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1.
Drugs Today (Barc) ; 56(8): 505-514, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33025946

RESUMO

Peficitinib hydrobromide is a small Janus kinase inhibitor (JAK1, JAK2, JAK3 and TYK2) molecule for the treatment of rheumatoid arthritis (RA). Phase II and phase III clinical trials and extension studies with different doses have been conducted to assess the drug's efficacy and safety with substantially improved outcomes observed in RA. This JAK inhibitor oral drug demonstrated clinical response as once-daily monotherapy in patients with moderate to severe RA, also in combination with methotrexate (MTX), who had an inadequate response to MTX. The findings from studies of this new JAK inhibitor have shown that, both in monotherapy as well as in combination with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), it has efficacy, safety and tolerability in RA patients.


Assuntos
Adamantano/análogos & derivados , Artrite Reumatoide/tratamento farmacológico , Niacinamida/análogos & derivados , Adamantano/uso terapêutico , Ensaios Clínicos como Assunto , Humanos , Janus Quinases/antagonistas & inibidores , Niacinamida/uso terapêutico , Resultado do Tratamento
2.
Nutrients ; 12(6)2020 May 31.
Artigo em Inglês | MEDLINE | ID: covidwho-437160

RESUMO

Nicotinamide riboside (NR) has recently become one of the most studied nicotinamide adenine dinucleotide (NAD+) precursors, due to its numerous potential health benefits mediated via elevated NAD+ content in the body. NAD+ is an essential coenzyme that plays important roles in various metabolic pathways and increasing its overall content has been confirmed as a valuable strategy for treating a wide variety of pathophysiological conditions. Accumulating evidence on NRs' health benefits has validated its efficiency across numerous animal and human studies for the treatment of a number of cardiovascular, neurodegenerative, and metabolic disorders. As the prevalence and morbidity of these conditions increases in modern society, the great necessity has arisen for a rapid translation of NR to therapeutic use and further establishment of its availability as a nutritional supplement. Here, we summarize currently available data on NR effects on metabolism, and several neurodegenerative and cardiovascular disorders, through to its application as a treatment for specific pathophysiological conditions. In addition, we have reviewed newly published research on the application of NR as a potential therapy against infections with several pathogens, including SARS-CoV-2. Additionally, to support rapid NR translation to therapeutics, the challenges related to its bioavailability and safety are addressed, together with the advantages of NR to other NAD+ precursors.


Assuntos
Suplementos Nutricionais , Niacinamida/análogos & derivados , Envelhecimento , Animais , Betacoronavirus , Disponibilidade Biológica , Doenças Cardiovasculares/terapia , Infecções por Coronavirus/terapia , Humanos , Longevidade , Metabolismo , Doenças Neurodegenerativas/terapia , Niacinamida/farmacocinética , Niacinamida/farmacologia , Pandemias , Pneumonia Viral/terapia
3.
Nutrients ; 12(6)2020 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-32486488

RESUMO

Nicotinamide riboside (NR) has recently become one of the most studied nicotinamide adenine dinucleotide (NAD+) precursors, due to its numerous potential health benefits mediated via elevated NAD+ content in the body. NAD+ is an essential coenzyme that plays important roles in various metabolic pathways and increasing its overall content has been confirmed as a valuable strategy for treating a wide variety of pathophysiological conditions. Accumulating evidence on NRs' health benefits has validated its efficiency across numerous animal and human studies for the treatment of a number of cardiovascular, neurodegenerative, and metabolic disorders. As the prevalence and morbidity of these conditions increases in modern society, the great necessity has arisen for a rapid translation of NR to therapeutic use and further establishment of its availability as a nutritional supplement. Here, we summarize currently available data on NR effects on metabolism, and several neurodegenerative and cardiovascular disorders, through to its application as a treatment for specific pathophysiological conditions. In addition, we have reviewed newly published research on the application of NR as a potential therapy against infections with several pathogens, including SARS-CoV-2. Additionally, to support rapid NR translation to therapeutics, the challenges related to its bioavailability and safety are addressed, together with the advantages of NR to other NAD+ precursors.


