Angiotensin-converting Inhibitors Research Articles

Genotype/phenotype relationship in mild congenital nephrotic syndrome

Introduction. Congenital nephrotic syndrome (CNS) is a severe disease complicated by hemodynamic instability, infections, thrombosis, growth disorder and progressive renal failure leading to end-stage kidney disease within a few years. The mutations of NPHS1 encoding nephrin is the most common cause of the CNS. The aim of this paper was to present a patient with NPHS1 homozygous Ser350Pro missense mutation that unexpectedly caused a mild clinical course of CNS. Case outline. We present a female patient who was diagnosed with severe nephrotic syndrome at 2.5 months of age. While waiting for the result of the genetic analysis, she was treated unsuccessfully with corticosteroids and angiotensin converting inhibitor (ACEI) four weeks, and then under Cyclosporine A (CsA) and ACEI she achieved partial remission within three months. Initially, the milder clinical course was explained by the positive effect of CsA, but as partial remission persisted even after the discontinuation of this drug, it remains unclear what influenced the improvement of the clinical course of the disease. At the time of writing this paper, the patient was 10.9 years old with normal serum creatinine, normal blood pressure and non-nephrotic proteinuria. Conclusion. NPHS1 homozygous Ser350Pro missense mutation may be presented by a mild clinical course of CNS. Further studies are needed to clarify a more predictive CNS genotype/phenotype relationship.

Pharmacogenomics of Hypertension in Africa: Paving the Way for a Pharmacogenetic-Based Approach for the Treatment of Hypertension in Africans.

In Africa, the burden of hypertension has been rising at an alarming rate for the last two decades and is a major cause for cardiovascular disease (CVD) mortality and morbidity. Hypertension is characterised by elevated blood pressure (BP) ≥ 140/90 mmHg. Current hypertension guidelines recommend the use of antihypertensives belonging to the following classes: calcium channel blockers (CCB), angiotensin converting inhibitors (ACEI), angiotensin receptor blockers (ARB), diuretics, β-blockers, and mineralocorticoid receptor antagonists (MRAs), to manage hypertension. Still, a considerable number of hypertensives in Africa have their BP uncontrolled due to poor drug response and remain at the risk of CVD events. Genetic factors are a major contributing factor, accounting for 20% to 80% of individual variability in therapy and poor response. Poor response to antihypertensive drug therapy is characterised by elevated BPs and occurrence of adverse drug reactions (ADRs). As a result, there have been numerous studies which have examined the role of genetic variation and its influence on antihypertensive drug response. These studies are predominantly carried out in non-African populations, including Europeans and Asians, with few or no Africans participating. It is important to note that the greatest genetic diversity is observed in African populations as well as the highest prevalence of hypertension. As a result, this warrants a need to focus on how genetic variation affects response to therapeutic interventions used to manage hypertension in African populations. In this paper, we discuss the implications of genetic diversity in CYP11B2, GRK4, NEDD4L, NPPA, SCNN1B, UMOD, CYP411, WNK, CYP3A4/5, ACE, ADBR1/2, GNB3, NOS3, B2, BEST3, SLC25A31, LRRC15 genes, and chromosome 12q loci on hypertension susceptibility and response to antihypertensive therapy. We show that African populations are poorly explored genetically, and for the few characterised genes, they exhibit qualitative and quantitative differences in the profile of pharmacogene variants when compared to other ethnic groups. We conclude by proposing prioritization of pharmacogenetics research in Africa and possible adoption of pharmacogenetic-guided therapies for hypertension in African patients. Finally, we outline the implications, challenges, and opportunities these studies present for populations of non-European descent.

Hypertension and COVID-19: Current Evidence and Perspectives.

