Combination Of Amlodipine Research Articles

Adherence to treatment in patients with arterial hypertension at the wartime conditions in Ukrainian population

Abstract Background Adherence to therapy significantly affects the course and prognosis of the disease. However, the impact of military operations and related factors on adherence to therapy has not been studied. Purpose The aim of the study was to evaluate additional factors influencing adherence to antihypertensive treatment in wartime. Materials and Methods A total of 1299 patients with arterial hypertension from different regions of Ukraine included into the study. All regions were divided into 3 zones: active hostilities; regions with moderate intensity; relatively calm regions. Besides traditional factors (age, education, concomitant pathology, type of therapy), the individual patients’ status was included to analysis as being a resident of a given region, an immigrant from an occupied territory or from a region of hostilities, or a person temporarily displaced. Analysis was performed in 4 treatment groups: 1 – fixed three-component combination olmesartan medoxomil/ amlodipine/ hydrochlorothiazide, 2 – fixed two-component combination olmesartan/ hydrochlorothiazide, 3 – fixed two-component therapy with olmesartan/ amlodipine, 4 - other antihypertensive therapy. Adherence was assessed at 1, 2 and 3 treatment months. Uni- and multivariate statistical analyses was performed to identify factors independently associated with treatment adherence. Results In total, 50 patients stopped the drug during the first month (3.8%), 9.8% stopped medication after 2 months, and 19.1% after 3 months. When analyzing patients' adherence depending on whether or not the doctor arrived from another region, we found that the percentage of patients who stopped treatment was almost twice higher if the doctor was displaced (32%), compared to doctors who remained in the places (18%). Based on results of comparative analysis, adherence to therapy was influenced by several factors: age, presence of concomitant coronary artery disease, staying in a high-risk region, number of pills, and prescribed drug. After 3 months adherence was 89% in patients who received 1 tablet per day, 84% - 2 tablets, 82% - 3-5 tablets, and 52% - more than 5 pills. The highest adherence was observed with the three-component pill and with combination of olmesartan and amlodipine. These combinations showed higher adherence compared to other types of therapy. Patient's level of education had no effect on adherence to therapy. Multivariate regression analysis showed, that age over 55 years (p=0.01) and patient’s being in dangerous area (p<0.0001) had significant independent negative influence on adherence. The use of two-component combination olmesartan/amlodipine or three-component therapy significantly increased adherence (p<0.0001). Conclusion In the wartime adherence to antihypertensive treatment depends both on previously known and specific factors - activity of hostilities in the region, as well as relocation of both patients and prescribing physicians to another region.

Efficacy and safety of a novel low-dose triple single-pill combination of telmisartan, amlodipine and indapamide, compared with dual combinations for treatment of hypertension: a randomised, double-blind, active-controlled, international clinical trial

Single-pill combinations (SPCs) of three low-dose antihypertensive drugs can improve hypertension control but are not widely available. A key issue for any combination product is the contribution of each component to efficacy and tolerability. This trial compared a new triple SPC called GMRx2, containing telmisartan, amlodipine, and indapamide, with dual combinations of components for efficacy and safety. In this international, randomised, double-blind, active-controlled trial, we enrolled adults with hypertension receiving between zero and three antihypertensive drugs, with a screening systolic blood pressure (SBP) ranging from 140-179 mm Hg (on no drugs) to 110-150 mm Hg (on three drugs). Participants were recruited from Australia, the Czech Republic, New Zealand, Poland, Sri Lanka, the UK, and the USA. In a 4-week active run-in, existing medications were switched to GMRx2 half dose (telmisartan 20 mg, amlodipine 2·5 mg, and indapamide 1·25 mg). Participants were then randomly allocated (2:1:1:1) to continued GMRx2 half dose or to each possible dual combination of components at half doses (telmisartan 20 mg with amlodipine 2·5 mg, telmisartan 20 mg with indapamide 1·25 mg, or amlodipine 2·5 mg with indapamide 1·25 mg). At week 6, doses were doubled in all groups, unless there was a clinical contraindication. The primary efficacy outcome was mean change in home SBP from baseline to week 12, and the primary safety outcome was withdrawal of treatment due to an adverse event from baseline to week 12. Secondary efficacy outcomes included differences in clinic and home blood pressure levels and control rates. This study is registered with ClinicalTrials.gov, NCT04518293, and is completed. The trial was conducted between July 9, 2021 and Sept 1, 2023. We randomly allocated 1385 participants to four groups: 551 to GMRx2, 276 to telmisartan-indapamide, 282 to telmisartan-amlodipine, and 276 to amlodipine-indapamide groups. The mean age was 59 years (SD 11), 712 (51%) participants self-reported as female and 673 (48·6%) male, and the mean clinic blood pressure at the screening visit was 142/85 mm Hg when taking an average of 1·6 blood pressure medications. Following the run-in on GMRx2 half dose, the mean clinic blood pressure level at randomisation was 133/81 mm Hg and the mean home blood pressure level was 129/78 mm Hg. At week 12, the mean home SBP was 126 mm Hg in the GMRx2 group, which was lower than for each of the dual combinations: -2·5 (95% CI -3·7 to -1·3, p<0·0001) versus telmisartan-indapamide, -5·4 (-6·8 to -4·1, p<0·0001) versus telmisartan-amlodipine, and -4·4 (-5·8 to -3·1, p<0·0001) versus amlodipine-indapamide. For the same comparisons, differences in clinic blood pressure at week 12 were 4·3/3·5 mm Hg, 5·6/3·7 mm Hg, and 6·3/4·5 mm Hg (all p<0·001). Clinic blood pressure control rate below 140/90 mm Hg at week 12 was superior with GMRx2 (74%) to with each dual combination (range 53-61%). Withdrawal of treatment due to adverse events occurred in 11 (2%) participants in the GMRx2 group, four (1%) in telmisartan-indapamide, three (1%) in telmisartan-amlodipine, and four (1%) in amlodipine-indapamide, with none of the differences being statistically significant. A novel low-dose SPC product of telmisartan, amlodipine, and indapamide provided clinically meaningful improvements in blood pressure reduction compared with dual combinations and was well tolerated. This SPC provides a new therapeutic option for the management of hypertension and its use could result in a substantial improvement in blood pressure control in clinical practice. George Medicines.

