Comparative Efficacy and Safety of Amlodipine and Losartan Potassium in Essential Hypertension in a Tertiary Hospital of Bangladesh.

Hypertension is a common disorder of major clinical, public health and economic importance. It affects men and women of all ages, and the prevalence is increasing in most countries. Maintenance of blood pressure below 140/90 mm of Hg is recommended by most of the guideline available around the world. Various classes of drugs are being used in the treatment of hypertension. Losartan potassium and amlodipine are two different antihypertensive agents belonging to two different groups used commonly around the world in treating essential hypertension. Losartan potassium is non-peptide Angiotensin-II receptor antagonist. Amlodipine which is the third generation dihydropyridine group of calcium channel blocker. The aim of the study was to compare the efficacy and safety of amlodipine and losartan for the treatment of essential hypertensive patients (18-75 years). A non-randomized comparative observational study was conducted in the Department of Pharmacology and Therapeutics in collaboration with Department of Medicine, Sylhet, MAG Osmani Medical College, Sylhet, Bangladesh from July 2021 to June 2022. In this study non-randomization was in two groups. Group A received amlodipine 5mg daily at morning and Group B received losartan potassium 50mg daily at night. The study parameters were systolic blood pressure (SBP), diastolic blood pressure (DBP), ankle oedema, serum K+ level. The result of treatment outcome was compared between two groups. After treatment the reduction of SBP was 5.19±2.93mm of Hg versus 3.27±1.34mm of Hg (p<0.001); reduction of DBP was 1.7±0.70 mm of Hg versus 0.68 mm of Hg (p<0.001) and serum K+ level 4.22±0.27mmol/L versus 4.21±0.16mmol/L (p<0.719) in amlodipine and losartan group respectively. Amlodipine is more effective than losartan potassium in respect to treatment of essential hypertension. Regarding adverse events losartan potassium causes angioedema, hyperkalemia, headache, dizziness etc. The study concluded that amlodipine is superior to losartan potassium in treating essential hypertension.

Amlodipine inhibits Synaptotagmin-4's oncogenic activity on gastric cancer proliferation by targeting calcium signaling.

BACKGROUND: Gastric cancer (GC) remains a leading cause of cancer mortality globally. Synaptotagmin-4 (SYT4), a calcium-sensing synaptic vesicle protein, has been implicated in the oncogenesis of diverse malignancies. PURPOSE: This study delineates the role of SYT4 in modulating clinical outcomes and biological behaviors in GC. METHODS: We evaluated SYT4 expression in GC specimens using bioinformatics analyses and immunohistochemistry. Functional assays included CCK8 proliferation tests, apoptosis assays via flow cytometry, confocal calcium imaging, and xenograft models. Western blotting elucidated MAPK pathway involvement. Additionally, we investigated the impact of the calcium channel blocker amlodipine on cellular dynamics and MAPK pathway activity. RESULTS: SYT4 was higher in GC tissues, and the elevated SYT4 was significantly correlated with adverse prognosis. Both univariate and multivariate analyses confirmed SYT4 as an independent prognostic indicator for GC. Functionally, SYT4 promoted tumorigenesis by fostering cellular proliferation, inhibiting apoptosis, and enhancing intracellular Ca2+ influx, predominantly via MAPK pathway activation. Amlodipine pre-treatment attenuated SYT4-driven cell growth and potentiated apoptosis, corroborated by in vivo xenograft assessments. These effects were attributed to MAPK pathway suppression by amlodipine. CONCLUSION: SYT4 emerges as a potential prognostic biomarker and a pro-oncogenic mediator in GC through a Ca2+-dependent MAPK mechanism. Amlodipine demonstrates significant antitumor effects against SYT4-driven GC, positing its therapeutic promise. This study underscores the imperative of targeting calcium signaling in GC treatment strategies.

Amlodipine inhibits the proliferation and migration of esophageal carcinoma cells through the induction of endoplasmic reticulum stress.

