Aging-Exacerbated Acute Axon and Myelin Injury Is Associated with Microglia-Derived Reactive Oxygen Species and Is Alleviated by the Generic Medication Indapamide.

Age is a critical risk factor for many neurologic conditions, including progressive multiple sclerosis. Yet the mechanisms underlying the relationship are unknown. Using lysolecithin-induced demyelinating injury to the mouse spinal cord, we characterized the acute lesion and investigated the mechanisms of increased myelin and axon damage with age. We report exacerbated myelin and axon loss in middle-aged (8-10 months of age) compared with young (6 weeks of age) female C57BL/6 mice by 1-3 d of lesion evolution in the white matter. Transcriptomic analysis linked elevated injury to increased expression of Cybb, the gene encoding the catalytic subunit of NADPH oxidase gp91phox. Immunohistochemistry in male and female Cx3cr1CreER/+:Rosa26tdTom/+ mice for gp91phox revealed that the upregulation in middle-aged animals occurred primarily in microglia and not infiltrated monocyte-derived macrophages. Activated NADPH oxidase generates reactive oxygen species and elevated oxidative damage was corroborated by higher malondialdehyde immunoreactivity in lesions from middle-aged compared with young mice. From a previously conducted screen for generic drugs with antioxidant properties, we selected the antihypertensive CNS-penetrant medication indapamide for investigation. We report that indapamide reduced superoxide derived from microglia cultures and that treatment of middle-aged mice with indapamide was associated with a decrease in age-exacerbated lipid peroxidation, demyelination and axon loss. In summary, age-exacerbated acute injury following lysolecithin administration is mediated in part by microglia NADPH oxidase activation, and this is alleviated by the CNS-penetrant antioxidant, indapamide.SIGNIFICANCE STATEMENT Age is associated with an increased risk for the development of several neurologic conditions including progressive multiple sclerosis, which is represented by substantial microglia activation. We demonstrate that in the lysolecithin demyelination model in young and middle-aged mice, the latter group developed greater acute axonal and myelin loss attributed to elevated oxidative stress through NADPH oxidase in lineage-traced microglia. We thus used a CNS-penetrant generic medication used in hypertension, indapamide, as we found it to have antioxidant properties in a previous drug screen. Following lysolecithin demyelination in middle-aged mice, indapamide treatment was associated with decreased oxidative stress and axon/myelin loss. We propose indapamide as a potential adjunctive therapy in aging-associated neurodegenerative conditions such as Alzheimer's disease and progressive multiple sclerosis.

Anticancer activity of indapamide adsorbed on gold nanoparticles: DFT, in-silico, and in-vitro analysis.

The adsorption properties of the lung cancer agent indapamide (IND) on gold nanoparticles (AuNPs), were studied with the help of surface-enhanced Raman scattering techniques. The structure-activity of the IND and INDA molecule has been studied using DFT/B3LYP methodology. NBO analysis reveals that, both the molecules are stabilized by a C─H… O intramolecular hydrogen bonding, apart from the conjugative and intramolecular charge transfer interactions. The analysis of the electron density of frontier molecular orbital analysis gives a comparative idea of the reactivity, the low kinetic stability, and low value of energy gap indicating the electron transport in the molecule and thereby its bioactivity. The molecular electrostatic potential, local and global reactivity indicators predict the reactive site of the molecules. FT-IR, FT-Raman, and surface-enhanced Raman scattering have been investigated and compared with the theoretical prediction. Effective in-silico (molecular docking) biological activity screening of the molecules was checked on lung cancer cells. In-vitro (surface-enhanced Raman scattering techniques and MTT assay) analysis confirms the results from the in-silico analysis. This study promotes the potential of SERS agents for targeted drug delivery and photothermal therapy and the novelty of the IND and INDA molecule against lung cancer activity.

Synthesis of pro-apoptotic indapamide derivatives as anticancer agents.

