Angiotensin-converting Enzyme Receptor Blockers Research Articles

#5734 RENAL AUTOLOGOUS CELL THERAPY (REACT™) FOR DIABETIC CHRONIC KIDNEY DISEASE: PHASE II TRIAL WITH BILATERAL CORTEX INJECTIONS AND RE-DOSING TRIGGERS

Abstract Background and Aims Well-based therapies may repair diseased nephrons and stabilize and enhance kidney function to delay the onset of end-stage kidney disease and improve co-morbidities. REACT™ is a novel product formed of cryopreserved autologous homologous selected renal cells, undergoing phase III clinical trials for diabetic kidney disease (DKD). We describe an open label phase II study to evaluate how patients respond to REACT™ injections in both kidneys and a redosing trigger, as being evaluated in a Phase III blinded data trial (proact 1 & 2 trials). Method REGEN 007 is a multi-center Phase II, open label 1:1 randomized controlled trial enrolling up to 50 patients ages 30-80 years with DKD, who have an eGFR of 20 - 50 mL/min/1.73 m2. Each patient undergoes a percutaneous kidney biopsy and ex vivo culture expansion of their selected renal cells. Patients are then randomized to an arm where they receive two REACT™ injections, one in each kidney, three months apart if they meet inclusion criteria, or an arm with an initial single REACT™ dose in one kidney and a 2nd REACT™ dose in the contralateral kidney > 90 days apart, based on a sustained eGFR decline of ≥ 20%, and/or an increase in the urine albumin to creatinine ratio (UACR) from baseline of ≥ 30% and ≥ 30 mg/g. CT-guided bilateral percutaneous renal cortex injections of REACT™ are performed under conscious sedation. Trial design, inclusion and exclusion criteria can be found at the National Clinical Trial Registry (Trial number 05018416). Results Thirty-one of the targeted 50 participants have been enrolled with the following characteristics at screening: 64.0% males, 97.0% Non-Hispanic/Latino. Mean age 62.9 years, serum creatinine (sCr) 2.0 mg/dL ±0.50, Cystatin C 2.0 mg/L ±0.40, eGFR (sCr + Cystatin C) 31.2 ml/min/1.72m2 ±7.88, HgbA1C 7.4% ± 1.14, Hgb 12.9 g/dL ± 1.78, K+ 4.6 mEq/L ± 0.44, Bicarbonate 20.3 mEq/L ± 3.0, and a median UACR 662 mg/g [SD 705.8]. Percent baseline medications are: Angiotensin Converting Enzyme inhibitors 25.8, Angiotensin Converting Enzyme receptor Blockers 48.4, beta blockers 64.5, diuretics 64.4, glucose lowering agents 100, Sodium glucose Cotransporter 2 inhibitors 32.3, and platelet inhibitors 67.7. Efficacy endpoint is an eGFR slope improvement from first injection to 18 months after last injection. REACT™ and procedure related serious adverse events are expected to be commensurate with ongoing trials and standard of care Conclusion REACT™ cell-based therapy has the potential to effect nephron structure and function by stabilizing or improving DKD progression and its comorbidities. Current phase II and III trials are underway to determine efficacy, safety, renal function-dependent dosing, and time to treatment with bilateral kidney injections of REACT™.

Sickle Hemoglobin-Related Nephropathy: an Overview on Pathophysiology, Diagnosis, and Treatment

Abstract Sickle cell disease (SCD) is a common hemoglobinopathy in the world with progressive multi organ failure. Many organs have been affected in this disease, but sickle cell nephropathy (SCN) is a major complication which affects the quality of life in these patients. SCN has a wide range of renal manifestations such as asymptomatic microalbuminuria, hyposthenuria, hematuria, frank proteinuria, nephrotic syndrome and end stage renal disease (ESRD). Nowadays novel biomarkers such as N-acetyl-beta-D-glucosaminidase (NAG), kidney injury molecule-1 (KIM-1) and transforming growth factor β (TGF-β) has allowed the early detection of the kidney involvement in sickle cell disease. The angiotensin converting enzyme (ACE) inhibitor drugs such as captopril or enalapril and also ACE receptor blockers (losartan) have beneficial effects in albuminuria or proteinuria. Also endothelin-1 (ET-1) receptor antagonists have a promising role in glomerular injury in SCD. In sickle patients who develop ESRD, renal replacement therapy can be life- saving. In recent years, kidney transplantation is the only curative treatment for advanced chronic kidney disease in these patients. Keywords: Sickle cell; Nephropathy; Kidney.