BACKGROUND: L-type calcium channels are the only protein channels sensitive to calcium channel blockers, and are expressed in various cancer types. The Cancer Genome Atlas database shows that the mRNA levels of multiple L-type calcium channel subunits in esophageal squamous cell carcinoma tumor tissue are significantly higher than those in normal esophageal epithelial tissue. Therefore, we hypothesized that amlodipine, a long-acting dihydropyridine L-type calcium channel blocker, may inhibit the occurrence and development of esophageal cancer (EC). AIM: To investigate the inhibitory effects of amlodipine on EC through endoplasmic reticulum (ER) stress. METHODS: Cav1.3 protein expression levels in 50 pairs of EC tissues and corresponding paracancerous tissues were examined. Subsequently, the inhibitory effects of amlodipine on proliferation and migration of EC cells in vitro were detected using 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide and Transwell assays. In vivo experiments were performed using murine xenograft model. To elucidate the underlying mechanisms, in vitro cell studies were performed to confirm that ER stress plays a role in inhibition proliferation and migration of EC cells treated with amlodipine. RESULTS: The expression level of Cav1.3 in esophageal carcinoma was 1.6 times higher than that in paracancerous tissues. Amlodipine treatment decreased the viability of esophageal carcinoma cells in a dose- and time-dependent manner. In vivo animal experiments also clearly indicated that amlodipine inhibited the growth of EC tumors in mice. Additionally, amlodipine reduces the migration of tumor cells by inhibiting epithelial-mesenchymal transition (EMT). Mechanistic studies have demonstrated that amlodipine induces ER stress-mediated apoptosis and suppresses EMT. Moreover, amlodipine-induced autophagy was characterized by an increase in autophagy lysosomes and the accumulation of light chain 3B protein. The combination of amlodipine with the ER stress inhibitor 4-phenylbutyric acid further confirmed the role of the ER stress response in amlodipine-induced apoptosis, EMT, and autophagy. Furthermore, blocking autophagy increases the ratio of apoptosis and migration. CONCLUSION: Collectively, we demonstrate for the first time that amlodipine promotes apoptosis, induces autophagy, and inhibits migration through ER stress, thereby exerting anti-tumor effects in EC.

Effect of amlodipine on the circulating renin-angiotensin-aldosterone system in healthy cats.

BACKGROUND: Systemic hypertension (SH) is a common cardiovascular disease in older cats that is treated primarily with the calcium channel blocker amlodipine besylate (AML). The systemic effect of AML on the classical and alterative arms of the renin-angiotensin-aldosterone system (RAAS) in cats is incompletely characterized. HYPOTHESIS/OBJECTIVES: To determine the effect of AML compared to placebo on circulating RAAS biomarkers in healthy cats using RAAS fingerprinting. ANIMALS: Twenty healthy client-owned cats. METHODS: Cats were administered amlodipine besylate (0.625 mg in toto) or placebo by mouth once daily for 14 days in a crossover design with a 4-week washout period. Plasma AML concentrations and RAAS biomarker concentrations were measured at multiple timepoints after the final dose in each treatment period. Time-weighted averages for RAAS biomarkers over 24 hours after dosing were compared between treatment groups using Wilcoxon rank-sum testing. RESULTS: Compared to placebo, AML treatment was associated with increases in markers of plasma renin concentration (median 44% increase; interquartile range [IQR] 19%-86%; P = .009), angiotensin I (59% increase; IQR 27-101%; P = .006), angiotensin II (56% increase; IQR 5-70%; P = .023), angiotensin IV (42% increase; -19% to 89%; P = .013); and angiotensin 1-7 (38% increase; IQR 9-118%; P = .015). CONCLUSIONS AND CLINICAL IMPORTANCE: In healthy cats, administration of AML resulted in nonspecific activation of both classical and alternative RAAS pathways.

Gene Polymorphisms and Drug-Drug Interactions Determine the Metabolic Profile of Blonanserin.

This study aimed to evaluate the effects of cytochrome P450 3A4 (CYP3A4) gene polymorphism and drug interaction on the metabolism of blonanserin. Human recombinant CYP3A4 was prepared using the Bac-to-Bac baculovirus expression system. A microsomal enzyme reaction system was established, and drug-drug interactions were evaluated using Sprague-Dawley rats. Ultra-performance liquid chromatography-tandem mass spectrometry was used to detect the concentrations of blonanserin and its metabolite. Compared with wild type CYP34A, the relative clearance of blonanserin by CYP3A4.29 significantly increased to 251.3%, while it decreased notably with CYP3A4.4, 5, 7, 8, 9, 10, 12, 13, 14, 16, 17, 18, 23, 24, 28, 31, 33, and 34, ranging from 6.09% to 63.34%. Among 153 tested drugs, nimodipine, felodipine, and amlodipine were found to potently inhibit the metabolism of blonanserin. Moreover, the inhibitory potency of nimodipine, felodipine, and amlodipine varied with different CYP3A4 variants. The half-maximal inhibitory concentration and enzymatic kinetics assay demonstrated that the metabolism of blonanserin was noncompetitively inhibited by nimodipine in rat liver microsomes and was inhibited in a mixed manner by felodipine and amlodipine in both rat liver microsomes and human liver microsomes. When nimodipine and felodipine were coadministered with blonanserin, the area under the blood concentration-time curve (AUC)(0-t), AUC(0-∞), and C max of blonanserin increased. When amlodipine and blonanserin were combined, the C max of blonanserin C increased remarkably. The vast majority of CYP3A4 variants have a low ability to catalyze blonanserin. With combined administration of nimodipine, felodipine, and amlodipine, the elimination of blonanserin was inhibited. This study provides the basis for individualized clinical use of blonanserin. SIGNIFICANCE STATEMENT: The enzyme kinetics of novel CYP3A4 enzymes for metabolizing blonanserin were investigated. Clearance of blonanserin by CYP3A4.4, 5, 7-10, 12-14, 16-18, 23-24, 28, 31, 33, and 34 decreased notably, but increased with CYP3A4.29. Additionally, we established a drug interaction spectrum for blonanserin, in which nimodipine, felodipine, and amlodipine kinetics exhibited mixed inhibition. Moreover, their inhibitory potencies decreased with CYP3A4.4 and 5 compared to CYP3A4.1. This study provides essential data for personalized clinical use of blonanserin.

