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 Valsartan and Amlodipine Tablets Combined with α-Lipoic Acid on T-AOC, IL-6 and ß2-MG Levels in Patients with Diabetic Nephropathy.

Diabetic nephropathy (DN) is the most important cause of chronic renal and end-stage kidney disease in China. Hypertension (HTN) is highly prevalent in individuals with diabetic nephropathy. Arterial HTN affects two-thirds of people with type 2 diabetes (T2D). In these patients, HTN increased the potential of both micro- and macrovascular complications, and the co-occurrence of 2 such principal causes results in a 4-fold increased risk for cardiovascular disease (CVD) when contrasted with normotensive controls without diabetes. Therefore, the results of valsartan and amlodipine tablets combined with alpha-lipoic acid on total antioxidant capacity (T-AOC) need to be investigated. The aim of this study was to analyze the effects of valsartan (VA) and amlodipine tablets combined with alpha-lipoic acid (α-LA) on T-AOC, IL-6 and ß2-MG levels in patients with DN. We performed statistical analysis including the chi-square test, independent t-test, paired t-test and Analysis of Variance (ANOVA). Our findings indicate that VA, amlodipine and α-LA has a significant effect in patients with DN.

Single-Pill Combination with Three Antihypertensive Agents to Improve Blood Pressure Control in Hypertension: Focus on Olmesartan-Based Combinations.

Blood pressure control remains an unmet clinical need. Only about half of patients achieve their blood pressure (BP) targets and of these, the majority require combination and double or triple therapies. International guidelines recommend the association of drugs with complementary mechanisms of action and, in particular, the combination of renin-angiotensin system (RAS) inhibitors, calcium channel blockers (CCBs), and diuretics. Among the various angiotensin receptor blockers, olmesartan (OM) is available as a monotherapy and in dual and triple single-pill combinations (SPCs) with amlodipine (AML) and/or hydrochlorothiazide (HCTZ). Several phase III and IV studies, together with real-world studies, have demonstrated the additional benefits of combining OM either with AML or with HCTZ in terms of BP control and target BP achievements both in the general population and in special subgroups of hypertensive patients, such as the elderly, diabetic, chronic kidney disease or obese patients. Ambulatory BP monitoring studies assessing 24h BP have also demonstrated that dual, as well as triple, OM-based SPCs induce a more sustained and smoother BP reduction than placebo and monotherapy. Furthermore, triple OM-based SPC has been shown to improve therapeutic adherence in hypertensive patients compared to free combinations. The availability of OM combined with HCTZ, AML or both at different dosages makes it a valuable option to customize therapy based on the levels of BP and the clinical characteristics of hypertensive patients.

Efficacy and safety of calcium channel blockers in preventing cardiac siderosis in thalassemia patients: An updated meta-analysis with trial sequential analysis.

OBJECTIVES: Iron overload in patients with thalassemia represents a serious complication by affecting numerous organ systems. This meta-analysis aims to establish an evidence regarding the effect of amlodipine on cardiac iron overload in thalassemia patients. METHODS: We searched PubMed, Scopus, Web of Science, Cochrane Central, and EMBASE for all relevant randomized controlled trials (RCTs). The primary outcomes were cardiac T2* and myocardial iron concentration (MIC). Secondary outcomes were liver iron concentration (LIC), risk of Gastrointestinal (G.I.) upset and risk of lower limb edema. We used Hedges' g to pool continuous outcomes, while odds ratio was used for dichotomous outcomes. RESULTS: Seven RCTs were eligible for this systematic review and meta-analysis, comprising of 233 patients included in the analysis. Amlodipine had a statistically significant lower MIC (Hedges' g = -0.82, 95% confidence interval [CI] [-1.40, -0.24], p < .001) and higher cardiac T2* (Hedges' g = 0.36, 95% CI [0.10, 0.62], p = .03). Amlodipine was comparable to standard chelation therapy in terms of the risk of lower limb edema and GI upset. CONCLUSION: Our meta-analysis found that amlodipine significantly increases cardiac T2* and decreases MIC, hence decreasing the incidence of cardiomyopathy-related iron overload in thalassemia patients.

Amlodipine: Can act as an antioxidant in patients with transfusion-dependent ß-thalassemia? A double-blind, controlled, crossover trial.