Assuntos
Suplementos Nutricionais , Niacinamida/análogos & derivados , Envelhecimento , Animais , Betacoronavirus , Disponibilidade Biológica , Doenças Cardiovasculares/terapia , Infecções por Coronavirus/terapia , Humanos , Longevidade , Metabolismo , Doenças Neurodegenerativas/terapia , Niacinamida/farmacocinética , Niacinamida/farmacologia , Pandemias , Pneumonia Viral/terapia
4.
PLoS One ; 15(5): e0228759, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32437449

RESUMO

The contribution of astrocytes to the BOLD fMRI and DfMRI responses in visual cortex of mice following visual stimulation was investigated using TGN-020, an aquaporin 4 (AQP4) channel blocker, acting as an astrocyte function perturbator. Under TGN-020 injection the amplitude of the BOLD fMRI response became significantly higher. In contrast no significant changes in the DfMRI responses and the electrophysiological responses were observed. Those results further confirm the implications of astrocytes in the neurovascular coupling mechanism underlying BOLD fMRI, but not in the DfMRI responses which remained unsensitive to astrocyte function perturbation.


Assuntos
Aquaporina 4/antagonistas & inibidores , Astrócitos/metabolismo , Mapeamento Encefálico/métodos , Córtex Visual/fisiologia , Animais , Astrócitos/citologia , Imagem de Difusão por Ressonância Magnética/métodos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Niacinamida/análogos & derivados , Niacinamida/farmacologia , Tiadiazóis/farmacologia
5.
PLoS One ; 15(5): e0229702, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32413082

RESUMO

The Glymphatic System (GS) has been proposed as a mechanism to clear brain tissue from waste. Its dysfunction might lead to several brain pathologies, including the Alzheimer's disease. A key component of the GS and brain tissue water circulation is the astrocyte which is regulated by acquaporin-4 (AQP4), a membrane-bound water channel on the astrocytic end-feet. Here we investigated the potential of diffusion MRI to monitor astrocyte activity in a mouse brain model through the inhibition of AQP4 channels with TGN-020. Upon TGN-020 injection, we observed a significant decrease in the Sindex, a diffusion marker of tissue microstructure, and a significant increase of the water diffusion coefficient (sADC) in cerebral cortex and hippocampus compared to saline injection. These results indicate the suitability of diffusion MRI to monitor astrocytic activity in vivo and non-invasively.


Assuntos
Aquaporina 4/metabolismo , Astrócitos/metabolismo , Encéfalo/efeitos dos fármacos , Niacinamida/análogos & derivados , Tiadiazóis/farmacologia , Animais , Aquaporina 4/antagonistas & inibidores , Astrócitos/efeitos dos fármacos , Encéfalo/citologia , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Imagem de Difusão por Ressonância Magnética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Niacinamida/farmacologia
6.
Clin Nucl Med ; 45(7): 561-562, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32433166

RESUMO

We present a 78-year-old man with suspicion of prostate cancer due to a PSA of 200 ng/mL, who underwent F-PSMA-1007 (prostate specific membrane antigen) PET/CT for primary staging. Besides heterogeneous uptake to the prostate, an increased PSMA uptake in the cecum was observed, located in the thickened cecal wall with suspicion of a secondary malignancy. Colonoscopic biopsy followed by hemicolectomy confirmed the diagnosis of colon adenocarcinoma. This case demonstrates the importance of bioptic workup of suspicious findings on PSMA PET/CT, which are unlikely to be related to prostate cancer as PSMA ligand uptake is not exclusively prostate cancer specific.


