Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 2.886
Filtrar
1.
JAMA ; 324(7): 642-650, 2020 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-32809003

RESUMO

Importance: The combination of ascorbic acid, corticosteroids, and thiamine has been identified as a potential therapy for septic shock. Objective: To determine whether the combination of ascorbic acid, corticosteroids, and thiamine attenuates organ injury in patients with septic shock. Design, Setting, and Participants: Randomized, blinded, multicenter clinical trial of ascorbic acid, corticosteroids, and thiamine vs placebo for adult patients with septic shock. Two hundred five patients were enrolled between February 9, 2018, and October 27, 2019, at 14 centers in the United States. Follow-up continued until November 26, 2019. Interventions: Patients were randomly assigned to receive parenteral ascorbic acid (1500 mg), hydrocortisone (50 mg), and thiamine (100 mg) every 6 hours for 4 days (n = 103) or placebo in matching volumes at the same time points (n = 102). Main Outcomes and Measures: The primary outcome was change in the Sequential Organ Failure Assessment (SOFA) score (range, 0-24; 0 = best) between enrollment and 72 hours. Key secondary outcomes included kidney failure and 30-day mortality. Patients who received at least 1 dose of study drug were included in analyses. Results: Among 205 randomized patients (mean age, 68 [SD, 15] years; 90 [44%] women), 200 (98%) received at least 1 dose of study drug, completed the trial, and were included in the analyses (101 with intervention and 99 with placebo group). Overall, there was no statistically significant interaction between time and treatment group with regard to SOFA score over the 72 hours after enrollment (mean SOFA score change from 9.1 to 4.4 [-4.7] points with intervention vs 9.2 to 5.1 [-4.1] points with placebo; adjusted mean difference, -0.8; 95% CI, -1.7 to 0.2; P = .12 for interaction). There was no statistically significant difference in the incidence of kidney failure (31.7% with intervention vs 27.3% with placebo; adjusted risk difference, 0.03; 95% CI, -0.1 to 0.2; P = .58) or in 30-day mortality (34.7% vs 29.3%, respectively; hazard ratio, 1.3; 95% CI, 0.8-2.2; P = .26). The most common serious adverse events were hyperglycemia (12 patients with intervention and 7 patients with placebo), hypernatremia (11 and 7 patients, respectively), and new hospital-acquired infection (13 and 12 patients, respectively). Conclusions and Relevance: In patients with septic shock, the combination of ascorbic acid, corticosteroids, and thiamine, compared with placebo, did not result in a statistically significant reduction in SOFA score during the first 72 hours after enrollment. These data do not support routine use of this combination therapy for patients with septic shock. Trial Registration: ClinicalTrials.gov Identifier: NCT03389555.


Assuntos
Corticosteroides/uso terapêutico , Ácido Ascórbico/uso terapêutico , Insuficiência de Múltiplos Órgãos/prevenção & controle , Choque Séptico/tratamento farmacológico , Tiamina/uso terapêutico , Corticosteroides/efeitos adversos , Adulto , Idoso , Ácido Ascórbico/efeitos adversos , Infecção Hospitalar , Quimioterapia Combinada , Feminino , Humanos , Hiperglicemia/induzido quimicamente , Hipernatremia/induzido quimicamente , Masculino , Pessoa de Meia-Idade , Insuficiência de Múltiplos Órgãos/etiologia , Escores de Disfunção Orgânica , Modelos de Riscos Proporcionais , Choque Séptico/complicações , Tiamina/efeitos adversos , Falha de Tratamento
2.
PLoS One ; 15(8): e0237660, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32841254

RESUMO

This study evaluated the influence of type 2 diabetes mellitus on bone loss, bone repair and cytokine production in hyperglycemic rats, treated or not with metformin. The animals were distributed as follow: Non-Hyperglycemic (NH), Non Hyperglycemic with Ligature (NH-L), Treated Non Hyperglycemic (TNH), Treated Non Hyperglycemic with Ligature Treated (TNH-L), Hyperglycemic (H), Treated Hyperglycemic (TH), Hyperglycemic with Ligature (H-L), Treated Hyperglycemic with Ligature (TH-L). At 40th day after induction of hyperglycemia, the groups NH-L, TNH-L, H-L, TH-L received a ligature to induce periodontitis. On the 69th, the TNH, TNH-L, TH, TH-L groups received metformin until the end of the study. Bone repair was evaluated at histometric and the expression levels of Sox9, RunX2 and Osterix. Analysis of the ex-vivo expression of TNF-α, IFN-γ, IL-12, IL-4, TGF-ß, IL-10, IL-6 and IL-17 were also evaluated. Metformin partially reverse induced bone loss in NH and H animals. Lower OPG/RANKL, increased OCN and TRAP expression were observed in hyperglycemic animals, and treatment with metformin partially reversed hyperglycemia on the OPG/RANKL, OPN and TRAP expression in the periodontitis. The expression of SOX9 and RunX2 were also decreased by hyperglycemia and metformin treatment. Increased ex vivo levels of TNF-α, IL-6, IL-4, IL-10 and IL-17 was observed. Hyperglycemia promoted increased IL-10 levels compared to non-hyperglycemic ones. Treatment of NH with metformin was able to mediate increased levels of TNF-α, IL-10 and IL-17, whereas for H an increase of TNF-α and IL-17 was detected in the 24- or 48-hour after stimulation with LPS. Ligature was able to induce increased levels of TNF-α and IL-17 in both NH and H. This study revealed the negative impact of hyperglycemia and/or treatment with metformin in the bone repair via inhibition of transcription factors associated with osteoblastic differentiation.


