Angiotensin-converting Enzyme Inhibitor Lisinopril Research Articles

Effectiveness lisinopril and amlodipine combination in the prevention of patients with hypertonic disease in comorbidity witn obliterative atherosclerosis of lower extremities in family practice

The article presents the results of 40 patients with hypertonic disease (HD) with 2–3 degrees of arterial hypertension in combination with obliterative atherosclerosis of the lower extremities (OALE), in which hyperkinetic, eukinetic and hypokinetic types of central hemodynamics with the prevalence of the sympathetic nervous system were detected. It has been proved that in the absence of individual contraindications, the combination of an ACE inhibitor lisinopril and calcium antagonist amlodipine is optimal and universal for the effective treatment of patients with HD in combination with OALE in all types of central hemodynamics. Since after 6 months of treatment the highest positive dynamics of hemodynamic parameters, in particular, increase the pulse index – by 24,8%, the decrease in the resistance index – by 21,1%, the increase in the linear and volume velocity of blood – respectively, by 25,6% and 27,4% at the same time achievement of the target blood pressure level.

Lisinopril Preserves Physical Resilience and Extends Life Span in a Genotype-Specific Manner in Drosophila melanogaster.

Physical resiliency declines with age and comorbid conditions. In humans, angiotensin-converting enzyme (ACE) has been associated with attenuation of the decline in physical performance with age. ACE-inhibitor compounds, commonly prescribed for hypertension, often have beneficial effects on physical performance however the generality of these effects are unclear. Here, we tested the effects of the ACE-inhibitor Lisinopril on life span, and age-specific speed, endurance, and strength using three genotypes of the Drosophila melanogaster Genetic Reference Panel. We show that age-related decline in physical performance and survivorship varies with genetic background. Lisinopril treatment increased mean life span in all Drosophila Genetic Reference Panel lines, but its effects on life span, speed, endurance, and strength depended on genotype. We show that genotypes with increased physical performance on Lisinopril treatment experienced reduced age-related protein aggregation in muscle. Knockdown of skeletal muscle-specific Ance, the Drosophila ortholog of ACE, abolished the effects of Lisinopril on life span, implying a role for skeletal muscle Ance in survivorship. Using transcriptome profiling, we identified genes involved in stress response that showed expression changes associated with genotype and age-dependent responsiveness to Lisinopril. Our results demonstrate that Ance is involved in physical decline and demonstrate genetic variation in phenotypic responses to an ACE inhibitor.

Addition of cyclic angiotensin-(1-7) to angiotensin-converting enzyme inhibitor therapy has a positive add-on effect in experimental diabetic nephropathy

The Renin-Angiotensin System (RAS) possesses a counter-regulatory axis composed of angiotensin converting enzyme (ACE)2, angiotensin-(1-7) [Ang-(1-7)] and the Mas receptor, which opposes many AT1-receptor-mediated effects of ligand angiotensin II. Ang-(1-7), as a ligand of the Mas receptor, has inhibitory effects on renal inflammation and fibrosis in experimental diabetes. However, Ang-(1-7) has a short half-life in plasma, which may render it unsuitable for use in clinics. Here, we investigated the effects of the lanthionine-stabilized Ang-(1-7), cyclic (c)Ang-(1-7), a lanthipeptide that is more peptidase-resistant than the linear peptide, in BTBR ob/ob mice with type 2 diabetic nephropathy. BTBR ob/ob mice received vehicle, cAng-(1-7), or the ACE inhibitor lisinopril. The treatment started at ten weeks of age, when the animals had already developed albuminuria, and ended at 19-20 weeks of age. cAng-(1-7) limited albuminuria progression, and limited podocyte dysfunction similarly to lisinopril. cAng-(1-7), unlike lisinopril, reduced glomerular fibrosis and inflammation, and counteracted glomerular capillary rarefaction. Furthermore, when cAng-(1-7) was combined with lisinopril, a superior antiproteinuric effect than with lisinopril alone was found, in association with better preservation of podocyte proteins and amelioration of capillary density. Thus, adding cAng-(1-7) to ACE-inhibitor therapy could benefit those diabetic patients who do not respond completely to ACE-inhibitor therapy.