Assuntos
Adenocarcinoma/diagnóstico por imagem , Adenocarcinoma/metabolismo , Neoplasias do Colo/diagnóstico por imagem , Neoplasias do Colo/metabolismo , Achados Incidentais , Niacinamida/análogos & derivados , Oligopeptídeos/metabolismo , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Idoso , Transporte Biológico , Humanos , Masculino , Niacinamida/metabolismo
8.
Org Biomol Chem ; 18(15): 2877-2885, 2020 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-32236231

RESUMO

The nutraceutical Nicotinamide Riboside (NR), an efficacious biosynthetic precursor to NAD, is readily metabolized by the purine nucleoside phosphorylase (PNP). Access to the PNP-stable versions of NR is difficult because the glycosidic bond of NR is easily cleaved. Unlike NR, NRH, the reduced form of NR, offers sufficient chemical stability to allow the successful functionalisation of the ribosyl-moiety. Here, we report on a series of NRH and NR derived amino acid conjugates, generated in good to excellent yields and show that O5'-esterification prevents the PNP-catalyzed phosphorolysis of these NR prodrugs.


Assuntos
Aminoácidos/metabolismo , Niacinamida/análogos & derivados , Pró-Fármacos/metabolismo , Purina-Núcleosídeo Fosforilase/metabolismo , Aminoácidos/química , Biocatálise , Estrutura Molecular , Niacinamida/química , Niacinamida/metabolismo , Pró-Fármacos/química , Purina-Núcleosídeo Fosforilase/química
9.
Clin Drug Investig ; 40(5): 469-484, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32274653

RESUMO

BACKGROUND AND OBJECTIVE: Peficitinib pharmacokinetics and pharmacodynamics have been characterized mainly in Caucasian subjects. This study investigated the pharmacokinetics, pharmacodynamics, safety, and tolerability of peficitinib in healthy Japanese subjects compared with Caucasian subjects. METHODS: In this single-center, randomized, double-blind, placebo-controlled study, a cohort of healthy Japanese (n = 24) and Caucasian (n = 24) men received a single oral dose of peficitinib (20, 60, or 200 mg) or placebo. Another cohort of Japanese men (n = 24) received peficitinib (10, 30, or 100 mg) or placebo twice daily for 7 days. Pharmacokinetic and pharmacodynamic parameters were assessed, and adverse events (AEs) monitored throughout. RESULTS: Dose proportionality of maximum plasma drug concentration (Cmax) and area under the plasma concentration-time curve extrapolated to infinity (AUCinf) was demonstrated for both ethnicities. The geometric mean ratio for dose-normalized Cmax was 45.7-98.8% higher and AUCinf was 33.8-66.4% higher in Japanese versus Caucasian subjects. Mean peak inhibition of STAT5 phosphorylation was higher in Japanese than Caucasian subjects for a given peficitinib dose, but inhibition was comparable across ethnicities for a given plasma peficitinib concentration. In the multiple-dose study, plasma peficitinib concentrations were similar on day 1 and day 7. All AEs were mild, and none resulted in study discontinuation. CONCLUSIONS: Peficitinib was well tolerated at doses up to 200 mg daily for 7 days in healthy Japanese subjects. Dose-proportional exposure was demonstrated across the single-dose range of 20-200 mg, with greater peficitinib exposure in Japanese compared with Caucasian subjects. The pharmacokinetic/pharmacodynamic relationships were considered comparable between these populations. CLINICALTRIALS. GOV IDENTIFIER: NCT01225224.


Assuntos
Adamantano/análogos & derivados , Grupo com Ancestrais do Continente Asiático , Grupo com Ancestrais do Continente Europeu , Niacinamida/análogos & derivados , Adamantano/efeitos adversos , Adamantano/farmacocinética , Adamantano/farmacologia , Adulto , Área Sob a Curva , Método Duplo-Cego , Nível de Saúde , Voluntários Saudáveis , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Niacinamida/efeitos adversos , Niacinamida/farmacocinética , Niacinamida/farmacologia , Placebos , Adulto Jovem
10.
Nat Commun ; 11(1): 1962, 2020 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-32327659