Assuntos
Perda do Osso Alveolar/prevenção & controle , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Tipo 2/complicações , Hiperglicemia/complicações , Metformina/administração & dosagem , Periodontite/prevenção & controle , Perda do Osso Alveolar/etiologia , Perda do Osso Alveolar/metabolismo , Processo Alveolar/citologia , Processo Alveolar/efeitos dos fármacos , Processo Alveolar/metabolismo , Processo Alveolar/patologia , Animais , Regeneração Óssea/efeitos dos fármacos , Regeneração Óssea/genética , Diferenciação Celular/efeitos dos fármacos , Citocinas/metabolismo , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/induzido quimicamente , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Humanos , Hiperglicemia/induzido quimicamente , Hiperglicemia/tratamento farmacológico , Hiperglicemia/metabolismo , Osteoblastos/fisiologia , Periodontite/etiologia , Periodontite/metabolismo , Ratos , Estreptozocina/toxicidade , Fatores de Transcrição/metabolismo
3.
Pol Merkur Lekarski ; 48(285): 209-214, 2020 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-32564049

RESUMO

Viral infections lead to many disorders with a different course and prognosis. Clinical trials are ongoing on new groups of antiviral drugs, which are very promising. However, treatment with antiviral drugs causes numerous adverse effects (AEs) including hormonal dysfunctions. The aim of this article is to discuss endocrine abnormalities induced by the antiviral drugs including frequency of their occurrence. The review is based on the available literature in the Medline database and considers the latest articles describing endocrine disorders with relation to antiviral therapy. The hormonal and metabolic dysfunctions were discussed, including the AEs like: osteoporosis, osteomalacia, hypoand hyperthyroidism, metabolic syndrome, lipodystrophy, hyperglycemia, diabetes mellitus and others. Awareness of frequency and type of complications caused by antiviral drugs, enables faster linking of the disease with the therapy, so it allows the personalization of treatment. It's necessary to monitor the general condition of the patients and appropriate diagnostic parameters that it can help diagnose hormonal disorders and adjust an individual antiviral therapy for the patient with endocrinopathy.


Assuntos
Antivirais , Diabetes Mellitus , Hiperglicemia , Osteoporose , Antivirais/efeitos adversos , Diabetes Mellitus/induzido quimicamente , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Humanos , Hiperglicemia/induzido quimicamente , Osteoporose/induzido quimicamente
4.
PLoS One ; 15(6): e0235076, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32584876

RESUMO

Due to the complexity and fragility of biological drug products, several challenges exist in their formulation development. Excipients are added to increase product stability, maintain tonicity, and facilitate drug delivery. The potential implications of these additive substances merit clinical consideration. We assessed the safety risk of excipients on the basis of their type and variability through an assessment framework, which quantifies excipient complexity in 230 biological formulations, and identifies excipient-related adverse events through published case reports. A biologic on average contained 4.45 excipients, half of that found in oral medications. The frequency distribution was heavily skewed towards the most commonly occurring excipients: water (40.4%), sodium chloride (38.3%), polysorbate 80 (28.7%), sucrose (24.4%), and mannitol (20.9%), with 44.4% of formulations not listing the concentration of the most commonly occurring inactive ingredients. A literature search revealed only 17 case reports of excipient-related adverse events, suggesting the need for more clarity for clinicians on the safety of chemical additives. These cases included injection site reactions, anaphylaxis, hyperglycemia, and acute renal failure. With the expansion of the biopharmaceutical market, it is important to consider the safety data of biologic excipients, so that therapy can be tailored appropriately for a specific patient.


Assuntos
Lesão Renal Aguda/induzido quimicamente , Anafilaxia/induzido quimicamente , Excipientes/efeitos adversos , Hiperglicemia/induzido quimicamente , Química Farmacêutica , Excipientes/uso terapêutico , Humanos , Manitol/efeitos adversos , Manitol/uso terapêutico , Polissorbatos/efeitos adversos , Polissorbatos/uso terapêutico , Cloreto de Sódio/efeitos adversos , Cloreto de Sódio/uso terapêutico , Sacarose/efeitos adversos , Sacarose/uso terapêutico , Água/efeitos adversos
5.
Am J Physiol Regul Integr Comp Physiol ; 319(1): R11-R18, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32401628

