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Glioblastoma multiforme (GBM) is a highly aggressive and incurable disease accounting for about 10,000 deaths in the USA each year. Despite the current treatment approach which includes surgery with chemotherapy and radiation therapy, there remains a high prevalence of recurrence. Notable improvements have been observed in persons receiving concurrent antihypertensive drugs such as renin angiotensin inhibitors (RAS) or the antidiabetic drug metformin with standard therapy. Anti-tumoral effects of RAS inhibitors and metformin have been observed in in vitro and in vivo studies. Although clinical trials have shown mixed results, the potential for the use of RAS inhibitors and metformin as adjuvant GBM therapy remains promising. Nevertheless, evidence suggest that these drugs exert multimodal antitumor actions; by particularly targeting several cancer hallmarks. In this review, we highlight the results of clinical studies using multidrug cocktails containing RAS inhibitors and or metformin added to standard therapy for GBM. In addition, we highlight the possible molecular mechanisms by which these repurposed drugs with an excellent safety profile might elicit their anti-tumoral effects. RAS inhibition elicits anti-inflammatory, anti-angiogenic, and immune sensitivity effects in GBM. However, metformin promotes anti-migratory, anti-proliferative and pro-apoptotic effects mainly through the activation of AMP-activated protein kinase. Also, we discussed metformin's potential in targeting both GBM cells as well as GBM associated-stem cells. Finally, we summarize a few drug interactions that may cause an additive or antagonistic effect that may lead to adverse effects and influence treatment outcome. [ABSTRACT FROM AUTHOR]

In the last decades, several classifications and definitions have been proposed for advanced heart failure (ADVHF) patients, including clinical, functional, hemodynamic, imaging, and electrocardiographic features. Despite different inclusion criteria, ADVHF is characterized by some common items, such as drug intolerance, low arterial pressure, multiple organ dysfunction, chronic kidney disease, and diuretic use dependency. Additional features include fatigue, hypotension, hyponatremia, and unintentional weight loss associated with a specific laboratory profile reflecting systemic multiorgan dysfunction. Notably, studies evaluating guideline-directed medical therapy recently endorsed by guidelines in stable HF, including the 4 drug classes all together (i.e., betablocker, mineral corticoid antagonist, renin angiotensin inhibitors/neprilysin inhibitors, and sodium glucose transporter inhibitors), remain scarcely analyzed in ADVHF and New York Heart Association (NYHA) Class IV. Additionally, due to the common conditions associated with advanced stages, the balance between drug tolerance and potential benefits of the contemporary use of all agents is questioned. Therefore, less hard endpoints, such as exercise tolerance, quality of life (QoL) and self-competency, are not clearly demonstrated. Specific analyses evaluating outcome and rehospitalization of each drug provided conflicting results and are often limited to subjects with stable conditions and less advanced NYHA class. Current European Society of Cardiology/American Heart Association (ESC/AHA) Guidelines do not indicate the type of treatment, dosage, and administration modalities, and they do not suggest specific indications for ADVHF patients. Due to these concerns, there is an impelling need to understand what drugs may be used as the first line, what management leads to the better outcome, and what is the best treatment algorithm in this setting. In this paper, we summarize the most common pitfalls and limitations for the use of the traditional agents, and we propose a personalized approach aiming at preserve drug tolerance and maintaining adverse event protection and satisfactory QoL. [ABSTRACT FROM AUTHOR]

Hypertension is frequent in children with chronic kidney disease (CKD). Its prevalence varies according to CKD stage and cause. It is relatively uncommon in children with congenital kidney disease, while acquired kidney disease is associated with a higher prevalence of hypertension. Studies in children with CKD utilizing ambulatory blood pressure monitoring also showed a high prevalence of masked hypertension. Uncontrolled and longstanding hypertension in children is associated with progression of CKD. Aggressive treatment of high blood pressure should be an essential part of care to delay CKD progression in children. [ABSTRACT FROM AUTHOR]

