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1.
Lancet Diabetes Endocrinol ; 8(10): 834-844, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32946820

RESUMO

BACKGROUND: Although metformin is increasingly being used in women with type 2 diabetes during pregnancy, little data exist on the benefits and harms of metformin use on pregnancy outcomes in these women. We aimed to investigate the effects of the addition of metformin to a standard regimen of insulin on neonatal morbidity and mortality in pregnant women with type 2 diabetes. METHODS: In this prospective, multicentre, international, randomised, parallel, double-masked, placebo-controlled trial, women with type 2 diabetes during pregnancy were randomly assigned from 25 centres in Canada and four in Australia to receive either metformin 1000 mg twice daily or placebo, added to insulin. Randomisation was done via a web-based computerised randomisation service and stratified by centre and pre-pregnancy BMI (<30 kg/m2 or ≥30 kg/m2) in a ratio of 1:1 using random block sizes of 4 and 6. Women were eligible if they had type 2 diabetes, were on insulin, had a singleton viable pregnancy, and were between 6 and 22 weeks plus 6 days' gestation. Participants were asked to check their fasting blood glucose level before the first meal of the day, before the last meal of the day, and 2 h after each meal. Insulin doses were adjusted aiming for identical glucose targets (fasting glucose <5·3 mmol/L [95 mg/dL], 2-h postprandial glucose <6·7 mmol/L [120 mg/dL]). Study visits were done monthly and patients were seen every 1-4 weeks as was needed for standard clinical care. At study visits blood pressure and bodyweight were measured; patients were asked about tolerance to their pills, any hospitalisations, insulin doses, and severe hypoglycaemia events; and glucometer readings were downloaded to the central coordinating centre. Participants, caregivers, and outcome assessors were masked to the intervention. The primary outcome was a composite of fetal and neonatal outcomes, for which we calculated the relative risk and 95% CI between groups, stratifying by site and BMI using a log-binomial regression model with an intention-to-treat analysis. Secondary outcomes included several relevant maternal and neonatal outcomes. The trial was registered with ClinicalTrials.gov, NCT01353391. FINDINGS: Between May 25, 2011, and Oct 11, 2018, we randomly assigned 502 women, 253 (50%) to metformin and 249 (50%) to placebo. Complete data were available for 233 (92%) participants in the metformin group and 240 (96%) in the placebo group for the primary outcome. We found no significant difference in the primary composite neonatal outcome between the two groups (40% vs 40%; p=0·86; relative risk [RR] 1·02 [0·83 to 1·26]). Compared with women in the placebo group, metformin-treated women achieved better glycaemic control (HbA1c at 34 weeks' gestation 41·0 mmol/mol [SD 8·5] vs 43·2 mmol/mol [-10]; 5·90% vs 6·10%; p=0·015; mean glucose 6·05 [0·93] vs 6·27 [0·90]; difference -0·2 [-0·4 to 0·0]), required less insulin (1·1 units per kg per day vs 1·5 units per kg per day; difference -0·4 [95% CI -0·5 to -0·2]; p<0·0001), gained less weight (7·2 kg vs 9·0 kg; difference -1·8 [-2·7 to -0·9]; p<0·0001) and had fewer caesarean births (125 [53%] of 234 in the metformin group vs 148 [63%] of 236 in the placebo group; relative risk [RR] 0·85 [95% CI 0·73 to 0·99]; p=0·031). We found no significant difference between the groups in hypertensive disorders (55 [23%] in the metformin group vs 56 [23%] in the placebo group; p=0·93; RR 0·99 [0·72 to 1·35]). Compared with those in the placebo group, metformin-exposed infants weighed less (mean birthweight 3156 g [SD 742] vs 3375 g [742]; difference -218 [-353 to -82]; p=0·002), fewer were above the 97th centile for birthweight (20 [9%] in the metformin group vs 34 [15%] in the placebo group; RR 0·58 [0·34 to 0·97]; p=0·041), fewer weighed 4000 g or more at birth (28 [12%] in the metformin group vs 44 [19%] in the placebo group; RR 0·65 [0·43 to 0·99]; p=0·046), and metformin-exposed infants had reduced adiposity measures (mean sum of skinfolds 16·0 mm [SD 5·0] vs 17·4 [6·2] mm; difference -1·41 [-2·6 to -0·2]; p=0·024; mean neonatal fat mass 13·2 [SD 6·2] vs 14·6 [5·0]; p=0·017). 30 (13%) infants in the metformin group and 15 (7%) in the placebo group were small for gestational age (RR 1·96 [1·10 to 3·64]; p=0·026). We found no significant difference in the cord c-peptide between groups (673 pmol/L [435] in the metformin group vs 758 pmol/L [595] in the placebo group; p=0·10; ratio of means 0·88 [0·72 to 1·02]). The most common adverse event reported was gastrointestinal (38 events in the metformin group and 38 events in the placebo group). INTERPRETATION: We found several maternal glycaemic and neonatal adiposity benefits in the metformin group. Along with reduced maternal weight gain and insulin dosage and improved glycaemic control, the lower adiposity and infant size measurements resulted in fewer large infants but a higher proportion of small-for-gestational-age infants. Understanding the implications of these effects on infants will be important to properly advise patients who are contemplating the use of metformin during pregnancy. FUNDING: Canadian Institutes of Health Research, Lunenfeld-Tanenbaum Research Institute, University of Toronto.