Amlodipine and lufenuron as repurposing drugs against Sporothrix brasiliensis.

Background: Sporotrichosis caused by Sporothrix brasiliensis is a globally emerging infectious disease with limited therapeutic options. Thus, we aimed to evaluate the in vitro activity of amlodipine (AML) and lufenuron (LUF) alone and their interaction with itraconazole (ITZ), the first-choice drug against S. brasiliensis. Methods: Twenty clinical isolates of S. brasiliensis from two hyperendemic regions were tested through a microdilution assay to evaluate the minimal inhibitory concentration (MIC) and minimal fungicidal concentration (MFC) of AML and LUF. Checkerboard assay was performed with 10 isolates for both drug interactions with ITZ. Results: AML showed inhibitory and fungicidal activity against all isolates included, with MIC values ranging from 32 to 256 µg/mL, and MFC from 64 to 256 µg/mL. However, none of the S. brasiliensis isolates were inhibited by the highest soluble concentration of LUF (MIC >64 µg/mL for all strains). Synergic interaction of AML and LUF with ITZ occurred in 50% and 40% of the isolates tested, without any antagonistic effects. Conclusion: Both repurposing drugs evaluated in our study showed a promising in vitro activity, especially in synergy with ITZ against S. brasiliensis, warranting future in vivo investigations regarding its activity.

S-AMLODIPINE AS A MODERN EFFECTIVE ANTIHYPERTENSIVE AND AN ANTIANGINAL AGENT.

OBJECTIVE: The aim: Study of the clinical and hemodynamic effects of S-amlodipine in patients with arterial hypertension associated with coronary artery disease, in individuals with preserved LV systolic function. PATIENTS AND METHODS: Materials and methods: The study includes 51 patients with arterial hypertension associated with coronary artery disease, who were treated with S-amlodipine. RESULTS: Results: This study shows the high clinical effectiveness of the use of S-amlodipine in patients with arterial hypertension associated with coronary artery disease. We reveal that treatment of hypertensive patients with coronary artery disease with S-amlodipine leads to improvement of LV diastolic dysfunction, bringing it closer to normal values. CONCLUSION: Conclusions: Clinical effectiveness was associated with positive changes in hemodynamics, and was expressed in the normalization of the left ventricle diastolic function parameters, about which indirectly indicates decreasing of end-diastolic pressure.

Cancer Stem Cells of Hepatocellular Carcinoma Are Suppressed by the Voltage-gated Calcium Channel Inhibitor Amlodipine.

BACKGROUND/AIM: The membrane transporters activated in cancer stem cells (CSCs) are the target of novel cancer therapies for hepatocellular carcinoma (HCC). The present investigation demonstrated the expression profiles of ion channels in CSCs of HCC. MATERIALS AND METHODS: Cells that highly expressed aldehyde dehydrogenase 1 family member A1 (ALDH1A1) were separated from HepG2 cells, a human HCC cell line, by fluorescence-activated cell sorting, and CSCs were identified based on the formation of tumorspheres. Gene expression profiles in CSCs were investigated using microarray analysis. RESULTS: Among HepG2 cells, ALDH1A1 messenger RNA level was higher in CSCs than in non-CSCs. Furthermore, CSCs exhibited resistance to cisplatin and had the capacity to redifferentiate. The results of the microarray analysis of CSCs showed the up-regulated expression of several genes related to ion channels, such as calcium voltage-gated channel auxiliary subunit gamma 4 (CACNG4). The cytotoxicity of the CACNG4 inhibitor amlodipine was higher at lower concentrations in CSCs than in non-CSCs, and markedly decreased the number of tumorspheres. The cell population among HepG2 cells that highly expressed ALDH1A1 was also significantly reduced by this inhibitor. CONCLUSION: CACNG4 plays a role in maintaining CSCs, and its inhibitor, amlodipine, could potentially be a targeted therapeutic agent against HCC.

