RESUMO
Fibroblast growth factors (FGFs) act as proangiogenic and mitogenic cytokines in several cancers, including multiple myeloma (MM). Indeed, corrupted FGF autocrine and paracrine secretion induces an aberrant activation of the FGF receptor (FGFR) signaling sustaining cancer cell spreading and resistance to pharmacological treatments. Thus, FGF traps may represent a promising anti-cancer strategy to hamper the ligand-dependent activation of the FGF/FGFR system. We previously identified NSC12 as the first orally available small molecule FGF trap able to inhibit the growth and progression of several FGF-dependent tumor models. NSC12 is a pregnenolone derivative carrying a 1,1-bis-trifluoromethyl-1,3-propanediol chain in position 17 of the steroid nucleus. Investigation of structure-activity relationships (SARs) provided more potent and specific NSC12 steroid derivatives and highlighted that the C17-side chain is pivotal for the FGF trap activity. Here, a scaffold hopping approach allowed to obtain two FGF trap compounds (22 and 57) devoid of the steroid nucleus and able to efficiently bind FGF2 and to inhibit FGFR activation in MM cells. Accordingly, these compounds exert a potent anti-tumor activity on MM cell lines both in vitro and in vivo and on MM patient-derived primary cells, strongly affecting the survival of both proteasome-inhibitor sensitive and resistant MM cells. These results propose a new therapeutic option for relapsed/refractory MM patients and set the bases for the development of novel FGF traps prone to chemical diversification to be used in the clinic for the treatment of those tumors in which the FGF/FGFR system plays a pivotal role, including MM.
Assuntos
Antineoplásicos , Fatores de Crescimento de Fibroblastos , Mieloma Múltiplo , Receptores de Fatores de Crescimento de Fibroblastos , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/metabolismo , Humanos , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Antineoplásicos/química , Linhagem Celular Tumoral , Receptores de Fatores de Crescimento de Fibroblastos/antagonistas & inibidores , Receptores de Fatores de Crescimento de Fibroblastos/metabolismo , Fatores de Crescimento de Fibroblastos/metabolismo , Relação Estrutura-Atividade , Descoberta de Drogas , Camundongos , Fator 2 de Crescimento de Fibroblastos/metabolismoRESUMO
The human fibroblast growth factor/fibroblast growth factor receptor (FGF/FGFR) axis deregulation is largely involved in supporting the pathogenesis of hematologic malignancies, including Waldenström macroglobulinemia (WM). WM is still an incurable disease, and patients succumb because of disease progression. Therefore, novel therapeutics designed to specifically target deregulated signaling pathways in WM are required. We aimed to investigate the role of FGF/FGFR system blockade in WM by using a pan-FGF trap molecule (NSC12). Wide-transcriptome profiling confirmed inhibition of FGFR signaling in NSC12-treated WM cells; unveiling a significant inhibition of MYD88 was also confirmed at the protein level. Importantly, the NSC12-dependent silencing of MYD88 was functionally active, as it led to inhibition of MYD88-driven pathways, such as BTK and SYK, as well as the MYD88-downstream target HCK. Of note, both canonical and noncanonical NF-κB cascades were downregulated in WM cells upon NSC12 treatment. Functional sequelae exerted by NSC12 in WM cells were studied, demonstrating significant inhibition of WM cell growth, induction of WM cell apoptosis, halting MAPK, JAK/STAT3, and PI3K-Akt pathways. Importantly, NSC12 exerted an anti-WM effect even in the presence of bone marrow microenvironment, both in vitro and in vivo. Our studies provide the evidence for using NSC12 as a specific FGF/FGFR system inhibitor, thus representing a novel therapeutic strategy in WM.
