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Aqueous chlorination of acebutolol: kinetics, transformation by-products, and mechanism

Khalit WN, Tay KS

Environ Sci Pollut Res Int, 2016 Feb;23(3):2521-9.
PMID: 26423291 DOI: 10.1007/s11356-015-5470-y

This study investigated the reaction kinetics and the transformation by-products of acebutolol during aqueous chlorination. Acebutolol is one of the commonly used β-blockers for the treatment of cardiovascular diseases. It has been frequently detected in the aquatic environment. In the kinetics study, the second-order rate constant for the reaction between acebutolol and chlorine (k app) was determined at 25 ± 0.1 °C. The degradation of acebutolol by free available chlorine was highly pH dependence. When the pH increased from 6 to 8, it was found that the k app for the reaction between acebutolol and free available chlorine was increased from 1.68 to 11.2 M(-1) min(-1). By comparing with the reported k app values, the reactivity of acebutolol toward free available chlorine was found to be higher than atenolol and metoprolol but lower than nadolol and propranolol. Characterization of the transformation by-products formed during the chlorination of acebutolol was carried out using liquid chromatography-quadrupole time-of-flight high-resolution mass spectrometry. Seven major transformation by-products were identified. These transformation by-products were mainly formed through dealkylation, hydroxylation, chlorination, and oxidation reactions.

Matched MeSH terms: Adrenergic beta-1 Receptor Antagonists/chemistry*
Fulltext Age Does Not Affect Metoprolol's Effect on Perioperative Outcomes (From the POISE Database)

Jacka MJ, Guyatt G, Mizera R, Van Vlymen J, Ponce de Leon D, Schricker T, et al.

Anesth Analg, 2018 04;126(4):1150-1157.
PMID: 29369093 DOI: 10.1213/ANE.0000000000002804

BACKGROUND: Perioperative β-blockade reduces the incidence of myocardial infarction but increases that of death, stroke, and hypotension. The elderly may experience few benefits but more harms associated with β-blockade due to a normal effect of aging, that of a reduced resting heart rate. The tested hypothesis was that the effect of perioperative β-blockade is more significant with increasing age.
METHODS: To determine whether the effect of perioperative β-blockade on the primary composite event, clinically significant hypotension, myocardial infarction, stroke, and death varies with age, we interrogated data from the perioperative ischemia evaluation (POISE) study. The POISE study randomly assigned 8351 patients, aged ≥45 years, in 23 countries, undergoing major noncardiac surgery to either 200 mg metoprolol CR daily or placebo for 30 days. Odds ratios or hazard ratios for time to events, when available, for each of the adverse effects were measured according to decile of age, and interaction term between age and treatment was calculated. No adjustment was made for multiple outcomes.
RESULTS: Age was associated with higher incidences of the major outcomes of clinically significant hypotension, myocardial infarction, and death. Age was associated with a minimal reduction in resting heart rate from 84.2 (standard error, 0.63; ages 45-54 years) to 80.9 (standard error, 0.70; ages >85 years; P < .0001). We found no evidence of any interaction between age and study group regarding any of the major outcomes, although the limited sample size does not exclude any but large interactions.
CONCLUSIONS: The effect of perioperative β-blockade on the major outcomes studied did not vary with age. Resting heart rate decreases slightly with age. Our data do not support a recommendation for the use of perioperative β-blockade in any age subgroup to achieve benefits but avoid harms. Therefore, current recommendations against the use of β-blockers in high-risk patients undergoing noncardiac surgery apply across all age groups.

Matched MeSH terms: Adrenergic beta-1 Receptor Antagonists/administration & dosage*; Adrenergic beta-1 Receptor Antagonists/adverse effects
Numerical optimization studies of cardiovascular-rotary blood pump interaction

Lim E, Dokos S, Salamonsen RF, Rosenfeldt FL, Ayre PJ, Lovell NH

Artif Organs, 2012 May;36(5):E110-24.
PMID: 22489799 DOI: 10.1111/j.1525-1594.2012.01449.x

A heart-pump interaction model has been developed based on animal experimental measurements obtained with a rotary blood pump in situ. Five canine experiments were performed to investigate the interaction between the cardiovascular system and the implantable rotary blood pump over a wide range of operating conditions, including variations in cardiac contractility and heart rate, systemic vascular resistance (SVR), and total blood volume (V(total) ). It was observed in our experiments that SVR decreased with increasing mean pump speed under the healthy condition, but was relatively constant during the speed ramp study under reduced cardiac contractility conditions. Furthermore, we also found a significant increase in pulmonary vascular resistance with increasing mean pump speed and decreasing total blood volume, despite a relatively constant SVR. Least squares parameter estimation methods were utilized to fit a subset of model parameters in order to achieve better agreement with the experimental data and to evaluate the robustness and validity of the model under various operating conditions. The fitted model produced reasonable agreement with the experimental measurements, both in terms of mean values and steady-state waveforms. In addition, all the optimized parameters were within physiological limits.