BACKGROUND AND AIM: This study aimed to assess the antioxidant effects of amlodipine in transfusion-dependent ß-thalassemia (TDT) patients. METHODS: This crossover trial consisted of two sequences (AP and PA). In the AP sequence, nine cases received amlodipine 5 mg daily (phase I) and then were switched to placebo (phase II). In PA sequence, 10 patients took the placebo (phase I) and were shifted to amlodipine (phase II). The washout period was 2 weeks. The length of each phase was 6 months. Serum malondialdehyde (MDA, µmol/L), carbonyl (protein CO, µM/L), glutathione (GSH, nM/L), and total antioxidant capacity (TAC, µmol FeSO4/L) were measured in the beginning and at the end of phases I and II. The clinical significance was viewed as a minimum change difference of 5% for each outcome between amlodipine and placebo. RESULTS: Seventeen cases completed the study. According to the baseline MDA values, the adjusted Hedges's g for MDA was -0.59, 95% confidence interval [CI] -1.26 to 0.08. After controlling the baseline protein CO values, Hedges's g computed for protein CO was -0.11, 95% CI -0.76 to 0.55. The estimated values of the adjusted Hedges's g for GSH and TAC were also 0.26, 95% CI -0.40 to 0.91, and 0.42, 95% CI -0.24 to 1.09, respectively. The change difference for MDA was 8.3% (protein CO 2.2%, GSH 3.1%, and TAC 12.9%). CONCLUSION: Clinically, amlodipine therapy is an efficacious adjuvant treatment with conventional iron chelators for improving the levels of MDA and TAC in patients with TDT.

Vasodilation in patients with calcium channel blocker poisoning treated with high-dose insulin: a comparison of amlodipine versus non-dihydropyridines.

Background: High dose insulin (HDI), an inotrope and vasodilator, is a standard therapy for calcium channel blocker (CCB) poisoning. HDI causes vasodilation by stimulating endothelial nitric oxide synthase (eNOS). Most literature supporting HDI for CCB poisoning involves verapamil toxicity; however, amlodipine now causes more CCB poisonings. Unlike other CCBs, amlodipine stimulates eNOS and may cause synergistic vasodilation with HDI. The purpose of this study was to determine if amlodipine-poisoned patients treated with HDI had more evidence of vasodilation than similarly treated patients with non-dihydropyridine (non-DHP) poisoning.Methods: This was a retrospective study from a single poison center. Cases were identified via the generic code "Calcium Antagonists" in which the therapy "High Dose Insulin/Glucose" was "performed, whether or not recommended" from 2019-2021. Evidence of vasodilation was assessed via maximum number of vasopressor infusions per case, vasopressor doses, and use of rescue methylene blue to treat refractory vasoplegia.Results: Thirty-three patients were enrolled: 18 poisoned with amlodipine, 15 with non-DHPs (verapamil n = 10, diltiazem n = 5). The median number of maximum concomitant vasopressors in the amlodipine group was 3 (IQR: 2-5; range 0-6) and 2 in the non-DHP group (IQR: 1-3; range 0-5; p = 0.04); median difference in maximum concomitant vasopressors between groups was 1 (95% confidence interval: 0-2). Median maximum epinephrine dosing was higher in the amlodipine group (0.31 mcg/kg/min) compared to non-DHPs (0.09 mcg/kg/min; p = 0.03). Use of rescue methylene blue was more common in the amlodipine group (7/18 [39%]) than in the non-DHP group (0; p = 0.009).Conclusions: Amlodipine poisoned patients treated with HDI required more vasopressors, higher doses of epinephrine, and more often received rescue methylene blue than similarly treated patients with verapamil or diltiazem poisoning. These differences suggest amlodipine-poisoned patients had more evidence of vasodilation. Further study is warranted to determine if synergistic vasodilation occurs when HDI is used to treat amlodipine poisoning.

Effect of 3, 2-Drug Combinations of Antihypertensive Therapies on Blood Pressure Variability in Black African Patients: Secondary Analyses of the CREOLE Trial.