Assuntos
Biomarcadores Tumorais/metabolismo , Colesterol/análogos & derivados , Fatores de Crescimento de Fibroblastos/antagonistas & inibidores , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Fator 88 de Diferenciação Mieloide/antagonistas & inibidores , Receptores de Fatores de Crescimento de Fibroblastos/antagonistas & inibidores , Macroglobulinemia de Waldenstrom/prevenção & controle , Animais , Apoptose , Biomarcadores Tumorais/genética , Proliferação de Células , Colesterol/farmacologia , Perfilação da Expressão Gênica , Humanos , Camundongos , Transdução de Sinais , Células Tumorais Cultivadas , Microambiente Tumoral , Macroglobulinemia de Waldenstrom/genética , Macroglobulinemia de Waldenstrom/metabolismo , Macroglobulinemia de Waldenstrom/patologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
With the aim of identifying novel antagonists selective for the EphA receptor family, a combined experimental and computational approach was taken to investigate the molecular basis of the recognition between a prototypical Eph-ephrin antagonist (UniPR1447) and two representative receptors of the EphA and EphB subfamilies, namely, EphA2 and EphB2 receptors. The conformational free-energy surface (FES) of the binding state of UniPR1447 within the ligand binding domain of EphA2 and EphB2, reconstructed from molecular dynamics (MD) simulations performed on the microsecond time scale, was exploited to drive the design and synthesis of a novel antagonist selective for EphA2 over the EphB2 receptor. The availability of compounds with this pharmacological profile will help discriminate the importance of these two receptors in the insurgence and progression of cancer.
Assuntos
Receptor EphA2 , Receptor EphB2 , Humanos , Ligantes , Simulação de Dinâmica Molecular , Ligação Proteica , Receptor EphA2/antagonistas & inibidores , Receptor EphB2/antagonistas & inibidoresAssuntos
Dermatite Alérgica de Contato , Sesquiterpenos , Humanos , Dermatite Alérgica de Contato/diagnóstico , Dermatite Alérgica de Contato/tratamento farmacológico , Dermatite Alérgica de Contato/etiologia , Testes do Emplastro , Seguimentos , Alérgenos , Sesquiterpenos/efeitos adversos , LactonasRESUMO
BACKGROUND: Numerous clinical studies have shown a correlation between increased matrix metalloproteinase (MMP)/a disintegrin and metalloproteinase (ADAM) activity and poor outcome of cancer. Various MMP inhibitors (MMPIs) have been developed for therapeutic purposes in oncology. In addition, molecular imaging of MMP/ADAM levels in vivo would allow the diagnosis of tumors. We selected the dual inhibitor of MMPs and ADAMs, ML5, which is a hydroxamate-based inhibitor with affinities for many MMPs and ADAMs. ML5 was radiolabelled with (18)F and the newly obtained radiolabelled inhibitor was evaluated in vitro and in vivo. MATERIALS AND METHODS: ML5 was radiolabelled by direct acylation with N-succinimidyl-4-[(18)F]fluorobenzoate ([(18)F]SFB) for PET (positron emission tomography). The resulting radiotracer [(18)F]FB-ML5 was evaluated in vitro in human bronchial epithelium 16HBE cells and breast cancer MCF-7 cells. The non-radioactive probe FB-ML5 and native ML5 were tested in a fluorogenic inhibition assay against MMP-2, -9, -12 and ADAM-17. The in vivo kinetics of [(18)F]FB-ML5 were examined in a HT1080 tumor-bearing mouse model. Specificity of probe binding was examined by co-injection of 0 or 2.5mg/kg ML5. RESULTS: ML5 and FB-ML5 showed high affinity for MMP-2, -9, -12 and ADAM-17; indeed IC50 values were respectively 7.4 ± 2.0, 19.5 ± 2.8, 2.0 ± 0.2 and 5.7 ± 2.2 nM and 12.5 ± 3.1, 31.5 ± 13.7, 138.0 ± 10.9 and 24.7 ± 2.8 nM. Radiochemical yield of HPLC-purified [(18)F]FB-ML5 was 13-16% (corrected for decay). Cellular binding of [(18)F]FB-ML5 was reduced by 36.6% and 27.5% in MCF-7 and 16 HBE cells, respectively, after co-incubation with 10 µM of ML5. In microPET scans, HT1080 tumors exhibited a low and homogeneous uptake of the tracer. Tumors of mice injected with [(18)F]FB-ML5 showed a SUVmean of 0.145 ± 0.064 (n=6) which decreased to 0.041 ± 0.027 (n=6) after target blocking (p<0.05). Ex vivo biodistribution showed a rapid excretion through the kidneys and the liver. Metabolite assays indicated that the parent tracer represented 23.2 ± 7.3% (n=2) of total radioactivity in plasma, at 90 min post injection (p.i.). CONCLUSION: The nanomolar affinity MMP/ADAM inhibitor ML5 was successfully labelled with (18)F. [(18)F]FB-ML5 demonstrated rather low binding in ADAM-17 overexpressing cell lines. [(18)F]FB-ML5 uptake showed significant reduction in the HT1080 tumor in vivo after co-injection of ML5. [(18)F]FB-ML5 may be suitable for the visualization/quantification of diseases overexpressing simultaneously MMPs and ADAMs.
