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.

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.

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.

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.

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.

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.

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.

Hydrochlorothiazide vs chlorthalidone, indapamide, and potassium-sparing/hydrochlorothiazide diuretics for reducing left ventricular hypertrophy: A systematic review and meta-analysis.

Left ventricular hypertrophy develops in 36%-41% of hypertensive patients and independently predicts cardiovascular events and total mortality. Moreover, drug-induced reduction in left ventricular mass (LVM) correlates with improved prognosis. The optimal thiazide-type diuretic for reducing LVM is unknown. Evidence regarding potency, cardiovascular events, sodium, and potassium suggested the hypothesis that "CHIP" diuretics (CHlorthalidone, Indapamide, and Potassium-sparing diuretic/hydrochlorothiazide [PSD/HCTZ]) would reduce LVM more than HCTZ. Systematic searches of five databases were conducted. Among the 38 randomized trials, a 1% reduction in systolic blood pressure (SBP) predicted a 1% reduction in LVM, P = 0.00001. CHIP-HCTZ differences in reducing LVM differed across trials (ie, heterogeneity), making interpretation uncertain. However, among the 28 double-blind trials, heterogeneity was undetectable, and HCTZ reduced LVM (percent reduction [95% CI]) by -7.3 (-10.4, -4.2), P < 0.0001. CHIP diuretics surpassed HCTZ in reducing LVM: chlorthalidone -8.2 (-14.7, -1.6), P = 0.015; indapamide -7.5 (-12.7, -2.3), P = 0.005; and all CHIP diuretics combined -7.7 (-12.2, -3.1), P < 0.001. The comparison of PSD/HCTZ with HCTZ had low statistical power but favored PSD/HCTZ: -6.0 (-14.1, +2.1), P = 0.149. Thus, compared to HCTZ, CHIP diuretics had twice the effect on LVM. CHIP diuretics did not surpass HCTZ in reducing systolic or diastolic blood pressure: -0.3 (-5.0, +4.3) and -1.6 (-5.6, +2.4), respectively. The strength of evidence that CHIP diuretics surpass HCTZ for reducing LVM was high (GRADE criteria). In conclusion, these novel results have demonstrated that CHIP diuretics reduce LVM 2-fold more than HCTZ among hypertensive patients. Although generally related to LVM, blood pressure fails to explain the superiority of CHIP diuretics for reducing LVM.

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.

Blood pressure-lowering efficacy of indapamide SR/amlodipine combination in older patients with hypertension: A post hoc analysis of the NESTOR trial (Natrilix SR vs Enalapril in Hypertensive Type 2 Diabetics With Microalbuminuria).

To examine the antihypertensive efficacy and safety of indapamide sustained-release (SR)/amlodipine compared with enalapril/amlodipine in patients 65 years and older with uncontrolled blood pressure (BP) on monotherapy, a post hoc analysis of the NESTOR trial (Natrilix SR vs Enalapril in Hypertensive Type 2 Diabetics With Microalbuminuria) was conducted. NESTOR randomized 570 patients (n=197, aged ≥65 years) with hypertension (systolic BP 140-180/diastolic BP <110 mm Hg) to indapamide SR 1.5 mg or enalapril 10 mg. If target BP (<140/85 mm Hg) was not achieved at 6 weeks, amlodipine 5 mg was added with uptitration to 10 mg if required. A total of 107 patients aged 65 years and older received dual therapy (53 indapamide SR/amlodipine and 54 enalapril/amlodipine). Amlodipine uptitration occurred in 22 and 24 patients, respectively. At 52 weeks, mean systolic BP (±SE) reduction was significantly greater with indapamide SR/amlodipine vs enalapril/amlodipine 6.2±2.7 mm Hg (P=.02). Indapamide SR/amlodipine was also associated with a greater BP response rate (88% vs 75%, respectively). Both regimens were well tolerated. Indapamide SR/amlodipine may be more effective than enalapril/amlodipine for lowering systolic BP in patients with hypertension aged 65 years and older.

Comparison between the effects of hydrochlorothiazide and indapamide on the kidney in hypertensive patients inadequately controlled with losartan.

