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1.
N Engl J Med ; 387(12): 1089-1098, 2022 09 22.
Article in English | MEDLINE | ID: covidwho-2036975

ABSTRACT

BACKGROUND: Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of hospitalization for heart failure and cardiovascular death among patients with chronic heart failure and a left ventricular ejection fraction of 40% or less. Whether SGLT2 inhibitors are effective in patients with a higher left ventricular ejection fraction remains less certain. METHODS: We randomly assigned 6263 patients with heart failure and a left ventricular ejection fraction of more than 40% to receive dapagliflozin (at a dose of 10 mg once daily) or matching placebo, in addition to usual therapy. The primary outcome was a composite of worsening heart failure (which was defined as either an unplanned hospitalization for heart failure or an urgent visit for heart failure) or cardiovascular death, as assessed in a time-to-event analysis. RESULTS: Over a median of 2.3 years, the primary outcome occurred in 512 of 3131 patients (16.4%) in the dapagliflozin group and in 610 of 3132 patients (19.5%) in the placebo group (hazard ratio, 0.82; 95% confidence interval [CI], 0.73 to 0.92; P<0.001). Worsening heart failure occurred in 368 patients (11.8%) in the dapagliflozin group and in 455 patients (14.5%) in the placebo group (hazard ratio, 0.79; 95% CI, 0.69 to 0.91); cardiovascular death occurred in 231 patients (7.4%) and 261 patients (8.3%), respectively (hazard ratio, 0.88; 95% CI, 0.74 to 1.05). Total events and symptom burden were lower in the dapagliflozin group than in the placebo group. Results were similar among patients with a left ventricular ejection fraction of 60% or more and those with a left ventricular ejection fraction of less than 60%, and results were similar in prespecified subgroups, including patients with or without diabetes. The incidence of adverse events was similar in the two groups. CONCLUSIONS: Dapagliflozin reduced the combined risk of worsening heart failure or cardiovascular death among patients with heart failure and a mildly reduced or preserved ejection fraction. (Funded by AstraZeneca; DELIVER ClinicalTrials.gov number, NCT03619213.).


Subject(s)
Heart Failure , Sodium-Glucose Transporter 2 Inhibitors , Stroke Volume , Ventricular Function, Left , Benzhydryl Compounds/adverse effects , Benzhydryl Compounds/therapeutic use , Diabetes Mellitus, Type 2/complications , Diabetes Mellitus, Type 2/drug therapy , Glucosides/adverse effects , Glucosides/therapeutic use , Heart Failure/complications , Heart Failure/drug therapy , Heart Failure/mortality , Heart Failure/physiopathology , Humans , Sodium-Glucose Transporter 2 Inhibitors/adverse effects , Sodium-Glucose Transporter 2 Inhibitors/pharmacology , Sodium-Glucose Transporter 2 Inhibitors/therapeutic use , Stroke Volume/drug effects , Ventricular Function, Left/drug effects
2.
Medicina (Kaunas) ; 58(9)2022 Aug 27.
Article in English | MEDLINE | ID: covidwho-2006132

ABSTRACT

Background and Objectives: Individuals with type 2 diabetes mellitus (T2DM) have an increased risk of cardiovascular disease. Arterial stiffness is an independent prognostic marker for cardiovascular disease development. We aimed at determining the effect of two different sodium-glucose co-transporter-2 (SGLT-2) inhibitors on ambulatory arterial stiffness in individuals with T2DM. Materials and Methods: In this single-center, single-arm, prospective study performed from January 2020 to August 2021, we planned to enroll adult subjects with T2DM and stable antidiabetic and antihypertensive treatment, assigned either to empagliflozin or dapagliflozin for 6 months. All eligible subjects underwent ambulatory blood pressure monitoring. We set as the primary efficacy outcome the change in ambulatory pulse wave velocity (PWV) from baseline to week 24. Results: We finally enrolled 46 diabetic subjects, with a mean age of 62.89 (8.53) years and mean T2DM duration of 9.72 (6.37) years. Thirty patients received dapagliflozin, while sixteen patients received empagliflozin. Due to COVID-19 pandemic restrictive measures during the study, the mean follow-up period extended from 6 months to 9.98 (3.27) months. Regarding the prespecified primary efficacy outcome, we found that the SGLT-2 inhibitor treatment did not have a significant effect on PWV (p = 0.65). Prior history of cardiovascular disease did not significantly affect the observed effects. Other indices of arterial stiffness, such as augmentation index and central pulse pressure, were not significantly affected, neither by empagliflozin nor by dapagliflozin. Conclusions: SGLT-2 inhibitor treatment with empagliflozin or dapagliflozin in subjects with T2DM failed to improve ambulatory PWV over a mean follow-up of 10 months. Registration number: ISRCTN88851713.