Assuntos
Biomarcadores/análise , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Metformina/uso terapêutico , Adolescente , Adulto , Glicemia/análise , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Método Duplo-Cego , Feminino , Seguimentos , Hemoglobina A Glicada/análise , Humanos , Agências Internacionais , Pessoa de Meia-Idade , Gravidez , Resultado da Gravidez , Estudos Prospectivos , Adulto Jovem
3.
Medicine (Baltimore) ; 99(37): e21687, 2020 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-32925714

RESUMO

BACKGROUND: Increased risk and cancer-related mortality is observed in pancreatic cancer (PC) patients with diabetes mellitus (DM). Whether using metformin as glucose-lowering therapy can result in survival benefit in this group of patients is still unclear. METHODS: A meta-analysis of 21 studies that including 38,772 patients was performed to investigate the association between metformin and overall survival in patients with PC and concurrent DM. RESULTS: A significant survival benefit was observed in metformin treatment group compared with non-metformin group (hazard ratio [HR] = 0.83, 95% confidence interval [CI]: 0.74-0.91). These associations were observed in both subgroups of Asian countries (HR = 0.69, 95% CI: 0.60-0.79) and Western countries (HR = 0.86, 95% CI: 0.76-0.95), the former was more obvious. Survival benefit was gained for patients at early stage (HR = 0.75, 95% CI: 0.64-0.85) and mixed stage (HR = 0.81, 95% CI: 0.70-0.91), but not for patients at advanced stage (HR = 0.99, 95% CI: 0.74-1.24). Similarly, survival benefit was also observed in patients receiving surgery (HR = 0.82, 95% CI: 0.69-0.94) and comprehensive treatment (HR = 0.85, 95% CI: 0.77-0.93), but not in chemotherapy group (HR = 0.99, 95% CI: 0.67-1.30). No obvious benefit was suggested when pooled by time-varying COX model (HR = 0.94, 95% CI: 0.86-1.03). CONCLUSIONS: These results suggest that metformin is associated with survival benefit in patients with PC and concurrent DM. Further randomized controlled trials and prospective studies with larger sample sizes are required to confirm our findings.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Metformina/uso terapêutico , Neoplasias Pancreáticas/mortalidade , Idoso , Ensaios Clínicos como Assunto , Diabetes Mellitus Tipo 2/complicações , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Pancreáticas/complicações , Modelos de Riscos Proporcionais , Taxa de Sobrevida
4.
Front Immunol ; 11: 2056, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32973814

RESUMO

The pandemic of coronavirus disease 2019 (COVID-19), a disease which causes severe lung injury and multiple organ damage, presents an urgent need for new drugs. The case severity and fatality of COVID-19 are associated with excessive inflammation, namely, a cytokine storm. Metformin, a widely used drug to treat type 2 diabetes (T2D) mellitus and metabolic syndrome, has immunomodulatory activity that reduces the production of proinflammatory cytokines using macrophages and causes the formation of neutrophil extracellular traps (NETs). Metformin also inhibits the cytokine production of pathogenic Th1 and Th17 cells. Importantly, treatment with metformin alleviates various lung injuries in preclinical animal models. In addition, a recent proteomic study revealed that metformin has the potential to directly inhibit SARS-CoV-2 infection. Furthermore, retrospective clinical studies have revealed that metformin treatment reduces the mortality of T2D with COVID-19. Therefore, metformin has the potential to be repurposed to treat patients with COVID-19 at risk of developing severe illness. This review summarizes the immune pathogenesis of SARS-CoV-2 and addresses the effects of metformin on inhibiting cytokine storms and preventing SARS-CoV-2 infection, as well as its side effects.


Assuntos
Antivirais/uso terapêutico , Betacoronavirus , Infecções por Coronavirus/tratamento farmacológico , Fatores Imunológicos/uso terapêutico , Lesão Pulmonar/tratamento farmacológico , Metformina/uso terapêutico , Pneumonia Viral/tratamento farmacológico , Animais , Antivirais/efeitos adversos , Antivirais/farmacologia , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Citocinas/antagonistas & inibidores , Reposicionamento de Medicamentos/métodos , Armadilhas Extracelulares/efeitos dos fármacos , Humanos , Fatores Imunológicos/efeitos adversos , Fatores Imunológicos/farmacologia , Inflamação/tratamento farmacológico , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Metformina/efeitos adversos , Metformina/farmacologia , Pandemias , Pneumonia Viral/imunologia , Pneumonia Viral/virologia , Células Th1/efeitos dos fármacos , Células Th1/imunologia , Células Th17/efeitos dos fármacos , Células Th17/imunologia
5.
Cochrane Database Syst Rev ; 8: CD005552, 2020 08 13.
Artigo em Inglês | MEDLINE | ID: mdl-32794179