4-Chloro-3-({[(substitutedamino)carbonothioyl]amino}sulfonyl)-N-(2-methyl-2,3-dihydro-1H-indole-1-yl)benzamide (1-20) and 4-chloro-3-({[3-(substituted)-4-oxo-1,3-thiazolidine-2-ylidene]amino}sulfonyl)-N-(2-methyl-2,3-dihydro-1H-indole-1-yl)benzamide derivatives (21-31) were synthesized from 4-chloro-N-(2-methyl-2,3-dihydroindol-1-yl)-3-sulfamoylbenzamide (indapamide). 4-Chloro-3-({[(4-chlorophenyl) amino) carbonothioyl]amino}sulfonyl)-N-(2-methyl-2,3-dihydro-1H-indole-1-yl)benzamide 12 demonstrated the highest proapoptotic activity among all synthesized compounds on melanoma cell lines MDA-MB-435 with 3.7% growth inhibition at the concentration of 10 µM. Compound 12 (SGK 266) was evaluated in vitro using the MTT colorimetric method against melanoma cancer cell line MDA-MB435 growth inhibition for different doses and exhibited anticancer activity with IC50 values of 85-95 µM against melanoma cancer cell line MDA-MB435. In addition, this compound was investigated as inhibitors of four physiologically relevant human carbonic anhydrase isoforms, hCA I, II, IX and XII. The compund inhibited these enzymes with IC50 values ranging between 0.72 and 1.60 µM.

[STRUCTURAL AND FUNCTIONAL CHANGES MYOCARDIUM HYPERTENSIVE RATS IN APPLYING INDAPAMIDE AND ELLAGIC ACID].

The article investigates the effectiveness of antihypertensive properties of indapamide and ellagic acid in hypertensive rats. As a result of experimental studies determined the effect of drugs on blood pressure and structural recovery of the myocardium of hypertensive rats. Indapamid with ellagic acid reduces the degradation of contractile myofibrils, mitochondria lysis and swelling of the cytoplasm of cardiomyocytes. The study drug is a normalizing effect on the se parameters. The combined use of indapamid and ellagic acid enhances the structural and functional recovery of myocardium energy metabolism normalizes organelles.

Rationale for a New Low-Dose Triple Single Pill Combination for the Treatment of Hypertension.

Two recent large trials showed the potential of single pill combinations (SPCs) with ≥3 low-dose components among people with hypertension who were untreated or receiving monotherapy. In both trials, these 'hypertension polypills' were superior to usual care, achieving >80% BP control without increasing withdrawal due to side effects. However, there are no such products available for prescribers. To address this unmet need, George Medicines developed GMRx2 with telmisartan/amlodipine/indapamide in three strengths (mg): 10/1.25/0.625, 20/2.5/1.25; 40/5/2.5. Two pivotal trials are ongoing to support FDA submission for the treatment of hypertension, including initial treatment. These assess efficacy and safety of GMRx2 compared to: placebo, and each of the three possible dual combinations. Regulatory submissions are planned for 2024, with the aim of providing access to GMRx2 in developed and developing regions. Wider implementation of GMRx2-based treatment strategies will be guided by further research to inform access and appropriate scale up.

Indapamide lowers blood pressure by increasing production of epoxyeicosatrienoic acids in the kidney.

