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Frontiers in Medicine 2021This study was performed to investigate the effects of common polymorphisms in and on the plasma concentrations and antihypertensive effects of bisoprolol in...
This study was performed to investigate the effects of common polymorphisms in and on the plasma concentrations and antihypertensive effects of bisoprolol in hypertensive Chinese patients. One hundred patients with essential hypertension were treated with open-label bisoprolol 2.5 mg daily for 6 weeks. Clinic blood pressure (BP) and ambulatory BP (ABP) were measured after the placebo run-in and after 6 weeks treatment. Peak plasma concentrations of bisoprolol were measured at 3 h after the first dose and 3 h after the dose after 6 weeks treatment. Trough levels were measured before the dose after 6 weeks treatment. Bisoprolol plasma concentrations were measured with a validated liquid chromatography tandem mass spectrometry method. Six common polymorphisms in and the polymorphism were genotyped by TaqMan® assay. After 6 weeks of treatment, clinic BP and heart rate were significantly reduced by 14.3 ± 10.9/8.4 ± 6.2 mmHg ( < 0.01) and 6.3 ± 7.6 BPM ( < 0.01), respectively. Similar reductions were seen in ABP values. Bisoprolol plasma concentration at 3 h after the first dose and 3 h post-dose after 6 weeks of treatment were significantly associated with baseline body weight ( < 0.001) but there was no significant effect of the and polymorphisms on these or the trough plasma concentrations. There was no significant association of the and polymorphisms or plasma bisoprolol concentrations with the clinic BP or ABP responses to bisoprolol. Bisoprolol 2.5 mg daily effectively reduced BP and HR. The common polymorphisms in that were examined and the polymorphism appear to have no benefit in predicting the hemodynamic response to bisoprolol in these patients.
PubMed: 34568359
DOI: 10.3389/fmed.2021.683498 -
Journal of Oncology Pharmacy Practice :... Mar 2023The tyrosine-kinase inhibitor osimertinib is an oral anti-cancer agent that is used for the treatment of patients with metastatic non-small cell lung cancer harbouring...
INTRODUCTION
The tyrosine-kinase inhibitor osimertinib is an oral anti-cancer agent that is used for the treatment of patients with metastatic non-small cell lung cancer harbouring sensitising mutations. Patients receiving osimertinib are at higher risk of developing cardiac toxicity, and here we present the case of a 72-year-old male who developed multiple cardiotoxicities during therapy (i.e. QTc prolongation, atrial fibrillation, heart failure).
CASE REPORT
A 72-year-old white British, ex-smoker male patient was admitted to our cancer centre with adenocarcinoma of the lung. Afatinib, gefitinib, osimertinib, and carboplatin plus pemetrexed chemotherapy were the treatments he received. At the 15th month of osimertinib therapy, the patient developed QTc prolongation. Two weeks after the first incidence of QTc prolongation, electrocardiography showed rate-controlled atrial fibrillation. In addition to his atrial fibrillation, echocardiography revealed severely impaired left ventricular systolic function (left ventricular ejection fraction: 30%).
MANAGEMENT AND OUTCOMES
Baseline to osimertinib, an electrocardiography investigation was carried out as per the protocol. Baseline drug history was reviewed and rosuvastatin was discontinued before initiating osimertinib as both drugs contribute to QTc prolongation. Dabigatran, bisoprolol, and digoxin were started for the treatment of atrial fibrillation. Ramipril and spironolactone were prescribed for the treatment of heart failure but osimertinib continued uneventfully. The patient died of non-small cell lung cancer.
DISCUSSION
Recommendations for practical and clinically relevant baseline and on-treatment assessments are considered which may reduce the risk of cardiac toxicity during osimertinib therapy. These include baseline cardiac risk stratification, consideration of concomitant medications that may result in additive cardiac risk, and use of electrocardiography and echocardiography surveillance.
PubMed: 36942434
DOI: 10.1177/10781552231164301 -
Advances in Therapy Jun 2021Combination antihypertensive therapy is required by most patients to achieve guideline-recommended blood pressure (BP) goals. This study assessed the effectiveness and... (Observational Study)
Observational Study
Effectiveness and Tolerability of the Single-Pill Combination of Bisoprolol and Perindopril in Patients with Arterial Hypertension and Stable Coronary Artery Disease in Daily Clinical Practice: The STYLE Study.
INTRODUCTION
Combination antihypertensive therapy is required by most patients to achieve guideline-recommended blood pressure (BP) goals. This study assessed the effectiveness and tolerability of bisoprolol/perindopril (Bis/Per) single-pill combination (SPC) in Russian patients with hypertension and coronary artery disease (CAD) treated in routine clinical practice.