RESUMO

BACKGROUND: Metformin has been proposed as possibly a safer and more effective long-term treatment than the oral contraceptive pill (OCP) in women with polycystic ovary syndrome (PCOS). It is important to directly compare the efficacy and safety of metformin versus OCP in the long-term treatment of women with PCOS. This is an update of a Cochrane Review comparing insulin sensitising agents with the OCP and only includes studies on metformin. OBJECTIVES: To assess the effectiveness and safety of metformin versus the OCP (alone or in combination) in improving clinical, hormonal, and metabolic features of PCOS. SEARCH METHODS: In August 2019 we searched the Cochrane Gynaecology and Fertility Group Trials Register, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase and CINAHL, the trial registers, handsearched references of the identified articles, and contacted experts in the field to identify additional studies. SELECTION CRITERIA: We included randomised controlled trials (RCTs) of the use of metformin versus the OCP (alone or in combination) for women with PCOS. DATA COLLECTION AND ANALYSIS: We used standard methods recommended by Cochrane. The primary review outcomes were the clinical parameters of hirsutism and adverse events, both severe (requiring stopping of medication), and minor. In the presence of substantial heterogeneity (I2 statistic > 50), which could be explained by pre-specified subgroup analyses on the basis of BMI, we reported the subgroups separately. MAIN RESULTS: This is a substantive update. We identified 38 additional studies. We included 44 RCTs (2253 women), which comprised 39 RCTs on adult women (2047 women) and five RCTs on adolescent women (206 women). Evidence quality ranged from very low to low. The main limitations were risk of bias, imprecision and inconsistency. Metformin versus the OCP In adult women, we are uncertain of the effect of metformin compared to the OCP on hirsutism in subgroup body mass index (BMI) < 25 kg/m2 (mean difference (MD) 0.38, 95% confidence interval (CI) -0.44 to 1.19, 3 RCTs, n = 134, I2 = 50%, very low-quality evidence) and subgroup BMI > 30 kg/m2 (MD -0.38, 95% CI -1.93 to 1.17; 2 RCTs, n = 85, I2 = 34%, low-quality evidence). Metformin may be less effective in improving hirsutism compared to the OCP in the subgroup BMI 25 kg/m2 to 30 kg/m2 (MD 1.92, 95% CI 1.21 to 2.64, 5 RCTs, n = 254, I2 = 0%, low-quality evidence). Metformin may increase severe gastro-intestinal adverse events rate compared to the OCP (Peto odds ratio (OR) 6.42, 95% CI 2.98 to 13.84, 11 RCTs, n = 602, I2 = 0%, low-quality evidence). Metformin may decrease the incidence of severe other adverse events compared to the OCP (Peto OR 0.20, 95% CI 0.09 to 0.44, 8 RCTs, n = 363, I2 = 0%, low-quality evidence). There were no trials reporting on minor adverse events. In adolescents, we are uncertain whether there is a difference between Metformin and the OCP, on hirsutism and adverse events. Metformin versus metformin combined with the OCP In adult women, metformin may be less effective in improving hirsutism compared to Metformin combined with the OCP (MD 1.36, 95% CI 0.62 to 2.11, 3 RCTs, n = 135, I2= 9%, low-quality evidence). We are uncertain if there was a difference between metformin and metformin combined with the OCP for severe gastro-intestinal adverse events (OR 0.74, 95% CI 0.21 to 2.53, 3 RCTs, n = 171, I2 = 0%, low-quality evidence), or for severe other adverse events (OR 0.56, 95% CI 0.11 to 2.82, 2 RCTs, n = 109, I2 = 44%, low-quality evidence). There were no trials reporting on minor adverse events. In adolescents, there were no trials for this comparison. The OCP versus metformin combined with the OCP In adult women, the OCP may be less effective in improving hirsutism compared to metformin combined with the OCP (MD 0.54, 95% CI 0.20 to 0.89, 6 RCTs, n = 389, I2= 1%, low-quality evidence). The OCP may decrease the incidence of severe gastro-intestinal adverse events compared to metformin combined with the OCP (OR 0.20, 95% CI 0.06 to 0.72, 5 RCTs, n = 228, I2 = 0%, low-quality evidence). We are uncertain if there is a difference between the OCP and metformin combined with the OCP for severe other adverse events (OR 1.61, 95% CI 0.49 to 5.37, 4 RCTs, n = 159, I2 = 12%, low-quality evidence). The OCP may decrease the incidence of minor (gastro-intestinal) adverse events compared to metformin combined with the OCP (OR 0.06, 95% CI 0.01 to 0.44, 2 RCTs, n = 98, I2 = 0%, low-quality evidence). In adolescents, we are uncertain whether there is a difference between the OCP, compared to metformin combined with the OCP, on hirsutism or adverse events. AUTHORS' CONCLUSIONS: In adult women with PCOS, metformin may be less effective in improving hirsutism compared to the OCP in the subgroup BMI 25 kg/m2 to 30 kg/m2 but we are uncertain if there was a difference between metformin and the OCP in subgroups BMI < 25 kg/m2 and BMI > 30kg/m2. Compared to the OCP, metformin may increase the incidence of severe gastro-intestinal adverse events and decrease the incidence of severe other adverse events with no trials reporting on minor adverse events. Either metformin alone or the OCP alone may be less effective in improving hirsutism compared to metformin combined with the OCP. We are uncertain whether there is a difference between the OCP alone and metformin alone compared to metformin combined with the OCP for severe or minor adverse events except for the OCP versus metformin combined with the OCP where the OCP may decrease the incidence of severe and minor gastro-intestinal adverse events. In adolescent women with PCOS, we are uncertain whether there is a difference between any of the comparisons for hirsutism and adverse events due to either no evidence or very low-quality evidence. Further large well-designed RCTs that stratify for BMI are needed to evaluate metformin versus the OCP and combinations in women with PCOS, in particular adolescent women.


Assuntos
Anticoncepcionais Orais Combinados/uso terapêutico , Hirsutismo/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Distúrbios Menstruais/tratamento farmacológico , Metformina/uso terapêutico , Síndrome do Ovário Policístico/tratamento farmacológico , Acne Vulgar/tratamento farmacológico , Adolescente , Adulto , Índice de Massa Corporal , Doenças Cardiovasculares/prevenção & controle , Anticoncepcionais Orais Combinados/efeitos adversos , Quimioterapia Combinada , Neoplasias do Endométrio/prevenção & controle , Feminino , Humanos , Metformina/efeitos adversos , Síndrome do Ovário Policístico/complicações , Ensaios Clínicos Controlados Aleatórios como Assunto , Adulto Jovem
6.
Medicine (Baltimore) ; 99(31): e20750, 2020 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-32756078

RESUMO

BACKGROUND: Type 2 diabetes is a kind of metabolic disease. Its clinical characteristic is hyperglycemia. Recently, more and more elderly people suffer from type 2 diabetes, and the glycemic variability of the elderly is greater. In addition, blood sugar variation is more likely to cause diabetes complications than simple hyperglycemia. Sancai podwer (SC) is based on the theory of traditional Chinese medicine and gradually formed in the summary of clinical experience. It has the effect of lowering blood sugar and alleviating clinical symptoms of diabetes. But the existing evidence of its efficacy on glycemic variability is insufficient. So, in our study, the randomized controlled trials will be used as a research method to explore the effects of SC on glycemic variability of type 2 diabetes. METHOD: We will use randomized controlled experiments based on the recommended diagnostic criteria, inclusion and exclusion criteria. A total of 60 elderly patients with type 2 diabetes will be randomly divided into treatment group and control group, 30 cases in each group. The control group will receive conventional western medicine and the intervention group will receive SC combined with western medicine. The standard deviation and coefficient of variation of blood glucose level will be used as evaluation indexes. DISCUSSION: This study can provide evidence for the clinical efficacy and safety of SC in elderly patients with type 2 diabetes mellitus. TRIAL REGISTRATION: This study is registered on the Chinese Clinical Trial Registry: ChiCTR2000032611.