Diuretics are widely used in the treatment of hypertension, although the precise mechanisms remain unknown. Epoxyeicosatrienoic acids (EETs), cytochrome P450 (P450) epoxygenase metabolites of arachidonic acid, play critical roles in regulation of blood pressure. The present study was carried out to investigate whether EETs participate in the antihypertensive effect of thiazide diuretics [hydrochlorothiazide (HCTZ)] and thiazide-like diuretics (indapamide). Male spontaneously hypertensive rats (SHRs) were treated with indapamide or HCTZ for 8 weeks. Systolic blood pressure, measured via tail-cuff plethysmography and confirmed via intra-arterial measurements, was significantly decreased in indapamide- and HCTZ-treated SHRs compared with saline-treated SHRs. Indapamide increased kidney CYP2C23 expression, decreased soluble epoxide hydrolase expression, increased urinary and renovascular 11,12- and 14,15-EETs, and decreased production of 11,12- and 14,15-dihydroxyeicosatrienoic acids in SHRs. No effect on expression of CYP4A1 or CYP2J3, or on 20-hydroxyeicosatetraenoic acid production, was observed, suggesting indapamide specifically targets CYP2C23-derived EETs. Treatment of SHRs with HCTZ did not affect the levels of P450s or their metabolites. Increased cAMP activity and protein kinase A expression were observed in the renal microvessels of indapamide-treated SHRs. Indapamide ameliorated oxidative stress and inflammation in renal cortices by down-regulating the expression of p47phox, nuclear factor-κB, transforming growth factor-ß1, and phosphorylated mitogen-activated protein kinase. Furthermore, the p47phox-lowering effect of indapamide in angiotensin II-treated rat mesangial cells was partially blocked by the presence of N-(methylsulfonyl)-2-(2-propynyloxy)-benzenehexanamide (MS-PPOH) or CYP2C23 small interfering RNA. Together, these results indicate that the hypotensive effects of indapamide are mediated, at least in part, by the P450 epoxygenase system in SHRs, and provide novel insights into the blood pressure-lowering mechanisms of diuretics.

Blood pressure and metabolic efficacy of fixed-dose combination of perindopril and indapamide in everyday practice.

The aim of the PICASSO study was to evaluate the efficacy and safety of fixed-dose perindopril 10 mg/indapamide 2.5 mg in everyday medical practice. In this 3-month, open-label, observational study, outpatients with primary hypertension who did not reach the blood pressure goal (< 140/90 mmHg) with antihypertensive treatment were enrolled if their treating physician had planned, as part of their ongoing therapy, to switch them to fixed-dose perindopril 10 mg/indapamide 2.5 mg. Blood pressure, heart rate, and metabolic parameters and - optionally - ambulatory blood pressure were measured. Data from 9257 patients were evaluated. Over the course of 3 months, mean blood pressure decreased from 159/93 mmHg to 132/80 mmHg (p < 0.001) and heart rate decreased from 79 to 73 beats/min (p < 0.001). The target blood pressure was reached by 72.7% of patients. Reductions in total cholesterol, low-density lipoprotein-cholesterol (LDL-c), triglycerides, fasting glucose and uric acid levels were clinically significant. Blood levels of high-density lipoprotein-cholesterol (HDL-c), sodium and potassium remained unchanged. Beneficial changes in metabolic parameters were primarily attributed to the reduction in therapy with drugs with unfavourable metabolic profiles (thiazides and beta-blockers). Perindopril/indapamide is an effective and safe antihypertensive treatment in everyday medical practice.

[Optimization of pharmacotherapy in patients with essential hypertension with neurohumoral modulators with consideration of data on heart rate variability].

Long-term treatment of patients with essential hypertension (EH) and autonomic dysfunction (sympathicotonia type) with lisinopril in combination with indapamide augmented activity of humoral systems and improved heart rate variability. Addition of a selective beta-blocker bisoprolol to lisinopril/indapamide combination promoted normalization of humoral activity. This gives reason to apply tiered RAAS blockade in order to ensure more effective control of activity of neurohumoral systems in patients with EH ant initial sympathicotonia.

Effects of blood pressure lowering on major vascular events among patients with isolated diastolic hypertension: the perindopril protection against recurrent stroke study (PROGRESS) trial.