Cardiac Remodeling and Reversible Pulmonary Hypertension During Pneumonitis in Rats after 13-Gy Partial-Body Irradiation with Minimal Bone Marrow Sparing: Effect of Lisinopril.

Total-body irradiation causes acute and delayed toxicity to hematopoietic, pulmonary, cardiac, gastrointestinal, renal, and other organ systems. Angiotensin-converting enzyme inhibitors mitigate many of the delayed injuries to these systems. The purpose of this study was to define echocardiographic features in rats at two times after irradiation, the first before lethal radiation pneumonitis (50 d) and the second after recovery from pneumonitis but before lethal radiation nephropathy (100 d), and to determine the actions of the angiotensin-converting enzyme inhibitor lisinopril. Four groups of female WAG/RijCmcr rats at 11-12 wk of age were studied: nonirradiated, nonirradiated plus lisinopril, 13-Gy partial-body irradiation sparing one hind leg (leg-out partial-body irradiation), and 13-Gy leg-out partial-body irradiation plus lisinopril. Lisinopril was started 7 d after radiation. Echocardiograms were obtained at 50 and 100 d, and cardiac histology was assessed after 100 d. Irradiation without lisinopril demonstrated echocardiographic transient pulmonary hypertension by 50 d which was largely resolved by 100 d in survivors. Irradiated rats given lisinopril showed no increase in pulmonary artery pressures at 50 d but exhibited left ventricular remodeling. By 100 d these rats showed some signs of pulmonary hypertension. Lisinopril alone had no impact on echocardiographic end points at either time point in nonirradiated rats. Mild increases in mast cells and fibrosis in the heart were observed after 100 d following 13-Gy leg-out partial-body irradiation. These data demonstrate irradiation-induced pulmonary hypertension which was reversed in survivors of pneumonitis. Lisinopril modified cardiovascular remodeling to enhance survival in this model from 41% to 86% (p = 0.0013).

Effect of antihypertensive therapy on development of incident conduction system disease in hypertensive patients.

Previous work has demonstrated that treatment of hypertensive patients with the angiotensin-converting enzyme inhibitor lisinopril was associated with a reduced incidence of a composite conduction system disease endpoint and also left bundle branch block (LBBB) compared with chlorthalidone therapy. The relationship of incident conduction system disease to angiotensin receptor blocker therapy has not been examined. Risk of new right (RBBB) or LBBB in relation to losartan-based vs. atenolol-based treatment was assessed in 8342 hypertensive patients without baseline RBBB or LBBB. Risk of incident intraventricular conduction delay (IVCD), defined as new QRS duration at least 110 ms was assessed in the 7110 patient subset who also had baseline QRS duration less than 110 ms. QRS duration and BBB were determined on in-study ECGs done at 6 months, 1 year and then yearly. During 4.8 ± 1.0 years follow-up, 459 patients developed new LBBB (5.5%), 184 (2.2) new RBBB and 1173 (16.5%) a new IVCD. In univariate Cox analyses, losartan-based treatment was not associated with a significantly reduced risk of either new LBBB (hazard ratio 0.95, 95% CI 0.79-1.14, P = 0.583) or RBBB (hazard ratio 1.02, 95% CI 0.76-1.36, P = 0.903), but resulted in a 15% lower risk of new IVCD (hazard ratio 0.85, 95% CI 0.76-0.95, P = 0.005). In a multivariable Cox model that adjusted for other statistically significant predictors of incident IVCD in this population (age, sex, race, history of ischemic heart disease, MI, heart failure, diabetes or atrial fibrillation, prior antihypertensive treatment, baseline total and HDL cholesterol, serum glucose and creatinine and baseline QRS duration as standard covariates and incident MI and on-treatment systolic and diastolic pressure, BMI and Cornell voltage as time-dependent covariates), losartan treatment remained associated with a 13% lower risk of new IVCD (hazard ratio 0.87, 95% CI 0.77-0.98, P = 0.021). Incident IVCD, but not BBB, is significantly reduced by losartan-based treatment. Further study is warranted to assess the potential differential impact of this therapy on QRS prolongation vs. development of more discrete conduction system block. .