Matched MeSH terms: Adrenergic beta-1 Receptor Antagonists/pharmacology
Evaluation of a technique to measure heart rate variability in anaesthetised cats

Khor KH, Shiels IA, Campbell FE, Greer RM, Rose A, Mills PC

Vet J, 2014 Feb;199(2):229-35.
PMID: 24321367 DOI: 10.1016/j.tvjl.2013.11.006

Analysis of heart rate (HR) and heart rate variability (HRV) are powerful tools to investigate cardiac diseases, but current methods, including 24-h Holter monitoring, can be cumbersome and may be compromised by movement artefact. A commercially available data capture and analysis system was used in anaesthetised healthy cats to measure HR and HRV during pharmacological manipulation of HR. Seven healthy cats were subjected to a randomised crossover study design with a 7 day washout period between two treatment groups, placebo and atenolol (1mg/kg, IV), with the efficacy of atenolol to inhibit β1 adrenoreceptors challenged by epinephrine. Statistical significance for the epinephrine challenge was set at P<0.0027 (Holm-Bonferroni correction), whereas a level of significance of P<0.05 was set for other variables. Analysis of the continuous electrocardiography (ECG) recordings showed that epinephrine challenge increased HR in the placebo group (P=0.0003) but not in the atenolol group. The change in HR was greater in the placebo group than in the atenolol group (P=0.0004). Therefore, compared to cats pre-treated with placebo, pre-treatment with atenolol significantly antagonised the tachycardia while not significantly affecting HRV. The increased HR in the placebo group following epinephrine challenge was consistent with a shift of the sympathovagal balance towards a predominantly sympathetic tone. However, the small (but not significant at the critical value) decrease in the normalised high-frequency component (HFnorm) in both groups of cats suggested that epinephrine induced a parasympathetic withdrawal in addition to sympathetic enhancement (increased normalised low frequency component or LFnorm). In conclusion, this model is a highly sensitive and repeatable model to investigate HRV in anaesthetised cats that would be useful in the laboratory setting for short-term investigation of cardiovascular disease and subtle responses to pharmacological agents in this species.

Matched MeSH terms: Adrenergic beta-1 Receptor Antagonists/pharmacology
Fulltext The International Polycap Study-3 (TIPS-3): Design, baseline characteristics and challenges in conduct

Joseph P, Pais P, Dans AL, Bosch J, Xavier D, Lopez-Jaramillo P, et al.

Am Heart J, 2018 Dec;206:72-79.
PMID: 30342297 DOI: 10.1016/j.ahj.2018.07.012

BACKGROUND: It is hypothesized that in individuals without clinical cardiovascular disease (CVD), but at increased CVD risk, a 50% to 60% reduction in CVD risk could be achieved using fixed dose combination (FDC) therapy (usually comprised of multiple blood-pressure agents and a statin [with or without aspirin]) in a single "polypill". However, the impact of a polypill in preventing clinical CV events has not been evaluated in a large randomized controlled trial.
METHODS: TIPS-3 is a 2x2x2 factorial randomized controlled trial that will examine the effect of a FDC polypill on major CV outcomes in a primary prevention population. This study aims to determine whether the Polycap (comprised of atenolol, ramipril, hydrochlorothiazide, and a statin) reduces CV events in persons without a history of CVD, but who are at least at intermediate CVD risk. Additional interventions in the factorial design of the study will compare the effect of (1) aspirin versus placebo on CV events (and cancer), (2) vitamin D versus placebo on the risk of fractures, and (3) the combined effect of aspirin and the Polycap on CV events.
RESULTS: The study has randomized 5713 participants across 9 countries. Mean age of the study population is 63.9 years, and 53% are female. Mean INTERHEART risk score is 16.8, which is consistent with a study population at intermediate CVD risk.
CONCLUSION: Results of the TIP-3 study will be key to determining the appropriateness of FDC therapy as a strategy in the global prevention of CVD.

Matched MeSH terms: Adrenergic beta-1 Receptor Antagonists/administration & dosage
Medication prescribing patterns among chronic kidney disease patients in a hospital in Malaysia

Al-Ramahi R

Saudi J Kidney Dis Transpl, 2012 Mar;23(2):403-8.
PMID: 22382249

To determine the medication prescribing patterns in hospitalized patients with chronic kidney disease (CKD) in a Malaysian hospital, we prospectively studied a cohort of 600 patients in two phases with 300 patients in each phase. The first phase was carried out from the beginning of February to the end of May 2007, and the second phase was from the beginning of March to the end of June 2008. Patients with CKD who had an estimated creatinine clearance ≤ 50 mL/min and were older than 18 years were included. A data collection form was used to collect data from the patients' medical records and chart review. All systemic medications prescribed during hospitalization were included. The patients were prescribed 5795 medications. During the first phase, the patients were prescribed 2814 medication orders of 176 different medications. The prescriptions were 2981 of 158 medications during the second phase. The mean number of medications in the first and second phases was 9.38 ± 3.63 and 9.94 ± 3.78 respectively (P-value = 0.066). The top five used medications were calcium carbonate, folic acid/vitamin B complex, metoprolol, lovastatin, and ferrous sulfate. The most commonly used medication classes were mineral supplements, vitamins, antianemic preparations, antibacterials, and beta-blocking agents. This study provides an overview of prescription practice in a cohort of hospitalized CKD patients and indicates possible areas of improvement in prescription practice.

Matched MeSH terms: Adrenergic beta-1 Receptor Antagonists/therapeutic use