BACKGROUND AND PURPOSE: Despite clear evidence that blood pressure (BP) lowering is effective for prevention of cardiovascular events among patients with isolated systolic hypertension and systolic-diastolic hypertension, there is ongoing uncertainty about its effects in those with isolated diastolic hypertension. The objective of the present analysis is to determine whether BP lowering provides benefits to patients with isolated diastolic hypertension. METHODS: Patients with cerebrovascular disease and hypertension at baseline (n=4283) were randomly assigned to either active treatment (perindopril in all participants plus indapamide for those with neither an indication for nor a contraindication to a diuretic) or matching placebo(s). The primary outcome was total major vascular events. RESULTS: There were 1923 patients with isolated systolic hypertension (systolic BP ≥ 140 mm Hg and diastolic BP < 90 mm Hg), 315 with isolated diastolic hypertension (systolic BP <140 mm Hg and diastolic BP ≥ 90 mm Hg), and 2045 with systolic-diastolic hypertension (systolic BP ≥ 140 mm Hg and diastolic BP ≥ 90 mm Hg) at baseline. Active treatment reduced the relative risk of major vascular events by 27% (95% CI, 10% to 41%) among patients with isolated systolic hypertension, by 28% (-29% to 60%) among those with isolated diastolic hypertension, and by 32% (17% to 45%) among those with systolic-diastolic hypertension. There was no evidence of differences in the magnitude of the effects of treatment among different types of hypertension (P homogeneity=0.89). CONCLUSIONS: BP lowering is likely to provide a similar level of protection against major vascular events for patients with isolated diastolic hypertension as for those with isolated systolic hypertension and systolic-diastolic hypertension. Clinical Trial Registration Information- This trial was not registered because patients were enrolled before July 1, 2005.

[Correction of aldosterone level as marker of RAAS dysfunction in patients with arterial hypertension degree II-III and chronic kidney diseases].

The hyperactivation of renin-angiotensin-aldosterone system (RAAS) underlies the development and the progression of arterial hypertension and chronic kidney diseases. Aldosterone is the main unit of RAAS and self-sufficient predictor of the development of cardiovascular events. In this study, the angiotensin receptor blocker valsartan, ACE inhibitor enalapril, and direct renin inhibitor aliskiren were used for the correction of blood pressure and aldosterone levels in patients with hypertension and chronic kidney diseases. The data obtained suggest that the proposed complex therapy provides the most complete blood pressure reduction and aldosterone level correction (as evidence of RAAS activity recovery), greatly improves the prognoses, and ensures maximum nephroprotection in the patients with arterial hypertension and chronic kidney diseases.

Combination blood pressure lowering in the presence or absence of background statin and aspirin therapy: a combined analysis of PROGRESS and ADVANCE Trials.

OBJECTIVES: To assess the effects of combination BP lowering on cardiovascular events and mortality in the presence of aspirin and/or statin therapy in a combined analysis of the ADVANCE and PROGRESS trials. METHODS: We conducted an analysis of 14 682 participants allocated combination therapy with perindopril and indapamide or placebo followed up for a mean of 4.2 years. Participants were stratified into four groups defined by background use of medications at baseline: statin, aspirin, both or neither. Linear mixed effect models were used to assess differences in BP and Cox proportional hazard models were used to estimate the risks of major cardiovascular events, all-cause mortality and treatment discontinuation. RESULTS: At baseline, 14% of patients were on both aspirin and statin, 35% on aspirin, 9% on statins and 42% on neither aspirin/statins. Compared with placebo, combination BP therapy reduced mean SBP by 5.7 mmHg in ADVANCE and 12.1 mmHg in PROGRESS, with no difference (P > 0.447) between patients by baseline use of aspirin/statin. Combination BP therapy reduced the risk of major cardiovascular events (hazard ratio 0.78, 95% CI 0.71-0.86), with no significant difference (P = 0.600) between aspirin/statin subgroups. Rates of treatment discontinuation were similar with combination BP therapy compared with placebo (18.4 versus 18%), with no evidence of difference across the subgroups (P = 0.340). CONCLUSION: BP lowering with perindopril and indapamide reduces the risk of major cardiovascular events independent of baseline use of aspirin and/or statins.

Tissue and salinity specific Na+/Cl- cotransporter (NCC) orthologues involved in the adaptive osmoregulation of sea lamprey (Petromyzon marinus).