Summary: The skeletal renin-angiotensin system contributes to the development of osteoporosis. The renin inhibitor aliskiren exhibited beneficial effects on trabecular bone of osteoporotic mice, and this action might be mediated through angiotensin and bradykinin receptor pathways. This study implies the potential application of renin inhibitor in the management for postmenopausal osteoporosis. Introduction: The skeletal renin-angiotensin system plays key role in the pathological process of osteoporosis. The present study is designed to elucidate the effect of renin inhibitor aliskiren on trabecular bone and its potential action mechanism in ovariectomized (OVX) mice. Methods: The OVX mice were treated with low dose (5 mg/kg) or high dose (25 mg/kg) of aliskiren or its vehicle for 8 weeks. The bone turnover markers were measured by ELISA. The structural parameters of trabecular bone at lumbar vertebra (LV) and distal femoral metaphysis were measured by micro-CT. The expression of messenger RNA (mRNA) and protein was studied by RT-PCR and immunoblotting, respectively. Results: Aliskiren treatment reduced urinary excretion of calcium and serum level of tartrate-resistant acid phosphatase in OVX mice. The treatment with aliskiren significantly increased bone volume (BV/TV) and connectivity density (Conn.D) of trabecular bone at LV-2 and LV-5 as well as dramatically enhanced BV/TV, Conn.D, bone mineral density (BMD/BV) and decreased bone surface (BS/BV) at the distal femoral end. Aliskiren significantly down-regulated the expression of angiotensinogen, angiotensin II (Ang II), Ang II type 1 receptor, bradykinin receptor (BR)-1, and osteocytic-specific gene sclerostin as well as the osteoclast-specific genes, including carbonic anhydrase II, matrix metalloproteinase-9, and cathepsin K. Conclusions: This study revealed that renin inhibitor aliskiren exhibited the beneficial effects on trabecular bone of ovariectomy-induced osteoporotic mice, and the underlying mechanism for this action might be mediated through Ang II and BR signaling pathways in bone. [ABSTRACT FROM AUTHOR]

Renin inhibitors pertain to a new generation class of antihypertensive agents. There are only a few studies on the computational modeling of such class of compounds and only one available drug in the market used as renin inhibitor for the treatment of hypertension, aliskiren. The present study reports the QSAR modeling of the activities of a series of indole-3-carboxamide derivatives using MIA-QSAR in order to propose new promising analogs as renin inhibitor candidates. The proposed structures were submitted to docking evaluation to search for the interaction modes responsible for the calculated bioactivities. In addition, the drug likeness of the proposed compounds was investigated using theoretical data related to pharmacokinetic properties. Overall, at least two promising candidates are proposed as highly active and pharmacokinetically acceptable renin inhibitors. [ABSTRACT FROM AUTHOR]

A series of substituted 4- and 6-azaindole-3-carboxamides derivatives displaying potent activities against renin inhibitors were selected to establish quantitative structure-activity relationships using two dimensional, k-nearest neighbor ( kNN), and pharmacophore analysis methods. The QSAR models of the substituted 4- and 6-azaindole-3-carboxamides derivatives have been developed by partial least square (PLS) methodology coupled genetic algorithm, simulated annealing and stepwise, for the purpose of an effective comparison and some interesting results are obtained. The statistically best significant 2D-QSAR model having r = 0.8644 and q = 0.7630 with pred_ r = 0.8009 was developed by GA-PLS method with the descriptors like positive contribution of SsCHE-index, T_C_F_5 T_2_Cl_1, SssOE-index. The result model of the QSAR study suggests the methyl, methoxy, fluorine, chlorine substituents in the nucleus will increase the binding affinity of 4- and 6-azaindole-3-carboxamides derivatives and positive contribution of descriptors illustrates that increase in branching and presence of methyl, methoxy, fluorine, chlorine is favorable for renin inhibitory activity. Further analysis using kNN methodology with GA-PLS, SA-PLS, and SW-PLS was used for building the QSAR models. The most significant model is having internal predictivity 74 % ( q = 0.7408) and external predictivity 78.3 % (pred_ r = 0.7837). Model showed that electrostatic (E_886, E_561) steric (S_522), and hydrophobic (H_1136) interactions play important role in determining renin inhibitory activity. The pharmacophore analysis of the molecules demonstrated that the AroC feature (aromatic), hydrogen-bond donor (HDr), hydrogen-bond acceptor (HAc), and PosC features are important pharmacophore contours favorable for these activities. The information obtained from 2D descriptors, three-dimensional contour maps and pharmacophore approach can be used for further design of substituted 4- and 6-azaindole-3-carboxamides analogs as renin inhibitors. [ABSTRACT FROM AUTHOR]

