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A fixed‐dose combination (FDC) of ezetimibe, atorvastatin, and amlodipine has been developed to improve medication adherence among patients with cardiovascular diseases. In a randomized, open‐label, multiple‐dose, fixed‐sequence study involving 34 participants (Study 1), the potential drug‐drug interaction between ezetimibe/atorvastatin FDC and amlodipine was evaluated. Additionally, a randomized, open‐label, crossover study with 60 participants (Study 2) compared the pharmacokinetics (PKs) of ezetimibe/atorvastatin/amlodipine FDC to those of individual formulations. Co‐administration of the ezetimibe/atorvastatin FDC and amlodipine did not significantly alter the PKs of either drug. However, amlodipine resulted in a slight increase in systemic exposure to atorvastatin by approximately 23%. Geometric mean ratios (FDC to individual formulations) and 90% confidence intervals of area under the time‐concentration curve at steady state during dosing interval (AUCτ, ss) and maximum concentration at steady state (Cmax, ss) or amlodipine, atorvastatin, and ezetimibe were all within the bioequivalent range (0.8‐1.25), confirming bioequivalence. Moreover, the FDC of ezetimibe, atorvastatin, and amlodipine exhibited comparable tolerability to corresponding individual formulations. [ABSTRACT FROM AUTHOR]

Aims Methods Results Conclusions Calcium channel blocker (CCB) overdose remains an important poisoning, with increasing availability of dihydropyridines. We aimed to compare the severity and treatment of CCB overdoses.We reviewed CCB overdoses presenting to two toxicology services from 2014 to 2023. We extracted prospectively collected data from a clinical database, including demographics, dose, co‐ingestants, complications, treatments and outcomes, to compare different CCBs.There were 236 overdoses; median age 55 years (interquartile range [IQR]: 41–65 years); 130 (55%) were females. Dihydropyridine overdoses increased significantly: median of nine cases annually (IQR: 8.8–12.3) during the study compared to a median of three cases annually (IQR: 1–4.3; P < 0.001) in the 10 years prior. The commonest agent was amlodipine (147), then lercanidipine (28), diltiazem (27), verapamil (23) and felodipine (11). Median defined daily dose ingested was higher for dihydropyridines, and cardiac co‐ingestants were common except verapamil. Median length of stay was 21 h (IQR: 13–43 h), which was similar except longer for diltiazem (median, 39 h). Fifty‐six patients (24%) were admitted to intensive care, more often for diltiazem (14; 52%) and verapamil (7; 30%). Dysrhythmias occurred in 19 patients (diltiazem [9], verapamil [8], amlodipine [2]), and included 13 junctional dysrhythmias. Hypotension occurred in 91 patients (39%), 62 (26%) received inotropes/vasopressors (adrenaline 32 [52%], noradrenaline 48 [77%]), 21 (9%) high‐dose insulin and 44 (19%) calcium. Adrenaline and high‐dose insulin were more commonly given in diltiazem and verapamil overdoses, compared to vasopressors in dihydropyridine overdoses. Acute kidney injury occurred in 39 patients. Seven (3%) patients died.Dihydropyridines were the commonest CCB overdoses, with amlodipine making up half. More severe toxicity occurred with diltiazem and verapamil. [ABSTRACT FROM AUTHOR]

Background and Purpose: This study analyses whether first‐line antihypertensive drugs ameliorate the dysbiosis state in hypertension, and to test if this modification contributes to their blood pressure (BP) lowering properties in a genetic model of neurogenic hypertension. Experimental Approach: Twenty‐week‐old male Wistar Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) were untreated or treated with captopril, amlodipine or hydrochlorothiazide. A faecal microbiota transplantation (FMT) experiment was also performed by gavage of faecal content from donor SHR‐treated groups to SHR recipients for 3 weeks. Key results: Faeces from SHR showed gut dysbiosis, characterized by lower acetate‐ and higher lactate‐producing bacteria and lower strict anaerobic bacteria. All three drugs increased the anaerobic bacteria proportion, captopril and amlodipine restored the proportion of acetate‐producing bacterial populations to WKY levels, whereas hydrochlorothiazide decreased butyrate‐producing bacteria. Captopril and amlodipine decreased gut pathology and permeability and attenuated sympathetic drive in the gut. Both drugs decreased neuroinflammation and oxidative stress in the hypothalamic paraventricular nuclei. Hydrochlorothiazide was unable to reduce neuroinflammation, gut sympathetic tone and gut integrity. FMT from SHR‐amlodipine to SHR decreased BP, ameliorated aortic endothelium‐dependent relaxation to acetylcholine, lowered NADPH oxidase activity, aortic Th17 infiltration and reduced neuroinflammation, whereas FMT from SHR‐hydrochlorothiazide did not have these effects. Conclusions and Implications: First‐line antihypertensive drugs induced different modifications of gut integrity and gut dysbiosis in SHR, which result in no contribution of microbiota in the BP lowering effects of hydrochlorothiazide, whereas the vasculo‐protective effect induced by amlodipine involves gut microbiota reshaping and gut‐immune system communication. [ABSTRACT FROM AUTHOR]

Objectives: Hypertension is one of the major modifiable risk factors for cardiovascular mortality and morbidity throughout the world. Increased life expectancy leads to increase prevalence of non‐communicable diseases among the elderly people including Bangladesh. However, different studies reported high prevalence of uncontrolled hypertension ranging from 52.6% to 67.9% among the elderly people in different countries. With this view, we aimed to assess the frequency of uncontrolled blood pressure (BP) among the elderly hypertensive people and its associated risk factors and treatment pattern in Bangladesh. Methodology: This cross‐sectional type of observational study recruited 246 eligible hypertensive elderly patients attending in 250 Bedded General Hospital, Jashore, Bangladesh dated from 1st July to 31st December 2022. A structured questionnaire was developed and data on associated risk factors, treatment pattern and current blood pressure (BP) measurement were collected by face‐to‐face interview for the purposive sampling technique. Results: The mean age of our study patients was 72 ± 7 years with a male and female ratio nearly 1:1. Of the total hypertensive patients aged over 65 years or more, 56.5% remained with uncontrolled hypertension even on their prescribed antihypertensive medications. The mean systolic (SBP) and diastolic (DBP) blood pressure were significantly high (P < 0.001) as 167 ± 22 mm Hg and 95 ± 11 mm Hg, respectively, among the uncontrolled hypertensive patients. However, we noticed the mean SBP and DBP among the total hypertensive patients were also significantly high (P < 0.001) as 148 ± 27 mm Hg and 87 ± 13 mm Hg, respectively. In this study, we reported that the mean number of last prescribed antihypertensive medications used by the total patients was 2 ± 1 (P =0.224) which was similar among the controlled and uncontrolled hypertensive patient groups. Among the elderly hypertensive patients, the most commonly prescribed antihypertensive medications were Amlodipine 39.8% (P =0.006), Olmesartan 29.3% (P = 0.186), Losartan 24.4% (P = 0.127), Bisoprolol 15.0% (P = 0.266) and Atenolol 14.6% (P = 0.224). Conclusion: We noticed high frequency of uncontrolled blood pressure among the elderly hypertensive patients, despite of using multiple antihypertensive medications in Jashore, Bangladesh. [ABSTRACT FROM AUTHOR]