Ocular kinetics and safety of intravitreally injected angiotensin converting enzyme inhibitor lisinopril

Background and objectivesThe study investigated the intravitreal safety and vitreous disposition of lisinopril, an angiotensin converting enzyme inhibitor in rabbits for its projected use in retinopathy.MethodsFor the safety study, following the baseline ERG recording and fundus photography, 40 µg/50 µl of lisinopril sterile injection was injected unilaterally in the rabbit eyes (n = 4), where other eye served as a control. The electroretinogram and fundus images were obtained at 24, 48, 72 and 168 h following the intravitreal injection. For pharmacokinetics evaluation of the lisinopril, one eye of each rabbit (n = 4) received an intravitreal injection of lisinopril (40 µg/50 µl). The concentration of lisinopril in the ocular tissues, humours, plasma, lung, kidney and liver were measured through ESI-LC-MS/MS.ResultsUpon the electroretinography studies, no significant difference was observed in the ERG pattern in the lisinopril injected eye when compared to the baseline of the respective animals till the 7th day of the study. In the fundus imaging, no morphological changes were observed in the retina of the animal. The concentration of the lisinopril was found to be above to the IC50 in the retina-choroid till 36 h. The concentration found in the plasma and body tissues were many folds less than the IC50 of the lisinopril.ConclusionsIntravitreal injection of 40 µg/50 µl of lisinopril found to be safe in the rabbit eye as evidenced by the electroretinography and fundus imaging studies. The average half-life of lisinopril is 12.6 h and the above-mentioned dose able to sustain its IC50 value till the 36 h.

A method using angiotensin converting enzyme immobilized on magnetic beads for inhibitor screening

Angiotensin converting enzyme (ACE), fusing with FLAG tag, was overexpressed in human embryonic kidney 293T cells. This recombinant FLAG-tagged ACE was immobilized on anti-FLAG antibody coated magnetic beads by affinity method in crude cell lysate for the first time. The enzyme-immobilized magnetic beads (ACE-MB), without further cleavage procedure, were used directly to establish a cost-effective and reliable method for screening ACE inhibitors by coupling with fluorescence detection. The enzymatic activity of the ACE-MB was validated based on its Michaelian kinetic behavior towards hippuryl-histidyl-leucine by UHPLC-MS/MS method firstly. Then, several conditions were optimized including amount of magnetic beads, incubation temperature and time in the procedure of ACE immobilization and amount of ACE-MB in the microplate operation. Moreover, this screening assay was validated with Z′ factors between 0.71 and 0.81 using four known ACE inhibitors (captopril, lisinopril, fosinopril and fosinoprilat). The developed method was applied for the screening of ACE inhibitors from a small compound library of 45 natural products. As a result, epiberberine and fangchinoline with certain ACE inhibitory activities were screened out in the assay and validated. The results demonstrate the usefulness of this screening method using ACE immobilized on magnetic beads and the advantage of great efficiency with respect to both time and reagents for screening ACE inhibitors.

The fixed combination of lisinopril and indapamide: optimization of cardioprotection in hypertensive patients

The article presents current knowledge of рro- and antihypertensive mechanisms involved in the development of hypertension (HTN), and antihypertensive management strategies. Particular attention is paid to the angiotensin converting enzyme inhibitor lisinopril and thiazide-like diuretic indapamide. The mechanisms and effects are described. The paper discusses the results of multicenter randomized clinical trials, and the antihypertensive effects of lisinopril and indapamide and their impact on myocardial hypertrophy in hypertensive patients. The potential advantages of fixed combination of lisinopril and indapamide in the treatment of patients with HTN are also discussed.

Involvement of Endothelial Nitric Oxide Synthase Activation in Midkine-Mediated Central Hypotensive Effects.

