RESUMO
Advancing cure rates for high-risk acute lymphoblastic leukemia (ALL) has been limited by the lack of agents that effectively kill leukemic cells, sparing normal hematopoietic tissue. Molecular glues direct the ubiquitin ligase cellular machinery to target neosubstrates for protein degradation. We developed a novel cereblon modulator, SJ6986, that exhibits potent and selective degradation of GSPT1 and GSPT2 and cytotoxic activity against childhood cancer cell lines. Here, we report in vitro and in vivo testing of the activity of this agent in a panel of ALL cell lines and xenografts. SJ6986 exhibited similar cytotoxicity to the previously described GSPT1 degrader CC-90009 in a panel of leukemia cell lines in vitro, resulting in apoptosis and perturbation of cell cycle progression. SJ6986 was more effective than CC-90009 in suppressing leukemic cell growth in vivo, partly attributable to favorable pharmacokinetic properties, and did not significantly impair differentiation of human CD34+ cells ex vivo. Genome-wide CRISPR/Cas9 screening of ALL cell lines treated with SJ6986 confirmed that components of the CRL4CRBN complex, associated adaptors, regulators, and effectors were integral in mediating the action of SJ6986. SJ6986 is a potent, selective, orally bioavailable GSPT1/2 degrader that shows broad antileukemic activity and has potential for clinical development.
Assuntos
Antineoplásicos , Piperidonas , Leucemia-Linfoma Linfoblástico de Células Precursoras , Humanos , Criança , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Antineoplásicos/química , Piperidonas/uso terapêutico , Isoindóis/uso terapêuticoRESUMO
Completion of the Lassa virus (LASV) life cycle critically depends on the activities of the virally encoded, RNA-dependent RNA polymerase in replication and transcription of the viral RNA genome in the cytoplasm of infected cells. The contribution of cellular proteins to these processes remains unclear. Here, we applied proximity proteomics to define the interactome of LASV polymerase in cells under conditions that recreate LASV RNA synthesis. We engineered a LASV polymerase-biotin ligase (TurboID) fusion protein that retained polymerase activity and successfully biotinylated the proximal proteome, which allowed the identification of 42 high-confidence LASV polymerase interactors. We subsequently performed a small interfering RNA (siRNA) screen to identify those interactors that have functional roles in authentic LASV infection. As proof of principle, we characterized eukaryotic peptide chain release factor subunit 3a (eRF3a/GSPT1), which we found to be a proviral factor that physically associates with LASV polymerase. Targeted degradation of GSPT1 by a small-molecule drug candidate, CC-90009, resulted in strong inhibition of LASV infection in cultured cells. Our work demonstrates the feasibility of using proximity proteomics to illuminate and characterize yet-to-be-defined host-pathogen interactome, which can reveal new biology and uncover novel targets for the development of antivirals against highly pathogenic RNA viruses.
Assuntos
Acetamidas , Antivirais , Isoindóis , Vírus Lassa , Fatores de Terminação de Peptídeos , Piperidonas , RNA Polimerase Dependente de RNA , Proteínas Virais , Acetamidas/farmacologia , Acetamidas/uso terapêutico , Antivirais/farmacologia , Antivirais/uso terapêutico , Linhagem Celular Tumoral , Humanos , Isoindóis/farmacologia , Isoindóis/uso terapêutico , Febre Lassa/tratamento farmacológico , Vírus Lassa/efeitos dos fármacos , Fatores de Terminação de Peptídeos/metabolismo , Piperidonas/metabolismo , Piperidonas/farmacologia , Piperidonas/uso terapêutico , Mapas de Interação de Proteínas/efeitos dos fármacos , Proteólise/efeitos dos fármacos , Proteoma , Proteômica , RNA Polimerase Dependente de RNA/metabolismo , Proteínas Virais/metabolismoRESUMO
The smallpox infection with the variola virus was one of the most fatal disorders until a global eradication was initiated in the twentieth century. The last cases were reported in Somalia 1977 and as a laboratory infection in the UK 1978; in 1980, the World Health Organization (WHO) declared smallpox for extinct. The smallpox virus with its very high transmissibility and mortality is still a major biothreat, because the vaccination against smallpox was stopped globally in the 1980s. For this reason, new antivirals (cidofovir, brincidofovir, and tecovirimat) and new vaccines (ACAM2000, LC16m8 and Modified Vaccine Ankara MVA) were developed. For passive immunization, vaccinia immune globulin intravenous (VIGIV) is available. Due to the relationships between orthopox viruses such as vaccinia, variola, mpox (monkeypox), cowpox, and horsepox, the vaccines (LC16m8 and MVA) and antivirals (brincidofovir and tecovirimat) could also be used in the mpox outbreak with positive preliminary data. As mutations can result in drug resistance against cidofovir or tecovirimat, there is need for further research. Further antivirals (NIOCH-14 and ST-357) and vaccines (VACΔ6 and TNX-801) are being developed in Russia and the USA. In conclusion, further research for treatment and prevention of orthopox infections is needed and is already in progress. After a brief introduction, this chapter presents the smallpox and mpox disease and thereafter full overviews on antiviral treatment and vaccination including the passive immunization with vaccinia immunoglobulins.
