Enalapril attenuated CFA provoked arthritic manifestation by modulating proinflammatory and anti-inflammatory cytokine network.

Enalapril with documented anti-inflammatory potential was evaluated in current investigation to explore its anti-arthritic efficacy. For anti-arthritic evaluation of enalapril, CFA-instigated arthritic model was employed after which various parameters comprising paw volume, body weight, arthritic index, hematological and biochemical parameters, radiographic analysis and level of various cytokines were estimated. Enalapril demonstrated significant (p˂0.001) anti-arthritic activity by suppressing paw volume, arthritic index while preserved CFA instigated weight loss. Likewise, enalapril also normalized the hematological and biochemical alterations, suppressed the level of proinflammatory cytokines with elevation of anti-inflammatory cytokines. Radiographic and histopathological analysis also further validates the anti-arthritic attribute of enalapril where enalapril preserved the normal architecture of arthritis induced joints. Outcomes of the study pointed out a notable anti-arthritic activity of enalapril. However detailed mechanistic studies are still required to point out the exact mechanism of action.

Risk Factors of Dementia in Patients with Cerebral Vascular Diseases Based on Taiwan National Health Insurance Data.

INTRODUCTION: Vascular factors have been shown to be associated with increased risk of dementia. However, clinical trials have so far been unsuccessful, suggesting new approaches are needed. The aim of this study was to use population-based real-world data to investigate risk factors and preventive factors for dementia, including the effects of traditional Chinese medicine (TCM). METHODS: This is a retrospective cohort study using LHID2000, a dataset randomly selected from Taiwan's National Health Insurance Research Database. Subjects with occlusion and stenosis of precerebral and cerebral arteries, cerebral atherosclerosis without mention of cerebral infarction, and transient cerebral ischemia were included. Subjects with dementia at baseline were excluded. The primary endpoint was dementia. Data for demographic and clinical comorbid status and treatments administered at baseline in 2000 and at the end of follow-up in 2013 were included. RESULTS: A total of 4,207 subjects with cerebral vascular disease and no cognitive impairment were included, of whom 392 converted to dementia during an average 5.15-year (SD: 3.79) follow-up. Depression (adjusted HR: 1.54, 95% confidence interval [CI]: 1.13-2.09), osteoporosis (adjusted HR: 1.34, 95% CI: 1.04-1.74), and the use of enalapril (adjusted HR: 1.37, 95% CI: 1.09-1.73) were risk factors for dementia, while nitroglycerin (adjusted HR: 0.67, 95% CI: 0.53-0.85) was a protecting factor, in subjects with cerebrovascular diseases without mention of cerebral infarction. In total, statins were shown to be associated with decreased risk of dementia (HR: 0.73, 95% CI: 0.59-0.91); however, no one statin subtype or TCM had such an effect. CONCLUSION: Depression, osteoporosis, and the use of enalapril were associated with a higher risk of dementia, while nitroglycerin might be a protecting factor for dementia, in subjects with cerebrovascular diseases without mention of cerebral infarction.

Plasma selenium and the risk of first stroke in adults with hypertension: a secondary analysis of the China Stroke Primary Prevention Trial.

BACKGROUND: Previous studies have indicated that selenium (Se) may play an important role in cardio-cerebrovascular disease. However, the relation between circulating selenium and risk of first stroke remains inconclusive. OBJECTIVES: We conducted a secondary analysis of the China Stroke Primary Prevention Trial (CSPPT), using a nested case-control design, and aimed to investigate the correlation between Se concentration and first stroke risk in adults with hypertension and examine the potential effect modifiers. METHODS: In the CSPPT, a total of 20,702 adults with hypertension were randomly assigned to a double-blind daily treatment with either 10 mg enalapril and 0.8 mg folic acid or 10 mg enalapril alone. A total of 618 first stroke cases and 618 controls matched for age, sex, treatment group, and study site were included in this study. RESULTS: During a median follow-up duration of 4.5 y (IQR: 4.2-4.6 y), there was a significant inverse association between plasma Se and the risk of first stroke (per SD increment; adjusted OR: 0.81; 95% CI: 0.68, 0.96) and ischemic stroke (per SD increment; adjusted OR: 0.76; 95% CI: 0.62, 0.93). Furthermore, a stronger inverse association between plasma Se and first stroke was observed in participants with higher folate concentrations at baseline [≥7.7 ng/mL (median), adjusted OR: 0.67; 95% CI: 0.54, 0.85, compared with <7.7 ng/mL, adjusted OR: 0.98; 95% CI: 0.80, 1.21; P-interaction = 0.008] and those with higher time-averaged systolic blood pressure (SBP) over the treatment period (≥140 mm Hg, adjusted OR: 0.71; 95% CI: 0.58, 0.86, compared with <140 mm Hg, adjusted OR: 0.96; 95% CI: 0.77, 1.20; P-interaction = 0.023). CONCLUSIONS: There was a significant inverse association between plasma Se and risk of first stroke in Chinese adults with hypertension, especially among those with higher baseline folate concentrations and those with higher time-averaged SBP over the treatment period. This trial was registered at clinicaltrials.gov as NCT00794885.