Coronavirus disease 2019 (COVID-19) outbreak, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), represents a real challenge for health-care systems worldwide. Male sex, older age and the coexistence of chronic comorbidities have been described as the most relevant conditions associated with a worse prognosis. Early reports suggested that hypertension might represent a risk factor for susceptibility to SARS-CoV-2 infection, a more severe course of COVID-19 and increased COVID-19-related deaths. Nevertheless, the independent role of hypertension remains under debate, since hypertension is often associated with the older age and other cardiovascular (CV) risk factors in the general population, which may also contribute to the SARS-Cov-2 infection and COVID-19. Moreover, the role of antihypertensive drugs, primarily angiotensin-converting inhibitors (ACEIs) and ARBs (angiotensin receptor blockers) in COVID-19 development and outcome appears controversial. Indeed, preclinical studies using these classes of drugs have suggested a potential upregulation of angiotensin-converting-enzyme 2 (ACE2) which is the key binding receptor promoting cell entry of SARS-CoV-2 in the organism. Renin–angiotensin system (RAS) blockers may potentially upregulate ACE2, hence, it has been initially hypothesized that these agents might contribute to a higher risk of SARS-CoV-2 infection and progressive course of COVID-19. However, several clinical reports do not support a detrimental role of RAS blockers in COVID-19, and an intense debate about the withdrawal or maintenance of chronic therapy with ACEi/ARB has been developed. In this review we will discuss the available evidence on the role of hypertension and antihypertensive drugs on SARS-CoV-2 infection and COVID-19 development.

The mineralocorticoid receptor blocker spironolactone lowers plasma interferon-γ and interleukin-6 in patients with type 2 diabetes and treatment-resistant hypertension.

The mineralocorticoid receptor antagonist spironolactone lowers blood pressure in patients with resistant hypertension despite antihypertensive treatment with angiotensin-converting inhibitors (ACEi) and angiotensin-II receptor blockers (ARB). In preclinical studies, spironolactone suppresses pro-hypertensive interleukin 17A (IL-17A). Plasma samples were analysed from a randomized, double-blind placebo-controlled trial with spironolactone given to patients with type 2 diabetes mellitus (T2DM) and resistant hypertension on three antihypertensive drugs. We tested the hypothesis that spironolactone-induced antihypertensive effects are associated with suppression of IL-17A and related cytokines. Interferon-γ (IFN-γ), IL-17A, tumor necrosis factor-α (TNF-α), IL-6, IL-1β and IL-10 were assessed in plasma with immunoassay in samples before and after 16 weeks of treatment with placebo or spironolactone (12.5-25-50 mg/day). Spironolactone significantly reduced plasma IFN-γ and IL-6 while IL-17A, TNF-α, IL-1β and IL-10 were unchanged. IL-6 was more sensitive to higher doses of spironolactone. At baseline, serum aldosterone correlated positively with diastolic night blood pressure. Urine albumin/creatinine-ratios correlated positively with plasma IL-6 at baseline. There were no relations between aldosterone and cytokine concentrations at baseline; between cytokine concentration and blood pressure at baseline; and between cytokine concentration decrease and blood pressure decrease, except for IFN-γ, after treatment. The spironolactone-induced elevation in plasma potassium related inversely to blood pressure but not to changes in cytokines. In macrophages in vitro, spironolactone suppressed lipopolysaccharide (LPS)-induced TNF-α, IL-6, IL-1β and IL-10 levels. The antihypertensive action of spironolactone in resistant hypertensive patients is associated with suppressed IFN-γ and IL-6 and not IL-17A. Spironolactone exerts anti-inflammatory actions in vivo on macrophages and T-cells.

The efficacy of the combined antihypertensive and statin therapy in patients with hypertension and excessive body mass