Phase III randomized clinical trial of efficacy and safety of amlodipine and candesartan cilexetil combination for hypertension treatment

Effective antihypertensive therapy is essential for achieving optimal blood pressure (BP) control and reducing cardiovascular events. This double-blind, multicenter, randomized trial aimed to compare the antihypertensive efficacy and safety of a combination of amlodipine (AML) and candesartan cilexetil (CC) versus AML monotherapy in patients with essential hypertension (HTN). After a 4-week run-in period with AML 5 mg, patients whose HTN remained uncontrolled (diastolic BP [DBP]) ≥ 90 mmHg and < 120 mmHg) were randomized to receive either AML + CC or AML alone for 8 weeks. Efficacy was assessed by measuring changes in DBP and systolic BP (SBP). The primary safety measure was the incidence of adverse events (AEs). A total of 174 participants were included in the efficacy analysis. After 8 weeks, DBP decreased by -9.92 ± 0.86 mmHg in the AML + CC arm and - 2.08 ± 0.86 mmHg in the AML arm (p < 0.0001). SBP decreased by -14.27 ± 1.39 mmHg in the AML + CC arm versus - 2.77 ± 1.39 mmHg in the AML arm (p < 0.0001). AEs occurred in 11.24% of the AML + CC group and 5.62% of the AML group (p = 0.1773). AML + CC combination therapy demonstrated superior efficacy with good tolerance, making it a promising option for patients with inadequately controlled hypertension on amlodipine alone.

Attenuation of L-NAME-induced Hypertension in Rats with Elettaria cardamomum–Low-dose Amlodipine Combination: A Possible Synergism of Covasodilatory Effect

Background Hypertension is a prevalent chronic disorder that affects approximately 1.28 billion adults worldwide. In the use of amlodipine, though it is a cost-effective antihypertensive agent, it causes side effect that may lead to discontinuation of the medication. Purpose To examine the effect of the combination of Elettaria cardamomum plus a low dose of amlodipine on Nω-nitro-l-arginine methyl ester (L-NAME)-induced hypertensive rat model. Materials and Methods Thirty adult male Wistar rats were randomized into five groups of six rats, respectively. The standard control group received only normal saline (first group). The other four groups received L-NAME (40 mg/kg/day, orally) for 21 days as follows: Group 2 served as L-NAME group only; Group 3 was given E. cardamomum (400 mg/kg/day, orally); Group 4 received amlodipine (5 mg/kg/day, orally); Group 5 received E. cardamomum (400 mg/kg/day, orally) + a low dose of amlodipine (2.5 mg/kg/day, orally) and served as the combination treatment group. Twenty-four hours after the last treatment, blood pressure was measured, then blood samples were collected, rats were sacrificed, and hearts and kidneys were harvested. Serum levels of lipids, liver enzymes, urea, and creatinine were determined. Results L-NAME administration induced a notable increase in systolic, diastolic, and mean arterial blood pressure, with significant changes in biochemical parameters. However, administration of E. cardamomum alone or in combination with a low dose of amlodipine showed a better reduction in systolic and diastolic blood pressure than amlodipine alone. Consequently, effects on liver enzymes, lipid profile, and cardiorenal pathology were significantly improved with combination treatment compared with amlodipine alone. Conclusion The present study has shown that the E. cardamomum–low-dose amlodipine combination could be beneficial in lowering blood pressure without the attendant adverse effects associated with the normal dose of amlodipine alone. This could be due to covasorelaxant effects.

O92 EFFICACY AND SAFETY OF LOW-DOSE ANTIHYPERTENSIVE COMBINATION DRUGS INCLUDING AMLODIPINE, TELMISARTAN, AND CHLORTHALIDONE: A MULTICENTER, RANDOMIZED, DOUBLE-BLINDED, PARALLEL, PHASE II CLINICAL TRIAL

Background and Objective: Although single pill high-dose triple antihypertensive combinations are already available on South Korea, there are no reports evaluating the efficacy and safety of the low-dose combination of amlodipine, telmisartan, and chlorthalidone. The aim of this clinical trial was to assess the efficacy and safety of low-dose combination drug containing telmisartan (20 mg), amlodipine (2.5 mg), and chlorthalidone (6.25 mg). Methods: This study was a randomized, double-blinded, parallel, multicenter, phase II clinical trial. In total, 221 subjects from 21 clinical trial sites in South Korea were randomly assigned to groups 1 (AD-209; telmisartan 20 mg/amlodipine 2.5 mg/chlorthalidone 6.25 mg), 2 (AD-209-1A; telmisartan 20 mg/amlodipine 2.5 mg), 3 (AD-209-1B; amlodipine 2.5 mg/chlorthalidone 6.25 mg), and 4 (AD-209-1C; telmisartan 20 mg/chlorthalidone 6.25 mg) in a 1:1:1:1 ratio, and the treatments lasted 8 weeks. After the initial drug administration, the subjects visited the clinical trial sites at weeks 4 and 8 to evaluate drug efficacy and safety. Results: In patients with mild-moderate hypertension, the mean change in MSSBP from baseline to week 8 between group 1 and groups 2, 3, and 4 was -5.93, -8.69, and -1.51 mmHg, respectively. The blood pressure of the subjects in group 1 was significantly lower than that of those in groups 2 and 3. It was also lower than that of subjects in group 4 although this difference was not significant. Among the 221 subjects enrolled, 20 (9.05%) experienced 25 treatment-emergent adverse events (TEAEs); of these, 14 (6.33%) experienced 17 adverse drug reactions (ADRs). No significant differences in the TEAE or ADR incidence rates were found between group 1 and groups 2, 3, and 4. Conclusions: AD-209 (telmisartan 20 mg/amlodipine 2.5 mg/chlorthalidone 6.25 mg), a low-dose triple combination drug, demonstrated a higher blood pressure lowering effect than the corresponding a low-dose dual combination drugs in patients with essential hypertension. Its safety was similar to that of the dual-combination drugs.