Assuntos
Proteínas ADAM/antagonistas & inibidores , Metaloproteinases da Matriz/química , Tomografia por Emissão de Pósitrons/métodos , Succinimidas/química , Proteínas ADAM/química , Animais , Humanos , Marcação por Isótopo/métodos , Células MCF-7 , Inibidores de Metaloproteinases de Matriz/síntese química , Inibidores de Metaloproteinases de Matriz/química , Camundongos , Modelos Moleculares , Sondas Moleculares , Compostos Radiofarmacêuticos/síntese química , Compostos Radiofarmacêuticos/química , Succinimidas/síntese química , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The EPH receptor A2 (EPHA2) represents an attractive anticancer target. With the aim to identify novel EPHA2 receptor antagonists, a virtual screening campaign, combining shape-similarity and docking calculations, was conducted on a set of commercially available compounds. A combined score, taking into account both ligand- and structure-based results, was then used to identify the most promising candidates. Two compounds, selected among the best-ranked ones, were identified as EPHA2 receptor antagonists with micromolar affinity.
Assuntos
Antineoplásicos/química , Butiratos/química , Ácidos Cólicos/química , Descoberta de Drogas , Efrina-A1/antagonistas & inibidores , Naftalenos/química , Inibidores de Proteínas Quinases/química , Receptor EphA2/antagonistas & inibidores , Sítios de Ligação , Efrina-A1/química , Ensaios de Triagem em Larga Escala , Humanos , Ligantes , Simulação de Acoplamento Molecular , Ligação Proteica , Receptor EphA2/química , Relação Estrutura-Atividade , Interface Usuário-ComputadorRESUMO
In our continuing effort devoted at developing agents targeting the EphA2 receptor by means of protein-protein interaction (PPI) inhibitors, we report here the design and synthesis of a new class of l-ß-homotryptophan conjugates of 3-ß-hydroxy-Δ5-cholenic acid bearing a set of arylsulfonyl substituents at the indole nitrogen atom. An extensive structure-activity relationship (SAR) analysis indicates that the presence of a bulky lipophilic moiety at the indole nitrogen is fundamental for improving potency on the EphA2 receptor, while abrogating activity on the EphB1-EphB3 receptor subtypes. A rational exploration, guided by the combined application of an experimental design on σp and π physicochemical descriptors and docking simulations, led to the discovery of UniPR1454, a 1-(4-(trifluoromethyl)phenyl)sulfonyl derivative acting as potent and competitive EphA2 antagonist able to inhibit ephrin-A1 dependent signals and to reduce proliferation of glioblastoma (U251) cell line at micromolar concentration.