This article provides a review of the role of aliskiren, a direct renin inhibitor, in pediatric hypertension and kidney diseases. Among the many mechanisms involved in regulating blood pressure, the renin-angiotensin-aldosterone system (RAAS) plays a major role. Additionally, the RAAS has been identified as a contributing factor to cardiovascular and renal diseases for more than three decades. The potential benefits of inhibiting the RAAS by aliskiren alone or in combination with other RAAS blockers (ACEIs, ARBs) seem to be theoretically promising. However, caution should be exercised in treating children, especially in those with significant chronic kidney disease until there is more evidence regarding the safety and efficacy of this new drug in the pediatric population from ongoing clinical trials. [ABSTRACT FROM AUTHOR]

Partial least squares regression method was used to analyze a peptide dataset and construct inhibitory models for renin-inhibitory natural dipeptides. The models were computed with the renin-inhibitory activity as dependent variable ( Y) and the peptide structural properties as predictors ( X); validation was conducted using cross-validation and permutation tests. The amino acid descriptors were based on the 3- and 5- z scales of 20 coded amino acids to produce models that explained 71.6% of Y with a 33.8% predictive ability and 75.2% of Y with a predictive power of 50.8%, respectively. In both models, low molecular size amino acids with hydrophobic side chains were preferred at the N-terminus, while amino acids with bulky side chains were preferred at the C-terminus for potency. Based on the 5- z model, four Trp (W)-containing antihypertensive dipeptides (IW, LW, VW and AW) were predicted as the most potent renin inhibitors. The peptides were synthesized and in vitro inhibition assay showed that IW and LW inhibited 70% (IC, 2.3 mM) and 37% renin activity at 3.2 mM, respectively, whereas VW and AW were inactive. There was no correlation between the observed renin-inhibitory activities and angiotensin-converting enzyme inhibitory activities of the dipeptides. We concluded that the structural similarities between isoleucine and leucine could have contributed to their distinct inhibitory activity when compared to alanine and valine. Therefore, IW may be a useful template for the development of advanced forms of highly active low molecular size antihypertensive peptides and peptidomimetics. [ABSTRACT FROM AUTHOR]

The renin-angiotensin system (RAS) is the most important mechanism leading to cardiovascular and renal damage in diabetic patients. Studies conducted until now have unequivocally demonstrated that antihypertensive treatment with RAS blockers (angiotensin-converting enzyme (ACE) inhibitors or angiotensin-receptor blockers) improve the prognosis of patients with diabetes, by reducing rates of cardiovascular events and preventing or delaying the progression of diabetic nephropathy. However, despite the benefits of such treatment, cardio-renal events are still very frequent in diabetics. Several strategies for reducing this cardiovascular and renal risk have been proposed, but among them, a more complete blockade of the RAS seems the most attractive. Direct renin inhibitors are RAS blockers with some particularities, such as their ability to reduce plasma renin activity or the possibility to modulate tissue and intracellular RAS, which could represent a theoretical advantage when treating diabetic patients. In experimental and clinical studies conducted until now, aliskiren is able to reduce blood pressure in diabetics, alone or in combination with ACE inhibitors or angiotensin-receptor blockers. Moreover, aliskiren reduces markers of cardiac and renal disease, such as left ventricular hypertrophy or post-infarction ventricular remodeling, as well as proteinuria in diabetics already treated with other RAS blockers. The translation of these promising results to the clinical arena is currently being investigated in the Aliskiren Trial in Type 2 Diabetes Using Cardio-Renal Endpoints (ALTITUDE), where more than 8600 diabetic patients with chronic kidney disease and at high-risk of cardio-renal events are treated with aliskiren or placebo added to the current treatment consisting of another RAS blocker. If positive, aliskiren will be the treatment of choice in the prevention of cardiorenal disease in diabetics. [ABSTRACT FROM AUTHOR]