Objective — to assess the effects of the of the combined therapy with fixed combinations of antihypertensive medications in combination with statin on the indices of systemic hemodynamics, lipid profile, carbohydrate metabolism and adipocytokines production in overweight patients with essential hypertension of II stage.Materials and methods. The investigation involved in-hospital 64 hypertensive (stage II) patients, the mean age 59.0 (48.0 — 63.0) years with excessive body mass (body mass index > 25 kg/m2), who were treated in the therapeutic department No. 1 of the medical and sanitary unit of JSC “Motor Sich” in the years 2016 — 2018. and met the study inclusion criteria. All patients underwent general clinical, laboratory and instrumental examination to verify the diagnosis, determine complications and comorbidities. The patients were randomized into two subgroups who were administered fixed combinations of antihypertensive drugs for 120 days. Patients of the first subgroup (n = 32) received a combined drug «Equator» («Gedeon Richter», Hungary) in an initial dose of 1 tablet (amlodipine — 5 mg and lisinopril — 10 mg) per day, patients of the second subgroup (n = 32) received Valodip (KRKA, Slovenia) in an initial dose of 1 tablet (amlodipine — 5 mg and valsartan — 80 mg) per day. Within 2 weeks, the dose of drugs was adjusted if necessary. All patients were administered Rosuvastatin (Roxera, KRKA) in a dose of 10 mg/day.Results. The change in the doses wasn’t required for 10 (31.3 %) patients from the first subgroup and 13 (40.6 %) from the second subgroup; for the rest of patients, the doses of drugs were increased as follows: Equator (amlodipine — 5 mg and lisinopril — 20 mg) 1 tablet per day and «Valodip» (amlodipine — 5 mg and valsartan — 160 mg) 1 tablet per day. The target blood pressure level (130/85 mm Hg) was achieved in 24 (75.0 %) patients in the first group and in 26 (81.3 %) in the second. During treatment in both subgroups, the following positive changes were observed: in systemic hemodynamic parameters there were normalization of systolic and diastolic blood pressure and improved cardiac pumping function; in lipid spectrum — the decreased levels of total cholesterol, low-density lipoprotein cholesterol against the background of an increase in high-density lipoprotein cholesterol. Moreover the carbohydrate metabolism improved (fasting blood glucose decreased) and adipocytes production normalized — the levels of proinflammatory cytokines (interleukin-1β (IL-1β) and tumor necrosis factor-α) decreased and anti-inflammatory IL-10, adiponectin increased.Conclusions. The reduced production of pro-inflammatory and increased production of anti-inflammatory cytokines and adiponectin against the background of normalization of the indices of systemic hemodynamics, the decrease of pro-atherogenic and raise in the antiatherogenic fraction of blood lipids, reduction of the glycemia level in the patients with hypertension and excessive body mass under the influence of the therapy with fixed combinations of antihypertensive drugs with the use of both angiotensin-converting inhibitors and sartans, with the addition of statins, showed the efficacy of such therapy and its capability to considerably reduce the cardiovascular risk in this category of patients.

Possible contribution of the neprilysin/ACE pathway to sepsis in mice

AimOmapatrilat is an antagonist of angiotensin-converting (ACE) and neprilysin-neuropeptidase (NEP) enzymes. The aim of our study is to show that omapatrilat may have beneficial effects as a treatment for polymicrobial sepsis. Main methodsA cecal ligation and puncture (CLP) sepsis model was used to evaluate 10 and 20 mg/kg doses of omapatrilat in mice (n = 30) fasted for 12 h. The lungs were removed 12 h after CLP, and lung levels of cytokines (tumor necrosis factor-alpha [TNF-α], interleukin-6 [IL-6], NF-κB), iNOS and eNOS mRNA expression, GSH and MDA levels, and ACE and NEP activities were determined. Histopathological examinations were also performed. Key findingsOmapatrilat treatment provided a dose-dependent reduction in oxidative stress and inflammatory parameters in lung tissues. Omapatrilat administration decreased lung iNOS and eNOS mRNA levels at 20 mg/kg dose. Histopathological analysis revealed a decline in the thickening and edema areas in the alveolar septa in the Sepsis+OMA20 group. SignificanceOmapatrilat, a dual ACE and NEP inhibitor, protected lung tissue from sepsis damage by reducing ACE and NEP activities, by decreasing the mRNA expression levels of pro-inflammatory cytokines (TNF-α, IL-6, and NF-κB), by suppressing leukocyte infiltration and edema, by restoring iNOS and eNOS levels, and by restoring SOD activity and GSH and MDA levels, thereby reducing oxidative stress.

Interpreting stimulated plasma renin and aldosterone to select physiologically individualized therapy for resistant hypertension: importance of the class of stimulating drugs.

In the treatment of resistant hypertension, physiologically individualized therapy based on phenotyping with plasma renin activity (PRA) and plasma aldosterone significantly improves blood pressure control. Patients with a low-renin/low aldosterone (Liddle) phenotype respond best to amiloride, while those with low-renin/high aldosterone respond best to aldosterone antagonists, and those with high renin/high aldosterone (renal phenotype) respond best to angiotensin receptor blockers (ARB). However, it is important to measure PRA in a stimulated condition to distinguish between low levels due to high salt intake, licorice or nonsteroidal inflammatory drugs and low levels due to suppression by excess aldosterone secretion or renal tubular genetic variants causing retention of salt and water (Liddle phenotype). In the past, both diuretics and angiotensin converting inhibitors (ACEi) have been used for this purpose, and it has been assumed that these classes of drugs are equivalent. In this study of 2896 patients with hypertension, we evaluated that assumption. We found important differences among diuretics alone, ACEi/ARB alone, and ACEi/ARB + diuretics, which all stimulated PRA. However, ACEi/ARB lowers plasma aldosterone, and beta blockers lower PRA. Among patients with systolic pressure ≥ 180 mmHg ± diastolic pressure ≥ 100 mmHg stimulated only by diuretics, the phenotypes were 25% Liddle, 38% IA, 8.7% renal, and 28.3% mixed. In choosing physiologically individualized therapy based on PRA and aldosterone, it is important to consider the classes of stimulating drugs. Phenotypes are best distinguished by taking into account the aldosterone/PRA ratio in addition to the levels of PRA and aldosterone.