METHODS
STYLE (NCT03730116) was an open-label, uncontrolled, prospective observational study conducted in patients who were already receiving Bis/Per SPC, switched to SPC from Bis or Per monotherapy, or switched from a free combination of Bis and Per. Primary endpoint criteria were assessed at 1 and 3 months and included change in mean office systolic/diastolic blood pressure (SBP/DBP), proportion achieving target BP (< 140/90 mmHg), and measures of antianginal effectiveness.
RESULTS
The full analysis set comprised 1892 subjects. Mean age was 61.9 ± 8.8 years, 53.2% were women, and mean durations of hypertension and CAD were 12.5 ± 7.9 and 7.2 ± 6.4 years, respectively. Mean SBP/DBP decreased by 22.3/11.0 mmHg and 31.5/15.9 mmHg at 1 and 3 months, respectively (P < 0.0001 vs baseline). Target BP was achieved by 49.2% and 86.7% of patients at 1 and 3 months, respectively. Reductions in mean number of angina attacks and nitrate consumption and improvements in heart rate were statistically significant. Treatment was well tolerated.
CONCLUSION
Treatment of patients with hypertension and CAD with Bis/Per SPC for 3 months was associated with significant decreases in SBP/DBP and a high proportion of patients achieving BP treatment goals. This was accompanied by an improvement in angina symptoms. Treatment was well tolerated in a broad patient population representative of those seen in everyday clinical practice.
Topics: Aged; Antihypertensive Agents; Bisoprolol; Blood Pressure; Coronary Artery Disease; Drug Combinations; Female; Humans; Hypertension; Male; Middle Aged; Perindopril; Russia; Treatment Outcome
PubMed: 33991323
DOI: 10.1007/s12325-021-01754-2 -
Pharmacogenomics and Personalized... 2022Bisoprolol is a widely used beta-blocker in patients with cardiovascular diseases. As with other beta-blockers, there is variability in response to bisoprolol, but the...
PURPOSE
Bisoprolol is a widely used beta-blocker in patients with cardiovascular diseases. As with other beta-blockers, there is variability in response to bisoprolol, but the underlying reasons for this have not been clearly elucidated. Our aim was to investigate genetic factors that affect bisoprolol pharmacokinetics (PK) and pharmacodynamics (PD), and potentially the clinical outcomes.
PATIENTS AND METHODS
Patients with non-ST elevation acute coronary syndrome were recruited prospectively on admission to hospital and followed up for up to 2 years. Patients from this cohort who were on treatment with bisoprolol, at any dose, had bisoprolol adherence data and a plasma sample, one month after discharge from index hospitalisation were included in the study. Individual bisoprolol clearance values were estimated using population pharmacokinetic modeling. Genome-wide association analysis after genotyping was undertaken using an Illumina HumanOmniExpressExome-8 v1.0 BeadChip array, while CYP2D6 copy number variations were determined by PCR techniques and phenotypes for CYP2D6 and CYP3A were inferred from the genotype. GWAS significant SNPs were analysed for heart rate response to bisoprolol in an independent cohort of hypertensive subjects.
RESULTS
Six hundred twenty-two patients on bisoprolol underwent both PK and genome wide analysis. The mean (IQR) of the estimated clearance in this population was 13.6 (10.0-18.0) L/h. Bisoprolol clearance was associated with rs11029955 (p=7.17×10) mapped to the region of coiled-coil domain containing 34 region (CCDC34) on chromosome 11, and with rs116702638 (p=2.54×10). Each copy of the minor allele of rs11029955 was associated with 2.2 L/h increase in clearance. In an independent cohort of hypertensive subjects, rs11029955 was associated with 24-hour heart rate response to 4-week treatment with bisoprolol (p= 9.3×10), but not with rs116702638.
CONCLUSION
A novel locus on the chromosomal region 11p14.1 was associated with bisoprolol clearance in a real-world cohort of patients and was validated in independent cohort with a pharmacodynamic association.
PubMed: 35356681
DOI: 10.2147/PGPM.S352719 -
Advances in Therapy Jun 2023This study assessed the real-life effectiveness of a single-pill combination (SPC) of bisoprolol/perindopril for controlling blood pressure (BP) and symptoms of angina... (Observational Study)
Observational Study
Effectiveness and Tolerability of Bisoprolol/Perindopril Single-Pill Combination in Patients with Arterial Hypertension and a History of Myocardial Infarction: The PRIDE Observational Study.
INTRODUCTION
This study assessed the real-life effectiveness of a single-pill combination (SPC) of bisoprolol/perindopril for controlling blood pressure (BP) and symptoms of angina in patients with hypertension and a history of myocardial infarction (MI).
METHODS
Eligible patients with arterial hypertension and a history of MI were aged 18-79 years and had initiated bisoprolol/perindopril SPC within 3 months of study enrollment as part of routine Russian clinical practice. The primary endpoint was mean change in systolic and diastolic BP (SBP/DBP) at week 12 compared with baseline (data collected retrospectively). Secondary endpoints were assessed at weeks 4 and 12 and included mean change in resting heart rate (HR), proportion of patients reaching target level of resting HR, antianginal effectiveness of the SPC, and proportion of patients reaching target BP levels.
