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1.
Int J Mol Sci ; 23(24)2022 Dec 19.
Artigo em Inglês | MEDLINE | ID: mdl-36555852

RESUMO

Bexarotene is an FDA-approved drug for the treatment of cutaneous T-cell lymphoma (CTCL); however, its use provokes or disrupts other retinoid-X-receptor (RXR)-dependent nuclear receptor pathways and thereby incites side effects including hypothyroidism and raised triglycerides. Two novel bexarotene analogs, as well as three unique CD3254 analogs and thirteen novel NEt-TMN analogs, were synthesized and characterized for their ability to induce RXR agonism in comparison to bexarotene (1). Several analogs in all three groups possessed an isochroman ring substitution for the bexarotene aliphatic group. Analogs were modeled for RXR binding affinity, and EC50 as well as IC50 values were established for all analogs in a KMT2A-MLLT3 leukemia cell line. All analogs were assessed for liver-X-receptor (LXR) activity in an LXRE system to gauge the potential for the compounds to provoke raised triglycerides by increasing LXR activity, as well as to drive LXRE-mediated transcription of brain ApoE expression as a marker for potential therapeutic use in neurodegenerative disorders. Preliminary results suggest these compounds display a broad spectrum of off-target activities. However, many of the novel compounds were observed to be more potent than 1. While some RXR agonists cross-signal the retinoic acid receptor (RAR), many of the rexinoids in this work displayed reduced RAR activity. The isochroman group did not appear to substantially reduce RXR activity on its own. The results of this study reveal that modifying potent, selective rexinoids like bexarotene, CD3254, and NEt-TMN can provide rexinoids with increased RXR selectivity, decreased potential for cross-signaling, and improved anti-proliferative characteristics in leukemia models compared to 1.


Assuntos
Leucemia , Linfoma Cutâneo de Células T , Neoplasias Cutâneas , Humanos , Bexaroteno/farmacologia , Receptores X de Retinoides/metabolismo , Tetra-Hidronaftalenos/farmacologia , Receptores X do Fígado , Retinoides/farmacologia , Triglicerídeos
2.
Mar Drugs ; 20(11)2022 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-36354979

RESUMO

Mammalian cells act as reservoirs of internalized bacteria to circumvent extracellular antibacterial compounds, resulting in relapse and reinfection diseases. The intracellular persistence of Staphylococcus aureus renders most traditional antibiotics useless, due to their inadequate subcellular accumulation. To replenish our antibiotic arsenal, we found that a marine-derived compound, equisetin, efficiently eliminates intracellular S. aureus by potentiating the host autophagy and inducing mitochondrial-mediated ROS generation to clear the invading S. aureus. The remarkable anti-infection activity of equisetin was validated in a peritonitis-infected mouse model. The marine product equisetin utilizes a unique dual mechanism to modulate the host-pathogen interaction in the clearance of intracellular bacteria. Thus, equisetin is an inspiring host-acting candidate for overcoming intracellular pathogens.


Assuntos
Infecções Estafilocócicas , Staphylococcus aureus , Camundongos , Animais , Infecções Estafilocócicas/tratamento farmacológico , Infecções Estafilocócicas/microbiologia , Pirrolidinonas , Tetra-Hidronaftalenos , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Mamíferos
3.
J Med Chem ; 65(21): 14409-14423, 2022 11 10.
Artigo em Inglês | MEDLINE | ID: mdl-36318154

RESUMO

Compound 1 is a potent rexinoid that is highly effective in cancer chemoprevention but elevates serum triglycerides. In an effort to separate the lipid toxicity from the anticancer activity of 1, we synthesized four new analogs of rexinoid 1, of which three rexinoids did not elevate serum triglycerides. Rexinoids 3 and 4 are twice as potent as rexinoid 1 in binding to Retinoid X receptor (RXR). All-trans retinoic acid (ATRA) plays a key role in maintaining skin homeostasis, and rexinoids 3-6 are highly effective in upregulating the genes responsible for the biosynthesis of ATRA. Inflammation plays a key role in skin cancer, and rexinoids 3 and 4 are highly effective in diminishing LPS-induced inflammation. Rexinoids 3 and 4 are highly effective in preventing UVB-induced nonmelanoma skin cancer (NMSC) without displaying any overt toxicities. Biophysical studies of rexinoids 3 and 5 bound to hRXRα-ligand binding domain (LBD) reveal important conformational and dynamical differences in the ligand binding domain.