This study aims to assess clinical outcomes following switching from originator to generic amlodipine. This population‐based, matched, cohort study included users of originator amlodipine using claims data during 2018–2020 from a health system in Tianjin, China, in which usage of generic amlodipine was promoted by a drug procurement policy, the national volume‐based procurement. Non‐switchers refer to those remained on originator after the policy, while pure‐switchers were those who switched to and continued using generic amlodipine, and back‐switchers were those switched to generic amlodipine but then back to the originator. Propensity score matching generates comparable non‐switchers and pure‐switchers pairs, and non‐switchers and back‐switchers pairs. The primary outcome was major adverse cardiovascular events (MACEs), defined as all‐cause mortality, stroke, and myocardial infarction during follow‐up (April 1, 2019 to December 30, 2020). Secondary outcomes included heart failure, atrial fibrillation, and adherence to amlodipine. The hazard ratio (HR) for each clinical outcome was assessed through Cox proportional hazard regression. In total, 5943 non‐switchers, 2949 pure‐switchers, and 3061 back‐switchers were included (mean age: 62.9 years; 55.5% men). For the matched pairs, pure‐switchers (N = 2180) presented no additional risks of clinical outcomes compared to non‐switchers (N = 4360) (e.g., MACEs: 2.86 vs. 2.95 events per 100 person‐years; HR = 0.97 [95%CI: 0.70–1.33]). Back‐switchers (N = 1998) also presented no additional risk compared to non‐switchers (N = 3996) for most outcomes except for stroke (HR = 1.55 [95%CI: 1.03–2.34]). Pure‐switchers and back‐switchers all had better amlodipine adherence than non‐switchers. Generic substitution of amlodipine is not associated with increased risk of cardiovascular events or all‐cause mortality, but improves medicine adherence. [ABSTRACT FROM AUTHOR]

Background: Little evidence exists about the comparative effects of first‐line antihypertensive medications (i.e., renin‐angiotensin‐aldosterone converting enzyme inhibitors (RAASi), amlodipine, or thiazide diuretics) in older adults with limited life expectancy. We compared the rates of injurious falls and short‐term cardiovascular events between different first‐line antihypertensive medication classes in adults receiving care in nursing homes (NH). Methods: This was a retrospective cohort of Medicare fee‐for‐service beneficiaries receiving care in NHs. Patients newly dispensed first‐line antihypertensive medications were identified using Part D claims (2015–2018) and linked with clinical assessments (i.e., Minimum Data Set). Fall‐related injuries (FRI), hip fractures, and major adverse cardiac events (MACE) outcomes were identified using hospitalization claims. Patients were followed from the date of antihypertensive dispensing until the occurrence of outcomes, death, disenrollment, or 6‐month follow‐up. Inverse‐probability‐of‐treatment‐weighted (IPTW) cause‐specific hazards regression models were used to compare outcomes between patients who were new users of RAASi, amlodipine, or thiazides. Results: Our cohort included 16,504 antihypertensive users (RAASi, n = 9574; amlodipine, n = 5049; thiazide, n = 1881). Mean age was 83.5 years (± 8.2), 70.6% were female, and 17.2% were non‐white race. During a mean follow‐up of 5.3 months, 326 patients (2.0%) experienced an injurious fall, 1590 (9.6%) experienced MACE, and 2123 patients (12.9%) died. The intention‐to‐treat IPTW hazard ratio (HR) for injurious falls for amlodipine (vs RAASi) use was 0.85 (95% confidence interval (CI) 0.66–1.08) and for thiazides (vs RAASi) was 1.22 (95% CI 0.88–1.66). The rates of MACE were similar between those taking anti‐hypertensive medications. Thiazides were discontinued more often than other classes; however, inferences were largely unchanged in as‐treated analyses. Subgroup analyses were generally consistent. Conclusions: Older adults with limited life expectancy experience similar rates of injurious falls and short‐term cardiovascular events after initiating any of the first‐line antihypertensive medications. [ABSTRACT FROM AUTHOR]

The purpose of this study was to compare the blood concentration and pharmacokinetic (PK) parameters of 2 formulations under fasting and ed conditions in healthy Chinese volunteers and to evaluate whether the 2 preparations were bioequivalent. This trial screened 170 subjects. Thirteen subjects were assigned to the fasting trial and 18 subjects to the fed trial; 1 subject in the fed trial group was automatically withdrawn for personal reasons. Two cycles had a 14‐day washout period. This clinical study was a bioequivalence study, with PK parameters as end point indicators. The bioequivalence PK parameters were the maximal concentration (Cmax), area under the blood drug concentration‐time curve from 0 to 72 hours (AUC0‐72 h), and the time to peak plasma concentration (tmax) which were determined in human plasma by the liquid chromatography‐tandem mass spectrometry method, and nonatrioventricular model analysis was used to determine Cmax, AUC0‐72 h, tmax, and other PK parameters. The incidence of adverse events was calculated on the basis of System Organ Classification and Preferred Terms. The results showed that the amlodipine besylate tablets met the equivalence range requirements of bioequivalence in the guidelines for human bioavailability and bioequivalence testing under fasting and fed conditions, compared to the fasting test; the tmax of the fed test was almost unchanged; and the Cmax and AUC0‐72 h showed no difference between fasting and fed conditions. It was confirmed that both formulations were well tolerated, and no new safety signals were observed. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The suggested study adheres to a particular protocol to ensure that the process is environmentally friendly and sustainable. It is worth mentioning that several tools have been adopted as prospective measures of the method greenness. Fortunately, the established analytical method is identified as white by the white analytical chemistry (WAC) concept, which uses the red/ green/blue color scheme (RGB 12 tool) to combine ecological and functional factors for the first time in studying of the cited drug. Amlodipine (AMD), a cardiovascular treating agent, belongs to the dihydropyridine class of oral calcium channel‐blocking agents. This article presents a novel, simple, green, one‐pot‐processed, fast, and ultrasensitive fluorimetric approach for monitoring and assessment of AMD using molecular‐size‐dependent fluorescence augmentation of the light scattering‐driven signal of eosin, a biological stain at a wavelength of 415 nm. This enhancement was directly proportional to the size of the produced complex. The linearity range was from 30 to 900 ng mL−1, with corresponding sensitivity limits (detection and quantitation levels) of 9.2 and 28 ng mL−1, respectively. The planned approach was also successfully used to track AMD content in bulk, dosage forms, and bio‐fluids (human plasma and urine). The developed method's eco‐friendliness was established by different eco‐rating metric tools. [ABSTRACT FROM AUTHOR]

Data on substituting one antihypertensive medication with the proper dose of another antihypertensive medication, in certain medical conditions, are scarce. Herein, we present the results of replacing angiotensin‐converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) with the calcium channel blocker (CCB) amlodipine, with or without the alpha‐ and beta‐blocker carvedilol, to control high blood pressure in patients with coronavirus disease 2019 (COVID‐19). Iranian hypertensive patients with COVID‐19 and a history of taking ACEI or ARB were randomized to "continue" and "change" groups. The continue group comprised patients who continued using their previous antihypertensive medication regimen as normal, whereas patients in the change group had their antihypertensive drugs changed to the CCB amlodipine, with or without the alpha‐ and beta‐blocker carvedilol, based on their response to amlodipine. Patients' blood pressures were measured for 8 days following their recruitment. A total of 31 and 33 patients were randomly allocated to the ACEI/ARB continue and ACEI/ARB change groups, respectively. No significant deviations were seen in patients' systolic blood pressure by substituting an ACEI/ARB agent with the CCB amlodipine, with or without the alpha‐ and beta‐blocker carvedilol. Moreover, the change group had a more balanced systolic blood pressure (ie, 110–130 mmHg) compared with the continue group (ie, 111.5–140.0 mmHg) throughout their hospitalization period. During their hospitalization, the blood pressure of the change group was well controlled with the proposed equivalent doses. Further investigations of the proposed equivalent doses in larger randomized clinical trials, populations other than Iranian COVID‐19 patients, and extended duration are encouraged (clinical trial registration ID: IRCT20151113025025N3). [ABSTRACT FROM AUTHOR]

Key Clinical Message: Drug‐induced gingival overgrowth can occur as a side effect of specific drugs and lead to poor oral function. Appropriate dental management of the overgrowth may improve oral function and improve cognitive deficits after cerebrovascular accidents. [ABSTRACT FROM AUTHOR]