A REVIEW ON ANALYTICAL METHOD DEVELOPMENT AND VALIDATION OF CALCIUM CHANNEL BLOCKERS AND ANGIOTENSIN- CONVERTING ENZYME INHIBITORS IN BULK AND PHARMACETICAL FORMULATION

A simple, economical and rapid by UV detector and PDA Detector was used for Estimation of Trandolapril and Verapamil in combination and other drugs in various Pharmaceutical formulation. Calcium channel blockers(CCBs) and angiotensin- converting enzyme (ACE) inhibitors has been developed and fully validated by High performance liquid Chromatographic Methods. Calcium channel blockers (CCBs) or Calcium antagonists are among the most widely used drugs in cardiovascular medicine and hypertension also in angina. CCBs promote vasodilator activity by reducing calcium influx into vascular smooth muscle cells by interfering with calcium channels in the cell membrane. Trandolapril is a potent nonsulfhydryl and dicarboxyl containing Angiotensin converting inhibitor (ACE). Trandolapril used to treatment of hypertension appears to result the inhibition of tissue ACE activity and to improve survival myocardial infarction thereby reduce angiotensin II formation.
 It includes drugs like Trandolapril, Norverapamil, Nifedipine, Verapamil. This Review enlists different method Developed, Validated and determination of Calcium channel blockers and angiotensin- converting enzyme inhibitors Like, RP-HPLC, LC-MS/MS and HPLC UV- Spectophotometric method. This method was also validated for various validation terms indicates that precise, accurate, linearly, and limit of Detection and limit of Quantitation as per ICH guidelines.
 Keywords: HPLC Chromatography, Calcium Channel blocker, angiotensin- converting enzyme (ACE) inhibitors, Hypertension, Validation etc.

Angiotensin-converting enzyme inhibitors or angiotensin receptor blocker monotherapy retard deterioration of renal function in Taiwanese chronic kidney disease population

It remains unclear how different uses of angiotensin-converting inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) influence the progression of chronic kidney disease (CKD). This study explored CKD progression in a multicentre, longitudinal cohort study that included 2639 patients with CKD stage 1–5 and hypertension. Patients treated with ACEI or ARB for ≥90 days during a 6-mo period comprised the study group, or no treatment, comprised the control group. The study group was subdivided on the basis of treatment: ACEI monotherapy or ARB monotherapy. Progression of renal deterioration was defined by an average eGFR decline of more than 5 mL/min/1.73 m2/yr or the commencement of dialysis. With at least 1-year follow up, a progression of renal deterioration was demonstrated in 29.70% of the control group and 25.09% of the study group. Patients in the study group had significantly reduced progression of CKD with adjusted odds ratio 0.79 (95% confidence interval: 0.63–0.99). However, when ACEI monotherapy and ARB monotherapy were analyzed separately, none of their associations with CKD progression was statistically significant. In conclusion, ACEI or ARB monotherapy may retard the deterioration of renal function among patients with CKD and hypertension.

Study of Interaction Between Angiotensin-converting Enzyme ACE and Diuretic Inhibitor by Molecular Modeling

Background: Molecular modeling methods are now used routinely to investigate the structure, dynamics, surface properties, and thermodynamics of inorganic, biological, and polymeric systems. Most current drugs target enzymes. This theoretical approach enables to predict the mode of interaction of a ligand with its receptor. The inhibition of Angiotensin-converting enzyme (ACE) is an important approach in the treatment of Heart failure (HF). The three families of Diuretic are used for inhibiting ACE. Our work is the study of molecular interaction between the enzyme (Angiotensin Converting) and the substrates (inihibitor for ACE). Various tools of molecular modeling are used to carry out this work (molecular mechanics, molecular dynamics and molecular docking) (MOE). The introduction of bulky groups causes a conformational rearrangement in thea ctive site pocket, which will probably be reinforced and thus complement its activity. The results obtained from this work, in which the inhibitions of Angiotensin Converting by molecular modeling methods have been demonstrated. In conclusion, taking into account the results obtained in this study, inhibition of Angiotensin Converting by molecular modeling methods has been elucidated, which allow us to conclude that Bumetanide (loopDiuretic) when water is included in the docking simulation has a better inhibition of Angiotensin Converting.

