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2.
Medicine (Baltimore) ; 100(22): e26253, 2021 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-34087915

RESUMO

ABSTRACT: Pathophysiological changes are important risk factors for critically ill patients with pneumonia manifesting sub-therapeutic antibiotic exposures during empirical treatment. The effect of coronavirus disease 2019 (COVID-19) on antibiotic dosing requirements is uncertain. We aimed to determine the effect of COVID-19 on ß-lactam pharmacokinetics (PK) and PK target attainment in critically ill patients with a personalized dosing strategy.Retrospective, single-center analysis of COVID-19 ± critically ill patients with pneumonia (community-acquired pneumonia or hospital-acquired pneumonia) who received continuous infusion of a ß-lactam antibiotic with dosing personalized through dosing software and therapeutic drug monitoring. A therapeutic exposure was defined as serum concentration between (css) 4 to 8 times the EUCAST non-species related breakpoint).Data from 58 patients with pneumonia was analyzed. Nineteen patients were tested COVID-19-positive before the start of the antibiotic therapy for community-acquired pneumonia or hospital-acquired pneumonia. Therapeutic exposure was achieved in 71% of COVID-19 patients (68% considering all patients). All patients demonstrated css above the non-species-related breakpoint. Twenty percent exceeded css above the target range (24% of all patients). The median ß-lactam clearance was 49% compared to ß-lactam clearance in a standard patient without a significant difference regarding antibiotic, time of sampling or present COVID-19 infection. Median daily doses were 50% lower compared to standard bolus dosing.COVID-19 did not significantly affect ß-lactam pharmacokinetics in critically ill patients. Personalized ß-lactam dosing strategies were safe in critically ill patients and lead to high PK target attainment with less resources.


Assuntos
COVID-19/tratamento farmacológico , beta-Lactamas/administração & dosagem , beta-Lactamas/farmacocinética , Idoso , Idoso de 80 Anos ou mais , Índice de Massa Corporal , Estado Terminal , Relação Dose-Resposta a Droga , Monitoramento de Medicamentos , Feminino , Humanos , Infusões Intravenosas , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Estudos Retrospectivos , SARS-CoV-2 , Índice de Gravidade de Doença , beta-Lactamas/economia , beta-Lactamas/uso terapêutico
3.
AAPS PharmSciTech ; 22(5): 171, 2021 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-34100170

RESUMO

Macrophages act as a cellular reservoir in HIV infection. Elimination of HIV from macrophages has been an unfulfilled dream due to the failure of drugs to reach them. To address this, we developed CD44 receptor-targeted, novel hyaluronic acid (HA)-coated nanostructured lipid carriers (NLCs) of efavirenz via washless layer-by-layer (LbL) assembly of HA and polyallylamine hydrochloride (PAH). NLCs were subjected to TEM analysis, size and zeta potential, in vitro release and encapsulation efficiency studies. The uptake of NLCs in THP-1 cells was studied using fluorescence microscopy and flow cytometry. The anti-HIV efficacy was evaluated using p24 antigen inhibition assay. NLCs were found to be spherical in shape with anionic zeta potential (-23.66 ± 0.87 mV) and 241.83 ± 5.38 nm particle size. NLCs exhibited prolonged release of efavirenz during in vitro drug release studies. Flow cytometry revealed 1.73-fold higher uptake of HA-coated NLCs in THP-1 cells. Cytotoxicity studies showed no significant change in cell viability in presence of NLCs as compared with the control. HA-coated NLCs distributed throughout the cell including cytoplasm, plasma membrane and nucleus, as observed during fluorescence microscopy. HA-coated NLCs demonstrated consistent and significantly higher inhibition (81.26 ± 1.70%) of p24 antigen which was 2.08-fold higher than plain NLCs. The obtained results suggested preferential uptake of HA-coated NLCs via CD44-mediated uptake. The present finding demonstrates that HA-based CD44 receptor targeting in HIV infection is an attractive strategy for maximising the drug delivery to macrophages and achieve effective viral inhibition.


Assuntos
Portadores de Fármacos/administração & dosagem , HIV-1/efeitos dos fármacos , Receptores de Hialuronatos , Macrófagos/efeitos dos fármacos , Nanoestruturas/administração & dosagem , Inibidores da Transcriptase Reversa/administração & dosagem , Alcinos/administração & dosagem , Alcinos/síntese química , Alcinos/metabolismo , Benzoxazinas/administração & dosagem , Benzoxazinas/síntese química , Benzoxazinas/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Ciclopropanos/administração & dosagem , Ciclopropanos/síntese química , Ciclopropanos/metabolismo , Relação Dose-Resposta a Droga , Portadores de Fármacos/síntese química , Portadores de Fármacos/metabolismo , Sistemas de Liberação de Medicamentos/métodos , Células HEK293 , Infecções por HIV/tratamento farmacológico , Infecções por HIV/metabolismo , HIV-1/fisiologia , Humanos , Receptores de Hialuronatos/metabolismo , Lipídeos/administração & dosagem , Lipídeos/síntese química , Macrófagos/metabolismo , Nanoestruturas/química , Inibidores da Transcriptase Reversa/síntese química , Inibidores da Transcriptase Reversa/metabolismo , Células THP-1
4.
Int J Mol Sci ; 22(10)2021 May 12.
Artigo em Inglês | MEDLINE | ID: mdl-34065957