BACKGROUND: The effect of 3 commonly recommended combinations of anti-hypertensive agents-amlodipine plus hydrochlorothiazide (calcium channel blocker [CCB]+thiazide), amlodipine plus perindopril (CCB+ACE [angiotensin-converting enzyme]-inhibitor), and perindopril plus hydrochlorothiazide (ACE-inhibitor+thiazide) on blood pressure variability (V) are unknown. METHODS: We calculated the blood pressure variability (BPV) in 405 patients (130, 146, and 129 randomized to ACE-inhibitor+thiazide, CCB+thiazide, and CCB+ACE-inhibitor, respectively) who underwent ambulatory blood pressure monitoring after 6 months of treatment in the Comparisons of Three Combinations Therapies in Lowering Blood Pressure in Black Africans trial (CREOLE) of Black African patients. BPV was calculated using the SD of 30-minute interval values for 24-hour ambulatory BPs and for confirmation using the coefficient of variation. Linear mixed model regression was used to calculate mean differences in BPV between treatment arms. Within-clinic BPV was also calculated from the mean SD and coefficient of variation of 3 readings at clinic visits. RESULTS: Baseline distributions of age, sex, and blood pressure parameters were similar across treatment groups. Participants were predominately male (62.2%) with mean age 50.4 years. Those taking CCB+thiazide had significantly reduced ambulatory systolic and diastolic BPV compared with those taking ACE-inhibitor+thiazide. The CCB+thiazide and CCB+ACE-inhibitor groups showed similar BPV. Similar patterns of BPV were apparent among groups using within-clinic blood pressures and when assessed by coefficient of variation. CONCLUSIONS: Compared with CCB-containing combinations, ACE-inhibitor plus thiazide was associated with higher levels, generally significant, of ambulatory and within-clinic systolic and diastolic BPV. These results supplement the differential ambulatory blood pressure-lowering effects of these therapies in the CREOLE trial.

Eco-friendly spectrophotometric evaluation of triple-combination therapies in the treatment strategy of patients suffering from hypertension during coronavirus pandemic - Spectralprint recognition study.

Recent studies have reported that using certain antihypertensive therapies such as angiotensin II receptor blockers (ARBs) and calcium channel blocker (CCBs) is associated with reduction of fatal outcomes and improving clinical characteristics of patients suffering from hypertension during coronavirus pandemic. Thus, in the current work an effective, innovative and eco-friendly spectrophotometric manner namely, parent spectrum extraction (PSE)was established for evaluation of recommended triple antihypertensive combination therapies incorporate valsartan (VAL) as ARBs, amlodipine besylate as CCBs (AML) and hydrochlorothiazide (HCT)as diuretic into single-pill in challengeable ratio. PSE manner composed of two complementary steps, auxiliary resolution coupled with data analysis resolution(DAR)and it is characterized by resolving the spectral bands of the drugs and extraction of their discrete parent spectra (D0); accordingly, enabling determination of each analyte at its λmax. Auxiliary resolution of AML in triple mixture was applied to decrease complexity of overlapped spectra via constant multiplication (CM) followed by spectrum subtraction (SS) to obtain resolved mixture of VAL and HCT while data analysis resolution (DAR) of this binary mixture was applied via one of three novel methods namely, absorbance extraction (AE), peak-amplitude extraction (PE) and ratio extraction (RE) along with SS method. The proposed methods had analyzed VAL, AML and HCT in the range of 4.0-44.0 µg/mL, 4.0-40.0 µg/mL and 2.0-24.0 µg/mL, respectively with an excellent correlation coefficient (r ≥ 0.9999). Further, the proposed methods in PSR manner were validated as stated by ICH guidelines and it was found that accuracy and precision results are within the acceptable limit. The suggested procedures were effectively utilized for the concurrent quantification of VAL, AML and HCT in synthetic mixtures and tablets. The greenness of the proposed spectrophotometric methods was evaluated by National Environmental Methods Index (NEMI), the Analytical Eco-Scale, the Green Analytical Procedure Index (GAPI) and Analytical greenness metric (AGREE) where the four tools affirmed the eco-friendly nature of the proposed methods. A comparison between the outcomes of the studied methods with the official and reported ones was performed and no statistical difference was arisen between the methods regarding to accuracy and precision.The achieved results along with the simplicity, affordability and low-cost of the proposed methods recommended their appropriateness for the regular quality control examination and analysis of pure materials and pharmaceutical formulations as well as their applicability for the spectralprint recognition of the studied drugs.