RESUMO

Topoisomerase 1 (TOP1) relieves torsional stress in DNA during transcription and facilitates the expression of long (>100 kb) genes, many of which are important for neuronal functions. To evaluate how loss of Top1 affected neurons in vivo, we conditionally deleted (cKO) Top1 in postmitotic excitatory neurons in the mouse cerebral cortex and hippocampus. Top1 cKO neurons develop properly, but then show biased transcriptional downregulation of long genes, signs of DNA damage, neuroinflammation, increased poly(ADP-ribose) polymerase-1 (PARP1) activity, single-cell somatic mutations, and ultimately degeneration. Supplementation of nicotinamide adenine dinucleotide (NAD+) with nicotinamide riboside partially blocked neurodegeneration, and increased the lifespan of Top1 cKO mice by 30%. A reduction of p53 also partially rescued cortical neuron loss. While neurodegeneration was partially rescued, behavioral decline was not prevented. These data indicate that reducing neuronal loss is not sufficient to limit behavioral decline when TOP1 function is disrupted.


Assuntos
DNA Topoisomerases Tipo I/deficiência , Instabilidade Genômica , Doenças Neurodegenerativas/enzimologia , Neurônios/enzimologia , Animais , Apoptose/efeitos dos fármacos , Córtex Cerebral/enzimologia , Córtex Cerebral/patologia , Dano ao DNA , DNA Topoisomerases Tipo I/genética , Hipocampo/enzimologia , Hipocampo/patologia , Inflamação , Camundongos , Camundongos Knockout , Mortalidade Prematura , Atividade Motora , Mutação , NAD/administração & dosagem , Doenças Neurodegenerativas/tratamento farmacológico , Doenças Neurodegenerativas/patologia , Doenças Neurodegenerativas/fisiopatologia , Neurônios/efeitos dos fármacos , Neurônios/patologia , Niacinamida/administração & dosagem , Niacinamida/análogos & derivados , Poli(ADP-Ribose) Polimerase-1/metabolismo
11.
Expert Opin Pharmacother ; 21(9): 1015-1025, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32345068

RESUMO

INTRODUCTION: The treatment of rheumatoid arthritis (RA), a chronic, systemic, autoimmune disease, has been greatly advanced by the introduction of biologic disease-modifying antirheumatic drugs (DMARDs); however, many patients still fail to achieve disease remission. Peficitinib, an orally bioavailable inhibitor of the Janus kinase (JAK) receptor family, was approved in Japan in 2019 and Korea in 2020 for the treatment of RA. AREAS COVERED: This review provides an overview of JAK inhibitors currently marketed or in development; the pharmacodynamics and pharmacokinetics of peficitinib; and the efficacy and safety data for peficitinib from Phase 2b and 3 trials. EXPERT OPINION: Peficitinib has proven clinical efficacy in Asian patients (Japan, Korea, and Taiwan) with RA who have an inadequate response to conventional DMARDs. In Phase 3 trials, clinical improvements and prevention of joint destruction were demonstrated for both 100 mg and 150 mg once-daily peficitinib versus placebo, and treatment for up to 52 weeks was well tolerated. Safety signals, in particular the increased incidence of herpes zoster-related disease, appeared in line with other JAK inhibitors. Post-launch monitoring will establish the long-term safety and effectiveness of this drug, and further studies are necessary to determine its potential use in non-Asian populations.


Assuntos
Adamantano/análogos & derivados , Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Imunossupressores/uso terapêutico , Niacinamida/análogos & derivados , Adamantano/farmacologia , Adamantano/uso terapêutico , Antirreumáticos/farmacologia , Humanos , Niacinamida/farmacologia , Niacinamida/uso terapêutico
12.
Am J Clin Nutr ; 112(2): 413-426, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32320006