The authors performed this study to investigate the efficacy and safety of a rosuvastatin (RSV)/amlodipine (AML) polypill compared with those of atorvastatin (ATV)/AML polypill. We included 259 patients from 21 institutions in Korea. Patients were randomly assigned to 1 of 3 treatment groups: RSV 10 mg/AML 5 mg, RSV 20 mg/AML 5 mg, or ATV 20 mg /AML 5 mg. The primary endpoint was the efficacy of the RSV 10.20 mg/AML 5 mg via percentage changes in LDL‐C after 8 weeks of treatment, compared with the ATV 20 mg /AML 5 mg. There was a significant difference in the mean percentage change of LDL‐C at 8 weeks between the RSV 10 mg/AML 5 mg and the ATV 20 mg/AML 5 mg (full analysis set [FAS]: −7.08%, 95% CI: −11.79 to −2.38, p =.0034, per‐protocol analysis set [PPS]: −6.97%, 95% CI: −11.76 to −2.19, p =.0046). Also, there was a significant difference in the mean percentage change of LDL‐C at 8 weeks between the RSV 20 mg/AML 5 mg and the ATV 20 mg/AML 5 mg (FAS: −10.13%, 95% CI: −15.41 to −4.84, p =.0002, PPS: −10.96%, 95% CI: −15.98 to −5.93, p <.0001). There was no significant difference in the adverse events rates between RSV 10 mg/AML 5 mg, RSV 20 mg/AML 5 mg, and ATV 20 mg/AML 5 mg. In conclusion, while maintaining safety, RSV 10 mg/AML 5 mg and the RSV 20 mg/AML 5 mg more effectively reduced LDL‐C compared with the ATV 20 mg /AML 5 mg (Clinical trial: NCT03951207). [ABSTRACT FROM AUTHOR]

Hypertension is the leading cause of death worldwide, affecting 1.4 billion people. Treatment options include the widely used calcium channel blockers, among which amlodipine, a dihydropyridine, has unique characteristics that distinguish it from other drugs within this class. This review aims to provide an updated overview of the evidence supporting the use of amlodipine over the past 30 years and highlights its cardiovascular benefits in current hypertension management. Amlodipine has low renal clearance (7 mL/min/mg) and long half‐life (35–50 h) and duration of action, which allows it to sustain its anti‐hypertensive effect for more than 24 h following a single dose. Additionally, blood pressure (BP) control is maintained even when a dose has been missed, providing continuous protection in case of incidental noncompliance. It has proven to reduce BP variability and successfully lower BP. Amlodipine also controls BP in patients with a systolic/diastolic BP of 130/80 mm Hg or higher, diabetes, or chronic kidney disease without worsening glycemic or kidney function. Additionally, amlodipine is a wise choice for older adults due to its ability to control BP and protect against stroke and myocardial infarction. Side effects of amlodipine include edema, palpitations, dizziness, and flushing, which are more common with the higher dose of 10 mg. Amlodipine is cost effective and predicted to be cost saving when compared with usual care. [ABSTRACT FROM AUTHOR]

The authors evaluated the efficacy, safety, and characteristics of patients who respond well to standard dose triple combination therapy including chlorthalidone 25 mg with telmisartan 80 mg plus amlodipine 5 mg in hypertensive patients. This is a multicenter, double‐blind, active‐controlled, phase 3, randomized trial. Patients are randomized to triple combination (telmisartan 40 mg/amlodipine 5 mg/chlorthalidone 12.5 mg, TEL/AML/CHTD group) or dual combination (telmisartan 40 mg/amlodipine 5 mg, TEL/AML group) treatment and then dose up titration to TEL 80/AML5/CHTD25mg and TEL80/AML5, respectively. The primary endpoint is the change of mean sitting systolic blood pressure (MSSBP) at week 8. A Target BP achievement rate, a response rate, and the safety endpoints are also evaluated. Total 374 patients (mean age = 60.9 ± 10.7 years, male = 78.3%) were randomized to the study. The baseline MSSBPs/diastolic BPs were 149.9 ± 12.2/88.5 ± 10.4 mm Hg. After 8 weeks treatment, the change of MSSBPs at week 8 are −19.1 ± 14.9 mm Hg (TEL/AML/CHTD) and −11.4 ± 14.7 mm Hg (TEL/AML) (p <.0001). The achievement rates of target BP (53.8% vs. 37.8%, p =.0017) and responder rate (54.8% vs. 35.6%, p =.0001) at week 8 were significantly higher in TEL/AML/CHTD. There are no serious adverse event and no one discontinued medication due to adverse event. Among the TEL 80/AML5/CHTD25mg treatment group, patients of female or age ≥ 65 years old showed higher rate of target BP achievement than relatively young male. (61.4 vs. 46.8%, p =.042) Our study showed standard dose triple combination of telmisartan 80 mg/amlodipine 5 mg/chlorthalidone 25 mg is efficacious and safe in treatment of primary hypertension. Target BP achievement with triple therapy would be facilitated in female or old age. [ABSTRACT FROM AUTHOR]

A spectrofluorimetric approach that is sensitive, simple, validated, and cost‐effective has been proposed for the estimation of amlodipine (AML) and perindopril (PER) in their bulk powders, pharmaceutical formulations, and spiked human plasma. The recommended approach utilized the quantitative quenching effect of the two cited drugs on the fluorescence intensity of erythrosine B, as a result of complex binary reactions among each drug with erythrosine B at pH 3.5 (Teorell and Stenhagen buffer). The quenching of erythrosine B fluorescence was recorded at 554 nm after excitation at 527 nm. The calibration curve was detected in the range 0.25–3.0 μg ml−1, with a correlation coefficient of 0.9996 for AML, and 0.1–1.5 μg ml−1, with a correlation coefficient of 0.9996 for PER. The established spectrofluorimetric approach was validated for the estimation of the cited drugs with high sensitivity regarding International Council on Harmonization guidelines. Therefore, the established approach could be utilized for quality control of the cited drugs in their pharmaceutical formulations. [ABSTRACT FROM AUTHOR]

Amlodipine belongs to the class of calcium channel blocker that is used to reduce high blood pressure (hypertension). Two related substances of amlodipine namely 3‐(2‐[1.3‐dioxo‐1,3‐dihydro‐2H‐isoindol‐2‐yl]ethyl)‐5‐methyl‐(4RS)‐4(2‐chlorophenyl)‐2‐([2‐(1,3‐dioxo‐1,3‐dihydro‐2H‐isoin‐dol‐2‐yl)ethoxy]methyl)‐6‐methyl‐1,4‐dihydropyridine‐3,5‐dicarboxylate (11) and 3‐([2‐aminoethyl]‐5‐aminoethoxy)‐4‐(2‐chlorophenyl)‐1,4‐dihydro‐6‐methylpyridine‐3,5‐dicarboxylate (12) were identified. The present work describes the origin, synthesis, and characterization of these related substances. [ABSTRACT FROM AUTHOR]

Summary: Posterior reversible encephalopathy syndrome is a rare and serious condition that presents with acute neurological symptoms with characteristic changes on imaging. It can lead to substantial morbidity and mortality, but can be reversible if recognised and treated. Here, we report a case of posterior reversible encephalopathy syndrome in a child post‐splenectomy under general anaesthesia with spinal anaesthesia. As far as we are aware, this condition has not previously been described in relation to spinal anaesthesia in the paediatric population. This case demonstrates the importance of recognising blood pressure changes in children, which can be challenging due to age‐, sex‐ and height‐related centiles for blood pressure measurements. Posterior reversible encephalopathy syndrome should be considered as a differential diagnosis for headache in a patient that has had a spinal anaesthesia. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

This study was designed to evaluate the synergism of two couples of antihypertensive drugs (amlodipine + telmisartan and amlodipine + candesartan) on blood pressure reduction in vivo by both SynergyFinder 3.0 and probability sum test. Spontaneously hypertensive rats were treated with intragastric administration of amlodipine (0.5, 1, 2, and 4 mg/kg), telmisartan (4, 8, and 16 mg/kg), candesartan (1, 2, and 4 mg/kg), nine combinations for amlodipine and telmisartan, and nine combinations for amlodipine and candesartan. The control rats were treated by 0.5% carboxymethylcellulose sodium. Blood pressure was recorded continuously up to 6 h after administration. Both SynergyFinder 3.0 and the probability sum test were used to evaluate the synergistic action. The synergisms calculated by SynergyFinder 3.0 are consistent with the probability sum test both in two different combinations. There is an obviously synergistic interaction between amlodipine and telmisartan or candesartan. The combinations of amlodipine and telmisartan (2 + 4 and 1 + 4 mg/kg) and amlodipine and candesartan (0.5 + 4 and 2 + 1 mg/kg) might exert an optimum synergism against hypertension. Compared with the probability sum test, SynergyFinder 3.0 is more stable and reliable to analyze the synergism. [ABSTRACT FROM AUTHOR]

