Effect of Spironolactone on Atrial Fibrillation in Patients with Heart Failure with Preserved Ejection Fraction: Post-Hoc Analysis of the Randomized,Placebo-Controlled TOPCAT Trial

Mineralocorticoid receptor antagonists (MRAs) reduce the risk of atrial fibrillation (AF) in patients with heart failure (HF) and a reduced ejection fraction. The efficacy of MRAs for AF prevention in patients with HF and a preserved ejection fraction (HFpEF) is unclear. We performed a secondary analysis of a randomized placebo-controlled trial to determine the efficacy of spironolactone in reducing new-onset AF and recurrence of AF in 2733 patients with symptomatic HFpEF. Patients with and without prevalent AF at baseline were included, and those with permanent AF were excluded. Patients were randomized 1:1 to spironolactone or placebo. The risk of new-onset AF or the recurrence of AF was quantified using hazard ratios (HRs) with corresponding 95% confidence intervals (CIs). At baseline, 2228 (64.7%) patients had no history of AF (spironolactone, n = 1111; placebo, n = 1117), whereas 505 (18.4%) patients had prevalent AF (spironolactone, n = 260; placebo, n = 245). During a median follow-up of 3.1 years (interquartile range [IQR] 2.0–4.9), the incidence of new-onset AF was similar in both treatment arms: spironolactone 5.2% (n = 58) versus placebo 4.4% (n = 49); p = 0.41. The risk of new-onset AF was similar in both treatment arms: HR 1.19; 95% CI 0.81–1.74; p = 0.38. AF recurrence was also similar in both treatment arms during a median follow-up of 3.3 years (IQR 1.9–4.7): spironolactone 11.5% (n = 30) versus placebo 11.8% (n = 29); p = 1.00. The risk of recurrence of AF did not differ per treatment arm: HR 0.94; 95% CI 0.57–1.58; p = 0.83. Spironolactone does not reduce the risk of new-onset AF or AF recurrence in patients with HFpEF. This is in contrast to results in cohorts of patients with HF and a reduced ejection fraction. ClinicalTrials.gov identifier no. NCT00094302 (TOPCAT).     

Locust bean gum safety in neonates and young infants: An integrated review of the toxicological database and clinical evidence

Locust bean gum (LBG) is a galactomannan polysaccharide used as thickener in infant formulas with the therapeutic aim to treat uncomplicated gastroesophageal reflux (GER). Since its use in young infants below 12 weeks of age is not explicitly covered by the current scientific concept of the derivation of health based guidance values, the present integrated safety review aimed to compile all the relevant preclinical toxicological studies and to combine them with substantial evidence gathered from the clinical paediatric use as part of the weight of evidence supporting the safety in young infants below 12 weeks of age. LBG was demonstrated to have very low toxicity in preclinical studies mainly resulting from its indigestible nature leading to negligible systemic bioavailability and only possibly influencing tolerance. A standard therapeutic level of 0.5 g/100 mL in thickened infant formula is shown to confer a sufficiently protective Margin of Safety. LBG was not associated with any adverse toxic or nutritional effects in healthy term infants, while there are limited case-reports of possible adverse effects in preterms receiving the thickener inappropriately. Altogether, it can be concluded that LBG is safe for its intended therapeutic use in term-born infants to treat uncomplicated regurgitation from birth onwards.     

The size of infarction as judged enzymatically in 1974 patients with acute myocardial infarction. Relation with symptomatology, infarct localization and type of infarction

A common data base of six coronary care units containing personal and clinical data of 17462 patients was used to investigate the relation between clinical symptoms of patients with acute myocardial infarction and size of infarction. In 1974 of the 5110 patients, in whom a final diagnosis of infarction was made, size of infarction was determined according to serially measured levels of serum alpha-hydroxybutyrate dehydrogenase. The episode of infarction was the first in 1396 patients, was recurrent in 497, and undetermined in 81 patients. We calculated the size factor (defined as the mean size of infarction of patients with a particular symptom divided by the mean size of infarction of patients without that symptom) to evaluate the role of the size of infarction to manifestation of certain clinical symptoms. Bradycardia, shock and right-sided failure when noted on admission to the coronary care unit, had factors for size of infarction significantly greater than 1.0 (1.15, 1.79 and 1.30, respectively) in patients suffering an initial infarction, but not significantly different from 1.0 in patients with recurrent infarction. The occurrence of primary and secondary ventricular tachycardia and/or fibrillation, left heart failure (Killip class II-IV), symptomatic supraventricular tachycardia, high-degree atrioventricular blocks, ruptures and death in the coronary care unit was associated with factors significantly greater than 1.0 in those patients having both initial and recurrent infarctions. The size of infarction as judged enzymatically was significantly larger in patients with anterior than inferior and lateral infarction. The size of infarctions without Q waves was judged to be generally 35% smaller than infarctions producing Q waves. It is concluded that the size of infarction determines the occurrence of several symptoms and complications diagnosed at admission or during stay in the coronary care unit.     