RESUMO

The presented research concerns the triple activity of trans-cinnamic (tCA), ferulic (FA) and syringic acids (SA). They act as thyroid peroxidase (TPO) activators, lipoxygenase (LOX) inhibitors and show antiradical activity. All compounds showed a dose-dependent TPO activatory effect, thus the AC50 value (the concentration resulting in 50% activation) was determined. The tested compounds can be ranked as follows: tCA > FA > SA with AC50 = 0.10, 0.39, 0.69 mM, respectively. Strong synergism was found between FA and SA. The activatory effects of all tested compounds may result from interaction with the TPO allosteric site. It was proposed that conformational change resulting from activator binding to TPO allosteric pocket results from the flexibility of a nearby loop formed by residues Val352-Tyr363. All compounds act as uncompetitive LOX inhibitors. The most effective were tCA and SA, whereas the weakest was FA (IC50 = 0.009 mM and IC50 0.027 mM, respectively). In all cases, an interaction between the inhibitors carboxylic groups and side-chain atoms of Arg102 and Arg139 in an allosteric pocket of LOX was suggested. FA/tCA and FA/SA acted synergistically, whereas tCA/SA demonstrated antagonism. The highest antiradical activity was found in the case of SA (IC50 = 0.22 mM). FA/tCA and tCA/SA acted synergistically, whereas antagonism was found for the SA/FA mixture.


Assuntos
Autoantígenos/metabolismo , Ativadores de Enzimas/farmacologia , Iodeto Peroxidase/metabolismo , Proteínas de Ligação ao Ferro/metabolismo , Inibidores de Lipoxigenase/farmacologia , Compostos Fitoquímicos/farmacologia , Proteína-Lisina 6-Oxidase/metabolismo , Autoantígenos/química , Cinamatos/química , Cinamatos/farmacologia , Ácidos Cumáricos/química , Ácidos Cumáricos/farmacologia , Relação Dose-Resposta a Droga , Ativadores de Enzimas/química , Ácido Gálico/análogos & derivados , Ácido Gálico/química , Ácido Gálico/farmacologia , Humanos , Concentração Inibidora 50 , Iodeto Peroxidase/química , Proteínas de Ligação ao Ferro/química , Inibidores de Lipoxigenase/química , Modelos Moleculares , Compostos Fitoquímicos/química , Proteína-Lisina 6-Oxidase/química , Relação Estrutura-Atividade
5.
Viruses ; 13(6)2021 05 25.
Artigo em Inglês | MEDLINE | ID: mdl-34070524

RESUMO

SARS-CoV-2 emerged in 2019 as a devastating viral pathogen with no available preventative or treatment to control what led to the current global pandemic. The continued spread of the virus and increasing death toll necessitate the development of effective antiviral treatments to combat this virus. To this end, we evaluated a new class of organometallic complexes as potential antivirals. Our findings demonstrate that two pentamethylcyclopentadienyl (Cp*) rhodium piano stool complexes, Cp*Rh(1,3-dicyclohexylimidazol-2-ylidene)Cl2 (complex 2) and Cp*Rh(dipivaloylmethanato)Cl (complex 4), have direct virucidal activity against SARS-CoV-2. Subsequent in vitro testing suggests that complex 4 is the more stable and effective complex and demonstrates that both 2 and 4 have low toxicity in Vero E6 and Calu-3 cells. The results presented here highlight the potential application of organometallic complexes as antivirals and support further investigation into their activity.


Assuntos
Antivirais/farmacologia , Compostos Organometálicos/farmacologia , SARS-CoV-2/efeitos dos fármacos , Animais , Antivirais/química , COVID-19/virologia , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Chlorocebus aethiops , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Compostos Organometálicos/química , SARS-CoV-2/fisiologia , Células Vero , Replicação Viral/efeitos dos fármacos
6.
Int J Nanomedicine ; 16: 3555-3564, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34079248