Drug treatment of coronavirus disease COVID-19: evidence exists?

The article provides a review of foreign literature for 2020 on existing methods of drug treatment of coronavirus disease COVID-19. To date, in the treatment of COVID-19 in different countries, a little more than 10 drugs are used. The largest number of studies on the testing of these drugs is carried out by scientists from China, the USA, and European countries. It should be noted that among these drugs there is not a single new drug developed specifically for the treatment of COVID-19, the recommended and used drugs have previously been used to treat, as a rule, diseases of the viral etiology, less often another pathology. These suggestions are often based on analogy, the hypothesis of their supposed effectiveness for COVID-19. It can be assumed that a brake on the development of a drug specific for coronavirus disease is a poor knowledge of the pathogenesis of virus invasion in the body's adhesives and the development of complications. The review provides detailed literature data on drugs such as hydroxychloroquine / chloroquine, lopinavir/natinavir, remdesivir, ACE inhibitors and angiotensin converting enzyme receptor blockers, tissue plasminogen activator, as well as plasma transfusion transfusions.

Precipitant profile of acute heart failure: experience of a tertiary level cardiac centre in Sri Lanka

Introduction and objectivesHeart failure (HF) is a common cause of hospitalisation in most countries. Data on acute precipitants of HF and hospitalisation is not available in Sri Lanka.Background and methodsA...

The personalised medicine. A paradigm of evidence-based medicine.

The practice of "evidence-based medicine" aims at the conscientious, explicit and judicious use of the current best evidence in making decisions about the individualised patient care. The clinical genetics evolved from translational genetics research and contributes to the clinical care of patients and families through evidence-based health care in managing inherited disorders through accurate diagnosis, molecular pathology and assessing phenotypic correlations. Translational genetics and genomics research has led to the development of powerful tools for clinical diagnosis, assessing individual's genomic profile for disease prediction/prevention, high-throughput genome-wide screening for predisposition and/or protection to complex medical conditions, and discovery and development of new drugs and vaccines. Gene mapping and deciphering pathogenic mutations have helped in unravelling the basic biological mechanisms leading to new drug discovery and development. Targeted pharmacotherapy is now possible for managing the highly penetrant multi-system dominantly inherited conditions. Notable examples include rapamycin (sirolimus) in suppressing the mTOR pathway associated hamartomas in dominantly inherited cancer family syndromes and angiotensin converting enzyme receptor blockers (ACE-RB) in preventing aortic dilatation in Marfan syndrome and related familial arteriopathies. The translational genomic research is the essential prerequisite for developing sound evidence-based diagnostic, therapeutic and prognostic clinical protocols for the practice of personalised clinical medicine.