Clinical outcomes following the surgery of new autologous arteriovenous fistulas proximal to the failed ones in end-stage renal disease patients: a retrospective cohort study

Background: Most prior studies have explored surgery for the treatment of failed autologous arteriovenous fistulas (AVFs) with limited follow-up times and a lack of end point mortality. Accordingly, we conducted a retrospective cohort study to evaluate the clinical outcomes of the surgery of new AVF proximal to the failed forearm AVF.Methods: In this study, 538 end-stage renal disease patients (group A, 418 with primary AVF; and group B, 120 with failed AVF) were consecutively enrolled between January 2013 and June 2016, with a median follow-up time of 41 months. Primary and secondary patency, all-cause mortality, and risk factors associated with AVF failure were explored by the Kaplan–Meier method or Cox proportional hazards model.Results: In group A (n = 418), the primary and secondary patencies of AVF were 85.6% vs. 96.8%, 79.7% vs. 95.0%, 75.1% vs.93.9%, 73.2% vs. 93.6% and 73.2% vs. 93.6% at 12, 24, 36, 48 and 60 months, respectively. The primary patencies of AVF in group B were 95.0%, 91.7%, 89.2%, 88.3% and 88.3% at 12, 24, 36, 48 and 60 months, respectively. After adjusting for potential confounders, age, angiotensin-converting inhibitors or angiotensin-receptor blockers (anti-RAAS) drugs and D-dimer were independent predictors of AVF failure. However, there were no differences between functional and failed AVF regarding all-cause mortality.Conclusions: The study revealed that the primary and secondary patiencies of the surgery of new AVF proximal to the failed ones were ideal operations to restore failed forearm AVF.

The effectiveness of combination antihypertensive therapy in patients with arterial hypertension and additional risk factors: obesity and obstructive sleep apnea syndrome.

To study the effectiveness of a fixed combination of perindopril and amlodipine, with the subsequent addition of indapamide-retard in male patients with arterial hypertension (AH), obesity and severe sleep apnea (OSAS). The study included 43 male patients in whom antihypertensive therapy titration was performed to achieve target blood pressure values with a fixed combination of calcium antagonist amlodipine (10 mg) and an angiotensin-converting inhibitor perindopril (5-10 mg) and indapamide-retard. At baseline and after 4-6 weeks, the effectiveness of antihypertensive therapy was monitored according to clinical measurements and ambulatory blood pressure monitoring (ABPM). An assessment of the carotid-femoral pulse wave velocity (cfPWV), aortic PWV (aoPWV), and ankle-brachial PWV (abPWV) was performed. Target blood pressure values (according to clinical blood pressure, 24-hour blood pressure monitoring) during therapy with amlodipine 10 mg and perindopril 10 mg reached 65% of patients and another 30% reached target blood pressure when adding indapamide-retard 1.5 mg, that is - 95% of all patients included in the study. Upon reaching the target blood pressure values, a significant decrease in cfPWV, aoPWV and abPWV was observed. The fixed combination of perindopril arginine and amplodipine, with the addition of indapamide retard in male patients with hypertension 1st degree in the presence of obesity and severe OSAS allows to reach effective control of blood pressure and improve the elastic properties of large arteries, which can lead to a favorable organoprotective effect in this category of patients.

TPA-Induced Angioedema in a Patient Taking Angiotensin Converting Enzyme Inhibitors: A Case Report and Review of the Literature

