Calcium Channel Blocker Amlodipine Research Articles

Impact of non-conventional rescue therapies on quantification of cardiac agents following severe poisoning: Analytical considerations

To assess whether a TurboFlow-LC-MS/MS (TF-LC-MS/MS) method that quantifies calcium channel blockers (CCB) and beta-blockers (BB) in plasma is suitable for monitoring severely-poisoned patients when non-conventional rescue therapies, i.e. lipid emulsions (LE) and Molecular Adsorbent Recirculating System (MARS ® ) are instituted. CCB amlodipine (A), nicardipine (Nic), nifedipine (Nif) and BB nebivolol (Neb) were quantified in plasma with or without lipid emulsion (PLE) and in dialysates (D) by TF-LC-MS/MS using a TLX-1 System interfaced with a TSQ Quantum Ultra ® (ThermoFisher). Impact of intravenous LE was studied with blank plasma spiked with Intralipid 20% (final concentrations between 5 to 30%). The albumin-containing dialysate that circulates through the MARS ® was replicated with an Ydralbum ® solution diluted in physiologic serum to obtain final concentrations of 0, 5, 10 and 15% of human albumin. All samples were analyzed by TF-LC-MS/MS after protein precipitation with acetonitrile containing deuterated internal standards (IS). Calibration curves were established by plotting the area of each analyte with dedicated deuterated IS in plasma samples. Impact of LE and MARS ® was studied with Quality Controls (QCs) spiked with analytes at low and high level concentrations (5 and 150 ng/mL) in PLE and in D, respectively. The method was finally applied to analyze samples obtained from two patients severely poisoned to amlodipine and treated with MARS ® and LE. Calibrations were linear from 2.5 to 200 ng/mL in plasma using 1/X 2 weighted least square regression. When plasma was spiked with LE, intra-day precisions were less than 4, 3, 4, and 8% (expressed as relative standard deviation) for A, Nic, Nif and Neb, respectively, irrespective of the LE final concentration. Intra-day accuracies were not statistically different in PLE compared to blank plasma. QCs prepared artificially with human albumin were confronted to the calibrations established in plasma. Precisions were less than 7% for all analytes, and accuracies did not exceed ±15% as requested by the European Medicine Agency (EMA). Intensities of absolute areas (AA) measured by TF-LC-MS/MS for each analyte and IS were similar in PLE, D and blank plasma. Concentrations of amlodipine were determined in plasma and dialysates sampled from 2 patients treated with MARS ® and ILE. Peak amlodipine concentrations were measured at 664 and 708 ng/mL (therapeutic range: 1–25), respectively. For patient 1, 30% of circulating amlodipine was trapped in LE, and for both patients, 2% of the toxicant was extracted by the MARS ® membrane. Time course levels of amlodipine were followed in plasma until patient's 1 death and patient's 2 full recovery. Massive overdoses with CCB and BB are often responsible for fatal refractory cardiovascular failure. In adjunction with symptomatic pharmacological agents, efficacy of extracorporeal life support like MARS ® and trapping strategy with IL is currently being assessed. Thus, concentrations of toxicants should be monitored in plasma but also in hyperlipemic plasma due to IV LE and in dialysates resulting from the extracorporeal circuitry of MARS ® . Hence, the analytical method must be validated for all the involved matrices. Irrespective of LE rates in plasma and albumin concentrations in physiologic serum, all QCs fulfilled acceptability criteria for precision and accuracy according to EMA. Furthermore, similar intensities of AA were found in blank plasma, PLE and D. Thus, combination of protein precipitation, TF-LC-MS/MS and use of deuterated IS contributes to a polyvalent and robust analytical method. In conclusion, our method initially validated to monitor A, Nic, Nif and/or Neb in plasma was also applicable to patients severely poisoned and treated with non-conventional therapies such as LE and MARS ® .

Anti-diabetic Properties of Calcium Channel Blockers: Inhibition Effects on Aldose Reductase Enzyme Activity.