Drug‐induced cutaneous pseudolymphoma (CPL) is a common form of pseudolymphoma and there are numerous drugs associated with it. In this study, we performed a systematic review of the literature by searching PubMed/Medline and Embase databases to determine the most common drugs responsible for CPL and to define the demographic, clinical, histopathological and immunopathological characteristics of patients (updated on 30 December 2020). From 883 initially found articles, 56 studies (89 reported cases) were included. The mean age of patients was 54.4 ± 17.7 (ranging 8–86) years, and 46 (51.7%) were men. The median time interval between drug intake and CPL occurrence was 120 days (range 1–7300 days). The shortest median time interval between taking the drug and the onset of the disease was observed among patients taking antidepressants (60 days) (range 7–540) and the longest median time interval was observed in individuals using immunomodulators (300 days) (range 3–7300). The most‐reported drug categories causing CPL were anti‐hypertensives (17.9%), anticonvulsants (14.6%), monoclonal antibodies (13.4%) and antidepressants (11.2%). Moreover, the most common drugs were phenytoin (6.7%), amlodipine (5.6%), fluoxetine (5.6%) and carbamazepine (4.4%). Histopathological evaluation of 76 cases revealed 62 (81.5%) reports of T‐cell infiltrations. Furthermore, positive reports of CD4 (94.0%), CD8 (93.0%) and CD30 (87.5%) were noted. The lowest prevalence of CD30‐positive reports was observed among monoclonal antibodies. In conclusion, anti‐hypertensives, anti‐convulsants, monoclonal antibodies and anti‐depressants are the most common drugs responsible for CPL. It mostly presents in middle‐aged patients with almost no gender difference as pruritic papules, nodules and plaques. [ABSTRACT FROM AUTHOR]

The development of selective and simple methods for the determination of different analytes is of great interest. This is the first time to show the applicability of graphene oxide‐chitosan (GO‐CS) nanocomposite for designing an electrochemical nanosensor for determination of Amlodipine, Valsartan, and Hydrochlorothiazide, simultaneously. Differential pulse voltammetrics current of AML, HCT, and VAL increased linearly in the ranges of 0.1–110, 0.1–110, and 1–230 μM with LOD of 5.5×10−2, 3.5×10−2 and 8.6×10−2 μM, respectively. Finally, GO‐CS/GCE was used for the detection of these drugs in commercial tablets and compared with the reference method (HPLC). [ABSTRACT FROM AUTHOR]

In this study, tetracarboxylic manganese phthalocyanine coated nano‐zinc oxide (MnC4Pc‐ZnO) composite material was prepared by in‐situ growth method and modified with indium tin oxide (ITO) glass electrode to construct a photoelectrochemical (PEC) sensor. A PEC sensor for the determination of amlodipine besylate (AB) was developed for the first time based on the principle of precipitation reaction between heavy metal ions and dihydropyridine and the recombination suppression effect of the material. The morphology and optical properties of the MnC4Pc‐ZnO composites were characterized by scanning electron microscopy (SEM) and ultraviolet‐visible diffuse reflectance spectroscopy (UV‐vis DRS). Chronoamperometry (i‐t) and electrochemical impedance spectroscopy (EIS) were used to study the PEC behavior of ITO electrodes modified by MnC4Pc‐ZnO composite material. The study found that the MnC4Pc‐ZnO composite material has a good photocurrent response to AB, and there was a good linear relationship between the concentration range of 75 nM‐250 μM, the linear equation was I(μA)=−5.2×10−8×lgC+3.2×10−8 (r=0.9947), a limit of detection (LOD) of 20 nM. In addition, MnC4Pc‐ZnO/ITO also has good selectivity and stability. The PEC sensor detects amlodipine besylate tablets, amlodipine besylate dispersible tablets, and biological samples, with standard addition recovery rates of 96.11 % and 103.96 %, respectively. The determination result has good accuracy, and the PEC sensor provides a new method for detecting AB. [ABSTRACT FROM AUTHOR]

Several regulatory organizations encourage the quantitative analysis of potentially genotoxic impurities in finished pharmaceutical preparation. For the first time, a sensitive, accurate, and reliable reversed phase‐high‐performance liquid chromatography method was developed and validated for two antihypertensive drugs, three genotoxic impurities of Amlodipine namely methyl benzene sulfonate, ethyl benzene sulfonate, and ethyl‐p‐toluene sulfonate, as well as N‐methyl O‐phenylenediamine dihydrochloride as genotoxic impurities of Telmisartan that is marketed in a single pill combination. reversed phase‐high‐performance liquid chromatography method was developed using a C18 column Agilent (Zorbax C18; 250 × 4.6 mm internal diameter, 5 μm) along with 50 mM ammonium acetate (pH 4.5) and ACN as a mobile phase in gradient mode to achieve the retention of all analytes. The new method's sensitivity allowed the quantification of namely methyl benzene sulfonate, ethyl benzene sulfonate, and N‐methyl‐O‐phenylenediamine dihydrochloride at test concentrations as low as 0.025%. Amlodipine and Telmisartan each had a test concertation of 100 and 800 μg/ml, respectively. The developed analytical method was validated for different applications, that is, for assay and related substance methods. The calibration curves for genotoxic impurities were linear in the range of the Limit of quantitation to 1.2% of the test concentration of the respective drugs. Forced degradation investigations were conducted on selected drugs, and targeted analytes were then quantified. The stability of both drugs in acid and basic hydrolysis was improved compared to when they were evaluated separately, although Amlodipine showed an inverted degradation pattern in a more recent investigation when combined with Telmisartan under oxidative degradation conditions. The validated method was successfully applied for the quantification of the genotoxic impurities of Amlodipine and Telmisartan in finished pharmaceutical preparation. [ABSTRACT FROM AUTHOR]

Background: Amlodipine, a dihydropyridine calcium-channel blocker, is currently being investigated as a treatment for myxomatous mitral valvular degeneration (MMVD). However, the effects of amlodipine on moderate or severe spontaneous MMVD, based on changes in echocardiographic indices, remain unclear. Animals: Client-owned small-breed dogs (n = 24) with naturally occurringMMVD of the American College of Veterinary Internal Medicine (ACVIM) stage B2 or higher. Methods: Basic dog information including previous medication treatments were recorded. All subjects received amlodipine 0.1 mg/kg, administered per os, twice daily for 7 days, in addition to their existingmedication. We measured systolic blood pressure, obtained x-ray, echocardiography, blood test data before and after 1 week of amlodipine administration. Results: Left ventricular end-diastolic internal diameter, left atrial diameter and E wave reduced statistically after 1 week of amlodipine treatment (all p < 0.001). No adverse effects were reported. Conclusions: These findings suggest that low-dose amlodipine should be considered as treatment for dogs with ACVIM stage B2?C MMVD. [ABSTRACT FROM AUTHOR]

Background: Children and adolescents undergoing kidney transplantation may present oral conditions after the procedure, but a few studies have recently described them. Aim: To describe the oral conditions of post‐renal transplant children and adolescents. Design: Two calibrated dentists examined all the participants by assessing caries experience, enamel defects, periodontal condition and soft tissue lesions. Results: A total of 120 participants were included in the study, in which 63 (52.5%) were male and 57 (47.5%) were female, with a mean age of 12.78 ± 3.9 years. Among the participants, 104 (86.7%) showed at least one oral change directly related to kidney disease. The most frequent oral findings were enamel defect (49/120; 40.8%) and drug‐induced gingival overgrowth (DIGO) (20/120; 16.7%). Gingival bleeding was observed on probing in 115 (95.8%) participants, whereas 69 (57.5%) presented dental calculus and 51 (42.5%) had caries experience. Conclusion: Gingival bleeding, enamel defects and DIGO were the most frequent oral findings in kidney transplant children and adolescents. The use of amlodipine and anticonvulsants was associated with DIGO, and there was a positive correlation between oral ulcers and use of everolimus. [ABSTRACT FROM AUTHOR]

