

RESUMO

BACKGROUND: Poly (ADP-ribose) polymerase (PARP) inhibitors are a new maintenance therapy option for patients with ovarian cancer (OC). OBJECTIVE: To evaluate the efficacy and influencing factors of the novel PARP inhibitor niraparib for maintenance treatment of Chinese patients with advanced OC. PATIENTS AND METHODS: In this retrospective multicenter real-world study patients with advanced OC from 15 hospitals throughout China were enrolled. The primary endpoint was progression-free survival (PFS) and the secondary endpoints included the time to treatment discontinuation and safety. Least Absolute Shrinkage and Selection Operator (LASSO) regression was used to identify possible risk factors for PFS, after which a prediction model was established to evaluate the likelihood of achieving an 18-month PFS. The relationship between the dose of niraparib and PFS was also evaluated. RESULTS: The PFS rates of 199 patients at 6, 12, 18, 24, and 30 months were 87.4%, 75.9%, 63.6%, 56.1%, and 51.8%, respectively. LASSO regression model revealed that only age < 65 years (P = 0.011), BRCA mutations (P < 0.001), and R0 status after cytoreductive surgery (P = 0.01) were significant factors associated with prolonged PFS times. Based on the LASSO logistic regression analysis, a clinical prediction formula was developed: - 2.412 + 1.396Age≥65yr + 2.374BRCAwt + 1.387R1 + 0.793Interval≥12w + 0.178BMI>24kg/m2 which yielded a cut-off value of 0.091, an area under the curve (AUC) of 0.839 (0.763-0.916), a sensitivity of 94.3%, and an accuracy of 78.5%. A nomogram was then built to visualize the results. The major treatment-emergent adverse events of ≥ grade 3 included a platelet count decrease (19.1%), white blood cell count decrease (15.1%), neutrophil count decrease (13.1%), and anemia (18.6%). The 18-month PFS rates in patients treated with 200 mg niraparib were somewhat higher than in patients treated with 100 mg after 3-months of therapy. CONCLUSIONS: For Chinese OC patients, niraparib, particularly at a 200 mg individual starting dose, was an effective therapy with easily manageable safety.


Maintenance therapy with poly (ADP-ribose) polymerase inhibitors is a new option for patients with ovarian cancer (OC) after they have received platinum-based chemotherapy to reduce the recurrence or relapse rates, but it remains unclear whether there are any changes in efficacy and safety when different starting doses of niraparib are administrated to Chinese patients, who typically have a bodyweight < 77 kg. We found that niraparib exhibited satisfactory efficacy with tolerable safety during maintenance therapy for advanced OC whether administered at 100 mg or 200 mg doses. We believe these regimens can serve as a valuable addition to the previous results of randomized controlled trials.


Assuntos
Neoplasias Ovarianas , Humanos , Feminino , Idoso , Carcinoma Epitelial do Ovário/tratamento farmacológico , Indazóis/farmacologia , Indazóis/uso terapêutico , Piperidinas/farmacologia , Piperidinas/uso terapêutico
11.
Xenobiotica ; 53(8-9): 547-558, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37880944

RESUMO

Evobrutinib is a highly selective, covalent, central nervous system-penetrant Bruton's tyrosine kinase (BTK) inhibitor, currently in Phase III trials for the treatment of relapsing multiple sclerosis. One major circulating metabolite of evobrutinib has been previously identified as the racemic dihydro-diol M463-2 (MSC2430422) in a Phase I human mass balance study.Phenotyping experiments were conducted to confirm the metabolic pathway of evobrutinib to M463-2. Ratio of the enantiomers was determined by enantioselective liquid chromatography with tandem mass spectrometry analysis of plasma samples from humans and preclinical species. Drug-drug interaction (DDI) characterisation, evaluation of pharmacological activity on BTK, and off-target screening experiments followed assessing safety of the metabolite.The biotransformation of evobrutinib to M463-2 was determined to be a two-step process with a CYP-mediated oxidation acting to form an epoxide intermediate, which was further hydrolysed by soluble and mitochondrial epoxide hydrolase. Only the (S)-enantiomer was determined to be a major metabolite, the (R)-enantiomer was minor. In vitro studies demonstrated the (S)-enantiomer lacked clinically relevant pharmacological activity, off-target effects and DDIs.The biotransformation of evobrutinib to its major metabolite has been elucidated, with the major (S)-enantiomer being shown to pose no on/off target or DDI risks.