Increased renin-angiotensin-aldosterone system (RAAS) activity contributes to target-organ damage and increases cardiovascular risk by elevating blood pressure (BP) and through direct effects on the heart, kidneys, brain, and vascular endothelium. Pharmacologic blockade of RAAS effectively reduces BP and limits or reverses various forms of target-organ damage, including cardiac heart failure, coronary artery disease, chronic kidney disease, and left ventricular hypertrophy. Direct renin inhibitors selectively inhibit human renin and have a therapeutic potential similar to angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers. Aliskiren is the only orally active direct renin inhibitor that has been approved for the treatment of hypertension and has been shown to have favorable effects on target-organ damage. It effectively reduces BP and has favorable effects on heart failure and proteinuria in diabetic patients. Additional outcome trials are needed to establish the role of this new class of antihypertensive medication in preventing cardiovascular outcomes. [ABSTRACT FROM AUTHOR]

The renin-angiotensin system has been a target in the treatment of hypertension for close to three decades. Several medication classes that block specific aspects of this system have emerged as useful therapies, including angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and, most recently, direct renin inhibitors. There has been a natural history to the development of each of these three drug classes, starting with their use as antihypertensive agents; thereafter, in each case they have been employed as end-organ protective agents. To date, there has been scant evidence to favor angiotensin receptor blockers or direct renin inhibitors over angiotensin-converting enzyme inhibitors in treating hypertension or in affording end-organ protection; thus, angiotensin-converting enzyme inhibitors remain the standard of care when renin-angiotensin system blockade is warranted. [ABSTRACT FROM AUTHOR]

We conducted a systematic review and meta-analysis of double-blind randomized controlled trials to quantify the dose-related systolic (SBP) and diastolic blood pressure (DBP) lowering efficacy of renin inhibitors vs placebo in the treatment of adults with primary hypertension. Databases searched were Medline (1966–March 2008), EMBASE (1988–March 2008) and Cochrane Central Register of Controlled Trials (CENTRAL). Six trials in 3694 patients met the inclusion criteria. All examined aliskiren, the only renin inhibitor licensed for marketing in Canada and the United States. Aliskiren caused a dose-related SBP/DBP lowering effect compared to placebo: weighted mean difference with 95% CI: aliskiren 75 mg, −2.9 (−4.6, −1.3)/−2.3 (−3.3, −1.3) mm Hg; aliskiren 150 mg, −5.5 (−6.5, −4.4)/−3.0 (−3.7, −2.3) mm Hg; aliskiren 300 mg, −8.7 (−9.7,−7.6)/−5.0 (−5.6, −4.3) and aliskiren 600 mg, −11.4 (−13.5, −9.2)/−6.6 (−7.9, −5.2) mm Hg. Aliskiren 300 mg significantly lowered both SBP −3.0 (−4.0, −2.0) and DBP −1.7 (−2.3, −1.0) as compared to aliskiren150 mg. Aliskiren has no effect on blood pressure variability. No data were available to assess the effect of aliskiren on heart rate or pulse pressure. This review found weak evidence that during 4- to 8-week use, aliskiren did not increase withdrawals due to adverse effects as compared to placebo. We concluded that aliskiren has a dose-related blood pressure lowering effect better than placebo and magnitude of effect is similar to that determined for angiotensin-converting enzyme inhibitors and angiotensin receptor blockers.Journal of Human Hypertension (2009) 23, 495–502; doi:10.1038/jhh.2008.162; published online 22 January 2009 [ABSTRACT FROM AUTHOR]

Direct renin inhibitors are the first new class of antihypertensive to emerge since angiotensin II receptor blockers. We discuss their reno- and cardioprotective potential, based on extrapolation from animal models and phase three trials that are currently ongoing. This paper reviews the potential benefits of direct renin inhibitors (DRIs), the only new anti-hypertensive class developed in the last decade, as compared to pre-existing classes of drug inhibiting more downstream, such as Angiotensin Converting Enzyme inhibitors (ACEI), Angiotensin 2 Receptor Blockers (ARBS). [ABSTRACT FROM AUTHOR]