Aldose reductase (AR) belongs to NADPH-dependent oxidoreductases and converts glucose to sorbitol in the polyol pathway. AR inhibition is essential to prevent diabetic complications. Here, AR was purified from sheep kidney using simple methods and determined the interactions between some calcium channel blockers and the enzyme. It was found that calcium channel blockers (cinnarizine, nilvadipine, amlodipine besylate, nifedipine, isradipine, and nitrendipine) exhibit potential inhibitor properties for sheep kidney AR with IC50 values in the range of 5.87-8.77μM and Ki constants in the range of 2.07 ± 0.72-5.62 ± 1.53μM. The calcium channel blockers showed different inhibition mechanisms. It was determined that all studied compounds showed competitive inhibition effect except for isradipine and nitrendipine. They showed non-competitive inhibition. Among these drugs, cinnarizine was found to be the most potent AR inhibitor (Ki: 2.07 ± 0.72μM). They may be useful in the treatment and/or prevention of diabetic complications.

A randomized controlled trial on the blood pressure-lowering effect of amlodipine and nifedipine-GITS in sustained hypertension.

In a multicenter, randomized trial, we investigated whether the long half-time dihydropyridine calcium channel blocker amlodipine was more efficacious than the gastrointestinal therapeutic system (GITS) formulation of nifedipine in lowering ambulatory blood pressure (BP) in sustained hypertension (clinic systolic/diastolic BP 140-179/90-109mmHg and 24-hour systolic/diastolic BP≥130/80mmHg). Eligible patients were randomly assigned to amlodipine 5-10mg/day or nifedipine-GITS 30-60mg/day. Ambulatory BP monitoring was performed for 24hours at baseline and 4-week treatment and for 48hours at 8-week treatment with a dose of medication missed on the second day. After 8-week treatment, BP was similarly reduced in the amlodipine (n=257) and nifedipine-GITS groups (n=248) for both clinic and ambulatory (24-hour systolic/diastolic BP10.3/6.5 vs 10.9/6.3mmHg, P≥0.24) measurements. However, after missing a dose of medication, ambulatory BP reductions were greater in the amlodipine than nifedipine-GITS group, with a significant (P≤0.04) between-group difference in 24-hour (-1.2mmHg) and daytime diastolic BP (-1.5mmHg). In conclusion, amlodipine and nifedipine-GITS were efficacious in reducing 24-hour BP. When a dose of medication was missed, amlodipine became more efficacious than nifedipine-GITS.

Modern combination antihypertensive pharmacotherapy

Achievement of target blood pressure levels is one of the main issues in antihypertensive pharmacotherapy. The article presents updated 2018 European Guidelines recommendations on target blood pressure levels in antihypertensive therapy and combined antihypertensive pharmacotherapy advantages. Modern fixed combinations including those with three active agents are discussed. A review of studies that show effectiveness and safety of long acting dihydropyridine calcium channel blocker amlodipine, thiazid-like diuretic indapamide, and angiotensin-converting enzyme inhibitor perindopril arginine fixed combination is presented

Evaluation of AML-VAL Nanoparticles as Combined Therapy in Cardiovascular Disease

The main aim of this study was to investigate a mixture of two poorly water-soluble active pharmaceutical ingredients (APIs): an angiotensin II receptor antagonist (valsartan) and a calcium channel blocker (amlodipine besylate), chosen in a fixed-dose, in order to obtain new polymeric nanoparticles (NPs) for cardiovascular diseases treatment. NPs were prepared via nanoprecipitation method using poly (D,L-lactide-co-glycolide) (PLGA) as matrix and Pluronic F127 as stabilizer. Three formulations were investigated with different ratios of AML:VAL:PLGA (1:16:5, 1:16:7.5 and 1:16:10). Particle size, polydispersity index and zeta-potential analyses were performed to characterize and optimize the formulation. The in vitro drug release study was determined by using a dialysis membrane method under sink conditions. All NPs loaded with both APIs showed nano-size, negative potential, a high homogeneity and a slow drugs release in physiological environment.