The aim of this clinical trial was to assess the efficacy and safety of low‐dose triple combinations of amlodipine, telmisartan, and chlorthalidone in patients with essential hypertension. After a 2‐week placebo run‐in period, 176 patients were randomized to seven treatment groups (placebo, quarter‐dose combination, third‐dose combination, half‐dose combination, amlodipine 5 mg, amlodipine 10 mg, and telmisartan 80 mg) and administered the assigned study drug orally for 8 weeks. The primary efficacy endpoint was the change in the mean sitting systolic blood pressure (BP) (MSSBP) at Week 8. The MSSBP and mean sitting diastolic BP in the quarter‐dose and half‐dose groups were significantly lower compared to the placebo and amlodipine 5 mg groups, with similar BP‐lowering effects observed compared to the amlodipine 10 mg and telmisartan 80 mg groups. However, the third‐dose group showed significant BP improvement only compared to the placebo group. A similar pattern was observed for the control rate of hypertension and response rates. Additional analysis was conducted after correcting for gender and age effects, and, as a result, the third‐dose group showed similar results with regard to the BP‐lowering effect as the quarter‐dose and half‐dose groups. In terms of safety, no special adverse events and clinically significant results were noted, and all dose groups of the triple combination are considered safe for use in essential hypertension patients. The current findings indicated that low‐dose triple combination of amlodipine, telmisartan, and chlorthalidone over 8 weeks effectively improved the BP‐lowering effect in patients with essential hypertension without any safety concerns. [ABSTRACT FROM AUTHOR]

We report a case of concurrent ingestion of Clonazepam and Amlodipine in a 25‐year‐old man, in a second attempt to take his life, which resulted in unconsciousness, hypotension, and hypokalemia. The clinical and/or biochemical presentation varied from the individual pattern when ingested. In the scarcity of consensus recommendations, supportive treatment helped. Supportive treatment is the rule of management of concomitant ingestion of Amlodipine and Clonazepam. The clinical and/or biochemical presentation of benzodiazepine and calcium channel blocker may vary from the individual pattern. [ABSTRACT FROM AUTHOR]

The control rate of hypertension remains concerning, indicating the requirement for better management strategies. The calcium channel blockers brand‐name amlodipine and nifedipine with extended‐release formulations demonstrate similar clinical efficacy. However, the efficacy of generic nifedipine remains obscure. We compared the efficacy of generic nifedipine and brand‐name amlodipine in terms of cardiovascular (CV) outcomes. Patients prescribed generic nifedipine (SRFC CYH) or brand‐name amlodipine besylate (Norvasc, Pfizer) between August 1, 2017, and July 31, 2018, were enrolled; patients with CV events within 3 months were excluded. CV outcomes included CV death, nonfatal myocardial infarction (MI), nonfatal ischemic stroke, hospitalization for heart failure, and composite endpoints of 3P‐ and 4P‐major adverse cardiac events (MACE). A total of 1625 patients treated with nifedipine (SRFC CYH) and 16 587 patients treated with Norvasc were included. After propensity score matching, there were 995 and 4975 patients in the nifedipine CYH and Norvasc groups, respectively. At a mean follow‐up period of 30.3 ± 6.4 months, nifedipine CYH was comparable to Norvasc in terms of CV death (P =.107), nonfatal MI (P =.121), nonfatal ischemic stroke (P =.453), hospitalization for heart failure (P =.330), 3P‐MACE (P =.584), and 4P‐MACE (P =.274). Cox regression analysis revealed that nifedipine CYH and Norvasc had similar efficacy in terms of 3P‐MACE (hazard ratio, 0.970; 95% confidence interval, 0.601–1.565, P =.900) and 4P‐MACE (hazard ratio, 0.880; 95% confidence interval, 0.628–1.233, P =.459). In conclusion, Nifedipine SRFC CYH and Norvasc have comparable clinical efficacy for hypertension management. [ABSTRACT FROM AUTHOR]

Combined antihypertensive drugs have become the basic method of treating hypertension. Olmesartan and amlodipine, as representative drugs of angiotensin receptor blockers and calcium channel blockers, were developed as a compound formulation for antihypertensive treatment. The purpose of this study was to evaluate the bioequivalence of olmesartan medoxomil/amlodipine besylate tablet (20 mg/5 mg) under fasting and fed conditions in healthy Chinese volunteers. A phase 1 randomized, open‐label, 2‐period, single‐dose crossover study (n = 56) was designed, with subjects under fasting (n = 28) or fed (n = 28) conditions. Of the 56 enrolled participants, 55 healthy volunteers completed the study. Blood samples for pharmacokinetic analysis were collected from 1.5 hours before dosing to 168 hours after dosing. The 90%CIs for the geometric mean ratios of maximum plasma drug concentration, area under the plasma concentration–time curve (AUC) from time 0 to the last measurable concentration and AUC from time 0 to infinity of the test/reference were all within the acceptance range for bioequivalence (80%‐125%). The data showed that the absorption of amlodipine is not affected by food, but the exposure of olmesartan (both AUC from time 0 to the last measurable concentration and AUC from time 0 to infinity were P <.05) reduced significantly after consuming a high‐fat meal, which indicates that the effects of food on olmesartan exposure in healthy Chinese were clinically relevant. During the study, there were no suspected serious adverse reactions or serious adverse events. All adverse events were determined to be mild after Common Terminology Criteria for Adverse Events 5.0 evaluation. These results indicated that both the test and reference formulations were bioequivalent with similar safety profiles. [ABSTRACT FROM AUTHOR]

This study aimed to evaluate the bioequivalence of 2 amlodipine besylate tablet formulations, a generic formulation and an original formulation, and to investigate their pharmacokinetic and safety profiles. This study was designed as a randomized, open‐label, single‐dose, crossover, dual‐period study and was divided into fasting and postprandial human bioequivalence trials. In the first trial after overnight fasting, 28 subjects were given 5‐mg amlodipine besylate tablets via oral administration, and blood specimens were obtained up to 144 hours after dosing; another 28 subjects had a high‐fat meal 1 hour before drug administration and proceeded the same as the fasting trial. Bioequivalence was evaluated using 90%CIs for the ratio test/reference of log area under the concentration–time curve (AUC) from time 0 to the last quantifiable concentration, log AUC from time 0 to infinity, and log peak concentration. The plasma concentrations were measured by high‐performance liquid chromatography–tandem mass spectrometry. The safety was assessed throughout the study. The results show that no significant differences were observed between the pharmacokinetic profiles of the test and reference amlodipine besylate tablets in the fasting and postprandial trials. The 90%CIs of the peak concentration, AUC from time 0 to the last quantifiable concentration and AUC from time 0 to infinity of amlodipine in the 2 trials were within the commonly accepted bioequivalence criteria of 80% to 125%. Compared with the pharmacokinetic parameters of the fasting and postprandial trials, food had no significant effect on exposure of amlodipine besylate. There was no significant difference in safety statistical results between the 2 groups. The results suggest that generic and original amlodipine besylate tablets are bioequivalent with similar safety profiles. [ABSTRACT FROM AUTHOR]