Abstract 28: A major effect of aprocitentan on albuminuria in patients with resistant hypertension

Background and Objectives: Micro- and macroalbuminuria measured by urinary albumin-to-creatinine ratio (UACR) (30–300 mg/g and &gt;300 mg/g, respectively), and high normal UACR (10–30 mg/g) are associated with higher risk of mortality, CV disease and CKD progression in patients with hypertension, diabetes, decreased renal function, or even the general population and reduction can lower these risks. The endothelin ETA/ETB receptor antagonist aprocitentan reduced albuminuria in patients with confirmed resistant hypertension (RHT). In the PRECISION trial, in addition to standard background therapy including valsartan, aprocitentan 12.5 mg reduced UACR by 30% compared to placebo (LS Geom Mean [95 CL] 0.70 [0.61, 0.80], p&lt;0.0001) and 25 mg by 34% (0.66 [0.58,0.75], p&lt;0.0001) at the end of double-blind part 1 (4 weeks) in the overall population. In this analysis, we evaluated the effect of aprocitentan on UACR at both doses according to the baseline (BL) albuminuria (30–300 mg/g and &gt;300 mg/g). Methods: 730 patients with RHT on a standardized fixed-dose combination of amlodipine/ valsartan/hydrochlorothiazide were randomized to aprocitentan (12.5 mg or 25 mg) or placebo. Of these, 174 and 90 had BL microalbuminuria or macroalbuminuria, respectively. Changes from BL in UACR and office systolic blood pressure measured at trough (SBP, the primary endpoint in PRECISION) after 4 weeks of double-blind treatment. Results: In subjects with microalbuminuria, aprocitentan reduced UACR by 43% in the 12.5 mg group (0.57 [0.42, 0.78], p=0.0005) and by 45% in the 25 mg group (0.55 [0.40,0.77], p=0.0004) compared to placebo. In subjects with macroalbuminuria, aprocitentan reduced UACR by 48% with 12.5 mg (0.52 [0.37, 0.75], p=0.0006) and by 61% with 25 mg (0.39 [0.27,0.57], p&lt;0.0001) compared to placebo. In contrast, placebo did not have any noticeable effect on albuminuria in any group. The effect of aprocitentan in lowering blood pressure, measured at trough, was independent of the level of albuminuria at baseline. After 4 weeks, 53.3% and 60% of patients achieved a decrease of ≥10 mmHg from baseline with 12.5 mg aprocitentan, respectively in the microalbuminuria and macroalbuminuria groups, compared to 64% with aprocitentan 25 mg (both cohorts) and 48% and 29% in the placebo group. Conclusion: Aprocitentan produced a major decrease of albuminuria regardless of baseline level in patients with RHT. These findings suggest substantial clinical benefit of aprocitentan in CKD patients.

Single-Pill Combination Therapy of Amlodipine, Telmisartan, and Chlorthalidone in the Management of Hypertension: A Systematic Review of Randomized Controlled Trials.

Hypertension is a major cause of cardiovascular disease and death worldwide. Low-dose combination therapy is a promising approach for managing hypertension due to its safety and efficacy. This systematic review evaluates the safety and efficacy of a single-pill, low-dose combination of amlodipine, telmisartan, and chlorthalidone for essential hypertension based on evidence from randomized controlled trials (RCTs). We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and searched the Cochrane, Scopus, PubMed, and Web of Science databases until July 01, 2024, using the following search string: (telmisartan) AND (amlodipine) AND (chlorthalidone) AND (randomized OR randomly). The quality of the RCTs was assessed using the revised Cochrane risk of bias tool. The primary endpoint was the mean change in sitting systolic blood pressure (BP), with secondary endpoints including BP target achievement rates, BP response rates, and serious treatment-related adverse events. Overall, three RCTs met the inclusion criteria and exhibited a low risk of bias. The doses in the combination pill ranged from 2.5 to 5 mg of amlodipine, 20 to 80 mg of telmisartan, and 4.167 to 25 mg of chlorthalidone. Control groups varied, including usual care, amlodipine 10 mg, and dual therapy of telmisartan and amlodipine. Results showed significant reductions in mean sitting systolic and diastolic BP, improved BP control and response rates, and a generally safe profile with no significant differences in serious adverse events. Despite encouraging data, results should be interpreted with caution due to heterogeneity in doses and control groups. Further research should address the long-term effects and explore predictors of response to this therapy.