SESSION TITLE: Nervous System Disorders in the ICU 1 SESSION TYPE: Affiliate Case Report Poster PRESENTED ON: Tuesday, October 31, 2017 at 01:30 PM - 02:30 PM INTRODUCTION: Asymmetric Orolingual Angioedema (AOA) is a rare, but important and potentially fatal adverse drug reaction that requires prompt recognition. We present a case of AOA in a 96-year-old woman after receiving tissue plasminogen activator (tPA). AOA is characterized by often unilateral swelling of the tongue and lips that in severe cases can result in airway obstruction. In this report, we describe a patient on angiotensin converting enzyme inhibitor (ACEI) who presented with angioedema after tPA administration. CASE PRESENTATION: This is a 96 year old female with a past medical history of two transient ischemic attacks, hypertension on lisinopril, presenting with 2 hours of right sided hemiparesis and slurred speech. In the emergency room, patient’s neurologic status continued to decline to severe aphasia, right upper and lower flaccidity. NIHSS score was 20. Stroke code was activated and computed tomography of the head without contrast revealed no acute hemorrhage. tPA was administered and 11 minutes later the nurse noticed partial swelling of left side of tongue and urticaria of the right cheek. Benadryl, Epinephrine and Solu-medrol were immediately given with no interval decrease in swelling. The decision was made to intubate for airway protection. During the course of her ICU stay, patient’s swelling improved and eventual MRI was found to be negative for acute stroke. DISCUSSION: In a systematic review of manuscripts between 1950-2012, only 41 cases of tPA induced angioedema are described with an incidence ranging from 1.7 to 5.8%. While thought to be very infrequent, a trend in the increase of primary stroke centers and therefore tPA use will likely lead to an increase in adverse event reports. The pathophysiologic mechanism of this disease is poorly understood, but thought to involve plasmin and complement mediated bradykinin release. While the relationship is unclear, reports have discovered an association of AOA with middle cerebral artery infarction and prior use of ACEI. Our patient was on Lisinopril at home, but was found not to have acute infarction on MRI. As the potential of catastrophic airway compromise is high, detailed history on ACEI use, previous tPA administration, and C1-esterase inhibitor deficiency must be taken. CONCLUSIONS: In conclusion, with the development and increasingly strong evidence of benefit of early fibrinolytics in acute ischemic stroke, tPA use has increased. This is the first case of AOA at our institution. In the setting of acute stroke in patients with previous angiotensin converting inhibitor use, close monitoring is necessary post-administration in case emergent intervention is necessary. Reference #1: Hill MD, et al. Hemi-orolingual angioedema and ACE inhibition after alteplase treatment of stroke. Neurology. 2003;60(9):1525-7. Reference #2: Hill MD, et al. Anaphylactoid reactions and angioedema during alteplase treatment of acute ischemic stroke. CMAJ. 2000;162(9):1281-4. DISCLOSURE: The following authors have nothing to disclose: Christian Castaneda, Samarth Beri, Sheelan Karim No Product/Research Disclosure Information

Physicians' experience and opinion on contraindications to allergen immunotherapy: The CONSIT survey

BackgroundAllergen immunotherapy (AIT) is the only disease-modifying treatment in allergy but several contraindications limit its use. ObjectiveTo collect the outcome of using AIT in theoretically contraindicated situations in real patients in the Contraindications to Specific ImmunoTherapy (CONSIT) survey. MethodsThe CONSIT is an electronic European Academy of Allergy and Clinical Immunology survey conducted to gather the safety outcomes of patients undergoing subcutaneous, sublingual, or venom AIT and the opinions of physicians on each of 17 selected conditions: children younger than 5 years; starting AIT during pregnancy; controlled severe asthma; arrhythmias; coronary disease; cancer; autoimmune disease; bone marrow and solid organ transplantation; human immunodeficiency virus and acquired immunodeficiency syndrome; previous anaphylaxis during AIT; use of β-blockers, angiotensin-converting inhibitors, cyclosporine, and methotrexate; and inability to communicate. Safety using AIT was reported in a 3-point scale: 1, “no problems”; 2, “minor problems” (requiring only dose modifications); and 3, “major problems” (AIT not tolerated). Each physician was asked about the degree of contraindication that each condition should have: no contraindication (score 1), relative contraindication (score 2), or absolute contraindication (score 3). ResultsFive hundred twenty physicians (75% Europeans, 89% allergists) reported on approximately 45,000 patients undergoing AIT with any of these conditions. Major problems were infrequent, occurring more frequently in patients with asthma (9.9%) and with previous anaphylaxis from AIT (9.5%). Regarding opinions, experienced physicians scored a significantly lower mean for all conditions than non-experienced physicians for all routes. ConclusionMajor problems were infrequent and experienced physicians were less likely to be restrictive in the use of AIT.

Patients with HFpEF and HFrEF have different clinical characteristics but similar prognosis: a retrospective cohort study.