Background: Activity of the circulating renin‐angiotensin‐aldosterone system (RAAS) has not been comprehensively characterized in cats with systemic hypertension (SH) or cardiomyopathy (CM), and the effects of furosemide or amlodipine treatment on the RAAS have not been fully evaluated in cats. Hypothesis/Objectives: To document RAAS activity in cats with SH or CM compared to healthy cats and determine how RAAS profiles change with furosemide or amlodipine treatment. Animals: Sixty‐six client‐owned cats: 15 with SH (7 amlodipine‐treated, 8 untreated), 17 with advanced CM (7 furosemide‐treated, 10 not furosemide‐treated), and 34 healthy cats. Methods: Equilibrium concentrations of RAAS peptides and aldosterone were quantified in serum samples by liquid chromatography‐mass spectrometry. Variables were compared between groups using Kruskal‐Wallis analysis with post hoc Holms‐corrected Dunn's testing. Results: Compared with healthy cats, cats with CM had higher concentrations of angiotensin I, aldosterone, and plasma renin activity (all P <.01), and these differences remained significant (P <.03) after considering subgroups of untreated or furosemide‐treated cats. Compared with healthy cats, untreated cats with SH showed no differences in RAAS biomarkers, whereas amlodipine‐treated cats had higher concentrations of angiotensins I, II, III, IV, and 1‐7, aldosterone, and plasma renin activity (all P <.03). Multivariable analysis determined that furosemide and amlodipine treatments were independent predictors of increased RAAS biomarker concentrations. Conclusions and Clinical Importance: Cats with CM had increased RAAS activity, whereas cats with untreated SH did not. Furosemide and amlodipine both led to nonspecific activation of both classical and alternative RAAS pathways in cats. [ABSTRACT FROM AUTHOR]

Objective: The aim of this report is to document the case of a dog that developed pleural effusion as a potential side‐effect to the administration of a high‐dose of amlodipine. Case summary: A Yorkshire terrier dog (13‐year‐old, castrated male, 4.5 kg) presented with severe systemic hypertension (>200 mmHg), hyperkalaemia, and acute pancreatitis. The dog had hyperadrenocorticism, chronic valvular heart disease, chronic kidney disease, and cerebellar infarction as underlying diseases. Additionally, the dog had laboured breathing and tachypnoea during hospitalization. Screening examinations revealed a pleural effusion (pure transudate) for which hypoalbuminemia and thromboembolism were ruled out as the causes. Therefore, the adverse drug event of an anti‐hypertensive drug (amlodipine) was tentatively diagnosed. Conclusions: Pleural effusion resolved within 24 h of reducing the dosage of amlodipine. Hence, the dog was diagnosed with amlodipine‐induced pleural effusion. Rarely, amlodipine can cause pleural effusion after high‐dose administrations in humans, but only two cases of peripheral edema have been reported in animals. If pleural effusion occurs in hypertensive patients administered amlodipine, it should be considered as the potential cause. [ABSTRACT FROM AUTHOR]

A new resolution method of racemic amlodipine has been developed. The racemic compound is reacted in a suitable solvent with 0.25‐mol equivalent of (R,R)‐tartaric acid. After the decomposition of the diastereomeric salt, the remaining racemic fraction is precipitated with half‐equivalent of fumaric acid, and the pure amlodipine enantiomer is obtained. A quarter equivalent of the same resolving agent, (R,R)‐tartaric acid has been also added to the mother liquor to obtain the other enantiomer. The advantage of this method is that both of the enantiomers of amlodipine could be obtained with high enantiomeric excess with the same resolving agent. The racemic excess can also be isolated and re‐resolved. Achiral reagents (urea and thiourea) have been added to the resolving agent. These neutral additives are incorporated as co‐crystals in the structure of the diastereomeric salts. The used solvate‐former solvents and achiral additives are structurally similar, and their presence can enable the fractional separation of the diastereomers. In addition, the racemate, the enantiomers, and some intermediate salts with high diastereomeric excess obtained in the resolution process of amlodipine have been also subjected to thermal (DSC, TG/DTA‐EGA‐MS, and ‐FTIR), analytical (FTIR spectroscopic), and structural (XRD) comparisons, which indicate that the key‐intermediate crystalline diastereomeric salts—as solvates and co‐crystals—inherit a kind of structural similarity from their related additives—solvents (DMF, DMAA, and DMSO) or (thio)ureas, respectively. [ABSTRACT FROM AUTHOR]

Hypertension is more effectively treated with coadministration of 2 or more antihypertensive drugs than with high‐dose monotherapy. Therefore, calcium channel blockers, angiotensin II receptor blockers, and thiazides are coadministered to treat hypertension. The objective of this study was to compare the pharmacokinetic (PK) profiles of HCP1401, a fixed‐dose combination of amlodipine 5 mg, losartan 100 mg, and chlorthalidone 25 mg, with the separate components (loose combination) of amlodipine/losartan 5/100 mg and chlorthalidone 25 mg. A randomized, open‐label, single‐dose, 2‐way crossover study was conducted. Blood samples for amlodipine and chlorthalidone were collected for up to 144 hours after dosing, whereas those for losartan were collected up to 48 hours after dosing. The PK parameters of these drugs were calculated using a noncompartmental method. Sixty subjects completed the study. The geometric mean ratios and 90% confidence intervals of maximum plasma concentration and area under the concentration–time curve to the last measurable point for amlodipine, losartan, and chlorthalidone were within the conventional bioequivalence range of 0.80 to 1.25. There were no clinically significant changes in safety assessments, and the treatments were well tolerated. The PK characteristics and tolerability profiles of a single oral FDC of amlodipine, losartan, and chlorthalidone were equivalent to those of individual tablets in a loose combination. [ABSTRACT FROM AUTHOR]

Metal organic frameworks (MOFs) have been recognized as promising materials for biomedical applications such as drug storage and drug delivery. In this study, grand canonical Monte Carlo simulations were carried out to investigate the adsorption of an antihypertensive drug amlodipine in 28 different MOFs. Among them, 19 MOFs, which were identified to outperform those traditional materials, were screened to perform molecular dynamic (MD) simulations in order to select promising candidates for drug carriers of amlodipine, and then five representative MOFs were explored further to elucidate the mechanism of amlodipine adsorption. This is the first study to investigate the correlations between self‐diffusion coefficients of drug molecule and its adsorption heat, pore volumes, and largest cavity diameters of MOF‐74 series. This work provides valuable insights in drug adsorption and diffusion mechanisms in MOFs at the molecular level enabling us to speed up the MD screening of suitable drug carriers prior to experiments. [ABSTRACT FROM AUTHOR]

Calcium‐channel blockers (CCBs) are widely used in people and animals. Overdose can result in cardiovascular collapse and death. Hyperinsulinemia/euglycemia therapy (HIET) and intralipid therapy (ILT) are reported treatment options in people. This is the first report describing HIET and ILT as treatments for amlodipine toxicosis in a cat. [ABSTRACT FROM AUTHOR]

This open‐label, repeat‐dose, fixed‐sequence study in healthy subjects examined pharmacokinetic drug‐drug interactions between the components of a novel fixed‐dose combination product containing ramipril, amlodipine, and atorvastatin. Sequential 5‐day monotreatments (MTs) of ramipril (5 mg/d) and atorvastatin (40 mg/d) were followed by a 9‐day amlodipine MT (5 mg/d), separated by 96 hours washout intervals. After amlodipine MT, all 3 single‐entity drugs were coadministered for 5 days. Blood samples were taken over the dosing intervals and drug concentrations quantified by high‐performance liquid chromatography–mass spectrometry. Pharmacokinetic parameters were assessed and compared between the MTs and combination treatments by analysis of variance. Eighteen healthy subjects were enrolled and completed the study. No significant difference in maximum concentration (Cmax) and area under the plasma concentration–time curve over the dosing interval (AUC0‐τ) for amlodipine and AUC0‐τ of atorvastatin was observed upon combination treatments versus MTs. Cmax of atorvastatin was slightly decreased (Cmax ratio, 89.3%) when given in combination. Increased exposure of ramipril and less pronounced exposure of ramiprilat were observed in the presence of amlodipine and atorvastatin, with Cmax ratios for ramipril and ramiprilat of 182.6% and 155.9%, and corresponding AUC0‐τ ratios of 150.0% and 112.1%, respectively. These ramiprilat increases are unlikely of clinical relevance, because complete angiotensin‐converting enzyme occupation is achieved with ≥5‐mg ramipril doses, and free ramiprilat is rapidly eliminated. As ramipril is known to be subject to a site‐dependent absorption in the upper small intestine, it is hypothesized that slowing of intestinal motility by atorvastatin or amlodipine or a combined effect of both, increased the residence time of ramipril in its "absorption window," thereby enhancing its bioavailability. [ABSTRACT FROM AUTHOR]