Assuntos
Glicemia/análise , Diabetes Mellitus Tipo 2/tratamento farmacológico , Medicamentos de Ervas Chinesas/uso terapêutico , Administração Oral , Idoso , Idoso de 80 Anos ou mais , Glicemia/efeitos dos fármacos , Quimioterapia Combinada , Medicamentos de Ervas Chinesas/administração & dosagem , Feminino , Humanos , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/uso terapêutico , Masculino , Metformina/administração & dosagem , Metformina/uso terapêutico , Pós , Ensaios Clínicos Controlados Aleatórios como Assunto
7.
Medicine (Baltimore) ; 99(30): e21409, 2020 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-32791755

RESUMO

BACKGROUND: This study aim at evaluating the efficacy and safety of dapagliflozin plus saxagliptin vs monotherapy as added to metformin in patients with type 2 diabetes mellitus (T2DM). METHOD: PubMed, Cochrane library, Embase, CNKI and Wanfang databases were searched up to 31 December 2019. Randomized controlled trials (RCTs) applicable in dapagliflozin plus saxagliptin vs monotherapy as added to metformin in the treatment of T2DM were included. The outcomes included changes in HbA1c, FPG, body weight, SBP, DBP and adverse reactions. Fixed or random effects model were used to assess these outcomes. RESULTS: In this study, 8 RCTs involved 7346 patients were included. Compared with dapagliflozin plus metformin(DM) group, patients treated with dapagliflozin plus saxagliptin add on to metformin(DSM) could significantly increase the adjusted mean change levels of HbA1c, FPG, SBP and DBP(P < .00001, SMD = -4.88, 95%CI = -6.93∼-2.83; P < .00001, SMD = -6.50, 95%CI = -8.55∼-4.45; P < .00001, SMD = -0.97, 95%CI = -1.15∼-0.78; P < .00001, SMD = -2.00, 95%CI = -2.20∼-1.80), but no major difference in body weight loss showed(P = .12, SMD = 0.92, 95%CI = -0.22∼2.06). Furthermore, DSM therapy displayed better effects than saxagliptin plus metformin(SM) in the adjusted mean change levels of HbA1c, FPG, body weight and SBP(P < .00001, SMD = -7.75, 95%CI = -8.84∼-6.66; P < .00001, SMD = -7.75, 95%CI = -8.84∼-6.66; P = .04, SMD = -3.40, 95%CI = -6.64∼-0.17; P = .04, SMD = -7.75, 95%CI = -8.84∼-6.66), whereas no obvious difference in lowering DBP(P = .18, SMD = -16.35, 95%CI = -40.12∼7.41). Additionally, compared with DM and SM groups, there were no remarkable difference in the incidence of nausea, influenza, headache, diarrhea, urinary tract infection and renal failure for patients taking DSM, but the incidence of genital infection and hypoglycemia were higher in DSM group. CONCLUSIONS: Patients taking the DSM therapy had better effects in reducing the level of HbA1c, FPG, body weight, SBP and DBP than the DM and SM therapy. However, patients treated with DSM therapy are more likely to have hypoglycemia and genital infection. Dapagliflozin plus saxagliptin may be a suitable therapy strategy for patients with T2DM inadequately controlled with metformin, and this will provide a clinical reference for the treatment of T2DM.


Assuntos
Adamantano/análogos & derivados , Compostos Benzidrílicos/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Dipeptídeos/uso terapêutico , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Glucosídeos/uso terapêutico , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Adamantano/farmacologia , Adamantano/uso terapêutico , Glicemia/efeitos dos fármacos , Pressão Sanguínea/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Diabetes Mellitus Tipo 2/sangue , Dipeptídeos/farmacologia , Inibidores da Dipeptidil Peptidase IV/farmacologia , Quimioterapia Combinada , Humanos , Hipoglicemiantes/uso terapêutico , Metformina/farmacologia , Metformina/uso terapêutico , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia
8.
Medicine (Baltimore) ; 99(34): e21894, 2020 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-32846852

RESUMO

BACKGROUND: At present, metformin is mainly used in the treatment of type 2 diabetes mellitus (T2DM). When the therapeutic effect is achieved, there are side effects and secondary failure will occur if taken for a long time. It is of great significance to actively explore the clinical scheme of reducing drug use while ensuring the therapeutic effect of T2DM. OBJECTIVE: To evaluate the feasibility of Chinese massage (CM) in the treatment of T2DM. METHODS: Literature retrieval is divided into 2 aspects: Electronic Retrieval and Personal Check. We will search PubMed, EMBASE, CNKI, Cochrane Central, which were registered in international clinical trials registry platform systems, select all eligible studies published before November 2, 2019, and use Personal Check method to retrieve papers, conference papers, ongoing experiments, internal reports, and so on. With fasting blood glucose, 2-hour fasting blood glucose, glycosylated hemoglobin, and insulin index as the main observation indexes, we also pay attention to traditional Chinese medicine syndrome score scale, insulin resisting index, body mass index , serum total cholesterol, Curative effect and the occurrence of all adverse reactions in drug treatment.Of the research group 2 researchers respective selected literature, extracted data, and evaluated the risk of bias. After that we used Revman 5.7 and Stata 12.1 statistical software for meta-analysis. RESULTS: A total of 769 subjects were included in 10 studies for meta-analysis. Compared with metformin hydrochloride tablets, CM plus baseline treatment can reduce fasting plasma glucose (weighted mean difference [WMD] = -0.33, 95% confidence interval [CI] [-0.54, -0.13], Z = 3.15, P = .002), 2 hours postprandial blood glucose (WMD = -0.52, 95% CI [-0.70, -0.34), Z = 5.66, P < .00001], hemoglobin A1c (WMD = 0.12, 95% CI [0.04, 0.20], Z = 2.94, P = .003), fasting insulin (WMD = -3.59, 95% CI [-5.56, -1.42], Z = 10.29,P < .00001), traditional Chinese medicine syndrome score scale (WMD = -4.55, 95% CI [-7.58, -1.51], Z = 2.94, P = .003),homeostasis model assessment of insulin resistance (WMD = -1.76, 95% CI [-2.25, -1.27), Z = 7.08, P < .00001),body mass index (WMD = -1.28, 95% CI [-1.65, -0.92], Z = 6.91, P < .00001), serum total cholesterol (WMD = -1.01, 95% CI [-1.14, -0.83], Z = 15.51, P < .00001), meanwhile, the effective rate was increased (risk ratio [RR] = 1.31, 95% CI [1.21, 1.42], Z = 6.57, P < .00001). CONCLUSION: CM combined with metformin hydrochloride tablet has a synergistic effect. It can not only be used as an auxiliary treatment of T2DM, but also as an important reference way of reducing drug treatment of T2DM, improving Clinical Efficacy and reducing adverse reactions. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42020158839.


