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1.
Medicine (Baltimore) ; 98(39): e17303, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31574857

RESUMO

Treatment with nitisinone (NTBC) has brought about a drastic improvement in the treatment and prognosis of hereditary tyrosinemia type I (HT1). We conducted a retrospective observational multicentric study in Spanish HT1 patients treated with NTBC to assess clinical and biochemical long-term evolution.We evaluated 52 patients, 7 adults and 45 children, treated with NTBC considering: age at diagnosis, diagnosis by clinical symptoms, or by newborn screening (NBS); phenotype (acute/subacute/chronic), mutational analysis; symptoms at diagnosis and clinical course; biochemical markers; doses of NTBC; treatment adherence; anthropometric evolution; and neurocognitive outcome.The average follow-up period was 6.1 ±â€Š4.9 and 10.6 ±â€Š5.4 years in patients with early and late diagnosis respectively. All patients received NTBC from diagnosis with an average dose of 0.82 mg/kg/d. All NBS-patients (n = 8) were asymptomatic at diagnosis except 1 case with acute liver failure, and all remain free of liver and renal disease in follow-up. Liver and renal affectation was markedly more frequent at diagnosis in patients with late diagnosis (P < .001 and .03, respectively), with ulterior positive hepatic and renal course in 86.4% and 93.2% of no-NBS patients, although 1 patient with good metabolic control developed hepatocarcinoma.Despite a satisfactory global nutritional evolution, 46.1% of patients showed overweight/obesity. Interestingly lower body mass index was observed in patients with good dietary adherence (20.40 ±â€Š4.43 vs 24.30 ±â€Š6.10; P = .08) and those with good pharmacological adherence (21.19 ±â€Š4.68 vs 28.58 ±â€Š213.79).intellectual quotient was ≥85 in all NBS- and 68.75% of late diagnosis cases evaluated, 15% of which need pedagogical support, and 6.8% (3/44) showed school failure.Among the 12 variants identified in fumarylacetoacetate hydrolase gene, 1 of them novel (H63D), the most prevalent in Spanish population is c.554-1 G>T.After NTBC treatment a reduction in tyrosine and alpha-fetoprotein levels was observed in all the study groups, significant for alpha-fetoprotein in no NBS-group (P = .03), especially in subacute/chronic forms (P = .018).This series confirms that NTBC treatment had clearly improved the prognosis and quality of life of HT1 patients, but it also shows frequent cognitive dysfunctions and learning difficulties in medium-term follow-up, and, in a novel way, a high percentage of overweight/obesity.


Assuntos
Cicloexanonas/uso terapêutico , Diagnóstico Tardio , Nitrobenzoatos/uso terapêutico , Obesidade , Qualidade de Vida , Tirosinemias , Adulto , Criança , Disfunção Cognitiva/diagnóstico , Disfunção Cognitiva/etiologia , Diagnóstico Tardio/efeitos adversos , Diagnóstico Tardio/prevenção & controle , Inibidores Enzimáticos/uso terapêutico , Feminino , Seguimentos , Humanos , Recém-Nascido , Nefropatias/diagnóstico , Nefropatias/etiologia , Masculino , Determinação de Necessidades de Cuidados de Saúde , Triagem Neonatal/métodos , Obesidade/diagnóstico , Obesidade/etiologia , Prognóstico , Estudos Retrospectivos , Espanha , Tempo para o Tratamento , Tirosinemias/complicações , Tirosinemias/diagnóstico , Tirosinemias/tratamento farmacológico , Tirosinemias/psicologia
3.
JAMA ; 322(10): 936-945, 2019 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-31503307

RESUMO

Importance: Methotrexate and mycophenolate mofetil are commonly used immunomodulatory therapies for achieving corticosteroid-sparing control of noninfectious uveitis, but there is uncertainty about which drug is more effective. Objective: To compare the effect of methotrexate and mycophenolate for achieving corticosteroid-sparing control of noninfectious intermediate uveitis, posterior uveitis, and panuveitis. Design, Setting, and Participants: The First-line Antimetabolites as Steroid-sparing Treatment (FAST) uveitis trial screened 265 adults with noninfectious uveitis requiring corticosteroid-sparing immunosuppressive therapy from 9 referral eye centers in India, the United States, Australia, Saudi Arabia, and Mexico between August 22, 2013, and August 16, 2017. Follow-up ended on August 20, 2018. Interventions: Patients were randomized to receive oral methotrexate, 25 mg weekly (n = 107), or oral mycophenolate mofetil, 3 g daily (n = 109). Main Outcomes and Measures: The primary outcome was treatment success at 6 months, which was defined as having control of inflammation in both eyes, no more than 7.5 mg prednisone daily and less than or equal to 2 drops of prednisolone acetate 1%, and no treatment failure due to safety or intolerability. Patients underwent follow-up to 12 months while receiving the same treatment or switched to the other antimetabolite, depending on their 6-month outcome. Results: Among 216 patients who were randomized (median age, 38 years; 135 (62.5%) women), 194 (89.8%) completed follow-up through 6 months. Treatment success occurred in 64 (66.7%) patients in the methotrexate group vs 56 (57.1%) in the mycophenolate group (difference, 9.5% [95% CI, -5.3% to 21.8%]; odds ratio [OR], 1.50 [95% CI, 0.81 to 2.81]; P = .20). Among patients with posterior uveitis or panuveitis, treatment success was achieved in 58 (74.4%) in the methotrexate group vs 42 (55.3%) in the mycophenolate group (difference, 19.1% [95% CI, 3.6% to 30.6%]; OR, 2.35 [95% CI, 1.16 to 4.90]; P = .02); whereas among patients with intermediate uveitis treatment success occurred in 6 (33.3%) in the methotrexate group vs 14 (63.6%) in the mycophenolate group (difference, -30.3% [95% CI, -51.6% to 1.1%]; OR, 0.29 [95% CI, 0.08 to 1.05]; P = .07; P for interaction = .004). Elevated liver enzymes were the most common nonserious laboratory adverse event, occurring in 14 patients (13.0%) in the methotrexate group and 8 patients (7.4%) in the mycophenolate group. Conclusions and Relevance: Among adults with noninfectious uveitis, the use of mycophenolate mofetil compared with methotrexate as first-line corticosteroid-sparing treatment did not result in superior control of inflammation. Further research is needed to determine if either drug is more effective based on the anatomical subtype of uveitis. Trial Registration: ClinicalTrials.gov Identifier: NCT01829295.