The aim of the study is to compare the effects of hydrochlorothiazide and indapamide on the kidney in patients with hypertension inadequately controlled with losartan. A total of 140 patients who met the criteria and inadequately controlled with losartan 50 mg per day for 2 weeks were randomized in two groups and administered either hydrochlorothiazide 12.5 mg per day (n=70) or indapamide (sustained release) 1.5 mg per day (n=70) in combination with losartan 50 mg per day. Office blood pressure (BP) were collected at baseline and upon each follow-up visit. Creatinine, urine albumin-creatinine ratio (ACR), urine neutrophil gelatinase-associated lipocalin (NGAL) and renal resistive index (RRI) were also collected at baseline and at the 24-week follow-up. None of the baseline characteristics was statistically significantly different between the two groups. After excluding those patients with office BP uncontrolled, 46 patients in the hydrochlorothiazide group (45.7% males, 58.8±10.8 years) and 44 patients in the indapamide group (38.4% males, 61.5±10.9 years) were analysed. There were insignificant changes in creatinine and significant decreases in ACR, NGAL and RRI compared to baseline levels in the two groups. The decrease in ACR (3.8 (0, 28.7) vs 4.2 (0.4, 64.8) mg g-1, P=0.485) was not significantly different between the two groups, while the decrease in NGAL (16.07±7.07 vs 28.77±7.64 ng ml-1, P<0.001) and RRI (0.04±0.02 vs 0.07±0.04, P<0.001) was more significant in the indapamide group than in the hydrochlorothiazide group. In conclusion, indapamide is superior to hydrochlorothiazide to improve renal tubular injury and renal haemodynamics in combination with losartan in hypertensive patients with controlled BP.

Effects of antihypertensive treatment on plasma apelin, resistin, and visfatin concentrations.

INTRODUCTION Adipose tissue has been recently recognized as an endocrine organ secreting a number of adipokines contributing to the development of atherosclerosis, hypertension, chronic kidney disease, endothelial dysfunction, insulin resistance, and vascular remodeling. OBJECTIVES The aim of this study was to determine whether treatment with a ß-blocker, calcium antagonist, thiazide-like diuretic, or angiotensin II receptor type 1 influences plasma concentrations of apelin, resistin, and visfatin in obese hypertensive patients. PATIENTS AND METHODS The study included 84 obese patients with essential hypertension. One control group included obese subjects without hypertension, and the other, lean subjects without hypertension. Patients with hypertension were randomized into 4 groups treated for 6 weeks with bisoprolol, amlodipine, indapamide, or candesartan, respectively. RESULTS Mean daily plasma apelin concentrations in patients treated with amlodipine was significantly higher than the baseline values, whereas the difference in plasma apelin concentrations in other treatment groups was not significant. Mean daily plasma resistin concentrations were significantly lower after 6-week treatment with amlodipine, bisoprolol, or indapamide compared with the baseline values. In patients treated with candesartan, no significant differences in resistin concentrations were shown. After 6-week treatment with bisoprolol, mean daily plasma concentrations of visfatin were significantly lower compared with the baseline values. Treatment with amlodipine, candesartan, or indapamide did not significantly affect plasma visfatin levels. CONCLUSIONS Antihypertensive treatment exerts significant and varied effects on adipokine secretion in obese hypertensive patients. Changes in apelin secretion, caused by the use of different antihypertensive drugs, may protect the cardiovascular system and kidneys. The involvement of adipokins in the mechanism of diverse protective effects of antihypertensive drugs, independently of the effect on blood pressure, requires further research.

Addition of indapamide to frusemide increases natriuresis and creatinine clearance, but not diuresis, in fluid overloaded ICU patients.