Assuntos
Diabetes Mellitus Tipo 2/terapia , Hipoglicemiantes/uso terapêutico , Massagem/métodos , Metformina/uso terapêutico , Adulto , Idoso , Glicemia/análise , Estudos de Casos e Controles , China/epidemiologia , Terapia Combinada/métodos , Sinergismo Farmacológico , Jejum/sangue , Estudos de Viabilidade , Hemoglobina A Glicada/análise , Humanos , Hipoglicemiantes/efeitos adversos , Insulina/sangue , Resistência à Insulina , Massagem/tendências , Metformina/efeitos adversos , Pessoa de Meia-Idade
9.
Medicine (Baltimore) ; 99(31): e21438, 2020 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-32756155

RESUMO

RATIONALE: Mutations in the hepatocyte nuclear factor-1-beta (HNF1B) gene result in a very variable presentation, including maturity onset diabetes of the young (MODY), renal cysts, renal dysplasia, and autosomal dominant tubulointerstitial kidney disease (ADTKD), which is characterized by tubular damage, renal fibrosis, and progressive renal dysfunction. PATIENT CONCERNS: A 22-year-old man came to the hospital presenting with hyperglycemia, hyperuricemia and elevated serum creatinine. His urine protein was within the normal range. The ultrasound examination revealed shrunken kidneys with renal cysts. The patient's mother was diagnosed with diabetes mellitus when she was 25 years old. Her laboratory results showed elevated serum creatinine. Her ultrasonography revealed shrunken kidneys with renal cysts and hydronephrosis without kidney stones. The next-generation sequencing revealed that the proband and his mother held the same heterozygous missense mutation (c.530G>A, NM_000458, p.R177Q) in the HNF1B gene. Bioinformatic analyses predicted that the mutation was likely pathogenic. DIAGNOSIS: The patient and his mother were diagnosed as ADTKD and MODY5 due to HNF1B mutation. INTERVENTION: The proband was administered metformin at a dose of 500 mg/day. OUTCOMES: The patient had well-controlled blood glucose levels and a stable renal function at his 12-month follow-up. LESSONS: We should take into account the diagnoses of ADTKD and MODY5 if patients present with early onset diabetes and multiple renal cysts or evidence of renal tubulointerstitial dysplasia, especially those with negative proteinuria results. Genetic testing helps detect the HNF1B gene mutations.


Assuntos
Doenças do Sistema Nervoso Central/genética , Esmalte Dentário/anormalidades , Diabetes Mellitus Tipo 2/genética , Fator 1-beta Nuclear de Hepatócito/genética , Doenças Renais Císticas/genética , Nefrite Intersticial/genética , Assistência ao Convalescente , Doenças do Sistema Nervoso Central/complicações , Doenças do Sistema Nervoso Central/tratamento farmacológico , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Heterozigoto , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Hiperglicemia/etiologia , Hiperuricemia/etiologia , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/uso terapêutico , Rim/diagnóstico por imagem , Rim/patologia , Rim/fisiopatologia , Doenças Renais Císticas/complicações , Doenças Renais Císticas/tratamento farmacológico , Doenças Renais Císticas/patologia , Masculino , Metformina/administração & dosagem , Metformina/uso terapêutico , Mutação de Sentido Incorreto , Nefrite Intersticial/complicações , Nefrite Intersticial/patologia , Linhagem , Ultrassonografia/métodos , Adulto Jovem
11.
Neurology ; 95(4): e362-e373, 2020 07 28.
Artigo em Inglês | MEDLINE | ID: mdl-32601121

RESUMO

OBJECTIVE: To evaluate whether pretreatment with metformin (MET) is associated with less stroke severity and better outcome after IV thrombolysis (IVT), we analyzed a cohort of 1,919 patients with stroke with type 2 diabetes mellitus in a multicenter exploratory analysis. METHODS: Data from patients with diabetes and ischemic stroke treated with IVT were collected within the European Thrombolysis in Ischemic Stroke Patients (TRISP) collaboration. We applied propensity score matching (PSM) to obtain balanced baseline characteristics of patients treated with and without MET. RESULTS: Of 1,919 patients with stroke with type 2 diabetes who underwent IVT, 757 (39%) had received MET before stroke (MET+), whereas 1,162 (61%) had not (MET-). MET+ patients were younger with a male preponderance. Hypercholesterolemia and pretreatment with statins, antiplatelets, or antihypertensives were more common in the MET+ group. After PSM, the 2 groups were well balanced with respect to demographic and clinical aspects. Stroke severity on admission (NIH Stroke Scale 10.0 ± 6.7 vs 11.3 ± 6.5), 3-month degree of independence on modified Rankin Scale (2 [interquartile range (IQR) 1.0-4.0] vs 3 [IQR 1.0-4.0]), as well as mortality (12.5% vs 18%) were significantly lower in the MET+ group. The frequency of symptomatic intracerebral hemorrhages did not differ between groups. HbA1c levels were well-balanced between the groups. CONCLUSIONS: Patients with stroke and diabetes on treatment with MET receiving IVT had less severe strokes on admission and a better functional outcome at 3 months. This suggests a protective effect of MET resulting in less severe strokes as well as beneficial thrombolysis outcome.


