Chronic kidney disease presents a health challenge that has a complex underlying pathophysiology, both acquired and inherited. The pharmacotherapeutic treatment options available today lower the progression of the disease and improve the quality of life but cannot completely cure it. This poses a challenge to the healthcare provider to choose, from the available options, the best way to manage the disease as per the presentation of the patient. As of now, the recommended first line of treatment to control the blood pressure in chronic kidney disease is the administration of renin-angiotensin-aldosterone system modulators. These are represented mainly by the direct renin inhibitor, angiotensin-converting enzyme inhibitors, and angiotensin II receptor blockers. These modulators are varied in their structure and mechanisms of action, hence showing varying treatment outcomes. The choice of administration of these modulators is determined by the presentation and the co-morbidities of the patient, the availability and affordability of the treatment option, and the expertise of the healthcare provider. A direct head-to-head comparison between these significant renin-angiotensin-aldosterone system modulators is lacking, which can benefit healthcare providers and researchers. In this review, a comparison has been drawn between the direct renin inhibitor (aliskiren), angiotensin-converting enzyme inhibitors, and angiotensin II receptor blockers. This can be of significance for healthcare providers and researchers to find the particular loci of interest, either in structure or mechanism, and to intervene as per the case presentation to obtain the best possible treatment option.

Aliskiren is a newly developed drug. Its role in lowering BP has been recognized. However, the role of aliskiren in treating heart and renal diseases are still controversial.
To evaluate the existing evidence about clinical efficacy, safety and tolerability of aliskiren monotherapy (AM).
An umbrella review of systematic reviews of interventional studies. We searched Pubmed, Embase and Cochrane Library up to June 2019. Two reviewers applied inclusion criteria to the select potential articles independently. The extract and analyze of accessible data were did by two reviewers independently too. Discrepancies were resolved with discussion or the arbitration of the third author.
Eventually, our review identified 14 eligible studies. Results showed that for essential hypertension patients, aliskiren showed a great superiority over placebo in BP reduction, BP response rate and BP control rate. Aliskiren and placebo, ARBs or ACEIs showed no difference in the number or extent of adverse events. For heart failure patients, AM did not reduce BNP levels (SMD -0.08, - 0.31 to 0.15) or mortality rate (RR 0.76, 0.32 to 1.80), but it decreased NT-proBNP (SMD -0.12, - 0.21 to - 0.03) and PRA levels (SMD 0.52, 0.30 to 0.75), increased PRC levels (SMD -0.66, - 0.8 to - 0.44). For patients who are suffered from hypertension and diabetes and/or nephropathy or albuminuria at the same time, aliskiren produced no significant effects (RR 0.97, 0.81 to 1.16).
We found solid evidence to support the benefits of aliskiren in the treatment of essential hypertension, aliskiren can produce significant effects in lowering BP and reliable safety. However, the effects of aliskiren in cardiovascular and renal outcomes were insignificant.
Study has been registered in PROSPERO (CRD42019142141).

Aliskiren is an oral antihypertensive medication that acts by directly inhibiting renin. High levels of circulating renin and prorenin activate the pathological signaling pathway of fibrosis. This drug also reduces oxidative stress. Thus, the aim of this systematic review is to analyze experimental studies that show the actions of aliskiren on fibrosis. PubMed and LILACS databases were consulted using the keywords aliskiren and fibrosis within the period between 2005 and 2017. Fifty-three articles were analyzed. In the heart, aliskiren attenuated remodeling, hypertrophy, inflammatory cytokines, collagen deposition, and oxidative stress. In the kidneys, there was a reduction in interstitial fibrosis, the infiltration of inflammatory cells, apoptosis, proteinuria, and in the recruitment of macrophages. In diabetic models, an improvement in the albumin/creatinine relationship and in the insulin pathway in skeletal muscles was observed; aliskiren was beneficial to pancreatic function and glucose tolerance. In the liver, aliskiren reduced fibrosis, steatosis, inflammatory cytokines, and collagen deposition. In the lung and peritoneal tissues, there was a reduction in fibrosis. Many studies have reported on the beneficial effects of aliskiren on endothelial function and arterial rigidity. A reduction in fibrosis in different organs is cited by many authors, which complies with the results found in this review. However, studies diverge on the use of the drug in diabetic patients. Aliskiren has antifibrotic potential in several experimental models, interfering with the levels of fibrogenic cytokines and oxidative stress. Therefore, its use in diseases in which fibrosis plays an important pathophysiological role is suggested.