Pooled analysis of the three trials of the TRIUMF series: efficacy of a triple fixed combination of antihypertensive drugs in the practice of physicians of different specialties in Ukraine

Study objectives – to compare the data obtained in the TRIUMF (antihyperTensive theRapy in UkraIne – BP optiMization in Focus) trials, in particular, TRIUMF-1, TRIUMF-2, TRIUMF-3, to determine possible patterns and significant factors affecting BP control in patients taking 2 or more antihypertensive drugs and switching to the original single pill combination (SPC) of perindopril arginine/indapamide/amlodipine.Materials and Methods. For the pooled analysis, data on 5960 patients obtained from the three trials of the TRIUMF series were selected. All the studies were multicenter prospective trials conducted at different times in Ukraine with the involvement of general practitioners (TR-1), cardiologists (TR-2), and family practitioners (TR-3). According to the inclusion criteria, patients over 18 years of age with hypertension and a history of taking 2 or 3 antihypertensive drugs for at least 1 month whose BP remained above 140/90 mm Hg could be included in the study. The drug of choice for further therapy was Triplixam (Servier, France) – a single pill combination (SPC) of perindopril arginine, amlodipine and indapamide. Each patient was observed for 3 months. Patients visited physicians in 1–2 weeks, 2 months after the start of the study and the corresponding therapy adjustment. The adherence rate was assessed before and after 2 months. The use of beta-blockers (BBs) in the treatment of the cohort of patients with hypertension was analyzed separately. The final analysis included a comparison of the data obtained in the TRIUMF trial series.Results and Discussion. The use of a SPC of perindopril arginine/indapamide/amlodipine allowed to achieve the target BP levels (140/90 or less) after 2 months of therapy in 84 % of patients with a history of taking a combination therapy (2 drugs – 65 %, 3 drugs – 35 %). One of the important criteria for choosing the dose of a triple SPC is the baseline BP values. The higher the degree of hypertension, the higher the dose prescribed by physicians. The minimum dose of the SPC of perindopril arginine, indapamide and amlodipine (5/1.25/5 mg) was prescribed for stage 1 hypertension in 62 %, stage 2 hypertension in 38 %, and stage 3 hypertension in 15 % of patients; the maximum dose (10/2.5/10 mg) was prescribed for stage 1 hypertension in 9 %, stage 2 hypertension in 15 %, and stage 3 hypertension in 43 % of patients included in the study (p&lt;0.05). Therapy with the triple SPC of perindopril arginine, indapamide and amlodipine was well tolerated: adverse events were observed in 0.63 % (TR-1), 1 % (TR-3) and 1.86 % (TR-2) of cases, which was largely due to the previous use of two (65 %) or three (35 %) antihypertensive drugs comprising the SPC by the study patients. Beta-blockers (n=2012) were prescribed due to the presence of a comorbidity (coronary heart disease, angina pectoris – 33.5 %, heart failure – 28.3 %) rather than due to lowered BP. The combination of perindopril arginine/indapamide/amlodipine with BB was well tolerated and 83.9 % of patients achieved BP ≤ 140/90 mm Hg, while 9.36 % achieved ≤ 130/80 mm Hg after 2 months of treatment. There was a significant improvement in the adherence to treatment (TR-2, TR-3) in the majority of patients (75 and 70 %), due to high antihypertensive efficacy, convenience of pill’s administration (one pill instead of three) and good tolerability of the original SPC.Conclusions. Regular medical supervision (cardiologists, family practitioners, general practitioners), high antihypertensive efficacy of the SPC (84 % of patients reached the target BP levels after 2 months of therapy ), convenience of pill’s administration (one pill instead of three), high adherence to treatment confirmed in TR-2 and TR-3 in most patients, and good tolerability of the original SPC of perindopril arginine, indapamide and amlodipine led to a significant improvement in the effectiveness of treatment of patients with hypertension.

Low-Dose Triple-Pill vs Standard-Care Protocols for Hypertension Treatment in Nigeria

With the high burden of hypertension in sub-Saharan Africa, there is a need for effective, safe and scalable treatment strategies. To compare, among Black African adults, the effectiveness and safety of a novel low-dose triple-pill protocol compared with a standard-care protocol for blood pressure lowering. Randomized, parallel-group, open-label, multicenter trial conducted in public hospital-based family medicine clinics in Nigeria. Black African adults with uncontrolled hypertension (≥140/90 mm Hg) who were untreated or receiving a single blood pressure-lowering drug. Participants were randomly allocated to low-dose triple-pill or standard-care protocols. The triple-pill protocol involved a novel combination of telmisartan, amlodipine, and indapamide in triple one-quarter, one-half, and standard doses (ie, 10/1.25/0.625 mg, 20/2.5/1.25 mg, and 40/5/2.5 mg), with accelerated up-titration. The standard-care protocol was the Nigeria hypertension treatment protocol starting with amlodipine (5 mg). The primary effectiveness outcome was the reduction in home mean systolic blood pressure, and the primary safety outcome was discontinuation of trial treatment due to adverse events, both from randomization to month 6. The first participant was randomized on July 19, 2022, and the last follow-up visit was on July 18, 2024. Among 300 randomized participants (54% female; mean age, 52 years; baseline mean home blood pressure, 151/97 mm Hg; and clinic blood pressure, 156/97 mm Hg), 273 (91%) completed the trial. At month 6, mean home systolic blood pressure was on average 31 mm Hg (95% CI, 28 to 33 mm Hg) lower in the triple-pill protocol group and 26 mm Hg (95% CI, 22 to 28 mm Hg) lower in the standard-care protocol group (adjusted difference, -5.8 mm Hg [95% CI, -8.0 to -3.6]; P < .001]). At month 6, clinic blood pressure control (<140/90 mm Hg) was 82% vs 72% (risk difference, 10% [95% CI, -2% to 20%]) and home blood pressure control (<130/80 mm Hg) was 62% vs 28% (risk difference, 33% [95% CI, 22% to 44%]) in the triple-pill compared with the standard-care protocol group; these were 2 of 21 prespecified secondary effectiveness end points. No participants discontinued trial treatment due to adverse events. Among Black African adults with uncontrolled hypertension, a low-dose triple-pill protocol achieved better blood pressure lowering and control with good tolerability compared with the standard-care protocol. Pan African Clinical Trials Registry Identifier: PACTR202107579572114.