Establishment of a Drug Screening Model for Cardiac Complications of Acute Renal Failure.

Acute renal failure (ARF) is a clinical critical syndrome with rapid and severe decline of renal function. Complications of ARF, especially its cardiac complications (cardiorenal syndrome type 3, CRS-3), are the main causes of death in patients with ARF. However, the shortage and limited efficacy of therapeutic drugs make it significant to establish new large-scale drug screening models. Based on the Nitroreductase/Metronidazole (NTR/MTZ) cell ablation system, we constructed a Tg(cdh17:Dendra2-NTR) transgenic zebrafish line, which can specifically ablate renal tubular epithelial cells. The absence of renal tubular epithelial cells can lead to ARF in zebrafish larvae. The ARF symptoms, such as heart enlargement, slow heart rate and blood stasis, are similar to the clinical manifestations of human CRS-3. Furthermore, two therapeutic drugs (digoxin and enalapril) commonly used in the clinical treatment of heart failure were also effective in alleviating the symptoms of CRS-3 in zebrafish, which proved the effectiveness of this model. Drug screening further discovered a potential drug candidate, α-lipoic acid, which can effectively alleviate the symptoms of CRS-3 through its antioxidant function. Accordingly, we established a new ARF model of zebrafish, which laid a foundation for large-scale screening of new therapeutic drugs for its complications.

Cardiac and Noncardiac Disease Burden and Treatment Effect of Sacubitril/Valsartan: Insights From a Combined PARAGON-HF and PARADIGM-HF Analysis.

BACKGROUND: The net clinical benefit of cardiac disease-modifying drugs might be influenced by the interaction of different domains of disease burden. We assessed the relative contribution of cardiac, comorbid, and demographic factors in heart failure (HF) and how their interplay might influence HF prognosis and efficacy of sacubitril/valsartan across the spectrum of left ventricular ejection fraction. METHODS: We combined data from 2 global trials that evaluated the efficacy of sacubitril/valsartan compared with a renin-angiotensin antagonist in symptomatic HF patients (PARADIGM-HF [Prospective Comparison of Angiotensin Receptor Neprilysin Inhibitor With an Angiotensin-Converting Enzyme Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure; n=8399] and PARAGON-HF [Prospective Comparison of Angiotensin-Converting Enzyme Inhibitor With Angiotensin Receptors Blockers Global Outcomes in Heart Failure With Preserved Ejection Fraction; n=4796]). We decomposed the previously validated Meta-Analysis Global Group in Chronic Heart Failure risk score into cardiac (left ventricular ejection fraction, New York Heart Association class, blood pressure, time since HF diagnosis, HF medications), noncardiac comorbid (body mass index, creatinine, diabetes, chronic obstructive pulmonary disease, smoking), and demographic (age, gender) categories. Based on these domains, an index representing the balance of cardiac to noncardiac comorbid burden was created (cardiac-comorbid index). Clinical outcomes were time to first HF hospitalization or cardiovascular deaths and all-cause mortality. RESULTS: Higher scores of the cardiac domain were observed in PARADIGM-HF (10 [7-13] versus 5 [3-6], P<0.001) and higher scores of the demographic domain in PARAGON-HF (10 [8-13] versus 5 [2-9], P<0.001). In PARADIGM-HF, the contribution of the cardiac domain to clinical outcomes was greater than the noncardiac domain (P<0.001), while in PARAGON-HF the attributable risk of the comorbid and demographic categories predominated. Individual scores from each sub-domain were linearly associated with the risk of clinical outcomes (P<0.001). Beneficial effects of sacubitril/valsartan were observed in patients with preponderance of cardiac over noncardiac comorbid burden (cardiac-comorbid index >5 points), suggesting a significant treatment effect modification (interaction P<0.05 for both outcomes). CONCLUSIONS: Domains of disease burden are clinically relevant features that influence the prognosis and treatment of patients with HF. The therapeutic benefits of sacubitril/valsartan vary according to the balance of components of disease burden, across different ranges of left ventricular ejection fraction.