Assuntos
Hipoglicemiantes/uso terapêutico , Metformina/uso terapêutico , Recuperação de Função Fisiológica/efeitos dos fármacos , Acidente Vascular Cerebral , Idoso , Diabetes Mellitus Tipo 2/tratamento farmacológico , Feminino , Fibrinolíticos/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Acidente Vascular Cerebral/tratamento farmacológico , Acidente Vascular Cerebral/mortalidade , Acidente Vascular Cerebral/fisiopatologia , Terapia Trombolítica/métodos
12.
PLoS One ; 15(7): e0236603, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32706828

RESUMO

BACKGROUND AND OBJECTIVE: Dipeptidyl peptidase-4 (DPP-4) inhibitors have been suggested to have pancreatic beta-cell preserving effect according to studies using homeostatic model of assessment for beta-cell function (HOMA-ß). However, whether HOMA-ß is a suitable biomarker for comparisons between hypoglycemic drugs with different mechanisms of action remains unclear. Therefore, we conducted a meta-analysis to compare the effects of DPP-4 inhibitors and other classes of hypoglycemic drugs on HOMA-ß and proinsulin-to-insulin ratio (PIR). METHODS: We searched MEDLINE, CENTRAL, and Ichushi-web for the period of 1966 to May 2020. We collected randomized, controlled clinical trials in patients with type 2 diabetes mellitus comparing DPP-4 inhibitors and other classes of hypoglycemic agents [α-glucosidase inhibitors (α-GIs), glucagon-like peptide-1 (GLP-1) analogues, metformin, sodium-glucose cotransporter 2 (SGLT2) inhibitors, sulfonylureas, or thiazolidinediones]. Weighted mean differences and 95% confidence intervals of changes in HOMA-ß or PIR during study periods were calculated for pairwise comparisons. RESULTS: Thirty-seven and 21 relevant trials were retrieved for comparisons of HOMA-ß and PIR, respectively. HOMA-ß and PIR consistently showed superiority of DPP-4 inhibitors compared with α-GIs. Both biomarkers consistently supported inferiority of DPP-4 inhibitors compared with GLP-1 analogues. However, PIR showed inferiority of DPP-4 inhibitors compared with metformin, and superiority compared with SGLT2 inhibitors, whereas HOMA-ß showed no significant differences between DPP-4 inhibitors and the two other agents. CONCLUSION: DPP-4 inhibitors appear to be superior to α-GIs but inferior to GLP-1 analogues in preservation of beta-cell function assessed by either HOMA-ß or PIR. DPP-4 inhibitors seem to be superior to SGLT2 inhibitors but inferior to metformin on islet function assessed only by PIR. Because HOMA-ß and PIR may indicate different aspects of beta-cell function, results of beta-cell function preserving effects of hypoglycemic agents should be interpreted with caution.


Assuntos
Biomarcadores/metabolismo , Inibidores da Dipeptidil Peptidase IV/farmacologia , Hipoglicemiantes/farmacologia , Células Secretoras de Insulina/efeitos dos fármacos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/patologia , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Humanos , Hipoglicemiantes/uso terapêutico , Insulina/metabolismo , Células Secretoras de Insulina/citologia , Células Secretoras de Insulina/metabolismo , Metformina/farmacologia , Metformina/uso terapêutico , Proinsulina/metabolismo , Compostos de Sulfonilureia/farmacologia , Compostos de Sulfonilureia/uso terapêutico , Tiazolidinedionas/farmacologia , Tiazolidinedionas/uso terapêutico
13.
Medicine (Baltimore) ; 99(29): e21202, 2020 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-32702885

RESUMO

RATIONALE: Capillary leak syndrome is a condition that increases systemic capillary permeability and causes characteristic manifestations such as recurrent hypovolemia, systemic edema, and hemoconcentration. Acute limb compartment syndrome is a possible complication of severe capillary leak syndrome. However, timely diagnosis and prompt treatment are challenging because of atypical presentation. PATIENT CONCERNS: An 18-year-old woman with a history of clinical depression was admitted to our intensive care unit (ICU) because of metformin and vildagliptin overdose. She developed marked vasodilatory shock with recurrent severe hypovolemia and disseminated intravascular coagulation. After urgent hemodialysis and plasma exchange, she started to stabilize hemodynamically. However, her limbs became stone-hard with massive edema. Her serum creatinine kinase level increased to an extremely high level. DIAGNOSIS: Extremities were distended, and her skin developed pallor with blistering. Intramuscular pressure in both forearms and lower legs was significantly elevated. INTERVENTIONS: Decompressive fasciotomy was performed. Hemodialysis was continued because of rhabdomyolyses-induced acute kidney injury. OUTCOMES: The patient was finally able to walk by herself at the time of hospital discharge on day 109. LESSONS: The possibility of acute compartment syndrome should be considered in patients with marked capillary leakage, especially after aggressive fluid resuscitation. It is important to be aware of the compartment syndrome in an ICU setting because communication barriers often mask typical symptoms and make diagnosis difficult.


Assuntos
Síndrome de Vazamento Capilar/etiologia , Síndromes Compartimentais/etiologia , Inibidores da Dipeptidil Peptidase IV/toxicidade , Metformina/efeitos adversos , Adolescente , Síndrome de Vazamento Capilar/complicações , Síndrome de Vazamento Capilar/fisiopatologia , Síndromes Compartimentais/fisiopatologia , Síndromes Compartimentais/cirurgia , Descompressão Cirúrgica/métodos , Inibidores da Dipeptidil Peptidase IV/efeitos adversos , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Feminino , Hidratação/efeitos adversos , Humanos , Hipoglicemiantes/efeitos adversos , Hipoglicemiantes/uso terapêutico , Unidades de Terapia Intensiva/organização & administração , Metformina/uso terapêutico , Rabdomiólise/complicações , Vildagliptina/efeitos adversos , Vildagliptina/uso terapêutico , Vildagliptina/toxicidade
14.
J Assoc Physicians India ; 68(7): 57-61, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32602682