Formulation and physicotechnical evaluation of a fixed dose combination of amlodipine, metformin and glibenclamide in the management of hypertension-diabetes mellitus comorbidity

The concept of fixed dose combination (FDC) dates as far back as the early 17th century and still finds relevance till today. Almost every disease condition has at least one approved FDC commercially available for its treatment. The prevalence of hypertension-diabetes mellitus (HTN-DM) comorbidity is high globally. However, there are no available FDC formulation approved to be used in managing patients with this comorbidity. This study was designed to fill this gap by formulating an FDC of Amlodipine (antihypertensive), Metformin (antidiabetic) and Glibenclamide (antidiabetic), which are already being used clinically as monotherapies in management of HTN-DM comorbid patients. The APIs were granulated using wet granulation method with the aid of the excipients, after which the granules properties were examined and subsequently compressed into tablets. The physicotechnical properties and in-vitro release profile were evaluated on the tablets. The results of granule properties such as angle of repose (22.8o), Hausner ratio (1.16) and Carr’s compressibility index (13) for the 8% binder batch show excellent flow properties and is indicative of forming tablets with good qualities. “8% binder” tablets batch has the following properties; hardness (kgF), friability (0.55%), disintegration time (220 secs), all within the acceptable official requirements. The release profile showed that the drugs were bioavailable from the tablets in good time. It can be concluded that the formulation of an FDC for HTN-DM comorbidity was a success and studies to confirm the compatibility of the APIs and excipients are recommended.

Sequential Administration of Febuxostat, Amlodipine and Vitamin E Attenuate Oxidative Stress and Improve Spermatogenesis in Testicular Ischemia Reperfusion Injury in Wistar Rats

This study investigated the effects of sequential administration of febuxostat, amlodipine, and vitamin E on oxidative stress and spermatogenesis following testicular ischemia-reperfusion injury (TIRI) in Wistar rats. Ninety male rats (120-150 g) were divided into 9 groups (n=10 each): sham operation (SO), torsion-detorsion (TD), and seven treatment groups receiving different combinations of the drugs. The treatment groups included torsion + febuxostat + detorsion (TFD), torsion + detorsion + amlodipine (TDA), torsion + detorsion + vitamin E (TDV), and combinations thereof (TFDA, TFDV, TDAV, TFDAV). TIRI was induced by 720° clockwise testicular torsion for 1 hour followed by detorsion. Febuxostat (5 mg/kg) was administered 30 minutes after torsion, amlodipine (2.5 mg/kg) immediately upon detorsion, and vitamin E (10 mg/kg) 30 minutes after detorsion. Rats were sacrificed 56 days post-reperfusion. Testicular tissue was analyzed for antioxidant enzymes (superoxide dismutase, catalase), lipid peroxidation (malondialdehyde), total protein, inflammatory markers (serum nitrite, IL-1β), and spermatogenesis indices (testicular biopsy score, Leydig cell count). Results showed that TIRI significantly decreased antioxidant enzymes, significantly increased lipid peroxidation and inflammatory markers, and impaired spermatogenesis. In the TD group, superoxide dismutase (SOD) and catalase (CAT) activities were significantly decreased, while malondialdehyde (MDA) increased significantly compared to the SO group (p&lt;0.01). Serum nitrite and IL-1β levels in the TD group were also increased (p&lt;0.001). Furthermore, the testicular biopsy score and Leydig cell count in the TD group were significantly decreased in this study (p&lt;0.01). Sequential administration of febuxostat, amlodipine and vitamin E, particularly when all three were used (TFDAV group), significantly attenuated these changes. In the TFDAV group, SOD and CAT activities were improved, while MDA decreased compared to the TD group (p&lt;0.05). Serum nitrite and IL-1β levels in the TFDAV group were also decreased (p&lt;0.001). In addition, the testicular biopsy score and Leydig cell count in the TFDAV group increased in comparison with the TD group (p&lt;0.001). The study concludes that this sequential multi-drug approach shows promise in mitigating the long-term detrimental effects of TIRI on testicular function and fertility. The combination of febuxostat (a xanthine oxidase inhibitor), amlodipine (a calcium channel blocker), and vitamin E (an antioxidant) appears to provide protection against oxidative stress and inflammation induced by TIRI, thereby preserving spermatogenesis.

Amlodipine-Candesartan Combination: A Cost-Effective Strategy for Successful Therapy of Hypertension

Introduction: The combination of amlodipine and candesartan can have a better effect, although the cost-effectiveness analysis was not yet determined. This research aimed to establish the Incremental Cost-Effectiveness Ratio (ICER) value among outpatients with hypertension who used amlodipine-candesartan. Method: This research is a descriptive study that retrospectively gathered data from medical records. It focused on information for hypertensive patients at Universitas Andalas Hospital in 2021. This study compared the standard treatment involving amlodipine-candesartan and sole amlodipine, next to calculate the ICER using cost-effectiveness analysis. Results: Out of the total population of 284, as many as 73 patients were involved in this study. Among these, 21 patients (28.77%) were treated with amlodipine alone, while 52 (71.23%) received an amlodipine-candesartan combination. The Incremental Cost-Effectiveness Ratio (ICER) for reducing systolic blood pressure was IDR 74,738.10 per one mmHg decrease in the northeast quadrant of the cost-effectiveness chart. The ICER for lowering diastolic blood pressure was IDR 205,918.24 per one mmHg decrease in the northeast quadrant on the cost-effectiveness chart. Conclusion: The cost of the amlodipine-candesartan combination yields superior effects; however, warranting a probabilistic sensitivity analysis to determine its ICER robustness is essential for its effective implementation

Efficacy of combined antihypertensive therapy in patients with type 2 diabetes mellitus and non-alcoholic fatty liver disease with various polymorphisms of the CYP2C9 gene