Various single‐pill combinations (SPCs) have been introduced to improve drug compliance and clinical efficacy. However, there is a lack of real‐world evidence regarding the effectiveness of these SPCs for hypertension. This study evaluated the real‐world clinical efficacy and safety of amlodipine/losartan‐based SPC therapies in patients with hypertension in a real‐world setting. A total of 15 538 patients treated with amlodipine/losartan‐based SPCs [amlodipine + losartan (AL), amlodipine + losartan + rosuvastatin (ALR), and amlodipine + losartan + chlorthalidone (ALC)] were selected from the database of three tertiary hospitals in Korea. The efficacy endpoints were target blood pressure (BP) and low‐density lipoprotein cholesterol (LDL‐C) achievement rates. Safety was evaluated based on laboratory parameters. Drug adherence was defined as the proportion of medication days covered (PDC). The target BP attainment rate was above 90% and was similar among the three groups. Although many patients in the AL and ALC groups took statins, the target LDL‐C attainment rate was significantly higher in the ALR group than in the AL and ALC groups. Safety endpoints were not significantly different among the groups, except serum uric acid level and incidence rate of new‐onset hyperuricemia, which were significantly lower in the AL and ALR groups than in the ALC group. The PDC was > 90% in all groups. In the real‐world hypertensive patients, amlodipine/losartan‐based SPC therapy demonstrated good target BP achievement rates. Especially, rosuvastatin‐combination SPC showed better target LDL‐C goal achievement rate compared to the other SPCs. All three amlodipine/losartan‐based SPC had excellent drug adherence. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Objective: The purpose of this study was to evaluate the occurrence rate of drug‐induced gingival overgrowth (DIGO) in patients treated with angiotensin‐converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), and calcium channel blockers (CCBs) such as amlodipine, lercanidipine, and benidipine, as well as to assess the relationship of those mentioned above with medication variables and oral hygiene. Methods: Sociodemographic details, DIGO, and clinical periodontal parameters were obtained from one hundred and thirty‐one patients receiving ACE inhibitors, ARBs, and CCBs for a period of at least 2 years. Results: The occurrence rate of DIGO was 19.6% in patients using CCB, 12.5% in the ARB group, and 7.5% in the ACE inhibitor group. In a subgroup analysis of CCBs, DIGO was found to be 31.8% in the amlodipine group, 13.3% in the lercanidipine group, and 7.1% in the benidipine group. While there was a significant relationship between amlodipine drug dosage and DIGO, no association was found between the duration of therapy and DIGO in all CCB subgroups. Conclusion: There was no difference between the groups in terms of DIGO. Duration of therapy and drug dosage did not affect the severity of DIGO in both ACE inhibitors and ARB groups. [ABSTRACT FROM AUTHOR]

This post hoc analysis of the Systolic Blood Pressure Intervention Trial (SPRINT) examined the performance of chlorthalidone (C) versus amlodipine (A) monotherapies. ANOVA was used to analyze the differences in systolic blood pressure (SBP) response between C and A. Logistic regression was used to examine monotherapy failure (adding a second antihypertensive agent or switching to a different antihypertensive agent) rates. Four hundred ninety‐one participants were treated with C monotherapy (n = 210, mean dose = 22 mg/day) or A monotherapy (n = 281, mean dose = 7 mg/day). There was a significant difference in mean SBP reduction between the C and A monotherapies at the third visit (higher reduction with A, adjusted p =.018). Unadjusted analysis showed a higher failure with C in the standard treatment group. Although the average SBP at failure was higher and above the 140 mm Hg cutoff that indicated monotherapy failure with A (142.60) compared with C (138.40), more participants on C failed despite having SBP below the 140 cutoff. This was probably due to decisions made by the investigative teams to change the antihypertensive regimen, because, in their opinion, the clinical picture required it. After adjusting for baseline characteristics, C had higher failure than A only in the standard treatment group (1.64 odds ratio [OR], 95% CI 1.06–2.56, p =.028). A sub‐analysis including participants who had never used antihypertensive treatment before randomization had similar results (2.57 OR, 95% CI 1.34–5.02, p =.004). Overall, in SPRINT chlorthalidone was associated with higher monotherapy failure than amlodipine in the standard treatment group because of decisions of the investigative teams. [ABSTRACT FROM AUTHOR]

A robust and rapid UPLC–MS/MS method has been developed, optimized and validated for determination of amlodipine (AML), indapamide (IND) and perindopril (PRN) in human plasma. A positive electrospray ionization mode was used in a Xevo TQD LC–MS/MS instrument. A single sample preparation step using extraction technique was applied to extract the three analytes from plasma samples. There was no need to extract indapamide from blood samples in a further step. Extraction of the three drugs and internal standards was done using a solvent mixture composed of methyl tertiary butyl ether, dichloromethane and ethyl acetate. The prepared samples were analyzed using an Acquity UPLC HSS C18 (100 × 2.1 mm, 1.7 μm) column. Ammonium acetate and methanol, pumped at a flow rate of 0.3 ml/min, were used as a mobile phase. Method validation was done as per the US Food and Drug Administration guidelines. Linearity was achieved in the range of 0.2–15 ng/ml for AML, 0.5–50 ng/ml for IND and 0.5–120 ng/ml for PRN. Accuracy and precision were estimated and found to be within the acceptable ranges. The rapid chromatography permits analysis of many samples per batch, making the method suitable for clinical and pharmacokinetic investigations. The developed and validated method was applied to estimate AML, IND, and PRN in a fasting bioequivalence study in healthy human volunteers. [ABSTRACT FROM AUTHOR]

Objectives: To determine the prevalence of ocular fundus abnormalities in cats with a diagnosis of systemic hypertension, to characterize the abnormalities observed, and to evaluate ophthalmoscopic evolution during treatment with amlodipine besylate. Animals studied: Cats diagnosed as affected by SHP in a 2‐year period. Procedures: Systemic hypertension was assessed by oscillometric blood pressure measurement, and its etiology was also established. All the cats received an ophthalmic examination, and ocular lesions were classified with a score from 0 (no abnormalities) to 4 (severe abnormalities). All cats received amlodipine besylate by mouth, and those that showed fundus abnormalities were regularly rechecked from 7 to 365 days after diagnosis. Data were statistically analyzed to compare Psys and Pdia with all the variables and to correlate Psys and Pdia with the fundus score. Results: A total of 225 cats were enrolled in the study, and the prevalence of fundus abnormalities was 58.6% (21.2%: grade 1; 18.2%: grade 2; 36.4%: grade 3; and 24.2%: grade 4). Systemic hypertension was diagnosed concurrently with chronic renal failure (60.4%), hyperthyroidism (28.9%), both chronic renal failure and hyperthyroidism (7.6%), and hypertrophic myocardiopathy (3.1%). A significant effect of Psys values on the fundus score was detected. Amlodipine therapy improved fundus abnormalities in 50% of cases at the 21‐day follow‐up. Conclusions: This study showed that fundus abnormalities are common in hypertensive cats at the time of the systemic diagnosis, and most of the abnormalities are moderate to severe. Treatment with amlodipine appeared to improve ophthalmic lesions over time. [ABSTRACT FROM AUTHOR]

For efficient cardiovascular risk protection antihypertensive treatment is often combined with cholesterol‐lowering treatment, although solid data of interaction and side effects are missing. This is a prospective, single‐center interaction study conducted in a fixed sequence design at steady state of candesartan, amlodipine, and atorvastatin. Five‐day monotherapy of candesartan 8 mg was followed by 5‐day atorvastatin 40 mg monotherapy and subsequently 9‐day amlodipine 5 mg monotherapy; each treatment separated by washout phases. Immediately after amlodipine monotherapy, all 3 drugs were administered concomitantly for 5 days. Pharmacokinetic parameters as well as safety were assessed. Eighteen healthy subjects enrolled and completed the study. No significant difference in the maximum concentration (Cmax) and the area the under plasma concentration–time curve (AUC) for amlodipine and AUC of atorvastatin was detected following combination versus monotherapy. Cmax of atorvastatin decreased slightly but clinically not relevantly when given in combination. A statistically significant but not below 0.80‐fold decrease between candesartan following combination vs monotherapy was detected for Cmax and AUC. In general, all treatments were well tolerated. Concluding, systemic exposure of candesartan, amlodipine, and atorvastatin is not clinically significantly changed upon coadministration. These data support a fixed‐dose combination of the 3 components for dual cardiovascular risk prevention. [ABSTRACT FROM AUTHOR]