Subject(s)
COVID-19 , Cardiovascular Diseases , Diabetes Mellitus, Type 2 , Sodium-Glucose Transporter 2 Inhibitors , Symporters , Vascular Stiffness , Antihypertensive Agents/pharmacology , Benzhydryl Compounds , Blood Pressure Monitoring, Ambulatory , Cardiovascular Diseases/chemically induced , Diabetes Mellitus, Type 2/complications , Diabetes Mellitus, Type 2/drug therapy , Glucose , Glucosides , Humans , Hypoglycemic Agents/adverse effects , Middle Aged , Morbidity , Pandemics , Prospective Studies , Pulse Wave Analysis , Sodium , Sodium-Glucose Transporter 2 Inhibitors/adverse effects , Symporters/pharmacology , Treatment Outcome
3.
ESC Heart Fail ; 9(4): 2233-2238, 2022 08.
Article in English | MEDLINE | ID: covidwho-1940839

ABSTRACT

AIMS: In this prospective, placebo-controlled, double-blind, exploratory study, we examined early and more delayed effects of empagliflozin treatment on haemodynamic parameters (primary endpoint: cardiac output) and kidney function including parameters of acute kidney injury (AKI) in patients with acute decompensated heart failure (HF). METHODS AND RESULTS: Patients with acute decompensated HF with or without diabetes were randomized to empagliflozin 10 mg or placebo for 30 days. Haemodynamic, laboratory, and urinary parameters were assessed after 6 h, 1 day, 3 days, 7 days, and 30 days of treatment. Median time between hospital admission and randomization was 72 h. Baseline characteristics were not different in the empagliflozin (n = 10) and placebo (n = 9) groups. Empagliflozin led to a significant increase in urinary glucose excretion throughout the study (baseline: 37 ± 15 mg/24 h; Day 1: 14 565 ± 8663 mg/24 h; P = 0.001). Empagliflozin did not affect the primary endpoint of cardiac index or on systemic vascular resistance index at any time point. However, empagliflozin significantly reduced parameters of AKI (urinary TIMP-2 and IGFBP7 by NephroCheck® as indicators of tubular kidney damage), which became significant after 3 days of treatment [placebo: 1.1 ± 1.1 (ng/mL)2 /1000; empagliflozin: 0.3 ± 0.2 (ng/mL)2 /1000; P = 0.02] and remained significant at the 7 day time point [placebo: 2.5 ± 3.8 (ng/mL)2 /1000; empagliflozin: 0.3 ± 0.2 (ng/mL)2 /1000; P = 0.003]. CONCLUSIONS: In this study, empagliflozin treatment did not affect haemodynamic parameters but significantly reduced markers of tubular injury in patients with acute decompensated HF.


Subject(s)
Acute Kidney Injury , Heart Failure , Acute Kidney Injury/drug therapy , Benzhydryl Compounds , Biomarkers , Glucosides/therapeutic use , Heart Failure/complications , Heart Failure/drug therapy , Humans , Prospective Studies
7.
Int J Mol Sci ; 23(6)2022 Mar 09.
Article in English | MEDLINE | ID: covidwho-1732072

ABSTRACT

BPA is one of the most common endocrine disruptors that is widely being manufactured daily nationwide. Although scientific evidence supports claims of negative effects of BPA on humans, there is also evidence suggesting that a low level of BPA is safe. However, numerous in vivo trials contraindicate with this claim and there is a high possibility of BPA exposure could lead to obesity. It has been speculated that this does not stop with the exposed subjects only, but may also cause transgenerational effects. Direct disruption of endocrine regulation, neuroimmune and signaling pathways, as well as gut microbiata, has been identified to be interrupted by BPA exposure, leading to overweight or obesity. In these instances, cardiovascular complications are one of the primary notable clinical signs. In regard to this claim, this review paper discusses the role of BPA on obesity in the perspective of endocrine disruptions and possible cardiovascular complications that may arise due to BPA. Thus, the aim of this review is to outline the changes in gut microbiota and neuroimmune or signaling mechanisms involved in obesity in relation to BPA. To identify potentially relevant articles, a depth search was done on the databases Nature, PubMed, Wiley Online Library, and Medline & Ovid from the past 5 years. According to Boolean operator guideline, selected keywords such as (1) BPA OR environmental chemical AND fat OR LDL OR obese AND transgenerational effects or phenocopy (2) Endocrine disruptors OR chemical AND lipodystrophy AND phenocopy (3) Lipid profile OR weight changes AND cardiovascular effect (4) BPA AND neuroimmune OR gene signaling, were used as search terms. Upon screening, 11 articles were finalized to be further reviewed and data extraction tables containing information on (1) the type of animal model (2) duration and dosage of BPA exposure (3) changes in the lipid profile or weight (4) genes, signaling mechanism, or any neuroimmune signal involved, and (5) transgenerational effects were created. In toto, the study indicates there are high chances of BPA exposure affecting lipid profile and gene associated with lipolysis, leading to obesity. Therefore, this scoping review recapitulates the possible effects of BPA that may lead to obesity with the evidence of current in vivo trials. The biomarkers, safety concerns, recommended dosage, and the impact of COVID-19 on BPA are also briefly described.