Efficacy of zofenopril in combination with amlodipine in patients with acute myocardial infarction: a pooled individual patient data analysis of four randomized, double-blind, controlled, prospective studies

Objective: In the four SMILE (Survival of Myocardial Infarction Long-Term Evaluation) studies, early administration of zofenopril in acute myocardial infarction (AMI) showed beneficial effects as compared to placebo and other angiotensin converting enzyme inhibitors (ACEIs). This study investigated whether the concomitant administration of the dihydropyridine calcium channel-blocker amlodipine may improve zofenopril efficacy to prevent cardiovascular events in post-AMI patients.Methods: This was a post-hoc analysis of pooled individual patient data from the four large randomized SMILE studies. The primary endpoint was the 1-year combined occurrence of death or hospitalization for cardiovascular causes.Results: In total, 3488 patients were considered, 303 (8.7%) treated with concomitant amlodipine. Baseline systolic blood pressure and prevalence of metabolic syndrome were higher in amlodipine treated patients. The 1-year occurrence of major cardiovascular outcomes was significantly reduced in patients receiving concomitant treatment with amlodipine (hazard ratio, HR = 0.66; and 95% confidence interval, CI = 0.44–0.98; p = .039). After accounting for treatment with amlodipine, the risk of cardiovascular events was significantly reduced with zofenopril compared to placebo (HR = 0.78; 95% CI = 0.63–0.97; p = .026]. Among ACEI-treated patients, the zofenopril plus amlodipine combination reduced the risk of cardiovascular events by 38%, compared to the combination of other ACEIs plus amlodipine [HR = 0.76; 95% CI = 0.61–0.94); p = .013). The prognostic benefit of concomitant treatment with zofenopril plus amlodipine was independent from blood pressure lowering.Conclusions: Zofenopril had a positive impact on prognosis in post-AMI patients, compared to other ACEIs. Concomitant administration of amlodipine may help to reduce the risk of cardiovascular events at 1 year.

Effect of omeprazole on antihypertensive efficacy of amlodipine in patients with comorbid pathology – arterial hypertension and acid-dependent disease

Objective:The problem of drug interactions is increasingly important today because they may induce serious adverse events as well as interfere with efficacy of pharmacotherapy. Combinations of drugs are most often prescribed to patients presenting with comorbid pathology. The incidence of a combination of arterial hypertension (AH) and acid-dependent diseases (ADDs) varies widely ranging from 11.6 to 50%. One of combinations of drugs prescribed to such patients is a combination of calcium channel blocker amlodipine and proton pump inhibitor omeprazole. The latter in the human body undergoes biotransformation mediated at the level of cytochrome P450 by isoenzymes CYP2C19 and CYP3A4. Amlodipine is a substrate of the isoenzyme CYP3A4, which increases the probability of the development of interaction between these drugs. The purpose of our study was to investigate antihypertensive efficacy of amlodipine in patients suffering from arterial hypertension combined with acid-dependent diseases and additionally taking omeprazole.Method:Study included a total of 150 patients with AH and ADD. Antihypertensive therapy was evaluated by means of office measuring of arterial pressure (AP) and circadian monitoring of AP (CMAP). The followed-up patients with AH and ADD were divided into 2 groups. Group One was composed of hypertensive patients undergoing pharmacotherapy with 10 mg amlodipine, whose condition required due to exacerbation of ADD administration of omeprazole at a dose of 20 mg for a period from 3 to 4 weeks. Group Two comprised hypertensive patients receiving antihypertensive therapy consisting of 10 mg amlodipine, who were found to have remission of acid-dependent diseases, with no additional medication taken.Results:The obtained findings demonstrated that one of the commonly used drug combinations in treatment of patients with AH and ADD in ambulatory conditions was a combination of omeprazole and amlodipine, accounting for 7.1%. The results of office measurement of arterial pressure (AP) 2 weeks after initiating pharmacotherapy with omeprazole in patients with AH and ADD demonstrated that the patients receiving omeprazole in addition to antihypertensive therapy were found to have a statistically significant decrease in systolic arterial pressure (SAP) and statistically significantly more pronounced dynamics of a decrease in diastolic arterial pressure (SAP) (p<0.05) compared with those not receiving therapy with omeprazole. Also, in the group of patients taking omeprazole, the findings of circadian monitoring of blood pressure (CMAP) showed a statistically significant decrease in average circadian SAP, average circadian DAP, mean value of daytime SAP and mean value of nighttime SAP (p<0.05).Conclusion:The obtained findings demonstrated that simultaneous prescription of amlodipine and omeprazole to patients with concomitant pathology, i.e., AH and ADD, turned out to enhance the antihypertensive affect of amlodipine, which probably resulted from substrate competition of amlodipine and omeprazole at the level isoenzyme CYP 3A4 of cytochrome P450.