RESUMO

Purpose: A silver nanoparticle obtained by reducing salts with solid dispersion of curcumin (130 nm, 0.081 mg mL-1) was used to counteract against the toxic - edematogenic, myotoxic, and neurotoxic - effects of Philodryas olfersii venom. Methods: The edematogenic effect was evaluated by plasma extravasation in rat dorsal skin after injection of 50 µg per site of venom alone or preincubated with 1, 10, and 100 µL of AgNPs; the myotoxicity was evaluated by measuring the creatine kinase released into the organ-bath before the treatment and at the end of each experiment; and neurotoxicity was evaluated in chick biventer cervicis using the conventional myographic technique, face to the exogenous acetylcholine (ACh) and potassium chloride (KCl) added into the bath before the treatment and after each experiment. Preliminarily, a concentration-response curve of AgNPs was carried out to select the concentration to be used for neutralizing assays, which consists of neutralizing the venom-induced neuromuscular paralysis and edema by preincubating AgNPs with venom for 30 min. Results: The P. olfersii venom-induced edema (n=6) and a complete neuromuscular blockade (n=4) that includes the total and unrecovered block of ACh and KCl contractures. AgNPs produced a concentration-dependent decrease the venom-induced edema (n=6) from 223.3% to 134.4% and to 100.5% after 10 and 100 µL AgNPs-preincubation, respectively. The preincubation of venom with AgNPs (1 µL; n=6) was able to maintain 46.5 ± 10.9% of neuromuscular response under indirect stimuli, 39.2 ± 9.7% of extrinsic nicotinic receptors functioning in absence of electrical stimulus and 28.3 ± 8.1% of responsiveness to potassium on the sarcolemmal membrane. The CK release was not affected by any experimental protocol which was like control. Conclusion: AgNPs interact with constituents of P. olfersii venom responsible for the edema-forming activity and neuromuscular blockade, but not on the sarcolemma membrane-acting constituents. The protective effect of the studied AgNPs on avian preparation points out to molecular targets as intrinsic and extrinsic nicotinic receptors.


Assuntos
Colubridae , Nanopartículas Metálicas , Prata/química , Prata/farmacologia , Venenos de Serpentes/antagonistas & inibidores , Venenos de Serpentes/toxicidade , Animais , Galinhas , Creatina Quinase/metabolismo , Curcumina/química , Relação Dose-Resposta a Droga , Edema , Masculino , Contração Muscular/efeitos dos fármacos , Músculo Esquelético/efeitos dos fármacos , Neurotoxinas/antagonistas & inibidores , Neurotoxinas/toxicidade , Nervo Frênico/efeitos dos fármacos , Ratos
7.
Bull Math Biol ; 83(7): 79, 2021 05 26.
Artigo em Inglês | MEDLINE | ID: mdl-34037874

RESUMO

The pandemic outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has quickly spread worldwide, creating a serious health crisis. The virus is primarily associated with flu-like symptoms but can also lead to severe pathologies and death. We here present an ordinary differential equation model of the intrahost immune response to SARS-CoV-2 infection, fitted to experimental data gleaned from rhesus macaques. The model is calibrated to data from a nonlethal infection, but the model can replicate behavior from various lethal scenarios as well. We evaluate the sensitivity of the model to biologically relevant parameters governing the strength and efficacy of the immune response. We also simulate the effect of both anti-inflammatory and antiviral drugs on the host immune response and demonstrate the ability of the model to lessen the severity of a formerly lethal infection with the addition of the appropriately calibrated drug. Our model emphasizes the importance of tight control of the innate immune response for host survival and viral clearance.


Assuntos
/imunologia , Imunidade Inata , Macaca mulatta/imunologia , Modelos Imunológicos , Imunidade Adaptativa , Envelhecimento/imunologia , Animais , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/farmacologia , Antivirais/administração & dosagem , Antivirais/farmacologia , /epidemiologia , Simulação por Computador , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Interações entre Hospedeiro e Microrganismos/efeitos dos fármacos , Interações entre Hospedeiro e Microrganismos/imunologia , Humanos , Conceitos Matemáticos , Pandemias , Sistema Respiratório/imunologia , Sistema Respiratório/virologia , Carga Viral/imunologia
8.
AAPS PharmSciTech ; 22(5): 157, 2021 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-34008089

RESUMO

The apoptotic, cytotoxic, and cytostatic activities for [10]-gingerol in triple-negative breast cancer cells (TNBCs) were already reported. However, despite these important antitumor activities, the compound has the disadvantage to have a hydrophobic characteristic, hindering in vivo administration. To surpass this issue, in this study we have created a [10]-gingerol-loaded nanoemulsion (10GNE) in order to increase the stability and solubility of the compound. The nanoemulsion was characterized and tested for its cytotoxic, cytostatic, and apoptotic effects on a panel of murine and human TNBC cell lines, as well as non-tumor cells, and compared with a [10]-gingerol-free nanoemulsion (NE) and with [10]-gingerol itself. Except for the murine 4T1.13 cell line, the IC50 of the free 10G molecule, after 72 h of incubation, was higher in all cell lines tested, both murine and human, demonstrating therefore the efficacy of the 10GNE regarding cytotoxicity. In murine tumor cells, 60 µM 10GNE was able to arrest cell cycle at sub-G0 phase and induce apoptosis, leading to 48% and 78% of total cell death in 4T1.13 and 4T1Br4 murine tumor cells, respectively. This represents an improvement compared to 10G-free molecule that only induced 74% of total apoptosis at 100 µM in 4T1Br4 cells. Taken together, our results show that nanoformulation preserved the [10]-gingerol cytotoxic and cytostatic properties and improved its apoptotic function on murine TNBC cell lines. These data open new perspectives to a more suitable drug-delivery approach for [10]-gingerol for TNBC treatment that should be further demonstrated using in vivo assays.