BackgroundGlobally, heart failure (HF) has been recognized as one of the major cardiovascular disorder with high morbidity, mortality and considerable social impact. In Sub Saharan African countries, HF has turned out as a leading form of cardiovascular diseases, and has considerable socioeconomic impact. However, there are differences in clinical characteristics and survival status among patients with preserved (HFpEF) and reduced (HFrEF) ejection fraction. The aim of this study is to outline the clinical characteristics and medication profile, assess the survival status and prognostic factors of Ethiopian HF patients with HFrEF and HFpEF.MethodsA retrospective cohort study was carried out and we employed medical records of patient’s, admitted as a result of HF to the University of Gondar Referral Hospital in the period between December 02, 2010 and December 01, 2015 due to HF. Kaplan Meier curve was used to analyze the survival status and log rank test was used to compare the curves. Cox regression was used to analyze independent predictors of mortality in all HF patients.ResultsOf the 850 patients who were admitted due to HF, 311 patients met the inclusion criteria. Majority of the patients had HFpEF (52.73%) and tend to be women (76.22%). They predominantly had etiologies of valvular and hypertensive heart diseases, and took calcium channel blockers and anticoagulants. Conversely, patients with HFrEF had etiologies of ischemic heart disease and dilated cardiomyopathy and were prescribed angiotensine converting inhibitors (ACEI) and beta blockers. Kaplan Meier curves and Log rank test (p = 0.807) showed that there was no statistically significant difference in the mortality difference among patients with HFpEF and HFrEF. On the other hand, Cox regression analysis showed advanced age, lower sodium level, higher creatinine level and absence of medications like ACEI, spironolactone and statins independently predicted mortality in all HF patients.ConclusionsDifferent clinical characteristics were found in both groups of HF patients. There was no difference in survival outcome between patients with HFrEF and HFpEF.

Classes of antihypertensive agents and mortality in hypertensive patients with type 2 diabetes—Network meta-analysis of randomized trials

AimsThe aim of this study was to evaluate the effects of antihypertensive drug classes in mortality in patients with type 2 diabetes. MethodsMEDLINE, EMBASE, Clinical Trials and Cochrane Library were searched for randomized trials comparing thiazides, beta-blockers, calcium channel blockers (CCBs), angiotensin-converting inhibitors (ACEi) and angiotensin-receptor blockers (ARBs), alone or in combination for hypertension treatment in patients with type 2 diabetes. Outcomes were overall and cardiovascular mortality. Network meta-analysis was used to obtain pooled effect estimate. ResultsA total of 27 studies, comprising 49,418 participants, 5647 total and 1306 cardiovascular deaths were included. No differences in total or cardiovascular mortality were observed with isolated antihypertensive drug classes compared to each other or placebo. The ACEi and CCB combination showed evidence of reduction in cardiovascular mortality comparing to placebo [median HR, 95% credibility intervals: 0.16, 0.01–0.82], betablockers (0.20, 0.02–0.98), CCBs (0.21, 0.02–0.97) and ARBs (0.18, 0.02–0.91). In included trials, this combination was the treatment that most consistently achieved both lower systolic and diastolic end of study blood pressure. ConclusionsThere is no benefit of a single antihypertensive class in reduction of mortality in hypertensive patients with type 2 diabetes. Reduction of cardiovascular mortality observed in patients treated with ACEi and CCB combination may be related to lower blood pressure levels.

Valsartan/Sacubitril for Heart Failure

Valsartan/sacubitril (Entresto, Novartis) is a combination of the neprilysin inhibitor sacubitril and the angiotensin receptor antagonist valsartan. In July 2015, the US Food and Drug Administration (FDA) approved valsartan/sacubitril through the fast-track pathway for the treatment of patients with New York Heart Association class II through IV heart failure symptoms and a reduced ejection fraction. The approval was based on the results of a single phase 3 clinical trial (PARADIGM-HF)1 that included 8400 patients. In this trial, valsartan/sacubitril was associated with a 20% (hazard ratio, 0.80) decrease in the primary end point of death from cardiovascular cause or first hospitalization for heart failure (from 26.5% to 21.8%), when compared with the angiotensin-converting inhibitor enalapril, and a 16% (hazard ratio, 0.84) reduction in all-cause mortality (from 19.8% to 17.0%). However, recent translational science studies involving the central nervous system and the eye suggest that other effects of valsartan/sacubitril might influence its use in some patients.