Pitavastatin and Lovastatin Exhibit Calcium Channel Blocking Activity Which Potentiate Vasorelaxant Effects of Amlodipine: A New Futuristic Dimension in Statin's Pleiotropy.

Background and Objectives: We have recently reported that Fluvastatin, Atorvastatin, Simvastatin and Rosuvastatin have calcium channel antagonistic activities using rabbits' intestinal preparations. The current study is focused on the effects of Pitavastatin and Lovastatin for possible inhibition of vascular L-Type calcium channels, which may have vasorelaxant effect(s). Combined effects of Pitavastatin and Lovastatin in the presence of Amlodipine were also tested for vasorelaxation. Materials and Methods: Possible relaxing effects of Pitavastatin and Lovastatin on 80 mM Potassium chloride (KCL)-induced contractions and on 1 µM norepinephrine (N.E)-induced contractions were studied in isolated rabbit's aortic strips preparations. Relaxing effects on 80 mM KCL-induced vascular contractions were further verified by constructing Calcium Concentration Response Curves (CCRCs), in the absence and presence of three different concentrations of Pitavastatin and Lovastatin using CCRCs as negative control. Verapamil was used as a standard drug that has L-Type calcium channel binding activity. In other series of experiments, we studied drug interaction(s) among Pitavastatin, Lovastatin, and amlodipine. Results: The results of this study imply that Lovastatin is more potent than Pitavastatin for having comparatively lower EC50 (7.44 × 10-5 ± 0.16 M) in intact and (4.55 × 10-5 ± 0.10 M) in denuded aortae for KCL-induced contractions. Lovastatin amplitudes in intact and denuded aortae for KCL-induced contractions were, respectively, 24% and 35.5%; whereas amplitudes for Pitavastatin in intact and denuded aortae for KCL-induced contractions were 34% and 40%, respectively. A left shift in the EC50 values for the statins was seen when we added amlodipine in EC50 (Log Ca++ M). Right shift for CCRCs state that Pitavastatin and Lovastatin have calcium channel antagonistic effects. Lovastatin in test concentration (6.74 × 10-7 M) produced a right shift in relatively lower EC50 (-2.5 ± 0.10) Log Ca++ M as compared to Pitavastatin, which further confirms that lovastatin is relatively more potent. The right shift in EC50 resembles the right shift of Verapamil. Additive effect of Pitavastatin and Lovastatin was noted in presence of amlodipine (p < 0.05). Conclusions: KCL (80 mM)-induced vascular contractions were relaxed by Pitavastatin and Lovastatin via inhibitory effects on L-Type voltage-gated calcium channels. Lovastatin and Pitavastatin also relaxed Norepinephrine (1 µM)-induced contractions giving an insight for involvement of dual mode of action of Pitavastatin and Lovastatin.

Effect of blood pressure-lowering agents on microvascular function in people with small vessel diseases (TREAT-SVDs): a multicentre, open-label, randomised, crossover trial.