Assuntos
Piperidinas , Pirimidinas , Humanos , Piperidinas/farmacologia , Biotransformação , Interações Medicamentosas , Inibidores de Proteínas Quinases/farmacologia
12.
Psychiatr Danub ; 35(Suppl 2): 66-71, 2023 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-37800205

RESUMO

Bipolar disorder and Parkinson's disease are two distinct neurological conditions that share common features related to dopaminergic dysfunction. This article presents a comprehensive review of the existing literature to investigate the association between bipolar disorder and Parkinson's disease, focusing on the dopaminergic hypothesis and potential therapeutic options. The dopaminergic hypothesis suggests that both bipolar disorder and Parkinson's disease involve impairments in the nigrostriatal or mesolimbic dopaminergic pathways. Studies have demonstrated alterations in dopamine regulation during manic and depressive phases of bipolar disorder. Similarly, Parkinson's disease is characterized by the loss of dopaminergic neurons in the substantia nigra, resulting in motor symptoms. Recent analyses have highlighted a predisposition to Parkinson's disease in individuals with bipolar disorder. Longitudinal studies and meta-analyses have demonstrated an increased risk of developing Parkinson's disease in patients with bipolar disorder. However, differentiating idiopathic Parkinson's disease from parkinsonism induced by medications used in bipolar disorder can be challenging. Dopamine transporter (DAT) scans can aid in making a differential diagnosis. Treatment options for patients with both bipolar disorder and Parkinson's disease are limited. Neuroleptics, commonly used to manage psychotic symptoms in Parkinson's disease, may worsen motor symptoms and have limitations in bipolar disorder patients. Clozapine has shown efficacy in treating psychosis without worsening motor symptoms. Pimavanserin, an inverse agonist of the 5-HT2A receptor can offer new opportunities. However, its efficacy in bipolar disorder patients with Parkinson's disease remains unexplored. In conclusion, the association between bipolar disorder and Parkinson's disease is supported by the involvement of the dopaminergic system in both conditions. The identification of shared mechanisms opens new avenues for potential therapeutic interventions. Further research is needed to investigate the efficacy of pimavanserin and explore other treatment options for individuals with both bipolar disorder and Parkinson's disease.


Assuntos
Transtorno Bipolar , Doença de Parkinson , Humanos , Doença de Parkinson/tratamento farmacológico , Transtorno Bipolar/tratamento farmacológico , Transtorno Bipolar/complicações , Agonismo Inverso de Drogas , Piperidinas/farmacologia , Piperidinas/uso terapêutico , Dopamina/metabolismo
13.
Future Microbiol ; 18: 1279-1299, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37882762

RESUMO

Aim: To review in vitro, in vivo, and in silico studies examining the antibacterial and immunomodulatory properties of piperine (PPN). Methods: This systematic review followed PRISMA guidelines, and five databases were searched. Results: A total of 40 articles were included in this study. Six aspects of PPN activity were identified, including antibacterial spectrum, association with antibiotics, efflux pump inhibition, biofilm effects, protein target binding, and modulation of immune functions/virulence factors. Most studies focused on Mycobacterium spp. and Staphylococcus aureus. Cell lineages and in vivo models were employed to study PPN antibacterial effects. Conclusion: We highlight PPN as a potential adjuvant in the treatment of bacterial infections. PPN possesses several antibacterial properties that need further exploration to determine the mechanisms behind its pharmacological activity.