Two orthologues of the gene encoding the Na+-Cl- cotransporter (NCC), termed ncca and nccb, were found in the sea lamprey genome. No gene encoding the Na+-K+-2Cl- cotransporter 2 (nkcc2) was identified. In a phylogenetic comparison among other vertebrate NCC and NKCC sequences, the sea lamprey NCCs occupied basal positions within the NCC clades. In freshwater, ncca mRNA was found only in the gill and nccb only in the intestine, whereas both were found in the kidney. Intestinal nccb mRNA levels increased during late metamorphosis coincident with salinity tolerance. Acclimation to seawater increased nccb mRNA levels in the intestine and kidney. Electrophysiological analysis of intestinal tissue ex vivo showed this tissue was anion absorptive. After seawater acclimation, the proximal intestine became less anion absorptive, whereas the distal intestine remained unchanged. Luminal application of indapamide (an NCC inhibitor) resulted in 73% and 30% inhibition of short-circuit current (Isc) in the proximal and distal intestine, respectively. Luminal application of bumetanide (an NKCC inhibitor) did not affect intestinal Isc. Indapamide also inhibited intestinal water absorption. Our results indicate that NCCb is likely the key ion cotransport protein for ion uptake by the lamprey intestine that facilitates water absorption in seawater. As such, the preparatory increases in intestinal nccb mRNA levels during metamorphosis of sea lamprey are likely critical to development of whole animal salinity tolerance.

Assessment of suitable antihypertensive therapies: Combination with high-dose amlodipine/irbesartan vs triple combination with amlodipine/irbesartan/indapamide (ASAHI-AI study).

Angiotensin receptor blockers (ARBs) plus calcium channel blockers (CCBs) are a widely used combination therapy for hypertensive patients. In order to determine which combination was better as the next-step therapy for standard-dose combination of ARBs and CCBs, a combination with high-dose CCBs or a triple combination with diuretics, the authors conducted a prospective, randomized, open-label trial to determine which of the following combination is better as the next-step treatment: a combination with high-dose CCBs or a triple combination with diuretics. Hypertensive outpatients who did not achieve their target blood pressure (BP) with usual dosages of ARBs and amlodipine 5 mg were randomly assigned to treatment with irbesartan 100 mg/amlodipine 10 mg (Group 1: n = 48) or indapamide 1 mg in addition to ARBs plus amlodipine 5 mg (Group 2: n = 46). The primary end point was changes in the systolic BP (SBP) and diastolic BP (DBP) after the 12-week treatment period, while secondary end points were changes in BP after the 24-week treatment period and laboratory values. At 12 weeks, the SBP/DBP significantly decreased from 152.1/83.4 mm Hg to 131.5/76.1 mm Hg in Group 1 and 153.9/82.1 mm Hg to 132.7/75.9 mm Hg in Group 2. Although both groups produced a similar efficacy in reducing the SBP/DBP (-19.2/-9.2 mm Hg in Group 1 and -21.6/-8.8 mm Hg in Group 2; SBP P = .378, DBP P = .825), high-dose CCBs combined with ARBs controlled hypertension without elevation of serum uric acid. These results will provide new evidence for selecting optimal combination therapies for uncontrolled hypertensive patients.

Genetic factors associated with elevation of uric acid after treatment with thiazide-like diuretic in patients with essential hypertension.

We investigated changes in blood pressure (BP) and metabolic adverse effects, especially elevation of uric acid (UA), after treatment with a thiazide-like diuretic (TD) in patients with essential hypertension. Furthermore, the role of genetic factors in the elevation of UA by TD was assessed by a 500 K SNP DNA microarray. The subjects included 126 hypertensive patients (57 women and 69 men, mean age 59 ± 12 years) who registered for the GEANE (Gene Evaluation for ANtihypertensive Effects) study. After one month of the nontreatment period, TD, indapamide, angiotensin II receptor antagonist valsartan, and Ca channel blocker amlodipine were administered to all patients for 3 months each in a randomized crossover manner. BP, renal function, serum UA level, and electrolytes were measured at baseline and at the end of each treatment period. Single nucleotide polymorphisms (SNPs) associated with UA elevation after treatment with indapamide were investigated by a genome-wide association study (GWAS). Indapamide significantly decreased both office and home BP levels. Treatment with indapamide also significantly reduced the estimated glomerular filtration rate and serum potassium and increased serum UA. Patients whose UA level increased more than 1 mg/dl showed significantly higher baseline office SBP and plasma glucose and showed greater decline in renal function compared with those who showed less UA increase (<1 mg/dl). Some SNPs strongly associated with an increase in UA after treatment with indapamide were identified. This study is the first report on SNPs associated with UA elevation after TD treatment. This information may be useful for the prevention of adverse effects after treatment with TD.