RESUMO

Consumption of a single, sugar-sweetened beverage (SSB) impairs vascular endothelial function. Regular aerobic exercise improves endothelium-dependent vasodilation; however, it is unknown whether these beneficial effects persist with frequent SSB consumption. Therefore, the purpose of this study was twofold; we studied the effects of repetitive SSB consumption (75 g d-glucose, 3 times/day) for 1 wk (Glu, n = 13, 23 ± 4 yr, 23.5 ± 3.4 kg/m2) on endothelium-dependent vasodilation (FMD). Then, in a separate cohort, we investigated whether 45 min of moderate-intensity aerobic exercise on five separate days offset the hypothesized decrease in FMD during the Glu protocol (Glu+Ex, n = 11, 21 ± 3 yr, 23.8 ± 2.4 kg/m2). Baseline, fasting [glucose] (P = 0.15), [insulin] (P = 0.25), %FMD (P = 0.48), absolute FMD (P = 0.66), and shear rate area under the curve (SRAUC; P = 0.82) were similar between groups. Following the interventions, fasting [glucose] (Glu: 94 ± 6 to 92 ± 6 mg/dL, Glu+Ex: 89 ± 8 to 87 ± 6 mg/dL, P = 0.74) and [insulin] (Glu: 11.3 ± 6.2 to 11.8 ± 8.9 µU/mL, Glu+Ex: 8.7 ± 2.9 to 9.4 ± 3.2 µU/mL, P = 0.89) were unchanged. %FMD was reduced in Glu (6.1 ± 2.2 to 5.1 ± 1.3%) and increased in Glu+Ex (6.6 ± 2.2 to 7.8 ± 2.4%, P < 0.05 for both). SRAUC increased similarly in both Glu [17,715 ± 8,275 to 22,922 ± 4,808 arbitrary units (A.U.)] and Glu+Ex (18,216 ± 4,516 to 21,666 ± 5,392 A.U., main effect of time P < 0.05). When %FMD was adjusted for SRAUC, attenuation was observed in Glu (0.41 ± 0.18 to 0.23 ± 0.08%/s × 103, P < 0.05) but not Glu+Ex (0.38 ± 0.14 to 0.38 ± 0.13%/s × 103, P = 0.88). Despite unchanged fasting [glucose] and [insulin], repeated consumption of SSBs impaired conduit artery vascular endothelial function. Additionally, subjects who engaged in regular moderate-intensity aerobic exercise did not demonstrate the same SSB-induced endothelial dysfunction. Collectively, these data suggest aerobic exercise may offset the deleterious effects of repetitive SSB consumption.


Assuntos
Endotélio Vascular/fisiologia , Exercício Físico/fisiologia , Bebidas Adoçadas com Açúcar/efeitos adversos , Adolescente , Adulto , Glicemia/análise , Estudos de Coortes , Dieta , Humanos , Hiperglicemia/induzido quimicamente , Hiperglicemia/fisiopatologia , Hiperinsulinismo/induzido quimicamente , Hiperinsulinismo/fisiopatologia , Insulina/sangue , Masculino , Vasodilatação/efeitos dos fármacos , Adulto Jovem
6.
An. sist. sanit. Navar ; 43(1): 87-91, ene.-abr. 2020. ilus
Artigo em Espanhol | IBECS | ID: ibc-193681

RESUMO

Presentamos un caso de hiperglucemia secundaria a intoxicación por cannabinoides sintéticos (CS). Los CS son drogas de abuso con efectos similares a la marihuana pero con diferente estructura química, lo que evita su detección con los test de drogas utilizados habitualmente, dificultando su diagnóstico. Entre los posibles efectos secundarios de su uso se encuentra la hiperglucemia. Su consumo debe sospecharse ante hiperglucemias no explicables por otra causa, especialmente en pacientes jóvenes que presenten, además, otra clínica compatible con consumo de CS, tales como agitación, cuadro confusional o psicosis; debería interrogarse al paciente sobre su uso. Es importante, además, que la población diabética conozca los efectos secundarios de los cannabinoides sintéticos, para evitar su consumo por un sector de la población especialmente vulnerable a las consecuencias de su empleo


We present a case of intoxication by synthetic cannabinoids (SC). SC are substances of abuse with effects similar to Marijuana but with a different chemical structure, which avoids its detectability by regular drug tests, making diagnosis difficult. Among the possible side effects of their use is hyperglycemia. Their presence should be suspected in cases of hyperglycemia that cannot be explained by any other cause, especially in young patients presenting another clinical picture suggestive of SC consumption such as agitation, confusional symptoms or psychosis; the patient should be questioned about their use. It is important that the diabetic population knows the side effects of synthetic cannabinoids to avoid their consumption, as it is a sector of the population especially vulnerable to the consequences of their use


Assuntos
Humanos , Masculino , Adulto , Canabinoides/toxicidade , Hiperglicemia/induzido quimicamente , Drogas Desenhadas/toxicidade , Canabinoides/efeitos adversos , Transtornos Relacionados ao Uso de Substâncias/complicações , Insulina/administração & dosagem , Soro , Canabinoides/farmacocinética
7.
Metabolism ; 107: 154231, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32298723