Assuntos
Catecóis/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Álcoois Graxos/administração & dosagem , Nanosferas/administração & dosagem , Neoplasias de Mama Triplo Negativas , Animais , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Células 3T3 BALB , Catecóis/síntese química , Divisão Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Emulsões , Álcoois Graxos/síntese química , Humanos , Camundongos , Nanosferas/química , Neoplasias de Mama Triplo Negativas/tratamento farmacológico
9.
Int J Mol Sci ; 22(9)2021 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-33946862

RESUMO

Lumican, a ubiquitously expressed small leucine-rich proteoglycan, has been utilized in diverse biological functions. Recent experiments demonstrated that lumican stimulates preosteoblast viability and differentiation, leading to bone formation. To further understand the role of lumican in bone metabolism, we investigated its effects on osteoclast biology. Lumican inhibited both osteoclast differentiation and in vitro bone resorption in a dose-dependent manner. Consistent with this, lumican markedly decreased the expression of osteoclastogenesis markers. Moreover, the migration and fusion of preosteoclasts and the resorptive activity per osteoclast were significantly reduced in the presence of lumican, indicating that this protein affects most stages of osteoclastogenesis. Among RANKL-dependent pathways, lumican inhibited Akt but not MAP kinases such as JNK, p38, and ERK. Importantly, co-treatment with an Akt activator almost completely reversed the effect of lumican on osteoclast differentiation. Taken together, our findings revealed that lumican inhibits osteoclastogenesis by suppressing Akt activity. Thus, lumican plays an osteoprotective role by simultaneously increasing bone formation and decreasing bone resorption, suggesting that it represents a dual-action therapeutic target for osteoporosis.


Assuntos
Reabsorção Óssea/fisiopatologia , Lumicana/farmacologia , Osteoclastos/metabolismo , Osteogênese/fisiologia , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Fusão Celular , Movimento Celular/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Lumicana/fisiologia , Fator Estimulador de Colônias de Macrófagos/farmacologia , Macrófagos/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos ICR , Osteogênese/efeitos dos fármacos , Osteoprotegerina/biossíntese , Ligante RANK/biossíntese , Ligante RANK/farmacologia , Proteínas Recombinantes/farmacologia
10.
Anticancer Res ; 41(5): 2247-2256, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33952451

RESUMO

BACKGROUND/AIM: Adjuvant therapeutic options are limited for triple negative breast cancer (TNBC). Thus, we evaluated the cytotoxic effects of the newly synthesized antineoplastic agent 1,4,5-Oxathiazinane-4,4-dioxide (OTD) on TNBC cells as a potential cancer therapeutic strategy. MATERIALS AND METHODS: TNBC primary BT-20 and metastatic MDA-MB-231 cell lines were treated with increasing concentrations of OTD for various time periods to assess cell viability. Cell necrosis, apoptosis, necroptosis, autophagy, and ROS generation were evaluated using assay kits or specific inhibitors. RESULTS: Treatment with OTD resulted in a dose- and time-dependent cell death of TNBC BT-20 and MDA-MB-231 cells. OTD also dose-dependently arrested TNBC cell proliferation. Notably, treatment with OTD induced both necrosis and apoptosis of TNBC cells, while the pan-caspase inhibitor Z-VAD-FMK partially attenuated OTD-induced cell death. Importantly, abrogated OTD-induced cell death was observed in the presence of the ROS scavenger N-acetylcysteine (NAC), whereas enhanced OTD-induced cell death was observed after the addition of the glutathione synthesis inhibitor BSO, indicating OTD-induced killing of TNBC cells via a reactive oxygen species-dependent mechanism. CONCLUSION: OTD is strongly cytotoxic to both primary and metastatic TNBC cells, possibly by inducing multiple cell death pathways.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Antineoplásicos/química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos/métodos , Humanos , Estrutura Molecular , Espécies Reativas de Oxigênio/metabolismo , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologia
11.
Anticancer Res ; 41(5): 2277-2286, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33952453

RESUMO

BACKGROUND/AIM: Poly (ADP-ribose) polymerase inhibitors (PARPis) are one of the targeted therapies proven to treat breast cancer gene (BRCA)-mutant ovarian cancer. Because most ovarian cancers are BRCA wild-type, it is necessary to extend the usage of PARPis. In the present study, we combined the PARPi, talazoparib, and the IL-6 inhibitor, bazedoxifene, for the treatment of human ovarian cancer cells. MATERIALS AND METHODS: The human ovarian cancer cell lines, SKOV3, UWB1.289 (BRCA1-null) and OV75, were treated with talazoparib and bazedoxifene, as monotherapy or combination treatment. The effects of treatment on cell viability, migration, growth and colony formation were examined. Western blot was used to investigate pathways that may be involved in the antitumor effects of the two agents. RESULTS: The combination of talazoparib and bazedoxifene showed synergistic inhibition of cell viability, cell migration, cell growth, and cell colony formation on all the studied cell lines. The expression of p-AKT, c-myc, p-ERK, ERα was inhibited, and γ-H2AX expression was induced. CONCLUSION: Combined inhibition of PARP and IL-6 may be an efficacious treatment for ovarian cancer, independently of BRCA mutation status.