Subject(s)
COVID-19 , Endocrine Disruptors , Animals , Benzhydryl Compounds/toxicity , Endocrine Disruptors/toxicity , Humans , Lipids , Obesity/complications , Phenols
8.
Mol Biol Rep ; 49(3): 2321-2324, 2022 Mar.
Article in English | MEDLINE | ID: covidwho-1664478

ABSTRACT

Numerous studies demonstrate parallels between CVD, type 2 diabetes mellitus (T2DM) and COVID-19 pathology, which accentuate pre-existing complications in patients infected with COVID-19 and potentially exacerbate the infection course. Antidiabetic drugs such as sodium-glucose transporter-2 (SGLT-2) inhibitors have garnered substantial attention recently due to their efficacy in reducing the severity of cardiorenal disease. The effect of SGLT-2 inhibitors in patients with COVID-19 remains unclear particularly since SGLT-2 inhibitors contribute to altering the RAAS cascade activity, which includes ACE-2, the major cell entry receptor for SARS-CoV2. A study, DARE-19, was carried out to unveil the effects of SGLT-2 inhibitor treatment on comorbid disease complications and concomitant COVID-19 outcomes and demonstrated no statistical significance. However, the need for further studies is essential to provide conclusive clinical findings.


Subject(s)
Benzhydryl Compounds/therapeutic use , COVID-19/complications , Glucosides/therapeutic use , Renin-Angiotensin System/drug effects , Respiratory Insufficiency/drug therapy , SARS-CoV-2 , Sodium-Glucose Transporter 2 Inhibitors/therapeutic use , Angiotensin-Converting Enzyme 2/physiology , Clinical Trials, Phase III as Topic , Double-Blind Method , Drug Repositioning , Heart Diseases/prevention & control , Humans , Kidney Diseases/prevention & control , Mitochondria/drug effects , Multicenter Studies as Topic , Oxidative Stress/drug effects , Randomized Controlled Trials as Topic , Receptors, Virus/physiology , Respiratory Insufficiency/etiology , Sodium-Glucose Transporter 2/physiology , Sodium-Glucose Transporter 2 Inhibitors/pharmacology
9.
Lancet Diabetes Endocrinol ; 10(2): 97-98, 2022 02.
Article in English | MEDLINE | ID: covidwho-1569157
11.
Lancet Diabetes Endocrinol ; 9(9): 586-594, 2021 09.
Article in English | MEDLINE | ID: covidwho-1545532

ABSTRACT

BACKGROUND: COVID-19 can lead to multiorgan failure. Dapagliflozin, a SGLT2 inhibitor, has significant protective benefits for the heart and kidney. We aimed to see whether this agent might provide organ protection in patients with COVID-19 by affecting processes dysregulated during acute illness. METHODS: DARE-19 was a randomised, double-blind, placebo-controlled trial of patients hospitalised with COVID-19 and with at least one cardiometabolic risk factor (ie, hypertension, type 2 diabetes, atherosclerotic cardiovascular disease, heart failure, and chronic kidney disease). Patients critically ill at screening were excluded. Patients were randomly assigned 1:1 to dapagliflozin (10 mg daily orally) or matched placebo for 30 days. Dual primary outcomes were assessed in the intention-to-treat population: the outcome of prevention (time to new or worsened organ dysfunction or death), and the hierarchial composite outcome of recovery (change in clinical status by day 30). Safety outcomes, in patients who received at least one study medication dose, included serious adverse events, adverse events leading to discontinuation, and adverse events of interest. This study is registered with ClinicalTrials.gov, NCT04350593. FINDINGS: Between April 22, 2020 and Jan 1, 2021, 1250 patients were randomly assigned with 625 in each group. The primary composite outcome of prevention showed organ dysfunction or death occurred in 70 patients (11·2%) in the dapagliflozin group, and 86 (13·8%) in the placebo group (hazard ratio [HR] 0·80, 95% CI 0·58-1·10; p=0·17). For the primary outcome of recovery, 547 patients (87·5%) in the dapagliflozin group and 532 (85·1%) in the placebo group showed clinical status improvement, although this was not statistically significant (win ratio 1·09, 95% CI 0·97-1·22; p=0·14). There were 41 deaths (6·6%) in the dapagliflozin group, and 54 (8·6%) in the placebo group (HR 0·77, 95% CI 0·52-1·16). Serious adverse events were reported in 65 (10·6%) of 613 patients treated with dapagliflozin and in 82 (13·3%) of 616 patients given the placebo. INTERPRETATION: In patients with cardiometabolic risk factors who were hospitalised with COVID-19, treatment with dapagliflozin did not result in a statistically significant risk reduction in organ dysfunction or death, or improvement in clinical recovery, but was well tolerated. FUNDING: AstraZeneca.