Clinical assessment of levamlodipine besylate combination therapy for essential hypertension: A protocol for systematic review and meta-analysis.

BACKGROUND: Essential hypertension has been regarded a significant risk factor for cardiovascular disease across the globe, and a significant escapable causation of early death as well as morbidity in the U.S. When angiotensin II receptor blockers and calcium channel blockers are used to treat essential hypertension, most patients will have inadequate blood pressure management. As a result, including a diuretic in the regimen is necessary. The current study's aim is to investigate the effectiveness as well as safety of levamlodipine besylate combination therapy in treating essential hypertension at varying degrees of severity. METHODS: In establishing the effectiveness and safety of the mix of levamlodipine besylate and dihydropyridine for essential hypertension, the authors will conduct a systematic review and, where applicable, a meta-analysis of randomized controlled clinical trials. A total of 8 electronic databases will be used in the search, including 4 English databases (PubMed, Web of Science, EMBASE, and Cochrane Library) and 4 Chinese databases (China National Knowledge Infrastructure, Chinese BioMedical Literature database, Chinese Scientific Journal database, and WanFang database). All articles published in the databases will be considered between their inception and January 18, 2022. Only articles published in English or Mandarin Chinese will be picked. A group of writers will independently evaluate each reference to see if it is eligible and whether there are any duplicates. The same authors will do data extraction for all eligible studies and use the Cochrane risk of bias tool to evaluate the risk of bias in the trials chosen for inclusion. RESULTS: The analysis will evaluate the efficiency and level of safeness of levamlodipine besylate combined treatment for essential hypertension. CONCLUSIONS: Our systematic review will offer evidence for judging whether levamlodipine besylate combination therapy can be considered an effective intercession for essential hypertension. ETHICS AND DISSEMINATION: Ethical approval will not be required as no original data will be collected as part of this review. REGISTRATION NUMBER: DOI 10.17605/OSF.IO/H8ZR2.

Multi-organ dysfunction as a presentation of calcium channel blocker intoxication.

SummaryWe report the case of a 73-year-old woman who intentionally ingested 400 mg of amlodipine in a suicidal attempt who initially presented with hypotension which persisted despite aggressive therapy with fluid resuscitation, multiple pressor support, high-dose insulin therapy and calcium infusion. Her haemodynamic instability evolved to include bradycardia requiring atropine and transcutaneous pacing. Eventually she required salvage therapy with intravenous lipid emulsion (ILE) therapy . Despite all aggressive therapy, she developed multi-organ failure resulting in death. The literature on high-dose insulin euglycaemic therapy (HIET) and ILE therapy shows mixed results with some showing significant improvement in haemodynamic status. In our case, it had no significant positive impact on the outcome.

Comparison of the effects of calcium channel blockers plus iron chelation therapy versus chelation therapy only on iron overload in children and young adults with transfusion-dependent thalassemia: A randomized double-blind placebo-controlled trial.

BACKGROUND: Myocardial iron deposition is a significant cause of morbidity and mortality in patients with transfusion-dependent thalassemia (TDT). Amlodipine, L-type calcium channel blocker with regular chelation therapy may reduce myocardial iron overload. Lack of randomized trials prompted this study to assess the effect of calcium channel blocker (amlodipine) in combination with iron chelation therapy on iron overload in patients with TDT. METHODS: Sixty-four eligible patients were randomized to receive either amlodipine and chelation (group A) or chelation alone (group B) in double-blind placebo-controlled trial. Myocardial iron concentration (MIC) using T2* magnetic resonance imaging (MRI), liver iron concentration (LIC), left ventricular ejection fraction (LVEF), and serum ferritin were measured at baseline and 12 months. RESULTS: In the amlodipine group, mean cardiac T2* value significantly increased from 18.11 ± 8.47 to 22.15 ± 7.61 (p = .002) at 12 months, whereas in control group, there was a nonsignificant increase (p = .62) in cardiac T2* value from 19.50 ± 8.84 to 20.03 ± 9.07. There was a significant decrease in MRI-derived MIC in the amlodipine group compared to control group (1.93 ± 1.61 to 1.29 ± 0.90, p = .01). Changes in the LVEF (p = .45), MRI-derived LIC (p = .09), and serum ferritin (p = .81) were not significant between the two groups. CONCLUSION: Amlodipine is safe and when combined with chelation therapy appears to be more effective in reducing cardiac iron overload than chelation only in children and young adults with TDT.