Assuntos
Antivirais , Mpox , Vacina Antivariólica , Varíola , Varíola/prevenção & controle , Varíola/epidemiologia , Varíola/imunologia , Varíola/história , Humanos , Antivirais/uso terapêutico , Vacina Antivariólica/imunologia , Vacina Antivariólica/uso terapêutico , Mpox/epidemiologia , Mpox/prevenção & controle , Mpox/imunologia , Vacinação/métodos , Vírus da Varíola/imunologia , Vírus da Varíola/genética , Animais , Citosina/análogos & derivados , Citosina/uso terapêutico , Monkeypox virus/imunologia , Monkeypox virus/patogenicidade , Monkeypox virus/genética , Imunização Passiva/métodos , Organofosfonatos/uso terapêutico , Isoindóis/uso terapêutico , Cidofovir/uso terapêutico , Imunoglobulinas Intravenosas/uso terapêutico , Benzamidas , FtalimidasRESUMO
As of September 11, 2022, 57 669 reports of monkeypox infection raised global concern. Previous vaccinia virus vaccination can protect from monkeypox. However, after smallpox eradication, immunization against that was stopped. Indeed, therapeutic options following the disease onset are of great value. This study aimed to review the available evidence on virology and treatment approaches for monkeypox and provide guidance for patient care and future studies. Since no randomized clinical trials were ever performed, we reviewed monkeypox animal model studies and clinical trials on the safety and pharmacokinetics of available medications. Brincidofovir and tecovirimat were the most studied medications that got approval for smallpox treatment according to the Animal Rule. Due to the conserved virology among Orthopoxviruses, available medications might also be effective against monkeypox. However, tecovirimat has the strongest evidence to be effective and safe for monkeypox treatment, and if there is a choice between the two drugs, tecovirimat has shown more promise so far. The risk of resistance should be considered in patients who failed to respond to tecovirimat. Hence, the target-based design of novel antivirals will enhance the availability and spectrum of effective anti-Orthopoxvirus agents.
Assuntos
Mpox , Orthopoxvirus , Varíola , Animais , Mpox/tratamento farmacológico , Mpox/prevenção & controle , Varíola/tratamento farmacológico , Vacinação , Benzamidas , Isoindóis/uso terapêuticoRESUMO
A number of clinically validated drugs have been developed by repurposing the CUL4-DDB1-CRBN-RBX1 (CRL4CRBN) E3 ubiquitin ligase complex with molecular glue degraders to eliminate disease-driving proteins. Here, we present the identification of a first-in-class GSPT1-selective cereblon E3 ligase modulator, CC-90009. Biochemical, structural, and molecular characterization demonstrates that CC-90009 coopts the CRL4CRBN to selectively target GSPT1 for ubiquitination and proteasomal degradation. Depletion of GSPT1 by CC-90009 rapidly induces acute myeloid leukemia (AML) apoptosis, reducing leukemia engraftment and leukemia stem cells (LSCs) in large-scale primary patient xenografting of 35 independent AML samples, including those with adverse risk features. Using a genome-wide CRISPR-Cas9 screen for effectors of CC-90009 response, we uncovered the ILF2 and ILF3 heterodimeric complex as a novel regulator of cereblon expression. Knockout of ILF2/ILF3 decreases the production of full-length cereblon protein via modulating CRBN messenger RNA alternative splicing, leading to diminished response to CC-90009. The screen also revealed that the mTOR signaling and the integrated stress response specifically regulate the response to CC-90009 in contrast to other cereblon modulators. Hyperactivation of the mTOR pathway by inactivation of TSC1 and TSC2 protected against the growth inhibitory effect of CC-90009 by reducing CC-90009-induced binding of GSPT1 to cereblon and subsequent GSPT1 degradation. On the other hand, GSPT1 degradation promoted the activation of the GCN1/GCN2/ATF4 pathway and subsequent apoptosis in AML cells. Collectively, CC-90009 activity is mediated by multiple layers of signaling networks and pathways within AML blasts and LSCs, whose elucidation gives insight into further assessment of CC-90009s clinical utility. These trials were registered at www.clinicaltrials.gov as #NCT02848001 and #NCT04336982).