Assuntos
Antineoplásicos , Proliferação de Células , Descoberta de Drogas , Ensaios de Seleção de Medicamentos Antitumorais , Glioblastoma , Indóis , Receptor EphA2 , Humanos , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Glioblastoma/tratamento farmacológico , Glioblastoma/patologia , Glioblastoma/metabolismo , Indóis/farmacologia , Indóis/química , Indóis/síntese química , Simulação de Acoplamento Molecular , Estrutura Molecular , Receptor EphA2/antagonistas & inibidores , Receptor EphA2/metabolismo , Relação Estrutura-Atividade , Hidrocarbonetos Fluorados/síntese química , Hidrocarbonetos Fluorados/química , Hidrocarbonetos Fluorados/farmacologiaRESUMO
Alzheimer's disease (AD) is a neurodegenerative form of dementia characterized by the loss of synapses and a progressive decline in cognitive abilities. Among current treatments for AD, acetylcholinesterase (AChE) inhibitors have efficacy limited to symptom relief, with significant side effects and poor compliance. Pharmacological agents that modulate the activity of type-2 cannabinoid receptors (CB2R) of the endocannabinoid system by activating or blocking them have also been shown to be effective against neuroinflammation. Herein, we describe the design, synthesis, and pharmacological effects in vitro and in vivo of dual-acting compounds that inhibit AChE and butyrylcholinesterase (BChE) and target CB2R. Within the investigated series, compound 4g proved to be the most promising. It achieved IC50 values in the low micromolar to submicromolar range against both human cholinesterase isoforms while antagonizing CB2R with Ki of 31 nM. Interestingly, 4g showed neuroprotective effects on the SH-SY5Y cell line thanks to its ability to prevent oxidative stress-induced cell toxicity and reverse scopolamine-induced amnesia in the Y-maze forced alternation test in vivo.
Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Neuroblastoma , Fármacos Neuroprotetores , Humanos , Butirilcolinesterase/metabolismo , Acetilcolinesterase/metabolismo , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Receptores de Canabinoides , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/uso terapêutico , Doença de Alzheimer/metabolismo , Disfunção Cognitiva/tratamento farmacológico , Simulação de Acoplamento Molecular , Relação Estrutura-AtividadeRESUMO
Carbohydrate-based sensors, that specifically detect sugar binding molecules or cells, are increasingly important in medical diagnostic and drug screening. Here we demonstrate that cantilever arrays functionalized with different mannosides allow the real-time detection of several Escherichia coli strains in solution. Cantilever deflection is thereby dependent on the bacterial strain studied and the glycan used as the sensing molecule. The cantilevers exhibit specific and reproducible deflection with a sensitivity range over four orders of magnitude.
Assuntos
Carga Bacteriana/instrumentação , Técnicas Biossensoriais/instrumentação , Escherichia coli/classificação , Escherichia coli/isolamento & purificação , Manosídeos/química , Análise em Microsséries/instrumentação , Polissacarídeos/química , Desenho de Equipamento , Análise de Falha de Equipamento , Sistemas Microeletromecânicos/instrumentaçãoRESUMO
The Eph-ephrin system plays a critical role in tumor growth and vascular functions during carcinogenesis. We had previously identified cholanic acid as a competitive and reversible EphA2 antagonist able to disrupt EphA2-ephrinA1 interaction and to inhibit EphA2 activation in prostate cancer cells. Herein, we report the synthesis and biological evaluation of a set of cholanic acid derivatives obtained by conjugation of its carboxyl group with a panel of naturally occurring amino acids with the aim to improve EphA2 receptor inhibition. Structure-activity relationships indicate that conjugation of cholanic acid with linear amino acids of small size leads to effective EphA2 antagonists whereas the introduction of aromatic amino acids reduces the potency in displacement studies. The b-alanine derivative 4 was able to disrupt EphA2-ephrinA1 interaction in the micromolar range and to dose-dependently inhibit EphA2 activation on PC3 cells. These findings may help the design of novel EphA2 antagonists active on cancer cell lines.