Effects of blood pressure lowering and intensive glucose control on the incidence and progression of retinopathy in patients with type 2 diabetes mellitus: a randomised controlled trial.

AIMS/HYPOTHESIS: The aim of the present study was to investigate the effect of blood pressure lowering and intensive glucose control on the incidence and progression of retinopathy in type 2 diabetic patients. METHODS: The Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) Retinal Measurements study, a substudy of ADVANCE, is a randomised (using a central, computer-based procedure) controlled 2 x 2 factorial trial comprising a double-blind comparison of blood pressure lowering with perindopril-indapamide vs placebo, and an open comparison of standard vs intensive glucose control targeting a HbA(1c) of < or = 6.5% in 1,602 diabetic patients from ADVANCE centres with access to retinal cameras conducted from 2001 to 2008. At baseline and the final visit, seven-field stereoscopic retinal photographs were taken and graded by blinded readers (gradeable baseline and final photographs from 1,241 patients). Progression of > or =2 steps in the Early Treatment of Diabetic Retinopathy Study classification (using the eye with worst grading) was the primary outcome. RESULTS: Retinopathy progressed in 59 (4.8%) patients and developed in 128 (10.3%) patients over 4.1 years. Fewer patients on blood pressure-lowering treatment (n = 623) experienced incidence or progression of retinopathy compared with patients on placebo (n = 618), but the difference was not significant (OR 0.78; 95% CI 0.57-1.06; p = 0.12). Blood pressure-lowering treatment reduced the occurrence of macular oedema (OR 0.50; 95% CI 0.29-0.88; p = 0.016) and arteriovenous nicking compared with placebo (OR 0.60; 95% CI 0.38-0.94; p = 0.025). Compared with standard glucose control (n = 611), intensive glucose control (n = 630) did not reduce (p = 0.27) the incidence and progression of retinopathy (OR 0.84; 95% CI 0.61-1.15). Lower, borderline significant risks of microaneurysms, hard exudates and macular oedema were observed with intensive glucose control, adjusted for baseline retinal haemorrhages. These effects of the two treatments were independent and additive. Adverse events in the ADVANCE study are reported elsewhere. CONCLUSIONS/INTERPRETATION: Blood pressure lowering or intensive glucose control did not significantly reduce the incidence and progression of retinopathy, although consistent trends towards a benefit were observed, with significant reductions in some lesions observed with both interventions. TRIAL REGISTRATION: ClinicalTrials.gov ID no. NCT00145925. FUNDING: Grants from Servier and the National Health and Medical Research Council of Australia.

Alendronate and indapamide alone or in combination in the management of hypercalciuria associated with osteoporosis: a randomized controlled trial of two drugs and three treatments.