BACKGROUND: Fluid and sodium overload are a common problem in critically ill patients. Frusemide may result in diuresis in excess of natriuresis. The addition of indapamide may achieve a greater natriuresis, and also circumvent some of the problems associated with frusemide. The objective of this study was to examine the effect of adding indapamide to frusemide on diuresis, natriuresis, creatinine clearance and serum electrolytes. METHODS: Fluid overloaded ICU patients were randomised to either intravenous frusemide (Group F) or intravenous frusemide and enteral indapamide (Group F + I). Comprehensive exclusion criteria were applied to address confounders. 24 hour urine was analysed for electrolytes and creatinine. Serum electrolytes were measured before and 24 hours after administration of diuretics. RESULTS: Forty patients (20 in each group) were included in the study. The groups were similar in their baseline characteristics. Over the 24 h study period, patients in Group F + I, had a larger natriuresis (P = 0.01), chloride loss (P = 0.01) and kaliuresis (P = 0.047). Patients in Group F + I also had a greater 24 hour urinary creatinine clearance (P = 0.01). The 24 hour urine volume and fluid balance was similar between the groups. Patients in Group F had an increase in serum sodium (P = 0.04), while patients in Group F + I had a decrease in both serum chloride (P = 0.01) and peripheral oedema (P < 0.001) during the study duration. CONCLUSION: In fluid overloaded ICU patients, addition of indapamide to frusemide led to a greater natriuresis and creatinine clearance. Such a strategy might be utilised in optimising sodium balance in ICU patients.

Antihypertensive therapy increases natural immunity response in hypertensive patients.

AIMS: The aim of this work was to evaluate the effects of treatment of hypertension on the autoantibodies to apolipoprotein B-derived peptides (anti-ApoB-D peptide Abs) response, inflammation markers and vascular function. MAIN METHODS: Eighty-eight patients with hypertension (stage 1 or 2) were recruited and advised to receive perindopril (4mg), hydrochlorothiazide (25mg), or indapamide (1.5mg) for 12weeks in a blinded fashion. Office and 24-h ambulatory blood pressure monitoring (24h ABPM), flow-mediated dilatation (FMD), nitrate-induced dilatation (NID), titers of IgG and IgM anti-ApoB-D peptide Abs, hsCRP, and interleukins (IL-8 and IL-10) were evaluated at baseline and 12weeks after therapies. KEY FINDINGS: All treatments reduced office BP, and improved FMD (P<0.05 vs. baseline). The NID was improved only in the perindopril arm (P<0.05 vs. baseline). The 24h-ABPM was reduced with perindopril and hydrochlorothiazide therapies (P<0.05 vs. baseline), but not with indapamide, and this effect was followed by increase in titers of IgM Anti-ApoB-D peptide Abs (P<0.05 vs. baseline), without modifications in titers IgG Anti-ApoB-D peptide Abs and interleukins. Multivariable regression analysis has shown that change in the titers of IgM anti-ApoB-D peptide was associated with the changes in FMD (ß -0.347; P<0.05). SIGNIFICANCE: These findings shed light to a possible modulator effect of the antihypertensive therapy on the natural immunity responses and vascular function.

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.

Prevention of metabolic disorders with telmisartan and indapamide in a Chinese population with high-normal blood pressure.

High-normal blood pressure is considered a precursor of stage 1 hypertension that is associated with metabolic disorders. This study aims to investigate whether the pharmacologic treatment of high-normal blood pressure affects metabolism, especially in abdominally obese individuals, and the pharmacoeconomics of two antihypertensive agents, telmisartan and indapamide. Subjects with high-normal blood pressure were randomly assigned to receive telmisartan, indapamide or placebo for 3 years. All the subjects were instructed to modify their lifestyle to reduce blood pressure throughout the study. A total of 221 subjects were randomly assigned to telmisartan, 213 to indapamide and 230 to placebo. After the 3-year intervention, blood pressure was lower in the telmisartan and indapamide groups (P<0.05), FPG in the telmisartan group was lower during the first 2 years (P<0.05) and no characteristic differences were found in those with abdominal obesity among the three groups (P>0.05). The percentage of subjects with metabolic syndrome was significantly decreased in the telmisartan and indapamide groups (P<0.05), but was only significantly decreased in the telmisartan group for subjects with abdominal obesity (P<0.05). The acquisition cost for telmisartan was ~1.86 times higher than for indapamide for a similar antihypertensive effect. The intervention for high-normal blood pressure with telmisartan and indapamide appeared to be feasible and reduced the risk of metabolic syndrome. Telmisartan was more effective, whereas indapamide had better pharmacoeconomic benefits.

[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.

Evaluation of nutritional and biochemical parameters in spontaneously hypertensive rats following antihypertensive treatment.

INTRODUCTION: One side effect of antihypertensive drugs is their impact on nutritional status and metabolism. The purpose of this study was to assess the nutritional and biochemical parameters in spontaneously hypertensive rats following treatment with antihypertensive drugs. MATERIAL AND METHODS: The experiment was performed on 50 male spontaneously hypertensive rats (SHR), which were assigned to five groups: control (C), with perindopril (PR), with metoprolol (MT), with indapamide (ID), and with amlodipine (AM). All rats were provided ad libitum standard diet (with or without drugs) and distilled water. After 45 days, the animals were weighed and killed. Liver, kidney, heart, spleen, pancreas, and blood samples were collected. Concentrations of glucose, cholesterol, triglycerides, and albumin were assayed in serum. Morphology parameters, such as white blood cell, red blood cell, hematocrit, and lymphocyte counts were measured in the blood. Blood pressure was measured using a tail-cuff plethysmograph. RESULTS: The results obtained indicate that the hypotensive drugs under investigation had no effect on the selected nutritional parameters. Perindopril significantly decreased the relative mass of the heart and amlodipine markedly decreased the relative mass of the pancreas. A markedly higher concentration of glucose in the group with indapamid, and a significantly lower concentration of triglycerides in the group with metoprolol, were observed. Indapamide and amlodipine markedly increased the value of red blood cells and hematocrit in the blood of SHR. CONCLUSIONS: Long-term therapy with antihypertension drugs may influence tissue mass and biochemical and morphological status in the body.

Efficacy of single-pill perindopril/indapamide in patients with hypertension and type 2 diabetes.

OBJECTIVE: Hypertension and type 2 diabetes in combination are associated with a significantly higher level of cardiovascular events. The aim of this prospective study was to evaluate the antihypertensive efficacy and tolerability of single-pill perindopril/indapamide in patients with hypertension and type 2 diabetes. DESIGN AND METHODS: Patients with both hypertension and type 2 diabetes were enrolled in this multicenter, prospective, open clinical study. Single-pill perindopril/indapamide was either prescribed on its own (started or switched to from previous treatment) or added to previous therapy. Perindopril/indapamide dosage could be increased, from 5/1.25 mg to 10/2.5 mg once daily, if blood pressure (BP) was uncontrolled. BP and tolerability were assessed at 4 visits over a 6-month period. Microalbuminuria was assessed at baseline and 6 months in a subgroup. RESULTS: 397 patients were analyzed (age 57.6 ± 9.4 years, men 46 %). At baseline, systolic blood pressure (SBP) was 160.0 ± 14.3 mmHg, diastolic blood pressure (DBP) 95.2 ± 8.3 mmHg, and pulse pressure 64.8 ± 12.7 mmHg. Nearly half (45 %) of patients received perindopril/indapamide alone and 55 % added this single-pill combination to existing therapy. After 6 months, SBP fell by 30 mmHg, DBP by 14 mmHg, and pulse pressure by 16 mmHg (all p < 0.0001). SBP was normalized (<140 mmHg) in 84 % of patients who took perindopril/indapamide 5/1.25 mg alone and in 90 % of patients who took perindopril/indapamide 10/2.5 mg alone. Tolerability was rated "good" or "better" by nearly all (99 %) patients. In a microalbuminuria subgroup (n = 59; baseline microalbuminuria 20-200 mg/L; average age 60.5 ± 11.5 years; 28 men [47 %]), there was a significant decrease in SBP (from 160.5 ± 13.9 mmHg to 132.6 ± 12.0 mmHg) and DBP (from 95.3 ± 7.8 mmHg to 81.6 ± 8.4 mmHg) (p < 0.001). Target SBP was reached by 71 % of these patients. Microalbuminuria decreased in 75 % of the subgroup during the follow-up period; levels fell significantly from 45 mg/L (30-88 mg/L) to 30 mg/L (20-50 mg/L) (p < 0.0001). CONCLUSION: Treatment with single-pill perindopril/indapamide 5/1.25 or 10/2.5 mg significantly reduced BP, improved BP control, and enhanced kidney protection in patients with hypertension and type 2 diabetes in everyday clinical practice.