The growth factor midkine (MK) has been implicated in various biologic and pathologic events. It has been shown that the peripheral influence of MK on cardiovascular regulation is due to an influence on the renin-angiotensin system (RAS). The nucleus tractus solitarii (NTS) is the primary integrative center for cardiovascular control and other autonomic functions in the central nervous system. However, the signaling mechanisms involved in MK-mediated cardiovascular effects in the NTS remain unclear. In this study, we investigated whether the RAS and/or N-methyl-D-aspartate (NMDA) receptor-calmodulin-endothelial nitric oxide synthase (eNOS) signaling pathways were both involved in MK-mediated blood pressure (BP) regulation in the NTS of Wistar-Kyoto (WKY) rats. Intra-NTS microinjection and immunoblot analysis were used to evaluate the signal pathway. WKY rats were anesthetized with urethane. Unilateral microinjection of MK (600 fmol) into the NTS produced a dose-dependent decrease in BP and heart rate (HR). The depressor effects were observed before and after microinjection of the angiotensin-converting enzyme (ACE) inhibitor lisinopril (2.4 fmol), or the angiotensin receptor blockers (ARB) inhibitor valsartan (7.5 pmol). However, lisinopril and valsartan did not diminish the MK-mediated cardiovascular effects in the NTS. Microinjection of the NMDA receptor antagonist MK801 (1 nmol) or the NOS inhibitor N-nitro l-arginine methyl ester (L-NAME), (33 nmol), into the NTS attenuated the MK-induced hypotensive effects. Pretreatment with an eNOS inhibitor N5-iminoethyl-l-ornithine (L-NIO) (6 nmol) attenuated the MK-induced hypotensive effects. In this study, the data showed that MK might play a role in central cardiovascular regulation in the NTS. These results suggest that MK decreased BP and HR in the NTS probably acting via the NMDA receptor-calmodulin-eNOS signaling pathway.

Abstract P415: ACE N-domain Regulates High-glucose Mediated Interleukin-1 beta Production by Renal Epithelial Cells Independently From Angiotensin II Generation

Research studies demonstrated that interleukin (IL)-1β contributes to the development of diabetic nephropathy and hypertension. However, the origin and regulation of IL-1β synthesis during diabetic kidney injury are still unknown. Here, we hypothesize that renal epithelial cells produce IL-1β in response to a high glucose stress and that angiotensin converting enzyme (ACE) plays a key role in this process. To study this, we isolated proximal tubular (PT) epithelial cells from wild-type (WT) and mice lacking either the ACE N-domain (NKO) or the C-domain (CKO) catalytic activity. These cells were exposed to normal (5 mM) or high (30 mM) glucose for 24 hours. IL-1β produced by PT cells were assessed by ELISA and RT-PCR. High glucose induced WT PT cells to release significant amounts of IL-1β (from 5±1 to 70±6 pg/ml, p<0.001; n=6). When WT PT cells were exposed to a high glucose media in the presence of an ACE inhibitor (lisinopril, 10 mM), IL-1β levels were significantly reduced (from 70±6 to 38±6 pg/ml, p<0.01). In contrast, AT1 receptor blockade by losartan did not change the amount of IL-1β produced by WT PT cells. To determine which ACE domain is associated with IL-1β production, NKO and CKO PT cells were exposed to high glucose. Strikingly, NKO PT cells released lower amounts of IL-1β when exposed to high glucose compared to WT (NKO: 15±7 vs. WT: 79±9 pg/ml, p<0.01, n=4). No differences were observed between WT and CKO PT cells. Since the ACE N-domain degrades the anti-inflammatory tetrapeptide N-acetyl-Ser-Asp-Lys-Pro (AcSDKP), we tested whether the lower IL-1β production in NKO PT cells was due to an accumulation of AcSDKP. For this, we pre-treated NKO PT cells with a prolyl endopeptidase inhibitor (S17092, 50μM) to prevent the production of AcSDKP. Notably, this treatment increased the IL-1β response to high glucose in NKO PT cells (2.1±0.3-fold increase, p<0.01, n=4). Our data indicate that: 1) PT cells can sense and respond to high glucose by secreting IL-1β and 2) the absence of the ACE N-domain blunts the production of IL-1β through a mechanism that involves AcSDKP accumulation. In conclusion, ACE might contribute to the inflammatory response that underlays diabetic nephropathy independently from angiotensin II generation.

AT1 and AT2 Receptors in the Prelimbic Cortex Modulate the Cardiovascular Response Evoked by Acute Exposure to Restraint Stress in Rats.