Assuntos
Imunossupressores/uso terapêutico , Metotrexato/uso terapêutico , Ácido Micofenólico/uso terapêutico , Uveíte/tratamento farmacológico , Adulto , Anti-Inflamatórios/administração & dosagem , Quimioterapia Combinada , Inibidores Enzimáticos/uso terapêutico , Feminino , Humanos , Imunossupressores/administração & dosagem , Imunossupressores/efeitos adversos , Testes de Função Hepática , Masculino , Metotrexato/administração & dosagem , Metotrexato/efeitos adversos , Pessoa de Meia-Idade , Ácido Micofenólico/administração & dosagem , Ácido Micofenólico/efeitos adversos , Prednisolona/administração & dosagem
4.
Adv Exp Med Biol ; 1161: 89-100, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31562624

RESUMO

The importance of prostaglandin E2 in cancer progression is well established, but research on its role in cancer has so far mostly been focused on epithelial cancer in adults while the knowledge about the contribution of prostaglandin E2 to childhood malignancies is limited. Neuroblastoma, an extracranial solid tumor of the sympathetic nervous system, mainly affects young children. Patients with tumors classified as high-risk have poor survival despite receiving intensive treatment, illustrating a need for new treatments complimenting existing ones. The basis of neuroblastoma treatment e.g. chemotherapy and radiation therapy, target the proliferating genetically unstable tumor cells leading to treatment resistance and relapses. The tumor microenvironment is an avenue, still to a great extent, unexplored and lacking effective targeted therapies. Cancer-associated fibroblasts is the main source of prostaglandin E2 in neuroblastoma contributing to angiogenesis, immunosuppression and tumor growth. Prostaglandin E2 is formed from its precursor arachidonic acid in a two-step enzymatic reaction. Arachidonic acid is first converted by cyclooxygenases into prostaglandin H2 and then further converted by microsomal prostaglandin E synthase-1 into prostaglandin E2. We believe targeting of microsomal prostaglandin E synthase-1 in cancer-associated fibroblasts will be an effective future therapeutic strategy in fighting neuroblastoma.


Assuntos
Dinoprostona , Neuroblastoma , Prostaglandina-E Sintases , Prostaglandina-Endoperóxido Sintases , Antineoplásicos/uso terapêutico , Ácido Araquidônico/metabolismo , Inibidores Enzimáticos/uso terapêutico , Humanos , Neuroblastoma/tratamento farmacológico , Neuroblastoma/enzimologia , Neuroblastoma/fisiopatologia , Prostaglandina-E Sintases/metabolismo , Prostaglandina-Endoperóxido Sintases/metabolismo , Microambiente Tumoral
5.
J Assoc Physicians India ; 67(4): 74-85, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31311223

RESUMO

The burden of atherosclerotic cardiovascular (CV) disease is alarmingly high and increasing in our country. Dyslipidemia is one of the major modifiable risk factors, and INTERHEART study showed that dyslipidemia had the highest population attributable risk for myocardial infarction. In the management of dyslipidemia, low-density lipoprotein cholesterol (LDL-C) is the primary therapeutic target. In addition to therapeutic lifestyle changes, statins and ezetimibe effectively lower LDL-C and consequently improve CV outcomes. However, there are situations where these drugs fall short of achieving the target or they may not be well tolerated.


Assuntos
Inibidores Enzimáticos/uso terapêutico , Pró-Proteína Convertase 9/antagonistas & inibidores , Anticolesterolemiantes , LDL-Colesterol , Índia , Pró-Proteína Convertase 9/metabolismo
6.
Rinsho Ketsueki ; 60(6): 594-599, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31281150

RESUMO

Standard treatment for acute myeloid leukemia (AML) comprises (1) induction therapy with both cytarabine and anthracycline and (2) consolidation therapy that is modified according to patients' conditions, including prognostic factors. However, this strategy is not satisfactory, especially for elderly patients. Novel technologies have revealed several driver mutations of numerous critical genes in AML, which can be targeted by novel drugs; the discovery of such targetable genes and the development of novel drugs have evolved the treatment strategy for AML. We should always monitor these advances in hematology. In the United States, the FDA has already approved several new drugs for AML, including FLT3 inhibitors and IDH neoenzyme inhibitors. In Japan, gilteritinib, an FLT3 inhibitor, was also approved at the end of 2018. These promising drugs will facilitate performing "precision medicine" on patients with AML soon.