Assuntos
Acetamidas/farmacologia , Proteínas Adaptadoras de Transdução de Sinal/antagonistas & inibidores , Isoindóis/farmacologia , Leucemia Mieloide Aguda/patologia , Terapia de Alvo Molecular , Proteínas de Neoplasias/antagonistas & inibidores , Células-Tronco Neoplásicas/efeitos dos fármacos , Piperidonas/farmacologia , Ubiquitina-Proteína Ligases/antagonistas & inibidores , Acetamidas/uso terapêutico , Animais , Sistemas CRISPR-Cas , Linhagem Celular Tumoral , Humanos , Isoindóis/uso terapêutico , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Modelos Moleculares , Células-Tronco Neoplásicas/enzimologia , Proteína do Fator Nuclear 45/fisiologia , Proteínas do Fator Nuclear 90/fisiologia , Fatores de Terminação de Peptídeos/metabolismo , Piperidonas/uso terapêutico , Complexo de Endopeptidases do Proteassoma/metabolismo , Conformação Proteica , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Proteólise , Bibliotecas de Moléculas Pequenas , Estresse Fisiológico , Serina-Treonina Quinases TOR/fisiologia , Células U937 , Ubiquitinação/efeitos dos fármacos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Tecovirimat is an antiviral drug initially developed against variola virus (VARV) to treat smallpox infection. Due to its mechanism of action, it has activity against the family of orthopoxviruses, including vaccinia and the human monkeypox virus (HMPXV). Efficacy studies have thus far been limited to animal models, with human safety trials showing no serious adverse events. Currently approved by the FDA only for the treatment of smallpox, tecovirimat shows promise for the treatment of HMPXV. Tecovirimat has been prescribed via an expanded access for an investigational new drug protocol during the 2022 outbreak. This review will examine the literature surrounding tecovirimat's mechanism of action, pharmacokinetics, safety, efficacy, and potential for resistance.
Assuntos
Mpox , Varíola , Vírus da Varíola , Animais , Humanos , Varíola/tratamento farmacológico , Monkeypox virus , Antivirais/efeitos adversos , Benzamidas/farmacologia , Benzamidas/uso terapêutico , Isoindóis/uso terapêutico , Isoindóis/farmacologia , Mpox/tratamento farmacológicoRESUMO
The main protease (Mpro or 3CLpro) of SARS-CoV-2 virus is a cysteine enzyme critical for viral replication and transcription, thus indicating a potential target for antiviral therapy. A recent repurposing effort has identified ebselen, a multifunctional drug candidate as an inhibitor of Mpro. Our docking of ebselen to the binding pocket of Mpro crystal structure suggests a noncovalent interaction for improvement of potency, antiviral activity and selectivity. To test this hypothesis, we designed and synthesized ebselen derivatives aimed at enhancing their non-covalent bonds within Mpro. The inhibition of Mpro by ebselen derivatives (0.3 µM) was screened in both HPLC and FRET assays. Nine ebselen derivatives (EBs) exhibited stronger inhibitory effect on Mpro with IC50 of 0.07-0.38 µM. Further evaluation of three derivatives showed that EB2-7 exhibited the most potent inhibition of SARS-CoV-2 viral replication with an IC50 value of 4.08 µM in HPAepiC cells, as compared to the prototype ebselen at 24.61 µM. Mechanistically, EB2-7 functions as a noncovalent Mpro inhibitor in LC-MS/MS assay. Taken together, our identification of ebselen derivatives with improved antiviral activity may lead to developmental potential for treatment of COVID-19 and SARS-CoV-2 infection.