RESUMO

BACKGROUND: The mechanism of pyruvate kinase M2 (PKM2)-mediated inflammatory signalling in macrophages when plaques rupture and the impact of hyperglycaemia on the signalling are unclear. The present study aimed to explore the impact of hyperglycaemia on PKM2-mediated NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome/stress granule signalling in macrophages and its correlation with plaque vulnerability in vivo and in vitro. METHODS: From July to December 2019, 80 patients with coronary heart disease (CHD) were divided into acute ST-segment elevation myocardial infarction (STEMI) (n = 57) (DM-STEMI, n = 21; non-DM-STEMI, n = 36) and stable CHD (SCHD) groups (n = 23). Circulating mononuclear cells were isolated. The value of peak troponin I (TnI), the Global Registry of Acute Coronary Events (GRACE) risk score, and the expression levels of the related markers were quantified and compared. In vitro studies on the THP-1 cells were also performed. RESULTS: The DM-STEMI group had a higher value of peak TnI and a higher GRACE risk score than the non-DM-STEMI group (p < 0.05). The highest expression levels of PKM2, NLRP3, interleukin (IL)-1ß, and IL-18 and the lowest expression level of GTPase activating protein (SH3 domain)-binding protein 1 (G3BP1) (a stress granule marker protein) were observed in the DM-STEMI group, and they were followed by the non-DM-STEMI group and the SCHD group (p < 0.05). In vitro studies showed similar results and that TEPP-46 (a PKM2 activator) and 2-deoxy-d-glucose (a toxic glucose analogue) reversed the hyperglycaemia-induced increase in the NLRP3 inflammasome and decrease in G3BP1 expression. CONCLUSION: Hyperglycaemia might increase the activation of PKM2-mediated NLRP3 inflammasome/stress granule signalling and increase plaque vulnerability, associating it with worse prognosis. PKM2 may be a novel prognostic indicator and a new target for the treatment of patients with CHD and DM.


Assuntos
Proteínas de Transporte/metabolismo , Grânulos Citoplasmáticos , Hiperglicemia/fisiopatologia , Inflamassomos , Macrófagos/metabolismo , Proteínas de Membrana/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Placa Aterosclerótica/metabolismo , Hormônios Tireóideos/metabolismo , Idoso , Linhagem Celular , Doença das Coronárias/metabolismo , DNA Helicases/sangue , Feminino , Humanos , Hiperglicemia/induzido quimicamente , Interleucinas/sangue , Masculino , Pessoa de Meia-Idade , Proteínas de Ligação a Poli-ADP-Ribose/sangue , RNA Helicases/sangue , Proteínas com Motivo de Reconhecimento de RNA/sangue , Infarto do Miocárdio com Supradesnível do Segmento ST/metabolismo , Troponina I/metabolismo
8.
Yakugaku Zasshi ; 140(4): 591-598, 2020.
Artigo em Japonês | MEDLINE | ID: mdl-32238642

RESUMO

Few studies have examined the relationship between the use of antidepressants and the onset of hyperglycemia and diabetes mellitus in Japan. We herein explored the possibility of this relationship using the Japanese Adverse Drug Event Report database (JADER). The present study included 20 individual antidepressants, consisting of 6 subclasses, which have been approved for use in Japan. We used Standardized MedDRA Queries 20000041 to extract patients who developed hyperglycemia/new onset diabetes mellitus (NODM) in JADER between April 2004 and September 2016. We calculated reporting odds ratios (RORs) with 95% confidence intervals (CI). We also calculated odds ratios defined as the ratio of odds of hyperglycemia/NODM to all other adverse drug events (ADEs) by the age cut-off group or sex in the cases of antidepressants. The lower limit of 95%CI of RORs for 13 antidepressants (imipramine, clomipramine, nortriptyline, amitriptyline, amoxapine, maprotiline, mianserin, sertraline, paroxetine, escitalopram, duloxetine, mirtazapine, and trazodone), which included all subclasses, exceeded 1. Younger age group was associated with hyperglycemia/NODM for 5 antidepressants (imipramine, amitriptyline, maprotiline, duloxetine, and trazodone), and female was associated with the ADEs for trazodone, although these results should be interpreted cautiously. Healthcare personnel need to be aware that the use of antidepressants may lead to hyperglycemia/NODM.


Assuntos
Sistemas de Notificação de Reações Adversas a Medicamentos , Antidepressivos/efeitos adversos , Diabetes Mellitus/induzido quimicamente , Hiperglicemia/induzido quimicamente , Adulto , Diabetes Mellitus/epidemiologia , Feminino , Humanos , Hiperglicemia/epidemiologia , Japão/epidemiologia , Masculino , Razão de Chances , Fatores de Tempo , Adulto Jovem
9.
Ann Hematol ; 99(4): 737-741, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32030447

RESUMO

For patients with pure red cell aplasia (PRCA), cyclosporine (CsA) is the first line therapy. Occasionally, some patients who suffer from renal insufficiency cannot tolerate CsA. To explore the efficacy and tolerance of sirolimus treatment for those patients, twelve PRCA patients with renal insufficiency from May 2014 to May 2018 in Peking Union Medical College Hospital were enrolled, treated with sirolimus, and followed up at the median time of 16 (10-50) months. Eleven patients (91.7%) responded to sirolimus, with 58.3% complete response (CR) and 41.7% partial response (PR). The median time to achieve the optimum effect was 4 (1-7) months. The serum creatinine level remained stable or even reduced during the treatment period for eleven patients. Seven patients (58.3%) reported adverse events during sirolimus therapy, including increased blood glucose, infection, skin rash, elevated triglyceride or total cholesterol, and elevated serum creatinine compared with baseline. No treatment-related death was noticed during the follow-up time. Three patients relapsed with an overall response rate of 75.0% at 1 year. These results suggested that sirolimus was effective and tolerable for patients with PRCA complicated with renal insufficiency.