Evaluation of Danzhi Xiaoyao powder and amlodipine sustained-release tablets in follow-up treatment of the hypertensive crisis and the interleukin-6 gene expression.

Danzhi Xiaoyao powder (DXP) is an herbal formula with eight different herbs. This herbal medicine can play multiple roles in various disease treatments through its several components. In this study, the effect of DXP was evaluated on the treatment of hypertensive patients with and without amlodipine. For this purpose, 252 patients were studied with high blood pressure. The 126 patients received DXP, and the others received DXP + amlodipine for four weeks. Besides demographic and biochemical assessments (gender, BMI, age, SBP, DBP, etc.), the expression of the interleukin-6 gene was evaluated in these two groups. The results showed that the blood pressure decreased by DPX, and there was no significant difference in control of blood pressure by DPX and DXP + amlodipine. But it did not affect interleukin-6 gene expression. Therefore, it can be concluded that this drug probably uses a different mechanism than amlodipine to control blood pressure.

A double-blind, controlled, crossover trial of amlodipine on iron overload status in transfusion dependent ß-thalassemia patients.

BACKGROUND AND AIM: This study examined whether administration of amlodipine could improve myocardial iron loading status in patients with transfusion dependent ß-thalassemia (TDT), through a placebo-controlled, crossover study. METHODS: Amlodipine (5 mg, daily) or placebo were prescribed to all patients (n = 19) for 6 months, and after a 2-week washout period, patients were crossed over to the other group. The efficacy of amlodipine on iron loading was assessed by measuring myocardial T2*-weighted magnetic resonance imaging (MRI T2*, millisecond [ms]) and serum ferritin (ng/mL). RESULTS: Seventeen patients completed the study. The mean ± standard deviation [SD] of myocardial MRI T2* at baseline was 9.83 ± 2.67 ms Myocardial MRI T2* value rose to 11.44 ± 4.14 ms post amlodipine treatment in all patients. After placebo, myocardial MRI T2* value reached 10.29 ± 4.01 ms After controlling the baseline measures, Hedges's g for ferritin and myocardial MRI T2* outcomes were estimated 3.84 (95% confidence interval [CI] 2.68 to 4.97) and -1.80 (95% CI -2.58 to -0.10), respectively. CONCLUSION: Amlodipine might improve myocardial MRI T2* and serum ferritin level compared to placebo. However, larger clinical studies are needed to confirm the results.

Amlodipine as adjuvant therapy to current chelating agents for reducing iron overload in thalassaemia major: a systematic review, meta-analysis and simulation of future studies.

BACKGROUND AND OBJECTIVES: Iron overload in thalassaemia is a crucial prognostic factor and a major cause of death due to heart failure or arrhythmia. Therefore, previous research has recommended amlodipine as an auxiliary treatment to current chelating agents for reducing iron overload in thalassaemia patients. MATERIALS AND METHODS: A systematic review and meta-analysis of the results of three randomized clinical trials evaluating the use of amlodipine in thalassaemia patients through 12 databases were carried out. RESULTS: Our final cohort included 130 patients. Insignificant difference in decreasing liver iron concentrations was found between amlodipine and control groups {weighted mean difference = -0·2, [95% confidence interval = (-0·55-0·15), P = 0·26]}. As regards serum ferritin, our analysis also showed no significant difference in serum ferritin between amlodipine and control groups {weighted mean difference [95% confidence interval = -0·16 (-0·51-0·19), P = 0·36]}. Similarly, there was insignificant difference in cardiac T2* between amlodipine and control groups {weighted mean difference [95% confidence interval = 0·34 (-0·01-0·69), P = 0·06]}. CONCLUSIONS: Despite the growing evidence supporting the role of amlodipine in reducing iron overload in thalassaemia patients, our meta-analysis did not find that evidence collectively significant. The results of our simulation suggest that when more data are available, a meta-analysis with more randomized clinical trials could provide more conclusive insights.