Left Ventricular Hypertrophy

AN INCREASE IN THE MASS OF LEFT VENTRICULAR muscle is intimately associated with most chronic diseases of the heart. Classically, left ventricular hypertrophy, which represents an extreme increase in left ventricular mass, has been thought to represent a reaction to pressure or volume overload. In the short run, increases in left ventricular mass may be beneficial by allowing the heart to compensate for increased wall stress and potential hemodynamic compromise; in the long run, left ventricular hypertrophy is harmful. Although the development of left ventricular hypertrophy has been related to a number of conditions, including obesity, diabetes, prior myocardial infarction, aortic stenosis, and regurgitant valvular heart disease, hypertension may well be the condition about which the most is known. Data from the Framingham Heart Study have shown that even mild increases in blood pressure are associated with increased left ventricular mass. Furthermore, left ventricular hypertrophy associated with hypertension appears to be reversible—ie, a long-term reduction of blood pressure has been shown to be associated with reductions in left ventricular mass. Some data have suggested that specific types of drugs, such as angiotensin-converting enzyme receptor blockers or calcium blockers, may be more effective than others in reducing increased left ventricular mass associated with hypertension, whereas other reports suggest that the specific drug used to reduce blood pressure may not be that important. For more than 30 years, it has also been recognized that left ventricular hypertrophy is a risk factor for premature death and cardiovascular events. A landmark article from the Framingham Heart Study published in 1970 reported that left ventricular hypertrophy, as noted on the electrocardiogram, is associated with a mortality rate that is as high as having a Q-wave myocardial infarction. Although subsequent studies have confirmed the strong association between electrocardiographic left ventricular hypertrophy and cardiovascular risk, it has also been recognized that the electrocardiogram may be relatively insensitive for detecting prognostically important increases in left ventricular mass. With the advent of echocardiography, milder increases in left ventricular mass could be easily detected. Additional data from the Framingham Study, as well as data from Cornell University and the Cardiovascular Health Study, among others, have demonstrated that a strong gradient exists between increased echocardiographic left ventricular mass and increased cardiovascular risk. Despite the wealth of literature linking electrocardiographic and echocardiographic left ventricular mass to increased cardiovascular risk, left ventricular hypertrophy is often not thought of as a “standard” or “classic” risk factor. One explanation is that left ventricular hypertrophy— similar to, for example, increased carotid intimal-medial thickness detected by ultrasound—may be considered in the category of subclinical disease—intermediate on the continuum from standard risk factors to clinically manifest cardiovascular disease. However, another reason may be that relatively little data are available on the impact that reversing left ventricular hypertrophy has on outcomes. In contrast, a wealth of literature now shows that reduction of blood pressure, levels of cholesterol and blood glucose, and use of tobacco are associated with important clinical benefits. Observational data have suggested that a decrease in left ventricular mass with treatment for hypertension is associated with a better outcome. However, prospective and systematic clinical trial data have been meager. In this issue of JAMA, 2 reports systematically document that changes in left ventricular mass in the setting of a trial of hypertension treatment have been correlated with longterm cardiovascular outcome. Okin and colleagues report on more than 9000 patients who were enrolled in the LIFE hypertension trial. This randomized trial involved a comparison of losartan-based therapy with atenolol-based therapy. Although the degree of blood pressure reduction was similar with the 2 drugs, losartan was associated with a greater reduction in left ventricular mass and a variety of cardiovascular outcomes. In the current study reported by Okin et al, patients enrolled in the trial had electrocardio-

Determining the appropriateness of selected surgical and medical management options in recurrent stroke prevention: A guideline for primary care physicians from the National Stroke Association work group on recurrent stroke prevention