Assuntos
Imunossupressores/uso terapêutico , Aplasia Pura de Série Vermelha/tratamento farmacológico , Insuficiência Renal/etiologia , Sirolimo/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Creatinina/sangue , Ciclosporina/efeitos adversos , Ciclosporina/uso terapêutico , Erupção por Droga/etiologia , Avaliação de Medicamentos , Substituição de Medicamentos , Feminino , Humanos , Hiperglicemia/induzido quimicamente , Hipertrigliceridemia/induzido quimicamente , Imunossupressores/efeitos adversos , Masculino , Pessoa de Meia-Idade , Recidiva , Aplasia Pura de Série Vermelha/complicações , Indução de Remissão , Insuficiência Renal/sangue , Estudos Retrospectivos , Sirolimo/efeitos adversos , Resultado do Tratamento
10.
J Nutr ; 150(4): 704-711, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32060554

RESUMO

BACKGROUND: The association between high selenium (Se) intake and metabolic disorders such as type 2 diabetes has raised great concern, but the underlying mechanism remains unclear. OBJECTIVE: Through targeted metabolomics analysis, we examined the liver sugar and acylcarnitine metabolism responses to supranutritional selenomethionine (SeMet) supplementation in pigs. METHODS: Thirty-six castrated male pigs (Duroc-Landrace-Yorkshire, 62.0 ± 3.3 kg) were fed SeMet adequate (Se-A, 0.25 mg Se/kg) or SeMet supranutritional (Se-S, 2.5 mg Se/kg) diets for 60 d. The Se concentration, biochemical, gene expression, enzyme activity, and energy-targeted metabolite profiles were analyzed. RESULTS: The Se-S group had greater fasting serum concentrations of glucose (1.9-fold), insulin (1.4-fold), and free fatty acids (FFAs,1.3-fold) relative to the Se-A group (P < 0.05). The liver total Se concentration was 4.2-fold that of the Se-A group in the Se-S group (P < 0.05), but expression of most selenoprotein genes and selenoenzyme activity did not differ between the 2 groups. Seven of 27 targeted sugar metabolites and 4 of 21 acylcarnitine metabolites significantly changed in response to high SeMet (P < 0.05). High SeMet supplementation significantly upregulated phosphoenolpyruvate carboxy kinase (PEPCK) activity by 64.4% and decreased hexokinase and succinate dehydrogenase (SDH) activity by 46.5-56.7% (P < 0.05). The relative contents of glucose, dihydroxyacetone phosphate, α-ketoglutarate, fumarate, malate, erythrose-4-phosphate, and sedoheptulose-7-phosphate in the Se-S group were 21.1-360% greater than those in the Se-A group (P < 0.05). The expression of fatty acid synthase (FASN) and the relative contents of carnitine, hexanoyl-carnitine, decanoyl-carnitine, and tetradecanoyl-carnitine in the Se-S group were 35-97% higher than those in the Se-A group (P < 0.05). CONCLUSIONS: Dietary high SeMet-induced hyperglycemia and hyperinsulinemia were associated with suppression of sugar metabolism and elevation of lipid synthesis in pig livers. Our research provides novel insights into high SeMet intake-induced type 2 diabetes.


Assuntos
Carnitina/análogos & derivados , Dieta , Fígado/metabolismo , Selenometionina/administração & dosagem , Açúcares/metabolismo , Animais , Carnitina/metabolismo , Diabetes Mellitus Tipo 2/induzido quimicamente , Suplementos Nutricionais , Relação Dose-Resposta a Droga , Homeostase/efeitos dos fármacos , Hiperglicemia/induzido quimicamente , Hiperinsulinismo/induzido quimicamente , Lipídeos/biossíntese , Fígado/química , Fígado/enzimologia , Masculino , Metabolômica/métodos , Modelos Animais , Oxirredução , RNA Mensageiro/análise , Selênio/administração & dosagem , Selênio/efeitos adversos , Selênio/análise , Selenometionina/efeitos adversos , Selenoproteínas/genética , Sus scrofa
12.
Oxid Med Cell Longev ; 2020: 9585047, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32104545

RESUMO

Quercetin, a flavonoid found in fruits and vegetables, is widely distributed as a secondary metabolite in the plant kingdom. Oxidative stress plays a role in the pathogenesis of diabetes mellitus (DM). The present study investigated the effects of quercetin dietary supplementation on streptozotocin- (STZ-) induced hyperglycemic Arbor Acre (AA) broilers by determining the levels of fasting blood glucose (FBG), fasting insulin (FINS), biochemical indicators, oxidative stress markers, inflammatory cytokines content, antioxidant enzymes activities in tissues, and mRNA expression of genes relating to the insulin signaling pathway. Three hundred one-day-old healthy AA broilers were randomly assigned into 5 treatments; A, control healthy broilers; B, STZ-induced broilers; C, STZ-induced broiler dietary supplemented with 0.02% quercetin; D, STZ-induced broiler dietary supplemented with 0.04% quercetin; and E, STZ-induced broiler dietary supplemented with 0.06% quercetin. The results showed that quercetin supplementation relieved the side effects of STZ-induced oxidative stress by changing activities of antioxidant enzymes, decreasing malondialdehyde (MDA) and nitric oxide (NO) levels, activating expression of genes relating to PI3K/PKB signaling pathway that modulate glucose metabolism and reduce oxidative damage, thereby decreasing FBG and increasing FINS levels. These findings suggest that quercetin exhibits a protective effect in STZ-induced hyperglycemic AA broilers via decreasing oxidative stress.