BACKGROUND: Hypertension is the leading risk factor for cerebral small vessel disease. We aimed to determine whether antihypertensive drug classes differentially affect microvascular function in people with small vessel disease. METHODS: We did a multicentre, open-label, randomised crossover trial with blinded endpoint assessment at five specialist centres in Europe. We included participants aged 18 years or older with symptomatic sporadic small vessel disease or cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) and an indication for antihypertensive treatment. Participants were randomly assigned (1:1:1) to one of three sequences of antihypertensive treatment using a computer-generated multiblock randomisation, stratified by study site and patient group. A 2-week washout period was followed by three 4-week periods of oral monotherapy with amlodipine, losartan, or atenolol at approved doses. The primary endpoint was change in cerebrovascular reactivity (CVR) determined by blood oxygen level-dependent MRI response to hypercapnic challenge in normal-appearing white matter from the end of washout to the end of each treatment period. Efficacy analyses were done by intention-to-treat principles in all randomly assigned participants who had at least one valid assessment for the primary endpoint, and analyses were done separately for participants with sporadic small vessel disease and CADASIL. This trial is registered at ClinicalTrials.gov, NCT03082014, and EudraCT, 2016-002920-10, and is terminated. FINDINGS: Between Feb 22, 2018, and April 28, 2022, 75 participants with sporadic small vessel disease (mean age 64·9 years [SD 9·9]) and 26 with CADASIL (53·1 years [7·0]) were enrolled and randomly assigned to treatment. 79 participants (62 with sporadic small vessel disease and 17 with CADASIL) entered the primary efficacy analysis. Change in CVR did not differ between study drugs in participants with sporadic small vessel disease (mean change in CVR 1·8 × 10-4%/mm Hg [SE 20·1; 95% CI -37·6 to 41·2] for amlodipine; 16·7 × 10-4%/mm Hg [20·0; -22·3 to 55·8] for losartan; -7·1 × 10-4%/mm Hg [19·6; -45·5 to 31·1] for atenolol; poverall=0·39) but did differ in patients with CADASIL (15·7 × 10-4%/mm Hg [SE 27·5; 95% CI -38·3 to 69·7] for amlodipine; 19·4 × 10-4%/mm Hg [27·9; -35·3 to 74·2] for losartan; -23·9 × 10-4%/mm Hg [27·5; -77·7 to 30·0] for atenolol; poverall=0·019). In patients with CADASIL, pairwise comparisons showed that CVR improved with amlodipine compared with atenolol (-39·6 × 10-4%/mm Hg [95% CI -72·5 to -6·6; p=0·019) and with losartan compared with atenolol (-43·3 × 10-4%/mm Hg [-74·3 to -12·3]; p=0·0061). No deaths occurred. Two serious adverse events were recorded, one while taking amlodipine (diarrhoea with dehydration) and one while taking atenolol (fall with fracture), neither of which was related to study drug intake. INTERPRETATION: 4 weeks of treatment with amlodipine, losartan, or atenolol did not differ in their effects on cerebrovascular reactivity in people with sporadic small vessel disease but did result in differential treatment effects in patients with CADASIL. Whether antihypertensive drug classes differentially affect clinical outcomes in people with small vessel diseases requires further research. FUNDING: EU Horizon 2020 programme.

Effects of Aliskiren Monotherapy versus Amlodipine Monotherapy in Hypertensive Patients with Obesity or Type 2 Diabetes Mellitus.

INTRODUCTION: Renin-angiotensin system inhibitors have been reported to exert protective effects against organ damage and failure; however, the impact of the direct renin inhibitor as monotherapy has not been assessed. Here, we investigated the effects of 24-week monotherapy with aliskiren compared to amlodipine in hypertensive patients with type 2 diabetes or obesity. METHODS: In this randomized intervention study, 62 adult hypertensive patients with visceral obesity (defined as a body mass index [BMI] greater than 25 kg/m2 and a visceral adipose tissue area [VFA] greater than 100 cm2) or type 2 diabetes mellitus (age 57 ± 13, 65% men, BMI 28.8 ± 4.8 kg/m2, VFA 134.8 ± 47.0 cm2, blood pressure 141 ± 16/86 ± 13 mm Hg) were randomized to receive 24-week treatment with aliskiren (max. 300 mg) or amlodipine (max. 10 mg). The primary outcome was the change in VFA at 24 weeks post-treatment. RESULTS: Change in VFA did not differ significantly from baseline in either group. Systolic blood pressure significantly decreased at 12 weeks (-10 mm Hg, p = 0.001) and 24 weeks (-10 mm Hg, p = 0.001) in the amlodipine group and at 24 weeks (-11 mm Hg, p = 0.001) in the aliskiren group. Diastolic blood pressure significantly decreased at 24 weeks (-6 mm Hg, p = 0.009) only in the amlodipine group. Although the estimated glomerular filtration rates did not significantly change in either group, the logarithm of urinary albumin excretion significantly decreased at 24 weeks only in the aliskiren group (-0.60, p < 0.001). The 24-week changes in the urinary albumin excretion significantly correlated with the changes in the plasma renin activity in the aliskiren group (r = 0.51, p = 0.008). CONCLUSION: Aliskiren monotherapy did not show any superiority to amlodipine monotherapy on VFA, estimated glomerular filtration rates, or urinary albumin excretion in obese or type 2 diabetic hypertensive patients.

A Reappraisal of the Effects of L-type Ca2+ Channel Blockers on Store-Operated Ca2+ Entry and Heart Failure.