BACKGROUND: The role of bisphosphonates (BPs) in the management of patients with hypercalciuria (HC) associated with osteoporosis is still uncertain. The aim of the study was to evaluate the effect of alendronate and indapamide alone or in combination on bone mineral density (BMD) and 24-h urinary calcium excretion (24-CaU) in post-menopausal women with HC and low BMD. METHODS: A total of 77 post-menopausal women with HC (24-CaU > 4 mg/kg/day) and low BMD [T-score < -2.0 at lumbar spine (LS), femoral neck (FN) or total hip (TH)] from two centres of Northern Italy were randomized to receive indapamide 2.5 mg daily alone (24 patients, IND group), alendronate 70 mg weekly alone (27 patients, ALN group) or the combination therapy (26 patients, ALN + IND group). Throughout the study, all subjects received daily calcium supplements, depending on their dietary intake, to maintain a daily input of 1000 mg. Patients were instructed to increase water intake up to 2000 mL daily. The percentage and absolute changes of BMD at LS, FN and TH, and the variation of 24-CaU from baseline at 1 year were the primary outcomes. Serum calcium, phosphate, parathyroid hormone and bone alkaline phosphatase were also measured. RESULTS: Overall 67 women completed the study and were included in the final analysis. Patients in the three groups were similar with regard to baseline characteristics. BMD did not significantly change from baseline after 1 year of treatment with indapamide (LS: +1 +/- 3.1%; FN: -0.3 +/- 3.5%; TH: -0.4 +/- 3.1%), while it showed a significant increase from baseline in the other two groups (ALN; LS: +5.8 +/- 4.2%, P < 0.001; FN: +3.9 +/- 7.9%, P = 0.018; TH: +2 +/- 3.6%, P = 0.006) (ALN + IND; LS: +8.2 +/- 5.3%, P < 0.001; FN: +4.9 +/- 6.7%, P = 0.007; TH: +2.9 +/- 4.2%, P = 0.004). Patients in the combination group showed a significantly higher increase of BMD at LS compared to ALN (P = 0.04). After 1 year, 24-CaU values significantly decreased from baseline in all groups (IND, 239 +/- 78 versus 364 +/- 44, P < 0.001) (ALN, 279 +/- 68 versus 379 +/- 79, P < 0.001) (ALN + IND, 191 +/- 68 versus 390 +/- 55, P < 0.001). The mean percentage decrease of 24-CaU in ALN + IND group (-50%) was significantly greater compared to ALN (-24%, P < 0.001) and IND (-35%, P = 0.012). CONCLUSIONS: These results show a benefit, in terms of BMD improvement and 24-CaU reduction, associated with BPs' therapy in combination with indapamide in HC associated with osteoporosis. The combination therapy demonstrated a reduction of 24-CaU and an increase in LS BMD superior to that observed with alendronate alone. Our results support a new potential approach with BPs associated with thiazide diuretics or indapamide in the management of post-menopausal women with HC and associated bone loss. Studies on the larger sample size are needed to demonstrate the efficacy on the fracture outcome.

Feasibility of 24-h central blood pressure monitoring: experience from multinational clinical trial assessing the efficacy of perindopril/indapamide/amlodipine.

OBJECTIVES: Brachial blood pressure (BP) is a predictor of cardiovascular events. Evidence suggests that central BP (CBP) provides additional information for cardiovascular risk assessment. Methods to assess 24-h CBP are now available. Our objective was to assess the feasibility of 24-h CBP monitoring in clinical trials and its ability for drug evaluation. METHODS: Data are issued from an international phase 3 randomized clinical trial comparing the efficacy of perindopril/indapamide/amlodipine vs. perindopril/indapamide (Per/Ind), in uncontrolled hypertensive patients treated with Per/Ind. 24-h ambulatory BP monitoring (ABPM) was performed at baseline and after 1-month treatment using the Mobil-O-Graph device which provide brachial BP and CBP and arterial parameters. RESULTS: From the 345 patients included in the ABPM substudy, 276 had two valid ABPM (M0 and M1) for brachial BP assessment (80%). After applying device/software built-in and expert quality control criteria on these recordings, 210 (76%) had valid data at M0 and M1 for the assessment of CBP. After 1 month, superior ambulatory central SBP reductions were observed in the perindopril/indapamide/amlodipine (n = 101) vs. Per/Ind group (n = 109) for 24-h/daytime/night-time periods (-4.5 mmHg, P = 0.002/-5.0, P < 0001/-4.1 mmHg, P = 0.016, respectively). Similar trends were observed for pulse wave velocity and other central parameters. CONCLUSION: Recording 24-h central ABPM and its derived arterial parameters needs a strict expert quality control and must consider a loss of up to 39% of the population included in the ABPM substudy. This method can be used to assess drug effect.

Comparison of the effects of diuretics on blood pressure and arterial stiffness in patients with stroke.