Assuntos
Neoplasias Cutâneas , Tetra-Hidronaftalenos , Humanos , Tetra-Hidronaftalenos/química , Ligantes , Receptores X de Retinoides/metabolismo , Tretinoína/química , Tretinoína/metabolismo , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/prevenção & controle , Inflamação/tratamento farmacológico , Inflamação/prevenção & controle , Triglicerídeos
4.
Eur J Med Res ; 27(1): 264, 2022 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-36424620

RESUMO

BACKGROUND: Hepatic encephalopathy (HE) is a reversible syndrome of brain dysfunction caused by advanced liver disease. Weighted gene co-expression network analysis (WGCNA) could establish a robust co-expression network to identify the hub genes and underlying biological functions. This study was aimed to explore the potential therapeutic targets in HE by WGCNA. RESULTS: The green and brown modules were found to be significantly associated with the development of HE. Functional enrichment analyses suggested the neuroinflammation, neuroimmune, extracellular matrix (ECM), and coagulation cascade were involved in HE. CYBB and FOXO1 were calculated as hub genes, which were upregulated in the HE patients. Tamibarotene and vitamin E were suggested as possible drug candidates to alleviate HE. CONCLUSIONS: It is the first time to analyze transcriptomic data of HE by WGCNA. Our study not only promoted the current understanding of neuroinflammation in HE, but also provided the first evidence that CYBB and FOXO1 played pivotal roles in the pathogenesis of HE, which might be potential biomarkers and therapeutic targets. Tamibarotene might be a novel drug compound against HE.


Assuntos
Redes Reguladoras de Genes , Encefalopatia Hepática , Humanos , Perfilação da Expressão Gênica , Encefalopatia Hepática/tratamento farmacológico , Encefalopatia Hepática/genética , Tetra-Hidronaftalenos
5.
Cell Mol Biol (Noisy-le-grand) ; 68(6): 25-30, 2022 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-36227682

RESUMO

During lung resection surgery, the blood supply to the lungs increases the intrapulmonary shunt and reduces arterial oxygenation in patients. Ventilation anesthesia of a lung may affect oxygenation. The present study aimed to compare intravenous anesthesia with and without thoracic epidural block (dezocine and ropivacaine) on oxygen saturation during lung ventilation in patients undergoing lung resection surgery. For this purpose, this study was performed as a double-blind, randomized clinical trial. Sixty patients who were candidates for lung resection were divided into two intervention groups (thoracic epidural block with dezocine and ropivacaine and intravenous anesthesia) and a control group (placebo thoracic epidural block and intravenous anesthesia). Hemodynamic variables, Aldert score, and possible complications were compared between the two groups before surgery and after recovery. Also, the expression level of the IDO gene was evaluated using the real-time PCR technique. SPSS, t-test, Mann-Whitney U, Chi-square, and Fisher performed data analysis and comparison.  The results showed that the changes in hemodynamic variables and PaO2, SaO2, and ETCO2 were not statistically significant between the two groups. Aldrete's score at entry and exit of recovery was similar between the two groups. During the recovery period, the percentage of pain or chills in the group under complete intravenous anesthesia was significantly higher. There was no significant difference between the two groups regarding the frequency of nausea and hypotension. Also, the results of IDO gene expression showed that general anesthesia with the thoracic epidural block (dezocine and ropivacaine), which is involved in inducing immunological tolerance and suppressing immune responses, has no significant effect. The stress of performing surgery before surgery can play a role in suppressing the patient's immunity, and anesthesia of the thoracic epidural block (dezocine and ropivacaine) has no significant effect on IDO expression. In general, thoracic epidural block with complete intravenous anesthesia has no significant effect on oxygen saturation in ventilated lungs compared with intravenous anesthesia alone. Nevertheless, this combination significantly reduces postoperative pain and chills.


Assuntos
Anestésicos Locais , Bloqueio Nervoso , Amidas/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes , Expressão Gênica , Humanos , Pulmão/metabolismo , Pulmão/cirurgia , Bloqueio Nervoso/métodos , Oxigênio/metabolismo , Saturação de Oxigênio , Ventilação Pulmonar , Ropivacaina/farmacologia , Ropivacaina/uso terapêutico , Tetra-Hidronaftalenos
7.
ACS Chem Neurosci ; 13(19): 2863-2873, 2022 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-36099546