Assuntos
Proteína BRCA1/genética , Indóis/farmacologia , Mutação , Neoplasias Ovarianas/genética , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Feminino , Humanos , Interleucina-6/antagonistas & inibidores , Interleucina-6/metabolismo , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Fatores de Tempo
12.
Anticancer Res ; 41(5): 2297-2306, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33952455

RESUMO

BACKGROUND/AIM: Phosphodiesterase 5 (PDE5) holds clinical relevance in several pathological states, including lung, breast, and prostate cancer. In this study, we examined PDE5 expression in oral squamous cell carcinoma (OSCC)-derived cell lines and tissues, and the anti-tumour effect of PDE5 inhibitor, sildenafil citrate (SC). MATERIALS AND METHODS: Cell proliferation, cell invasion, and gap closure assays were performed in six OSCC-derived cell lines upon treatment with varying concentrations of SC. PDE5 expression was determined in primary OSCC tissues by western blotting and immunohistochemistry. RESULTS: Elevated PDE5 expression was observed in all cell lines. A concentration-dependent decrease in cell viability, invasion rate, and migration was observed after SC treatment. A significant correlation (p=0.05) was observed between elevated PDE5 expression and lymphatic infiltration in OSCC tissues. CONCLUSION: PDE5 plays an important role in carcinogenesis of OSCC, and the specific inhibition of PDE5 may be an effective chemotherapeutic strategy.


Assuntos
Carcinoma de Células Escamosas/enzimologia , Nucleotídeo Cíclico Fosfodiesterase do Tipo 5/metabolismo , Neoplasias Bucais/enzimologia , Citrato de Sildenafila/farmacologia , Western Blotting , Carcinoma de Células Escamosas/patologia , Linhagem Celular , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Imuno-Histoquímica , Neoplasias Bucais/patologia , Inibidores da Fosfodiesterase 5/farmacologia
13.
Anticancer Res ; 41(5): 2333-2347, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33952458

RESUMO

BACKGROUND/AIM: Glioblastoma multiforme (GBM) is a lethal disease with a high rate of chemoresistance to temozolomide (TMZ). The aim of the study was to establish a TMZ-resistant subline from the GBM-8401 cell line to determine the mechanisms of resistance and identify novel effective therapeutics for TMZ-resistant GBM. MATERIALS AND METHODS: Comparative transcriptome analysis of GBM-8401/TMZR cells and the parental line was performed using Ion Torrent sequencing. Differentially expressed genes (DEGs) between the GBM-8401/TMZR and GBM-8401 cell lines were analyzed. RESULTS: Transcriptomic profiling of GBM-8401/TMZR cells revealed DEGs involved in the retinoblastoma (RB) signaling, DNA damage response (DDR) pathway, and DNA repair mechanisms. CONCLUSION: In vitro and in vivo cell-based GBM models should be used in further biomedical studies to investigate the underlying mechanisms of TMZ-resistant GBM.


Assuntos
Resistencia a Medicamentos Antineoplásicos/genética , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glioblastoma/genética , Temozolomida/farmacologia , Antineoplásicos Alquilantes/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Dano ao DNA , Reparo do DNA/genética , Relação Dose-Resposta a Droga , Glioblastoma/patologia , Humanos , Modelos Genéticos , Proteína do Retinoblastoma/genética , Transdução de Sinais/genética
14.
Medicine (Baltimore) ; 100(18): e25857, 2021 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-33951000

RESUMO

RATIONALE: Focal segmental glomerulosclerosis (FSGS) is one of the most common glomerular diseases, leading to end-stage renal disease. Among the 5 variants of FSGS, the collapsing variant is rare and has the worst prognosis. Solid and hematologic malignancies are associated with glomerular diseases, such as membranous nephropathy, minimal change disease, and FSGS. However, squamous cell carcinoma of the oral cavity is rarely associated with nephrotic syndrome, especially FSGS. PATIENT CONCERNS: A 55-year-old woman diagnosed with oral cavity cancer presented with generalized edema with heavy proteinuria and renal dysfunction after neoadjuvant chemotherapy and wide surgical excision. DIAGNOSIS: Renal biopsy shows segmental or global collapse of glomerular capillaries with marked hyperplasia and swelling of overlying epithelial cells, suggesting a collapsing variant of FSGS. INTERVENTIONS: After the renal biopsy, we prescribed oral prednisolone at a dose of 1 mg/kg/day. Despite immunosuppressive treatment, renal function deteriorated, and hemodialysis was started. OUTCOMES: After 23 sessions of hemodialysis and high-dose oral glucocorticoid treatment, renal function gradually improved, and oral glucocorticoid therapy was discontinued after 8 months. Currently, this patient is in a cancer-free state and has normal renal function without proteinuria. LESSONS: Unusual collapsing FSGS might be associated with neoadjuvant chemotherapy and wide surgical excision in patients with oral cavity cancer. Proper diagnostic workup, such as renal biopsy and high-dose glucocorticoid therapy, might have helped recover from nephrotic syndrome and acute renal injury in cancer patients.