Despite a decade of successful clinical trials for stroke prevention, substantial gaps exist in the application and implementation of this information in community practice. The frequency of guideline use is low, and there remains controversy regarding the standard of practice. Patients with stroke may have multiple risk factors and concomitant stroke mechanisms, factors that are not addressed in stroke clinical trials and guideline statements. New guidelines are needed to account for these complexities and to provide primary care physicians a practical means to achieve stroke prevention. We sought to develop guidelines that can be implemented by primary care physicians to enhance the use of medical and surgical measures for recurrent stroke prevention. We sought to test the applicability of current evidence-based guidelines to daily practice with routine and complex patient case scenarios to determine whether these could be simplified into a more easily applied form for primary care physicians. We used RAND/UCLA Appropriateness Methodology to develop guidelines for the use of interventions supported by randomized controlled trials including carotid revascularization, anticoagulant therapy, antiplatelet therapy, and blood pressure management for the prevention of recurrent stroke. After a systematic literature review of randomized clinical trials we developed a comprehensive list of indications or clinical scenarios to capture decision making. A diverse multidisciplinary panel reviewed and rated each indication according to the RAND Appropriateness Method. First, panelists rated each scenario (1–3 for inappropriate, 4–6 for uncertain, and 7–9 for appropriate) without interaction with other panelists. “Appropriate” was defined as the expected health benefit exceeding its expected negative consequences by a sufficient margin. At a formal interactive session, panelists re-rated all indications. Overall carotid endarterectomy was rated as appropriate when there was 50% to 99% ipsilateral symptomatic carotid artery stenosis, inappropriate with <50% or 100% stenosis (total occlusion), and uncertain when the surgical risk was high. Carotid angioplasty was generally rated as of uncertain value. When there was atrial fibrillation, anticoagulation with warfarin was rated as appropriate when there was a low bleeding risk but of uncertain value when the bleeding risk was high. For patients who were not candidates for warfarin therapy, aspirin, aspirin plus extended-release dipyridamole, or clopidogrel were all rated as appropriate initial therapies. Ticlopidine was considered inappropriate and aspirin plus clopidogrel of uncertain value. With the exception of ticlopidine and aspirin, persons with a prior cerebral ischemic event while on aspirin could receive any of the aforementioned antiplatelet agents or combinations and be considered appropriately treated. The panelists rated a blood pressure of <130/80 mm Hg at 1 year after ischemic stroke as the target level and rated any of the following agents as appropriate initial therapies if there was no diabetes mellitus or proteinuria: diuretics, β-blockers, angiotensin-converting enzyme inhibitors, angiotensin-converting enzyme receptor blockers, or combinations of a diuretic and an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker. Patient risk played a significant role in deterring the panel from recommending certain therapies; however, the presence of atrial fibrillation or large or small cerebral vessel syndromes rarely had significant influence on treatment decisions. Appropriateness was less where bleeding or surgical risk was excessive. Using consensus evidence from clinical trials, we have developed recurrent stroke prevention guidelines for routine and more complex patient scenarios according to appropriateness methodology. Broad application of these guidelines in primary practice promises to reduce the burden of recurrent stroke.

The evolving management of migraine.

To review recent advances in acute and preventive migraine treatment. The number of migraine drugs continues to expand, allowing for more flexible and tolerable treatment plans. Two new triptans, frovatriptan and eletriptan, and a nasal formulation of zolmitriptan have been recently developed. Eletriptan is effective for acute migraine treatment and may have some pharmacologic and clinical advantages. Frovatriptan has a longer half-life and lower headache recurrence rates compared with other triptans. It may be useful for patients who have prolonged attacks and high headache recurrence rate. Zolmitriptan nasal spray has a rapid onset of action and high efficacy. It should be considered when patients have rapid-onset attacks, especially when associated with severe nausea or vomiting. The butyrophenone neuroleptic droperidol is very effective in aborting acute migraine attacks. Central nervous system side effects are common, however, and the ECG should be monitored. Botulinum toxin type A shows promise as a safe, tolerable and effective drug for migraine prevention, with the unique advantages of almost no systemic adverse events and a long interval between treatments. The anticonvulsant topiramate is effective for migraine prevention. Cognitive side effects are of less concern with the lower doses needed for migraine. The angiotensin converting enzyme receptor blocker candesartan appears to be effective and highly tolerable in the prevention of migraine, but needs to be further evaluated. New drugs expand the spectrum of migraine treatment both for the acute attack and for prevention.

Medical prevention of stroke, 2003.

Stroke is a preventable tragedy for nearly 750,000 people each year. Primary stroke prevention measures applicable to the general public include a healthy diet containing fruits, vegetables, fish, and low fat; exercise; smoking cessation; limiting alcohol to moderate use; and perhaps avoidance of stress. Screening for hypertension, cholesterol, heart disease, and carotid artery stenosiscan lead to even more effective stroke prevention in high-risk patients. Specific antihypertensive drugs such as angiotensin-converting enzyme inhibitors and angiotensin-converting enzyme receptor blockers may be especially protective against stroke. Secondary stroke prevention in patients who have already had a stroke or transient ischemic attack is even more effective in preventing more serious strokes. Measures include antihypertensive and cholesterol-lowering agents, carotid endarterectomy, anticoagulation for atrial fibrillation and other cardiac sources of embolic stroke, and antiplatelet therapy. Stroke prevention depends on the application of these well-known and widely available treatments to a large number of patients.