Assuntos
Inibidores Enzimáticos/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Citarabina/uso terapêutico , Genômica , Humanos , Japão , Inibidores de Proteínas Quinases/uso terapêutico
7.
Clin Biochem ; 71: 24-30, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31228435

RESUMO

OBJECTIVES: We have assessed the effect of elevated concentrations of hydroxyphenylpyruvic acid (HPPA), hydroxyphenyllactic acid (HPLA) and tyrosine, on a range of chemistry tests in serum and urine to explore the potential for chemical interference on routine laboratory analyses in patients with alkaptonuria (AKU) treated with nitisinone and similarly implications for patients with hereditary tyrosinemia type 1 (HT-1). MATERIALS AND METHODS: HPPA, HPLA and tyrosine were added separately to pooled serum from subjects without AKU in a range of assays with Roche Modular chemistries. Effects on urine were assessed by changes in urine strip chemistries after mixing a positive control urine with various amounts of the test compounds and reading on a Siemens urine strip meter. RESULTS: No significant effect (p > 0.1) was observed up to 225 µmol/L of HPPA and HPLA, and up to 5000 µmol/L tyrosine, on any of the serum-based assays including those with peroxidase-coupled reaction systems of enzymatic creatinine, urate, total cholesterol, HDL cholesterol and triglyceride. Both the monohydroxy HPPA, and the dihydroxy homogentisic acid (HGA), at increased urine concentrations typical of nitisinone-treated AKU and non-treated AKU respectively, did however show marked negative interference in strip assays for glucose and leucocytes; i.e. those with peroxide-linked endpoints. The effect of increased HPLA was less marked. CONCLUSIONS: In patients with AKU or on nitisinone treatment and HT-1 patients on nitisinone, urine strip chemistry testing should be used sparingly, if at all, to avoid false negative reporting. It is recommended that urine assays should be organised with a suitable specialist laboratory.


Assuntos
4-Hidroxifenilpiruvato Dioxigenase/metabolismo , Alcaptonúria/tratamento farmacológico , Alcaptonúria/metabolismo , Cicloexanonas/uso terapêutico , Inibidores Enzimáticos/uso terapêutico , Nitrobenzoatos/uso terapêutico , Fenilpropionatos/análise , Ácidos Fenilpirúvicos/análise , Tirosina/metabolismo , Alcaptonúria/sangue , Alcaptonúria/urina , Humanos , Fenilpropionatos/sangue , Fenilpropionatos/urina , Ácidos Fenilpirúvicos/sangue , Ácidos Fenilpirúvicos/urina
8.
Top Curr Chem (Cham) ; 377(4): 19, 2019 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-31165274

RESUMO

This review is an effort to summarize recent developments in synthesis of O-glycosides and N-, C-glycosyl molecules with promising antidiabetic potential. Articles published after 2000 are included. First, the O-glycosides used in the treatment of diabetes are presented, followed by the N-glycosides and finally the C-glycosides constituting the largest group of antidiabetic drugs are described. Within each group of glycosides, we presented how the structure of compounds representing potential drugs changes and when discussing chemical compounds of a similar structure, achievements are presented in the chronological order. C-Glycosyl compounds mimicking O-glycosides structure, exhibit the best features in terms of pharmacodynamics and pharmacokinetics. Therefore, the largest part of the article is concerned with the description of the synthesis and biological studies of various C-glycosides. Also N-glycosides such as N-(ß-D-glucopyranosyl)-amides, N-(ß-D-glucopyranosyl)-ureas, and 1,2,3-triazolyl derivatives belong to the most potent classes of antidiabetic agents. In order to indicate which of the compounds presented in the given sections have the best inhibitory properties, a list of the best inhibitors is presented at the end of each section. In summary, the best inhibitors were selected from each of the summarizing figures and the results of the ranking were placed. In this way, the reader can learn about the structure of the compounds having the best antidiabetic activity. The compounds, whose synthesis was described in the article but did not appear on the figures presenting the structures of the most active inhibitors, did not show proper activity as inhibitors. Thus, the article also presents studies that have not yielded the desired results and show directions of research that should not be followed. In order to show the directions of the latest research, articles from 2018 to 2019 are described in a separate Sect. 5. In Sect. 6, biological mechanisms of action of the glycosides and patents of marketed drugs are described.