RESUMO

Zebrafish (Danio rerio) are ideal model organisms for investigating nervous system function, both in health and disease. Nevertheless, functional characteristics of dopamine (DA) release and uptake regulation are still not well-understood in zebrafish. In this study, we assessed D3 autoreceptor function in the telencephalon of whole zebrafish brains ex vivo by measuring the electrically stimulated DA release ([DA]max) and uptake at carbon fiber microelectrodes with fast-scan cyclic voltammetry. Treatment with pramipexole and 7-OH-DPAT, selective D3 autoreceptor agonists, sharply decreased [DA]max. Conversely, SB277011A, a selective D3 antagonist, nearly doubled [DA]max and decreased k, the first-order rate constant for the DA uptake, to about 20% of its original value. Treatment with desipramine, a selective norepinephrine transporter blocker, failed to increase current, suggesting that our electrochemical signal arises solely from the release of DA. Furthermore, blockage of DA uptake with nomifensine-reversed 7-OH-DPAT induced decreases in [DA]max. Collectively, our data show that, as in mammals, D3 autoreceptors regulate DA release, likely by inhibiting uptake. The results of this study are useful in the further development of zebrafish as a model organism for DA-related neurological disorders such as Parkinson's disease, schizophrenia, and drug addiction.


Assuntos
Autorreceptores , Peixe-Zebra , Animais , Autorreceptores/metabolismo , Encéfalo/metabolismo , Fibra de Carbono , Desipramina , Dopamina , Estimulação Elétrica , Mamíferos/metabolismo , Nomifensina , Proteínas da Membrana Plasmática de Transporte de Norepinefrina , Pramipexol , Receptores de Dopamina D2/metabolismo , Tetra-Hidronaftalenos , Peixe-Zebra/metabolismo
8.
Curr Opin Oncol ; 34(6): 635-642, 2022 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-36000362

RESUMO

PURPOSE OF REVIEW: Oral SERDs are under extensive development to overcome fulvestrant main limitations, including intramuscular-only formulation and poor performance in early-stage hormone receptor-positive (HR+)/HER2-negative breast cancer. This review summarizes the most relevant evidence published so far and envisions the potential integration of oral SERDs in the therapeutic algorithm of HR+/HER2-negative metastatic breast cancer (MBC). RECENT FINDINGS: Amcenestrant and giredestrant, two of the most promising oral SERDs, recently failed to show a significant improvement in progression-free survival (PFS) in pivotal trials. Conversely, elacestrant demonstrated significant PFS superiority over standard-of-care endocrine therapy (aromatase inhibitors or fulvestrant) in MBC. Additionally, it did not show unusual side effects observed with other oral SERDs, like bradycardia, hematotoxicity and vision impairment, and proved to be effective also in case of ESR1 -mutant endocrine-resistant breast cancer. Combination trials of oral SERDs with target agents, such as CDK4/6-inhibitors, are ongoing. Finally, some window-of-opportunity trials showed promising on-target activity in early-stage for this drug class. SUMMARY: Promising results from early-phase trials are not translating into sufficient clinical benefit in pivotal trials of main oral SERDs in monotherapy, except for elacestrant. Whether oral SERDs might become the backbone for combination strategies in MBC or the preferred (neo)adjuvant endocrine agents is under evaluation.


Assuntos
Neoplasias da Mama , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Inibidores da Aromatase , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Feminino , Fulvestranto/uso terapêutico , Humanos , Receptor ErbB-2 , Receptores de Estrogênio , Tetra-Hidronaftalenos
9.
Molecules ; 27(15)2022 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-35956823

RESUMO

Fish consumption is an indicator of human exposure to personal care products (PCP) such as tonalide (AHTN) and benzophenone 3 (BP3). Although most fish consumed is cooked, the impact of cooking procedures on PCP levels is difficult to evaluate. Hence, the aim of this work was to provide thorough information on the stability and bioaccessibility of AHTN and BP3 upon cooking and in vitro digestion. A green tea (Camellia sinensis) marinade, rich in polyphenol, was used as mitigating strategy to reduce these contaminants. Roasting and frying reduced AHTN and BP3 levels in European seabass (Dicentrarchus labrax) spiked samples. Additionally, the green tea marinade promoted a reduction of up to 47% AHTN and 35% BP3. Bioaccessibility of AHTN was higher (up to 45%), and increased with the use of green tea marinades. BP3 showed a bioaccessibility below 19% in all cooked samples. Overall, a decrease in PCP levels was observed after cooking; this decrease was even more pronounced when marination was previously used. However, this decrease is cancelled out by the fact that the bioaccessible fraction of the contaminants increases in an inverse way; therefore, none of these processes can be considered a mitigating alternative.


