Search Results (8)

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

Background: The comparison of left ventricular mass (LVM) at different BP levels and the effects of antihypertensive drug treatment on LVM are unknown. Objective: To compare the LVM of individuals with prehypertension and Stage 1 hypertension and assess the effects of treatment on LVM at these stages of hypertension. Methods: We estimated LVM in the PREVER-Prevention trial using Sokolow–Lyon and Cornell voltage and voltage–duration products before and after randomization to 18 months of treatment with low doses of chlorthalidone and amiloride or placebo in adults with JNC 7 “prehypertension” (systolic BP [SBP] of 120–139 mm Hg and diastolic BP [DBP] of 80–89 mm Hg). Similarly, in the PREVER-Treatment trial, we assessed these indices before and after randomization to 18 months of treatment with the chlorthalidone/amiloride combination or losartan in adults with JNC 7 “stage 1” hypertension (140–159 mm Hg or DBP of 90–99 mm Hg). Results: At baseline, the participants in the stage I hypertension trial exhibited higher mean LVM indices than those in the prehypertension trial. In the PREVER-Prevention trial, those randomized to the chlorthalidone/amiloride combination experienced a significant reduction in Sokolow–Lyon LVM indices compared to placebo (p = 0.02). In the PREVER-Treatment trial, those randomized to the chlorthalidone/amiloride combination or losartan experienced a similar reduction in electrocardiographic LVM during the 18 months of treatment (p < 0.01). Conclusions: The institution of low-dose antihypertensive drug therapy in prehypertension and treatment of patients with stage 1 hypertension has the potential to interrupt the progress of hypertensive cardiomyopathy. Full article

Background: Fibrolamellar carcinoma (FLC) is a rare type of liver cancer that primarily affects adolescents and young adults without prior liver disease or viral infections. Patients with FLC generally have non-specific symptoms, are often diagnosed at a later stage, and experience a higher frequency of metastases compared to patients with other liver cancers. A fusion transcript of DNAJB1 and PRKACA, which can lead to increased activity of PKA and cellular proliferation, has been identified in all FLC patients, but the exact mechanism through which FLC develops remains unclear. In this study, we investigated common lncRNA profiles in various FLC samples using bioinformatics analyses. Methods: We analyzed differentially expressed (DE) lncRNAs from three RNA sequencing datasets. Using lncRNAs and DE mRNAs, we predicted potential lncRNA target genes and performed Gene Ontology (GO) and KEGG analyses with the DE lncRNA target genes. Moreover, we screened for small-molecule compounds that could act as therapeutic targets for FLC. Results: We identified 308 DE lncRNAs from the RNA sequencing datasets. In addition, we performed a trans-target prediction analysis and identified 454 co-expressed pairs in FLC. The GO analysis showed that the lncRNA-related up-regulated mRNAs were enriched in the regulation of protein kinase C signaling and cAMP catabolic processes, while lncRNA-related down-regulated mRNAs were enriched in steroid, retinol, cholesterol, and xenobiotic metabolic processes. The analysis of small-molecule compounds for FLC treatment identified vitexin, chlorthalidone, triamterene, and amiloride, among other compounds. Conclusions: We identified potential therapeutic targets for FLC, including lncRNA target genes as well as small-molecule compounds that could potentially be used as treatments. Our findings could contribute to furthering our understanding of FLC and providing potential avenues for diagnosis and treatment. Full article

Hypertension is highly prevalent in patients with obstructive sleep apnea (OSA), and fluid retention with its nighttime rostral distribution is one potential mechanism. We tested whether or not diuretics differ from amlodipine in their impact on echocardiographic parameters. Patients with moderate OSA and hypertension were randomized to receive diuretics (chlorthalidone plus amiloride) or amlodipine daily for 8 weeks. We compared their effects on left and right ventricular global longitudinal strain (LV-GLS and RV-GLS, respectively), on LV diastolic parameters, and on LV remodeling. In the 55 participants who had echocardiographic images feasible for strain analysis, all echocardiographic parameters were within normal ranges. After 8 weeks, the 24 h blood pressure (BP) reduction values were similar, while most echocardiographic metrics were kept unchanged, except for LV-GLS and LV mass. In conclusion, the use of diuretics or amlodipine had small and similar effects on echocardiographic parameters in patients with moderate OSA and hypertension, suggesting that they do not have important effects on mediating the interaction between OSA and hypertension. Full article

Hypertension is a leading risk factor for cardiovascular disease mortality. African Americans (AAs) have the highest prevalence of hypertension in the United States, and to alleviate the burden of hypertension in this population, better control of blood pressure (BP) is needed. Previous studies have shown considerable interpersonal differences in BP response to antihypertensive treatment, suggesting a genetic component. Utilizing data from 4297 AA participants randomized to chlorthalidone from the Genetics of Hypertension Associated Treatments (GenHAT) study, we aimed to identify variants associated with the efficacy of chlorthalidone. An additional aim was to find variants that contributed to changes in fasting glucose (FG) in these individuals. We performed genome-wide association analyses on the change of systolic and diastolic BP (SBP and DBP) over six months and FG levels over 24 months of treatment. We sought replication in the International Consortia of Pharmacogenomics Studies. We identified eight variants statistically associated with BP response and nine variants associated with FG response. One suggestive LINC02211-CDH9 intergenic variant was marginally replicated with the same direction of effect. Given the impact of hypertension in AAs, this study implies that understanding the genetic background for BP control and glucose changes during chlorthalidone treatment may help prevent adverse cardiovascular events in this population. Full article