Assuntos
Glomerulosclerose Segmentar e Focal/diagnóstico , Neoplasias Bucais/complicações , Síndrome Nefrótica/diagnóstico , Carcinoma de Células Escamosas de Cabeça e Pescoço/complicações , Biópsia , Quimioterapia Adjuvante , Relação Dose-Resposta a Droga , Feminino , Glomerulosclerose Segmentar e Focal/etiologia , Glomerulosclerose Segmentar e Focal/patologia , Glomerulosclerose Segmentar e Focal/terapia , Humanos , Glomérulos Renais/patologia , Pessoa de Meia-Idade , Neoplasias Bucais/terapia , Terapia Neoadjuvante/métodos , Síndrome Nefrótica/etiologia , Síndrome Nefrótica/patologia , Síndrome Nefrótica/terapia , Prednisolona/administração & dosagem , Diálise Renal , Carcinoma de Células Escamosas de Cabeça e Pescoço/terapia , Resultado do Tratamento
15.
Cancer Sci ; 112(6): 2335-2348, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33931930

RESUMO

Lysosomal degradation plays a crucial role in the metabolism of biological macromolecules supplied by autophagy. The regulation of the autophagy-lysosome system, which contributes to intracellular homeostasis, chemoresistance, and tumor progression, has recently been revealed as a promising therapeutic approach for pancreatic cancer (PC). However, the details of lysosomal catabolic function in PC cells have not been fully elucidated. In this study, we show evidence that suppression of acid alpha-glucosidase (GAA), one of the lysosomal enzymes, improves chemosensitivity and exerts apoptotic effects on PC cells through the disturbance of expression of the transcription factor EB. The levels of lysosomal enzyme were elevated by gemcitabine in PC cells. In particular, the levels of GAA were responsive to gemcitabine in a dose-dependent and time-dependent manner. Small interfering RNA against the GAA gene (siGAA) suppressed cell proliferation and promoted apoptosis in gemcitabine-treated PC cells. In untreated PC cells, we observed accumulation of depolarized mitochondria. Gene therapy using adenoviral vectors carrying shRNA against the GAA gene increased the number of apoptotic cells and decreased the tumor growth in xenograft model mice. These results indicate that GAA is one of the key targets to improve the efficacy of gemcitabine and develop novel therapies for PC.


Assuntos
Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/genética , Desoxicitidina/análogos & derivados , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias Pancreáticas/tratamento farmacológico , RNA Interferente Pequeno/administração & dosagem , alfa-Glucosidases/genética , Animais , Autofagia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Desoxicitidina/administração & dosagem , Desoxicitidina/farmacologia , Relação Dose-Resposta a Droga , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Lisossomos/efeitos dos fármacos , Lisossomos/enzimologia , Masculino , Camundongos , Camundongos Nus , Neoplasias Pancreáticas/enzimologia , Neoplasias Pancreáticas/genética , RNA Interferente Pequeno/farmacologia , Fatores de Tempo , Regulação para Cima , Ensaios Antitumorais Modelo de Xenoenxerto
16.
Medicine (Baltimore) ; 100(18): e25591, 2021 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-33950936

RESUMO

INTRODUCTION: Intravenous immunoglobulin (IVIg) is currently used with considerable success for the treatment of many autoimmune diseases, including systemic lupus erythematosus (SLE). Among its various indications, IVIg has also been found to be beneficial in myocarditis, whether or not it is associated with an autoimmune disease. Nevertheless, data regarding IVIg treatment for myocarditis/cardiomyopathy in patients with SLE are sparse. The objective of this case series was to describe our experience with IVIg as a treatment for lupus myocarditis and to review the literature for IVIg for this indication. PATIENT CONCERNS: We report 5 female patients with SLE, who presented with signs of acute heart failure including pulmonary congestion and arrhythmias. DIAGNOSIS: Echocardiography demonstrated new reduced left ventricular ejection fraction of 20% to 30%. Two patients underwent coronary artery angiography, which demonstrated normal coronary arteries, supporting the diagnosis of myocarditis or nonischemic cardiomyopathy. INTERVENTIONS: High-dose IVIg treatment was initiated in all 5 patients. OUTCOMES: Following the treatment, clinical and echocardiographic improvement in cardiac function occurred within a few days to 1 month. This dramatic improvement persisted for several years. CONCLUSION: Based on our case series, we believe that IVIg has an important role in the management of lupus acute cardiomyopathy. This safe, well-tolerated optional treatment should be considered, especially in severe cases.


Assuntos
Insuficiência Cardíaca/tratamento farmacológico , Imunoglobulinas Intravenosas/administração & dosagem , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Miocardite/tratamento farmacológico , Disfunção Ventricular Esquerda/tratamento farmacológico , Doença Aguda/terapia , Adulto , Angiografia Coronária , Relação Dose-Resposta a Droga , Ecocardiografia , Feminino , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/imunologia , Humanos , Lúpus Eritematoso Sistêmico/complicações , Lúpus Eritematoso Sistêmico/imunologia , Pessoa de Meia-Idade , Miocardite/diagnóstico , Miocardite/imunologia , Resultado do Tratamento , Disfunção Ventricular Esquerda/diagnóstico , Disfunção Ventricular Esquerda/imunologia
17.
JAMA ; 325(17): 1755-1764, 2021 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-33944875