Assuntos
Hiperglicemia/induzido quimicamente , Hiperglicemia/tratamento farmacológico , Quercetina/uso terapêutico , Estreptozocina/toxicidade , Animais , Antioxidantes/metabolismo , Glicemia/metabolismo , Galinhas , Suplementos Nutricionais , Hiperglicemia/metabolismo , Malondialdeído/metabolismo , Óxido Nítrico/metabolismo , Estresse Oxidativo/efeitos dos fármacos
13.
PLoS One ; 15(1): e0228320, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31999787

RESUMO

Interscapular brown adipose tissue (BAT) has the capability to take up glucose from the circulation. Despite the important role of BAT in the control of glucose homeostasis, the metabolic fate and function of glucose in BAT remain elusive as there is clear dissociation between glucose uptake and BAT thermogenesis. Interestingly, intracellular glycolysis and lactate production appear to be required for glucose uptake by BAT. Here, we specifically examine whether activation of lactate receptors in BAT plays a key role in regulating glucose homeostasis in mice fed a high-fat diet (HFD). When C57BL/6J mice are given HFD for 5 weeks at 28°C, male, but not female, mice gain body weight and develop hyperglycemia. Importantly, high-fat feeding upregulates expression of the lactate receptor hydroxycarboxylic acid receptor 1 (HCAR1) in female C57BL/6J mice, whereas male C57BL/6J mice show reduced HCAR1 expression in BAT. Treatment with the HCAR1 agonist lowers systemic glucose levels in male DIO mice. This reduction is associated with increased glucose uptake in BAT. Therefore, our results suggest that HCAR1 in BAT may contribute to the development of hyperglycemia in male C57BL/6J DIO mice.


Assuntos
Tecido Adiposo Marrom/metabolismo , Hiperglicemia/metabolismo , Obesidade/metabolismo , Receptores Acoplados a Proteínas-G/metabolismo , Animais , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Regulação para Baixo , Feminino , Glucose/metabolismo , Hiperglicemia/induzido quimicamente , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/induzido quimicamente , Caracteres Sexuais , Regulação para Cima
14.
Mar Drugs ; 18(1)2020 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-31968646

RESUMO

Chitooligosaccharides (COS) have a variety of biological activities due to their positively charged amino groups. Studies have shown that COS have antidiabetic effects, but their molecular mechanism has not been fully elucidated. The present study confirmed that COS can reduce hyperglycemia and hyperlipidemia, prevent obesity, and enhance histological changes in the livers of mice with type 2 diabetes mellitus (T2DM). Additionally, treatment with COS can modulate the composition of the gut microbiota in the colon by altering the abundance of Firmicutes, Bacteroidetes, and Proteobacteria. Furthermore, in T2DM mice, treatment with COS can upregulate the cholesterol-degrading enzymes cholesterol 7-alpha-hydroxylase (CYP7A1) and incretin glucagon-like peptide 1 (GLP-1) while specifically inhibiting the transcription and expression of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), the key enzyme in cholesterol synthesis. Furthermore, using an oleic acid-induced hepatocyte steatosis model, we found that HMGCR can be directly transactivated by SET and MYND domain containing 3 (SMYD3), a transcriptional regulator, via 5'-CCCTCC-3' element in the promoter. Overexpression of SMYD3 can suppress the inhibitory effect of COS on HMGCR, and COS might regulate HMGCR by inhibiting SMYD3, thereby exerting hypolipidemic functions. To the best of our knowledge, this study is the first to illustrate that COS mediate glucose and lipid metabolism disorders by regulating gut microbiota and SMYD3-mediated signaling pathways.


Assuntos
Quitosana/farmacologia , Microbioma Gastrointestinal/efeitos dos fármacos , Glucose/metabolismo , Histona-Lisina N-Metiltransferase/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Oligossacarídeos/farmacologia , Animais , Diabetes Mellitus Tipo 2/metabolismo , Disbiose/induzido quimicamente , Dislipidemias/tratamento farmacológico , Células Hep G2 , Humanos , Hidroximetilglutaril-CoA Redutases/genética , Hidroximetilglutaril-CoA Redutases/metabolismo , Hiperglicemia/induzido quimicamente , Hiperglicemia/tratamento farmacológico , Hiperlipidemias/tratamento farmacológico , Rim/efeitos dos fármacos , Rim/metabolismo , Lipogênese/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos
15.
Molecules ; 25(2)2020 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-31936547

RESUMO

Curcumin is the main secondary metabolite of Curcuma longa and other Curcuma spp, and has been reported to have some potential in preventing and treating some physiological disorders. This study investigated the effect of curcumin in inhibiting high-fat diet and streptozotocin (STZ)-induced hyperglycemia and hyperlipidemia in rats. Twenty-six male Sprague-Dawley (SD) rats (170-190 g) were randomly divided into a standard food pellet diet group (Control group), a high-fat diet and streptozotocin group (HF + STZ group), and a high-fat diet combined with curcumin and STZ group (HF + Cur + STZ group). Compared with the HF + STZ group, the HF + Cur + STZ group exhibited significantly reduced fasting blood glucose (FBG), total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), alanine aminotransferase (AST), and aspartate transaminase (ALT) levels, as well as liver coefficients. In the livers of these rats, the expression of malondialdehyde (MDA) and Bax was downregulated, whereas that of superoxide dismutase (SOD) and Bcl-2 was upregulated. Moreover, the liver histology of these rats was improved and resembled that of the control rats. These results suggest that curcumin prevents high-fat diet and STZ-induced hyperglycemia and hyperlipidemia, mainly via anti-oxidant and anti-apoptotic mechanisms in the liver.