Assuntos
Antivirais/química , Proteases 3C de Coronavírus/química , Isoindóis/química , Compostos Organosselênicos/química , SARS-CoV-2/enzimologia , Antivirais/metabolismo , Antivirais/farmacologia , Antivirais/uso terapêutico , Sítios de Ligação , COVID-19/virologia , Domínio Catalítico , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Cromatografia Líquida de Alta Pressão , Proteases 3C de Coronavírus/metabolismo , Desenho de Fármacos , Transferência Ressonante de Energia de Fluorescência , Humanos , Isoindóis/metabolismo , Isoindóis/farmacologia , Isoindóis/uso terapêutico , Simulação de Acoplamento Molecular , Compostos Organosselênicos/metabolismo , Compostos Organosselênicos/farmacologia , Compostos Organosselênicos/uso terapêutico , SARS-CoV-2/isolamento & purificação , Relação Estrutura-Atividade , Espectrometria de Massas em Tandem , Tratamento Farmacológico da COVID-19RESUMO
Noise overexposure leads to hair cell loss, synaptic ribbon reduction, and auditory nerve deterioration, resulting in transient or permanent hearing loss depending on the exposure severity. Oxidative stress, inflammation, calcium overload, glutamate excitotoxicity, and energy metabolism disturbance are the main contributors to noise-induced hearing loss (NIHL) up to now. Gene variations are also identified as NIHL related. Glucocorticoid is the only approved medication for NIHL treatment. New pharmaceuticals targeting oxidative stress, inflammation, or noise-induced neuropathy are emerging, highlighted by the nanoparticle-based drug delivery system. Given the complexity of the pathogenesis behind NIHL, deeper and more comprehensive studies still need to be fulfilled.
Assuntos
Perda Auditiva Provocada por Ruído/etiologia , Animais , Autofagia , Cálcio/metabolismo , Ensaios Clínicos Fase II como Assunto , Reparo do DNA/genética , Drogas em Investigação/uso terapêutico , Metabolismo Energético , Junções Comunicantes , Ácido Glutâmico/fisiologia , Células Ciliadas Auditivas/patologia , Perda Auditiva Provocada por Ruído/tratamento farmacológico , Perda Auditiva Provocada por Ruído/epidemiologia , Perda Auditiva Provocada por Ruído/genética , Humanos , Inflamação , Isoindóis/uso terapêutico , Nanopartículas , Compostos Organosselênicos/uso terapêutico , Estresse Oxidativo , Canais de Potássio/genética , Estereocílios/ultraestruturaRESUMO
The inhibition mechanism of the main protease (Mpro) of SARS-CoV-2 by ebselen (EBS) and its analog with a hydroxyl group at position 2 of the benzisoselenazol-3(2H)-one ring (EBS-OH) was studied by using a density functional level of theory. Preliminary molecular dynamics simulations on the apo form of Mpro were performed taking into account both the hydrogen donor and acceptor natures of the Nδ and Nε of His41, a member of the catalytic dyad. The potential energy surfaces for the formation of the Se-S covalent bond mediated by EBS and EBS-OH on Mpro are discussed in detail. The EBS-OH shows a distinctive behavior with respect to EBS in the formation of the noncovalent complex. Due to the presence of canonical H-bonds and noncanonical ones involving less electronegative atoms, such as sulfur and selenium, the influence on the energy barriers and reaction energy of the Minnesota hybrid meta-GGA functionals M06, M06-2X and M08HX, and the more recent range-separated hybrid functional wB97X were also considered. The knowledge of the inhibition mechanism of Mpro by the small protease inhibitors EBS or EBS-OH can enlarge the possibilities for designing more potent and selective inhibitor-based drugs to be used in combination with other antiviral therapies.
Assuntos
Antivirais/farmacologia , Tratamento Farmacológico da COVID-19 , Proteases 3C de Coronavírus/antagonistas & inibidores , Isoindóis/farmacologia , Compostos Organosselênicos/farmacologia , Inibidores de Proteases/farmacologia , Antivirais/uso terapêutico , Sítios de Ligação/efeitos dos fármacos , COVID-19/virologia , Domínio Catalítico/efeitos dos fármacos , Proteases 3C de Coronavírus/metabolismo , Desenho de Fármacos , Humanos , Isoindóis/química , Isoindóis/uso terapêutico , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Compostos Organosselênicos/química , Compostos Organosselênicos/uso terapêutico , Inibidores de Proteases/química , Inibidores de Proteases/uso terapêutico , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/metabolismoRESUMO
In late December 2019, coronavirus disease 2019 (COVID-19) first broke out in Wuhan, China, and has now become a global pandemic. However, there is no specific antiviral treatment for COVID-19. This study enrolled 33 COVID-19 patients in the nineth hospital of Nanchang from 27th January to 24th February 2020. Clinical indexes of patients upon admission/discharge were examined. Patients were divided into two groups according to different treatment plans (danoprevir and lopinavir/ritonavir). The days to achieve negative nucleic acid testing and the days of hospital stays were counted and statistically analyzed. COVID-19 patients treated with danoprevir or lopinavir/ritonavir were all improved and discharged. Indexes like blood routine, inflammation and immune-related indexes were significantly recovered after treatment. Additionally, under the circumstance that there was no significant difference in patients' general information between the two groups, we found that the mean time to achieve both negative nucleic acid testing and hospital stays of patients treated with danoprevir were significantly shorter than those of patients with lopinavir/ritonavir. Collectively, applying danoprevir is a good treatment plan for COVID-19 patients.