RESUMO

Importance: Sustained remission has become an achievable goal for patients with rheumatoid arthritis (RA) receiving conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), but how to best treat patients in clinical remission remains unclear. Objective: To assess the effect of tapering of csDMARDs, compared with continuing csDMARDs without tapering, on the risk of flares in patients with RA in sustained remission. Design, Setting, and Participants: ARCTIC REWIND was a multicenter, randomized, parallel, open-label noninferiority study conducted in 10 Norwegian hospital-based rheumatology practices. A total of 160 patients with RA in remission for 12 months who were receiving stable csDMARD therapy were enrolled between June 2013 and June 2018, and the final visit occurred in June 2019. Interventions: Patients were randomly assigned to half-dose csDMARDs (n = 80) or stable-dose csDMARDs (n = 80). Main Outcomes and Measures: The primary end point was the proportion of patients with a disease flare between baseline and the 12-month follow-up, defined as a combination of Disease Activity Score (DAS) greater than 1.6 (threshold for RA remission), an increase in DAS score of 0.6 units or more, and at least 2 swollen joints. A disease flare could also be recorded if both the patient and investigator agreed that a clinically significant flare had occurred. A risk difference of 20% was defined as the noninferiority margin. Results: Of 160 enrolled patients (mean [SD] age, 55.1 [11.9] years; 66% female), 156 received the allocated therapy, of which 155 without any major protocol violations were included in the primary analysis population (77 receiving half-dose and 78 receiving stable-dose csDMARDs). Flare occurred in 19 patients (25%) in the half-dose csDMARD group compared with 5 (6%) in the stable-dose csDMARD group (risk difference, 18% [95% CI, 7%-29%]). Adverse events occurred in 34 patients (44%) in the half-dose group and 42 (54%) in the stable-dose group, none leading to study discontinuation. No deaths occurred. Conclusions and Relevance: Among patients with RA in remission taking csDMARD therapy, treatment with half-dose vs stable-dose csDMARDs did not demonstrate noninferiority for the percentage of patients with disease flares over 12 months, and there were significantly fewer flares in the stable-dose group. These findings do not support treatment with half-dose therapy. Trial Registration: ClinicalTrials.gov Identifier: NCT01881308.


Assuntos
Antirreumáticos/administração & dosagem , Artrite Reumatoide/tratamento farmacológico , Metotrexato/administração & dosagem , Exacerbação dos Sintomas , Adulto , Idoso , Antirreumáticos/efeitos adversos , Artrite Reumatoide/diagnóstico por imagem , Artrite Reumatoide/patologia , Relação Dose-Resposta a Droga , Quimioterapia Combinada , Feminino , Humanos , Hidroxicloroquina/administração & dosagem , Leflunomida/administração & dosagem , Masculino , Metotrexato/efeitos adversos , Pessoa de Meia-Idade , Radiografia , Sulfassalazina/administração & dosagem , Ultrassonografia
18.
JAMA ; 325(17): 1744-1754, 2021 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-33944876

RESUMO

Importance: Proactive therapeutic drug monitoring (TDM), defined as individualized drug dosing based on scheduled monitoring of serum drug levels, has been proposed as an alternative to standard therapy to maximize efficacy and safety of infliximab and other biological drugs. However, whether proactive TDM improves clinical outcomes when implemented at the time of drug initiation, compared with standard therapy, remains unclear. Objective: To assess whether TDM during initiation of infliximab therapy improves treatment efficacy compared with standard infliximab therapy without TDM. Design, Setting, and Participants: Randomized, parallel-group, open-label clinical trial of 411 adults with rheumatoid arthritis, spondyloarthritis, psoriatic arthritis, ulcerative colitis, Crohn disease, or psoriasis initiating infliximab therapy in 21 hospitals in Norway. Patients were recruited from March 1, 2017, to January 10, 2019. Final follow-up occurred on November 5, 2019. Interventions: Patients were randomized 1:1 to receive proactive TDM with dose and interval adjustments based on scheduled monitoring of serum drug levels and antidrug antibodies (TDM group; n = 207) or standard infliximab therapy without drug and antibody level monitoring (standard therapy group; n = 204). Main Outcomes and Measures: The primary end point was clinical remission at week 30. Results: Among 411 randomized patients (mean age, 44.7 [SD, 14.9] years; 209 women [51%]), 398 (198 in the TDM group and 200 in the standard therapy group) received their randomized intervention and were included in the full analysis set. Clinical remission at week 30 was achieved in 100 (50.5%) of 198 and 106 (53.0%) of 200 patients in the TDM and standard therapy groups, respectively (adjusted difference, 1.5%; 95% CI, -8.2% to 11.1%; P = .78). Adverse events were reported in 135 patients (68%) and 139 patients (70%) in the TDM and standard therapy groups, respectively. Conclusions and Relevance: Among patients with immune-mediated inflammatory diseases initiating treatment with infliximab, proactive therapeutic drug monitoring, compared with standard therapy, did not significantly improve clinical remission rates over 30 weeks. These findings do not support routine use of therapeutic drug monitoring during infliximab induction for improving disease remission rates. Trial Registration: ClinicalTrials.gov Identifier: NCT03074656.