Assuntos
Curcumina/farmacologia , Hiperglicemia/tratamento farmacológico , Hiperlipidemias/tratamento farmacológico , Extratos Vegetais/farmacologia , Alanina Transaminase/sangue , Animais , Aspartato Aminotransferases/sangue , Glicemia , Curcuma/química , Dieta Hiperlipídica/efeitos adversos , Humanos , Hiperglicemia/sangue , Hiperglicemia/induzido quimicamente , Hiperglicemia/patologia , Hiperlipidemias/sangue , Hiperlipidemias/induzido quimicamente , Hiperlipidemias/patologia , Lipídeos/sangue , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Extratos Vegetais/química , Ratos , Estreptozocina/toxicidade , Superóxido Dismutase/metabolismo , Triglicerídeos/sangue
16.
Artigo em Inglês | MEDLINE | ID: mdl-31958298

RESUMO

Medication-induced hyperglycemia is a frequently encountered clinical problem in children. The intent of this review of medications that cause hyperglycemia and their mechanisms of action is to help guide clinicians in prevention, screening and management of pediatric drug-induced hyperglycemia. We conducted a thorough literature review in PubMed and Cochrane libraries from inception to July 2019. Although many pharmacotherapies that have been associated with hyperglycemia in adults are also used in children, pediatric-specific data on medication-induced hyperglycemia are scarce. The mechanisms of hyperglycemia may involve ß cell destruction, decreased insulin secretion and/or sensitivity, and excessive glucose influx. While some medications (eg, glucocorticoids, L-asparaginase, tacrolimus) are markedly associated with high risk of hyperglycemia, the association is less clear in others (eg, clonidine, hormonal contraceptives, amiodarone). In addition to the drug and its dose, patient characteristics, such as obesity or family history of diabetes, affect a child's risk of developing hyperglycemia. Identification of pediatric patients with increased risk of developing hyperglycemia, creating strategies for risk reduction, and treating hyperglycemia in a timely manner may improve patient outcomes.


Assuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/etiologia , Hiperglicemia/induzido quimicamente , Medicamentos sob Prescrição/efeitos adversos , Criança , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Humanos
17.
Am J Clin Oncol ; 43(2): 82-86, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31693508

RESUMO

OBJECTIVES: There is no study published regarding the benefit of radiation therapy (RT) in combination with immune checkpoint inhibitors (ICIs) for the treatment of metastatic renal cell cancer (mRCC). This report is part of an exploratory study aiming to determine the immunomodulatory activity of RT alone or in combination with pembrolizumab in solid tumors. MATERIALS AND METHODS: mRCC patients were treated with a combination of RT (8 Gy×1 or 4 Gy×5) followed by pembrolizumab with or without lead-in dose of pembrolizumab. Treatment response was measured based on the modified Response Evaluation Criteria in Solid Tumors criteria. Adverse events were monitored and graded. Pre-RT and post-RT tumor biopsies were obtained to evaluate programmed death-ligand 1 expression. Immune markers from peripheral blood before, during, and after treatment were analyzed using flow cytometry. RESULTS: Twelve mRCC patients who progressed on prior antiangiogenic therapy were enrolled. Half had 2 lines of prior therapy. Two patients (16.7%) had partial responses and were on study for 12.4 and 14.5 months. Three patients had stable disease for a period ranging from 4.2 to 10.4 months, whereas 7 patients had progressive disease. Median progression-free survival was 8.6 months and median overall survival was 32.3 months. Three patients had grade ≥3 events (hyperglycemia, thrombocytopenia, transaminitis). Biopsied tissue programmed death-ligand 1 expression and tumor-infiltrating lymphocytes were numerically higher in responders comparing to nonresponders (Modified Proportion Score 45% vs. 30.45%; tumor-infiltrating lymphocytes odds ratio 4.92). CONCLUSION: Combining RT with pembrolizumab in pretreated mRCC is well-tolerated and appears to have comparable efficacy with single-agent nivolumab.


Assuntos
Neoplasias das Glândulas Suprarrenais/terapia , Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Carcinoma de Células Renais/terapia , Quimiorradioterapia/métodos , Neoplasias Renais/patologia , Neoplasias Hepáticas/terapia , Neoplasias das Glândulas Suprarrenais/secundário , Adulto , Idoso , Idoso de 80 Anos ou mais , Alanina Transaminase , Inibidores da Angiogênese/uso terapêutico , Aspartato Aminotransferases , Carcinoma de Células Renais/secundário , Feminino , Humanos , Hiperglicemia/induzido quimicamente , Neoplasias Hepáticas/secundário , Neoplasias Pulmonares/secundário , Neoplasias Pulmonares/terapia , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Intervalo Livre de Progressão , Neoplasias de Tecidos Moles/secundário , Neoplasias de Tecidos Moles/terapia , Trombocitopenia/induzido quimicamente , Falha de Tratamento , Resultado do Tratamento
18.
Pediatr Blood Cancer ; 67(2): e28085, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31736211

