[Intraoperative management of potentially fatal arrhythmias after anesthesia induced by severe hypokalemia: A case report].

Severe hypokalemia is defined as the concentration of serum potassium lower than 2.5 mmol/L, which may lead to serious arrhythmias and cause mortality. We report an unusual case of potentially fatal ventricular arrhythmias induced by severe hypokalemia in a patient undergoing laparoscopic partial nephrectomy in Peking University Third Hospital due to irregular use of indapamide before operation. Indapamide is a sulfonamide diuretic with vasodilative and calcium antagonistic effects, which enhances sodium delivery to the renal distal tubules resulting in a dose-related increase in urinary potassium excretion and decreases serum potassium concentrations. The electrolyte disorder caused by the diuretic is more likely to occur in the elderly patients, especially those with malnutrition or long-term fasting. Hence, the serum potassium concentration of the patients under indapamide therapy, especially elderly patients, should be monitored carefully. Meanwhile, the potassium concentration measured by arterial blood gas analysis is different from that measured by venous blood or laboratory test. According to the previous research, the concentration of potassium in venous blood was slightly higher than that in arterial blood, and the difference value was 0.1-0.5 mmol/L. This error should be taken into account when rapid intravenous potassium supplementation or reduction of blood potassium level was carried out clinically. In the correction of severe hypokalemia, the standard approach often did not work well for treating severe hypokalemia. The tailored rapid potassium supplementation strategy shortened the time of hypokalemia and was a safe and better treatment option to remedy life-threatening arrhythmias caused by severe hypokalemia with a high success rate. Through the anesthesia management of this case, we conclude that for the elderly patients who take indapamide or other potassium excretion diuretics, the electrolyte concentration and the general volume state of the patients should be comprehensively measured and fully evaluated before operation. It may be necessary for us to reexamine the serum electrolyte concentration before anesthesia induction on the morning of surgery in patients with the history of hypokalemia. For severe hypokalemia detected after anesthesia, central venous cannulation access for individualized rapid potassium supplementation is an effective approach to reverse the life-threatening arrhythmias caused by severe hypokalemia and ensure the safety of the patients.

Intraoperative management of potentially fatal arrhythmias after anesthesia induced by severe hypokalemia: A case report / 北京大学学报(医学版)

Severe hypokalemia is defined as the concentration of serum potassium lower than 2.5 mmol/L, which may lead to serious arrhythmias and cause mortality. We report an unusual case of potentially fatal ventricular arrhythmias induced by severe hypokalemia in a patient undergoing laparoscopic partial nephrectomy in Peking University Third Hospital due to irregular use of indapamide before operation. Indapamide is a sulfonamide diuretic with vasodilative and calcium antagonistic effects, which enhances sodium delivery to the renal distal tubules resulting in a dose-related increase in urinary potassium excretion and decreases serum potassium concentrations. The electrolyte disorder caused by the diuretic is more likely to occur in the elderly patients, especially those with malnutrition or long-term fasting. Hence, the serum potassium concentration of the patients under indapamide therapy, especially elderly patients, should be monitored carefully. Meanwhile, the potassium concentration measured by arterial blood gas analysis is different from that measured by venous blood or laboratory test. According to the previous research, the concentration of potassium in venous blood was slightly higher than that in arterial blood, and the difference value was 0.1-0.5 mmol/L. This error should be taken into account when rapid intravenous potassium supplementation or reduction of blood potassium level was carried out clinically. In the correction of severe hypokalemia, the standard approach often did not work well for treating severe hypokalemia. The tailored rapid potassium supplementation strategy shortened the time of hypokalemia and was a safe and better treatment option to remedy life-threatening arrhythmias caused by severe hypokalemia with a high success rate. Through the anesthesia management of this case, we conclude that for the elderly patients who take indapamide or other potassium excretion diuretics, the electrolyte concentration and the general volume state of the patients should be comprehensively measured and fully evaluated before operation. It may be necessary for us to reexamine the serum electrolyte concentration before anesthesia induction on the morning of surgery in patients with the history of hypokalemia. For severe hypokalemia detected after anesthesia, central venous cannulation access for individualized rapid potassium supplementation is an effective approach to reverse the life-threatening arrhythmias caused by severe hypokalemia and ensure the safety of the patients.

Perindopril/Indapamide/Amlodipine in Hypertension: A Profile of Its Use.

The single-pill combination (SPC) of perindopril (PER)/indapamide (IND)/amlodipine (AML) is a valuable and convenient treatment option for patients with hypertension controlled with two-drug SPC of PER/IND + AML given as two separate pills at the same dose level. PER [an angiotensin-converting enzyme (ACE) inhibitor], IND (a thiazide-like diuretic) and AML (a calcium channel blocker) are well established antihypertensive agents, which have been available for a long time as monotherapies and dual SPCs and have complementary mechanisms of action. Once-daily PER/IND/AML provided effective BP control, with good tolerability, in patients with uncontrolled hypertension in clinical trials and in large observational prospective studies. The efficacy and tolerability of PER/IND/AML was similar to that of PER/IND + AML in a randomized clinical trial. The therapeutic effect of PER/IND/AML was associated with improved health-related quality of life. Thus, switching from the two-pill PER/IND + AML regimen to single-pill PER/IND/AML reduces pill burden and simplifies drug administration, which may improve adherence to treatment, leading to better BP control and clinical outcomes.

Approximately one-quarter of patients with hypertension require three antihypertensive agents to achieve BP control. However, complex treatment regimens and high pill burden reduce treatment adherence, which in turn leads to poor BP control. Perindopril (PER), indapamide (IND), amlodipine (AML) belong to the core drug classes for the treatment of hypertension. These drugs have been available for a long time as monotherapies and two-drug single-pill combinations. Once-daily PER/IND/AML provides very good BP control in patients with uncontrolled hypertension and is generally well tolerated. The single-pill PER/IND/AML has similar efficacy and tolerability to PER/IND + AML given as two separate pills. Therefore, switching from PER/IND + AML to PER/IND/AML reduces pill burden and simplifies the treatment regimen, which may improve adherence to treatment, leading to better BP control and clinical outcomes. Thus, PER/IND/AML is a valuable and convenient treatment option for patients with hypertension controlled with PER/IND + AML at the same dose level.

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.

Simultaneous Evaluation of Dissolution and Permeation of Oral Drug Solid Formulations for Predicting Absorption Rate-Limiting Factors and In Vitro-In Vivo Correlations: Case Study Using a Poorly Soluble Weakly Basic Drug.

Combined dissolution and permeation systems are designed to simultaneously assess the dissolution of a pharmaceutical dosage form and the permeation of dissolved drugs therefrom. However, there were still some limitations on predicting the possible absorption rate-limiting steps and improving the in vitro-in vivo correlation (IVIVC) of a complete dosage form. In this study, the modified biorelevant media with some solubilizers and pH modifiers were integrated into the drug dissolution/absorption simulating system (DDASS). Indapamide, a poorly soluble compound (pKa = 8.8), was selected to validate the applicability of the modified biorelevant media. The elution and permeation dynamics of indapamide were investigated by using appropriate solubilizing agents in the DDASS. The absorption behaviors were analyzed after oral administration of indapamide in beagle dogs. The absorption rate-limiting steps and IVIVCs were predicted from the dissolution-permeation-absorption dynamic parameters. As a result, the absorption fraction of indapamide in the FaSSIFmod of DDASS was estimated to be approximately 100%, in accordance with its high permeability. The ratios of permeation rate to elution rate were 2.55 and 3.34 for the immediate- and sustained-release tablets of indapamide, respectively, suggesting a dissolution rate-limiting absorption for indapamine. In addition, point-to-point correlations were established between in vitro elution and in vivo absorption by the nonlinear and linear regression analysis ways (r > 0.85). The findings indicate that DDASS is a promising technique to develop improved IVIVCs of a complete dosage form, and the FaSSIFmod is suitable to predict the possible absorption rate-limiting steps of poorly soluble drugs in DDASS.

Impact of long-term potassium supplementation on thiazide diuretic-induced abnormalities of glucose and uric acid metabolisms.

Treatment of hypertension with thiazide diuretics may trigger hypokalemia, hyperglycemia, and hyperuricemia. Some studies suggest simultaneous potassium supplementation in hypertensive patients using thiazide diuretics. However, few clinical studies have reported the impact of long-term potassium supplementation on thiazide diuretic-induced abnormalities in blood glucose and uric acid (UA) metabolisms. One hundred hypertensive patients meeting the inclusion criteria were equally randomized to two groups: IND group receiving indapamide (1.25-2.5 mg daily) alone, and IND/KCI group receiving IND (1.25-2.5 mg daily) plus potassium chloride (40 mmol daily), both for 24 weeks. At the end of 24-week follow-up, serum K+ level in IND group decreased from 4.27 ± 0.28 to 3.98 ± 0.46 mmol/L (P < 0.001), and fasting plasma glucose (FPG) and UA increased from 5.11 ± 0.52 to 5.31 ± 0.57 mmol/L (P < 0.05), and from 0.404 ± 0.078 to 0.433 ± 0.072 mmol/L (P < 0.05), respectively. Serum K+ level in IND/KCl group decreased from 4.27 ± 0.36 to 3.89 ± 0.28 mmol/L (P < 0.001), and FPB and UA increased from 5.10 ± 0.41 to 5.35 ± 0.55 mmol/L (P < 0.01), and from 0.391 ± 0.073 to 0.457 ± 0.128 mmol/L (P < 0.001), respectively. The difference value between the serum K+ level and FPG before and after treatment was not statistically significant between the two groups. However, the difference value in UA in IND/KCl group was significantly higher than that in IND group (0.066 (95% confidence interval (CI): 0.041-0.090) mmol/L vs. 0.029 (95% CI: 0.006-0.058) mmol/L, P < 0.05). The results showed that long-term routine potassium supplementation could not prevent or attenuate thiazide diuretic-induced abnormalities of glucose metabolism in hypertensive patients; rather, it may aggravate the UA metabolic abnormality.

Prospective direct comparison of antihypertensive effect and safety between high-dose amlodipine or indapamide in hypertensive patients uncontrolled by standard doses of angiotensin receptor blockers and amlodipine.

OBJECTIVE: When hypertension is uncontrolled by routine treatment with an angiotensin II receptor blocker (ARB) and the calcium channel blocker amlodipine (5 mg), the dose of amlodipine can be increased or a diuretic can be added. We investigated the more effective option in a prospective multicenter open-label study. METHODS: Hypertensive patients were recruited if the target blood pressure (BP) in The Japanese Society of Hypertension 2009 guideline could not be achieved with standard-dose ARB therapy and amlodipine (5 mg). PATIENTS: Patients were divided into three groups. Group-1 was switched to a combination of irbesartan (100 mg) and amlodipine (10 mg). Group-2A was changed to a combination of irbesartan (100 mg), amlodipine (5 mg), and indapamide, while Group-2B received a standard-dose ARB and amlodipine (5 mg) plus indapamide. Patients were assigned by their attending physicians and were followed for 6 months. The primary endpoint was the antihypertensive effect of each regimen. RESULTS: Group-1 contained 85 patients, Group-2A had 49 patients, and Group-2B had 4 patients. We only analyzed Group-1 and Group-2A due to the small size of Group-2B. In both groups, systolic BP and diastolic BP were significantly decreased up to 6 months (all p < 0.001). Reduction of systolic BP was greater in Group-1 than Group-2A after 1 month and 6 months (both p < 0.05). Uric acid was increased in Group-2A after 3 months, but not at 6 months. CONCLUSION: Although both regimens were effective for reducing BP, increasing amlodipine to 10 mg daily controlled hypertension without elevation of serum uric acid.

[Hronotherapy Aspects of Efficiency Azilsartan Medoxomil in Combination Therapy in Patients With Hypertension and Metabolic Syndrome].

OBJECTIVE: Determination of the effectiveness and safety of different dosing regimens during the day (in the morning or at bedtime) combination therapy including azilsartan medoxomil in patients with essential hypertension and metabolic syndrome (MS). DESIGN AND METHODS: The study included 60 patients with uncontrolled hypertension and MS (age median - 59 (54-65) years). Patients were randomized in two groups: group 1 (n=30) received azilsartan medoxomil 40 mg/day, and indapamide retard 1,5 mg/day in the morning; group 2 (n=30)- azilsartan medoxomoil 40 mg at bedtime and indapamide retard 1,5 mg in the morning. All patients at baseline, and after 4 and 12weeks assessed levels of office blood pressure (BP), heart rate (HR); at baseline and after 12 weeks was conducted ambulatory BPmonitoring (ABPM). Evaluated the main indicators of circadian blood pressure profile, as well as the central aortic pressure (CAP) and the rigidity of the vascular wall: systolic, diastolic, and mean arterial pressure in the aorta, aortic augmentation index, pulse wave velocity in the aorta, the augmentation index. Study results were processed using the program Statistica 6.1 by methods nonparametric statistics. RESULTS: Regardless of the regimen used azilsartan destination as part of combination therapy after 4 weeks showed a significant (p<0.05) reduction in SBP and DBP. After 12 weeks of observation target blood pressure was recorded 27 (90%) patients of group 1 and 29 (96.7%)- group2. As a result of ABPM after 12 weeks of treatment in both groups showed a statistically significant (p<0.05) improvement in all parameters investigated. However, positive changes such indicators as an index time of hypertension in the day and night hours, SBP, DBP, and BP variability during the night, the morning rise of systolic as well as the speed of morning rise in SBP and DBP were more pronounced in the appointment azilsartan medoxomil at bedtime compared to morning reception. The use of both treatment regimens provided significant (p<0.05) increase frequency registration profile dippear and reduction - non-dipper. Importantly, irrespective of the time of taking the drugs in both groups occurred significant (p <0.05), and a comparable improvement in rigidity and CAP vascular wall. CONCLUSION: When combined with essential hypertension and MS azilsartana use of combination drug therapy provided achievement of the target values of blood pressure in the majority of patients, a significant improvement in the main indicators of ABPM, CAP, and the rigidity of the vascular wall, as well as the normalization of daily profile of blood pressure in the majority of patients, regardless of dosing regimen during the day. However, the combination of indapamide retard morning - azilsartan medoxomil at bedtime accompanied by a significantly greater positive changes most ABPM parameters, especially at night.

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.

[Fixed dose combination perindopril-indapamide-amlodipine (Triplixam) for the treatment of arterial hypertension]. / Combinaison fixe périndopril-indapamide-amlodipine (Triplixam) pour le traitement de l'hypertension artérielle.

Triplixam is a fixed dose combination of three well known antihypertensive agents, with complementary activities, to control blood pressure in patients with arterial hypertension: perindopril, an angiotensin converting enzyme inhibitor, indapamide, a diuretic whith thiazide-like effects but also specific properties, and amlodipine, a long-acting calcium antagonist of the dihydropyridine family. The potential synergic action allows better control of blood pressure with once daily administration, while limiting the incidence of adverse events. Various presentations with different dosages are available to facilitate individualized therapy. Warnings and precautions for use of every molecule should of course be respected. Such a fixed dose combination should contribute to limit clinical inertia and to improve therapeutic compliance.

Are all diuretics equal for the treatment of hypertensive patients?

Thiazide (hydrochlorothiazide, etc.) and thiazide-like (chlortalidone, indapamide,etc.) diuretics are widely used to treat hypertensive patients. There is growing evidence that these diuretics are not interchangeable and that it might be preferable to choose a thiazide-likediuretic whenever the use of a diuretic is considered. This is in order to prevent optimally the development of cardiovascular complications and the occurrence of metabolic side effects, in particular diabetes (AU)

Las tiazidas (hidroclorotiazida, etc.) y los diuréticos de tipo tiazídico (clortalidona,indapamida, etc.) son fármacos ampliamente utilizados para tratar la hipertensión. Existe pruebas crecientes de que estos diuréticos no son intercambiables y sería preferible elegir un diurético de tipo tiazídico siempre que se considere el uso de los mismos. La razón para ello es evitar de manera óptima el desarrollo de complicaciones cardiovasculares y la aparición de efectos secundarios metabólicos, en particular la diabetes (AU)

A case of hypokalemia-induced fatal arrhythmia caused by indapamide in an anorexic elderly patient.

An 84-year-old man was referred to our hospital for atrioventricular block and severe hypokalemia. He had been treated for hypertension since 2007 with indapamide, a thiazide-like diuretic. His laboratory data had not been tested for a long time. One week before his first visit, he suffered from a common cold and anorexia. He was admitted to our hospital because his electrocardiogram showed ventricular flutter, and pulmonary arrest occurred at the time of his visit. Cardiopulmonary resuscitation was successfully performed. Hypokalemia (K, 1.7 mEq/L) was considered as the cause of acute cardiopulmonary failure. His oral intake of potassium decreased, but potassium loss from the kidney persisted (urinary potassium, 14.0 mEq/L; transtubular potassium gradient, 5.00). These results suggested that although hypokalemia was suspected to have been present for a long time due to indapamide, severe hypokalemia was induced during the period of anorexia. After discontinuation of indapamide and intravenous administration of potassium L: -aspartate for potassium supplementation, the patient's serum potassium levels increased and his general condition improved. Although it is well known that hypokalemia is caused by indapamide, the incidence is not frequent and if observed is not severe. However, we experienced an unusual case of hypokalemia-induced fatal arrhythmia caused by indapamide. Hence, the serum potassium concentration of patients under the drug, especially anorexic elderly patients, should be monitored.

Thiazides diuretics in the treatment of nephrolithiasis: are we using them in an evidence-based fashion?

In the 1980s a change occurred in hydrochlorothiazide prescribing practices for hypertension from high-dose (50 mg/day) to low-dose (12.5-25 mg/day) therapy. However, randomized controlled trials (RCT) for prevention of calcium-containing kidney stones (CCKS) employed only high doses (≥ 50 mg/day). We hypothesized that these practices have resulted in underdosing of hydrochlorothiazide for prevention of CCKS. Patients with a filled prescription for thiazide diuretics that underwent a 24-h urine stone risk factor analysis were eligible. Those with evidence that thiazide was prescribed for CCKS were further analyzed. Of 107 patients, 102 were treated with hydrochlorothiazide, 4 with indapamide, and one with chlorthalidone. Only 35% of hydrochlorothiazide-treated patients received 50 mg/day; a dose previously shown to reduce stone recurrence. Fifty-two percent were prescribed 25 mg and 13% 12.5 mg daily, doses that were not studied in RCT. Evidence-based hydrochlorothiazide use was suboptimal regardless of where the patient received care (Nephrology or Endocrinology clinic). In a small subset of patients (n = 6) with 24-h urinary calcium excretion measured at baseline and after 2 hydrochlorothiazide doses (25 and ≥ 50 mg), there was a trend toward decreased urinary calcium excretion as the dose was increased from 25 to ≥ 50 mg/day (p = 0.051). Low-dose hydrochlorothiazide was often used for prevention of CCKS despite the fact that there is no evidence that it is effective in this setting. This may have resulted from a practice pattern of using lower doses for hypertension therapy or a lack of knowledge of RCT results in treatment of CCKS.

The influence of selected hypotensive drugs on the bioavailability of minerals from buckwheat groats in vitro enzymatic digestion.

BACKGROUND: The mineral status in hypertensive patients may be affected by hypotensive drugs. The aim of this study was to estimate the influence of hypotensive drugs (angiotensine converting enzyme inhibitors (ACE-I), ß-blockers, Ca-antagonists, diuretics) on the potential bioavailability of magnesium, iron, zinc and copper from buckwheat groats in vitro enzymatic digestion. MATERIAL AND METHODS: The degree of release of magnesium, iron, zinc and copper from buckwheat groats was determined with and without (the control sample) an addition of hypotensive drugs. Four antihypertensive drugs in one dose (one tablet per sample) were analysed: metocard (a ß-blocker), cardilopin (a Ca-antagonist), apo-perindox (ACE-I) and indapen (a diuretic). The samples were subjected to enzymatic digestion under in vitro conditions. The content of minerals in buckwheat groats before and after enzymatic digestion was determined by flame atomic absorption spectrometry (AAS). RESULTS: It was found that cardilopin (amlodipine) and indapen (indapamide) significantly increased the release of zinc from groats. The degree of release of magnesium was higher and the release of iron was lower in samples with apo-perindox (perindopril) than in the control group. The release of copper was significantly decreased by indapen (indapamid). CONCLUSIONS: Amlodipine, perindopril and indapamide affected the release of magnesium, iron, zinc and copper from buckwheat groats in vitro enzymatic digestion.

Recent trends in hypertension treatment: perspectives from animal studies.

Several newer areas of hypertension research are presented in this supplement. First, the benefits of melatonin in the treatment of experimental hypertension including its cardioprotective effects are introduced. Second, the possible role of melatonin in the non-dipping blood pressure pattern is described. Third, two hypotheses discuss the potential reasons for the ineffectivness of antioxidants in hypertension treatment, and difficulties associated with interpretations of experimental findings in the model of the spontaneously hypertensive rat (SHR). Finally, interactions of indapamide with the nitric oxide system in SHR, the protective effect of angiotensin II type 1 receptor blockade against alterations in insulin-resistant rats, and the deleterious effect of a low protein diet on kidney maturation with the development of hypertension are presented.

Evaluation of high dose of perindopril/indapamide fixed combination in reducing blood pressure and improving end-organ protection in hypertensive patients.

BACKGROUND: Despite the widespread notion that controlling hypertension is essential to improve cardiovascular outcome, uncontrolled hypertension rates remain high. Fixed-dose combinations are used routinely to reduce the impact of hypertension. Treatment with fixed-combination perindopril/indapamide, for example, at the currently approved doses (perindopril 2 mg/indapamide 0.625 mg [Per2/Ind0.625] and perindopril 4 mg/indapamide 1.25 mg [Per4/Ind1.25]), reduces blood pressure, end-organ damage, and cardiovascular morbidity and mortality in a wide range of hypertensive patients. AIM AND SCOPE: This article reviews three published randomised trials that evaluated the efficacy and safety of the highest dose of perindopril/indapamide (perindopril 8 mg/indapamide 2.5 mg [Per8/Ind2.5]) in blood pressure lowering and end-organ protection studies. RESULTS: In the first (dose-finding) study, incremental reductions in SBP/DBP were observed with each dose doubling. After 8 weeks of treatment, decreases in supine SBP/DBP were statistically significant compared to placebo for all three doses, with incremental and progressive reductions with each dose doubling: ranging from SBP/DBP respectively -14/-9 mmHg for Per2/Ind0.625 to -23/-15 mmHg for Per8/Ind2.5 compared to -5/-5 mmHg for placebo. In the PICXEL and PREMIER trials, SBP/DBP decreases of 16.3/8.1 mmHg (p < 0.0001) and 2.5/2.6 mmHg, respectively, were noted when Per4/Ind1.25 was doubled to Per8/Ind2.5 (decreases from 167.7/101.7 to 151.4/93.6 in PICXEL and from 154.9/92.1 to 152.4/89.5 in PREMIER, respectively). As a consequence more patients had normalised blood pressure (22% and 17%), more patients responded to treatment (68% and 45%), and 29% and 10% of non-responders became responders, in PICXEL and PREMIER, respectively. Additional end-organ benefits were also noted with Per8/Ind2.5. In PICXEL, significant decreases from baseline in left ventricular mass were noted with all three doses, with a 17.5 g/m(2) decrease from baseline in patients whose maximum dose was Per8/Ind2.5 (from 148.5 g/m(2) +/- 39.5 (mean +/- SD) to 131 g/m(2); p < 0.0001). In PREMIER, changes in albumin excretion rate were also noted with all three doses, with a 45% reduction from baseline in patients whose maximum dose was Per8/Ind2.5 (p < 0.0001). When safety data, including potassium levels, were analysed, the increase in dose to Per8/Ind2.5 did not have a notable impact on the safety profile of perindopril/indapamide. CONCLUSIONS: Based on data available from an evaluation of three randomised clinical trials, fixed-combination Per8/Ind2.5 provided a significant, incremental reduction in blood pressure as well as cardiac and renal end-organ protection while remaining safe and well-tolerated.

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.

Carbonic anhydrase inhibitors. Sulfonamide diuretics revisited--old leads for new applications?

Sulfonamide diuretics such as hydrochlorothiazide, hydroflumethiazide, quinethazone, metolazone, chlorthalidone, indapamide, furosemide and bumetanide were tested as inhibitors of the zinc enzyme carbonic anhydrases (CAs, EC 4.2.1.1). These drugs were discovered in a period when only isoform CA II was known and considered physiologically/pharmacologically relevant. We prove here that although acting as moderate to weak inhibitors of CA II, all these drugs considerably inhibit other isozymes known nowadays to be involved in critical physiologic processes, among the 16 CAs present in vertebrates. Some low nanomolar/subnanomolar inhibitors against such isoforms were detected, such as among others metolazone against CA VII, XII and XIII, chlorthalidone against CA VB, VII, IX, XII and XIII, indapamide against CA VII, IX, XII and XIII, furosemide against CA I, II and XIV, and bumethanide against CA IX and XII. The X-ray crystal structure of the CA II-indapamide adduct was also resolved at high resolution, and the binding of this sulfonamide to the enzyme was compared to that of dichlorophenamide, sulpiride and a pyridinium containing sulfonamide. Indapamide binds to CA II in a manner not seen earlier for any other CA inhibitor, which might be important for the design of compounds with a different inhibition profile.

Antioxidative effects of melatonin administration in elderly primary essential hypertension patients.

The imbalance of the redox state of the aging organism may be involved in the development of primary essential hypertension. Melatonin, a potent antioxidant agent, was found to exert a hypotensive effect and improve the function of the cardiovascular system. The aim of this study was to determine the influence of melatonin supplementation on oxidative stress parameters in elderly primary essential hypertensive (EH) patients, controlled by a diuretic (indapamide) monotherapy. The levels of malondialdehyde (MDA) and reduced glutathione (GSH), activities of Cu-Zn superoxide dismutase (SOD-1), catalase (CAT) and glutathione peroxidase (GSH-Px) in erythrocytes, the plasma level of nitrate/nitrite, the content of carbonyl groups of plasma proteins and morning melatonin levels in the serum of 17 elderly EH patients were determined at the baseline and after the 15th and 30th days of melatonin supplementation (5 mg daily). Melatonin administration resulted in a significant increase in the morning melatonin concentration, SOD-1 and CAT activities, and a reduction in the MDA level. Statistically significant alterations in the levels of GSH, nitrate/nitrite and carbonyl groups and the activity of GSH-Px were not observed. These results indicate an improvement in the antioxidative defense of the organism by melatonin supplementation in the examined group and may suggest melatonin supplementation as an additional treatment supporting hypotensive therapy in elderly EH patients.

Chronic and acute effects of different antihypertensive drugs on femoral artery relaxation of L-NAME hypertensive rats.

We aimed to compare the effects of chronic and acute administration of structurally different antihypertensives, diuretics - indapamide and hydrochlorothiazide, ACE inhibitor - captopril and indapamide+captopril combination on endothelium-dependent relaxation of femoral artery isolated from nitric oxide (NO)-deficient rats. In the chronic experiment, femoral artery was isolated from Wistar rats receiving L-NAME (40 mg/kg/day) solely or with indapamide (1 mg/kg/day), hydrochlorothiazide (10 mg/kg/day), captopril (10 mg/kg/day), and indapamide+captopril combination for seven weeks. In the acute in vitro experiment, the incubation medium with femoral artery isolated from L-NAME-hypertensive rats was supplemented with investigated antihypertensives in the same concentration 10(-4) mol/l. Interestingly, chronic L-NAME treatment did not cause a reduction of vasorelaxation. Indapamide+captopril elevated relaxation above the control level and completely prevented blood pressure increase induced by L-NAME. Acute incubation with captopril only or indapamide+captopril improved relaxation of femoral artery isolated from L-NAME-hypertensive rats, while the incubation with all antihypertensives increased vasorelaxation of femoral artery isolated from control Wistar rats. In conclusion, NO might be involved in the indapamide- and hydrochlorothiazide-induced improvement of vasorelaxation, while different vasorelaxing factors (prostacyclin, EDHF) contribute to the captopril-induced improvement of vasorelaxation. During the chronic treatment additive and synergic effects of indapamide and captopril may contribute to the prevention of hypertension and increase of vasorelaxation.