RESUMO

BACKGROUND: Nicotinamide riboside (NR) is an NAD+ precursor that boosts cellular NAD+ concentrations. Preclinical studies have shown profound metabolic health effects after NR supplementation. OBJECTIVES: We aimed to investigate the effects of 6 wk NR supplementation on insulin sensitivity, mitochondrial function, and other metabolic health parameters in overweight and obese volunteers. METHODS: A randomized, double-blinded, placebo-controlled, crossover intervention study was conducted in 13 healthy overweight or obese men and women. Participants received 6 wk NR (1000 mg/d) and placebo supplementation, followed by broad metabolic phenotyping, including hyperinsulinemic-euglycemic clamps, magnetic resonance spectroscopy, muscle biopsies, and assessment of ex vivo mitochondrial function and in vivo energy metabolism. RESULTS: Markers of increased NAD+ synthesis-nicotinic acid adenine dinucleotide and methyl nicotinamide-were elevated in skeletal muscle after NR compared with placebo. NR increased body fat-free mass (62.65% ± 2.49% compared with 61.32% ± 2.58% in NR and placebo, respectively; change: 1.34% ± 0.50%, P = 0.02) and increased sleeping metabolic rate. Interestingly, acetylcarnitine concentrations in skeletal muscle were increased upon NR (4558 ± 749 compared with 3025 ± 316 pmol/mg dry weight in NR and placebo, respectively; change: 1533 ± 683 pmol/mg dry weight, P = 0.04) and the capacity to form acetylcarnitine upon exercise was higher in NR than in placebo (2.99 ± 0.30 compared with 2.40 ± 0.33 mmol/kg wet weight; change: 0.53 ± 0.21 mmol/kg wet weight, P = 0.01). However, no effects of NR were found on insulin sensitivity, mitochondrial function, hepatic and intramyocellular lipid accumulation, cardiac energy status, cardiac ejection fraction, ambulatory blood pressure, plasma markers of inflammation, or energy metabolism. CONCLUSIONS: NR supplementation of 1000 mg/d for 6 wk in healthy overweight or obese men and women increased skeletal muscle NAD+ metabolites, affected skeletal muscle acetylcarnitine metabolism, and induced minor changes in body composition and sleeping metabolic rate. However, no other metabolic health effects were observed.This trial was registered at clinicaltrials.gov as NCT02835664.


Assuntos
Acetilcarnitina/metabolismo , Composição Corporal/efeitos dos fármacos , Músculo Esquelético/metabolismo , Niacinamida/análogos & derivados , Obesidade/tratamento farmacológico , Sobrepeso/tratamento farmacológico , Idoso , Suplementos Nutricionais/análise , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/efeitos dos fármacos , NAD/biossíntese , Niacinamida/administração & dosagem , Obesidade/metabolismo , Obesidade/fisiopatologia , Sobrepeso/metabolismo , Sobrepeso/fisiopatologia
13.
Clin Nucl Med ; 45(6): e276-e278, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32332302

RESUMO

A 72-year-old man, who is known with a case of metastatic carcinoma of the breast, was referred for F-PMSA 1007 PET/CT with clinical suspicion of synchronous prostate cancer. F-PSMA 1007 PET/CT scan detected no abnormal tracer concentrating lesion in the prostate gland; however, abnormal tracer concentration was noted in soft tissue lesions in left breast, metastatic lymph nodes, and skeletal lesions. Compared with F-FDG PET/CT, more bone lesions were detected on F-PSMA 1007 imaging. The findings of our case open the possibility of imaging metastatic breast cancer with F-PSMA 1007 in men.


Assuntos
Neoplasias da Mama Masculina/metabolismo , Neoplasias da Mama Masculina/patologia , Radioisótopos de Flúor , Niacinamida/análogos & derivados , Oligopeptídeos/metabolismo , Idoso , Neoplasias da Mama Masculina/diagnóstico por imagem , Humanos , Masculino , Metástase Neoplásica , Niacinamida/metabolismo , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons
14.
Chem Biol Interact ; 324: 109093, 2020 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-32298659