Background. The difficulty of achieving target blood pressure (BP) levels in patients with arterial hypertension (AH) is often due to their type 2 diabetes mellitus (T2DM) and non-alcoholic fatty liver disease (NAFLD). In turn, taking into account the individual genetic characteristics of the body helps to personalize treatment and make it more effective. Aim. To compare the antihypertensive efficacy of a fixed combination of amlodipine and olmesartan medoxomil (Aml/Ol-M) in patients with hypertension and T2DM, with and without NAFLD, depending on the polymorphism of the CYP2C9 gene. Materials and methods. The study included 139 patients with uncontrolled hypertension and concomitant T2DM; after diagnosis of NAFLD, they were randomized into 2 groups: without NAFLD (group 1, n=70), with NAFLD (group 2, n = 69). After discontinuation of previous ineffective antihypertensive therapy, they were prescribed a combination of Aml/Ol-M in doses of 5-10/20-40 mg/day. At baseline, 4, 8, 12 and 24 weeks, their office BP levels were determined; Also, at the initial visit and after 24 weeks of treatment, the main indicators of 24-hour blood pressure monitoring (ABPM) were measured. Patients who did not reach the blood pressure target within 12 weeks of therapy were excluded from the study. Those who continued to participate in the amplifierThe Rotor Gene-Q allele discrimination method revealed the following distribution of polymorphic variants of the CYP2C9 gene: *1/*1 was found in 52 and 47, *1/*2 – in 6 and 5, *1/*3 – in 5 and 6 subjects, for groups 1 and 2, respectively. Results. The initial levels of office BP values were significantly higher in patients of group 2 and amounted to 153,5 mm Hg for systolic and 93 mm Hg for diastolic blood pressure, compared with 145 mm Hg and 88 mm Hg those included in group 1. After 12 weeks of therapy, the achievement of target blood pressure was registered in 63 (90 %) patients of group 1 and in 58 (84,1 %) of group 2. After 24 weeks of observation, in both groups a beneficial effect of the studied combination of drugs on all indicators of ABPM was noted, but a more pronounced improvement was noted in patients with NAFLD. Along with this, significant improvements in daily blood pressure profiles were registered in both groups 1 and 2: an increase in the number of patients with the “dipper” profile and a decrease in the number of patients with the pathological “non-dipper” profile. The antihypertensive effectiveness of Aml/Ol-M has been demonstrated for all isolated allelic variants of the CYP2C9 gene. Conclusions. A 24-week study with the use of Aml/Ol-M demonstrated a high incidence of achieving office BP target values in patients with hypertension and T2DM, with and without NAFLD. However, a more pronounced decrease in ABPM levels was found in patients with NAFLD. Carriage of any of the identified polymorphic gene variantsCYP2C9 had no effect on the clinical effects of the studied combination.

Development and Validation of Ultra-Performance Liquid Chromatography (UPLC) Method for Simultaneous Quantification of Hydrochlorothiazide, Amlodipine Besylate, and Valsartan in Marketed Fixed-Dose Combination Tablet

Fixed-dose combination therapy is considered a practical approach in the treatment of various diseases, as it can simultaneously target different mechanisms of action that achieve the required therapeutic efficacy through a synergistic effect. A combination of hydrochlorothiazide (HTZ), amlodipine (AMD), and valsartan (VLS) has been created for the treatment of hypertension. Therefore, the aim of this study was to develop an optimized UPLC method for the simultaneous quantification of this combination. A DoE at a level of 32 was used to investigate the effects of column temperature (20, 30, and 40 °C) and formic acid concentration (0.05, 0.15, and 0.25%) on the retention time of each active pharmaceutical ingredient (API), the peak area, and the peak symmetry, as well as the resolution between HTZ-AMD and AMD-VLS peaks. The optimized analytical method was validated and used to extract the three APIs from the marketed product. The optimized analytical condition with a column temperature of 27.86 °C and a formic acid concentration of 0.172% showed good separation of the three APIs in 1.62 ± 0.006, 3.59 ± 0.002, and 3.94 ± 0.002 min for HTZ, AMD, and VST, respectively. The developed method was linear with the LOQ for a HTC, AMD, and VST of 0.028, 0.038, and 0.101 ppm, respectively. Moreover, the developed assay was sustainable and robust, with an RSD % of less than 2%. The application of this method in the extraction of HTZ, AMD, and VST from the Exforge® marketed product showed good separation with a measurable drug content of 23.5 ± 0.7, 9.68 ± 0.1, and 165.2 ± 5.2 mg compared to the label claims of 25/10/160 for HTZ, AMD, and VST, respectively.

Clinical Effectiveness of the Fixed‐Dose vs Free‐Dose Triple Combinations in Patients with Uncontrolled Arterial Hypertension