The efficacy and safety of aliskiren combination therapy with angiotensin converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) in patients with hypertension and cardiovascular disease remains attractive attention. We searched the Cochrane Central Register, the Clinical Trials Registry, EMBASE, MEDLINE and PubMed for relevant literatures up to January 2017. A total of 13 randomized controlled trials (RCTs) with 12222 patients were included in this study, and the combined results indicated that aliskiren in combination therapy with ACEIs or ARBs had remarkable effects in reducing systolic blood pressure (SBP) [weighted mean differences (WMD), -4.20; 95% confidential intervals (CI) -5.44 to -2.97; I2 , 29.7%] and diastolic blood pressure (DBP: WMD, -2.09; 95% CI -2.90 to -1.27; I2 , 0%) when compared with ACEIs or ARBs monotherapy, but with significantly increased the risk of hyperkalaemia [relative risk (RR), 1.45; 95% CI 1.28 to 1.64; I2 ,10.6 %] and kidney injury ( RR, 1.92; 95% CI 1.14 to 3.21; I2 , 0%). Besides, there was no significant difference in the incidence of major cardiovascular events (RR, 0.95; 95% CI 0.89 to 1.02; I2 , 0%) between the combined therapy and ACEIs or ARBs monotherapy. In conclusion, this meta-analysis demonstrated that aliskiren in combination therapy with ACEs/ARBs could control BP effectively, but is associated with increasing risks of hyperkalaemia and kidney injury, and have no benefit in preventing of major cardiovascular events.

UNASSIGNED: To systematically review and synthesize the currently available evidence of aliskiren for the treatment of heart failure.
UNASSIGNED: We systematically searched the Cochrane, Embase and PubMed databases to identify the randomized controlled trials (RCT) on the effects of aliskiren on heart failure. Data were synthesized with random effects model and presented in forest plot. Publication bias was evaluated with funnel plot. Heterogeneity was evaluated with Begg\'s test and Egger\'s test.
UNASSIGNED: Of 124 studies, 6 RCT of 9845 heart failure patients were included for meta-analysis, including 3727 patients receiving aliskiren. Compared with the controls, aliskiren did not significantly reduce the all-cause mortality (1.02 [0.91-1.14], I2 = 0%) or cardiovascular mortality (1.02 [0.88-1.17], I2 = 7.3%) of heart failure patients. Total adverse events, renal dysfunction, hypotension and hyperkalaemia were not significantly different between the aliskiren group and control group. Begg\'s test and Egger\'s test indicated low heterogeneity. Funnel plots indicated low publication bias.
UNASSIGNED: Aliskiren, either used alone or combined with standard medical therapy, does not significantly reduce the all-cause mortality or cardiovascular mortality of heart failure patients. Although aliskiren does not cause statistically higher adverse events, its adverse events may not be neglected.

Aliskiren was shown to increase adverse events in patients with diabetes and concomitant renin-angiotensin blockade. We aim to investigate the efficacy and safety of aliskiren in patients with diabetes and increased cardiovascular risk or established cardiovascular disease.
MEDLINE and Embase were searched for prospective studies comparing addition of aliskiren to standard medical therapy in patients with diabetes and cardiovascular disease, or ⩾1 additional cardiovascular risk factor (hypertension, abnormal lipid profile, microalbuminuria/proteinuria, chronic kidney disease). Relative risk for efficacy (all-cause mortality, combined cardiovascular mortality and hospitalisation) and safety (hyperkalaemia, hypotension, renal impairment) outcomes was calculated.
Of 2151 studies identified in the search, seven studies enrolling 13,395 patients were included. Aliskiren had no effect on all-cause mortality (relative risk: 1.05, 95% confidence interval: 0.90 to 1.24, p = 0.53), or combined cardiovascular mortality or heart failure hospitalisation (relative risk: 1.07, 95% confidence interval: 0.81 to 1.40, p = 0.64). Patients receiving aliskiren had a greater risk of developing hyperkalaemia (relative risk: 1.32, 95% confidence interval: 1.14 to 1.53, p = 0.0003) and renal impairment (relative risk: 1.15, 95% confidence interval: 1.02 to 1.30, p = 0.03), but not hypotension.
Patients with diabetes and cardiovascular disease or cardiovascular risk do not benefit from the addition of aliskiren to standard medical therapy. Detrimental safety profile in pooled analysis supports current warnings.