RESUMO

Polycystic Ovary Syndrome (PCOS), as a common endocrine disorder is accompanied by hyperandrogenism, insulin resistance, ovulation problems, and infertility. Various types of off-label drugs like metformin have been used for the management of targeted problems caused by PCOS such as insulin resistance and hyperandrogenism. Nicotinamide (NAM) acts as a substrate of visfatin and Nicotinamide N-Methyltransferase (NNMT) leading to the generation of Nicotinamide Adenine Dinucleotide (NAD) and N1-Methylnicotinamide (MNAM), respectively. MNAM is known as an anti-inflammatory, anti-thrombosis, and anti-diabetic agent. In this study, the effects of NAM and MNAM on metabolic and endocrine abnormalities were evaluated in the adipose and ovarian tissues of a letrozole-induced rat model of PCOS. Our results showed that MNAM and NAM reversed abnormal estrous cycle and reduced the serum testosterone levels and CYP17A1 gene expression. Furthermore, all therapeutic factors improved HOMA-IR after treatment and NAM significantly increased the expression of GLUT4 and decreased the gene expression of visfatin. Also, MNAM diminished the gene expression of visfatin and resistin. It is noteworthy that all the therapeutic factors successfully activated the AMPK. In summary, this study is the first study reported beneficial effects of NAM and MNAM on the treatment of PCOS. Additionally, the alleviative effects of our therapeutic factors may be partially mediated by the AMPK-dependent manner due to the contribution of the AMPK in the expression of CYP17A1, visfatin, resistin, and GLUT4. Although more studies are required to unravel the exact mode of actions of MNAM and NAM in the PCOS, the findings of the current study shed light on an urgent need for discovering novel therapeutic pharmaceuticals regarding the treatment of PCOS.


Assuntos
Tecido Adiposo/efeitos dos fármacos , Niacinamida/análogos & derivados , Niacinamida/uso terapêutico , Ovário/efeitos dos fármacos , Síndrome do Ovário Policístico/tratamento farmacológico , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Citocinas/genética , Citocinas/metabolismo , Ciclo Estral/efeitos dos fármacos , Feminino , Expressão Gênica/efeitos dos fármacos , Transportador de Glucose Tipo 4/genética , Transportador de Glucose Tipo 4/metabolismo , Hiperandrogenismo/tratamento farmacológico , Hormônio Luteinizante/metabolismo , Metformina/uso terapêutico , Nicotinamida Fosforribosiltransferase/genética , Nicotinamida Fosforribosiltransferase/metabolismo , Ratos Wistar , Resistina/genética , Resistina/metabolismo , Esteroide 17-alfa-Hidroxilase/genética , Esteroide 17-alfa-Hidroxilase/metabolismo , Testosterona/metabolismo
17.
Drugs Today (Barc) ; 56(2): 151-163, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32163530

RESUMO

Janus kinase (JAK) inhibitors are novel small molecules with a mechanism of action in multiple signaling pathways that allows their application in a broad spectrum of autoimmune and autoinflammatory diseases. As far as the field of dermatology is concerned, chronic plaque psoriasis is currently one of the most studied indications regarding the potential use of JAK inhibitors. The purpose of this review is to provide a summarized overview of the existing information on the efficacy and safety of JAK inhibitors in plaque psoriasis, with a focus on tofacitinib, ruxolitinib, baricitinib, peficitinib and filgotinib. Although the published data on the therapeutic benefit of these agents in the therapy of this chronic condition are promising, further prospective studies and real-life data are necessary in order to sufficiently evaluate their role as an adequate treatment option for psoriatic patients.


Assuntos
Inibidores de Janus Quinases/uso terapêutico , Psoríase/tratamento farmacológico , Adamantano/análogos & derivados , Adamantano/uso terapêutico , Azetidinas/uso terapêutico , Humanos , Janus Quinases , Niacinamida/análogos & derivados , Niacinamida/uso terapêutico , Piperidinas/uso terapêutico , Estudos Prospectivos , Pirazóis/uso terapêutico , Piridinas/uso terapêutico , Pirimidinas/uso terapêutico , Pirróis/uso terapêutico , Sulfonamidas/uso terapêutico , Triazóis/uso terapêutico
18.
Clin Nucl Med ; 45(5): 377-378, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32209880

RESUMO

A 60-year-old man with suspected right renal cell carcinoma underwent F-FDG PET/CT and F prostate-specific membrane antigen (PSMA) 1007 PET/CT scan. Compared with the F-FDG PET/CT scan, F-PSMA 1007 PET/CT showed intense tracer concentration in the primary tumor in the right kidney and intense tracer concentration consistently in all lung nodules. Unlike noted in previous pilot studies with Ga-PSMA, we observed that the primary renal tumor also showed intense tracer avidity with F-PSMA 1007. F-PSMA 1007 PET/CT may provide preoperative insight into possible etiology, histopathological probability of tumor type, staging information, and theranostic potentials in evaluation of suspected renal cell carcinoma.