Assuntos
Bass , Chá , Animais , Benzofenonas , Culinária/métodos , Humanos , Tetra-Hidronaftalenos
10.
Mol Cancer Ther ; 21(9): 1485-1496, 2022 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-35793463

RESUMO

Bexarotene is a specific retinoid X receptor agonist that has been used for the treatment of cutaneous T-cell lymphoma (CTCL). Because bexarotene causes hypothyroidism, it requires the administration of levothyroxine. However, levothyroxine, in addition to its ubiquitous nuclear receptors, can activate the αVß3 integrin that is overexpressed in CTCL, potentially interfering the antineoplastic effect of bexarotene. We thus investigated the biological effect of levothyroxine in relation to bexarotene treatment. Although in isolated CTCL cells levothyroxine decreased, in an αVß3-dependent manner, the antineoplastic effect of bexarotene, levothyroxine supplementation in preclinical models was necessary to avoid suppression of lymphoma immunity. Accordingly, selective genetic and pharmacologic inhibition of integrin αVß3 improved the antineoplastic effect of bexarotene plus levothyroxine replacement while maintaining lymphoma immunity. Our results provide a mechanistic rationale for clinical testing of integrin αVß3 inhibitors as part of CTCL regimens based on bexarotene administration. TEASER: Inhibiting αVß3 integrin improves the antineoplastic effect of bexarotene while maintaining lymphoma immunity.


Assuntos
Anticarcinógenos , Antineoplásicos , Linfoma Cutâneo de Células T , Neoplasias Cutâneas , Anticarcinógenos/farmacologia , Anticarcinógenos/uso terapêutico , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Bexaroteno/farmacologia , Bexaroteno/uso terapêutico , Humanos , Integrina alfaVbeta3 , Linfoma Cutâneo de Células T/tratamento farmacológico , Linfoma Cutâneo de Células T/patologia , Neoplasias Cutâneas/patologia , Tetra-Hidronaftalenos/farmacologia , Tetra-Hidronaftalenos/uso terapêutico , Tiroxina/uso terapêutico
11.
Comput Math Methods Med ; 2022: 9889534, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35813440

RESUMO

Objective: To explore the application influence of dexmedetomidine (DEX) and dezocine in patients undergoing lung cancer surgery under general anesthesia and analysis of their roles in recovery time and cognitive function. Methods: A total of 120 patients who accepted thoracoscopic pulmonary wedge resection in our hospital from November 2021 to April 2022 were selected and randomly divided into group A (n =60) and group B (n =60). DEX combined with dezocine-assisted anesthesia was performed to group A, and the equal dose of normal saline was administered to group B, so as to compare their inflammatory influence level, brain function, arterial blood gas index, and cognitive function. Results: Compared with group B, group A obtained significantly lower intraoperative and postoperative inflammatory factor levels (P < 0.001), better postoperative brain function and arterial blood gas index (P < 0.001), and lower Loewenstein Occupational Therapy Cognitive Assessment (LOTCA) scores after surgery (P < 0.001). Combining DEX with dezocine-assisted general anesthesia can improve the inflammatory factors level of patients undergoing lung cancer surgery and maintain their brain function and oxygen saturation, so that they have better postoperative cognitive function. Therefore, such anesthesia modality should be promoted in practice.


Assuntos
Compostos Bicíclicos Heterocíclicos com Pontes , Dexmedetomidina , Neoplasias Pulmonares , Tetra-Hidronaftalenos , Anestesia Geral , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Cognição , Dexmedetomidina/uso terapêutico , Combinação de Medicamentos , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/cirurgia , Tetra-Hidronaftalenos/uso terapêutico
14.
Phytomedicine ; 104: 154257, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35738117