Subject(s)
Benzhydryl Compounds/administration & dosage , COVID-19/complications , Cardiometabolic Risk Factors , Glucosides/administration & dosage , Multiple Organ Failure/prevention & control , Sodium-Glucose Transporter 2 Inhibitors/administration & dosage , Aged , Double-Blind Method , Female , Humans , Male , Middle Aged , Multiple Organ Failure/complications , Treatment Outcome
12.
Lancet Diabetes Endocrinol ; 9(9): 550-551, 2021 09.
Article in English | MEDLINE | ID: covidwho-1322420
13.
J Cardiovasc Pharmacol ; 78(1): e12-e19, 2021 07 01.
Article in English | MEDLINE | ID: covidwho-1232234

ABSTRACT

ABSTRACT: Epidemiological studies indicate that diabetes is the second most common comorbidity in COVID-19 (coronavirus disease 2019). Dapagliflozin, a sodium-glucose co-transporter 2 inhibitor, exerts direct cardioprotective and nephroprotective effects. DARE-19 (Dapagliflozin in Respiratory Failure in Patients With COVID-19), an ongoing clinical trial, is designed to investigate the impact of dapagliflozin on COVID-19 progression. This article discusses the potential favorable impact of dapagliflozin on COVID-19 and its complications.


Subject(s)
Benzhydryl Compounds/therapeutic use , COVID-19/drug therapy , Diabetes Mellitus, Type 2/drug therapy , Glucosides/therapeutic use , Sodium-Glucose Transporter 2 Inhibitors/therapeutic use , Benzhydryl Compounds/adverse effects , COVID-19/diagnosis , COVID-19/mortality , Clinical Trials, Phase III as Topic , Comorbidity , Diabetes Mellitus, Type 2/diagnosis , Diabetes Mellitus, Type 2/mortality , Disease Progression , Glucosides/adverse effects , Humans , Randomized Controlled Trials as Topic , Sodium-Glucose Transporter 2 Inhibitors/adverse effects , Treatment Outcome
14.
Diabet Med ; 38(2): e14458, 2021 02.
Article in English | MEDLINE | ID: covidwho-1214788

ABSTRACT

Dapagliflozin (SGLT-2 inhibitor) and sotagliflozin (SGLT1/2 inhibitor) are two of the drugs of SGLT inhibitor class which have been recommended by the National Institute for Health and Care Excellence (NICE) in people with type 1 diabetes with BMI ≥27 kg/m2 . Dapagliflozin is licensed in the UK for use in the NHS while sotagliflozin may be available in future. These and possibly other SGLT inhibitors may be increasingly used in people with type 1 diabetes as new licences are obtained. These drugs have the potential to improve glycaemic control in people with type 1 diabetes with the added benefit of weight loss, better control of blood pressure and more time in optimal glucose range. However, SGLT inhibitors are associated with a higher incidence of diabetic ketoacidosis without significant hyperglycaemia. The present ABCD/Diabetes UK joint updated position statement is to guide people with type 1 diabetes and clinicians using these drugs help mitigate this risk and other potential complications. Particularly, caution needs to be exercised in people who are at risk of diabetic ketoacidosis due to low calorie diets, illnesses, injuries, starvation, excessive exercise, excessive alcohol consumption and reduced insulin administration among other precipitating factors for diabetic ketoacidosis.