Dihydropyridines such as amlodipine are widely used as antihypertensive agents, being prescribed to ∼70 million Americans and >0.4 billion adults worldwide. Dihydropyridines block voltage-gated Ca2+ channels in resistance vessels, leading to vasodilation and a reduction in blood pressure. Various meta-analyses show that dihydropyridines are relatively safe and effective in reducing hypertension. The use of dihydropyridines has recently been called into question as these drugs appear to activate store-operated Ca2+ entry in fura-2-loaded nonexcitable cells, trigger vascular remodeling, and increase heart failure, leading to the questioning of their clinical use. Given that hypertension is the dominant "silent killer" across the globe affecting ∼1.13 billion people, removal of Ca2+ channel blockers as antihypertensive agents has major health implications. Here, we show that amlodipine has marked intrinsic fluorescence, which further increases considerably inside cells over an identical excitation spectrum as fura-2, confounding the ability to measure cytosolic Ca2+. Using longer wavelength Ca2+ indicators, we find that concentrations of Ca2+ channel blockers that match therapeutic levels in serum of patients do not activate store-operated Ca2+ entry. Antihypertensive Ca2+ channel blockers at pharmacological concentrations either have no effect on store-operated channels, activate them indirectly through store depletion or inhibit the channels. Importantly, a meta-analysis of published clinical trials and a prospective real-world analysis of patients prescribed single antihypertensive agents for 6 mo and followed up 1 yr later both show that dihydropyridines are not associated with increased heart failure or other cardiovascular disorders. Removal of dihydropyridines for treatment of hypertension cannot therefore be recommended.

Rosuvastatin and Simvastatin potentiate antihypertensive effect of amlodipine through vasorelaxation phenomenon.

This study is carried out to assess the effects of rosuvastatin and simvastatin on blood vessels for possible vasorelaxant effect. The study is also translating the possible vasorelaxant effect in Wistar rats for a subsequent fall in systolic blood pressure. It is evident from the EC50, that rosuvastatin is more effective on relaxing N.E induced contractions, while simvastatin is more effective on relaxing KCL induced contractions. Simvastatin is equipotent when compared to effects of amlodipine on KCl induced contractions in denuded aortae. Simvastatin produced significant right shift in test concentration 1.1× 10-6M with its respective EC50 -1.85logCa++M as compared to its respective control EC50 -3logCa++M. Rosuvastatin also produced significant right shift in the EC50. In conclusion, it is stated that rosuvastatin and simvastatin relax the aortic strips preparations through inhibition of voltage gated calcium channels and inhibition of N.E induced contractions. Rosuvastatin and simvastatin have additive effects when used in the presence of a standard vaso-relaxant drug like amlodipine, which further confirms its additive effect on decreasing the systolic blood pressure of hypertensive rats (P<0.05).

Synergistic combination of carvedilol, amlodipine, amitriptyline, and antibiotics as an alternative treatment approach for the susceptible and multidrug-resistant A. baumannii infections via drug repurposing.

We evaluated in vitro activity of 13 drugs used in the treatment of some non-communicable diseases via repurposing to determine their potential use in the treatment of Acinetobacter baumannii infections caused by susceptible and multidrug-resistant strains. A. baumannii is a multidrug-resistant Gram-negative bacteria causing nosocomial infections, especially in intensive care units. It has been identified in the WHO critical pathogen list and this emphasises urgent need for new treatment options. As the development of new therapeutics is expensive and time consuming, finding new uses of existing drugs via drug repositioning has been favoured. Antimicrobial susceptibility tests were conducted on all 13 drugs according to CLSI. Drugs with MIC values below 128 µg/mL and control antibiotics were further subjected to synergetic effect and bacterial time-kill analysis. Carvedilol-gentamicin (FICI 0.2813) and carvedilol-amlodipine (FICI 0.5625) were determined to have synergetic and additive effect, respectively, on the susceptible A. baumannii strain, and amlodipine-tetracycline (FICI 0.75) and amitriptyline-tetracycline (FICI 0.75) to have additive effect on the multidrug-resistant A. baumannii strain. Most remarkably, both amlodipine and amitriptyline reduced the MIC of multidrug-resistant, including some carbapenems, A. baumannii reference antibiotic tetracycline from 2 to 0.5 µg/mL, for 4-folds. All these results were further supported by bacterial time-kill assay and all combinations showed bactericidal activity, at certain hours, at 4XMIC. Combinations proposed in this study may provide treatment options for both susceptible and multidrug-resistant A. baumannii infections but requires further pharmacokinetics and pharmacodynamics analyses and in vivo re-evaluations using appropriate models.

Effects of chlorthalidone plus amiloride compared with amlodipine on short-term blood pressure variability in individuals with hypertension and obstructive sleep apnea: a randomized controlled trial.