Recommended treatment protocols to improve management of hypertension globally: A statement by Resolve to Save Lives and the World Hypertension League (WHL).

Recommended treatment protocols to improve management of hypertension globally: A statement by Resolve to Save Lives and the World Hypertension League (WHL).

Influence of 3 calcium channel blockers on gingival overgrowth in a population of severe refractory hypertensive patients.

The aim of the current study was to assess the association between 3 different calcium channel blockers (CCBs) (nifedipine, amlodipine and felodipine) and gingival overgrowth in patients with a diagnosis of severe refractory hypertension. One hundred and sixty-two patients with severe refractory hypertension, taking CCBs, were selected. Gingival overgrowth was graded and periodontal measurements were recorded (probing pocket depth, clinical attachment level, plaque index and bleeding on probing). Unconditional multivariable binary logistic regression analyses were performed to assess the association between CCB intake and gingival overgrowth after adjusting for potential confounders. Of the 162 patients, 26 (16.0%) were current smokers and 101 (62.3%) were females. The mean age (SD) was 54.1 (8.5) years and the median age (range) 52.5 (39-78) years. Gingival overgrowth was observed in 55 patients (34.0%). Nifedipine was the most common medication (35.2%; 57 of 162). The results of multiple binary logistic regression showed statistically significant associations between CCB intake (exposure) and gingival overgrowth (outcome) after adjusting for the variables treatment time with antihypertensive and plaque index. Patients with gingival overgrowth were 2.5 (odds ratio=2.46; 95% confidence interval: 1.04-5.82) and 4.0 (odds ratio=3.90; 95% confidence interval: 1.47-10.35) times more likely to be taking nifedipine and amlodipine, respectively, than patients without gingival overgrowth. On the other hand, this significant association was not observed for felodipine. Nifedipine and amlodipine, but not felodipine, were associated with gingival overgrowth in patients with severe refractory hypertension.

Angiotensin II promotes pulmonary metastasis of melanoma through the activation of adhesion molecules in vascular endothelial cells

Hypertension is considered as one of the cancer progressive factors, and often found comorbidity in cancer patients. Renin-angiotensin system (RAS) plays an important role in the regulation of blood pressure, and angiotensin II (Ang II) is well known pressor peptide associated with RAS. Ang II has been reported to accelerate progression and metastasis of cancer cells. However, its precise mechanisms have not been fully understood. In this study, we sought to elucidate the mechanisms by which Ang II exacerbates hematogenous metastasis in mouse melanoma cells, focusing the adhesion pathway in vascular endothelial cells. For this purpose, B16/F10 mouse melanoma cells, which do not express the Ang II type 1 receptor (AT1R), were intravenously injected into C57BL/6 mice. Two weeks after cell injection, the number of lung metastatic colonies was significantly higher in the Ang II-treated group (1 μg/kg/min) than in the vehicle-treated group. The AT1R blocker valsartan (40 mg/kg/day), but not the calcium channel blocker amlodipine (5 or 10 mg/kg/day), significantly suppressed the effect of Ang II. In endothelium-specific Agtr1a knockout mice, Ang II-mediated acceleration of lung metastases of melanoma cells was significantly diminished. Ang II treatment significantly increased E-selectin mRNA expression in vascular endothelial cells collected from lung tissues, and thus promoted adherence of melanoma cells to the vascular endothelium. Ang II-accelerated lung metastases of melanoma cells were also suppressed by treatment with anti-E-selectin antibody (20 mg/kg). Taken together, Ang II-treatment exacerbates hematogenous cancer metastasis by promoting E-selectin-mediated adhesion of cancer cells to vascular endothelial cells.