Assuntos
Alcaloides , Antibacterianos , Antibacterianos/química , Alcaloides/farmacologia , Benzodioxóis/farmacologia , Piperidinas/farmacologia , Testes de Sensibilidade Microbiana
14.
J Anesth ; 37(6): 841-852, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37597005

RESUMO

PURPOSE: Generation of nociceptive sensory evoked potentials (NEPs) by selective stimulation of nociceptive intraepidermal nerve fibers is a simple technique which could be used as intraoperative nociception monitor. We evaluated the effects of remifentanil, propofol and sevoflurane on NEPs by this technique. METHODS: Patients undergoing general anesthesia were assigned to groups in two studies. A-δ fiber selective NEPs were recorded. Study 1: NEPs were recorded at control, under anesthetics administration: remifentanil at an effect-site concentration (Ce) of 1.0 ng/mL (n = 10), propofol at Ce of 0.5 µg/mL (n = 10), or sevoflurane at 0.2 minimum alveolar concentration (MAC) (n = 10), and recovery from the anesthetics. Study 2: NEPs were recorded at control and under administration of higher dose anesthetics: propofol at Ce of 0.5 and 1.0 µg/mL (n = 10) or sevoflurane at 0.2 and 0.5 MAC (n = 10). A P-value < 0.016 was considered statistically significant in multiple analyses. RESULTS: Study 1: Remifentanil at Ce of 1.0 ng/mL significantly suppressed the amplitude of NEPs (mean amplitude (standard deviation) of control vs. remifentanil administration: 16.8 µV (3.8) vs. 10.1 µV (2.5), P < 0.001). Propofol and sevoflurane did not suppress the amplitude significantly. Study 2: Propofol at Ce of 0.5 and 1.0 µg/mL and sevoflurane at 0.2 and 0.5 MAC did not suppress the amplitude significantly. CONCLUSION: The amplitude of A-δ fiber selective NEPs was suppressed by remifentanil but not propofol or sevoflurane. NEPs with intraepidermal electrical stimulation can assess the analgesic effect of anesthetics. CLINICAL TRIAL NUMBER: UMIN000038214 REGISTRY URL: https://center6.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000043328.


Assuntos
Anestésicos Inalatórios , Éteres Metílicos , Propofol , Humanos , Propofol/farmacologia , Sevoflurano , Remifentanil , Anestésicos Intravenosos/farmacologia , Éteres Metílicos/farmacologia , Anestésicos Inalatórios/farmacologia , Nociceptividade , Piperidinas/farmacologia , Potenciais Evocados , Estimulação Elétrica
15.
J Med Chem ; 66(16): 11428-11446, 2023 08 24.
Artigo em Inglês | MEDLINE | ID: mdl-37552807

RESUMO

Peroxisome proliferator-activated receptor δ (PPARδ) is considered to be a pharmaceutical target to treat metabolic diseases including atherosclerosis, but there is no PPARδ agonist available for clinical use. We have previously reported the discovery of piperidinyl/piperazinyl benzothiazole derivatives as a new series of PPARδ agonists using docking-based virtual screening methods. In the present study, we found that introduction of a pyrrolidine group into the 4-position of their central piperidine rings enhances hPPARδ activity and subtype selectivity. This led to the discovery of 21 having strong PPARδ agonist activity (EC50 = 3.6 nM) with excellent ADME properties. Furthermore, 21 significantly suppressed atherosclerosis progression by 50-60% with reduction of the serum level of MCP-1 in LDLr-KO mice.


Assuntos
Aterosclerose , PPAR delta , Camundongos , Animais , PPAR delta/agonistas , Aterosclerose/tratamento farmacológico , Anti-Inflamatórios , Tiazóis , Piperidinas/farmacologia
16.
Int J Mol Sci ; 24(16)2023 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-37628747