Even mild abnormalities of the renal structure or function can increase the risk of mortality and complications in other organs. Therefore, safe and effective treatments are necessary in order to influence the progression of renal disease. We used 2 methods to assess the renoprotective effects of aliskiren: 1) a statistical analysis of clinical trials that investigated aliskiren-induced renoprotection, in terms of changes in serum creatinine concentration (sCr) or estimated glomerular filtration rate (eGFR), and, 2) clinical trials that investigated the renoprotective effects of aliskiren with respect to changes in albuminuria or proteinuria. In the forest plot, the overall risk ratio (%) for renal impairment with respect to changes in sCr or eGFR was 0.97 (0.88-1.06; overall p=0.48). The tabulation of data from clinical trials included 10 entries for monotherapy with aliskiren and 6 entries for add-on aliskiren. All of the clinical trials, except one, showed a decrease in proteinuria or albuminuria following aliskiren treatment. In conclusion, inhibiting renin and prorenin with aliskiren is a more promising renoprotective treatment compared with blocking the renin/prorenin receptors (RPR). One of the main mechanisms by which aliskiren may confer renoprotection is by decreasing albuminuria and proteinuria. However, it does not seem to change sCr and eGFR in patients at risk of developing renal disease. Furthermore, co-administration of an angiotensinconverting- enzyme inhibitor (ACEI) or an angiotensin II receptor blocker (ARB) and aliskiren was shown to decrease albuminuria and proteinuria to a greater extent compared with monotherapy with these agents.

Hesperidin (Hsd) and its aglycone, hesperetin (Hst), are two flavonoids from citrus species that have various biological properties. Over the past decade, a large number of papers have been published regarding the biological activities of these compounds and their molecular mechanisms. In this paper, we reviewed the neuropharmacology of Hsd and Hst as a recently emerged topic that has not been addressed in the past. Some of molecular targets and signaling pathways for neuropharmacological effects of Hst and Hsd, including antidepressant, neuroprotective and the effects of Hsd/Hst on memory, have also been included in the review. We also discussed the mechanisms of actions for antidepressant activities of Hsd and Hst. In addition, pharmacokinetics of Hsd and Hst, their interaction with some drugs such as atenolol, diltiazem, felodipine and verapamil, as well as related underlying mechanisms have been discussed.

BACKGROUND: Wells syndrome is an uncommon inflammatory dermatosis first described in 1971 by Wells. The clinical eruption is characterized by varying morphology and severity and usually follows a relapsing remitting course. The majority of the reported cases are of unknown etiology, drug induced Wells syndrome has rarely been reported. A literature search using MEDLINE was performed. We recorded the features of our case and of the additional cases of drug induced Wells syndrome in the literature.
METHODS: Including our case there are 25 cases of drug-induced Wells syndrome reported. Causative drugs include antibiotics, anticholinergic agents, anaesthetics, non-steroidal anti-inflammatory agents, thyroid medications, chemotherapeutic agents, thiomersal containing vaccinations, anti-tumor necrosis factor agents and thiazide diuretics.
CONCLUSIONS: To the authors knowledge this is the first reported case of drug-induced Wells syndrome from thiazide diuretics. The diagnosis of Wells syndrome is often controversial and we propose a set of diagnostic criteria.

Aliskiren is the newest antihypertensive drug and the first orally active direct renin inhibitor to become available for clinical use. Clinical data have substantiated that the antihypertensive effectiveness of aliskiren is similar to that of the other major antihypertensive agents. Furthermore, aliskiren has a similar safety profile to placebo. Combination treatment with aliskiren showed significant blood pressure and proteinuria reductions compared with monotherapy. Aliskiren decreases plasma renin activity in contrast to other renin-angiotensin-aldosterone related drugs. The efficacy of aliskiren in treating major cardiovascular events and the prevention of end-organ damage are being investigated in the ASPIRE HIGHER program. Although the first studies of the ASPIRE HIGHER program such as ALOFT, AVOID, AGELESS showed favorable findings, ASPIRE and AVANT-GARDE studies provided contradictory results. Subsequently, the ALTITUDE study was terminated early because of safety issues and lack of beneficial effects. Most recently, the ASTRONAUT trial showed no reduction in cardiovascular death or heart failure rehospitalization with the addition of aliskiren to standard therapy in patients who were hospitalized for heart failure and with reduced left-ventricular ejection fraction. The results of ongoing studies in other patient groups such as the ATMOSPHERE trial are awaited.