Assuntos
Ácidos Cólicos/farmacologia , Receptor EphA2/antagonistas & inibidores , Sítios de Ligação , Linhagem Celular Tumoral , Ácidos Cólicos/síntese química , Ácidos Cólicos/química , Humanos , Ligação de Hidrogênio , Concentração Inibidora 50 , Simulação de Acoplamento Molecular , Fosforilação , Ligação Proteica , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Estrutura Secundária de Proteína , Receptor EphA1/antagonistas & inibidores , Receptor EphA1/química , Receptor EphA1/metabolismo , Receptor EphA2/química , Receptor EphA2/metabolismo , Relação Estrutura-AtividadeRESUMO
BACKGROUND: Xerosis is an extremely common condition, especially in the elderly population. It is the most common cause of pruritus in the older adult. Since xerosis is generally caused by a lack of epidermal lipids, the use of leave-on skin care products is the mainstay treatment. The aim of this open prospective analytical observational study was to investigate the clinical and self-reported hydrating efficacy of a moisturizer formulation containing a synergy between amino-inositol and urea (INOSIT-U 20) in patients with psoriasis and xerosis. METHODS: Twenty-two patients with psoriasis successfully treated with biologic therapy, and who presented xerosis, were recruited. Each patient was instructed to apply the topical with a frequency of two applications per die on the identified skin area. Corneometry values and a VAS itch questionnaire were measured at baseline (T0) and after 28 days (T4). To evaluate the cosmetic efficacy, the volunteers also completed a self-assessment questionnaire. RESULTS: Comparing Corneometry values at T0 and T4, a statistically significant increase value was observed in the area subjected to topical treatment (P<0.0001). A significant decrease in itch (P=0.001) was also observed. Moreover, the patients' ratings of the cosmetic properties of the moisturizer showed significant confirmation rates. CONCLUSIONS: This study provides preliminary evidence that INOSIT-U20 provides a good hydrating effect on xerosis, further reducing self-reported itch.
Assuntos
Doenças do Sistema Nervoso Autônomo , Psoríase , Dermatopatias , Humanos , Idoso , Emolientes/uso terapêutico , Estudos Prospectivos , Prurido/tratamento farmacológico , Prurido/etiologia , Dermatopatias/complicações , Doenças do Sistema Nervoso Autônomo/complicações , Doenças do Sistema Nervoso Autônomo/tratamento farmacológico , Psoríase/complicações , Psoríase/tratamento farmacológicoRESUMO
The Eph kinases are the largest receptor tyrosine kinases (RTKs) family in humans. PC3 human prostate adenocarcinoma cells are a well-established model for studying Eph-ephrin pharmacology as they naturally express a high level of EphA2, a promising target for new cancer therapies. A pharmacological approach with agonists did not show significant efficacy on tumor growth in prostate orthotopic murine models, but reduced distal metastasis formation. In order to improve the comprehension of the pharmacological targeting of Eph receptors in prostate cancer, in the present work, we investigated the efficacy of Eph antagonism both in vitro and in vivo, using UniPR1331, a small orally bioavailable Eph-ephrin interaction inhibitor. UniPR1331 was able to inhibit PC3 cells' growth in vitro in a dose-dependent manner, affecting the cell cycle and inducing apoptosis. Moreover, UniPR1331 promoted the PC3 epithelial phenotype, downregulating epithelial mesenchymal transition (EMT) markers. As a consequence, UniPR1331 reduced in vitro PC3 migration, invasion, and vasculomimicry capabilities. The antitumor activity of UniPR1331 was confirmed in vivo when administered alone or in combination with cytotoxic drugs in PC3-xenograft mice. Our results demonstrated that Eph antagonism is a promising strategy for inhibiting prostate cancer growth, especially in combination with cytotoxic drugs.
RESUMO
The role of the Eph-ephrin system in the etiology of pathological conditions has been consolidated throughout the years. In this context, approaches directed against this signaling system, intended to modulate its activity, can be strategic therapeutic opportunities. Currently, the most promising class of compounds able to interfere with the Eph receptor-ephrin protein interaction is composed of synthetic derivatives of bile acids. In the present review, we summarize the progresses achieved, in terms of chemical expansions and structure-activity relationships, both in the steroidal core and the terminal carboxylic acid group, along with the pharmacological characterization for the most promising Eph-ephrin antagonists in in vivo settings.
RESUMO
Acne fulminans (AF) is a rare and severe form of inflammatory acne that typically occurs in male adolescents with acne vulgaris and is characterized by the sudden onset of painful, bleeding, and ulcerated lesions. It has been described very rarely in association with hidradenitis suppurativa (HS). Its onset may be induced by drugs, particularly isotretinoin. We present a case of a 16-year-old patient with HS who developed AF following initiation of antibiotic therapy with lymecycline. In the literature, only 2 patients who developed a coexistence of AF and HS have been reported, and there are only 2 other similar cases of AF induced by doxycycline and lymecycline. We consider our case to be of particular interest not only because of the very rare concomitant presence of AF and HS but also because AF was induced by lymecycline, a drug commonly used to treat both acne and HS, and described only once as a drug responsible for AF, so it is an aspect that deserves to be considered by the clinician dealing with similar conditions.