Assuntos
Artrite/tratamento farmacológico , Monitoramento de Medicamentos , Doenças Inflamatórias Intestinais/tratamento farmacológico , Infliximab/uso terapêutico , Adulto , Doença Crônica , Relação Dose-Resposta a Droga , Feminino , Humanos , Quimioterapia de Indução , Infliximab/administração & dosagem , Masculino , Pessoa de Meia-Idade , Psoríase/tratamento farmacológico , Indução de Remissão , Padrão de Cuidado
19.
Medicine (Baltimore) ; 100(18): e25805, 2021 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-33950982

RESUMO

BACKGROUND: To evaluate the effect of recombinant human erythropoietin (rhEPO) in nervous system of premature infants including different dosage. METHODS: The multiple databases like Pubmed, Embase, Cochrane databases and China National Knowledge Database were used to search for the relevant studies, and full-text articles involved in the evaluation on effect of rhEPO for neurodevelopment among premature infants. Review Manager 5.2 was adopted to estimate the effects of the results among selected articles. Forest plots, sensitivity analysis and bias analysis for the articles included were also conducted. RESULTS: Finally, 10 eligible studies were eventually satisfied the included criteria. The results showed that rhEPO was much higher than placebo group in composite cognitive score (MD = 5.89, 95% confidential interval {CI} [1.95, 9.82], P = .003; I2 = 89%), there was no significant difference between rhEPO and placebo groups (RR = 0.93, 95% CI [0.60, 1.43], P = .74; I2 = 51%) and no difference in neurodevelopmental impairment between rhEPO and placebo was insignificant (RR = 0.55 95% CI [0.30, 1.02], P = .06). Composite cognitive score in high dose rhEPO was much higher than placebo group (MD = 10.39, 95% CI [8.84, 11.93], P < .0001, I2 = 0%) and low dose rhEPO also had higher composite cognitive score than placebo group (MD = 2.58, 95% CI [0.80, 4.37], P = .004, I2 = 11%). Limited publication bias was observed in this study. CONCLUSION: Recombinant human erythropoietin might be a promotor for neurodevelopment among premature infants with limited adverse events.


Assuntos
Desenvolvimento Infantil/efeitos dos fármacos , Eritropoetina/administração & dosagem , Recém-Nascido Prematuro/crescimento & desenvolvimento , Sistema Nervoso/crescimento & desenvolvimento , Transtornos do Neurodesenvolvimento/prevenção & controle , Relação Dose-Resposta a Droga , Eritropoetina/efeitos adversos , Humanos , Recém-Nascido , Sistema Nervoso/efeitos dos fármacos , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/efeitos adversos , Resultado do Tratamento
20.
Biomed Res Int ; 2021: 6640892, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33937405

RESUMO

Background: Inappropriate and unnecessary use of antibiotics can increase morbidity, mortality, medical expenses or patient cost, and microbial antibiotic resistance. However, in developing countries like Ethiopia, information regarding appropriateness of antibiotic prescribing pattern to guide improvement strategies is scant. Objective: The aim of this study was to assess appropriateness and pattern of antibiotic prescription in pediatric patients at pediatric ward of Adigrat General Hospital. Methods: Hospital-based retrospective cross-sectional study was conducted to assess the antibiotic prescribing pattern in pediatric inpatient and outpatient ward of Adigrat General Hospital from December 1, 2018 to April 30, 2019. Data was collected by using structured data collection checklist, and the systematic random sampling technique was employed to enroll the required sample size during the study period. Appropriateness of drug use in pediatrics was evaluated using Ethiopian Standard Treatment guideline and WHO pediatric guideline. Result: A total of 692 pediatric patients' medical charts were reviewed. The median age of patients on antibiotics was 3.26 years (IQR: 2-4). Majority (49.13%) of the patients were hospitalized for 5-9 days. SCAP (195), tonsillitis (114), and cellulitis (99) were most frequently encountered pediatric diseases. Penicillins (37.86%) followed by cephalosporins (31.79%) antibiotics were the most prescribed antibiotics in pediatric wards. This study also showed that ceftriaxone and ceftriaxone+amoxicillin were the most frequently used single and combination antibiotics, respectively. The prescribing practices were not stick to WHO core indicators and standards. Inappropriate prescription of antibiotics was observed in 28.3% of patients. Advanced age of children, children aged between 6 to 10 years (AOR = 3.225; CI = 1.080 - 9.630; P = .036) and 11-18 years (AOR = 18.691; CI = 5.156 - 67.756; P = .000), was the independent determinant of inappropriate drug use. Conclusion: Inappropriate antibiotic prescribing was encountered in 28.3% of children. The rate of generic prescription was not in line with WHO recommendation. Advanced age of children was the independent factor for inappropriate use of antibiotics.


Assuntos
Antibacterianos/uso terapêutico , Prescrições de Medicamentos , Hospitais Gerais , Padrões de Prática Médica , Adolescente , Criança , Pré-Escolar , Relação Dose-Resposta a Droga , Etiópia , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Organização Mundial da Saúde
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