The expression and function in growth and apoptosis of the renin-angiotensin system (RAS) was evaluated in human glioblastoma. Renin and angiotensinogen (AGT) mRNAs and proteins were found by in situ hybridisation and immunohistochemistry in glioblastoma cells. Angiotensinogen was present in glioblastoma cystic fluids. Thus, human glioblastoma cells produce renin and AGT and secrete AGT. Human glioblastoma and glioblastoma cells expressed renin, AGT, renin receptor, AT2 and/or AT1 mRNAs and proteins determined by RT-PCR and/or Western blotting, respectively. The function of the RAS in glioblastoma was studied using human glioblastoma cells in culture. Angiotensinogen, des(Ang I)AGT, tetradecapaptide renin substrate (AGT1-14), Ang I, Ang II or Ang III, added to glioblastoma cells in culture, did not modulate their proliferation, survival or death. Angiotensin-converting enzyme inhibitors did not diminish glioblastoma cell proliferation. However, the addition of selective synthetic renin inhibitors to glioblastoma cells decreased DNA synthesis and viable tumour cell number, and induced apoptosis. This effect was not counterbalanced by concomitant addition of Ang II. In conclusion, the complete RAS is expressed by human glioblastomas and glioblastoma cells in culture. Inhibition of renin in glioblastoma cells may be a potential approach to control glioblastoma cell proliferation and survival, and glioblastoma progression in combination therapy.British Journal of Cancer (2004) 90, 1059-1068. doi:10.1038/sj.bjc.6601646 www.bjcancer.com [ABSTRACT FROM AUTHOR]

Lipophilicity, often expressed as distribution coefficients (log D) in octanol/water, is an important physicochemical parameter influencing processes such as oral absorption, brain uptake and various pharmacokinetic (PK) properties. Increasing log D values increases oral absorption, plasma protein binding and volume of distribution. However, more lipophilic compounds also become more vulnerable to P450 metabolism, leading to higher clearance. Molecular size and hydrogen bonding capacity are two other properties often considered as important for membrane permeation and pharmacokinetics. Interrelationships among these physicochemical properties are discussed. Increasing size (molecular weight) often gives higher potency, but inevitably also leads to either higher lipophilicity, and hence poorer dissolution/solubility, or to more hydrogen bonding capacity, which limits oral absorption. Differences in optimal properties between gastrointestinal absorption and uptake into the brain are addressed. Special attention is given to the desired lipophilicity of CNS drugs. In examples using β-blockers, Ca channel antagonists and peptidic renin inhibitors we will demonstrate how potency and pharmacokinetic properties need to be balanced. [ABSTRACT FROM AUTHOR]

Pharmacological intervention in the renin-angiotensin system (RAS) by inhibition of angiotensin-converting enzyme (ACE) is an effective therapy for the majority of hypertensive patients and a major advance in the treatment of hypertension and congestive heart failure. The success achieved with ACE inhibitors has increased interest in inhibitors of renin. Renin catalyzes the first and rate-limiting step of the RAS and, unlike ACE, has a high specificity for its endogenous protein substrate. A therapeutic agent that inhibits this specific reaction could have advantages over antihypertensive drugs with less specific modes of action. Although inhibitors of renin have been studied for over two decades, only recently has substantial progress been made toward potent, low molecular weight inhibitors likely to become useful therapeutic agents. Recent advances in the development of renin inhibitors, especially progress toward clinically useful inhibitors, is reviewed. [ABSTRACT FROM AUTHOR]

Since the category of cardiovascular drugs comprises a considerable number of pharmacotherapeutic groups, an overview of future developments must necessarily be limited to those areas in which innovations are most likely to occur. Further extension of our knowledge of thrombolytic therapy may eventually lead to new choices of primary drugs. In the area of antiarrhythmic therapy, the clinical use of a number of drugs has been hampered by the pro-arrhythmogenic actions of these agents. The development of new class III anti-arrhythmics will continue, probably giving rise to new therapeutic options. In the vascular area a new group of drugs, the renin inhibitors, is likely to emerge for the treatment of hypertension. Moreover, exciting discoveries in vascular pharmacology should eventually translate into new pharmacotherapeutic approaches. Finally, the large-scale availability of blood fractions (coagulation factors) prepared by recombinant technology may help solve current shortages of products derived from donated blood. [ABSTRACT FROM AUTHOR]