The prelimbic cortex (PL) is an important structure in the neural pathway integrating stress responses. Brain angiotensin is involved in cardiovascular control and modulation of stress responses. Blockade of angiotensin receptors has been reported to reduce stress responses. Acute restraint stress (ARS) is a stress model, which evokes sustained blood pressure increase, tachycardia, and reduction in tail temperature. We therefore hypothesized that PL locally generated angiotensin and angiotensin receptors modulate stress autonomic responses. To test this hypothesis, we microinjected an angiotensin-converting enzyme (ACE) inhibitor or angiotensin antagonists into the PL, prior to ARS. Male Wistar rats were used; guide cannulas were bilaterally implanted in the PL for microinjection of vehicle or drugs. A polyethylene catheter was introduced into the femoral artery to record cardiovascular parameters. Tail temperature was measured using a thermal camera. ARS was started 10min after PL treatment with drugs. Pretreatment with ACE inhibitor lisinopril (0.5nmol/100nL) reduced the pressor response, but did not affect ARS-evoked tachycardia. At a dose of 1nmol/100nL, it reduced both ARS pressor and tachycardic responses. Pretreatment with candesartan, AT1 receptor antagonist reduced ARS-evoked pressor response, but not tachycardia. Pretreatment with PD123177, AT2 receptor antagonist, reduced tachycardia, but did not affect ARS pressor response. No treatment affected ARS fall in tail temperature. Results suggest involvement of PL angiotensin in the mediation of ARS cardiovascular responses, with participation of both AT1 and AT2 receptors. In conclusion, results indicate that PL AT1-receptors modulate the ARS-evoked pressor response, while AT2-receptors modulate the tachycardic component of the autonomic response.

The effect of swimming exercise on adenine-induced kidney disease in rats, and the influence of curcumin or lisinopril thereon

Patients with chronic kidney disease (CKD) have been reported to benefit from different types of exercises. It has also been shown that the ACE inhibitor lisinopril, and the natural product curcumin are also beneficial in different models of CKD in rats. We assessed the influence of moderate swimming exercise (SE) on rats with adenine-induced CKD, and tested the possible effects of lisinopril and/or curcumin thereon using several physiological, biochemical, histopathological and immunohistochemical parameters. Rats (either sedentary or subjected to SE) were randomly divided into several groups, and given for five weeks either normal food or food mixed with adenine (0.25% w/w) to induce CKD. Some of these groups were also concomitantly treated orally with curcumin (75 mg/kg), or lisinopril (10 mg/kg) and were subjected to moderate SE (45 min/day three days each week). Rats fed adenine showed the typical biochemical, histopathological signs of CKD such as elevations in blood pressure, urinary albumin / creatinine ratio, and plasma urea, creatinine, indoxyl sulfate and phosphorus. SE, curcumin or lisinopril, given singly, significantly ameliorated all the adenine-induced actions. Administering curcumin or lisinopril with SE improved the histopathology of the kidneys, a salutary effect not seen with SE alone. Combining SE to the nephroprotective agents’ curcumin or lisinopril might offer additional nephroprotection.

Gene expression effects of glucocorticoid and mineralocorticoid receptor agonists and antagonists on normal human skeletal muscle.

Mineralocorticoid and glucocorticoid receptors are closely related steroid hormone receptors that regulate gene expression through many of the same hormone response elements. However, their transcriptional activities and effects in skeletal muscles are largely unknown. We recently identified mineralocorticoid receptors (MR) in skeletal muscles after finding that combined treatment with the angiotensin-converting enzyme inhibitor lisinopril and MR antagonist spironolactone was therapeutic in Duchenne muscular dystrophy mouse models. The glucocorticoid receptor (GR) agonist prednisolone is the current standard-of-care treatment for Duchenne muscular dystrophy because it prolongs ambulation, likely due to its anti-inflammatory effects. However, data on whether glucocorticoids have a beneficial or detrimental direct effect on skeletal muscle are controversial. Here, we begin to define the gene expression profiles in normal differentiated human skeletal muscle myotubes treated with MR and GR agonists and antagonists. The MR agonist aldosterone and GR agonist prednisolone had highly overlapping gene expression profiles, supporting the notion that prednisolone acts as both a GR and MR agonist that may have detrimental effects on skeletal muscles. Co-incubations with aldosterone plus either nonspecific or selective MR antagonists, spironolactone or eplerenone, resulted in similar numbers of gene expression changes, suggesting that both drugs can block MR activation to a similar extent. Eplerenone treatment alone decreased a number of important muscle-specific genes. This information may be used to develop biomarkers to monitor clinical efficacy of MR antagonists or GR agonists in muscular dystrophy, develop a temporally coordinated treatment with both drugs, or identify novel therapeutics with more specific downstream targets.