New perspectives for the treatment of arterial hypertension: 2017 american guidelines

The key goal in the treatment for patients with AH is to reduce the risk of cardiovascular complications through reaching the target level of arterial pressure (AP) and organ protection, treatment of concomitant diseases and correction of risk factors. The new US guidelines for the management of hypertension indicate that the target blood pressure level for all patients was less than 130/80 mm Hg. This is due, among other things, to changing the blood pressure levels classification and categorizing all adults with blood pressure of 130/80 mm Hg. and higher as having hypertension. The need for not only wider combination therapy for the treatment of hypertensive patients, but also its earlier commencement has been strongly confirmed by these new guidelines for the management of AH. The wider use of combinations, especially in fixed doses, such as the calcium channel blocker amlodipine, and the angiotensin II receptor antagonist olmesartan for the treatment of hypertension, will help improve blood pressure monitoring, reduce the risk of complications and increase the AH patients’ life expectancy.

Evaluasi Rasionalitas Penggunaan Obat Antihipertensi di Puskesmas Siantan Hilir Kota Pontianak Tahun 2015

Hypertension is widely known as cardiovascular disease. In addition to resulting heart failure, hypertension can result in kidney failure and cerebrovascular disease. This study was aimed to determine the percentage of treatment rationality of hypertensive patient treatment outpatient in Puskesmas Siantan Hilir Pontianak 2015 which includes the appropriate indication, appropriate drug, appropriate patient, and appropriate dose based on the guideline JNC 7. This study was cross-sectional observational study using retrospective data such as medical records of outpatient hypertension patients in 2015. The total of sample for this research were 92 people . The percentage of using the angiotensin converting enzym inhibitor (captopril) was 47,46%; calcium channel blocker (amlodipine) was 34,75%; tiazid diuretic (hydrochlorothiazid) was 16,10%; loop diuretic (furosemid) was 0, 85%; and potassium sparing (spironolactone) was 0.85%. The therapy rasionality of hypertensive patients in this research were 100% appropriate indication, 70,65% appropriate drug, 100% appropriate patient and 98,91% appropriate dose. The conclusion of this study is that overall treatment that meets all four rational treatment criteria is 69.56%.

Endothelial transcriptomics reveals activation of fibrosis-related pathways in hypertension.

Hypertension poses a significant challenge to vasculature homeostasis and stands as the most common cardiovascular disease in the world. Its effects are especially profound on endothelial cells that form the inner lining of the vasculature and are directly exposed to the effects of excess pressure. Here, we characterize the in vivo transcriptomic response of cardiac endothelial cells to hypertension by rapidly isolating these cells from the spontaneous hypertension mouse model BPH/2J and its normotensive BPN/3J control strain and performing and RNA sequencing on both. Comparison of transcriptional differences between these groups reveals statistically significant changes in cellular pathways consistent with cardiac fibrosis found in hypertensive animals. Importantly, many of the fibrosis-linked genes identified also differ significantly between juvenile prehypertensive and adult hypertensive BPH/2J mice, suggesting that these transcriptional differences are hypertension related. We examined the dynamic nature of these transcriptional changes by testing whether blood pressure normalization using either a calcium channel blocker (amlodipine) or a angiotensin II receptor blocker (losartan) is able to reverse these expression patterns associated with hypertension. We find that blood pressure reduction is capable of reversing some gene-expression patterns, while other transcripts are recalcitrant to therapeutic intervention. This illuminates the possibility that unmanaged hypertension may irreversibly alter some endothelial transcriptional patterns despite later intervention. This study quantifies how endothelial cells are remodeled at the molecular level in cardiovascular pathology and advances our understanding of the transcriptional events associated with endothelial response to hypertensive challenge.

