Recent clinical trials have shown that distal nephron-acting diuretics are effective in managing fluid retention and salt-sensitive hypertension in people with chronic kidney disease (CKD). However, their use may be complicated by diuretic-induced hyponatremia. This study aimed to characterize the metabolomic effects of distal diuretics in people with CKD, including those who develop hyponatremia. Therefore, we analyzed plasma and 24-h urine samples from a previously completed randomized controlled trial including individuals with CKD (mean estimated glomerular filtration rate = 39 ± 13 mL/min/1.73 m[2]) treated with amiloride/hydrochlorothiazide (5 mg/50 mg daily) for 2 wk. The study included 26 participants in whom we analyzed a set of targeted metabolites. Global untargeted metabolomics was performed in a subcohort of 12 participants, including four patients who developed hyponatremia (plasma sodium <136 mmol/L) and eight diuretic-treated controls with stable sodium levels. Distal diuretic therapy decreased plasma glutamine levels and the excretion of several tricarboxylic acid cycle-related metabolites. Furthermore, distal diuretics significantly increased urinary ammonium excretion in the absence of hypokalemia or metabolic acidosis. Untargeted metabolomic analysis revealed 988 unique metabolites in the urine. Among those with hyponatremia, we observed a metabolomic signature of oxidative stress, likely due to altered glutamine and carnitine metabolism. These findings suggest that distal diuretics not only act locally in the distal convoluted tubule but also influence proximal tubular metabolism. In conclusion, our results highlight that distal diuretics induce significant metabolic changes in CKD, with urine metabolomics offering valuable insights into the physiological pathways and mechanisms underlying both therapeutic effects and adverse responses.NEW & NOTEWORTHY We assessed the urinary metabolomic fingerprint of treatment with amiloride and hydrochlorothiazide in individuals with CKD stages G3-G4. We identified enhanced ammoniagenesis in the absence of hypokalemia or metabolic acidosis. Patients who developed diuretic-induced hyponatremia exhibited a urinary metabolomic signature of oxidative stress. Our study highlights the interplay between "electrolyte and fluid balance" and "metabolic adaptations" in individuals with CKD who are treated with distal diuretics.

By using the FAERS database, we aim to identify and assess risk signals of adverse drug events (ADEs) potentially causing hypertensive crisis, to inform clinical drug management and promote rational drug use. All statistics were extracted from FAERS by four disproportional methods, which were reporting odds ratio (ROR), proportional reporting ratio (PRR), Bayesian confidence propagation neural network (BCPNN), and empirical Bayesian geometric mean (EBGM). These four methods were performed to identify hypertensive crisis-related adverse events (AEs) from FAERS. The Weibull shape parameter test was employed to perform a time to onset (TTO) analysis. From the first quarter of 2004 to the second quarter of 2025, a total of 10,281 drug-related hypertensive crisis reports were recorded. A total of 916 drugs were identified as having potential risk signals. The highest incidence of populations related to hypertensive crisis AEs was 37.9% in the 18-65 age group. Among the top 5 drugs with the highest number of reported drug-associated hypertensive crisis events, amlodipine (288 cases) ranked first. Ramipril (282 cases) and valsartan (192 cases) ranked as the second and third medications, respectively. The top 5 drugs associated with the risk of hypertensive crisis under the ROR algorithm were amlodipine perindopril (ROR = 136.64), methyl aminolevulinate (ROR = 122.78), tranylcypromine (ROR = 105.15), rifapentine (ROR = 39.46), and amiloride hydrochlorothiazide (ROR = 39.36). Additionally, the timing of AEs related to hypertensive crisis revealed that the highest incidence (30.69%) was observed within 3 days. The median TTO and interquartile range (IQR) for the top three positive drugs with the highest reported number were as follows: amlodipine 362 (48, 721); ramipril 320 (51, 572); and valsartan 89 (7, 468). These drugs exhibited an early failure type. Our study showed that numerous medications carry potential risks for drug-associated hypertensive crisis. Further investigation is required to establish causality and inform clinical decision-making.

Objectives: This study was to investigate whether long-term amlodipine-based combination therapy attenuates seasonal variation of office blood pressure (BP) in hypertensive patients. Methods: The data of 206 patients recruited in the Nanchang site of CHIEF trial were retrospectively analyzed. All patients received an amlodipine-based therapy for three years after reaching target BP with a 12-week titration treatment. Among them, 106 patients received amlodipine plus amiloride/hydrochlorothiazide (AA group) and 100 received amlodipine plus telmisartan (AT group) therapies. These patients were followed up every three months . The difference between the highest and lowest values of outdoor temperature in each three months was calculated as the seasonal temperature difference (T-d) and seasonal BP difference was calculated in the similar way. BP control rates in each season were calculated. Results: In the three years, the highest SBP and DBP values occurred in winter and the lowest values in summer. As a result, the BP control rate in summer was the highest and that in winter was the lowest, especially for SBP. Although T-d levels were similar during three following-up years, the seasonal SBP/DBP differences in 2011 were significantly lower than 2009 (10.03 ± 5.74/6.96 ± 3.72 vs 14.36 ± 8.19/9.78 ± 5.21 mmHg, P < .05), suggesting seasonal variation in BP was obviously reduced. Meanwhile, similar change was observed in AA and AT groups. Conclusions: Besides lower BP effectively, long-term amlodipine-based combination therapy could alleviate the seasonal BP variation in high-risk hypertensive patients.