RESUMO

The impact of JAK/STAT inhibitors, which are used in various inflammatory diseases, on cardiovascular risk is controversial and has recently raised safety concerns. Our study investigates the direct effects of tofacitinib on macrophage cholesterol metabolism, which is crucial for atherosclerosis plaque development and stability. Cultured human macrophages THP-1 were used to assess the impact of tofacitinib on cell cholesterol efflux and synthesis via radioisotopic methods, and on cholesterol uptake by measuring the cell cholesterol content with a fluorometric assay. The cholesterol acceptors and donors were either standard lipoproteins or sera from patients with juvenile idiopathic arthritis (JIA) and from control subjects. Tofacitinib significantly increased the macrophage cholesterol efflux to all acceptors; it reduced cholesterol uptake from both the normal and hypercholesterolemic sera; and it reduced cholesterol synthesis. The treatment of macrophages with tofacitinib was able to increase the cholesterol efflux and decrease cholesterol uptake when using sera from untreated JIA patients with active disease as cholesterol acceptors and donors, respectively. In conclusion, our in vitro data support the concept that tofacitinib has a favorable impact on macrophage cholesterol metabolism, even in the presence of sera from rheumatologic patients, and suggest that other mechanisms may be responsible for the cardiovascular risk associated with tofacitinib use in selected patient populations.


Assuntos
Artrite Juvenil , Inibidores de Janus Quinases , Humanos , Metabolismo dos Lipídeos , Piperidinas/farmacologia , Inibidores de Janus Quinases/efeitos adversos , Macrófagos
17.
ACS Chem Neurosci ; 14(15): 2743-2760, 2023 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-37433759

RESUMO

The naturally inspired multitarget-directed ligands (PC01-PC10 and PD01-PD26) were synthesized from piperine for the management of Alzheimer's disease (AD). The compound PD07 showed significant inhibitory activity on ChEs, BACE1, and Aß1-42 aggregation in in vitro studies. Further, compound PD07 effectively displaced the propidium iodide at the AChE PAS site. The compound PD07 exhibited significant lipophilicity in PAMPA studies. Additionally, PD07 demonstrated neuroprotective properties in the Aß1-42 induced SH-SY5Y cell line. Furthermore, DFT calculations were performed using B3LYP/6-311G(d,p) basis sets to explore the PD07 physical and chemical properties. The compound PD07 showed a similar binding interaction profile at active sites of AChE, BuChE, and BACE1 proteins as compared to reference ligands (donepezil, tacrine, and BSD) in molecular docking and dynamic simulation studies. In acute oral toxicity studies, compound PD07 exhibited no toxicity symptoms up to 300 mg/kg, po. The compound PD07 (10 mg/kg, po) improved memory and cognition in scopolamine-induced amnesia rats. Further, PD07 increased ACh levels in the brain by inhibiting the AChE activity. The results from in vitro, in silico, and in vivo studies suggested that compound PD07 is a potent multitarget-directed lead from piperine to overcome Alzheimer's disease.


Assuntos
Doença de Alzheimer , Neuroblastoma , Ratos , Humanos , Animais , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Secretases da Proteína Precursora do Amiloide/metabolismo , Simulação de Acoplamento Molecular , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/química , Ligantes , Ácido Aspártico Endopeptidases/metabolismo , Piperidinas/farmacologia , Piperidinas/química , Escopolamina , Desenho de Fármacos , Acetilcolinesterase/metabolismo , Relação Estrutura-Atividade , Peptídeos beta-Amiloides/metabolismo
18.
Iran J Med Sci ; 48(4): 379-384, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-37456209