Assuntos
Diabetes Mellitus/tratamento farmacológico , Descoberta de Drogas/métodos , Glicosídeos/química , Glicosídeos/farmacologia , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Animais , Diabetes Mellitus/enzimologia , Diabetes Mellitus/metabolismo , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacocinética , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Glicogênio Fosforilase/antagonistas & inibidores , Glicogênio Fosforilase/metabolismo , Glicosídeos/farmacocinética , Glicosídeos/uso terapêutico , Humanos , Hipoglicemiantes/farmacocinética , Hipoglicemiantes/uso terapêutico , Proteína Tirosina Fosfatase não Receptora Tipo 1/antagonistas & inibidores , Proteína Tirosina Fosfatase não Receptora Tipo 1/metabolismo , Inibidores do Transportador 2 de Sódio-Glicose/química , Inibidores do Transportador 2 de Sódio-Glicose/farmacocinética , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Relação Estrutura-Atividade
9.
Croat Med J ; 60(2): 121-126, 2019 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-31044583

RESUMO

Due to very limited therapeutic options, ischemic brain injury is one of the leading causes of death and lifelong disability worldwide, which imposes enormous public health burden. One of the main events occurring with ischemic brain stroke is cell death. Necroptosis is a type of cell death described as a regulated necrosis characterized by cell membrane disruption mediated by phosphorylated mixed lineage kinase like protein (MLKL). It can be triggered by activation of death receptors (eg, FAS, TNFR1), which lead to receptor-interacting serine/threonine-protein kinase 3 (RIPK3) activation by RIPK1 in the absence of active caspase-8. Here, we review articles that have reported that necroptosis significantly contributes to negative events occurring with the ischemic brain stroke, and that its inhibition is protective both in vitro and in vivo. We also review articles describing positive effects obtained by reducing necroptosis, including the reduction of infarct volume and improved functional recovery in animal models. Since necroptosis is characterized by cell content leakage and subsequent inflammation, in addition to reducing cell death, inhibition of necroptosis in ischemic brain stroke also reduces some inflammatory cytokines. By comparing various approaches in inhibition of necroptosis, we analyze the achieved effects from the perspective of controlling necroptosis as a part of future therapeutic interventions in brain ischemia.


Assuntos
Isquemia Encefálica/fisiopatologia , Morte Celular , Inibidores Enzimáticos/uso terapêutico , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Animais , Apoptose , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/etiologia , Isquemia Encefálica/patologia , Inibidores Enzimáticos/farmacologia , Humanos , Inflamação/metabolismo , Necrose , Fosforilação , Proteínas Quinases/metabolismo , Proteína Serina-Treonina Quinases de Interação com Receptores/antagonistas & inibidores , Receptores Tipo I de Fatores de Necrose Tumoral , Acidente Vascular Cerebral
10.
Cell Mol Life Sci ; 76(15): 2967-2985, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31104094

RESUMO

The methylation of proteins is integral to the execution of many important biological functions, including cell signalling and transcriptional regulation. Protein methyltransferases (PMTs) are a large class of enzymes that carry out the addition of methyl marks to a broad range of substrates. PMTs are critical for normal cellular physiology and their dysregulation is frequently observed in human disease. As such, PMTs have emerged as promising therapeutic targets with several inhibitors now in clinical trials for oncology indications. The discovery of chemical inhibitors and antagonists of protein methylation signalling has also profoundly impacted our general understanding of PMT biology and pharmacology. In this review, we present general principles for drugging protein methyltransferases or their downstream effectors containing methyl-binding modules, as well as best-in-class examples of the compounds discovered and their impact both at the bench and in the clinic.


Assuntos
Histona-Lisina N-Metiltransferase/metabolismo , Medicina de Precisão , Regulação Alostérica , Sítios de Ligação , Domínio Catalítico , Inibidores Enzimáticos/química , Inibidores Enzimáticos/metabolismo , Inibidores Enzimáticos/uso terapêutico , Histona-Lisina N-Metiltransferase/antagonistas & inibidores , Histona-Lisina N-Metiltransferase/classificação , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Neoplasias/patologia , Processamento de Proteína Pós-Traducional , Proteína-Arginina N-Metiltransferases/antagonistas & inibidores , Proteína-Arginina N-Metiltransferases/classificação , Proteína-Arginina N-Metiltransferases/metabolismo
11.
Eur J Med Chem ; 176: 228-247, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31103902

RESUMO

Alzheimer's disease (AD) is a multifactorial syndrome resulting in profound misery and poses a substantial burden on human health, economy, and society throughout the world. Based on the numerous AD-related targets in the disease network, multi-target design strategy is a crucial direction to seek for enhanced therapy, and multi-target drugs have the ability to regulate more targets than single-target drugs, affecting the disease network with more potency. Herein, we highlight nine major targets associated with AD, which are acetylcholine esterase (AChE), beta-site amyloid precursor protein cleaving enzyme 1 (ß-secretase, BACE-1), glycogen synthase kinase 3 beta (GSK-3ß), monoamine oxidases (MAOs), metal ions in the brain, N-methyl-D-aspartate (NMDA) receptor, 5-hydroxytryptamine (5-HT) receptors, the third subtype of histamine receptor (H3 receptor), and phosphodiesterases (PDEs), and their respective relationship to the disease network. Furthermore, eleven multi-target design strategies classified by the involvement of AChE and related promising compounds for improved therapy of AD in recent years are described based on the nine major targets.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Inibidores Enzimáticos/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Nootrópicos/uso terapêutico , Animais , Quelantes/uso terapêutico , Ensaios Clínicos como Assunto , Humanos , Receptores de Superfície Celular/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos
12.
N Engl J Med ; 380(26): 2518-2528, 2019 06 27.
Artigo em Inglês | MEDLINE | ID: mdl-31112379