Experimental model of congestive heart failure induced by transverse aortic constriction in BALB/c mice.

INTRODUCTION: Murine transverse aortic constriction (TAC) is a frequently used model of pressure overload-induced left ventricular (LV) remodeling. However, there is considerable variability in disease progression to overt heart failure (HF) development in the most commonly used strain of mice (i.e., C57BL/6J). Studies have shown that C57BL/6J mice are more resistant than BALB/c mice to congestive HF development following myocardial infarction or angiotensin II-induced hypertension. Therefore, we tested the hypothesis that BALB/c mice may be a better research model to study TAC-induced progressive HF. METHODS: Following sham or TAC surgery in both C57BL/6J (n = 29) and BALB/c (n = 32) mice, we evaluated cardiac dimensions and function by echocardiography at 2, 4, 8, and 12 weeks and monitored survival throughout the study. In a separate cohort of BALB/c mice, we repeated the study in the presence of the angiotensin converting enzyme inhibitor enalapril or a vehicle initiated 2 weeks post-TAC and administered for 6 weeks. At the end of the studies, we assessed the heart weight, lung weight, and plasma brain natriuretic peptide (BNP) concentration. RESULTS: Following comparable TAC, both C57BL/6J and BALB/c mice showed significant LV remodeling compared with the sham control mice. BALB/c mice progressively developed systolic dysfunction, LV dilation, lung congestion, and significant mortality, whereas C57BL/6J mice did not. In the separate cohort of BALB/c TAC mice, enalapril significantly reduced the heart weight, lung weight, and plasma BNP concentration and improved survival compared with the vehicle control. DISCUSSION: BALB/c mice uniformly developed congestive HF post-TAC. Enalapril was effective in improving survival and reducing lung congestion in this model. The data suggest that BALB/c mice may be a better research tool than C57BL/6J mice to study TAC-induced disease progression to HF and to evaluate novel therapies for the treatment of chronic HF with reduced ejection fraction.

Could angiotensin-modulating drugs be relevant for the treatment of Trypanosoma cruzi infection? A systematic review of preclinical and clinical evidence.

Although leucocytes are targets of renin-angiotensin system (RAS) effector molecules and RAS-modulating drugs exert immunomodulatory effects, their impact on Trypanosoma cruzi infection remains poorly understood. By using the framework of a systematic review, we integrated the preclinical and clinical evidence to investigate the relevance of angiotensin-inhibiting drugs on T. cruzi infections. From a comprehensive and structured search in biomedical databases, only original studies were analysed. In preclinical and clinical studies, captopril, enalapril and losartan were RAS-modulating drugs used. The main in vitro findings indicated that these drugs increased parasite uptake per host cells, IL-12 expression by infected dendritic cells and IFN-γ by T lymphocytes, in addition to attenuating IL-10 and IL-17 production by CD8 + T cells. In animal models, reduced parasitaemia, tissue parasitism, leucocytes infiltration and mortality were often observed in T. cruzi-infected animals receiving RAS-modulating drugs. In patients with Chagas' disease, these drugs exerted a controversial impact on cytokine and hormone levels, and a limited effect on cardiovascular function. Considering a detailed evaluation of reporting and methodological quality, the current preclinical and clinical evidence is at high risk of bias, and we hope that our critical analysis will be useful in mitigating the risk of bias in further studies.

Comparative effectiveness of antihypertensive drugs prescribed in Ethiopian healthcare practice: A pilot prospective, randomized, open label study.