Subject(s)
Diabetes Mellitus, Type 1/drug therapy , Diabetic Ketoacidosis/epidemiology , Overweight/metabolism , Sodium-Glucose Transporter 2 Inhibitors/therapeutic use , Benzhydryl Compounds/therapeutic use , Diabetes Mellitus, Type 1/complications , Diabetes Mellitus, Type 1/metabolism , Drug Therapy, Combination , Glucosides/therapeutic use , Glycosides/therapeutic use , Humans , Hypoglycemic Agents/therapeutic use , Insulin/therapeutic use , Overweight/complications , Practice Guidelines as Topic , United Kingdom
15.
Diabetes Obes Metab ; 23(4): 886-896, 2021 04.
Article in English | MEDLINE | ID: covidwho-1171152

ABSTRACT

AIMS: Coronavirus disease 2019 (COVID-19) is caused by a novel severe acute respiratory syndrome coronavirus 2. It can lead to multiorgan failure, including respiratory and cardiovascular decompensation, and kidney injury, with significant associated morbidity and mortality, particularly in patients with underlying metabolic, cardiovascular, respiratory or kidney disease. Dapagliflozin, a sodium-glucose cotransporter-2 inhibitor, has shown significant cardio- and renoprotective benefits in patients with type 2 diabetes (with and without atherosclerotic cardiovascular disease), heart failure and chronic kidney disease, and may provide similar organ protection in high-risk patients with COVID-19. MATERIALS AND METHODS: DARE-19 (NCT04350593) is an investigator-initiated, collaborative, international, multicentre, randomized, double-blind, placebo-controlled study testing the dual hypotheses that dapagliflozin can reduce the incidence of cardiovascular, kidney and/or respiratory complications or all-cause mortality, or improve clinical recovery, in adult patients hospitalized with COVID-19 but not critically ill on admission. Eligible patients will have ≥1 cardiometabolic risk factor for COVID-19 complications. Patients will be randomized 1:1 to dapagliflozin 10 mg or placebo. Primary efficacy endpoints are time to development of new or worsened organ dysfunction during index hospitalization, or all-cause mortality, and the hierarchical composite endpoint of change in clinical status through day 30 of treatment. Safety of dapagliflozin in individuals with COVID-19 will be assessed. CONCLUSIONS: DARE-19 will evaluate whether dapagliflozin can prevent COVID-19-related complications and all-cause mortality, or improve clinical recovery, and assess the safety profile of dapagliflozin in this patient population. Currently, DARE-19 is the first large randomized controlled trial investigating use of sodium-glucose cotransporter 2 inhibitors in patients with COVID-19.


Subject(s)
Benzhydryl Compounds/therapeutic use , COVID-19/drug therapy , Cardiovascular Diseases/prevention & control , Glucosides/therapeutic use , Kidney Diseases/prevention & control , Mortality , Respiratory Insufficiency/drug therapy , Sodium-Glucose Transporter 2 Inhibitors/therapeutic use , Atherosclerosis/epidemiology , COVID-19/complications , COVID-19/epidemiology , Cardiometabolic Risk Factors , Cardiovascular Diseases/etiology , Cause of Death , Comorbidity , Diabetes Mellitus, Type 2/epidemiology , Disease Progression , Double-Blind Method , Heart Failure/epidemiology , Humans , Hypertension/epidemiology , Kidney Diseases/etiology , Multicenter Studies as Topic , Randomized Controlled Trials as Topic , Renal Insufficiency, Chronic/epidemiology , Respiratory Insufficiency/etiology , SARS-CoV-2 , Treatment Outcome
16.
Circ Heart Fail ; 14(3): e007048, 2021 03.
Article in English | MEDLINE | ID: covidwho-1119347

ABSTRACT

BACKGROUND: Empagliflozin reduces the risk of hospitalization for heart failure in patients with type 2 diabetes and cardiovascular disease. We sought to elucidate the effect of empagliflozin as an add-on therapy on decongestion and renal function in patients with type 2 diabetes admitted for acute decompensated heart failure. METHODS: The study was terminated early due to COVID-19 pandemic. We enrolled 59 consecutive patients with type 2 diabetes admitted for acute decompensated heart failure. Patients were randomly assigned to receive either empagliflozin add-on (n=30) or conventional glucose-lowering therapy (n=29). We performed laboratory tests at baseline and 1, 2, 3, and 7 days after randomization. Percent change in plasma volume between admission and subsequent time points was calculated using the Strauss formula. RESULTS: There were no significant baseline differences in left ventricular ejection fraction and serum NT-proBNP (N-terminal pro-B-type natriuretic peptide), hematocrit, or serum creatinine levels between the 2 groups. Seven days after randomization, NT-proBNP level was significantly lower in the empagliflozin group than in the conventional group (P=0.040), and hemoconcentration (≥3% absolute increase in hematocrit) was more frequently observed in the empagliflozin group than in the conventional group (P=0.020). The decrease in percent change in plasma volume between baseline and subsequent time points was significantly larger in the empagliflozin group than in the conventional group 7 days after randomization (P=0.017). The incidence of worsening renal function (an increase in serum creatinine ≥0.3 mg/dL) did not significantly differ between the 2 groups. CONCLUSIONS: In this exploratory analysis, empagliflozin achieved effective decongestion without an increased risk of worsening renal function as an add-on therapy in patients with type 2 diabetes with acute decompensated heart failure. Registration: URL: https://www.umin.ac.jp/ctr/index.htm; Unique identifier: UMIN000026315.