Treatment of calcium channel blocker-induced gingival overgrowth without modifying medication.

Gingival overgrowth is a common side effect of calcium channel blockers used in the treatment of cardiovascular diseases. While controversial, management includes discontinuing the calcium channel blocker. We report the case of a 66-year-old Japanese man with hypertension and type 2 diabetes mellitus who was diagnosed with severe periodontitis covering almost all the teeth. The patient had been on nifedipine (40 mg/day) and amlodipine (10 mg/day) medication for 5 years. With his physician's consent, nifedipine was discontinued during his treatment for periodontitis, which consisted of oral hygiene instructions and scaling and root planing on all areas. Gingivectomy was performed on the areas of hard fibrous swelling. Nifedipine was resumed during periodontal treatment when the patient's hypertension worsened. His periodontal scores improved when he resumed treatment. We report that significant improvement in gingival overgrowth can occur with basic periodontal treatment, surgery and sustained intensive follow-up without adjusting calcium channel blockers.

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.

Amlodipine Improves Vessel Function and Remodeling in the Lewis Polycystic Kidney Rat Mesenteric Artery.

BACKGROUND: Hypertension is a common comorbidity associated with chronic kidney disease (CKD). Treatment in these patients often involves L-type Ca2+ channel (LTCC) blockers. The effect of chronic LTCC-blockade treatment on resistance vasculature was investigated in a genetic hypertensive rat model of CKD, the Lewis Polycystic Kidney (LPK) rat. METHODS: Mixed-sex LPK and Lewis control rats (total n = 38) were allocated to treated (amlodipine 20 mg/kg/day p.o. from 4 to 18 weeks) and vehicle groups. Following systolic blood pressure and renal function assessment, animals were euthanized and mesenteric vasculature was collected for functional and structural assessment using pressure myography and histology. RESULTS: Amlodipine treatment reduced LPK rat blood pressure (untreated vs. treated: 185 ± 5 vs. 165 ± 9 mm Hg; P = 0.019), reduced plasma creatinine (untreated vs. treated: 197 ± 17 vs. 140 ± 16 µmol/l; P = 0.002), and improved some vascular structural parameters (internal and external diameters and wall-lumen ratios); however wall thickness was still increased in LPK relative to Lewis despite treatment (Lewis vs. LPK: 31 ± 2 vs. 41 ± 2 µm, P = 0.047). Treatment improved LPK rats' endothelium dysfunction, and nitric oxide-dependent and endothelium-derived hyperpolarization vasorelaxation components, and downregulated prostanoid contributions. LTCC blockade had no effect on biomechanical properties of compliance and intrinsic stiffness, nor artery wall composition. CONCLUSIONS: Our results indicate that blockade of LTCCs with amlodipine is effective in improving, to a certain extent, detrimental structural and functional vascular features of resistance arteries in CKD.

Comparative efficacy and safety of oral antihypertensive agents in pregnant women with chronic hypertension: a network metaanalysis.