OBJECTIVE: To compare the effects of chlortalidone plus amiloride and amlodipine on blood pressure (BP) variability in patients with hypertension and obstructive sleep apnea syndrome (OSA). METHODS: A randomized, controlled, double-blind trial enrolled men and women aged 40 years or older with a diagnosis of OSA (apnea-hypopnea index 10-40 apneas/h of sleep) confirmed by overnight laboratory polysomnography and systolic BP 140-159 mmHg or diastolic BP 90-99 mmHg. Participants were randomized to receive chlortalidone 25 mg plus amiloride 5 mg daily or amlodipine 10 mg daily for 8 weeks. BP variability was calculated from 24-hour ambulatory BP monitoring at baseline and follow-up using the following indices: SD, coefficient of variation, average real variability (ARV), time-rate index, and variability independent of the mean (VIM). RESULTS: The study included 65 patients, with 33 assigned to the chlortalidone plus amiloride group and 32 to the amlodipine group. Participants in both groups had similar baseline characteristics. Short-term BP variability decreased within groups for SD and ARV indexes for 24-hour systolic BP and daytime systolic BP, but statistically significant time*group interactions were found for sleep systolic SD and VIM, with greater reduction in patients treated with amlodipine. CONCLUSION: In brief, our study has shown that the use of chlorthalidone in combination with amiloride and amlodipine produces comparable effects on short-term BP variability in patients with hypertension and OSA. Therefore, our findings suggest that BP variability may not be a significant factor when choosing between these medications for the treatment of hypertension and OSA.

Atorvastatin and Fluvastatin Potentiate Blood Pressure Lowering Effect of Amlodipine through Vasorelaxant Phenomenon.

Background and Objectives: We have recently reported that stains have calcium channel blocking activity in isolated jejunal preparations. In this study, we examined the effects of atorvastatin and fluvastatin on blood vessels for a possible vasorelaxant effect. We also studied the possible additional vasorelaxant effect of atorvastatin and fluvastatin, in the presence of amlodipine, to quantify its effects on the systolic blood pressure of experimental animals. Materials and Methods: Atorvastatin and fluvastatin were tested in isolated rabbits' aortic strip preparations using 80mM Potassium Chloride (KCl) induced contractions and 1 micro molar Norepinephrine (NE) induced contractions. A positive relaxing effect on 80 mM KCl induced contractions were further confirmed in the absence and presence of atorvastatin and fluvastatin by constructing calcium concentration response curves (CCRCs) while using verapamil as a standard calcium channel blocker. In another series of experiments, hypertension was induced in Wistar rats and different test concentrations of atorvastatin and fluvastatin were administered in their respective EC50 values to the test animals. A fall in their systolic blood pressure was noted using amlodipine as a standard vasorelaxant drug. Results: The results show that fluvastatin is more potent than amlodipine as it relaxed NE induced contractions where the amplitude reached 10% of its control in denuded aortae. Atorvastatin relaxed KCL induced contractions with an amplitude reaching 34.4% of control response as compared to the amlodipine response, i.e., 39.1%. A right shift in the EC50 (Log Ca++ M) of Calcium Concentration Response Curves (CCRCs) implies that statins have calcium channel blocking activity. A right shift in the EC50 of fluvastatin with relatively less EC50 value (-2.8 Log Ca++ M) in the presence of test concentration (1.2 × 10-7 M) of fluvastatin implies that fluvastatin is more potent than atorvastatin. The shift in EC50 resembles the shift of Verapamil, a standard calcium channel blocker (-1.41 Log Ca++ M). Conclusions: Atorvastatin and fluvastatin relax the aortic strip preparations predominantly through the inhibition of voltage gated calcium channels in high molar KCL induced contractions. These statins also inhibit the effects of NE induced contractions. The study also confirms that atorvastatin and fluvastatin potentiate blood pressure lowering effects in hypertensive rats.

Comparison of antihypertensive drugs amlodipine and perindopril on blood pressure variability after long-term treatment of hypertension induced by apatinib and bevacizumab.

The purpose of this study was to elucidate the therapeutic effect of different antihypertensive drugs (amlodipine and perindopril) on hypertension induced by apatinib and bevacizumab. Sixty patients with hypertension treated with apatinib or bevacizumab were selected and divided into two groups: one group was treated with amlodipine and the other group was treated with perindopril. Before and after treatment, the dynamic blood pressure (BP) measurement (systolic BP [SBP] and diastolic BP [DBP]), echocardiography (left ventricular end-diastolic diameter, interventricular septal thickness [IVST], left ventricular posterior wall thickness [LVPWT], and left atrial diameter [LAD]), and detection of nitric oxide (NO) content in venous blood were performed. In the amlodipine group, the 24hSBP, 24hSSD, 24hSCV, daytime mean SBP (dSBP), daytime mean SSD (dSSD), daytime mean SBP CV, night mean SBP (nSBP), night mean SSD, 24hDBP, 24hDSD, 24 h DBP CV, daytime mean DBP (dDBP), daytime mean DSD (dDSD), daytime mean DBP CV, night mean DBP (nDBP), LAD, and LAD index (LADi) after treatment were all lower than before treatment, while NO was higher than before treatment (all P < 0.05). In the perindopril group, the 24hSBP, dSBP, nSBP, 24hDBP, dDBP, nDBP, LAD, LADi, IVST, LVPWT, and left ventricular mass index (LVMI) after treatment were lower than before treatment, and NO level after treatment was higher than before treatment (all P < 0.05). After treatment, the 24hSBP, 24hSSD, dSBP, dSSD, nSBP, 24hDBP, 24hDSD, dDBP, dDSD, nDBP, night mean DSD, and NO were all lower while the LAD, LADi, IVST, LVPWT, and LVMI were higher in the amlodipine group than those in the perindopril group (all P < 0.05). Our study suggests that the SBP and DBP variability of amlodipine in the treatment of hypertension induced by apatinib and bevacizumab is slightly better than that of perindopril, but the effect of perindopril in improving endothelial function indices NO and echocardiographic data is better than that of amlodipine.