RESUMO

BACKGROUND: Interstitial lung disease (ILD) is a common manifestation of systemic sclerosis and a leading cause of systemic sclerosis-related death. Nintedanib, a tyrosine kinase inhibitor, has been shown to have antifibrotic and antiinflammatory effects in preclinical models of systemic sclerosis and ILD. METHODS: We conducted a randomized, double-blind, placebo-controlled trial to investigate the efficacy and safety of nintedanib in patients with ILD associated with systemic sclerosis. Patients who had systemic sclerosis with an onset of the first non-Raynaud's symptom within the past 7 years and a high-resolution computed tomographic scan that showed fibrosis affecting at least 10% of the lungs were randomly assigned, in a 1:1 ratio, to receive 150 mg of nintedanib, administered orally twice daily, or placebo. The primary end point was the annual rate of decline in forced vital capacity (FVC), assessed over a 52-week period. Key secondary end points were absolute changes from baseline in the modified Rodnan skin score and in the total score on the St. George's Respiratory Questionnaire (SGRQ) at week 52. RESULTS: A total of 576 patients received at least one dose of nintedanib or placebo; 51.9% had diffuse cutaneous systemic sclerosis, and 48.4% were receiving mycophenolate at baseline. In the primary end-point analysis, the adjusted annual rate of change in FVC was -52.4 ml per year in the nintedanib group and -93.3 ml per year in the placebo group (difference, 41.0 ml per year; 95% confidence interval [CI], 2.9 to 79.0; P = 0.04). Sensitivity analyses based on multiple imputation for missing data yielded P values for the primary end point ranging from 0.06 to 0.10. The change from baseline in the modified Rodnan skin score and the total score on the SGRQ at week 52 did not differ significantly between the trial groups, with differences of -0.21 (95% CI, -0.94 to 0.53; P = 0.58) and 1.69 (95% CI, -0.73 to 4.12 [not adjusted for multiple comparisons]), respectively. Diarrhea, the most common adverse event, was reported in 75.7% of the patients in the nintedanib group and in 31.6% of those in the placebo group. CONCLUSIONS: Among patients with ILD associated with systemic sclerosis, the annual rate of decline in FVC was lower with nintedanib than with placebo; no clinical benefit of nintedanib was observed for other manifestations of systemic sclerosis. The adverse-event profile of nintedanib observed in this trial was similar to that observed in patients with idiopathic pulmonary fibrosis; gastrointestinal adverse events, including diarrhea, were more common with nintedanib than with placebo. (Funded by Boehringer Ingelheim; SENSCIS ClinicalTrials.gov number, NCT02597933.).


Assuntos
Inibidores Enzimáticos/uso terapêutico , Indóis/uso terapêutico , Doenças Pulmonares Intersticiais/tratamento farmacológico , Proteínas Tirosina Quinases/antagonistas & inibidores , Escleroderma Sistêmico/complicações , Administração Oral , Adulto , Diarreia/induzido quimicamente , Progressão da Doença , Método Duplo-Cego , Inibidores Enzimáticos/efeitos adversos , Feminino , Humanos , Indóis/efeitos adversos , Doenças Pulmonares Intersticiais/etiologia , Doenças Pulmonares Intersticiais/fisiopatologia , Masculino , Pessoa de Meia-Idade , Escleroderma Sistêmico/tratamento farmacológico , Capacidade Vital
13.
Medicine (Baltimore) ; 98(18): e15329, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31045771

RESUMO

RATIONALE: Gain of function (GOF) mutations in PIK3CD gene encoding PI3K p110δ were recently associated with a novel combined immune deficiency characterized by recurrent sinopulmonary infections, CD4 lymphopenia, reduced class-switched memory B cells, lymphadenopathy, cytomegalovirus and/or epstein-Barr virus (EBV) viremia, and EBV-related lymphoma. A subset of affected patients also had elevated serum IgM. PATIENT CONCERNS: We report a patient who was diagnosed with systemic lupus erythematosus (SLE) at a young age and was recently found to carry heterozygous mutations in PIK3CD. The patient not only presented with recurrent sinopulmonary infections, CD4 lymphopenia, lymphadenopathy, EBV viremia, and elevated serum IgM, but also met classification criteria of SLE based on persistent proteinuria and hematuria, leukopenia and anemia, low level of serum complement, and positive autoantibody for antinuclear antibodies. DIAGNOSES: Activated PI3Kδ syndrome. INTERVENTIONS: Oral prednisolone and hydroxychloroquine combined with mycophenolate mofetil was given to the patient. He was currently receiving intravenous immunoglobulin per month in association with hydroxychloroquine, low-dose prednisolone, and mycophenolate mofetil. OUTCOMES: At present, the level of complement restored to normal, hematuria and proteinuria disappeared, and liver function returned to normal. LESSONS: SLE may be a novel phenotype of GOF mutation in PI3CKD gene (GOF PIK3CD).