Subject(s)
Benzhydryl Compounds/therapeutic use , Diabetes Mellitus, Type 2/drug therapy , Glucosides/therapeutic use , Heart Failure/drug therapy , Hospitalization , Kidney/drug effects , Sodium-Glucose Transporter 2 Inhibitors/therapeutic use , Stroke Volume/drug effects , Ventricular Function, Left/drug effects , Aged , Aged, 80 and over , Benzhydryl Compounds/adverse effects , Biomarkers/blood , Blood Glucose/drug effects , Blood Glucose/metabolism , COVID-19 , Creatinine/blood , Diabetes Mellitus, Type 2/blood , Diabetes Mellitus, Type 2/diagnosis , Diabetes Mellitus, Type 2/physiopathology , Early Termination of Clinical Trials , Female , Glucosides/adverse effects , Heart Failure/diagnosis , Heart Failure/physiopathology , Humans , Japan , Kidney/physiopathology , Male , Natriuretic Peptide, Brain/blood , Peptide Fragments/blood , Prospective Studies , Sodium-Glucose Transporter 2 Inhibitors/adverse effects , Time Factors , Treatment Outcome
17.
Environ Int ; 146: 106160, 2021 01.
Article in English | MEDLINE | ID: covidwho-1014467

ABSTRACT

BACKGROUND: Most pregnant women are exposed to bisphenols, a group of chemicals that can interfere with various components of the thyroid system. OBJECTIVES: To investigate the association of maternal urinary bisphenol concentrations during pregnancy with maternal, newborn and early childhood thyroid function. METHODS: This study was embedded in Generation R, a prospective, population-based birth cohort (Rotterdam, the Netherlands). Maternal urine samples were analyzed for eight bisphenols at early (<18), mid (18-25) and late (>25 weeks) pregnancy. Maternal serum thyroid stimulating hormone (TSH), free thyroxine (FT4) and total thyroxine (TT4) were measured in early pregnancy and child TSH and FT4 were measured in cord blood and childhood. RESULTS: The final study population comprised 1,267 mothers, 853 newborns and 882 children. Of the eight bisphenols measured, only bisphenol A (BPA) was detected in >50% of samples at all three time-points and bisphenol S (BPS) at the first time-point. There was no association of BPA or the bisphenol molar sum with maternal thyroid function. Higher BPS concentrations were associated with a higher maternal TT4 (ß [95% CI] per 1 (natural-log) unit increase: 0.97 [0.03 to 1.91]) but there was no association with TSH or FT4. Furthermore, higher BPS was associated with an attenuation of the association between maternal FT4 and TSH (Pinteraction = 0.001). There was no association of early or mid-pregnancy BPA or early pregnancy BPS with cord blood or childhood TSH and FT4. A higher late pregnancy maternal BPA exposure was associated with a higher TSH in female newborns (Pinteraction = 0.06) and a higher FT4 during childhood in males (Pinteraction = 0.08). DISCUSSION: Our findings show that exposure to bisphenols may interfere with the thyroid system during pregnancy. Furthermore, the potential developmental toxicity of exposure to bisphenols during pregnancy could affect the thyroid system in the offspring in a sex-specific manner.