Lisinopril or Coreg CR in reducing cardiotoxicity in women with breast cancer receiving trastuzumab: A rationale and design of a randomized clinical trial

Trastuzumab (TZB) is an established therapy for HER2-positive breast cancer. The use of TZB is commonly associated with cardiotoxicity manifesting as asymptomatic decrease in left ventricular ejection fraction (LVEF) or overt heart failure. Several studies demonstrated favorable effects of angiotensin-converting enzyme (ACE) inhibitors and β-blockers (BBs) in the prevention of chemotherapy-induced cardiotoxicity. We hypothesize that patients, randomized to receive an ACE inhibitor or a BB during trastuzumab therapy for breast cancer, will maintain a higher LVEF than patients randomized to placebo. We designed a prospective, multicenter, randomized, phase II placebo-controlled clinical trial to evaluate the effects of an ACE inhibitor (lisinopril) and a BB (carvedilol phosphate-extended release) on cardiotoxicity in patients with breast cancer who are receiving adjuvant or neoadjuvant TZB therapy. The primary objectives include (1) comparison of incidence of cardiotoxicity and (2) comparison of LVEF as a continuous variable in between the arms. Cardiotoxicity was defined as an absolute decrease in LVEF from baseline of ≥10% at follow-up or an absolute decrease of ≥5% in LVEF from baseline for individuals with <50% LVEF at follow-up. The target accrual is 468 participants, representing patients both with and without anthracycline exposure. The enrollment is completed. The trial is co-sponsored by University of South Florida and National Cancer Institute. The LVEF is being evaluated by echocardiography or multigated acquisition scan. If we can demonstrate that the use of an ACE inhibitor or a BB can reduce the degree of TZB-induced cardiotoxicity, it is hoped that patients will receive complete and uninterrupted TZB therapy for breast cancer without compromising cardiac function.

EFFECT OF ANTIHYPERTENSIVE THERAPY ON DEVELOPMENT OF INCIDENT CONDUCTION SYSTEM DISEASE IN HYPERTENSIVE PATIENTS: THE LIFE STUDY

Background: Previous work has demonstrated that treatment of hypertensive patients with the angiotensin-converting enzyme inhibitor lisinopril was associated with a reduced incidence of a composite conduction system disease endpoint and also left bundle branch block (LBBB) compared with either

Abstract B12: Adding angiotensin-system inhibitors to anti-angiogenic therapy reduces vasogenic edema in newly diagnosed glioblastomas but not in recurrent disease