Background: Hypertension and hypercholesterolemia are important risk factors for cardiovascular disease, and treatment with fixed-dose combination (FDC) regimens is recommended by current guidelines. However, the clinical outcomes of different FDC dosages remain unknown. This study aimed to examine the clinical outcomes of FDC regimens and the free combination of amlodipine and atorvastatin at different dosages., Methods and Results: Patients with concurrent hypertension and hypercholesterolemia treated daily with an FDC of 5 mg amlodipine and 10 mg atorvastatin (5/10 fixed group), and FDC of 5 mg amlodipine and 20 mg atorvastatin (5/20 fixed group), or free combination of 5 mg amlodipine and 20 mg atorvastatin (5/20 free group) were identified from the National Health Insurance Research Database of Taiwan. The primary outcome was the composite cardiovascular outcomes, including cardiovascular death, acute myocardial infarction, stroke, and coronary intervention. A total of 9095 patients were eligible for inclusion. The incidence of primary outcome per 1000 person-years was 16.6 in the 5/10 fixed group, 12.6 in the 5/20 fixed group, and 16.5 in the 5/20 free group (5/20 fixed versus 5/20 free: hazard ratio [HR], 0.76 [95% CI, 0.64-0.91]; 5/20 fixed versus 5/10 fixed: HR, 0.76 [95% CI, 0.63-0.90])., Conclusions: Among patients with concomitant hypertension and hypercholesterolemia, treatment with an FDC of amlodipine and high-dose atorvastatin led to a lower risk of a composite of cardiovascular outcomes than treatment with the free combination or a similar FDC with a lower dose of atorvastatin.

Mobility shift‐affinity capillary electrophoresis was employed for enantioseparation and simultaneous binding constant determination. Human serum albumin was used as a chiral selector in the background electrolyte composed of 20 mM phosphate buffer, pH 7.4. The applied setup supports a high mobility shift since albumin and the drug‐albumin complex hold negative net charges, while model compounds of amlodipine and verapamil are positively charged. In order to have an accurate effective mobility determination, the Haarhoff‐van der Linde function was utilized. Subsequently, the association constant was determined by nonlinear regression analysis of the dependence of effective mobilities on the total protein concentration. Differences in the apparent binding status between the enantiomers lead to mobility shifts of different extends (α). This resulted in enantioresolutions of Rs = 1.05–3.63 for both drug models. R‐(+)‐Verapamil (KA 1844 M−1) proved to bind stronger to human serum albumin compared to S‐(−)‐verapamil (KA 6.6 M−1). The association constant of S‐(−)‐amlodipine (KA 25 073 M−1) was found to be slightly higher compared to its antipode (KA 22 620 M−1) when applying the racemic mixture. The low measurement uncertainty of this approach was demonstrated by the close agreement of the association constant of the enantiopure S‐(−)‐form (KA 25 101 M−1). [ABSTRACT FROM AUTHOR]

Single risk factors, such as hypertension and dyslipidemia, can combine to exacerbate the development and severity of cardiovascular disease. Treatment goals may be more effectively achieved if multiple disease factors are targeted with combination treatment. We enrolled 202 patients who were randomly divided into the following three groups: telmisartan/amlodipine 80/5 mg + rosuvastatin 20 mg, telmisartan 80 mg + rosuvastatin 20 mg, and telmisartan/amlodipine 80/5 mg. The primary efficacy variables were changes from baseline in mean sitting systolic blood pressure (MSSBP) between telmisartan/amlodipine 80/5 mg + rosuvastatin 20 mg and telmisartan 80 mg + rosuvastatin 20 mg at 8 weeks, and the percent changes from baseline in low‐density lipoprotein (LDL) cholesterol between telmisartan/amlodipine 80/5 mg + rosuvastatin 20 mg and telmisartan/amlodipine 80/5 mg at 8 weeks. The secondary efficacy variables were changes in MSSBP, mean sitting diastolic blood pressure (MSDBP), LDL cholesterol and other lipid levels at 4 weeks and 8 weeks, as well as observed adverse events during follow‐up. There were no significant differences between the three groups in demographic characteristics and no significant difference among the three groups in terms of baseline characteristics for the validity evaluation variables. The mean overall treatment compliance in the three groups was, respectively, 98.42%, 96.68%, and 98.12%, indicating strong compliance for all patients. The Least‐Square (LS) mean (SE) for changes in MSSBP in the two (telmisartan/amlodipine 80/5 mg + rosuvastatin 20 mg and telmisartan 80 mg + rosuvastatin 20 mg) groups were −19.3 (2.68) mm Hg and −6.69 (2.76) mm Hg. The difference between the two groups was significant (−12.60 (2.77) mm Hg, 95% CI −18.06 to −7.14, P <.0001). The LS Mean for the percent changes from baseline in LDL cholesterol in the two (telmisartan/amlodipine 80/5 mg + rosuvastatin 20 mg and telmisartan/amlodipine 80/5 mg) groups were −52.45 (3.23) % and 2.68 (3.15) %. The difference between the two groups was significant (−55.13 (3.20) %, 95% CI −61.45 to −48.81, P <.0001). There were no adverse events leading to discontinuation or death. Combined administration of telmisartan/amlodipine 80/5 mg and rosuvastatin 20 mg for the treatment of hypertensive patients with dyslipidemia significantly reduces blood pressure and improves lipid control. ClinicalTrials.gov identifier: NCT03067688. [ABSTRACT FROM AUTHOR]

Background and objectives: Amlodipine, a calcium channel blocker derivative, is frequently used by patients with high blood pressure. Studies reported that it can induce gingival overgrowth. However, the underlying mechanism is not fully described yet. Interleukin‐17A (IL‐17A) is known as a proinflammatory cytokine, but current studies indicate that it has a role in fibrotic disorders and epithelial‐mesenchymal transition (EMT). The aim of this study was to figure out the possible role of IL‐17A in amlodipine‐induced gingival overgrowth. Materials and methods: Twenty‐nine (29) individuals participated in the study, and they were assigned into 3 groups based on medical status and clinical periodontal examination; 9 patients with amlodipine‐induced gingival overgrowth, 11 patients with inflammatory gingival overgrowth, and 9 healthy individuals as a control group. Clinical periodontal parameters including plaque index (PI), gingival index (GI), and gingival overgrowth index (GOI) were recorded. Blood and gingival crevicular fluid (GCF) samples were obtained. Gingival tissues were taken by appropriate periodontal surgery following initial periodontal therapy. To detect IL‐17A on tissue samples, immunohistochemistry (IHC) was performed. Quantitative analysis was done, and the expression level of IL‐17A was given as the percent positively stained cells. Enzyme‐linked immunosorbent assay (ELISA) kits were used to analyze IL‐17A in serum and GCF samples. Results: All recorded clinical parameters were significantly higher in gingival overgrowth groups compared with control. Evaluation of inflammation on tissue sections did not show any significant change within the groups. Immunohistochemistry findings showed that IL‐17A expression was increased in amlodipine samples (81.90%) compared with control samples (42.35%) (P <.001). There was an increase in the inflammatory group (66.08%) which is significantly less than the amlodipine group (P <.05). IL‐17A levels in serum and GCF samples were not different within the study groups. Conclusion: In this study, elevated IL‐17A expression regardless of inflammation shows that amlodipine might cause an increase of IL‐17A in gingival tissues. This increase might induce fibrotic changes and EMT in gingival overgrowth tissues. The association of IL‐17A with fibrosis and EMT in gingival tissues requires further investigation. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]