Recent Developments in the Classification, Evaluation, Pathophysiology, and Management of Scleroderma Renal Crisis.

Scleroderma renal crisis (SRC) is an uncommon complication of systemic sclerosis. Despite the advent of angiotensin-converting inhibitor therapy, SRC remains a life-threatening complication. Recent studies have contributed to a better understanding of SRC, but much remains unknown regarding its pathophysiology, risk factors, and optimal management. Genetic studies provide evidence that immune dysregulation might be a contributing factor, providing hope that further research in this direction might illuminate pathogenesis and provide novel predictors for this complication.

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Objective: Hypertension develops early in autosomal dominant polycystic kidney disease (ADPKD) and affects more than a half of patients with end stage renal disease. There are limited data about blood pressure changes in transplanted ADPKD patients and particulary in those who underwent native nephrectomy. Objective: To assess the prevalence of hypertension in transplanted patients with autosomal dominant polycystic kidney disease (ADPKD) and the relationship with pre-transplant native nephrectomy. Design and method: 53 patients after kidney transplantation with ADPKD have been followed-up for 14.5 years. 50 of them were enrolled into the final analysis. Depending on whether native pre-transplant nephrectomy was performed they were divided into three groups: I – no nephrectomy, II – unilateral nephrectomy, III – bilateral nephrectomy. Demographic data and data about time spent on dialysis before transplantation, donor type, graft function, blood pressure, antihypertensive medication, calcineurin inhibitor concentration, glycemia, proteinuria, native kidney size were collected. Results: Group I consisted of 24 patients, group II – 7, group III – 19. No significant differences were found among groups according to demographic characteristics, time spent on dialysis before transplantation, donor type, graft failure, proteinuria, steroid induced diabetes. The hypertension rate before and within 6 months after transplantation was I -70.8% vs 82.6%, II- 71.4% vs 80% and III- 78.9% vs 61.1% respectively. Hypertension after 6 months was more prevalent in I group (95.5%) than in II (40%), III (64.7%) groups (p = 0.008), despite the lower cyclosporine A concentration (p < 0.001). Patient in group I required more antihypertensive medication after kidney transplantation. Prescribing of angiotensin converting inhibitors, sartans and diuretics was also more prevalent in this group. There were 2 cases of steroid induced diabetes in III group, and 1 case in I group. There was no correlation between native kidney size after transplantation and hypertension. Conclusions: We observed that hypertension was more prevalent in patients after kidney transplantation with ADPKD without native nephrectomy compared to those who underwent either unilateral or bilateral nephrectomy.

Renal Artery Stenosis and Acute Pulmonary Edema-A Possible Correlation beyond Pickering Syndrome

Objectives: The association of renal artery stenosis (RAS) with acute pulmonary edema (APE) is considered specific for bilateral or solitary functioning kidney (SFK) RAS. We aimed to check if APE is also associated with unilateral RAS when both kidneys are functional. Method: A series of 189 patients with uncontrolled hypertension were investigated for RAS suspicion by duplex ultrasonography. Clinical criteria considered in current guidelines as predictors of RAS were recorded and analysed. Results: Potentially hemodynamically significant RAS (≥ 50%) was identified in 29% of cases (55/189): unilateral in 35 cases (group A), bilateral or on SFK in 20 cases (group B). The remaining 134 were designated controls (group C). Age, blood pressure and gender did not differ between groups. The presence of acute pulmonary edema was higher in both groups of patients with RAS (23%-group A (p<0.01) and 20%-group B vs 8% in control group). The prevalence of azotemia and of azotemia under angiotensin converting enzyme inhibitors or angiotensin II receptor blockers were significantly higher in group B (p<0.01 vs. group A, p<0.00001 vs. control). Linear discriminant analysis based on: age, gender, abdominal bruit, vascular disease, renal dysfunction and azotemia under angiotensin converting inhibitors or angiotensin II receptor blockers, had an accuracy of 0.70 for unilateral RAS, 0.85 for bilateral/SFK RAS, and 0.77 for both. This accuracy was not improved when adding APE as a predictive variable. Conclusions: In a series of hypertensive patients evaluated for renovascular disease the prevalence of APE is higher in patients with RAS. We have found a significant association of RAS with APE for unilateral RAS. This association, little emphasized until present, might contribute to the clarification of the flash pulmonary edema mechanisms beyond those related to bilateral/SFK RAS.