RESUMO

Background: In Indian clinical set-up, modern sulfonylurea, particularly glimepiride is still preferred as an add-on to metformin due to its efficacy, safety and cost effectiveness. In view of this, a case-based questionnaire survey was conducted to analyze the clinical utility of multiple strengths of glimepiride and metformin fixed dose combination in type 2 diabetes mellitus (T2DM). Methods: The case-based questionnaire survey was conducted with 174 health care professionals across India to assess the use of glimepiride and metformin fixed dose combination according to age, duration of diabetes, body mass index (BMI), diabetes complications, concomitant medications like insulin, and statin. Results: Overall, data from 2248 patients taking multiple strengths of glimepiride and metformin fixed dose combination were analyzed. All the doses were prescribed across all the age groups and irrespective of duration of diabetes. Overall, 1429 diabetes patients had body mass index (BMI) ≥25 kg/m2, among which 1176 (81.6%) patients were receiving combination of glimepiride 1 or 2 mg and metformin 500 or 850 or 1000 mg. Glimepiride and metformin fixed dose combinations were among the preferred choices in various complications like neuropathy, retinopathy, nephropathy, peripheral vascular disease, diabetic foot and cardiovascular disease. Insulin and statins were co-prescribed in 17.3% and 28.8% patients, respectively. Hypoglycemic episodes were reported in only a minority of patients, even with higher doses of glimepiride and metformin fixed dose combinations. Conclusion: Multiple strengths of glimepiride and metformin fixed dose combinations are beneficial in T2DM, irrespective of age, duration of diabetes, BMI, diabetes complications, use of concomitant medications such as insulin and statin. Glimepiride and metformin fixed dose combinations were not associated with a significant risk of hypoglycemia.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Metformina/uso terapêutico , Glicemia , Quimioterapia Combinada , Hemoglobina A Glicada/análise , Humanos , Hipoglicemiantes/uso terapêutico , Índia , Compostos de Sulfonilureia
17.
PLoS Med ; 17(7): e1003209, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32722720

RESUMO

BACKGROUND: Type 2 diabetes (T2D) is a progressive disease whereby there is often deterioration in glucose control despite escalation in treatment. There is significant heterogeneity to this progression of glycemia after onset of diabetes, yet the factors that influence glycemic progression are not well understood. Given the tremendous burden of diabetes in the Chinese population, and limited knowledge on factors that influence glycemia, we aim to identify the clinical and genetic predictors for glycemic progression in Chinese patients with T2D. METHODS AND FINDINGS: In 1995-2007, 7,091 insulin-naïve Chinese patients (mean age 56.8 ± 13.3 [SD] years; mean age of T2D onset 51.1 ± 12.7 years; 47% men; 28.4% current or ex-smokers; median duration of diabetes 4 [IQR: 1-9] years; mean HbA1c 7.4% ± 1.7%; mean body mass index [BMI] 25.3 ± 4.0 kg/m2) were followed prospectively in the Hong Kong Diabetes Register. We examined associations of BMI and other clinical and genetic factors with glycemic progression defined as requirement of continuous insulin treatment, or 2 consecutive HbA1c ≥8.5% while on ≥2 oral glucose-lowering drugs (OGLDs), with validation in another multicenter cohort of Hong Kong Diabetes Biobank. During a median follow-up period of 8.8 (IQR: 4.8-13.3) years, incidence of glycemic progression was 48.0 (95% confidence interval [CI] 46.3-49.8) per 1,000 person-years with 2,519 patients started on insulin. Among the latter, 33.2% had a lag period of 1.3 years before insulin was initiated. Risk of progression was associated with extremes of BMI and high HbA1c. On multivariate Cox analysis, early age at diagnosis, microvascular complications, high triglyceride levels, and tobacco use were additional independent predictors for glycemic progression. A polygenic risk score (PRS) including 123 known risk variants for T2D also predicted rapid progression to insulin therapy (hazard ratio [HR]: 1.07 [95% CI 1.03-1.12] per SD; P = 0.001), with validation in the replication cohort (HR: 1.24 [95% CI 1.06-1.46] per SD; P = 0.008). A PRS using 63 BMI-related variants predicted BMI (beta [SE] = 0.312 [0.057] per SD; P = 5.84 × 10-8) but not glycemic progression (HR: 1.01 [95% CI 0.96-1.05] per SD; P = 0.747). Limitations of this study include potential misdiagnosis of T2D and lack of detailed data of drug use during follow-up in the replication cohort. CONCLUSIONS: Our results show that approximately 5% of patients with T2D failed OGLDs annually in this clinic-based cohort. The independent associations of modifiable and genetic risk factors allow more precise identification of high-risk patients for early intensive control of multiple risk factors to prevent glycemic progression.


Assuntos
Glicemia/genética , Diabetes Mellitus Tipo 2/genética , Obesidade/complicações , Polimorfismo de Nucleotídeo Único , Adulto , Idoso , Grupo com Ancestrais do Continente Asiático/genética , Bancos de Espécimes Biológicos , Glicemia/análise , Índice de Massa Corporal , HDL-Colesterol/genética , Estudos de Coortes , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/epidemiologia , Feminino , Hemoglobina A Glicada/análise , Hemoglobina A Glicada/genética , Hong Kong/epidemiologia , Humanos , Masculino , Metformina/uso terapêutico , Pessoa de Meia-Idade , Obesidade/epidemiologia , Resultado do Tratamento
18.
Medicine (Baltimore) ; 99(21): e20228, 2020 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-32481295