RESUMO
Clinical management of adult patients with congenital heart disease (GUCH) is a difficult task for multiple reasons, which include their own pathology and clinical history complexity, diagnostic complexity and organization of care. GUCH specialists are present in very small numbers and are concentrated in few centers, thus generating considerable transfer problems for patients. During the COVID-19 pandemic, telemedicine has become the standard of care, ensuring health assistance continuity, and implementing communication channels between patients and health professionals. We suggest to stratify GUCH patients into three groups, which correspond to different levels of risk (low, moderate and high, respectively) to develop complications over time, using a GUCH-specific multiparametric complexity score; so, each patient pathway will be defined according to the specific group, with indication of site, timing and type of clinical and instrumental evaluations, including virtual visits and consults. In conclusion, practical tools are provided for the implementation of updated care pathways for GUCH patients, who finally are inserted in a new model of care in which even if in-person visit still represents the crucial moment of each patient care pathway, on the other hand, telemedicine incorporation could contribute to improving and making even more complete and effective GUCH patient care.
Assuntos
COVID-19 , Cardiopatias Congênitas , Telemedicina , Adulto , Procedimentos Clínicos , Cardiopatias Congênitas/diagnóstico , Cardiopatias Congênitas/terapia , Humanos , PandemiasRESUMO
In crystal structures of melatonin MT1 and MT2 receptors, a lipophilic subpocket has been characterized which accommodates the phenyl ring of the potent agonist 2-phenylmelatonin. This subpocket appears a key structural element to achieve high binding affinity and selectivity for the MT2 receptor. A series of 2-arylindole ligands was synthesized to probe the requirements for the optimal occupation and interaction with the 2-phenyl binding pocket. Thermodynamic integration simulations applied to MT1 and MT2 receptors in complex with the α-naphthyl derivative provided a rationale for the MT2-selectivity and investigation on the binding mode of a couple of atropisomers allowed to define the available space and arrangement of substituents inside the subpocket. Interestingly, more hydrophilic 2-aza-substituted compounds displayed high binding affinity and molecular dynamics simulations highlighted polar interaction with residues from the subpocket that could be responsible for their potency.
Assuntos
Melatonina , Receptor MT1 de Melatonina , Receptor MT2 de Melatonina , Ligantes , Melatonina/análogos & derivados , Melatonina/química , Melatonina/metabolismo , Simulação de Dinâmica Molecular , Receptor MT1 de Melatonina/química , Receptor MT1 de Melatonina/metabolismo , Receptor MT2 de Melatonina/química , Receptor MT2 de Melatonina/metabolismoRESUMO
Angiogenesis, the formation of new blood vessels from preexisting ones, is crucial for tumor growth and metastatization, and is considered a promising therapeutic target. Unfortunately, drugs directed against a specific proangiogenic growth factor or receptor turned out to be of limited benefit for oncology patients, likely due to the high biochemical redundancy of the neovascularization process. In this scenario, multitarget compounds that are able to simultaneously tackle different proangiogenic pathways are eagerly awaited. UniPR1331 is a 3ß-hydroxy-Δ5-cholenic acid derivative, which is already known to inhibit Eph-ephrin interaction. Here, we employed an analysis pipeline consisting of molecular modeling and simulation, surface plasmon resonance spectrometry, biochemical assays, and endothelial cell models to demonstrate that UniPR1331 directly interacts with the vascular endothelial growth factor receptor 2 (VEGFR2) too. The binding of UniPR1331 to VEGFR2 prevents its interaction with the natural ligand vascular endothelial growth factor and subsequent autophosphorylation, signal transduction, and in vitro proangiogenic activation of endothelial cells. In vivo, UniPR1331 inhibits tumor cell-driven angiogenesis in zebrafish. Taken together, these data shed light on the pleiotropic pharmacological effect of UniPR1331, and point to Δ5-cholenic acid as a promising molecular scaffold for the development of multitarget antiangiogenic compounds.