BACKGROUND: Previous research has been highly suggestive that patients of African ancestry are less responsive to beta-blockers and angiotensin converting enzyme inhibitors. However, clinical practice within Ethiopia has continued to recommend all drugs for treatment of hypertension despite the lack of evidentiary support. Therefore this study aims to compare the effectiveness of the three major antihypertensive drugs currently prescribed in an Ethiopian health care setting to further the potential for evidence based prescribing practices. METHODS: A prospective, randomized, open label comparative study was used to determine the mean reduction in blood pressure (primary outcome) and assess cardiovascular events (secondary outcomes) among patients receiving one or more of three common antihypertensive drugs (i.e., nifedipine, hydrochlorothiazide, and enalapril) in routine clinical practice between November 2016 and April 2017. Patients were followed for three months. Analysis was based on an intention-to-treat approach. One way analysis of covariance was used to compare the difference in therapeutic effectiveness in reducing blood pressure. RESULT: A total of 141 patients were randomized to one of three recipient groups-nifedipine (n = 47), enalapril (n = 47) or hydrochlorothiazide (n = 47). Three months after randomization, 44 patients in each group completed the follow-up. Patients randomized to nifedipine had significantly higher mean reduction in systolic blood pressure than those randomized to enalapril(p = 0.003) or hydrochlorothiazide(p = 0.036). The mean reduction in systolic blood pressure was -37.35(CI:-40, -34.2) in the nifedipine group; -30.3(CI: -33.5, -27.1) in patients receiving enalapril; and -32.1(CI:-35, -29.3) in patients assigned hydrochlorothiazide. However, nifedipine did not have a significance difference in reduction of mean diastolic blood pressure compared than those receiving enalapril (p = 0.57) or hydrochlorthiazide (p = 0.99). CONCLUSION: This study revealed that amongst the three drugs nifedipine was found to be the most effective drug in reduction of systolic blood pressure. Hydrochlorothiazide and enalapril did not show a difference in reduction of mean blood pressure. Further, long term randomized trials are highly recommended to inform revision of Ethiopia-centric hypertension treatment guidelines.

Angiotensin converting enzyme inhibitors enhance the hypotensive effects of propofol by increasing nitric oxide production.

Propofol anesthesia is usually accompanied by hypotension. Studies have shown that the hypotensive effects of propofol increase in patients treated with angiotensin-converting enzyme inhibitors (ACEi). Given that both propofol and ACEi affect nitric oxide (NO) signaling, the present study tested the hypothesis that ACEi treatment induces pronounced hypotensive responses to propofol by increasing NO bioavailability. In this study we evaluated 65 patients, divided into three groups: hypertensive patients chronically treated with ACEi (HT-ACEi; n = 21), hypertensive patients treated with other antihypertensive drugs instead of ACEi, such as angiotensin II receptor blockers, ß-blockers or diuretics (HT; n = 21) and healthy normotensive subjects (NT; n = 23). Venous blood samples were collected at baseline and after 10min of anesthesia with propofol 2mg/kg administrated intravenously by bolus injection. Hemodynamic parameters were recorded at each blood sample collection. Nitrite levels were determined by using an ozone-based chemiluminescence assay, while NOx (nitrites+nitrates) levels were measured by using the Griess reaction. Additionally, experimental approaches were used to validate our clinical findings. Higher decreases in blood pressure after propofol anesthesia were observed in HT-ACEi group as compared with those found in NT and HT groups. Consistently, rats treated with the ACEi enalapril showed more intense hypotensive responses to propofol. The hypotensive effects of propofol were associated with increased NO production in both clinical and experimental approaches. Enhanced increases in nitrite levels after propofol anesthesia were observed in HT-ACEi patients compared with NT and HT groups. Accordingly, rats treated with enalapril showed increased vascular NO formation after propofol anesthesia compared with rats receiving vehicle. Our data show that ACEi enhance the hypotensive responses to propofol anesthesia and increase nitrite concentrations. These findings suggest that increased NO bioavailability may account for the enhanced hypotensive effects of propofol in ACEi-treated patients.

Health-Related Quality of Life Outcomes in PARADIGM-HF.