Assuntos
Classe I de Fosfatidilinositol 3-Quinases/genética , Mutação com Ganho de Função/genética , Síndromes de Imunodeficiência/diagnóstico , Síndromes de Imunodeficiência/genética , Lúpus Eritematoso Sistêmico/genética , Adolescente , Anticorpos Antinucleares/sangue , Grupo com Ancestrais do Continente Asiático/genética , Classe I de Fosfatidilinositol 3-Quinases/efeitos dos fármacos , Proteínas do Sistema Complemento/análise , Proteínas do Sistema Complemento/efeitos dos fármacos , Inibidores Enzimáticos/uso terapêutico , Infecções por Vírus Epstein-Barr/diagnóstico , Infecções por Vírus Epstein-Barr/etiologia , Infecções por Vírus Epstein-Barr/imunologia , Glucocorticoides/uso terapêutico , Herpesvirus Humano 4/imunologia , Humanos , Hidroxicloroquina/administração & dosagem , Hidroxicloroquina/uso terapêutico , Imunoglobulinas Intravenosas/uso terapêutico , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Lúpus Eritematoso Sistêmico/etiologia , Lúpus Eritematoso Sistêmico/imunologia , Masculino , Ácido Micofenólico/administração & dosagem , Ácido Micofenólico/uso terapêutico , Fenótipo , Prednisolona/administração & dosagem , Prednisolona/uso terapêutico
14.
Nat Commun ; 10(1): 2261, 2019 05 21.
Artigo em Inglês | MEDLINE | ID: mdl-31113940

RESUMO

Cyclic GMP-AMP synthase (cGAS) is the primary sensor for aberrant intracellular dsDNA producing the cyclic dinucleotide cGAMP, a second messenger initiating cytokine production in subsets of myeloid lineage cell types. Therefore, inhibition of the enzyme cGAS may act anti-inflammatory. Here we report the discovery of human-cGAS-specific small-molecule inhibitors by high-throughput screening and the targeted medicinal chemistry optimization for two molecular scaffolds. Lead compounds from one scaffold co-crystallize with human cGAS and occupy the ATP- and GTP-binding active site. The specificity and potency of these drug candidates is further documented in human myeloid cells including primary macrophages. These novel cGAS inhibitors with cell-based activity will serve as probes into cGAS-dependent innate immune pathways and warrant future pharmacological studies for treatment of cGAS-dependent inflammatory diseases.


Assuntos
Descoberta de Drogas/métodos , Inibidores Enzimáticos/farmacologia , Nucleotidiltransferases/antagonistas & inibidores , Doenças Autoimunes/tratamento farmacológico , Doenças Autoimunes/imunologia , Doenças Autoimunes/patologia , Células Cultivadas , Cristalografia por Raios X , DNA/imunologia , DNA/metabolismo , Inibidores Enzimáticos/química , Inibidores Enzimáticos/uso terapêutico , Ensaios de Triagem em Larga Escala/métodos , Humanos , Imunidade Inata/efeitos dos fármacos , Interferons/imunologia , Interferons/metabolismo , Macrófagos , Modelos Moleculares , Nucleotídeos Cíclicos/imunologia , Nucleotídeos Cíclicos/metabolismo , Nucleotidiltransferases/imunologia , Nucleotidiltransferases/isolamento & purificação , Nucleotidiltransferases/metabolismo , Cultura Primária de Células , Proteínas Recombinantes/imunologia , Proteínas Recombinantes/isolamento & purificação , Proteínas Recombinantes/metabolismo
15.
Medicine (Baltimore) ; 98(19): e15573, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31083231

RESUMO

BACKGROUND: Rapid I-131 turnover Graves' disease patients have low cure rate. We aimed to compare cure percentage at 12 months among 3 treatment doses of I-131 with or without lithium carbonate (LiCO3) in rapid turnover Graves' disease patients. METHODS: Sixty Graves' disease patients referred for radioactive iodine treatment were randomised into three arms of treatment: Group A, 3.7 MBq I-131/g thyroid plus 600 mg/day LiCO3, Group B, 5.55 MBq I-131/g plus 600 mg/day LiCO3, and Group C, 7.4 MBq I-131/g without LiCO3. Data were collected at baseline, 3, 6, 9, and 12 months. The primary endpoint were cure rates (percentage of euthyroid or hypothyroid) at 12 months. Pairwise comparisons were made across 3 groups using an equality of proportions test. The secondary endpoint, the odds of cure over the total follow-up for group B and C versus group A, was analyzed using generalized estimating equation (GEE). Side effects of I-131 and LiCO3 treatment were evaluated at 1 to 2 weeks after treatment. RESULTS: The cure rate at 12 months was 45% (9/20) for group A, 60% (12/20) for group B and 80% (16/20) for group C. The mean difference in proportion cured at 12 months between group C and group A was 35 (7.0 to 66.8)%; P-value = .02. There was a statistically significant difference between cure rates over all follow-up of group C and A after adjustment for sex (adjusted OR = 3.09; 95%CI = 1.32-7.20; P-value = .009), but no significant difference was found between group B and A or C and B in the primary and/or secondary efficacy endpoints. Side effects from the treatment were found in 12% (7/60); 2 in group A, 4 in group B, and 1 in group C. Four of these were likely due to LiCO3 side effects. CONCLUSIONS: Treatment of rapid turnover Graves' disease patients with high dose I-131 (7.4 MBq/g) provides significantly higher cure rates at 12 months, and 3 times odds of cure than 3.7 MBq/g I-131 plus LiCO3 with lesser side effects. We thus recommend 7.4 MBq I-131/g for treatment in these patients.


