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We assessed whether concomitant use of CYP2D6-inhibiting drugs associates with increased risk of fall injuries after newly initiated therapy with beta-blockers. A case-crossover study design was applied which eliminates confounding from individual fixed characteristics by pairing cases with themselves across time. Data on prescribed and dispensed beta-blockers and hospitalizations for first-time fall injuries in the Swedish population aged ≥ 20 for the period 2006-01-01–2013-12-31 were extracted from national registers. Odds ratios (OR) with 95% confidence interval (CI) of fall injury associated with newly initiated beta-blocker therapy (prescription dispensed within the 28 days preceding the fall injury) while considering concomitant use of CYP2D6-inhibiting drugs, were estimated. Newly initiated beta-blocker therapy (any type) with concomitant use of CYP2D6-inhibiting drugs (any type) was associated with an increased risk of fall injury (OR 1.37, 1.24–1.52). This risk became elevated after restriction to concomitant use of moderate (OR 1.63, 1.26–2.10) or strong CYP2D6 inhibitors (OR 2.25, 1.39–3.63). The results remained similar independent of the beta-blockers’ degree of CYP2D6 metabolism (none, partial or major). Our study indicates the presence of drug-drug interaction for concomitant use of beta-blockers and CYP2D6 inhibitors in relation to the risk of fall injury, irrespective of degree of CYP2D6 metabolism.

Previous studies have demonstrated an anti-tumoral effect of beta-adrenergic blocking agents on cutaneous melanoma (CM). The aim of this study was to investigate if beta-adrenergic blocking agents have an impact on survival in Swedish patients with melanoma. A population-based retrospective registry study including all patients diagnosed with a primary invasive melanoma between 2009 and 2013 was performed. Data from the Swedish Melanoma Register were linked to the Swedish Prescribed Drug Registry and the Swedish Cause of Death Register. Cox regression analyses including competing risk assessments were performed. There were 12,738 patients included, out of which 3702 were exposed to beta-blockers vs. 9036 non-exposed patients. Age, male sex, Breslow thickness, ulceration, and nodal status were independent negative prognostic factors for melanoma-specific survival (MSS). Adding beta-blockers to the analysis did not add any prognostic value to the model (HR 1.00, p = 0.98), neither when adjusting for competing risks (HR 0.97, p = 0.61). When specifically analyzing the use of non-selective beta-blockers, the results were still without statistical significance (HR 0.76, p = 0.21). In conclusion, this population-based registry study could not verify that the use of beta-adrenergic blocking agents improve survival in patients with melanoma.

Ocular drug absorption after eye drop instillation has been widely studied, but partitioning phenomena and spatial drug distribution are poorly understood. We investigated partitioning of seven beta-blocking drugs in corneal epithelium, corneal stroma, including endothelium and conjunctiva, using isolated porcine tissues and cultured human corneal epithelial cells. The chosen beta-blocking drugs had a wide range (−1.76–0.79) of n-octanol/buffer solution distribution coefficients at pH 7.4 (Log D7.4). In addition, the ocular surface distribution of three beta-blocking drugs was determined by matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI-IMS) after their simultaneous application in an eye drop to the rabbits in vivo. Studies with isolated porcine corneas revealed that the distribution coefficient (Kp) between the corneal epithelium and donor solution showed a positive relationship and good correlation with Log D7.4 and about a 50-fold range of Kp values (0.1–5). On the contrary, Kp between corneal stroma and epithelium showed an inverse (negative) relationship and correlation with Log D7.4 based on a seven-fold range of Kp values. In vitro corneal cell uptake showed a high correlation with the ex vivo corneal epithelium/donor Kp values. Partitioning of the drugs into the porcine conjunctiva also showed a positive relationship with lipophilicity, but the range of Kp values was less than with the corneal epithelium. MALDI-IMS allowed simultaneous detection of three compounds in the cornea, showed data in line with other experiments, and revealed uneven spatial drug distribution in the cornea. Our data indicate the importance of lipophilicity in defining the corneal pharmacokinetics and the Kp values are a useful building block in the kinetic simulation models for topical ocular drug administration.