BACKGROUND: Patients with heart failure and reduced ejection fraction have impaired health-related quality of life (HRQL) with variable responses to therapies that target mortality and heart failure hospitalizations. In PARADIGM-HF trial (Prospective Comparison of ARNI [Angiotensin Receptor-Neprilysin Inhibitor] With ACEI [Angiotensin-Converting-Enzyme Inhibitor] to Determine Impact on Global Mortality and Morbidity in Heart Failure), sacubitril/valsartan reduced morbidity and mortality compared with enalapril. Another major treatment goal is to improve HRQL. Given improvements in mortality with sacubitril/valsartan, this analysis provides comprehensive assessment of impact of therapy on HRQL in survivors only. METHODS AND RESULTS: Patients (after run-in phase) completed disease-specific HRQL using Kansas City Cardiomyopathy Questionnaire (KCCQ) at randomization, 4 month, 8 month, and annual visits. Changes in KCCQ scores were calculated using repeated measures analysis of covariance model that adjusted for treatment and baseline values (principal efficacy prespecified at 8 months). Among the 8399 patients enrolled in PARADIGM-HF, 7623 (91%) completed KCCQ scores at randomization with complete data at 8 months for 6881 patients (90% of baseline). At 8 months, sacubitril/valsartan group noted improvements in both KCCQ clinical summary score (+0.64 versus -0.29; P=0.008) and KCCQ overall summary score (+1.13 versus -0.14; P<0.001) in comparison to enalapril group and significantly less proportion of patients with deterioration (≥5 points decrease) of both KCCQ scores (27% versus 31%; P=0.01). Adjusted change scores demonstrated consistent improvements in sacubitril/valsartan compared with enalapril through 36 months. CONCLUSIONS: Change scores in KCCQ clinical summary scores and KCCQ overall summary scores were better in patients treated with sacubitril/valsartan compared with those treated with enalapril, with consistency in most domains, and persist during follow-up beyond 8 months. These findings demonstrate that sacubitril/valsartan leads to better HRQL in surviving patients with heart failure. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01035255.

Folic acid therapy reduces the risk of mortality associated with heavy proteinuria among hypertensive patients.

OBJECTIVE: We aimed to evaluate whether proteinuria and estimated glomerular filtration rate (eGFR) levels can modify the efficacy of folic acid therapy on the risk of all-cause mortality among hypertensive patients in the China Stroke Primary Prevention Trial, a randomized, double-blind, and controlled trial. METHODS: A total of 20 702 hypertensive patients without a history of major cardiovascular diseases were randomly assigned to a double-blind daily treatment of a single tablet containing 10-mg enalapril and 0.8-mg folic acid (n = 10 348), or 10-mg enalapril alone (n = 10 354). All-cause mortality, a prespecified endpoint of the China Stroke Primary Prevention Trial, was the main outcome in this analysis. RESULTS: Over a median treatment duration of 4.5 years, in the enalapril alone group, both heavy proteinuria [vs. absent, 10.8 vs. 2.7%; hazard ratio = 3.30; 95% confidence interval (CI): 2.10-5.18] and lower eGFR levels (<60 vs. ≥90 ml/min per 1.73 m, 13.0 vs. 2.2%; hazard ratio = 1.93; 95% CI: 1.19-3.12) were significantly associated with increased risk of all-cause mortality. Folic acid supplementation significantly reduced the risk of all-cause mortality in patients with heavy proteinuria (6.4% in the enalapril-folic acid vs. 10.8% in the enalapril alone group, hazard ratio = 0.49; 95% CI: 0.26-0.94), but not in those with absent or mild proteinuria (2.8 vs. 2.9%, hazard ratio = 0.99; 95% CI: 0.84-1.17; P for interaction = 0.040). However, eGFR levels did not significantly modify the effect of folic acid supplementation in reducing the risk of all-cause mortality (P for interaction = 0.228). CONCLUSION: Among hypertensive patients without a history of major cardiovascular diseases, folic acid therapy could reduce the mortality risk associated with heavy proteinuria.

Herbal and dietary supplements related to diarrhea and acute kidney injury: a case report.