Personalised Single-Pill Combination Therapy in Hypertensive Patients: An Update of a Practical Treatment Platform.

Despite the improvements in the management of hypertension during the last three decades, it continues to be one of the leading causes of cardiovascular morbidity and mortality worldwide. Effective and sustained reductions in blood pressure (BP) reduce the incidence of myocardial infarction, stroke, congestive heart failure and cardiovascular death. However, the proportion of patients who achieve the recommended BP goal (< 140/90 mmHg) is persistently low, worldwide. Poor adherence to therapy, complex therapeutic regimens, clinical inertia, drug-related adverse events and multiple risk factors or comorbidities contribute to the disparity between the potential and actual BP control rate. Previously we published a practical therapeutic platform for the treatment of hypertension based on clinical evidence, guidelines, best practice and clinical experience. This platform provides a personalised treatment approach and can be used to improve BP control and simplify treatment. It uses long-acting, effective and well-tolerated angiotensin receptor blocker (ARB) olmesartan, in combination with a calcium channel blocker amlodipine, and/or a thiazide diuretic hydrochlorothiazide. These drugs were selected based on the availability in most European Countries of single-pill, fixed formulations in a wide range of doses for both dual- and triple-drug combinations. The platform approach could be applied to other ARBs or angiotensin-converting enzyme inhibitors available in single-pill, fixed-dose combinations. Here, we present an update, which takes into account the results of the recently published studies and extends the applicability of the platform to common conditions that are often neglected or poorly considered in clinical practice guidelines.Electronic supplementary materialThe online version of this article (doi:10.1007/s40292-017-0239-7) contains supplementary material, which is available to authorized users.

THE INVESTIGATION OF CONDITIONS OF API FROM GROUP OF CALCIUM CHANNEL BLOCKERS EXTRACTION BY ORGANIC SOLVENTS BY USING HIGH-PERFORMANCE LIQUID CHROMATOGRAPHY AS ASSAY METHOD

Objective: The objective of this research was to select the optimal conditions for extraction of API from calcium channel blockers (amlodipine, nifedipine, and verapamil) by organic solvents from water solutions in dependence on pH solutions.Methods: The chromatographic analysis of amlodipine, nifedipine, and verapamil performed on liquid chromatography Agilent 1200.Results: The quantitative determination of API from calcium channel blockers (amlodipine, nifedipine, and verapamil) by high-performance liquid chromatography - method has been conducted. As a result of studies, we have found that the optimal extragent is chloroform, which is extracted at pH 7-82.1% of amlodipine, pH 5-76.2% of nifedipine, and pH 8-95.1% verapamil hydrochloride. API from calcium channel blockers (amlodipine, nifedipine, and verapamil) least extracted with hexane at pH 2.0, so these conditions may be cleaned extract from coextractives impurities.Conclusion: The results obtained in this research work clearly indicated that the extraction of API from calcium channel blockers (amlodipine, nifedipine, and verapamil) by organic solvents from water solutions in dependence on pH solutions has been conducted.