Background: The purpose of our study was a comparative assessment of the antihypertensive effectiveness of 2 triple combination antihypertensive therapy (AHT) regimens in a free-dose and fixed-dose combination of perindopril, indapamide, and amlodipine in hypertensive patients with high cardiovascular risk and a poor response to the 2-drug combinations in the clinic practice. Methods and Results: Our study included 143 patients (79 men and 88 women) with arterial hypertension (AH) Grades 1-3 (ESC/ESH, 2018) and high cardiovascular risk who did not achieve the target blood pressure (TBP) on dual combination AHT. The mean age of patients was 55.76±9.35 years; the average duration of AH was 10.69±6.61 years. All patients underwent the examinations according to the 2018 ESC/ESH Guidelines for the management of arterial hypertension. Patients included in the study were divided into 2 groups using the envelope method: Group 1 (n=84) received a fixed-dose, triple combination of perindopril, indapamide, and amlodipine; Group 2 (n=83) received a free-dose combination of these drugs. In both groups, treatment began after discontinuation of previous therapy, with a low dose of a triple combination of antihypertensive drugs (perindopril [5 mg/day], indapamide [1.25 mg/day], amlodipine [5 mg/day]) in the form of a fixed or free combination. The initial doses of perindopril/indapamide/amlodipine in both groups were not statistically different: 6.9±2.4/1.74±0.6/7.1±2.4mg/day in Group 1 and 6.9±2.7/1.95±0.6/7.1±2.5 mg/day in Group 2. After 4 weeks of therapy, if necessary, the doses of drugs were increased, starting with perindopril; the next adjustment of drug doses was carried out after 12 weeks of therapy. The final treatment results were determined after 24 weeks of AHT. Target blood pressure (TBP) of &lt;140/90 mmHg was reached by 94.4% of patients in Group 1 and 83.3% in Group 2 (χ²=7.471, Р=0,006); TBP of &lt;130/80 mmHg was reached by 70% of patients in Group 1 and 42% in Group 2 (χ²=11.61, Р=0,0001). A significant improvement in the diurnal BP profile was also revealed during treatment. According to ABPM data, both groups achieved TBP in terms of the average 24-h and average daytime systolic blood pressure (SBP) and diastolic blood pressure (DBP). Regarding average nighttime SBP and DBP and normalization of average nighttime diastolic blood pressure variability, target values were achieved only in Group 1(P=0.028). In both groups, 24-week triple-combination therapy led to a significant decrease in central SBP, central DBP, and pulse wave velocity (PWV). At the same time, the positive dynamics of central SBP were more pronounced in Group 1 than in Group 2 (Table 4), and PWV in Group 1 reached standard values. Conclusion: The results of our study showed that in the treatment of uncontrolled hypertension on previous therapy in AH patients with high cardiovascular risk, a single-pill triple combination of the ACEI perindopril, the CCB amlodipine, and the thiazide-like diuretic indapamide contributed to the effective daily blood pressure control, the improvement of diurnal blood pressure profile, and a positive effect on central blood pressure and PWV, thereby having a positive impact on the prognosis and quality of life of AH patients with high cardiovascular risk.

Modern Fixed Combinations in the Correction of Arterial Hypertension and Dyslipidemia

Based on a clinical case report, the article shows the individual selection of effective therapy for a patient with arterial hypertension and dyslipidemia. Taking into account the risk factors for cardiovascular diseases, Equamer® was selected as a fixed combination of amlodipine + lisinopril + rosuvastatin capsules 10 mg+20 mg+10 mg (Gedeon Richter Plc, Budapest, Hungary). In the patient with hypertension, ischemic heart disease was verified, and stenting of the anterior descending artery was performed. According to the clinical guidelines, when arterial hypertension is associated with ischemic heart disease, the drug therapy of choice should be a combination of dihydropyridine slow calcium channel blockers with an angiotensin-converting enzyme inhibitor. The fixed triple combination of amlodipine, lisinopril, and rosuvastatin is one of the most appropriate in this clinical situation; this combination targets the two major risk factors for cardiovascular diseases, arterial hypertension and dyslipidemia.

Effect of antihypertensive agents on sleep apnea and ambulatory blood pressure in patients with hypertension: A randomized controlled trial

BackgroundObstructive sleep apnea (OSA) and hypertension are common conditions that may be linked through sympathetic activation and water retention. We hypothesized that diuretics, which reduce the body water content, may be more effective than amlodipine, a blood pressure (BP)-lowering agent implicated with edema, in controlling OSA in patients with hypertension. We also aimed to compare the effects of these treatments on ambulatory blood pressure monitoring (ABPM). MethodsIn a randomized, double-blind clinical trial, we compared the effects of chlorthalidone/amiloride 25/5 mg with amlodipine 10 mg on OSA measured by portable sleep monitor and BP measured by ABPM. The study included participants older than 40 who had moderate OSA (10–40 apneas/hour of sleep) and BP within the systolic range of 140–159 mmHg or diastolic range of 90–99 mmHg. ResultsThe individuals in the experimental groups were comparable in age, gender, and other relevant characteristics. Neither the combination of diuretics nor amlodipine alone reduced the AHI after 8 weeks of treatment (AHI 26.3 with diuretics and 25.0 with amlodipine. P = 0.713). Both treatments significantly lowered office, 24-h, and nighttime ABP, but the two groups had no significant difference. ConclusionChlorthalidone associated with amiloride and amlodipine are ineffective in decreasing the frequency of sleep apnea episodes in patients with moderate OSA and hypertension. Both treatments have comparable effects in lowering both office and ambulatory blood pressure. The notion that treatments could offer benefits for both OSA and hypertension remains to be demonstrated. Trial registration clinicaltrials. gov identifierNCT01896661.

Cost-effective analysis of enalapril, amlodipine, and enalapril plus amlodipine combination in newly diagnosed patients of hypertension: A pharmacoeconomic comparison of the antihypertensive efficacy of drugs

Hypertension (HTN) is a chronic condition with severe complications, so early detection and effective management are essential to prevent cardiovascular events and reduce the associated economic burden. This study aims to compare the cost-effectiveness of enalapril, amlodipine, and their combination in terms of blood pressure reduction, considering overall efficacy and economic implications. A prospective, observational cost-effectiveness analysis was conducted in 150 newly diagnosed hypertensive patients who were prescribed either enalapril (5 mg), amlodipine (5 mg), or enalapril plus amlodipine (2.5 mg each). The primary outcome was the difference in systolic and diastolic blood pressure between baseline and follow-up, as well as the evaluation of overall efficacy and cost. Based on the data, statistical analysis was carried out using ANOVA and post hoc Tukey tests for drug efficacy, and cost-effectiveness was compared using MS Excel. After 30 days, all treatments significantly reduced systolic and diastolic blood pressure (p = 0.0001). The combination therapy with a lower dose showed superior efficacy in blood pressure reduction and was most cost-effective, requiring less expense for a 1 mmHg reduction in blood pressure compared to individual drugs with a higher dose. Quality of life assessment favored low-dose combination therapy, with fewer reported adverse effects. The combinationof amlodipine and enalapril at a lower dose demonstrated superior cost-effectiveness, efficacy in blood pressure reduction, and a favorable impact on patients' quality of life compared to individual drugs at a higher dose. This suggests that combination therapy may be a preferred option in the management of hypertension, emphasizing the importance of considering both clinical and economic factors in treatment decisions.