Assuntos
Doença de Graves/terapia , Radioisótopos do Iodo/uso terapêutico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Inibidores Enzimáticos/uso terapêutico , Feminino , Seguimentos , Doença de Graves/metabolismo , Humanos , Radioisótopos do Iodo/efeitos adversos , Radioisótopos do Iodo/metabolismo , Carbonato de Lítio/uso terapêutico , Masculino , Pessoa de Meia-Idade , Dosagem Radioterapêutica , Resultado do Tratamento , Adulto Jovem
16.
Cell Mol Life Sci ; 76(13): 2571-2592, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30982078

RESUMO

Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer. It is the fourth leading cause of cancer-related death and is associated with a very poor prognosis. KRAS driver mutations occur in approximately 95% of PDAC cases and cause the activation of several signaling pathways such as mitogen-activated protein kinase (MAPK) pathways. Regulation of these signaling pathways is orchestrated by feedback loops mediated by the balance between protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs), leading to activation or inhibition of its downstream targets. The human PTPome comprises 125 members, and these proteins are classified into three distinct families according to their structure. Since PTP activity description, it has become clear that they have both inhibitory and stimulatory effects on cancer-associated signaling processes and that deregulation of PTP function is closely associated with tumorigenesis. Several PTPs have displayed either tumor suppressor or oncogenic characteristics during the development and progression of PDAC. In this sense, PTPs have been presented as promising candidates for the treatment of human pancreatic cancer, and many PTP inhibitors have been developed since these proteins were first associated with cancer. Nevertheless, some challenges persist regarding the development of effective and safe methods to target these molecules and deliver these drugs. In this review, we discuss the role of PTPs in tumorigenesis as tumor suppressor and oncogenic proteins. We have focused on the differential expression of these proteins in PDAC, as well as their clinical implications and possible targeting for pharmacological inhibition in cancer therapy.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Ductal Pancreático/tratamento farmacológico , Inibidores Enzimáticos/uso terapêutico , Terapia de Alvo Molecular , Neoplasias Pancreáticas/tratamento farmacológico , Proteínas Tirosina Fosfatases/antagonistas & inibidores , Animais , Carcinoma Ductal Pancreático/enzimologia , Humanos , Neoplasias Pancreáticas/enzimologia , Fosforilação
17.
Eur J Pharmacol ; 853: 371-380, 2019 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-31009635

RESUMO

Hyperuricaemia, which results from the overproduction and underexcretion of uric acid, has been linked with chronic renal dysfunction, cardiovascular diseases, diabetes and metabolic syndrome. However, available clinical drugs cannot simultaneously target the production and excretion of uric acid. Norathyriol, a natural xanthone, was expected to have the dual actions. We previously reported that norathyriol possessed potent anti-hyperuricaemic activity related to the inhibition of uric acid production. Here, we investigated the uricosuric actions in hyperuricaemic animals and explored the possible molecular mechanisms associated with renal urate transporters and xanthine oxidase (XO). The results showed that norathyriol (0.5-4.0 mg/kg) dose- and time-dependently decreased serum urate levels in uric acid-induced hyperuricaemic mice and markedly increased the fractional excretion of urate in oxonate-induced hyperuricaemic rats, demonstrating a promotion of urate excretion in the kidney. Further evidence showed that norathyriol markedly increased renal mRNA and protein expression of the secretory organic anion transporter 1 (OAT1) in hyperuricaemic mice and strengthened its transport function in vitro. Moreover, norathyriol also upregulated the mRNA expression of the secretory transporters OAT3, ATP-binding cassette transporter G2 and multidrug resistance protein 4, but not their protein expression. Changes in the expression of the reabsorptive transporters were not observed. This is the first report that norathyriol has uricosuric effects by targeting OAT1. Moreover, norathyriol significantly inhibited XO activity in an uncompetitive manner. Taken together, these findings suggest that norathyriol has the potential to be developed as a new anti-hyperuricaemic agent with dual actions that activate OAT1 and inhibit XO activity.


Assuntos
Inibidores Enzimáticos/farmacologia , Hiperuricemia/tratamento farmacológico , Ácido Úrico/sangue , Ácido Úrico/urina , Xantenos/farmacologia , Xantina Oxidase/antagonistas & inibidores , Animais , Inibidores Enzimáticos/uso terapêutico , Células HEK293 , Humanos , Rim/efeitos dos fármacos , Rim/metabolismo , Camundongos , Proteína 1 Transportadora de Ânions Orgânicos/metabolismo , Transportadores de Ânions Orgânicos/metabolismo , Xantenos/uso terapêutico
18.
Respir Res ; 20(1): 71, 2019 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-30971229