Erectile impotence: a clinical challenge

The wide range of factors that may contribute to impotence is reviewed in an attempt to establish a systematized approach for assessing etiologic factors. The effects on potency of ageing, general fitness, weight, debilitating disease, use of therapeutic and other drugsincluding alcohol and neurogenic, vasculogenic, endocrine/metabolic, urogenital and psychogenic factors are considered and discussed. The review also affords a rationale for the methodology employed.     

Safety evaluation of an alpha-cyclodextrin glycosyltranferase preparation

Alpha-cyclodextrin glucosyltransferase (alpha-CGTase, EC 2.4.1.19) is an amylolytic enzyme used for the production of alpha-cyclodextrin (alpha-CD), a novel, soluble dietary fiber, from food-grade starch. The safety of an alpha-CGTase preparation obtained by batch fermentation from a recombinant strain of Escherichia coli K12 harboring the alpha-CGTase gene from Klebsiella oxytoca strain M5a1 was examined. In a 13-week subchronic toxicity study in rats, the administration by gavage of the alpha-CGTase preparation at levels of up to 20 ml/kg bw/day, corresponding to a total organic solids dosage of 260 mg/kg bw/day, did not cause any systemic toxic effect. Some signs of irritation were observed in the respiratory tract which occurred, however, in one sex only and/or were not dose-related. Accordingly, these changes were considered to be an unspecific consequence of the reflux and aspiration of the dosing solution. There was no evidence of a genotoxic activity in Ames tests and a chromosome aberration test in cultured human lymphocytes. It is concluded that the examined alpha-CGTase preparation is safe when used for the production of alpha-CD.     

HLA and susceptibility to cervical neoplasia.

The association between cervical neoplasia and certain HLA phenotypes observed in different studies has not been consistent. By serological typing, the association between HLA antigens, cervical carcinoma and cervical intraepithelial neoplasia (CIN) was studied in a group of 172 and 116 patients, respectively. We demonstrated an increased frequency of B63 in patients with HPV types other than HPV 16 or 18, and B55 in patients that were negative for all HPV types. The association between cervical carcinoma and DQ3, described in various populations, was not observed in the present study. However, we confirmed other previously observed associations between cervical cancer and class II antigens, i.e., a positive correlation with DR15 irrespective of the HPV status, with DR3 in patients harboring HPV types other than HPV 16 or 18, and with DR11 among HPV 16 positive patients. In contrast, a negative correlation between DR13 and HPV positive cervical cancer was observed which suggests protection of this antigen against HPV-associated cervical cancer. A slight increase of DR15 and DQ4 antigens was observed in CIN patients, suggesting that these specific HLA antigens may be important in determining the risk of CIN.     

Methylated and demethylated tricyclic antidepressants and their binding to cell membranes

We studied the binding of methylated and demethylated tricyclic antidepressants (TCA) to synaptic plasma brain membranes (SPM) and to lymphocyte, platelet and erythrocyte membranes. In the synaptic plasma membranes, more demethylated than methylated dibenzazepine derivatives were bound and the binding affinity was decreased. By contrast, in lymphocyte and platelet membranes more methylated derivatives were bound. Phosphatidylserine (PS) enhanced significantly the binding of methylated TCA in SPM without changing the dissociation constant (Kd). Lysophosphatidylserine did not affect the binding. PS also caused an increase of 3H-imipramine binding to lymphocyte membranes but the binding to platelet membranes was not affected. PS also enhanced 3H-5-HT uptake into platelets and 3H-noradrenaline uptake into lymphocytes.     

Application of the threshold of toxicological concern (TTC) concept to the safety assessment of chemically complex food matrices

The toxicological assessment of chemically complex food matrices (CCFM) usually is very time consuming, expensive and uses many animal studies. Improvements to obtain a more efficient assessment process remain limited as long as we retain traditional approaches to toxicological risk assessment. New concepts would be needed to achieve real innovations in risk assessment. The threshold of toxicological concern (TTC) potentially is such a concept that has existed for many years and recently has been further developed.The safety of CCFM is difficult to assess as there are numerous unknown substances present (often referred to as ‘Forest-of-Peaks’ in chromatographic analysis). Usually, for the evaluation of CCFM, a full safety assessment approach involving animal studies is needed, but the exposure to most substances is low and TTC might be applicable. However, to apply TTC efficiently to CCFM, a strategy is needed to deal with large numbers of unknowns (substances of which structural information is lacking). Therefore, we have drafted a framework for application of TTC in safety assessment of CCFM. This paper describes the criteria and development of the framework proposing a stepwise approach for the application of TTC in safety assessment of CCFM and future developments required.