A cocrystal of the antihypertensive drug chlorthalidone (CTD) with caffeine (CAF) was obtained (CTD-CAF) by the slurry method, for which a 2:1 stoichiometric ratio was found by powder and single-crystal X-ray diffraction analysis. Cocrystal CTD-CAF showed a supramolecular organization in which CAF molecules are embedded in channels of a 3D network of CTD molecules. The advantage of the cocrystal in comparison to CTD is reflected in a threefold solubility increase and in the dose/solubility ratios, which diminished from near-unit values for D_0D to 0.29 for D_0CC. Furthermore, dissolution experiments under non-sink conditions showed improved performance of CTD-CAF compared with pure CTD. Subsequent studies showed that CTD-CAF cocrystals transform to CTD form I where CTD precipitation inhibition could be achieved in the presence of pre-dissolved polymer HPMC 80–120 cPs, maintaining supersaturation drug concentrations for at least 180 min. Finally, dissolution experiments under sink conditions unveiled that the CTD-CAF cocrystal induced, in pH-independent manner, faster and more complete CTD dissolution when compared to commercial tablets of CTD. Due to the stability and dissolution behavior of the novel CTD-CAF cocrystal, it could be used to develop solid dosage forms using a lower CTD dose to obtain the same therapeutic response and fewer adverse effects. Full article

Plasma renin activity (PRA) is a predictive biomarker of blood pressure (BP) response to antihypertensives in European–American hypertensive patients. We aimed to identify the metabolic signatures of baseline PRA and the linkages with BP response to β-blockers and thiazides. Using data from the Pharmacogenomic Evaluation of Antihypertensive Responses-2 (PEAR-2) trial, multivariable linear regression adjusting for age, sex and baseline systolic-BP (SBP) was performed on European–American individuals treated with metoprolol (n = 198) and chlorthalidone (n = 181), to test associations between 856 metabolites and baseline PRA. Metabolites with a false discovery rate (FDR) < 0.05 or p < 0.01 were tested for replication in 463 European–American individuals treated with atenolol or hydrochlorothiazide. Replicated metabolites were then tested for validation based on the directionality of association with BP response. Sixty-three metabolites were associated with baseline PRA, of which nine, including six lipids, were replicated. Of those replicated, two metabolites associated with higher baseline PRA were validated: caprate was associated with greater metoprolol SBP response (β = −1.7 ± 0.6, p = 0.006) and sphingosine-1-phosphate was associated with reduced hydrochlorothiazide SBP response (β = 7.6 ± 2.8, p = 0.007). These metabolites are clustered with metabolites involved in sphingolipid, phospholipid, and purine metabolic pathways. The identified metabolic signatures provide insights into the mechanisms underlying BP response. Full article

A new simple, precise, accurate and selective high-performance thin-layer chromatographic (HPTLC) method has been developed for the simultaneous deter-mination of five mixtures: atenolol and chlorthalidone (Mix. l), enalapril maleate and hydrochlorothiazide (Mix. ll), amiloride hydrochloride and hydrochlorothiazide (Mix. lll), atenolol, chlorthalidone and amiloride hydrochloride (Mix. lV) and atenolol, hydrochlorottriazide and amiloride hydrochloride (Mix. V) in bulk powders and in pharmaceutical dosage forms. The methods consist of dissolving the drugs in methanol and spotting these solutions on a thin layer Merck HPTLC plates (0.25 mm thickness) pre-coated wrth 60 GF₂₅₄ silica gel on aluminum sheet as the stationary phase, using dioxane:acetonrtrile: 1-propanol:hexane (30:18:23:1; v/v/v/v) , ethylacetate:chlo-roform:methanol:acetic acid (11:8:7.5:1.5; v/v/v/v). ethylacetate:chloroform:1-propanol:25% ammonia solution (12:9:1:0.2; v/v/v/v), di0xan:acetonitrile:1-propanol:tetrahydrofuran (20:13:4:15; v/v/v/v) and dioxane:ethylacetate:acetonitrile:1-propanol (10:7:5.5:3 v/v/v/v) as the mobile phases for mixtures l, ll, lll, lV and V, respectively. Detection was carried out densitometrically using UV detector at 283, 266, 257, 226 and 362 for atenolol, chlorthalidone, enalapril maleate, hydrochlorothiazide and amiloride hydrochloride, respectively. Calibration curves were linear in the range 1–100 µg/ml⁻¹ with correlation coefficients not less than 0.9996. The percentage recoveries ranged from 98.3 ± 1.42 to 100.8 ± 0.79. Full article