Background There is very little evidence relating to the association of herbal medicine with diarrhea and the development of acute kidney injury (AKI). This study reports a case of diarrhea-induced AKI, possibly related to an individual ingesting copious amounts of homemade mixed fruit and herb puree. Case presentation A 45-year-old Thai man with diabetes had diarrhea for 2 days, as a result of taking high amounts of a puree made up of eight mixed fruits and herbs over a 3-day period. He developed dehydration and stage 2 AKI, with a doubling of his serum creatinine. He had been receiving enalapril, as a prescribed medication, over one year. After he stopped taking both the puree and enalapril, and received fluid replacement therapy, within a week his serum creatinine had gradually decreased. The combination of puree, enalapril and AKI may also have induced hyperkalemia in this patient. Furthermore, the patient developed hyperphosphatemia due to his worsening kidney function, exacerbated by regularly taking some dietary supplements containing high levels of phosphate. His serum levels of potassium and phosphate returned to normal within a week, once the patient stopped both the puree and all dietary supplements, and had begun receiving treatment for hyperkalemia. Results The mixed fruit and herb puree taken by this man may have led to his diarrhea due to its effect; particularly if the patient was taking a high concentration of such a drink. Both the puree and enalapril are likely to attenuate the progression of kidney function. The causal relationship between the puree and AKI was probable (5 scores) assessed by the modified Naranjo algorithm. This is the first case report, as far as the authors are aware, relating the drinking of a mixed fruit and herbal puree to diarrhea and AKI in a patient with diabetes. Conclusions This case can alert health care providers to the possibility that herbal medicine could induce diarrhea and develop acute kidney injury.

Folic acid therapy reduces serum uric acid in hypertensive patients: a substudy of the China Stroke Primary Prevention Trial (CSPPT).

Background: The effect of folic acid supplementation on uric acid (UA) concentrations is still inconclusive.Objective: We aimed to test the efficacy of folic acid therapy in reducing serum UA in hypertensive patients.Design: A total of 15,364 hypertensive patients were randomly assigned to a double-blind daily treatment with a single tablet that contained 10 mg enalapril and 0.8 mg folic acid (n = 7685) or 10 mg enalapril alone (n = 7679). The main outcome was the change in serum UA, which was defined as UA at the exit visit minus that at baseline. Secondary outcomes were as follows: 1) controlled hyperuricemia (UA concentration <357 µmol/L after treatment) and 2) new-onset hyperuricemia in participants with normal UA concentrations (<357 µmol/L).Results: After a median of 4.4 y of treatment, the mean ± SD UA concentration increased by 34.7 ± 72.5 µmol/L in the enalapril-alone group and by 30.7 ± 71.8 µmol/L in the enalapril-folic acid group, which resulted in a mean group difference of -4.0 µmol/L (95% CI: -6.5, -1.6 µmol/L; P = 0.001). Furthermore, compared with enalapril alone, enalapril-folic acid treatment showed an increase in controlled hyperuricemia (30.3% compared with 25.6%; OR: 1.31; 95% CI: 1.01, 1.70) and a decrease in new-onset hyperuricemia (15.0% compared with 16.3%; OR: 0.89; 95% CI: 0.79, 0.99). A greater beneficial effect was observed in subjects with hyperuricemia (P-interaction = 0.07) or higher concentrations of total homocysteine (tHcy) (P-interaction = 0.02) at baseline. Furthermore, there was a significant inverse relation (P < 0.001) between the reduction of tHcy and the change in UA concentrations.Conclusions: Enalapril-folic acid therapy, compared with enalapril alone, can significantly reduce the magnitude of the increase of UA concentrations in hypertensive adults. This trial was registered at clinicaltrials.gov as NCT00794885.

Effect of folic acid supplementation on cancer risk among adults with hypertension in China: A randomized clinical trial.