Assuntos
Carcinoma de Células Renais/diagnóstico por imagem , Neoplasias Renais/diagnóstico por imagem , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons/métodos , Radioisótopos de Flúor , Humanos , Masculino , Pessoa de Meia-Idade , Niacinamida/análogos & derivados , Oligopeptídeos , Compostos Radiofarmacêuticos
19.
Leuk Res ; 91: 106337, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32200189

RESUMO

The tyrosine kinase inhibitors (TKIs) have revolutionized the management of chronic myeloid leukemia (CML) and BCR-ABL1 inhibitors form the mainstay of CML treatment. Although patients with CML generally do well under TKI therapy, there is a subgroup of patients who are resistant and/or intolerant to TKIs. In these group of patients, there is the need of additional treatment strategies. In this review, we provide an update on the current knowledge of these novel treatment approaches that can be used alone and/or in combination with TKIs.


Assuntos
Antineoplásicos/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Proteínas de Fusão bcr-abl/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Terapia de Alvo Molecular/métodos , Ensaios Clínicos como Assunto , Resistencia a Medicamentos Antineoplásicos/genética , Everolimo/uso terapêutico , Proteínas de Fusão bcr-abl/antagonistas & inibidores , Proteínas de Fusão bcr-abl/imunologia , Expressão Gênica , Inibidores de Histona Desacetilases/uso terapêutico , Mepesuccinato de Omacetaxina/uso terapêutico , Humanos , Imunoterapia/métodos , Interferon-alfa/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/imunologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Niacinamida/análogos & derivados , Niacinamida/uso terapêutico , Piperidinas/uso terapêutico , Polietilenoglicóis/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Pirazóis/uso terapêutico , Piridinas/uso terapêutico , Quinolonas/uso terapêutico , Proteínas Recombinantes/uso terapêutico
20.
Biochemistry ; 59(8): 933-942, 2020 03 03.
Artigo em Inglês | MEDLINE | ID: mdl-32049506

RESUMO

Sterile alpha and toll/interleukin receptor (TIR) motif-containing protein 1 (SARM1) plays a pivotal role in triggering the neurodegenerative processes that underlie peripheral neuropathies, traumatic brain injury, and neurodegenerative diseases. Importantly, SARM1 knockdown or knockout prevents degeneration, thereby demonstrating that SARM1 is a promising therapeutic target. Recently, SARM1 was shown to promote neurodegeneration via its ability to hydrolyze NAD+, forming nicotinamide and ADP ribose (ADPR). Herein, we describe the initial kinetic characterization of full-length SARM1, as well as the truncated constructs corresponding to the SAM1-2TIR and TIR domains, highlighting the distinct challenges that have complicated efforts to characterize this enzyme. Moreover, we show that bacterially expressed full-length SARM1 (kcat/KM = 6000 ± 2000 M-1 s-1) is at least as active as the TIR domain alone (kcat/KM = 1500 ± 300 M-1 s-1). Finally, we show that the SARM1 hydrolyzes NAD+ via an ordered uni-bi reaction in which nicotinamide is released prior to ADPR.


Assuntos
Proteínas do Domínio Armadillo/química , Proteínas do Citoesqueleto/química , Adenosina Difosfato Ribose/química , Animais , Proteínas do Domínio Armadillo/antagonistas & inibidores , Proteínas do Domínio Armadillo/isolamento & purificação , Caenorhabditis elegans/química , Proteínas de Caenorhabditis elegans/química , Proteínas do Citoesqueleto/antagonistas & inibidores , Proteínas do Citoesqueleto/isolamento & purificação , Ensaios Enzimáticos , Inibidores Enzimáticos/química , Humanos , Cinética , Niacinamida/análogos & derivados , Domínios Proteicos , Receptores Acoplados a Proteínas-G/química
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