RESUMO

Corticosteroids are incorporated into protocols for the treatment of acute lymphoblastic leukaemia, and hyperglycaemia is a recognised side effect. Corticosteroids exert their hyperglycaemic effect with a multifactorial mechanism. Complications of hyperglycaemia include an increased risk of infection - bacterial, viral and fungal. Approximately half of the children who develop corticosteroid-associated hyperglycaemia are predicted to require insulin treatment, with age and obesity having found to be predictive factors. Fasting and random glucose values can be used to define hyperglycaemia. This review focuses on the published evidence for significant predictive factors for the development of corticosteroid-induced hyperglycaemia and provides guidance on management.


Assuntos
Corticosteroides/efeitos adversos , Hiperglicemia/induzido quimicamente , Hiperglicemia/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Criança , Gerenciamento Clínico , Humanos , Hiperglicemia/patologia , Fatores de Risco
19.
Cancer ; 126(6): 1274-1282, 2020 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-31880826

RESUMO

BACKGROUND: PI3K pathway activation is common in endometrial cancer. We evaluated the safety and efficacy of the dual PI3K/mTOR inhibitor, LY3023414, in patients with advanced endometrial cancer harboring activating mutations in the PI3K pathway. METHODS: We conducted a single-arm phase 2 study of monotherapy LY3023414. Eligible patients had advanced endometrial cancer of any grade, prior management with 1-4 cytotoxic lines, and PI3K pathway activation prospectively defined as a loss-of-function PTEN alteration or activating alteration in PIK3CA, AKT1, PIK3R1, PIK3R2, or MTOR. The primary objective was best overall response rate (ORR) per RECIST 1.1. RESULTS: Twenty-eight patients were treated; histologies included endometroid (39%), carcinosarcoma (25%), serous (21%), and mixed (14%). Patients were heavily pretreated, with a median of 2 prior cytotoxic lines (range, 1-3). The most common alterations involved PIK3CA (68%), PTEN (43%), and PIK3R1 (32%). In the 25 efficacy-evaluable patients, the ORR was 16% (90% CI, 7%-100%), and the clinical benefit rate was 28% (90% CI, 16%-100%). Four patients had a confirmed partial response, and 2 responses lasted for >9 months. The median progression-free survival and overall survival were 2.5 months (95% CI, 1.2-3.0) and 9.2 months (95% CI, 5.0-15.9), respectively. The most common all-grade treatment-related adverse events were anemia (71%), hyperglycemia (71%), hypoalbuminemia (68%), and hypophosphatemia (61%). No correlation between molecular alterations and response was observed. CONCLUSION: In patients with heavily pretreated advanced endometrial cancer prospectively selected for tumors with activating PI3K pathway mutations, LY3023414 demonstrated modest single-agent activity and a manageable safety profile.


Assuntos
Neoplasias do Endométrio/tratamento farmacológico , Neoplasias do Endométrio/genética , Mutação , Fosfatidilinositol 3-Quinases/genética , Piridinas/uso terapêutico , Quinolonas/uso terapêutico , Idoso , Classe I de Fosfatidilinositol 3-Quinases , Classe Ia de Fosfatidilinositol 3-Quinase/genética , Neoplasias do Endométrio/patologia , Ativação Enzimática , Feminino , Humanos , Hiperglicemia/induzido quimicamente , Hipoalbuminemia/induzido quimicamente , Hipofosfatemia/induzido quimicamente , Pessoa de Meia-Idade , PTEN Fosfo-Hidrolase/genética , Intervalo Livre de Progressão , Proteínas Proto-Oncogênicas c-akt/genética , Piridinas/efeitos adversos , Quinolonas/efeitos adversos , Transdução de Sinais , Serina-Treonina Quinases TOR , Resultado do Tratamento
20.
Indian J Pharmacol ; 51(5): 352-353, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31831927

RESUMO

Carbamazepine is a commonly used iminostilbene antiepileptic medication and it is estimated that 46.9% of the total antiepileptic drug overdose in the United Kingdom is because of this drug. The overdose of Carbamazepine can show negative effects on multiple systems, these include neurologic (ataxia, seizures, and altered sensorium), cardiac (tachycardia, hypotension) and metabolic manifestations. We reported a case of a 17-year-old girl had an increase in glucose levels after voluntary ingestion carbamazepine tablets. After ingestion, her gross random blood sugar level was increased, then physician suspected that she might be a Type I diabetic,but HbA1C[glycosylated hemoglobin] levels was found normal.Carbamazepine was discontinued and patient received symptomatic therapy. The patient had decreased levels of blood sugar level,after removal of the drug within the next day after ingestion of carbamazepine. A Naranjo assessment was obtained, indicating a definite relationship between the patient's increased in blood glucose levels and her use of carbamazepine.


Assuntos
Anticonvulsivantes/envenenamento , Carbamazepina/envenenamento , Hiperglicemia/induzido quimicamente , Adolescente , Anticonvulsivantes/administração & dosagem , Glicemia/efeitos dos fármacos , Carbamazepina/administração & dosagem , Overdose de Drogas , Feminino , Humanos
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA