Search Results (18)

Pharmacological influence on nephron function has modified the clinical course of hypertension, heart failure, and chronic kidney disease. (CKD). This is a review of the efficacy of old diuretics and the incremental efficacy of new diuretics in managing hypertension, heart failure, and CKD, concluding with new evidence on the effectiveness of old agents. The efficacy of “older” diuretic agents, such as thiazide and loop diuretics, on heart failure and CKD has been primarily explored in nonrandomized studies. However, the efficacy of these agents and indapamide, a slightly newer but still “old” diuretic in preventing blood pressure-related cardiovascular disease, has been demonstrated in randomized controlled trials. Potassium-sparing agents counteract some of the adverse effects of thiazides and have been shown to prevent cardiovascular events in patients with heart failure. Newer drugs with a diuretic effect, such as gliflozins, act through a new mechanism of action in the kidney and have shown efficacy in controlling symptoms and preventing cardiovascular events in patients with heart failure, regardless of diabetes. Furthermore, gliflozins have prevented the progression of chronic kidney disease in patients with and without diabetes mellitus. New evidence detailing the efficacy of old agents has emerged. Chlorthalidone had a large blood-pressure-lowering effect in patients with stage IV CKD. Acetazolamide was effective in accelerating the clinical control of patients with acute heart failure, including patients with some reduction in kidney function. We anticipate investigating the comparative impact of combining different agents to optimize nephron function in the future. Full article

The antihypertensive drugs indapamide, atenolol, metoprolol, propranolol and bisoprolol were considered in this research. Because they have structures that are affected by pH, developing a chromatographic method was challenging. Based on the speciation diagram of these compounds versus pH scale, a mixed-mode stationary phase (hydrophobic stationary phase, C18 and strong cation exchanger (SCX)) was our first choice. Design of Experiments (DoE) was used to estimate how various factors such as pH, mobile phase composition and flow rate influenced chromatographic performance. As a result, the separation was achieved in 24 min using an aqueous phosphate buffer phase (pH 7.20) and 20 mM triethylamine, with methanol being used as organic modifier (30%). Their retention mechanism was investigated. The new method was validated in term of linearity, limits of detection and quantification, precision, accuracy, and robustness. The method was applied to river water samples, and good results were obtained. Full article

Background/Objectives: The importance of fixed-dose combinations (FDCs) for the treatment of hypertension is well established. However, from a stability perspective, FDCs present a challenge since the degradation of one active pharmaceutical ingredient (API) can be affected by the presence of another API. The aim of this study was to compare the degradation behaviors and evaluate the degradation kinetics of three antihypertensive drugs, perindopril tert-butylamine (PER), amlodipine besylate (AML), and indapamide (IND). Methods: The degradation processes were studied using the previously developed reverse phase high-performance liquid chromatographic (RP-HPLC) method after exposing each drug individually, as well as the combinations of two/three drugs, to different stress factors, such as light, oxidation, acidic, basic, or neutral pH values at different temperatures. Results: The results show that PER is most unstable under basic conditions and that AML displays a negative, while IND displays a positive effect, on PER stability when combined. AML is most affected by basic conditions and oxidation, and its stability is affected by both drugs positively; IND undergoes extreme photolysis, which is positively affected by AML but negatively by PER. Conclusions: Great care must be taken when formulating FDCs with these three drugs, as well as solutions or oral suspensions adjusted for geriatric or pediatric populations, since the stability of all three drugs is greatly affected by pH conditions, as well as light or oxidation factors and their interactions. Full article

Fluorometric method for detecting of five nitrogen-based drugs concentration based on inhibition of emission Eosin Y (EY). The selection of N-drugs comprised indapamide (INDP), clomipramine hydrochloride (CMI), promethazine hydrochloride (PMH), lisinopril (LSP), and trifluoperazine hydrochloride (TFPH). The Stern–Volmer style was plotted between relative emissions of EY vs. N-drugs concentration. The standard curves were linear over the concentration range of 5–50 µg mL⁻¹ with R² > 0.9, and the LOD for INDP, CMI, PMH, LSP, and TFPH were 2.07, 1.36, 3.02, 3.52, and 2.09 µmol·L⁻¹, respectively. The binding constant $K_{app}$ for LSP was greater than other N-drugs. Furthermore, the suggested method was hence applied for the routine detection of the concentration of N-drugs in bulk and tablet or syrup dosage forms. FTIR analysis and the electron-mapping density provided the chemical affinity of N-drugs towards EY. Full article

Laser engraving is a convenient, fast, one-step, and environmentally friendly technique used to produce more conductive surfaces by local pyrolysis. The laser’s thermal treatment can also remove non-conductive materials from the electrode surfaces and improve electrochemical performance. The improvement was assessed by electrochemical tools such as cyclic voltammograms and electrochemical impedance spectroscopy using [Fe(CN)₆]^3−/4− and dopamine as redox probes. The electrochemical results observed showed that a treated surface showed an improvement in electron transfer and less resistance to charge transfer. To optimize the electrode performance, it was necessary to search for the most favorable graphite mines and optimize the parameters of the laser machine (laser power, scan rate, and output distance). The resultant material was adequately characterized by Raman spectroscopy and scanning electron microscopy (SEM), where an irregular surface composed of crystalline graphite particles was noticed. Furthermore, as a proof-of-concept, it was applied to detect indapamide (IND) in synthetic urine by flow injection analysis (FIA), a diuretic drug often used by athletes to alter urine composition to hide forbidden substance consumption in doping tests. Full article

(1) Background: Gordon syndrome (GS) or familial hyperkalemic hypertension is caused by pathogenic variants in the genes WNK1, WNK4, KLHL3, and CUL3. Patients presented with hypertension, hyperkalemia despite average glomerular filtration rate, hyperchloremic metabolic acidosis, and suppressed plasma renin (PR) activity with normal plasma aldosterone (PA) and sometimes failure to thrive. GS is a heterogeneous genetic syndrome, ranging from severe cases in childhood to mild and sometimes asymptomatic cases in mid-adulthood. (2) Methods: We report here a sizeable Spanish family of six patients (four adults and two children) with GS. (3) Results: They carry a novel heterozygous missense variant in exon 7 of WNK1 (p.Glu630Gly). The clinical presentation in the four adults consisted of hypertension (superimposed pre-eclampsia in two cases), hyperkalemia, short stature with low body weight, and isolated hyperkalemia in both children. All patients also presented mild hyperchloremic metabolic acidosis and low PR activity with normal PA levels. Abnormal laboratory findings and hypertension were normalized by dietary salt restriction and low doses of thiazide or indapamide retard. (4) Conclusions: This is the first Spanish family with GS with a novel heterozygous missense variant in WNK1 (p.Glu630Gly) in the region containing the highly conserved acidic motif, which is showing a relatively mild phenotype, and adults diagnosed in mild adulthood. These data support the importance of missense variants in the WNK1 acidic domain in electrolyte balance/metabolism. In addition, findings in this family also suggest that indapamide retard or thiazide may be an adequate long-standing treatment for GS. Full article

The process of isothermal and non-isothermal physical ageing of amorphous polylactide (PLA) with the active pharmaceutical ingredient, indapamide (IND), was investigated. A PLA–IND system with a 50/50 weight ratio was obtained and characterized using differential scanning calorimetry (DSC). In the 50/50 (w/w) mixture, two glass transitions were observed: the first at 64.1 ± 0.3 °C corresponding to the glass transition temperature (T_g) of PLA, and the second at 102.6 ± 1.1 °C corresponding to the T_g of IND, indicating a lack of molecular mixing between the two ingredients. The PLA–IND system was subjected to the isothermal physical ageing process at different ageing temperatures (T_a) for 2 h. It was observed that the highest effect of physical ageing (enthalpy relaxation change) on IND in the PLA–IND system occurred at T_a = 85 °C. Furthermore, the system was annealed for various ageing times at 85 °C. The relaxation enthalpies were estimated for each experiment and fitted to the Kohlrausch–Williams–Watts (KWW) equation. The KWW equation allowed for the estimation of the relaxation time and the parameter describing the distribution of relaxation times of the isothermal physical ageing process of IND in the PLA–IND system. The physical ageing of the PLA–IND mixture (50/50) was also discussed in the context of heat capacity. Moreover, the activation energy and fragility parameters were determined for the PLA–IND (50/50) system. Full article

Indapamide is an effective and safe antihypertensive medication showing a beneficial effect in combination with other antihypertensive agents regarding morbidity and mortality. A comparative study was performed under fasting and fed conditions to investigate the effect of food and selected single nucleotide polymorphisms in the uridine diphosphate glucuronyl transferase (UGT2B7) gene on the pharmacokinetics and pharmacodynamics behavior of indapamide 1.5 mg sustained release. Forty-nine healthy volunteers aged 18–55 years were randomized into two groups; 25 volunteers were administered indapamide under fasting conditions and 24 under fed conditions. Genotyping of the UGT2B7 rs7438135 and rs11740316 was done before commencing the study using predesigned TaqMan assays. Results showed that food independently decreased the value of indapamide’ T_max by 5.5 h and increased the value of C_max by 8.7 ng/mL. On the other hand, all genetic variants of both UGT2B7 SNPs had no significant impact on the values of T_max, C_max, and AUC_0–t; however, it was found that rs11740316 variant AG was correlated with a 2.8 h lower MRT_inf. Finally, BMI positively correlated with longer MRT_inf. It was concluded that none of rs7438135, rs11740316, or food had a significant impact on the pharmacodynamic properties. Food had a modest impact on indapamide C_max and T_max values, while there were unremarkable differences in safety and efficacy. Full article

(1) Background: This study was planned to assess the concentration of antihypertensive drugs (AHD) in the blood serum in patients with controlled and uncontrolled arterial hypertension (AH). (2) Methods: We assessed 46 patients with AH. Based on the results of 24 h blood pressure monitoring (ABPM), the patients were randomized into two groups. The first group consisted of the patients with controlled AH; the second group consisted of the patients with uncontrolled AH. Venous blood was taken in both groups of patients in the morning before and 2 h after taking drugs to assess the concentration of lisinopril, amlodipine, valsartan, and indapamide. (3) Results. The first group included 27 patients, and the second group 19 patients. In patients with uncontrolled AH, the median concentrations of lisinopril, indapamide, amlodipine, and valsartan before and after taking the drugs did not differ from patients who reached the target BP values. (p > 0.05). In some patients with uncontrolled and controlled (shown for the first time) AH the concentration of AHD was below the limit of quantitative determination. (4) Conclusions. The obtained results indicate that the pharmacokinetics of AHD, apparently, does not play a significant role in the development of ineffectiveness of the ongoing therapy for AH. Therapeutic drug monitoring can be used to test adherence to the treatment. Full article

Arginases are often overexpressed in human diseases, and they are an important target for developing anti-aging and antineoplastic drugs. Arginase type 1 (ARG1) is a cytosolic enzyme, and arginase type 2 (ARG2) is a mitochondrial one. In this study, a dataset containing 2115-FDA-approved drug molecules is virtually screened for potential arginase binding using molecular docking against several ARG1 and ARG2 structures. The potential arginase ligands are classified into three categories: (1) Non-selective, (2) ARG1 selective, and (3) ARG2 selective. The evaluated potential arginase ligands are then compared with their clinical use. Remarkably, half of the top 30 potential drugs are used clinically to lower blood pressure and treat cancer, infection, kidney disease, and Parkinson’s disease thus partially validating our virtual screen. Most notable are the antihypertensive drugs candesartan, irbesartan, indapamide, and amiloride, the antiemetic rolapitant, the anti-angina ivabradine, and the antidiabetic metformin which have minimal side effects. The partial validation also favors the idea that the other half of the top 30 potential drugs could be used in therapeutic settings. The three categories greatly expand the selectivity of arginase inhibition. Full article

The current study aimed to evaluate the anti-diabetic effects of canagliflozin (CANA) and indapamide (INDA) and their impacts as adiponectin modulators in experimentally induced type 2 diabetes mellitus (T2DM). T2DM was associated with a significant rise in blood glucose level and HbA1C%, andreduced adiponectin and insulin secretions. Moreover, the malondialdehyde (MDA) contents in both the epididymal adipocytes and soleus muscle significantly escalated, while the total antioxidant capacity (TAC) and epididymal adipocyte Nrf2 expression significantly declined. Moreover, serum TNF-α, epididymal adipocyte’s NOD-like receptor protein 3, NLRP3, NF-κB and CD68 expressions markedly escalated, and serum IL-10 significantly declined. Furthermore, there was a significant escalation in PPARγ expression in epididymal adipocytes, with a significant reduction in soleus muscle’s expression of IRS1. CANA and INDA treatments markedly reduced blood glucose levels, increased adiponectin and insulin secretion, enhanced anti-oxidant defenses, and reduced oxidative burden, with marked anti-inflammatory impact. Interestingly, the impact of indapamide on DM indices and oxidative and inflammatory changes was comparable to that of canagliflozin. Nevertheless, indapamide had a superior effect compared to canagliflozin on HbA1c%, expression of IRS1 and reduction of NF-κB and CD68 expressions. INDA could be effective in regulating T2DM, with underlined anti-diabetic, antioxidant, and anti-inflammatory properties. INDA increased IRS1 expression and modified adiponectin/NLRP3/PPARγ crosstalk. The impacts of INDA are comparable to those of the standard anti-diabetic drug CANA. Full article

Solvent front position extraction procedure was used to prepare biological samples containing selected antihypertensive drugs (ramipril, lercanidipine, indapamide, valsartan, hydrochlorothiazide, perindopril, and nebivolol). Substances separated from the biological matrix components (bovine serum albumin) were quantified by means of liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). Sample preparation process was performed with the use of a prototype horizontal chamber with a moving pipette driven by a 3D printer mechanism enabling a controlled eluent flow velocity. Application of this device was advantageous for simultaneous preparation of several samples for further quantitative analysis, with a synchronized reduction of manual operations and solvent consumption. Quantitative results obtained for the majority of the investigated antihypertensive drugs in a complex biological matrix were satisfactory. The values of the %RSD were around 5% for six of the seven substances (with the exception of indapamide). The method exhibits a suitable accuracy (the relative error percentage was below 10% for most drugs). The values of LOD and LOQ were in the range of 1.19 µg/L–8.53 µg/L and 3.61 µg/L–25.8 µg/L, respectively. Full article

The aim of this study was to comparatively evaluate clinical, laboratory and hemodynamic effects on the long term of different triple combination antihypertensive medications in a well-characterized Italian cohort. We considered the data of a subset of Brisighella Heart Study (BHS) participants who were consecutively evaluated in three epidemiological surveys between 2012 and 2020. For the current analysis, we excluded normotensive subjects, patients treated with <3 or ≥3 antihypertensive drugs without taking angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), calcium-channel blockers (CCB) and/or thiazide/thiazide-like diuretics. The remaining participants were divided into three groups depending on whether they were treated with Perindopril/Amlodipine/Indapamide, ACE-inhibitors (other than perindopril)/CCBs/Thiazide or ARBs/CCBs/Thiazide, either with separate drugs or fixed pill combinations. A further group of age- and sex-matched volunteers was selected as control and included patients receiving other antihypertensive treatments. The long-term (8 years) effects of the different antihypertensive treatments were compared among the pre-defined groups. During the observation period, there was a trend towards increase in both systolic and diastolic blood pressure (BP) in all the investigated subgroups (p for trend <0.05), but in the subgroup of patients treated with Perindopril/Amlodipine/Indapamide, such increase was significantly lower than in the other groups (p < 0.05). The combination treatment with renin-angiotensin system (RAS) modulators, CCBs and thiazide/thiazide-like diuretics was associated with significantly lower diastolic BP (p < 0.05) and more strictly controlled lipid pattern than other triple combination of anti-hypertensive medications. Patients treated with Perindopril/Amlodipine/Indapamide did not experience any age-related increase in serum levels of total cholesterol. Moreover, during the follow up none of them developed type 2 diabetes, nor had a need for a greater number of antihypertensive drugs to improve BP control, mainly because of a more stable BP control. Based on our observations, combination treatment with RAS modulators, amlodipine and thiazides/thiazide-like diuretics is more effective than other triple antihypertensive medications for lowering the diastolic BP and has a better impact on serum lipids. Perindopril/Amlodipine/Indapamide is associated with more protective metabolic profile than any other considered combination antihypertensive medications. Full article

The objective of this study was to characterise amorphous indapamide (IND) subjected to the physical ageing process by differential scanning calorimetry (DSC). The amorphous indapamide was annealed at different temperatures below the glass transition, i.e., 35, 40, 45, 65, 75 and 85 °C for different lengths of time, from 30 min up to a maximum of 32 h. DSC was used to characterise both the crystalline and the freshly prepared glass and to monitor the extent of relaxation at temperatures below the glass transition (T_g). No ageing occurred at 35, 40 and 45 °C at the measured lengths of times. Molecular relaxation time constants (τ^KWW) for samples aged at 65, 75 and 85 °C were determined by the Kohlrausch-Williams-Watts (KWW) equation. The fragility parameter m (a measure of the stability below the glass transition) was determined from the T_g dependence from the cooling and heating rates, and IND was found to be relatively stable (“moderately fragile”) in the amorphous state. Temperature-modulated DSC was used to separate reversing and nonreversing processes for unaged amorphous IND. The enthalpy relaxation peak was clearly observed as a part of the nonreversing signal. Heat capacities data for unaged and physically aged IND were fitted to C_p baselines of solid and liquid states of IND, were integrated and enthalpy was presented as a function of temperature. Full article

This study explores the effect of physical aging and/or crystallization on the supersaturation potential and crystallization kinetics of amorphous active pharmaceutical ingredients (APIs). Spray-dried, fully amorphous indapamide, metolazone, glibenclamide, hydrocortisone, hydrochlorothiazide, ketoconazole, and sulfathiazole were used as model APIs. The parameters used to assess the supersaturation potential and crystallization kinetics were the maximum supersaturation concentration (C_max,app), the area under the curve (AUC), and the crystallization rate constant (k). These were compared for freshly spray-dried and aged/crystallized samples. Aged samples were stored at 75% relative humidity for 168 days (6 months) or until they were completely crystallized, whichever came first. The solid-state changes were monitored with differential scanning calorimetry, Raman spectroscopy, and powder X-ray diffraction. Supersaturation potential and crystallization kinetics were investigated using a tenfold supersaturation ratio compared to the thermodynamic solubility using the µDISS Profiler. The physically aged indapamide and metolazone and the minimally crystallized glibenclamide and hydrocortisone did not show significant differences in their C_max,app and AUC when compared to the freshly spray-dried samples. Ketoconazole, with a crystalline content of 23%, reduced its C_max,app and AUC by 50%, with C_max,app being the same as the crystalline solubility. The AUC of aged metolazone, one of the two compounds that remained completely amorphous after storage, significantly improved as the crystallization kinetics significantly decreased. Glibenclamide improved the most in its supersaturation potential from amorphization. The study also revealed that, besides solid-state crystallization during storage, crystallization during dissolution and its corresponding pathway may significantly compromise the supersaturation potential of fully amorphous APIs. Full article