OBJECTIVES: Indapamide (IND) and bendroflumethiazide (BDZ) are both widely used in patients with stroke. We compared their effects on arterial blood pressure (BP) and arterial stiffness in a group of patients with stroke. METHODS: In a prospective, randomized, double-blinded study we investigated the effect of 28-day treatment with BDZ (2.5 mg once daily) or IND (2.5 mg once daily) on BP and arterial stiffness in a group of patients with first-ever ischemic stroke. RESULTS: All data are expressed as mean (SD). In all, 23 patients completed the protocol (age 70.0 +/- 9.55 years). Group I (IND) and group B (BDZ) comprised 13 and 10 patients, respectively. Groups were well matched for demographics and baseline characteristics. Mean arterial pressure reduction from baseline was I = 14.3 +/- 10.3 mm Hg (P < .001) versus B = 9.1 +/- 11.2 mm Hg (P = .03). Augmentation index (AI) was reduced by: I = 4.94 +/- 7.22% (P = .037) versus B = 6.17 +/- 7.85% (P = .035). Time to reflection was increased by I = 3.22 +/- 9.57 milliseconds (P = .268) versus B = 4.71 +/- 5.30 milliseconds (P = .020). There was no significant difference between the two drugs with regard to change in BP or arterial stiffness. Pooled data showed a reduction in mean arterial pressure by 12.1 +/- 10.77 mm Hg (P < .0001) and in AI by 5.5 +/- 7.36% (P = .002), and a small increase in time to reflection by 3.9 +/- 7.79 milliseconds (P = .029). The change in BP explained up to 28% of the change in AI. CONCLUSION: Both diuretics altered hemodynamic parameters to a similar extent. The results are consistent with a direct effect of diuretic therapy on vascular function. The influence of both diuretics on arterial stiffness was similar.

[Endothelioprotective properties of L-arginine in a nitric oxide deficiency model].

In laboratory animals with endothelial dysfunction (nitric oxide deficiency) modeled by the introduction of NO-synthase inhibitor L-NAME, the activation of endothelioprotective effects of enalapril, lozartan, amlodipine, indapamide and nebivolol is revealed for their introduction in combination with L-arginine. This result was confirmed by the behavior of a generalizing parameter, the coefficient of endothelial dysfunction (CED) calculated using the results of tests on endothelium-dependent and -independent vasodilation.

Vascular legacy beyond blood pressure control: benefits of perindopril/indapamide combination in hypertensive patients with diabetes.

OBJECTIVES: Much of the chronic care of patients with type 2 diabetes mellitus and hypertension involves the prevention of diabetic complications. Renin-angiotensin system inhibitors are recommended as first-line therapies because of their nephroprotective properties. Their combination with metabolically neutral diuretics is recommended to reduce blood pressure, morbidity and mortality. Our objective was to review the mechanisms by which the combination of the angiotensin-converting enzyme inhibitor, perindopril, and metabolically neutral thiazide-like diuretic, indapamide, targets the pathways involved in microvascular and macrovascular diabetic complications. METHODS: For this narrative review, extensive literature searches were performed using PubMed/Medline. Articles published in English describing clinical trials and mechanism of action studies that were relevant to the treatment of patients with perindopril and/or indapamide were included. RESULTS: Perindopril/indapamide treatment has been shown to reduce blood pressure and to have significant beneficial effects on arterial distensibility, kidney structure and function, and endothelial function. Recent data also suggests that perindopril may reduce the deleterious accumulation of advanced glycation end products in diabetic tissue. In the Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation diabetes trial, perindopril/indapamide treatment significantly reduced the relative risk of microvascular and macrovascular events by 9%, cardiovascular mortality by 18%, and all-cause mortality by 14%. Interestingly, 6 years after the end of the double-blind period, follow-up data showed that the beneficial effects on mortality continued to be significant even though differences in blood pressure and glycated hemoglobin levels had not been significant for several years. Together this data suggests that treatment with perindopril/indapamide has microvascular and macrovascular effects that extend beyond blood pressure lowering and that this treatment might confer a long-lasting beneficial vascular legacy. CONCLUSION: Moving forward, understanding the pathophysiological bases of the effects that extend beyond those of blood pressure control will help us differentiate between anti-hypertensive choices.