Risk Factors Influencing Outcomes of Atrial Fibrillation in ALLHAT

Background and aimsALLHAT, a randomized, double-blind, active-controlled, multicenter clinical trial of high risk hypertensive participants, compared treatment with an ACE-inhibitor (lisinopril) or calcium channel blocker (amlodipine) with a diuretic (chlorthalidone). Primary outcome was the occurrence of fatal coronary heart disease or nonfatal myocardial infarction. For this report, post-hoc analyses were conducted to determine the contribution of baseline characteristics of participants with or without baseline or incident atrial fibrillation (AF) and atrial flutter (AFL) to stroke, heart failure (HF), coronary heart disease (CHD), and mortality outcomes. Methods and resultsMinnesota Coding of baseline and biennial in-trial ECGs was used to determine the 334 baseline and 537 incident AF/AFL cases, respectively participants with AF/AFL: Cox regression was used to estimate hazard ratios of presence versus absence of either baseline or incident AF/AFL (as time-dependent covariate) for occurrence of stroke, CHD, HF, or mortality, while adjusting for selected baseline characteristics. Adjusted Cox regression was used to obtain hazard ratios (HRs) for presence versus absence of selected baseline characteristics among those with and without either baseline or incident AF/AFL. After adjusting for baseline characteristics, baseline AF/AFL was associated with stroke, HF, and mortality (HRs [95% CIs] 3.18, [2.34–4.33]; 2.65 [2.02–3.49]; and 2.10 [CI, 1.73–2.55], respectively, P < 0.05). Incident AF/AFL was a significant risk factor for HF and mortality (HRs 2.80 and 2.06, respectively, P < 0.05). Risk factor profiles for clinical outcomes for those with and without baseline or incident AF/AFL were largely similar. ConclusionsAF/AFL is a significant risk factor for stroke, HF, and mortality. Additional risk factors for these outcomes were generally similar for participants with and without baseline or incident AF/AFL.

Prospective direct comparison of antihypertensive effect and safety between high-dose amlodipine or indapamide in hypertensive patients uncontrolled by standard doses of angiotensin receptor blockers and amlodipine

ABSTRACTObjective: When hypertension is uncontrolled by routine treatment with an angiotensin II receptor blocker (ARB) and the calcium channel blocker amlodipine (5 mg), the dose of amlodipine can be increased or a diuretic can be added. We investigated the more effective option in a prospective multicenter open-label study. Methods: Hypertensive patients were recruited if the target blood pressure (BP) in The Japanese Society of Hypertension 2009 guideline could not be achieved with standard-dose ARB therapy and amlodipine (5 mg). Patients: Patients were divided into three groups. Group-1 was switched to a combination of irbesartan (100 mg) and amlodipine (10 mg). Group‐2A was changed to a combination of irbesartan (100 mg), amlodipine (5 mg), and indapamide, while Group-2B received a standard-dose ARB and amlodipine (5 mg) plus indapamide. Patients were assigned by their attending physicians and were followed for 6 months. The primary endpoint was the antihypertensive effect of each regimen. Results: Group‐1 contained 85 patients, Group‐2A had 49 patients, and Group‐2B had 4 patients. We only analyzed Group‐1 and Group‐2A due to the small size of Group‐2B. In both groups, systolic BP and diastolic BP were significantly decreased up to 6 months (all p < 0.001). Reduction of systolic BP was greater in Group-1 than Group‐2A after 1 month and 6 months (both p < 0.05). Uric acid was increased in Group‐2A after 3 months, but not at 6 months. Conclusion: Although both regimens were effective for reducing BP, increasing amlodipine to 10 mg daily controlled hypertension without elevation of serum uric acid.

High-throughput quantification of 8 antihypertensive drugs and active metabolites in human plasma using UPLC-MS/MS.

To assess drug adherence of patients with hypertension, an analytical method was developed and validated using ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). The method includes eight frequently prescribed antihypertensive drugs from four classes and their active metabolites: angiotensin converting enzyme inhibitors enalapril and perindopril (active metabolites respectively enalaprilate and perindoprilate), angiotensin II receptor blockers losartan (with the active metabolite losartan carboxylic acid) and valsartan, calcium channel blockers amlodipine and nifedipine and diuretics hydrochlorothiazide and spironolactone (with the active metabolite canrenone). The antihypertensive drugs were analyzed using a simple and fast sample preparation protocol with protein precipitation followed by chromatographic separation using a gradient elution on a reversed phase column. Mass spectrometric detection was conducted by applying both positive and negative electrospray ionization (ESI+/ESI-) and selected reaction monitoring mode (MS/MS). Only 50μl of plasma sample is needed for the simultaneous quantification of all 12 compounds within 6min run-to-run analysis time. Enalapril-d5 was applied as internal standard for all compounds except hydrochlorothiazide (internal standard: Hydrochlorothiazide-13C,d2). The method was validated according to FDA guidelines. Matrix effects were examined using the method of Matuszewski. Correlation coefficients were higher than 0.995 for all compounds. Intra- and inter-day accuracies were <15% for all analytes except spironolactone (-16.8%) in the established linear range. Intra- and inter-day precision were <15% for all analytes. As a result of the lower sensitivity of hydrochlorothiazide, the lowest three calibration levels were excluded. The described method is suitable for the simultaneous quantitative analysis of the most commonly used antihypertensive drugs and their corresponding active metabolites. Major advantages are minimal sample volume and clean up and a short runtime. The method is now available to monitor drug adherence of patients with resistant hypertension in our hospital.