RESUMO

BACKGROUND: Nardostachys jatamansi DC. is a common medicinal herb used to treat cardiovascular diseases, particularly hypertension. Previously, our lab characterized the chemical compounds of N. jatamansi. However, the bioactive compounds of N. jatamansi and their mechanisms of action on blood pressure and blood vessels are unknown. PURPOSE: The vasorelaxant effects of the methanolic extract (MeOH ext.) of the roots and rhizomes of N. jatamansi, its main compounds, and their underlying mode of action, were investigated. METHODS: The main compounds of N. jatamansi were isolated and identified using UHPLC-TOF MS. The antihypertensive effect of N. jatamansi extracts and (-)-aristolone were determined using spontaneously hypertensive rats. The extracts, fractions, and compounds were also evaluated for their vasorelaxant effects on U46619 contractile responses in isolated thoracic aortic and mesenteric arterial rings. The endothelial-dependent relaxation, as well as the regulatory pathways and targets of (-)-aristolone, were studied in-vitro and ex-vivo. Molecular docking and biophysical characterization (Surface plasmon resonance) studies were utilized to investigate the molecular interaction between (-)-aristolone and the target protein. RESULTS: MeOH ext. (200 mg/kg) reduces the systolic and diastolic blood pressure in spontaneously hypertensive rats. MeOH ext. and its ethyl acetate fraction (EtOAc Fr.), but not the H2O fraction, had a significant relaxing effect on the thoracic aorta. (-)-aristolone and kanshone H from EtOAc Fr. induced vasorelaxation of the thoracic aorta and mesenteric artery. In human umbilical vein endothelial cells, (-)-aristolone treatment upregulated phosphorylation of Akt (T308) and eNOS. Molecular docking and surface plasmon resonance experiments revealed an interaction between (-)-aristolone and phosphoinositide-dependent protein kinase 1 (PDK1), an upstream protein kinase that phosphorylates Akt at T308. Treatment with PDK1 inhibitor PHT-427 and eNOS inhibitor L-NAME consistently inhibited (-)-aristolone-induced vasorelaxation. In addition, KATP channel inhibitor glibenclamide dramatically inhibited the vasorelaxant effects of (-)-aristolone and kanshone H in the endothelium-denuded thoracic aorta. Finally, (-)-aristolone lowers hypertensive rats' systolic and diastolic blood pressure. CONCLUSIONS: The extracts of N. jatamansi promote vasorelaxation and alleviate hypertension. The essential chemicals responsible for producing vasorelaxation effects are (-)-aristolone and kanshone H, which activate the PDK1-Akt-eNOS-NO relaxing pathway and stimulate the opening of the KATP channel. These findings point to N. jatamansi and aristolone as possible antihypertensive agents.


Assuntos
Hipertensão , Nardostachys , Trifosfato de Adenosina/metabolismo , Animais , Anti-Hipertensivos/uso terapêutico , Aorta Torácica , Ciclopropanos , Células Endoteliais/metabolismo , Endotélio Vascular , Humanos , Hipertensão/metabolismo , Simulação de Acoplamento Molecular , Nardostachys/química , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Ratos Endogâmicos SHR , Tetra-Hidronaftalenos , Vasodilatação , Vasodilatadores/química
15.
Eur Rev Med Pharmacol Sci ; 26(10): 3437-3443, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35647823

RESUMO

OBJECTIVE: The aim of this study was to explore the effects of dezocine combined with dexmedetomidine on adverse reactions and inflammatory factors in patients undergoing hyperthermic intraperitoneal chemotherapy (HIPEC) after intestinal surgery and its protective effect on the heart in the perioperative period. PATIENTS AND METHODS: A total of 80 patients treated with HIPEC after intestinal surgery in our hospital from September 2018 to December 2019 were enrolled as research subjects. All patients were evenly divided into two groups using a random number table. As to analgesia and sedation during treatment, dezocine was injected intramuscularly at 30 min before treatment in the control group. Meanwhile, dezocine combined with dexmedetomidine was given in the same way in the observation group. Adverse reactions and changes in numeric rating scale (NRS) pain score during intervention were compared between the two groups. The changes in the levels of inflammatory and myocardial injury-related factors, and vascular endothelial function and regeneration ability among cardiovascular indicators at 12 h after intervention were compared as well. Additionally, the correlations of left ventricular mass index (LVMI) with the changes in the levels of inflammatory factor high-sensitivity C-reactive protein (hs-CRP), myocardial injury-related factor lactic dehydrogenase (LDH), vascular endothelial function indicator endothelin-1 (ET-1) and cardiovascular regeneration ability index vascular endothelial growth factor (VEGF) were analyzed. RESULTS: Compared with control group, the total prevalence rate of severe pain, respiratory depression, nausea and vomiting, diarrhea, and muscle rigidity during intervention was significantly reduced in the observation group (p<0.05). NRS pain score at 1, 4, 8 and 12 h after intervention decreased remarkably in the observation group compared with the control group (p<0.05). Meanwhile, the levels of inflammatory factors tumor necrosis factor-α (TNF-α) and hs-CRP, and myocardial injury-related factors LDH and creatine kinase MB (CKMB) as well as ET-1 at 12 h after intervention declined remarkably in observation group compared with control group (p<0.05). However, the levels of nitric oxide (NO), VEGF and basic fibroblast growth factor (bFGF) rose significantly in the observation group (p<0.05). Besides, LVMI was positively correlated with hs-CRP and LDH, whereas was negatively associated with ET-1 and VEGF (p<0.05). CONCLUSIONS: In HIPEC, dezocine combined with dexmedetomidine used for sedation and analgesia is able to effectively reduce adverse reactions and relieve inflammatory responses in vivo, exerting a cardio-protective effect.