RESUMO

RATIONALE: Rare cases of euglycemic diabetic ketoacidosis (eu-DKA) have been reported after the administration of sodium-glucose cotransporter-2 (SGLT-2) inhibitors. No reports have described eu-DKA complicated by hypernatremia due to SGLT-2 inhibitors. PATIENT CONCERNS: A 76-year-old woman with a 40-year history of type 2 diabetes mellitus (DM), for which metformin (1000 mg/day) and dapagliflozin (10 mg/day) were prescribed, presented with malaise, fever, and oliguria. On presentation, her white blood cell count (11,800/µL), serum creatinine (3.2 mg/dL), and C-reactive protein (54 mg/L) were abnormal. Bilateral pyeloureteritis and diffuse paralytic ileus were present. She received intravenous antibiotics and total parenteral nutrition, and was asked to fast. Her renal function and ileus briefly improved. Oral hypoglycemic agents, metformin and dapagliflozin, along with enteral feeding were reinstituted on day 3 of hospitalization. However, on day 6 of hospitalization, the patient developed an altered state of consciousness including confusion, lethargy, and stupor. Several laboratory abnormalities suggestive of ketoacidosis with euglycemia were noted. DIAGNOSES: The patient was diagnosed with eu-DKA accompanied by severe hypernatremia (corrected serum Na concentration, 163 mEq/L) and hypokalemia following dapagliflozin re-administration. INTERVENTIONS: The patient was treated with indicated intravenous fluid therapy. Dapagliflozin use was discontinued. OUTCOMES: The patient's mental status and laboratory findings improved gradually, and she was discharged on maintenance doses of insulin and metformin on day 14 of hospitalization. LESSONS: Acute illnesses such as diffuse paralytic ileus and urinary tract infection, and dietary restrictions or fasting in patients with DM can be considered potential predisposing factors for SGLT-2 inhibitor-associated eu-DKA. For patients with diabetes in the setting of acute morbidity, timely resumption of the SGLT-2 inhibitor therapy should be carefully determined. In addition, eu-DKA due to SGLT-2 inhibitor use may be accompanied by electrolyte disturbances such as hypernatremia and hypokalemia.


Assuntos
Compostos Benzidrílicos/efeitos adversos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Cetoacidose Diabética/induzido quimicamente , Glucosídeos/efeitos adversos , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversos , Administração Intravenosa , Idoso , Antibacterianos/uso terapêutico , Compostos Benzidrílicos/administração & dosagem , Compostos Benzidrílicos/uso terapêutico , Glicemia/análise , Diabetes Mellitus Tipo 2/complicações , Cetoacidose Diabética/complicações , Cetoacidose Diabética/terapia , Feminino , Hidratação/métodos , Glucosídeos/administração & dosagem , Glucosídeos/uso terapêutico , Humanos , Hipernatremia/induzido quimicamente , Hipoglicemiantes/uso terapêutico , Hipopotassemia/induzido quimicamente , Insulina/uso terapêutico , Pseudo-Obstrução Intestinal/etiologia , Pelve Renal/microbiologia , Pelve Renal/patologia , Metformina/uso terapêutico , Alta do Paciente , Inibidores do Transportador 2 de Sódio-Glicose/administração & dosagem , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Ureter/microbiologia , Ureter/patologia , Suspensão de Tratamento
19.
Rev Med Suisse ; 16(697): 1200-1205, 2020 Jun 10.
Artigo em Francês | MEDLINE | ID: mdl-32520459

RESUMO

Post-transplantation diabetes (PTDM) exposes to increased morbidity (cardiovascular or infectious complications, early graft dysfunction) and to a risk of premature death. Recognition of risk factors is essential for early and individualized care. The management of a PTDM requires the use of oral antidiabetic treatments (metformin or DPP4 inhibitors) or GLP1 receptor agonists for their favorable effects on weight and kidney that seem ideal in this context. Corticosteroid-induced diabetes or the rare occurrence of diabetic ketoacidosis require insulin therapy. In the long term, the main objective remains to integrate PTDM treatment in a more comprehensive management, targeting the reduction of cardiovascular risk of vulnerable transplant patients.


Assuntos
Diabetes Mellitus/tratamento farmacológico , Diabetes Mellitus/etiologia , Transplante de Rim/efeitos adversos , Complicações Pós-Operatórias/tratamento farmacológico , Complicações Pós-Operatórias/etiologia , Diabetes Mellitus/metabolismo , Cetoacidose Diabética/tratamento farmacológico , Cetoacidose Diabética/metabolismo , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Humanos , Hipoglicemiantes/uso terapêutico , Insulina/metabolismo , Insulina/uso terapêutico , Metformina/uso terapêutico , Complicações Pós-Operatórias/metabolismo , Fatores de Risco
20.
Brasília; s.n; 16 jun. 2020.
Não convencional em Português | LILACS, BRISA/RedTESA, PIE | ID: biblio-1100418

RESUMO

O Informe Diário de Evidências é uma produção do Ministério da Saúde que tem como objetivo acompanhar diariamente as publicações científicas sobre tratamento farmacológico e vacinas para a COVID-19. Dessa forma, são realizadas buscas estruturadas em bases de dados biomédicas, referente ao dia anterior desse informe. Não são incluídos estudos pré-clínicos (in vitro, in vivo, in silico). A frequência dos estudos é demonstrada de acordo com a sua classificação metodológica (revisões sistemáticas, ensaios clínicos randomizados, coortes, entre outros). Para cada estudo é apresentado um resumo com avaliação da qualidade metodológica. Essa avaliação tem por finalidade identificar o grau de certeza/confiança ou o risco de viés de cada estudo. Para tal, são utilizadas ferramentas já validadas e consagradas na literatura científica, na área de saúde baseada em evidências. Cabe ressaltar que o documento tem caráter informativo e não representa uma recomendação oficial do Ministério da Saúde sobre a temática. Foram encontrados 15 artigos. Foram encontrados 8 artigos e 15 protocolos.


Assuntos
Humanos , Pneumonia Viral/tratamento farmacológico , Infecções por Coronavirus/tratamento farmacológico , Betacoronavirus/efeitos dos fármacos , Avaliação da Tecnologia Biomédica , Imunoglobulinas/uso terapêutico , Dexametasona/uso terapêutico , Vacinas/farmacologia , Hidroxicloroquina/uso terapêutico , Metformina/uso terapêutico , Anticorpos Monoclonais/uso terapêutico
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