Assuntos
Antivirais/uso terapêutico , Tratamento Farmacológico da COVID-19 , Teste de Ácido Nucleico para COVID-19/estatística & dados numéricos , COVID-19/diagnóstico , Tempo de Internação/estatística & dados numéricos , Adolescente , Adulto , Idoso , Ciclopropanos/uso terapêutico , Combinação de Medicamentos , Feminino , Humanos , Isoindóis/uso terapêutico , Lactamas Macrocíclicas/uso terapêutico , Lopinavir/uso terapêutico , Masculino , Pessoa de Meia-Idade , Prolina/análogos & derivados , Prolina/uso terapêutico , Ritonavir/uso terapêutico , Índice de Gravidade de Doença , Sulfonamidas/uso terapêutico , Adulto JovemRESUMO
PURPOSE: In this review, we summarize the importance of AR variants with a particular focus on clinically relevant members of this family. METHODS: A non-systematic literature review was performed based on Medline and PubMed. RESULTS: Endocrine therapy represents the central paradigm for the management of prostate cancer. Eventually, in response to androgen ablation therapy, several resistance mechanisms against the endocrine therapy might develop that can circumvent the therapy approaches. One specific resistance mechanism that has gained increasing attention is the generation of alternatively spliced variants of the androgen receptor, with AR-V7 being the most prominent. More broadly, AR-V7 is one member of a group of alternatively spliced AR variants that share a common feature, the missing ligand-binding domain. These ΔLBD androgen receptor variants have shown the capability to induce androgen receptor-mediated gene transcription even under conditions of androgen deprivation and to drive cancer progression. CONCLUSION: The methods used for detecting AR-Vs, at least on the mRNA level, are well-advanced and harbor the potential to be introduced into clinical diagnostics. It is important to note, that the testing, especially of AR-V7 has its limitations in predicting treatment response. More promising is the great number of active clinical trials aimed at reducing the AR-Vs, and using this to re-sensitize CRPC towards endocrine treatment might provide additional treatment options for CRPC patients in the future.
Assuntos
Antagonistas de Androgênios/uso terapêutico , Antineoplásicos Hormonais/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Receptores Androgênicos/genética , Processamento Alternativo , Androstadienos/uso terapêutico , Benzamidas/uso terapêutico , Compostos Benzidrílicos/uso terapêutico , Benzimidazóis/uso terapêutico , Benzoquinonas/uso terapêutico , Sítios de Ligação/genética , Cloridrinas/uso terapêutico , Inibidores Enzimáticos/uso terapêutico , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Humanos , Isoindóis/uso terapêutico , Isoxazóis/uso terapêutico , Lactamas Macrocíclicas/uso terapêutico , Masculino , Niclosamida/uso terapêutico , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Neoplasias de Próstata Resistentes à Castração/genética , Neoplasias de Próstata Resistentes à Castração/metabolismo , Domínios Proteicos/genética , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Proteínas/antagonistas & inibidores , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores Androgênicos/metabolismo , Resorcinóis/uso terapêuticoRESUMO
BACKGROUND: Pruritus, a common symptom of psoriasis, negatively affects quality of life; however, treatment of lesional skin does not consistently alleviate psoriatic itch. OBJECTIVE: To examine the effects of serlopitant, an oral, once-daily neurokinin 1 receptor antagonist, for treatment of psoriatic pruritus in a phase 2, randomized clinical trial (NCT03343639). METHODS: Patients (n = 204) were randomized to receive serlopitant, 5 mg, or placebo daily for 8 weeks. Eligible adult patients had plaque psoriasis for ≥6 months, plaques covering ≤10% of body surface area, pruritus for ≥4 weeks, and Worst Itch Numeric Rating Scale (WI-NRS) score ≥7 at the initial screening. RESULTS: Participants (54.2% women) had a mean age of 47.5 years and 85.2% were white. Mean baseline WI-NRS scores were 8.3 for serlopitant and 8.1 for placebo. The WI-NRS 4-point response rate at 8 weeks (primary end point) was 33.3% for serlopitant vs 21.1% for placebo (P = .028); at 4 weeks the rates were 20.8% for serlopitant vs 11.5% for placebo (P = .039). Treatment-related adverse events were reported for 4.9% of serlopitant-treated and 4.0% of placebo-treated patients. LIMITATIONS: This was a phase 2 study with a small study population. Patients with severe psoriasis were excluded. CONCLUSION: Serlopitant significantly reduced pruritus associated with mild to moderate psoriasis, supporting continued development of serlopitant for this patient population.