Assuntos
Compostos Bicíclicos Heterocíclicos com Pontes , Dexmedetomidina , Quimioterapia Intraperitoneal Hipertérmica , Tetra-Hidronaftalenos , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Proteína C-Reativa , Dexmedetomidina/uso terapêutico , Procedimentos Cirúrgicos do Sistema Digestório , Humanos , Quimioterapia Intraperitoneal Hipertérmica/efeitos adversos , Dor/tratamento farmacológico , Período Perioperatório , Tetra-Hidronaftalenos/uso terapêutico , Fator A de Crescimento do Endotélio Vascular
16.
Neurol Sci ; 43(10): 5821-5837, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35691972

RESUMO

BACKGROUND: Rotigotine transdermal patch (TP) is a useful dopaminergic medication for Parkinson's disease (PD). This meta-analysis attempted to evaluate the effects of rotigotine TP on motor performance, activities of daily living (ADL) limitations, and sleep disturbances in patients with PD. METHODS: Only randomized controlled clinical trials (RCTs) with placebo design were included in this study. The clinical outcomes, evaluated using the Unified Parkinson's Disease Rating Scale (UPDRS III), UPDRS-II, UPDRS Part II + III, Parkinson's Disease Sleep Scale (PDSS)-2, and adverse events (AEs) were evaluated. The Jadad scale was used to evaluate study quality. RESULTS: A total of 16 RCTs with 4682 patients with PD were enrolled in this study. We found that rotigotine TP significantly reduced the UPDRS-III, UPDRS-II, and UPDRS Part II + III scores, indicating that rotigotine TP led to a significant amelioration of movement symptoms and ADL limitations. Moreover, we found that rotigotine TP significantly reduced PDSS-2 scores, suggesting that rotigotine TP led to a remarkable improvement in sleep quality. Meanwhile, compared with the placebo group, patients taking rotigotine TP did not have added incidence of AEs. CONCLUSION: This study verified the efficacy and safety of rotigotine TP in treating PD. The findings of the present study provide compelling evidence concerning and insight into clinical usage of rotigotine TP. Future studies will focus on more non-motor symptoms affected by rotigotine TP.


Assuntos
Doença de Parkinson , Tetra-Hidronaftalenos , Tiofenos , Atividades Cotidianas , Agonistas de Dopamina/efeitos adversos , Humanos , Doença de Parkinson/tratamento farmacológico , Ensaios Clínicos Controlados Aleatórios como Assunto , Transtornos do Sono-Vigília/induzido quimicamente , Tetra-Hidronaftalenos/efeitos adversos , Tiofenos/efeitos adversos
17.
J Pharmacol Exp Ther ; 382(2): 208-222, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35764327

RESUMO

X-linked adrenoleukodystrophy (ALD) is a severe orphan disease caused by mutations in the peroxisomal ABCD1 transporter gene, leading to toxic accumulation of Very Long-Chain Fatty Acids (VLCFA - in particular C26:0) resulting in inflammation, mitochondrial dysfunction and demyelination. AMP-activated protein kinase (AMPK) is downregulated in ALD, and its activation is implicated as a therapeutic target. PXL770 is the first direct allosteric AMPK activator with established clinical efficacy and tolerability. Methods: We investigated its effects in ALD patient-derived fibroblasts/lymphocytes and Abcd1 KO mouse glial cells. Readouts included VLCFA levels, mitochondrial function and mRNA levels of proinflammatory genes and compensatory transporters (ABCD2-3). After PXL770 treatment in Abcd1 KO mice, we assessed VLCFA levels in tissues, sciatic nerve axonal morphology by electronic microscopy and locomotor function by open-field/balance-beam tests. Results: In patients' cells and Abcd1 KO glial cells, PXL770 substantially decreased C26:0 levels (by ∼90%), improved mitochondrial respiration, reduced expression of multiple inflammatory genes and induced expression of ABCD2-3 In Abcd1 KO mice, PXL770 treatment normalized VLCFA in plasma and significantly reduced elevated levels in brain (-25%) and spinal cord (-32%) versus untreated (P < 0.001). Abnormal sciatic nerve axonal morphology was also improved along with amelioration of locomotor function. Conclusion: Direct AMPK activation exerts beneficial effects on several hallmarks of pathology in multiple ALD models in vitro and in vivo, supporting clinical development of PXL770 for this disease. Further studies would be needed to overcome limitations including small sample size for some parameters, lack of additional in vivo biomarkers and incomplete pharmacokinetic characterization. SIGNIFICANCE STATEMENT: Adrenoleukodystrophy is a rare and debilitating condition with no approved therapies, caused by accumulation of very long-chain fatty acids. AMPK is downregulated in the disease and has been implicated as a potential therapeutic target. PXL770 is a novel clinical stage direct AMPK activator. In these studies, we used PXL770 to achieve preclinical validation of direct AMPK activation for this disease - based on correction of key biochemical and functional readouts in vitro and in vivo, thus supporting clinical development.