RESULTS
A total of 504 patients were enrolled, of whom 481 comprised the full analysis set (mean age 61.4 ± 8.9 years, 68% men). Mean baseline SBP/DBP and HR values were 148.9 ± 16.8/87.7 ± 11.0 mmHg and 77.4 ± 10.5 bpm, respectively. Mean durations of hypertension and CAD were 12.8 ± 8.4 and 6.1 ± 6.3 years, respectively, and time since MI was 3.8 ± 5.3 years. At week 12, SBP/DBP had decreased by 24.9/12.2 mmHg (P < 0.001 vs baseline). Target BP (< 140/90 mmHg) was achieved by 69.8% and 95.9% of patients at weeks 4 and 12, respectively, and target HR (55-60 bpm) by 17.3% and 34.5% at weeks 4 and 12 versus 3.1% at baseline (P < 0.001). Reductions in angina attacks, nitrate consumption, and improvements in HR were statistically significant. Treatment was well tolerated.
CONCLUSION
Treatment of symptomatic patients with CAD, hypertension, and a history of MI with a bisoprolol/perindopril SPC was associated with significant decreases in SBP/DBP and a high proportion of patients achieving BP treatment goals. This was accompanied by improvements in angina symptoms and reductions in HR in a broad patient population representative of those seen in everyday clinical practice.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier NCT04656847.
Topics: Male; Humans; Middle Aged; Aged; Female; Perindopril; Bisoprolol; Antihypertensive Agents; Retrospective Studies; Hypertension; Blood Pressure; Myocardial Infarction; Angina Pectoris; Drug Combinations; Treatment Outcome
PubMed: 37029871
DOI: 10.1007/s12325-023-02462-9 -
Advances in Therapy Jan 2022The combination of angiotensin-converting enzyme inhibitors and beta-blockers is recommended in a wide range of patients with hypertension, including those with stable... (Observational Study)
Observational Study
Concomitant Treatment of Hypertensive Patients with Bisoprolol and Perindopril in Routine Clinical Practice: A Post Hoc Analysis of the CONFIDENCE II, PROTECT I, and PROTECT III Observational Studies.
INTRODUCTION
The combination of angiotensin-converting enzyme inhibitors and beta-blockers is recommended in a wide range of patients with hypertension, including those with stable coronary artery disease and/or elevated heart rate. This post hoc analysis of three observational studies provides effectiveness and safety data on treatment with perindopril on top of bisoprolol-based therapy, in routine clinical practice.
METHODS
Data were analyzed from three open-label, prospective, multicenter, observational studies of Canadian patients with mild-to-moderate hypertension, which shared the same inclusion and exclusion criteria, treatment duration, and primary outcome. This post hoc analysis focused on the subpopulation of patients treated with perindopril on top of bisoprolol-based therapy. All patients were followed for 16 weeks and underwent baseline, week 4, and week 16 visits. Primary outcomes were mean changes in blood pressure (BP) and proportion of patients achieving BP control (< 140/90 mmHg) in the full analysis set (FAS).
RESULTS
A total of 845 patients (mean age 68.3 ± 11.3 years, mean baseline BP 151.5/86.0 mmHg) were analyzed in the FAS. After 16 weeks, mean SBP/DBP decreased by - 20.4/- 9.8 mmHg with statistically significant reductions observed at all visits in all three studies allowing 78% of patients to achieve the BP treatment goal. No statistically significant changes in heart rate were observed and no serious adverse events reported. The most frequent doses of bisoprolol and perindopril were 5 + 4 mg (34.9%), followed by 5 + 8 mg (16.9%), and 2.5 + 4 mg (12.5%).
CONCLUSION
The addition of perindopril on top of bisoprolol-based therapy in patients with mild-to-moderate hypertension was associated with significant reductions in BP compared with baseline and with achievement of BP targets in the majority of patients. The results suggest this strategy is safe and effective for use in routine clinical practice.
Topics: Aged; Antihypertensive Agents; Bisoprolol; Blood Pressure; Canada; Drug Combinations; Humans; Hypertension; Middle Aged; Perindopril; Prospective Studies; Treatment Outcome
PubMed: 34755324
DOI: 10.1007/s12325-021-01958-6 -
Respirology (Carlton, Vic.) Mar 2021
Topics: Adrenergic beta-Antagonists; Asthma; Fear; Heart; Humans
PubMed: 33210754
DOI: 10.1111/resp.13979 -
Frontiers in Physiology 2022Hypertension is a multifactorial disease arising from complex pathophysiological pathways. Individual characteristics of patients result in different responses to...