RESUMO

Background: Rhinoplasty is a complex but popular surgery in Iran. The main complications of the surgery are post-operative bleeding and nasal septal hematoma due to poor intra-operative controlled hypertension. This study aimed to compare the efficacy of isoflurane-remifentanil (I-R) versus propofol-remifentanil (P-R) to induce controlled hypotension and to assess surgeon satisfaction with each of these combinations during rhinoplasty. Methods: In 2020-2021, a single-blind clinical study was conducted on 98 patients aged 18-50 years undergoing rhinoplasty at Mother and Child Hospital (Shiraz, Iran). Patients were randomly divided into P-R (n=48) and I-R (n=50) groups. Changes in systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP), and heart rate (HR) were assessed during surgery and in the recovery room. A questionnaire was used to evaluate the level of surgeon satisfaction. Data were analyzed using independent samples t test, Chi-square test, and repeated measures ANOVA with SPSS software. P<0.05 was considered statistically significant. Results: Five minutes after anesthesia induction, the P-R combination had a greater effect on reducing SBP (P=0.010), DBP (P=0.007), MAP (P=0.003), and HR (P=0.026) than I-R. However, from the 40th minute to the end of surgery and after 30 minutes of recovery, the I-R combination had a slightly better effect on blood pressure reduction than P-R. There was no difference in surgeon satisfaction with either of the two drug combinations. Conclusion: Both P-R and I-R combinations are recommended to induce hypotension during rhinoplasty. However, I-R is more effective than P-R in inducing the desired controlled hypotension.


Assuntos
Hipotensão Controlada , Hipotensão , Isoflurano , Propofol , Rinoplastia , Cirurgiões , Criança , Humanos , Remifentanil/farmacologia , Remifentanil/uso terapêutico , Propofol/efeitos adversos , Anestésicos Intravenosos/farmacologia , Anestésicos Intravenosos/uso terapêutico , Rinoplastia/efeitos adversos , Método Simples-Cego , Piperidinas/farmacologia , Piperidinas/uso terapêutico , Satisfação Pessoal
19.
Int J Mol Sci ; 24(13)2023 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-37446125

RESUMO

The enhancement of the endocannabinoid tone might have a beneficial influence on hypertension. Polypharmacology proposes multi-target-directed ligands (MTDLs) as potential therapeutic agents for the treatment of complex diseases. In the present paper, we studied JZL195, a dual inhibitor of the two major endocannabinoid-degrading enzymes, fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), in spontaneously hypertensive rats (SHR) and normotensive Wistar Kyoto rats (WKY). Hemodynamic parameters were assessed in conscious animals via radiotelemetry and tail-cuff methods and then evaluated by the area under the curve (AUC). Single administration of JZL195 induced dose-dependent weak hypotensive and bradycardic responses in SHR but not in WKY. Similarly, its chronic application revealed only a slight hypotensive potential which, however, effectively prevented the progression of hypertension and did not undergo tolerance. In addition, multiple JZL195 administrations slightly decreased heart rate only in WKY and prevented the gradual weight gain in both groups. JZL195 did not affect organ weights, blood glucose level, rectal temperature and plasma oxidative stress markers. In conclusion, chronic dual FAAH/MAGL inhibition prevents the progression of hypertension in SHR without affecting some basal functions of the body. In addition, our study clearly proves the suitability of AUC for the evaluation of weak blood pressure changes.


Assuntos
Hipertensão , Monoacilglicerol Lipases , Ratos , Animais , Piperidinas/farmacologia , Ratos Endogâmicos SHR , Monoglicerídeos , Endocanabinoides , Amidoidrolases , Hipertensão/tratamento farmacológico
20.
Acta Gastroenterol Belg ; 86(2): 374-376, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37428175

RESUMO

Microscopic colitis is a chronic inflammatory condition of the colon. Firstline treatment consists of budesonide, with the consideration of biological agents in refractory cases. Celiac disease is a chronic immune mediated and gluten-induced enteropathy, with treatment consisting of a gluten-free diet. There is an association between microscopic colitis and instead of xand celiac disease, especially in refractory cases they can coincide. In this manuscript, we report for the first time the efficacy of tofacitinib, a pan Janus kinase inhibitor, in the treatment of concomitant microscopic colitis and celiac disease, resulting in persistent clinical and histological remission.


Assuntos
Doença Celíaca , Colite Microscópica , Humanos , Doença Celíaca/complicações , Doença Celíaca/tratamento farmacológico , Colite Microscópica/tratamento farmacológico , Colite Microscópica/complicações , Piperidinas/uso terapêutico , Piperidinas/farmacologia , Pirimidinas/uso terapêutico , Pirimidinas/farmacologia
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