Assuntos
Adrenoleucodistrofia , Piridonas/farmacologia , Tetra-Hidronaftalenos/farmacologia , Proteínas Quinases Ativadas por AMP/metabolismo , Membro 1 da Subfamília D de Transportadores de Cassetes de Ligação de ATP/genética , Transportadores de Cassetes de Ligação de ATP/genética , Monofosfato de Adenosina , Adenilato Quinase/metabolismo , Adrenoleucodistrofia/tratamento farmacológico , Adrenoleucodistrofia/genética , Adrenoleucodistrofia/metabolismo , Animais , Ácidos Graxos/metabolismo , Camundongos
18.
J Clin Oncol ; 40(28): 3246-3256, 2022 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-35584336

RESUMO

PURPOSE: Patients with pretreated estrogen receptor (ER)-positive/human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer have poor prognosis. Elacestrant is a novel, oral selective ER degrader that demonstrated activity in early studies. METHODS: This randomized, open-label, phase III trial enrolled patients with ER-positive/HER2-negative advanced breast cancer who had one-two lines of endocrine therapy, required pretreatment with a cyclin-dependent kinase 4/6 inhibitor, and ≤ 1 chemotherapy. Patients were randomly assigned to elacestrant 400 mg orally once daily or standard-of-care (SOC) endocrine monotherapy. Primary end points were progression-free survival (PFS) by blinded independent central review in all patients and patients with detectable ESR1 mutations. RESULTS: Patients were randomly assigned to elacestrant (n = 239) or SOC (n = 238). ESR1 mutation was detected in 47.8% of patients, and 43.4% received two prior endocrine therapies. PFS was prolonged in all patients (hazard ratio = 0.70; 95% CI, 0.55 to 0.88; P = .002) and patients with ESR1 mutation (hazard ratio = 0.55; 95% CI, 0.39 to 0.77; P = .0005). Treatment-related grade 3/4 adverse events occurred in 7.2% receiving elacestrant and 3.1% receiving SOC. Treatment-related adverse events leading to treatment discontinuations were 3.4% in the elacestrant arm versus 0.9% in SOC. Nausea of any grade occurred in 35.0% receiving elacestrant and 18.8% receiving SOC (grade 3/4, 2.5% and 0.9%, respectively). CONCLUSION: Elacestrant is the first oral selective ER degrader demonstrating a significant PFS improvement versus SOC both in the overall population and in patients with ESR1 mutations with manageable safety in a phase III trial for patients with ER-positive/HER2-negative advanced breast cancer.


Assuntos
Neoplasias da Mama , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Quinase 4 Dependente de Ciclina , Antagonistas de Estrogênios/uso terapêutico , Feminino , Humanos , Receptor ErbB-2/metabolismo , Receptores de Estrogênio/metabolismo , Tetra-Hidronaftalenos
19.
J Neural Transm (Vienna) ; 129(7): 889-894, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35503480