OBJECTIVE DATA: Chronic hypertension is associated with adverse perinatal outcomes, although the optimal treatment is unclear. The aim of this network metaanalysis was to simultaneously compare the efficacy and safety of antihypertensive agents in pregnant women with chronic hypertension. STUDY: Medline, Scopus, CENTRAL, Web of Science, Clinicaltrials.gov, and Google Scholar databases were searched systematically from inception to December 15, 2019. Both randomized controlled trials and cohort studies were held eligible if they reported the effects of antihypertensive agents on perinatal outcomes among women with chronic hypertension. STUDY APPRAISAL AND SYNTHESIS METHODS: The primary outcomes were preeclampsia and small-for-gestational-age risk. A frequentist network metaanalytic random-effects model was fitted. The main analysis was based on randomized controlled trials. The credibility of evidence was assessed by taking into account within-study bias, across-studies bias, indirectness, imprecision, heterogeneity, and incoherence. RESULTS: Twenty-two studies (14 randomized controlled trials and 8 cohorts) were included, comprising 4464 women. Pooling of randomized controlled trials indicated that no agent significantly affected the incidence of preeclampsia. Atenolol was associated with significantly higher risk of small-for-gestational age compared with placebo (odds ratio, 26.00; 95% confidence interval, 2.61-259.29) and is ranked as the worst treatment (P-score=.98). The incidence of severe hypertension was significantly lower when nifedipine (odds ratio, 0.27; 95% confidence interval, 0.14-0.55), methyldopa (odds ratio, 0.31; 95% confidence interval, 0.17-0.56), ketanserin (odds ratio, 0.29; 95% confidence interval, 0.09-0.90), and pindolol (odds ratio, 0.17; 95% confidence interval, 0.05-0.55) were administered compared with no drug intake. The highest probability scores were calculated for furosemide (P-score=.86), amlodipine (P-score=.82), and placebo (P-score=.82). The use of nifedipine and methyldopa were associated with significantly lower placental abruption rates (odds ratio, 0.29 [95% confidence interval, 0.15-0.58] and 0.23 [95% confidence interval, 0.11-0.46], respectively). No significant differences were estimated for cesarean delivery, perinatal death, preterm birth, and gestational age at delivery. CONCLUSION: Atenolol was associated with a significantly increased risk for small-for-gestational-age infants. The incidence of severe hypertension was significantly lower when nifedipine and methyldopa were administered, although preeclampsia risk was similar among antihypertensive agents. Future large-scale trials should provide guidance about the choice of antihypertensive treatment and the goal blood pressure during pregnancy.

Therapeutic lifestyle change intervention improved metabolic syndrome criteria and is complementary to amlodipine/atorvastatin.

AIMS: To examine whether addition of amlodipine (5 mg)/atorvastatin (10 mg) A/A to Therapeutic Lifestyle change intervention (TLC) would beneficially modulate Metabolic Syndrome (MetS) and oxidized low-density lipoprotein (Ox-LDL) levels. METHODS: Patients with MetS (n = 53) were randomized to TLC + placebo or TLC + A/A for 12 months. Anthropometric measurements, blood pressure (BP), lipid profile, plasma Ox-LDL, and area under the curve of free fatty acid (AUCFFA) during oral glucose tolerance test, a marker of adipose tissue health, were assessed before and after the intervention. RESULTS: Twenty-six patients completed the study with an overall improvement of MetS (p = 0.02). TLC + placebo was beneficial in reversing MetS comparable to TLC + A/A (54% vs. 39%; p = 0.08). Both treatments decreased systolic BP (p ≤ 0.01). TLC + A/A also decreased diastolic BP and triglyceride levels. The changes in Ox-LDL levels directly correlated with changes in weight in the TLC-placebo group (r = 0.64; p = 0.04). AUCFFA determined the loss of fat mass (r = 0.472, p = 0.03). CONCLUSIONS: 1) Addition of A/A has the advantage of improving the lipid profile and BP; but TLC alone was comparable to TLC + A/A in improving MetS; 2) weight change determines the TLC-associated change in Ox-LDL levels; and 3) AT metabolic health is a significant predictor of TLC-associated loss of body fat mass.

Calcium Channel Blockers in Conjunction with Standard Iron-Chelating Agents for ß-Thalassemia Major: Systematic Literature Search.

Thalassemia is a genetic mutation of the α- or ß-globin chains that lead to defective erythropoiesis. This study aimed to collect evidences from all published studies that investigated the clinical effectiveness of calcium channel blockers (CCBs) in conjunction with chelation therapy for reducing iron overload in patients with thalassemia. A systematic search was conducted in PubMed, Institute for Scientific Information (ISI) Web of Science, Scopus, Cochrane Central Register of Controlled Trials, and Virtual Health Library. Original studies reporting the use of CCBs in patients with thalassemia were included for meta-analysis. A total of five randomized studies including 210 patients were included with a follow-up period of 3-12 months. There was no significant difference between amlodipine and control groups in increasing the heart T2* magnetic resonance imaging (MRI) [mean difference (MD) 95% confidence interval (95% CI) = -1.9 (-4.4 to 0.5), p = 0.119] or reducing the liver iron concentration [MD 95% CI = -0.046 (-0.325 to 0.2), p = 0.746]. Although there were no serious adverse events reported in the included trials, further studies are recommended to strengthen our findings.