Abstract Introduction: Recent theoretical [1], pre-clinical [2] and human tumor data [3] suggest anti-hypertensives with an extracellular matrix-depleting effect improve vascular function by reducing the solid stress that can squeeze tumor vessels shut [4]. This work is contrasted by studies showing that certain matrix-depleting anti-hypertensives (angiotensin-II receptor blockers) are also associated with reduced peri-tumoral edema [5]. We here show that combined matrix-depleting and anti-angiogenic therapy does reduce vasogenic edema in newly diagnosed glioblastomas but not in recurrent disease and that the mechanisms of action are therefore not fully understood. Methods: We retrospectively assessed data from 40 patients with newly diagnosed glioblastomas (nGBM) and 30 patients with recurrent glioblastomas (rGBM) receiving cediranib, an oral pan-VEGFR inhibitor, with- (NCT00662506) and without (NCT00305656) chemoradiation, respectively. Conventional, perfusion and vessel caliber MRI were performed at baseline and repeated weekly (nGBM) or monthly (rGBM) [6, 7]. Vasogenic edema was measured as the relative volume of peri-tumoral hyper T2-Fluid Attenuated Inversion Recovery (FLAIR) signal on the conventional MRIs. For nGBM, after cediranib onset, 12/40 patients received angiotensin II receptor blockers (Valsartan), β1 receptor antagonists (Atenolol) or angiotensin-converting enzyme inhibitors (Lisinopril), while 8/40 patients received calcium antagonists (Norvasc, Amlodipine) [3]. Similarly, for rGBM, 15/30 patients received Atenolol and 7/30 patients Norvasc. Results: While angiotensin-system inhibitors (ASIs) significantly improved the perfused vessel fraction (% of tumor values &amp;gt;½ the value of healthy tissue; Wilcoxon P&amp;lt;0.05) and the relative small vessel fraction (&amp;lt;½ the size of healthy tissue; Wilcoxon P&amp;lt;0.01) for both cohorts, reduction of vasogenic edema was only observed in nGBM patients. Here, both cediranib alone and in combination with ASIs reduced the median relative vasogenic edema volume (82% and 54% over study period and compared to baseline values, respectively; Wilcoxon P&amp;lt;0.05), but not for non-ASI calcium antagonists (96%). For rGBMs, cediranib alone reduced the median relative vasogenic edema volume (90%; P&amp;lt;0.05), but not when adding ASIs. Instead, there was a trend towards reduced vasogenic edema with non-ASI calcium antagonists. Conclusion: The potential anti-edema effect associated with ASI anti-hypertensives is an attractive feature for reduced administration of steroids in patients with glioblastoma. However, our data indicate that the matrix-depleting activity of some anti-hypertensives improves vascular function in both nGBMs and rGBMs [3], but only reduces vasogenic edema in the newly diagnosed setting [5]. Further studies to understand the mechanisms of benefit of ASIs in cancer are warranted.

Lisinopril, Amlodipine, Rosuvastatin as a Novel Fixed Combination in the Fight Against Cardiovascular Disease

The prevalence of multicomponent therapy in treatment of cardiovascular diseases makes fixed combinations of drugs very useful. The fixed combination of rosuvastatin with ACE inhibitor lisinopril and calcium antagonist amlodipine allows to control effectively two main cardiovascular risk factors: hypercholesterolemia and arterial hypertension. The efficacy of each of the components and their combined administration in primary and secondary prevention of cardiovascular disease has been demonstrated in clinical studies. The convenience of several drugs combination in a single tablet increases adherence to therapy facilitating regular intake of all treatment components and reliably reducing the risk of cardiovascular complications.

Renin-angiotensin-aldosterone system inhibitors improve membrane stability and change gene-expression profiles in dystrophic skeletal muscles.

Angiotensin-converting enzyme inhibitors (ACEi) and mineralocorticoid receptor (MR) antagonists are FDA-approved drugs that inhibit the renin-angiotensin-aldosterone system (RAAS) and are used to treat heart failure. Combined treatment with the ACEi lisinopril and the nonspecific MR antagonist spironolactone surprisingly improves skeletal muscle, in addition to heart function and pathology in a Duchenne muscular dystrophy (DMD) mouse model. We recently demonstrated that MR is present in all limb and respiratory muscles and functions as a steroid hormone receptor in differentiated normal human skeletal muscle fibers. The goals of the current study were to begin to define cellular and molecular mechanisms mediating the skeletal muscle efficacy of RAAS inhibitor treatment. We also compared molecular changes resulting from RAAS inhibition with those resulting from the current DMD standard-of-care glucocorticoid treatment. Direct assessment of muscle membrane integrity demonstrated improvement in dystrophic mice treated with lisinopril and spironolactone compared with untreated mice. Short-term treatments of dystrophic mice with specific and nonspecific MR antagonists combined with lisinopril led to overlapping gene-expression profiles with beneficial regulation of metabolic processes and decreased inflammatory gene expression. Glucocorticoids increased apoptotic, proteolytic, and chemokine gene expression that was not changed by RAAS inhibitors in dystrophic mice. Microarray data identified potential genes that may underlie RAAS inhibitor treatment efficacy and the side effects of glucocorticoids. Direct effects of RAAS inhibitors on membrane integrity also contribute to improved pathology of dystrophic muscles. Together, these data will inform clinical development of MR antagonists for treating skeletal muscles in DMD.