RESUMO

BACKGROUND: Twenty-four-hour treatment options could provide a continuous drug delivery strategy in advanced Parkinson's disease and can ameliorate motor and non-motor complications. Use of levodopa infusion is often limited to 12-16 h/day due to its cost. Adjunctive overnight rotigotine transdermal patch is a continuous drug delivery option successfully used in clinical practice coupled with apomorphine infusion. However, real-life data addressing the tolerability of transdermal dopamine agonist therapy with concomitant use of intrajejunal levodopa infusion in advanced Parkinson's disease are not available. OBJECTIVE: To evaluate the tolerability and beneficial effects of combined therapy with overnight rotigotine transdermal patch and intrajejunal levodopa infusion over a follow-up period of 12 months in advanced Parkinson's disease. METHOD: In this retrospective data analysis, data before and after the initiation of the continuous drug delivery combined therapy using overnight rotigotine transdermal patch and intrajejunal levodopa infusion were collected from the ongoing non-motor-international-longitudinal study (NILS) and local clinical practice at King's College Hospital (London, United Kingdom). 12 advanced Parkinson's disease patients on intrajejunal levodopa therapy who were additionally treated with overnight rotigotine transdermal patch (mean dose 5.67 ± 4.19 mg) are included. Tolerability over a 12-month period was assessed. In addition, changes in motor symptoms (SCales for Outcomes in Parkinson's disease, SCOPA-Motor), non-motor symptoms (Non-Motor Symptoms Scale, NMSS) and quality of life (Parkinson's disease Questionnaire-8, PDQ-8) before and 12-month after continuous drug delivery combined therapy initiation are evaluated. RESULTS: Tolerability was 100% irrespective of age, disease duration, stages of disease. (Treatment with overnight rotigotine transdermal patch that was maintained for a minimum of 6 months was considered "tolerated", primary tolerability). In addition, we noted a significant reduction of the NMSS total score (p = 0.009) and the NMSS domain 3 score (mood and apathy domain) (p = 0.028), although the latter did not remain statistically significant after correction for multiple testing (p2 = 0.252) at 12 months. CONCLUSION: Combination of intrajejunal levodopa infusion with overnight rotigotine transdermal patch is well tolerated and extend the beneficial effects of infusion with excellent tolerability; and also improved aspects of mood and apathy sustained at 12 months in advanced Parkinson's disease.


Assuntos
Levodopa , Doença de Parkinson , Administração Cutânea , Agonistas de Dopamina/farmacologia , Humanos , Levodopa/efeitos adversos , Estudos Longitudinais , Doença de Parkinson/complicações , Doença de Parkinson/tratamento farmacológico , Qualidade de Vida , Estudos Retrospectivos , Tetra-Hidronaftalenos , Tiofenos , Adesivo Transdérmico
20.
Elife ; 112022 05 16.
Artigo em Inglês | MEDLINE | ID: mdl-35575456

RESUMO

Chemical manipulation of estrogen receptor alpha ligand binding domain structural mobility tunes receptor lifetime and influences breast cancer therapeutic activities. Selective estrogen receptor modulators (SERMs) extend estrogen receptor alpha (ERα) cellular lifetime/accumulation. They are antagonists in the breast but agonists in the uterine epithelium and/or in bone. Selective estrogen receptor degraders/downregulators (SERDs) reduce ERα cellular lifetime/accumulation and are pure antagonists. Activating somatic ESR1 mutations Y537S and D538G enable resistance to first-line endocrine therapies. SERDs have shown significant activities in ESR1 mutant setting while few SERMs have been studied. To understand whether chemical manipulation of ERα cellular lifetime and accumulation influences antagonistic activity, we studied a series of methylpyrollidine lasofoxifene (Laso) derivatives that maintained the drug's antagonistic activities while uniquely tuning ERα cellular accumulation. These molecules were examined alongside a panel of antiestrogens in live cell assays of ERα cellular accumulation, lifetime, SUMOylation, and transcriptional antagonism. High-resolution x-ray crystal structures of WT and Y537S ERα ligand binding domain in complex with the methylated Laso derivatives or representative SERMs and SERDs show that molecules that favor a highly buried helix 12 antagonist conformation achieve the greatest transcriptional suppression activities in breast cancer cells harboring WT/Y537S ESR1. Together these results show that chemical reduction of ERα cellular lifetime is not necessarily the most crucial parameter for transcriptional antagonism in ESR1 mutated breast cancer cells. Importantly, our studies show how small chemical differences within a scaffold series can provide compounds with similar antagonistic activities, but with greatly different effects of the cellular lifetime of the ERα, which is crucial for achieving desired SERM or SERD profiles.


Assuntos
Neoplasias da Mama , Receptor alfa de Estrogênio/genética , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Antagonistas de Estrogênios/farmacologia , Receptor alfa de Estrogênio/metabolismo , Feminino , Humanos , Ligantes , Mutação , Pirrolidinas , Moduladores Seletivos de Receptor Estrogênico/química , Tetra-Hidronaftalenos
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