The kinetics and photodegradation mechanism of the pharmaceutical mixture of hydrochlorothiazide (HCT) and amiloride (AML) has been studied in depth using a chemometric approach. Water solutions of HCT and AML, separately or in binary mixtures, were irradiated with forced light at different pH values (3, 7, 9 and 12). Multivariate Curve Resolution - Alternating Least Squares (MCR-ALS) modelling has been applied to the experimental data recorded by UV spectrophotometry and HPLC-UV/MS. 78 data sets were collected and their chemometric processing has allowed the simultaneous determination of the behaviour of the two drugs in the mixture when exposed to light and the dependence of their photodegradation kinetics on pH. MCR-ALS has been applied using three different implementations. Soft-MCR-ALS and hybrid Hard/Soft-MCR-ALS have been used to resolve the experimental data and to get the equilibrium and kinetic parameters of the investigated chemical processes. A third implementation of the MCR-ALS method has been used in the analysis of the incomplete data sets obtained when UV spectrophotometric and HPLC-UV/MS data were simultaneously analysed, using a row- and column-wise incomplete augmented data matrix arrangement. In these matrices, information from HPLC-UV detector was used as a bridge between the data recorded by UV spectrophotometry (acid-base and kinetic reactions monitoring) and the data obtained by HPLC-MS.

Green and sensitive spectrofluorometric methods have been developed and validated for the determination of timolol maleate (TML)/hydrochlorothiazide (HCT) and amiloride hydrochloride (AMH)/hydrochlorothiazide in tablets. The proposed spectrofluorometric procedures were found to be linear in the range of 4-12, 5-35 and 0.025-0.2 mg L-1 for HCT, TML and AMH, resp. The excitation and emission wavelengths for HCT, TML and AMH at room temperature were 270 and 375, 295 and 435, 330 and 415 nm, resp. The methods were validated with respect to ICH guidelines. The AMH showed higher sensitivity with lower values of LOD and LOQ values compared to HCT and TML. The proposed methods were applied to two pharmaceutical formulations; the method for HCT and AMH has proven as reliable assaying method, whereas the method for TML, when combined with HCT, is applicable to screening semi-quantitative analyses.

Our study aimed to explore changes in health-related quality of life (HRQoL) during blood pressure control and blood lipid-lowering therapies. We conducted a 2 × 2 factorial-designed randomized controlled trial in 180 clinical centers in China. At baseline, participants were randomly assigned to an amlodipine + amiloride/hydrochlorothiazide group or an amlodipine + telmisartan group for the blood pressure control treatment and to a statin group or a routine intervention group for the blood lipid-lowering treatment. The allocation ratio was 1:1 for both treatments. Follow-up lasted for 4 years. HRQoL was assessed using the EuroQol five dimensions three levels (EQ-5D-3L) questionnaire every year. Of 13,542 hypertensive patients enrolled in the clinical trial, 9885 were eligible for the analysis. The problems for all dimensions of the EQ-5D-3L descriptive system were slight at baseline and were well preserved in the follow-up period. The EuroQol visual analog scale (EQ VAS) score and the EQ-5D-3L index improved over time (Ptrend < 0.001), with improvements similar among interventions but different between patients who reached the treatment targets or not. Decreases in systolic/diastolic blood pressure and low-density lipoprotein cholesterol and increases in high-density lipoprotein cholesterol were independently correlated with increases in the EQ VAS score and the EQ-5D-3L index. In conclusion, HRQoL is associated with blood pressure/lipid levels but not with specific antihypertensive or lipid-lowering interventions. Blood pressure control and blood lipid-lowering therapies should not be denied to Chinese patients in consideration of their negative effects on quality of life.

There is a dearth of reports on possible additive blood pressure (BP)-reducing effect of aerobic exercise on antihypertensive drug in humans. This study investigated the additive BP-reducing effect of aerobic exercise on BP in individuals with uncontrolled hypertension. In this 12-week double-blind study, 120 new-diagnosed individuals with mild-to-moderate hypertension were randomized to receive coamilozide + 5/10 mg of amlodipine + aerobic dance or coamilozide + 5/10 mg of amlodipine alone. Forty-five and 43 participants in exercise and control groups, respectively, completed the 12-week intervention. Addition of aerobic exercise to antihypertensive drug therapy significantly reduced systolic BP (7.1 mm Hg [95% confidence interval: 5.0, 9.3]; P < .001) and diastolic BP (1.7 mm Hg [95% confidence interval: 0.4, 3.0]; P = .009) at 12 weeks. BP control rate differed significantly between exercise (53.9%) and control (35.3%) groups, P < .001. Postintervention, proportion of participants in exercise group who had their number of antihypertensive drug reduced to one (20.3%) differed from that in control group (11.1%); (χ(2) = 11.0; P = .001). Combination of aerobic dance and antihypertensive drugs reduces number of antihypertensive drugs needed to achieve BP control and enhances BP control in individuals with hypertension on two antihypertensive drugs.

Experiments were carried out to validate the use of F. glumosa extract as a diuretic in the treatment of hypertension as claimed by traditional healers. The experiments were performed under the same conditions with two synthetic pharmacological diuretics considered as check (Furosemide and Amiloride hydrochlorothiazide). The aqueous extract leaves of F. glumosa accelerated the elimination of overloaded fluid. At the maximum of diuretic response, urinary osmolarity decreased significantly when compared with controls. The single dose treatment of the aqueous extract leaves of F. glumosa has significantly increased urine volume 24 h after administration of the extract. The stability of aldosterone level, the absence of correlation with the plasma levels of sodium, and the increased clearance of free water in the animals receiving the extract show that increased diuresis and natriuresis moderate elevation are tubular in origin. The increase in Na(+), K(+), and Cl(-) induced by the extract caused alkalinization of the urine and showed a strong inhibitory effect of carbonic anhydrase and saluretic. These effects were mainly observed at the dose of 375 mg/kg. These observations confirm the traditional use in the treatment of hypertension and support the importance of the conservation of local knowledge as well as the conservation of Cameroonian biodiversity.