Association of 3 Different Antihypertensive Medications With Hip and Pelvic Fracture Risk in Older Adults

On the basis of observational studies, the use of thiazide diuretics for the treatment of hypertension is associated with reduced fracture risk compared with nonuse. Data from randomized clinical trials are lacking. To examine whether the use of thiazide diuretics for the treatment of hypertension is associated with reduced fracture risk compared with nonuse. Using Veterans Affairs and Medicare claims data, this study examined hip and pelvic fracture hospitalizations in Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial participants randomized to first-step therapy with a thiazide-type diuretic (chlorthalidone), a calcium channel blocker (amlodipine besylate), or an angiotensin-converting enzyme inhibitor (lisinopril). Recruitment was from February 1994 to January 1998; in-trial follow-up ended in March 2002. The mean follow-up was 4.9 years. Posttrial follow-up was conducted through the end of 2006, using passive surveillance via national databases. For this secondary analysis, which used an intention-to-treat approach, data were analyzed from February 1, 1994, through December 31, 2006. Hip and pelvic fracture hospitalizations. A total of 22 180 participants (mean [SD] age, 70.4 [6.7] years; 43.0% female; and 49.9% white non-Hispanic, 31.2% African American, and 19.1% other ethnic groups) were followed for up to 8 years (mean [SD], 4.9 [1.5] years) during masked therapy. After trial completion, 16 622 participants for whom claims data were available were followed for up to 5 additional years (mean [SD] total follow-up, 7.8 [3.1] years). During the trial, 338 fractures occurred. Participants randomized to receive chlorthalidone vs amlodipine or lisinopril had a lower risk of fracture on adjusted analyses (hazards ratio [HR], 0.79; 95% CI, 0.63-0.98; P = .04). Risk of fracture was significantly lower in participants randomized to receive chlorthalidone vs lisinopril (HR, 0.75; 95% CI, 0.58-0.98; P = .04) but not significantly different compared with those randomized to receive amlodipine (HR, 0.82; 95% CI, 0.63-1.08; P = .17). During the entire trial and posttrial period of follow-up, the cumulative incidence of fractures was nonsignificantly lower in participants randomized to receive chlorthalidone vs lisinopril or amlodipine (HR, 0.87; 95% CI, 0.74-1.03; P = .10) and vs each medication separately. In sensitivity analyses, when 1 year after randomization was used as the baseline (to allow for the effects of medications on bone to take effect), similar results were obtained for in-trial and in-trial plus posttrial follow-up. These findings from a large randomized clinical trial provide evidence of a beneficial effect of thiazide-type diuretic therapy in reducing hip and pelvic fracture risk compared with treatment with other antihypertensive medications. clinicaltrials.gov Identifier: NCT00000542.

Combined Hydration and Antibiotics with Lisinopril to Mitigate Acute and Delayed High-dose Radiation Injuries to Multiple Organs.

The NIAID Radiation and Nuclear Countermeasures Program is developing medical agents to mitigate the acute and delayed effects of radiation that may occur from a radionuclear attack or accident. To date, most such medical countermeasures have been developed for single organ injuries. Angiotensin converting enzyme (ACE) inhibitors have been used to mitigate radiation-induced lung, skin, brain, and renal injuries in rats. ACE inhibitors have also been reported to decrease normal tissue complication in radiation oncology patients. In the current study, the authors have developed a rat partial-body irradiation (leg-out PBI) model with minimal bone marrow sparing (one leg shielded) that results in acute and late injuries to multiple organs. In this model, the ACE inhibitor lisinopril (at ~24 mg m d started orally in the drinking water at 7 d after irradiation and continued to ≥150 d) mitigated late effects in the lungs and kidneys after 12.5-Gy leg-out PBI. Also in this model, a short course of saline hydration and antibiotics mitigated acute radiation syndrome following doses as high as 13 Gy. Combining this supportive care with the lisinopril regimen mitigated overall morbidity for up to 150 d after 13-Gy leg-out PBI. Furthermore, lisinopril was an effective mitigator in the presence of the growth factor G-CSF (100 μg kg d from days 1-14), which is FDA-approved for use in a radionuclear event. In summary, by combining lisinopril (FDA-approved for other indications) with hydration and antibiotics, acute and delayed radiation injuries in multiple organs were mitigated.