Folic acid enhances the cardiovascular protective effect of amlodipine in renal hypertensive rats with elevated homocysteine.

OBJECTIVES: To investigate the actions of amlodipine-folic acid (amlodipine-FA) preparation on hypertension and cardiovascular in renal hypertensive rats with hyperhomocysteinemia (HHcy), so as to provide experimental basis for clinical research of amlodipine folic acid tablets. METHODS: Rats model of renal hypertension with HHcy were established. The rats were randomly divided into groups of model, amlodipine, folic acid (FA) and amlodipine-FA of various dosages. Normal rats were used as normal control group. Blood pressure, Hcy as well as plasma NO, ET-1 and hemodynamics were assayed. Histological alterations of heart and abdominal aorta were also examined. RESULTS: Compared with the normal group, blood pressure, plasma Hcy, and NO of the rats in model group were significantly increased, while the plasma ET-1 was decreased. Compared with the normal group, the animals in the model group had reduced cardiac function, thickened wall of the aorta and narrowed lumen. In FA group and amlodipine group, the rat plasma NO was increased while ET-1 was decreased, the protective effect of amlodipine-FA group on endothelial cells was further enhanced. In amlodipine group, the rat hemodynamics (LVSP, LVEDP and ±dp/dtmax, et al.) and vascular damage were significantly reduced, while in amlodipine-FA group, the heart function were further improved, and myocardial and vascular hypertrophy were significantly reduced. CONCLUSIONS: As compared to amlodipine alone, amlodipine -FA can lower both blood pressure and plasma Hcy, significantly enhancing vascular endothelial function to protect the heart and blood vessel in renal hypertensive rats with HHcy.

Effects of 5-fluorouracil Co-administration on Blood Pressure in Patients Maintained on Antihypertensives: a Retrospective Case Series.

This study aimed to investigate the possible drug-drug interactions (DDIs) of 5-FU with antihypertensives metabolised by CYP3A4 and 2C9, using blood pressure (BP) as a pharmacodynamic (PD) parameter. Patients who received 5-FU in combination with antihypertensives metabolised by CYP3A4 or 2C9, specifically, a) amlodipine, nifedipine, or amlodipine + nifedipine, b) candesartan or valsartan, or c) amlodipine + candesartan, amlodipine + losartan, or nifedipine + valsartan, (Group A, n = 20) were identified. Patients who received 5-FU with WF and antihypertensives, specifically, a) amlodipine or b) amlodipine + telmisartan, amlodipine + candesartan, or amlodipine + valsartan, (Group B, n = 5) or 5-FU alone (Group C, n = 25) were also identified and analysed as a comparator and control group, respectively. Regarding the peak BP levels during chemotherapy, there was a significant increase in both SBP (P < 0.0002 and 0.0013) and DBP (P = 0.0243 and 0.0032) in Groups A and C, respectively (Tukey-Kramer test). In contrast, although SBP also increased in Group B during chemotherapy, the change was not statistically significant and there was a decrease in DBP. The significant increase in SBP can be attributed to chemotherapy-induced hypertension by 5-FU or other drugs in the chemotherapeutic regimens. However, when comparing the lowest BP levels during chemotherapy, there was a decrease in SBP and DBP in all groups from the baseline values. The median time to peak and lowest BP was at least 2 weeks and 3 weeks, respectively, for all groups, suggesting that a BP lowering effect was observed following the offset of the initial chemotherapy-induced hypertension. At least 1 month after 5-FU chemotherapy, the SBP and DBP returned to baseline values in all groups. Since Group B also showed a significant increase in PT-INR, possibly demonstrating 5-FU inhibition of CYP activity and, consequently, of WF metabolism, it is likely that 5-FU also inhibited the metabolism of the antihypertensive drugs. The findings suggest possible DDIs between 5-FU and antihypertensives metabolised by CYP3A4.