Assuntos
Efrinas , Receptor 2 de Fatores de Crescimento do Endotélio Vascular , Inibidores da Angiogênese/química , Inibidores da Angiogênese/farmacologia , Inibidores da Angiogênese/uso terapêutico , Animais , Células Endoteliais/metabolismo , Efrinas/metabolismo , Efrinas/farmacologia , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Peixe-Zebra/metabolismoRESUMO
This study aimed to compare adalimumab originator vs. biosimilar in HS patients, and to evaluate the effect of a switch to a biosimilar, or a switch back to the originator, in terms of treatment ineffectiveness. Patients with a diagnosis of HS were enrolled from 14 Italian sites. Treatment ineffectiveness was measured using Hurley score. The major analyses were 1) comparison between the two treatment groups (non-switcher analysis), and 2) the cross-over trend of Hurley score between treatment switchers (switcher analysis). Cox and Poisson regression models were used to compare the treatment ineffectiveness between groups. A total of 326 patients were divided into four groups: 171 (52.5%) taking originator; 61 (18.7%) patients taking biosimilar; 66 (20.2%) switchers; 28 (8.6%) switchers from originator to biosimilar and switched. A greater loss of efficacy was observed in the group allocated to the biosimilar than the originator group. The switcher analysis showed an effectiveness loss in the biosimilar compared to the originator. These results seem to indicate that a switch from one drug to the other may lead to a greater risk of inefficacy. A return to the previous treatment also does not ensure efficaciousness.
RESUMO
Carbohydrate films on gold based on dimannoside thiols (DMT) were prepared, and a complementary surface chemical analysis was performed in detail by X-ray photoelectron spectroscopy (XPS), time-of-flight secondary ion mass spectrometry (ToF-SIMS), near-edge X-ray absorption fine structure (NEXAFS), FT-IR, and contact angle measurements in order to verify formation of ω-carbohydrate-functionalized alkylthiol films. XPS (C 1s, O 1s, and S 2p) reveals information on carbohydrate specific alkoxy (C-O) and acetal moieties (O-C-O) as well as thiolate species attached to gold. Angle-resolved synchrotron XPS was used for chemical speciation at ultimate surface sensitivity. Angle-resolved XPS analysis suggests the presence of an excess top layer composed of unbound sulfur components combined with alkyl moieties. Further support for DMT attachment on Au is given by ToF-SIMS and FT-IR analysis. Carbon and oxygen K-edge NEXAFS spectra were interpreted by applying the building block model supported by comparison to data of 1-undecanethiol, poly(vinyl alcohol), and polyoxymethylene. No linear dichroism effect was observed in the angle-resolved C K-edge NEXAFS.
Assuntos
Dissacarídeos/química , Manosídeos/química , Compostos de Sulfidrila/química , Ouro , Espectroscopia Fotoeletrônica , Propriedades de SuperfícieRESUMO
BACKGROUND: Tildrakizumab is a high-affinity, humanized IgG1κ monoclonal antibody targeting the p19 subunit of IL-23, which is a key regulatory cytokine in psoriasis. Based on evidence from clinical trials, tildrakizumab is approved for the treatment of moderate-to-severe plaque psoriasis in patients eligible for systemic therapy. METHODS: We report our clinical experience with 26 patients followed up to 24 weeks. RESULTS: No adverse event was observed and no patient discontinued tildrakizumab. Whilst no patient had a Psoriasis Area and Severity Index (PASI) score of <5 at baseline, at week 4, 8 (32%) patients had a PASI score of <3 and 6 of these had a PASI score of 0. At week 12, 19 (79%) patients had a PASI score of <5 and, among these, 18 had a PASI score of <3 of whom 16 had a PASI score of 0. At week 24, 22 (96%) patients had a PASI score of <3 and 20 (87%) had a PASI score of 0. Quality of life was improved after 4 weeks and through the whole period of observation. CONCLUSION: Our experience in the real-life setting confirms the efficacy and safety of tildrakizumab as demonstrated by clinical trials.