Subject(s)
Fetal Blood , Thyroid Gland , Benzhydryl Compounds , Child , Child, Preschool , Female , Humans , Infant, Newborn , Male , Netherlands , Phenols , Pregnancy , Prospective Studies , Thyrotropin , Thyroxine
18.
Curr Atheroscler Rep ; 22(12): 72, 2020 10 03.
Article in English | MEDLINE | ID: covidwho-812523

ABSTRACT

PURPOSE OF REVIEW: The review highlights selected studies related to cardiovascular disease (CVD) prevention that were presented at the 2020 European Society of Cardiology (ESC) Congress-The Digital Experience. RECENT FINDINGS: The studies reviewed include clinical trials on novel RNA interference-based lipid-lowering therapies AKCEA-APOCIII-LRx and vupanorsen (AKCEA-ANGPTL3-LRx); the EVAPORATE trial assessing the effects of icosapent ethyl on coronary plaque volume progression; the LoDoCo2 trial evaluating the efficacy of low-dose colchicine in cardiovascular disease risk reduction among patients with chronic coronary artery disease; as well as the EMPEROR-Reduced trial evaluating cardiovascular and renal outcomes with empagliflozin in patients with heart failure and reduced ejection fraction. In addition, we review the BPLTTC analysis on blood pressure treatment across blood pressure levels and CVD status and discuss findings from the BRACE CORONA study that examined continuing versus suspending angiotensin-converting enzyme inhibitor or angiotensin receptor blockers in patients on these antihypertensive medications who were hospitalized with COVID-19 infection. The studies presented at the 2020 digital ESC Congress highlight the continuing advancements in the field of CVD prevention.


Subject(s)
Betacoronavirus/physiology , Cardiology , Cardiovascular Agents/pharmacology , Cardiovascular Diseases , Coronavirus Infections , Lipid Regulating Agents/pharmacology , Pandemics , Pneumonia, Viral , Benzhydryl Compounds/pharmacology , COVID-19 , Cardiology/methods , Cardiology/trends , Cardiovascular Diseases/epidemiology , Cardiovascular Diseases/prevention & control , Clinical Trials as Topic , Congresses as Topic , Coronavirus Infections/epidemiology , Coronavirus Infections/therapy , Eicosapentaenoic Acid/analogs & derivatives , Eicosapentaenoic Acid/pharmacology , Europe , Glucosides/pharmacology , Humans , Oligonucleotides/pharmacology , Pneumonia, Viral/epidemiology , Pneumonia, Viral/therapy , SARS-CoV-2 , Societies, Medical , Telecommunications
19.
Trials ; 21(1): 690, 2020 Jul 31.
Article in English | MEDLINE | ID: covidwho-690784

ABSTRACT

OBJECTIVES: To determine if a specific intervention reduces the composite of progression of patients with COVID-19-related disease to organ failure or death as measured by time to incidence of any one of the following: death, invasive mechanical ventilation, ECMO, cardiovascular organ support (inotropes or balloon pump), or renal failure (estimated Cockcroft Gault creatinine clearance <15ml/min). TRIAL DESIGN: Randomised, parallel arm, open-label, adaptive platform Phase 2/3 trial of potential disease modifying therapies in patients with late stage 1/stage 2 COVID-19-related disease, with a diagnosis based either on a positive assay or high suspicion of COVID-19 infection by clinical, laboratory and radiological assessment. PARTICIPANTS: Patients aged 18 and over, with a clinical picture strongly suggestive of COVID-19-related disease (with/without a positive COVID-19 test) AND a risk count (as defined below) >3 OR ≥3 if risk count includes "Radiographic severity score >3". A risk count is calculated by the following features on admission (1 point for each): radiographic severity score >3, male gender, non-white ethnicity, diabetes, hypertension, neutrophils >8.0 x109/L, age >40 years and CRP >40 mg/L. Patients should be considered an appropriate subject for intervention with immunomodulatory or other disease modifying agents in the opinion of the investigator and are able to swallow capsules or tablets. The complete inclusion and exclusion criteria as detailed in the Additional file 1 should be fulfilled. Drug specific inclusion and exclusion criteria will also be applied to the active arms. Patients will be enrolled prior to the need for invasive mechanical ventilation, cardiac or renal support. Participants will be recruited across multiple centres in the UK including initially at Cambridge University Hospitals NHS Foundation Trust and St George's University NHS Foundation Trust. Other centres will be approached internationally in view of the evolving pandemic. INTERVENTION AND COMPARATOR: There is increasing evidence of the role of immunomodulation in altering the course of COVID-19. Additionally, various groups have demonstrated the presence of pulmonary shunting in patients with COVID-19 as well as other cardiovascular complications. TACTIC-E will assess the efficacy of the novel immunomodulatory agent EDP1815 versus the approved cardio-pulmonary drugs, Dapagliflozin in combination with Ambrisentan versus the prevailing standard of care. EDP1815 will be given as 2 capsules twice daily (1.6 x 1011 cells) for up to 7 days with the option to extend up to 14 days at the discretion of the principal investigator or their delegate, if the patient is felt to be clinically responding to treatment, is tolerating treatment, and is judged to be likely to benefit from a longer treatment course. Ambrisentan 5mg and Dapagliflozin 10mg will be given in combination once daily orally for up to maximum of 14 days. Patients will be randomised in a 1:1:1 ratio across treatments. Each active arm will be compared with standard of care alone. Additional arms may be added as the trial progresses. No comparisons will be made between active arms in this platform trial. MAIN OUTCOMES: The primary outcome is the incidence (from baseline up to Day 14) to the occurrence of the any one of the following events: death, invasive mechanical ventilation, extra corporeal membrane oxygenation, cardiovascular organ support (inotropes or balloon pump), or renal failure (estimated Cockcroft Gault creatinine clearance <15ml/min). RANDOMISATION: Eligible patients will be randomised using a central web-based randomisation service (Sealed Envelope) in a 1:1:1 ratio, stratified by site to one of the treatment arms or standard of care. BLINDING (MASKING): This is an open-label trial. Data analysis will not be blinded. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): There is no fixed sample size for this study. There will be an early biomarker-based futility analysis performed at a point during the study. If this biomarker futility analysis is not conclusive, then a second futility analysis based on clinical endpoints will be performed after approximately 125 patients have been recruited per arm. Provisionally, further analyses of clinical endpoints will be performed after 229 patients per active arm and later 469 patients per arm have been recruited. Further additional analyses may be triggered by the independent data monitoring committee. TRIAL STATUS: TACTIC-E Protocol version number 1.0 date May 27th, 2020. Recruitment starts on the 3rd of July 2020. The end trial date will be 18 months after the last patient's last visit and cannot be accurately predicted at this time. TRIAL REGISTRATION: Registered on EU Clinical Trials Register EudraCT Number: 2020-002229-27 registered: 9 June 2020. The trial was also registered on ClinicalTrials.gov (NCT04393246) on 19 May 2020. FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.