Assuntos
Isoindóis/uso terapêutico , Antagonistas dos Receptores de Neurocinina-1/uso terapêutico , Prurido/tratamento farmacológico , Psoríase/complicações , Adulto , Diarreia/induzido quimicamente , Feminino , Cefaleia/induzido quimicamente , Humanos , Isoindóis/efeitos adversos , Masculino , Pessoa de Meia-Idade , Nasofaringite/induzido quimicamente , Antagonistas dos Receptores de Neurocinina-1/efeitos adversos , Prurido/etiologia , Índice de Gravidade de DoençaRESUMO
We have developed a versatile synthetic approach for the synthesis of new isoindole derivatives via the cleavage of ethers from tricyclic imide skeleton compounds. An exo-cycloadduct prepared from the Diels-Alder reaction of furan and maleic anhydride furnished imide derivatives. The epoxide ring was opened with Ac2O or Ac2O/AcCl in the presence of a catalytic amount of H2SO4 in order to yield new isoindole derivatives 8a-d and 9a-d. The anticancer activity of these compounds was evaluated against the HeLa cell lines. The synthesized compounds showed inhibitory effects on the viability of HeLa cells and the degree of cytotoxicity was increased with the level of bigger branched isoindole derivatives. To better understand the acting mechanism of these molecules, western blot analysis was performed with using mTOR and its downstream substrates. In addition, human mTOR and ribozomal S6 kinase ß1 (RS6Kß1) have been investigated with molecular modelling studies as possible targets for compound series 8 and 9.
Assuntos
Isoindóis/síntese química , Isoindóis/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Células HeLa , Humanos , Isoindóis/farmacologia , Modelos Moleculares , Inibidores de Proteínas Quinases/farmacologia , Relação Estrutura-AtividadeRESUMO
BACKGROUND: Accumulating evidence has implicated insulin resistance and inflammation in the pathophysiology of cognitive impairments associated with neuropsychiatric disorders. This post-hoc analysis based on a placebo-controlled trial investigated the effect of inflammation (indexed by CRP) and metabolic risk factors on cognitive performance in patients with schizophrenia treated with lurasidone. METHODS: Acutely exacerbated patients with schizophrenia were randomized to lurasidone (80 or 160 mg/day), quetiapine XR 600 mg/day, or placebo. A wide range CRP test and a cognitive assessment using the CogState computerized battery were performed at baseline and week 6 study endpoint. Associations between log-transformed CRP, high density lipoprotein (HDL), homeostatic model assessment of insulin resistance (HOMA-IR) and treatment response were evaluated. RESULTS: CRP combined with HDL, triglyceride-to-HDL (TG/HDL) ratio, or HOMA-IR at study baseline were significant moderators of the improvement in cognitive performance associated with lurasidone 160 mg/day (vs. placebo) treatment (p < .05). Greater placebo-corrected treatment effect size on the CogState composite score was observed for patients in the lurasidone 160 mg/day treatment group who had either low CRP and high HDL (d = 0.43), or low CRP and low HOMA-IR (d = 0.46). Interactive relationships between CRP, HDL, TG/HDL, HOMA-IR and the antipsychotic efficacy of lurasidone or quetiapine XR were not significant. There were no significant associations between antipsychotic treatment and changes in CRP level at study endpoint. CONCLUSIONS: Findings of this post-hoc analysis based on a placebo-controlled trial in patients with schizophrenia suggest that baseline CRP level combined with measures of metabolic risk significantly moderated the improvement in cognitive performance associated with lurasidone 160 mg/day (vs. placebo) treatment. Our findings underscore the importance of maintaining a low metabolic risk profile in patients with schizophrenia.