Hypertension is a multifactorial disease arising from complex pathophysiological pathways. Individual characteristics of patients result in different responses to various classes of antihypertensive medications. Therefore, evaluating the efficacy of therapy based on predictions is an important task. This study is a continuation of research on the modular agent-based model of the cardiovascular and renal systems (presented in the previously published article). In the current work, we included in the model equations simulating the response to antihypertensive therapies with different mechanisms of action. For this, we used the pharmacodynamic effects of the angiotensin II receptor blocker losartan, the calcium channel blocker amlodipine, the angiotensin-converting enzyme inhibitor enalapril, the direct renin inhibitor aliskiren, the thiazide diuretic hydrochlorothiazide, and the β-blocker bisoprolol. We fitted therapy parameters based on known clinical trials for all considered medications, and then tested the model's ability to show reasonable dynamics (expected by clinical observations) after treatment with individual drugs and their dual combinations in a group of virtual patients with hypertension. The extended model paves the way for the next step in personalized medicine that is adapting the model parameters to a real patient and predicting his response to antihypertensive therapy. The model is implemented in the BioUML software and is available at https://gitlab.sirius-web.org/virtual-patient/antihypertensive-treatment-modeling.
PubMed: 36589434
DOI: 10.3389/fphys.2022.1070115 -
International Journal of Molecular... Sep 2023Cardiac K4.3 channels contribute to the transient outward K current, I, during early repolarization of the cardiac action potential. Two different isoforms of K4.3 are...
Cardiac K4.3 channels contribute to the transient outward K current, I, during early repolarization of the cardiac action potential. Two different isoforms of K4.3 are present in the human ventricle and exhibit differential remodeling in heart failure (HF). Cardioselective betablockers are a cornerstone of HF with reduced ejection fraction therapy as well as ventricular arrhythmia treatment. In this study we examined pharmacological effects of betablockers on both K4.3 isoforms to explore their potential for isoform-specific therapy. K4.3 isoforms were expressed in Xenopus oocytes and incubated with the respective betablockers. Dose-dependency and biophysical characteristics were examined. HEK 293T-cells were transfected with the two K4.3 isoforms and analyzed with Western blots. Carvedilol (100 µM) blocked K4.3 L by 77 ± 2% and K4.3 S by 67 ± 6%, respectively. Metoprolol (100 µM) was less effective with inhibition of 37 ± 3% (K4.3 L) and 35 ± 4% (K4.3 S). Bisoprolol showed no inhibitory effect. Current reduction was not caused by changes in K4.3 protein expression. Carvedilol inhibited K4.3 channels at physiologically relevant concentrations, affecting both isoforms. Metoprolol showed a weaker blocking effect and bisoprolol did not exert an effect on K4.3. Blockade of repolarizing K4.3 channels by carvedilol and metoprolol extend their pharmacological mechanism of action, potentially contributing beneficial antiarrhythmic effects in normal and failing hearts.
Topics: Humans; Metoprolol; Bisoprolol; Carvedilol; Heart; Heart Failure; Protein Isoforms
PubMed: 37762145
DOI: 10.3390/ijms241813842 -
Royal Society Open Science Dec 2023Two bisoprolol derivatives, -acetyl bisoprolol and -formyl bisoprolol, belonging to the beta-blocker class of antihypertensive drugs, were synthesized using acetylation...
Two bisoprolol derivatives, -acetyl bisoprolol and -formyl bisoprolol, belonging to the beta-blocker class of antihypertensive drugs, were synthesized using acetylation and formylation reactions. The yields of the reactions were determined to be 32.40% for -acetyl bisoprolol and 20.20% for -formyl bisoprolol. methods such as molecular docking, molecular dynamics simulation and SwissADME prediction were employed to evaluate the potential of these bisoprolol derivatives as antihypertensive drugs. These methods were used to assess the interaction between the bisoprolol derivatives and various receptors associated with hypertension, including human angiotensin I-converting enzyme (PDB ID: 1O8A), renin (PDB ID: 2V0Z), beta-1 adrenergic receptors (PDB ID: 4BVN, 7BVQ), voltage-dependent L-type calcium channel subunit alpha-1S (PDB ID: 6JP5) and mineralocorticoid receptor (PDB ID: 6L88). Our results demonstrated the highest binding energy when bisoprolol and its derivatives bound to 4BVN, with binding energy values of 6.74 kcal mol, 7.03 kcal mol and 7.63 kcal mol for bisoprolol, -acetyl bisoprolol and -formyl bisoprolol, respectively. The stability of these complexes was confirmed by molecular dynamics simulations, with a root-mean-square deviation value of approximately 2. Furthermore, the SwissADME results indicated that both derivatives exhibited similar properties to the reference drug bisoprolol.
PubMed: 38126063
DOI: 10.1098/rsos.231112