Triple Combination Therapies Based on Olmesartan: A Personalized Therapeutic Approach to Improve Blood Pressure Control.

Recent epidemiological surveys have demonstrated that effective and sustained blood pressure (BP) control is achieved in a relatively small proportion of treated hypertensive patients. Indeed, treatment of hypertension represents a key strategy for preventing coronary artery disease, stroke, congestive heart failure and cardiovascular death. Several interventions have been proposed by international guidelines for ameliorating hypertension management and control, mostly including integrated and multi-dimensional pharmacological and non-pharmacological strategies. In particular, numerous evidence demonstrated that a more extensive use of combination therapy may represent a valid therapeutic option for treating hypertensive patients at different risk profile. This strategy has been definitely strengthened by the availability of single pill fixed-dose combinations. Among potential combination therapies, those based on the association of renin-angiotensin system antagonists, thiazide diuretics and calcium channel blockers are very effective in lowering BP levels and well tolerated. We will provide here an overview of clinical evidence supporting the use of triple combination therapy, with a focus on that based on olmesartan medoxomil, a thiazide diuretic (hydrochlorothiazide) and a calcium channel blocker (amlodipine besylate), which is available in multiple dosages. Finally, in view of the recognised importance of single-pill combination therapy for treating hypertension, we will examine the potential benefits of dual (fixed) combination therapy based on olmesartan medoxomil with either thiazide diuretic hydrochlorothiazide or calcium channel blocker amlodipine in terms of efficacy, safety and tolerability profile.

Calcium channel blockers use and overall survival in pancreatic cancer patients receiving gemcitabine.

e15756 Background: Preclinical studies have shown that calcium channel blockers (CCB) may potentiate anticancer effect of chemotherapy via intra-cellular drug accumulation. Gemcitabine-based chemotherapy is commonly used in pancreatic cancer (PC) patients. The aim of this study was to determine whether CCB may affect overall survival (OS) in PC patients receiving gemcitabine-based chemotherapy. Methods: The retrospective cohort of PC patients treated with gemcitabine between 2007 and 2016 was identified in the Polish National Health Fund databases. Electronic records of prescriptions were searched to identify in this cohort patients receiving CCB (amlodipine, nitrendipine, felodipine, lacidipine). The primary endpoint was OS and it was determined by Kaplan-Meier methods and compared by the log-rank test. Results: In total 4628 PC patients treated with gemcitabine (median OS 7.7 months; 95% CI: 7.4-7.9) were identified. Among these 380 patients were prescribed any CCB. There was a significant difference (p &lt; 0.001) in median OS between patients prescribed CCB (n = 380; OS 9.3 months; 95% CI: 7.8-11.0) and those who did not (n = 4214; OS 7.6 months; 95% CI: 7.3-7.8) with hazard ratio for death 0.70 (95% CI: 0.62-0.79). Notably, the survival curves tended to flatten in CCB group, with 24% of patients alive at 2 years (95% CI: 20-29%) and 15% alive at 5 years (95% CI: 11-19%), compared with 11% (95% CI: 10-12%) and 4% (95% CI: 4-5%) in controls respectively. Conclusions: The use of CCB in PC patients receiving gemcitabine-based chemotherapy was associated with improved OS. Further validation is needed to evaluate effectiveness of CCB-gemcitabine combinations in the management of PC.