The Efficacy and Tolerability of Irbesartan/Amlodipine Combination Therapy in Patients With Essential Hypertension Whose Blood Pressure Were not Controlled by Irbesartan Monotherapy

PurposeThis study aimed to evaluate the efficacy and tolerability of irbesartan (IRB) and amlodipine (AML) combination therapy in patients with essential hypertension whose blood pressure (BP) was not controlled by IRB monotherapy. MethodsTwo multicenter, randomized, double-blind, placebo-controlled, phase III studies were conducted in Korea (the I-DUO 301 study and the I-DUO 302 study). After a 4-week run-in period with either 150 mg IRB (I-DUO 301 study) or 300 mg IRB (I-DUO 302 study), patients with uncontrolled BP (ie, mean sitting systolic BP [MSSBP] ≥140 mmHg to <180 mmHg and mean sitting diastolic BP <110 mmHg) were randomized to the placebo, AML 5 mg, or AML 10 mg group. A total of 428 participants were enrolled in the 2 I-DUO studies. In the I-DUO 301 study, 271 participants were randomized in a 1:1:1 ratio to receive either IRB/AML 150/5 mg, IRB/AML 150/10 mg, or IRB 150 mg/placebo. In the I-DUO 302 study, 157 participants were randomized in a 1:1 ratio to receive IRB/AML 300/5 mg or IRB 300 mg/placebo. The primary endpoint was the change in MSSBP from baseline to week 8. Tolerability was assessed according to the development of treatment-emergent adverse events (TEAEs) and clinically significant changes in physical examination, laboratory tests, pulse, and 12-lead electrocardiography. FindingsIn I-DUO 301, the mean (SD) changes of MSSBP at week 8 from baseline were −14.78 (12.35) mmHg, −21.47 (12.78) mmHg, and −8.61 (12.19) mmHg in the IRB/AML 150/5 mg, IRB/AML 150/10 mg, and IRB 150 mg/placebo groups, respectively. In I-DUO 302, the mean (SD) changes of MSSBP at week 8 from baseline were −13.30 (12.47) mmHg and −7.19 (15.37) mmHg in the IRB/AML 300/5 mg and IRB 300 mg/placebo groups, respectively. In both studies, all combination groups showed a significantly higher reduction in MSSBP than the IRB monotherapy groups (P < 0.001 for both). TEAEs occurred in 10.00%, 10.99%, and 12.22% of participants in the IRB/AML 150/5 mg, IRB/AML 150/10 mg, and IRB 150 mg/placebo groups, respectively, in I-DUO 301 and in 6.33% and 10.67% of participants in the IRB/AML 300/5 mg and IRB 300 mg/placebo groups, respectively, in I-DUO 302, with no significant between-group differences. Overall, there was one serious adverse event throughout I-DUO study. ImplicationsThe combination of IRB and AML has superior antihypertensive effects compared with IRB alone over an 8-week treatment period, with placebo-like tolerability. Clinical Trial RegistrationClinicalTrials.gov identifier: NCT05476354 (I-DUO 301), NCT05475665 (I-DUO 302).

SINGLE-PILL, TRIPLE ANTIHYPERTENSIVE THERAPY IN RURAL SUB-SAHARAN AFRICA: PRELIMINARY EXPERIENCE

Objective: Arterial hypertension is worldwide the leading modifiable cardiovascular risk factor. Beside life-style changes, strong evidence supports the efficacy of pharmacological treatment in reducing the complications of hypertension. International guidelines have recommended single-pill, low-dose combinations as initial treatment strategy. We investigated whether management of hypertension through this approach is feasible and effective in a rural sub-Saharan Africa setting. Design and method: Diagnosis of hypertension was established over three sets of blood pressure measurements: during a community-based, house-to-house screening in 2020 and in 2022, and at the hypertension outpatient clinic. Blood pressure measurements were performed according to the ESH recommendations by trained personnel, using a validated, oscillometric device OMRON M7 IT-HEM-7322-E. In 98 individuals diagnosed to have arterial hypertension, once-daily, single-pill combination of olmesartan, amlodipine, and hydrochlorothiazide was prescribed at a dose suitable to their blood pressure values and clinical characteristics. They were instructed on its administration and potential side effects and encouraged towards lifestyle modifications. Treatment regimen was adjusted, if needed, at each outpatient clinic visit scheduled after 4, 8, 12, and 16 weeks Results: 79 patients (aged 61 [53-70] years; median and interquartile range) strictly adhered to the treatment schedule, while overall 19 individuals dropped-out (aged 70 [65-80] years) because of different reasons. About 20% were tobacco smokers and nearly all consumed alcohol. Blood pressure was &lt;140/90 mm Hg after 4 weeks in 44 (56%), after 8 weeks in 62 (78%), after 12 weeks in 69 (87%), and after 16 weeks in 74 (94%) participants. Excellent tolerance was widely reported. Conclusions: Management of hypertension with once-daily, single-pill combination of olmesartan, amlodipine, and hydrochlorothiazide as initial treatment was feasible and effective also in a rural sub-Saharan setting, with very high rate of hypertension control in patients adherent to treatment. Our results provide real life evidence in favor of extensive implementation of single-pill combination therapy also in low- and middle-income countries where local Health Care Systems should include recommendation on their usage in national guidelines and should make them available also in rural and remote areas at low or no cost as reliable first-line treatment strategy