Subject(s)
Benzhydryl Compounds/administration & dosage , Betacoronavirus , Coronavirus Infections/drug therapy , Glucosides/administration & dosage , Immunologic Factors/therapeutic use , Phenylpropionates/administration & dosage , Pneumonia, Viral/drug therapy , Pyridazines/administration & dosage , Randomized Controlled Trials as Topic , COVID-19 , Humans , Intensive Care Units , Pandemics , Respiration, Artificial , SARS-CoV-2 , Standard of Care
20.
Diabetes Metab Syndr ; 14(4): 405-406, 2020.
Article in English | MEDLINE | ID: covidwho-102280

ABSTRACT

It has been reported that frequent occurrence of COVID-19 infection in these patients is associated with low cytosolic pH. During virus infection, serum lactate dehydrogenase (LDH) level excessively rises. LDH is a cytosolic enzyme and the serum level increases as the cell break down. When anaerobic conditions develop, lactate formation increases from pyruvate. Cell pH is regulated by very complex mechanisms. When lactate increases in the extracellular area, this symporter carries lactate and H+ ion into the cell, and the intracellular pH quickly becomes acidic. Paradoxically, Na+/H+ exchanger activation takes place. While H+ ion is thrown out of the cell, Na+ and Ca+2 enter the cell. When Na+ and Ca+2 increase in the cell, the cells swell and die. Dapagliflozin is a sodium-glucose cotransporter-2 inhibitor. Dapagliflozin has been reported to reduce lactate levels by various mechanisms. Also, it reduces oxygen consumption in tissues and causes the use of glucose in the aerobic pathway, thereby reducing lactate production. A lactate decrease in the environment reduces the activation of lactate/H+ symporter. Thus, the H ion pumping into the cell by this symporter is reduced and the cytosolic pH is maintained. Dapagliflozin also directly inhibits NHE. Thus, Na+ and Ca+2 flow to the cell are inhibited. Dapagliflozin provides the continuation of the structure and functions of the cells. Dapagliflozin can prevent the severe course of COVID-19 infection by preventing the lowering of cytosolic pH and reducing the viral load.


Subject(s)
Benzhydryl Compounds/therapeutic use , Betacoronavirus , Coronavirus Infections/prevention & control , Diabetes Mellitus/drug therapy , Glucosides/therapeutic use , Pandemics/prevention & control , Pneumonia, Viral/prevention & control , Sodium-Glucose Transporter 2 Inhibitors/therapeutic use , COVID-19 , Comorbidity , Coronavirus Infections/epidemiology , Dehydration/prevention & control , Diabetes Mellitus/epidemiology , Humans , Insulin/therapeutic use , Lactic Acid/metabolism , Oxygen Consumption/drug effects , Pneumonia, Viral/epidemiology , SARS-CoV-2
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