BackgroundRecent literature revealed that medication histories obtained by physicians and nurses are often incomplete. However, the number of patients included was often low.Study objectiveIn this study, the authors compare medication histories obtained in the Emergency Department (ED) by pharmacists versus physicians and identify characteristics contributing to discrepancies.MethodsMedication histories were acquired by the pharmacist from patients admitted to the ED, planned to be hospitalised. A structured form was used to guide the pharmacist or technician to ensure a standardised approach. Discrepancies, defined as any difference between the pharmacist-acquired medication history and that obtained by the physician, were analysed.Results3594 medication histories were acquired by pharmacy staff. 59% (95% CI 58.2% to 59.8%) of medication histories recorded by physicians were different from those obtained by the pharmacy staff. Within these inaccurate medication histories, 5963 discrepancies were identified. The most common type of error was omission of a drug (61%; 95% CI 60.4% to 61.6%), followed by omission of dose (18%; 95% CI 17.6% to 18.4%). Drugs belonging to the class of psycholeptics, acid suppressors and beta blocking agents were related to the highest discrepancy rate. Acetylsalicylic acid, omeprazole and zolpidem were most commonly forgotten.ConclusionThis large prospective study demonstrates that medication history acquisition is very often incomplete in the ED. A structured form and a standardised method is necessary. Pharmacists are especially suited to acquire and supervise accurate medication histories, as they are educated and familiar with commonly used drugs.

Purpose To investigate the association between maternal use of antihypertensives in early pregnancy and delivery outcome, notably infant congenital malformations. Methods A cohort study of 1,418 women who had used antihypertensive drugs in early pregnancy but had no diabetes diagnosis were identified from the Swedish Medical Birth Register. Results There was an excess risk for placental abruption, caesarean section, delivery induction, and post-delivery hemorrhage in women taking hypertensives. Infants were more often than expected born preterm, were small for gestational age, and had an excess of various neonatal symptoms. Cardiovascular defects occurred with an adjusted odds ratio of 2.59 (95% CI 1.92-3.51). The results were similar when the woman had used ACE inhibitors or other antihypertensives, notably beta blockers. Stillbirth rate was increased (risk ratio 1.87, 95% CI 1.02-3.02), again without any clear drug specificity. Conclusions There seems to be little drug specificity in the association between maternal use of antihypertensives and an increased risk for infant cardiovascular defects.

Beta-blocking agents have been shown to reduce the risk of hospitalization and death in patients with mild to moderate heart failure, but little is known about the efficacy or safety of these agents in severe heart failure. A case of beta blocker administration in severe heart failure with ejection fraction less than 25% is reported. The reported benefits of beta blockers with regard to morbidity and mortality in patients with mild to moderate heart failure were also found in the patient with severe heart failure as reported in this case. (Med J Indones 2002; 11: 174-5)

SUMMARY Hypertension is common in people with diabetes with an estimated prevalence using the new criteria (> 140/90) at 70%. The recent large randomized controlled studies in diabetic subjects has clearly shown the benefit of blood pressure lowering with reduction in cardiovascular endpoints and microvascular disease. ACE inhibitors, calcium antagonists, thiazide diuretics and b-blocking agents have been the agents validated by the trials. The challenge now is to implement anti-hypertensive therapy to achieve tight blood pressure targets (< 140/80), usually requiring dual or even triple therapeutic regimens.

This chapter contains sections titled: Definition Pharmacologic therapy in patients with stage D heart failure Device management Surgical options Special considerations and end of life issues Conclusion References

A method for the sensitive detection of isopropyl substituted β-blocking agents in human urine is presented. The sample preparation step involves enzymatic hydrolysis, solid phase extraction and derivatisation withN-methyl-N-trimethylsilyl-trifluoroacetamide. The instrumental analysis was performed using gas chromatography-mass spectrometry with an ion trap mass spectromeler. The mass spectrometer was operated in the scan as well as in the MS-MS mode.

The aim of this study was to evaluate the pharmacokinetic variability of beta‐adrenergic blocking agents used in cardiology by reviewing single‐dose and steady‐state pharmacokinetic studies from the literature. PubMed was searched for pharmacokinetic studies of beta‐adrenergic blocking agents, both single‐dose and steady‐state studies. The studies included reported maximum plasma concentration (Cmax) and/or area under the concentration curve (AUC). The coefficient of variation (CV%) was calculated for all studies, and a CV% <40% was considered low or moderate variability, and a CV% >40% was considered high variability. The Cmax and AUC were reported a total of 672 times in 192 papers. Based on AUC, metoprolol, propranolol, carvedilol, and nebivolol showed high pharmacokinetic variability (highest first), whereas bisoprolol, atenolol, sotalol, labetalol, nadolol, and pindolol showed low to moderate variability (lowest first). We have shown a high interindividual pharmacokinetic variability that varies markedly in different beta‐adrenergic blocking agents; the extreme being steady state ratios as high as 30 in metoprolol. A more personalized approach to the medical treatment of patients may be obtained by combining known pharmacokinetic information about variability, pharmaco‐genetics and ‐dynamics, and patient characteristics, to avoid adverse events or lack of treatment effect.