The relationship of folic acid supplementation with the risk of cancer remains inconclusive. We aimed to evaluate the effects of folic acid supplementation on cancer incidence among adults with hypertension without history of stroke or myocardial infarction (MI) in the China Stroke Primary Prevention Trial (CSPPT). A total of 20,702 hypertensive adults without history of stroke or MI, stratified by MTHFR C677T genotypes(CC, CT and TT), were randomly assigned to receive double-blind daily treatment with a single pill containing 10 mg enalapril and 0.8 mg folic acid(n = 10,348) or a pill containing 10 mg enalapril alone(n = 10,354). During a median treatment duration of 4.5 years, cancer occurred in 116 participants(1.12%) in the enalapril-folic acid group versus 116 participants(1.12%) in the enalapril group (HR, 1.00; 95%CI, 0.77-1.29). There was also no significant difference in the HRs for specific types of cancer(esophageal, gastric, breast, lung, colorectal, head and neck, liver and gynecologic cancer or lymphoma) or cancer mortality(HR, 1.05; 95%CI, 0.69-1.58). For participants not receiving folic acid treatment (enalapril only group), MTHFR 677 TT genotype was an independent predictor of total cancer risk compared to CC genotype (HR, 1.86; 95%CI, 1.07-3.22). Consistently, a beneficial effect was observed in participants with MTHFR TT genotype and low folate levels (<9.0 ng/mL; HR, 0.47; 95%CI, 0.24-0.94). There is no evidence that 0.8 mg daily folic acid supplementation can increase the risk of cancer incidence among adults with hypertension without history of stroke or MI in China. Our data suggest a protective effect in participants with MTHFR TT genotype and low folate levels.

Mancha hiperpigmentada muy pruriginosa en la espalda / Highly pigmented stain on the back

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Renin-Angiotensin-Aldosterone Signaling Inhibitors-Losartan, Enalapril, and Cardosten-Prevent Infarction-induced Heart Failure Development in Rats.

CONTEXT: The activation of the renin-angiotensin-aldosterone system (RAAS) plays an important role in the pathophysiology of congestive heart failure, which is the reason that angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin 2 receptor blockers (ARBs) have become established therapies for heart failure. However, it is still not known whether preventive treatment with losartan or enalapril can reduce symptoms of infarction-induced heart failure. Ultra-low dose (ULD) drug therapy is thought to exert specific activity, with a lower chance of side effects. OBJECTIVES • The research team had hypothesized that preventive treatment with inhibitors of RAAS signaling-losartan, enalapril, and a preparation of a ULD antibody (ie, cardosten), which target the angiotensin type 1 (AT1) receptor-might alleviate pathological hypertrophy and/or functional decline in infarction-induced heart failure. METHODS: The research team treated male Wistar rats orally for 30 d with 20 mg/kg of losartan, 10 mg/kg enalapril, 5 or 7.5 mL/kg of cardosten, or a control solution, started 1 d prior to permanent coronary occlusion. A sham-operated group functioned as a second control group. SETTINGS: The study was conducted at the Department of Biochemistry of the Faculty of Medicine at the University of Szeged in Szeged, Hungary, in cooperation with the Pharmahungary Group, also in Szeged, Hungary, and with OOO "NPF" Materia Medica Holding Ltd in Moscow, Russia. OUTCOME MEASURES: To determine cardiac functional parameters in vivo, the research team inserted a catheter into the left ventricle of the rats and measured the parameters of ventricular pressure, and cardiac output was determined by thermodilution. Morphological parameters were measured after heart isolation in transverse sections by a digital caliper. RESULTS: A total of 30 d after permanent coronary ligation, both losartan and enalapril, significantly decreased mean arterial blood pressure (MABP), attenuated the development of the left-ventricular anterior-wall and septum hypertrophy, and reduced scar thickness compared with the vehicle control group. The deterioration of cardiac output and the increase in total peripheral resistance (TPR) due to coronary ligation were significantly inhibited by both losartan and enalapril. The effects of cardosten were comparable with those of losartan and enalapril on cardiac morphology, left ventricular function, and TPR; however, it did not influence MABP. Moreover, in contrast to losartan and enalapril, cardosten did not decrease the rate of survival. CONCLUSIONS: The study was the first to have demonstrated that preventive treatment with losartan, enalapril, or cardosten can attenuate pathological hypertrophy in infarction-induced heart failure in rats.

Effect of folic acid supplementation on risk of new-onset diabetes in adults with hypertension in China: Findings from the China Stroke Primary Prevention Trial (CSPPT).