Assuntos
Antipsicóticos , Esquizofrenia , Antipsicóticos/efeitos adversos , Proteína C-Reativa/uso terapêutico , Cognição , Método Duplo-Cego , Humanos , Isoindóis/uso terapêutico , Cloridrato de Lurasidona/efeitos adversos , Escalas de Graduação Psiquiátrica , Esquizofrenia/tratamento farmacológico , Tiazóis/uso terapêutico , Resultado do TratamentoAssuntos
Varíola Bovina/transmissão , Infecções Oculares Virais/etiologia , Orthopoxvirus/isolamento & purificação , Zoonoses Virais/transmissão , Adulto , Animais , Benzamidas/uso terapêutico , Gatos/virologia , Túnica Conjuntiva/virologia , Varíola Bovina/tratamento farmacológico , Olho/patologia , Infecções Oculares Virais/tratamento farmacológico , Infecções Oculares Virais/patologia , Feminino , Humanos , Isoindóis/uso terapêuticoRESUMO
BACKGROUND: Anecdotal evidence suggests that neurokinin 1 receptor antagonism reduces pruritus intensity in chronic pruritic conditions such as prurigo nodularis (PN). OBJECTIVE: This study assessed safety and efficacy of the neurokinin 1 receptor antagonist serlopitant for treatment of pruritus in PN. METHODS: In this randomized, double-blind, placebo-controlled study, 128 patients with chronic, treatment-refractory PN for more than 6 weeks received serlopitant, 5 mg, or placebo orally once daily for 8 weeks. The primary end point was change in average itch visual analog scale score at weeks 4 and 8. RESULTS: Average itch visual analog scale scores significantly improved with serlopitant versus with placebo at weeks 4 and 8: the least squares mean difference (serlopitant minus placebo) was -1.0 at week 4 (P = .02) and -1.7 at week 8 (P < .001). The least squares mean difference between serlopitant and placebo reached statistical significance at week 2 (-0.9 [P = .011]). The most frequently reported treatment-emergent adverse events in the serlopitant group were nasopharyngitis, diarrhea, and fatigue. LIMITATIONS: The 8-week duration may be insufficient to assess clinically relevant resolution of PN lesions. CONCLUSIONS: Serlopitant reduced pruritus in patients with treatment-refractory PN and was well tolerated.
Assuntos
Isoindóis/uso terapêutico , Antagonistas dos Receptores de Neurocinina-1/uso terapêutico , Prurido/tratamento farmacológico , Adulto , Idoso , Doença Crônica , Diarreia/induzido quimicamente , Método Duplo-Cego , Fadiga/induzido quimicamente , Feminino , Humanos , Isoindóis/efeitos adversos , Masculino , Pessoa de Meia-Idade , Nasofaringite/induzido quimicamente , Antagonistas dos Receptores de Neurocinina-1/efeitos adversos , Prurigo/complicações , Prurido/etiologia , Escala Visual AnalógicaRESUMO
BACKGROUND: Insulin injection, especially with insulin analogs, occasionally induces the production of insulin antibodies with high binding capacity and low affinity, similar to the insulin autoantibodies characteristic of insulin autoimmune syndrome (IAS). Production of these "IAS-like" insulin antibodies causes marked glycemic fluctuations with postprandial hyperglycemia and fasting hypoglycemia. CASE PRESENTATION: A 66-year-old man with a 27-year history of diabetes was admitted because of marked glycemic fluctuations. Human insulin treatment had been initiated at age 56, followed by multiple daily injections of insulin analogs 5 years later. After the initial year of insulin analog treatment, the patient began to experience frequent morning hypoglycemic attacks and day-time hyperglycemia. Marked hyperinsulinemia (4500 µU/mL) and high titers of insulin antibodies (80.4%) with high binding capacity and low affinity indicated that IAS-like insulin antibodies were causing severe glucose fluctuations. Altering insulin formulations (insulin aspart â regular human insulinâ insulin lispro) proved to be ineffective. After several therapeutic trials, cessation of exogenous insulin and addition of mitiglinide to liraglutide with voglibose finally attenuated glycemic fluctuations with increased postprandial insulin secretion. Continuous glucose monitoring revealed improvement of morning hypoglycemia and postprandial hyperglycemia with smaller mean amplitude of glycemic excursion. Therefore, compared to exogenously injected insulin, endogenously secreted insulin directly and rapidly acts on hepatocytes and suppresses postprandial glucose output. CONCLUSIONS: Proper enhancement of postprandial endogenous insulin aimed at suppressing postprandial glucose output without stimulating excessive glucose uptake in the periphery is potentially useful for treating diabetes with insulin antibody-induced glycemic instability.
Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Angiopatias Diabéticas/tratamento farmacológico , Hiperglicemia/tratamento farmacológico , Hipoglicemia/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Secreção de Insulina , Insulina/sangue , Período Pós-Prandial , Idoso , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/fisiopatologia , Angiopatias Diabéticas/sangue , Angiopatias Diabéticas/fisiopatologia , Quimioterapia Combinada , Hemoglobinas Glicadas/efeitos dos fármacos , Humanos , Hiperglicemia/etiologia , Hipoglicemia/etiologia , Inositol/análogos & derivados , Inositol/uso terapêutico , Insulina/uso terapêutico , Anticorpos Anti-Insulina/sangue , Isoindóis/uso terapêutico , Liraglutida/uso terapêutico , Masculino , Resultado do TratamentoAssuntos
Erradicação de Doenças/história , Reservatórios de Doenças/virologia , Varíola/tratamento farmacológico , Varíola/história , Animais , Benzamidas/farmacologia , Benzamidas/uso terapêutico , Citosina/análogos & derivados , Citosina/farmacologia , Citosina/uso terapêutico , Erradicação de Doenças/tendências , Modelos Animais de Doenças , Aprovação de Drogas/legislação & jurisprudência , Feminino , História do Século XX , História do Século XXI , Humanos , Isoindóis/farmacologia , Isoindóis/uso terapêutico , Organofosfonatos/farmacologia , Organofosfonatos/uso terapêutico , Coelhos , Varíola/epidemiologia , Vacina Antivariólica/provisão & distribuição , Biologia Sintética/tendências , Estados Unidos , United States Food and Drug Administration/legislação & jurisprudênciaRESUMO
BACKGROUND Worldwide, the treatment of patients with chronic kidney disease (CKD) remains a challenge as warfarin treatment can be associated with severe adverse events related to bleeding. Alternative anticoagulants that can be used in CKD remain to be identified. This study aimed to compare the effects of indobufen, a new antiplatelet agent, with warfarin in a rat model of adenine-induced CKD. MATERIAL AND METHODS Forty-eight male Wistar rats were treated with intragastric adenine to create the rat model of CKD and were divided into four groups: an untreated control group (N=12), a group treated with dimethyl sulfoxide (DMSO) (N=12), a group treated with indobufen, (N=12) and a group treated with warfarin (N-12). Treatment was given for 4 weeks and 8 weeks. Kidney histology was performed, and the degree of fibrosis was quantified using Masson trichrome staining. RESULTS In the rat model of adenine-induced CKD, Masson trichrome staining showed that the degree of kidney fibrosis in the indobufen group (26%) was significantly reduced (p<0.05) when compared the DMSO group (58%) and the warfarin group (49%). Kidney fibrosis was associated with upregulation of 6-keto-PGI2/TXB2 in the rat kidney tissue. CONCLUSIONS In a rat model of adenine-induced CKD, preliminary findings showed that indobufen was associated with reduced kidney fibrosis when compared with warfarin.
Assuntos
Isoindóis/uso terapêutico , Fenilbutiratos/uso terapêutico , Insuficiência Renal Crônica/tratamento farmacológico , Adenina/farmacologia , Animais , Anticoagulantes/uso terapêutico , China , Modelos Animais de Doenças , Fibrose/patologia , Rim/patologia , Falência Renal Crônica/complicações , Masculino , Inibidores da Agregação Plaquetária/uso terapêutico , Ratos , Ratos Wistar , Insuficiência Renal Crônica/complicações , Varfarina/uso terapêuticoRESUMO
Combination therapeutic regimen is becoming a primary direction for current cancer immunotherapy to broad the antitumor response. Functional nanomaterials offer great potential for steady codelivery of various drugs, especially small molecules, therapeutic peptides, and nucleic acids, thereby realizing controllable drug release, increase of drug bioavailability, and reduction of adverse effects. Herein, a therapeutic peptide assembling nanoparticle that can sequentially respond to dual stimuli in the tumor extracellular matrix was designed for tumor-targeted delivery and on-demand release of a short d-peptide antagonist of programmed cell death-ligand 1 (DPPA-1) and an inhibitor of idoleamine 2,3-dioxygenase (NLG919). By concurrent blockade of immune checkpoints and tryptophan metabolism, the nanoformulation increased the level of tumor-infiltrated cytotoxic T cells and in turn effectively inhibited melanoma growth. To achieve this, an amphiphilic peptide, consisting of a functional 3-diethylaminopropyl isothiocyanate (DEAP) molecule, a peptide substrate of matrix metalloproteinase-2 (MMP-2), and DPPA-1, was synthesized and coassembled with NLG919. The nanostructure swelled when it encountered the weakly acidic tumor niche where DEAP molecules were protonated, and further collapsed due to the cleavage of the peptide substrate by MMP-2 that is highly expressed in tumor stroma. The localized release of DPPA-1 and NLG919 created an environment which favored the survival and activation of cytotoxic T lymphocytes, leading to the slowdown of melanoma growth and increase of overall survival. Together, this study offers new opportunities for dual-targeted cancer immunotherapy through functional peptide assembling nanoparticles with design features that are sequentially responsive to the multiple hallmarks of the tumor microenvironment.