RESUMO

BACKGROUND: Given the broad definition of an acute exacerbation of IPF, it is likely that acute exacerbations are heterogeneous in their aetiology, severity and clinical course. We used pooled data from the INPULSIS® trials of nintedanib versus placebo to investigate whether acute exacerbations reported as serious adverse events were associated with higher mortality than those reported as non-serious adverse events and to assess the effect of nintedanib on these types of events. METHODS: Adverse events considered by an investigator to be an acute exacerbation were adjudicated as a confirmed acute exacerbation, suspected acute exacerbation, or not an acute exacerbation. Time to first investigator-reported acute exacerbation or confirmed/suspected acute exacerbation reported as a serious adverse event or non-serious adverse event over the 52-week treatment period was assessed post-hoc. Deaths were assessed based on data collected over the 52-week treatment period. RESULTS: Of 63 patients who had ≥1 investigator-reported acute exacerbation, 48 (76.2%) had a first acute exacerbation reported as a serious adverse event. Thirty-six (3.4%) patients had ≥1 confirmed/suspected acute exacerbation, of whom 31 had a first event reported as a serious adverse event. Investigator-reported acute exacerbations reported as serious adverse events occurred in 23 patients in the nintedanib group and 26 in the placebo group. Confirmed/suspected acute exacerbations reported as serious adverse events occurred in 10 and 21 patients in these groups, respectively. Nintedanib significantly reduced the risk of a first acute exacerbation reported as a serious adverse event (HR 0.57 [95% CI: 0.32, 0.99]; p = 0.0476) and the risk of a first confirmed/suspected acute exacerbation reported as a serious adverse event (HR 0.30 [95% CI: 0.14, 0.64]; p = 0.0019) versus placebo. A higher proportion of patients with investigator-reported acute exacerbations reported as serious adverse events died than patients with acute exacerbations reported as non-serious adverse events (61.2% versus 7.1%). CONCLUSION: Different severities of acute exacerbation of IPF may exist. Acute exacerbations reported as serious adverse events in the INPULSIS® trials were associated with high mortality. Nintedanib significantly reduced the risk of acute exacerbations reported as serious adverse events. TRIAL REGISTRATION: ClinicalTrials.gov NCT01335464 and NCT01335477 .


Assuntos
Progressão da Doença , Inibidores Enzimáticos/uso terapêutico , Fibrose Pulmonar Idiopática/tratamento farmacológico , Indóis/uso terapêutico , Índice de Gravidade de Doença , Doença Aguda , Idoso , Inibidores Enzimáticos/farmacologia , Feminino , Humanos , Fibrose Pulmonar Idiopática/diagnóstico , Fibrose Pulmonar Idiopática/mortalidade , Indóis/farmacologia , Masculino , Pessoa de Meia-Idade , Capacidade Vital/efeitos dos fármacos , Capacidade Vital/fisiologia
19.
Curr Gastroenterol Rep ; 21(5): 22, 2019 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-31016396

RESUMO

PURPOSE OF REVIEW: The biologic era revolutionized the medical management of inflammatory bowel disease (IBD) and allowed for a paradigm shift away from a therapeutic strategy that traditionally relied on corticosteroids and immunomodulators. IBD treatment has now further evolved to encompass novel non-biologic agents. RECENT FINDINGS: An electronic database search, spanning up to September 2018, was conducted using PubMed, Web of Science, Google Scholar, and Scopus. Abstracts were also reviewed from Digestive Diseases Week, European Crohn's and Colitis Organization congress, Canadian Digestive Diseases Week, and United European Gastroenterology Week. The JAK1/3 inhibitor, tofacitinib, was shown to both induce and maintain clinical remission and mucosal healing in ulcerative colitis (UC). Also, the sphingosine-1-phosphate (SIP) S1P1/S1P5 receptor agonist ozanimod showed benefit with clinical remission and mucosal healing in UC. Anti-trafficking non-biologic therapies such as AJM300 and a phosphodiesterase (PDE) PDE4 inhibitor, apremilast, have shown benefit in terms of clinical response, clinical remission, and mucosal healing in UC. Upadacitinib and filgotinib have shown initial favorable outcomes in CD patients, with further ongoing trials. Non-biologic agents comprise a growing number of mechanisms of action with the promise of safe and effective oral therapy for patients with IBD.


Assuntos
Anti-Inflamatórios/uso terapêutico , Inibidores Enzimáticos/uso terapêutico , Doenças Inflamatórias Intestinais/tratamento farmacológico , Neurotransmissores/uso terapêutico , Humanos
20.
Best Pract Res Clin Haematol ; 32(1): 89-97, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30927979

RESUMO

Patients with AML that develops after cytotoxic therapy (tAML) have overall inferior outcomes relative to de novo AML due to both patient-related factors and the intrinsic biology of the disease. Treatment of patients with tAML is challenging. The key initial clinical decision is whether a patient is a candidate for or likely to benefit from intensive induction chemotherapy, a determination which we argue should not be predicated on chronologic age alone. For those determined likely to tolerate intensive induction chemotherapy, CPX-351 is likely superior to conventional induction with cytarabine and daunorubicin. For those deemed inappropriate for intensive induction, hypomethylating agents have the strongest evidence base in elderly adults with AML, and are an attractive option in tAML. This is particularly true in patients with TP53 mutations who are less likely to respond to conventional induction chemotherapy. Exciting options on the therapeutic horizon for tAML include combination therapies incorporating BCL2 inhibitors, Hedgehog pathway inhibitors, and isocitrate dehydrogenase inhibitors.


Assuntos
Citarabina/uso terapêutico , Daunorrubicina/uso terapêutico , Inibidores Enzimáticos/uso terapêutico , Quimioterapia de Indução/métodos , Leucemia Mieloide Aguda/tratamento farmacológico , Segunda Neoplasia Primária/tratamento farmacológico , Humanos , Leucemia Mieloide Aguda/induzido quimicamente , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Mutação , Segunda Neoplasia Primária/genética , Segunda Neoplasia Primária/metabolismo
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