BACKGROUND: The aim of the present post hoc analysis of the China Stroke Primary Prevention Trial (CSPPT) was to evaluate the effect of folic acid supplementation on the risk of new-onset diabetes in hypertensive adults in China. METHODS: In all, 20 702 hypertensive adults with no history of stroke and/or myocardial infarction (MI) were randomly assigned to receive double-blind daily treatment with tablets containing either: (i) 10 mg enalapril and 0.8 mg folic acid (n = 10 348); or (ii) 10 mg enalapril alone (n = 10 354). New-onset diabetes was defined as either self-reported physician-diagnosed diabetes or the use of glucose-lowering drugs during the follow-up period of the CSPPT. RESULTS: Over a median treatment duration of 4.5 years, new-onset diabetes occurred in 198 (2.0%) and 214 (2.1%) subjects in the enalapril-folic acid and enalapril groups, respectively (hazard ratio [HR] 0.92; 95% confidence interval [CI] 0.76-1.12). Similar results were observed when analyses were limited to subjects with baseline fasting glucose (FG) <7.0 mmol/L (HR 0.85; 95% CI 0.62-1.14). Furthermore, there was no significant group difference in: (i) the risk of new-onset FG ≥7.0 mmol/L (defined as FG <7.0 at baseline and ≥7.0 mmol/L at the last visit; relative risk [RR] 1.07; 95% CI 0.96-1.20); or (ii) the composite of new-onset diabetes or new-onset FG ≥7.0 mmol/L (RR = 1.06; 95% CI 0.95-1.19). CONCLUSIONS: Among adults with hypertension with no history of stroke and/or MI in China, folic acid supplementation had no significant effect on the risk of new-onset diabetes.

Rat Models of Diet-Induced Obesity and High Fat/Low Dose Streptozotocin Type 2 Diabetes: Effect of Reversal of High Fat Diet Compared to Treatment with Enalapril or Menhaden Oil on Glucose Utilization and Neuropathic Endpoints.

We examined whether reversal of high fat diet, stimulating weight loss, compared to two treatments previously shown to have beneficial effects, could improve glucose utilization and peripheral neuropathy in animal models of obesity and type 2 diabetes. Rats were fed a high fat diet and treated with a low dose of streptozotocin to create models of diet induced obesity or type 2 diabetes, respectively. Afterwards, rats were transferred to a normal diet or treated with enalapril or dietary enrichment with menhaden oil for 12 weeks. Obesity and to a greater extent type 2 diabetes were associated with impaired glucose utilization and peripheral neuropathy. Placing obese rats on a normal diet improved glucose utilization. Steatosis but not peripheral neuropathy was improved after placing obese or diabetic rats on a normal diet. Treating obese and diabetic rats with enalapril or a menhaden oil enriched diet generally improved peripheral neuropathy endpoints. In summary, dietary improvement with weight loss in obese or type 2 diabetic rats was not sufficient to correct peripheral neuropathy. These results further stress the need for discovery of a comprehensive treatment for peripheral neuropathy.

Effect of combination therapy consisting of enalapril, α-lipoic acid, and menhaden oil on diabetic neuropathy in a high fat/low dose streptozotocin treated rat.

We have previously demonstrated that treating diabetic rats with enalapril, an angiotensin converting enzyme (ACE) inhibitor, α-lipoic acid, an antioxidant, or menhaden oil, a natural source of omega-3 fatty acids can partially improve diabetic peripheral neuropathy. In this study we sought to determine the efficacy of combining these three treatments on vascular and neural complications in a high fat fed low dose streptozotocin treated rat, a model of type 2 diabetes. Rats were fed a high fat diet for 8 weeks followed by a 30 mg/kg dose of streptozotocin. Eight weeks after the onset of hyperglycemia diabetic rats were treated with a combination of enalapril, α-lipoic acid and menhaden oil. Diabetic rats not receiving treatment were continued on the high fat diet. Glucose clearance was impaired in diabetic rats and significantly improved with treatment. Diabetes caused steatosis, elevated serum lipid levels, slowing of motor and sensory nerve conduction, thermal hypoalgesia, reduction in intraepidermal nerve fiber profiles, decrease in cornea sub-basal nerve fiber length and corneal sensitivity and impairment in vascular relaxation to acetylcholine and calcitonin gene-related peptide in epineurial arterioles of the sciatic nerve. Treating diabetic rats with the combination of enalapril, α-lipoic acid and menhaden oil reversed all these deficits to near control levels except for motor nerve conduction velocity which was also significantly improved compared to diabetic rats but remained significantly decreased compared to control rats. These studies suggest that a combination therapeutic approach may be most effective for treating vascular and neural complications of type 2 diabetes.