Calcium channel antagonists part IV: Side effects and contraindications drug interactions and combinations

Summary With the correct selection of drug and patient, the calcium antagonists as a group can be remarkably effective at relatively low cost of serious side effects. Almost all side effects are dose related. Minor side effects include those caused by vasodilation (flushing and headaches), constipation (verapamil), and ankle edema. Serious side effects are rare and result from improper use of these agents, as when intravenous verapamil (or diltiazem) is given to patients with sinus or atrioventricular nodal depression from drugs or disease, or nifedipine to patients with aortic stenosis. The potential of a marked negative inotropic effect is usually offset by afterload reduction, especially in the case of nifedipine which actually has the most marked negative inotropic effect. Yet caution is required when even calcium antagonists, especially verapamil, are given to patients with myocardial failure unless caused by hypertensive heart disease. Drug interactions of calcium antagonists occur with other cardiovascular agents such as -adrenergic blockers, -adrenergic blockers, digoxin, quinidine, and disopyramide. The most marked interaction with digoxin is that with verapamil, which may raise digoxin levels by over 50%. Combination therapy of calcium antagonists with -blockers is increasingly common, and is probably safest in the case of dihydropyridines. Other combinations being explored are those with angiotensinconverting enzyme inhibitors and diuretics.     

Electrophysiological effects of flecainide acetate on stretched guinea pig left atrial muscle fibers

Summary The electrophysiological effects of flecainide acetate (3×10^–6 M) on stretched atrial tissue were investigated using guinea-pig left atrial muscle fibers. Before stretching, the resting membrane potential was not affected by flecainide at 1 Hz, although the overshoot potential (Eov) and the action potential duration at 50% repolarization (APD₅₀) were slightly but significantly decreased by 2±1 mV and 2±1 msec, respectively. The effective refractory period (ERP) was increased by 3±1 msec. The reduction of max was 20.6±1.2%. The half-maximum potential (Vh) of the relationship between max and the resting potential was shifted to become more negative by flecainide (from –60.6±2.1 mV to –63.2±1.7 mV). After 90–120 min of washout with drug-free Tyrode's solution, the tissue was mechanically stretched to 150% of its slack length. Stretching significantly decreased the max by 16.9±3.1%, along with a slight but significant increase in ERP (3±1 msec) and shifted Vh to become more negative (from –60.6±2.1 to –63.1±1.8 mV). In the presence of flecainide, max further decreased by 20.2±2.6%, and Vh shifted from –63.1±1.8 to –65.0±1.5 mV. Comparison with the control unstretched fibers showed that flecainide significantly decreased max by 34.0±2.7%, reduced the resting membrane potential by 3±1 mV, decreased Eov by 4±1 mV, and shifted Vh from –60.6±2.1 to –65.0±1.5 mV, while the APD₅₀ and ERP did not change. In conclusion, the reduction of max in the presence of flecainide was much greater in the stretched atrial muscle fibers than in the unstretched fibers, because the max-resting potential relationship was shifted towards more negative potentials by both flecainide and stretching. These results suggest that flecainide exerts a stronger antiarrhythmic action on stretched atrial muscle fibers than on normal fibers.     

Cardiopulmonary function of cats with respiratory distress induced by N-nitroso N-methylurethane

The purposes of this study were to determine the effects of positive end-expiratory pressure (PEEP) and end-expiratory lung volume on systemic blood flow, whether PEEP levels yielding maximum systemic oxygen transport are associated with maximum lung compliance, and the effects of end-expiratory lung volume on pulmonary resistance to gas flow, in an animal model of respiratory distress. Twelve cats were inoculated with 12 mg/kg N-Nitroso N-Methylurethane (NNNMU) to induce respiratory distress. The NNNMU caused a 76% decrease in disaturated phosphatidyl-choline of lung lavage, a 34% decrease in functional residual capacity (FRC), an 80% decrease in lung compliance, an 88% increase in pulmonary resistance to gas flow, a 43% decrease in PaO2, and a 37% decrease in oxygen consumption. Systemic blood flow and systemic oxygen transport were not significantly altered by the chemically induced respiratory distress. PEEP levels of 5.1 +/- 0.8 cm H2O returned end-expiratory lung volume to normal FRC levels. Increases in PEEP caused systemic blood flow to decrease even when end-expiratory lung volume was below or equal to normal FRC levels but did not significantly affect systemic oxygen transport, lung compliance, or pulmonary resistance. We conclude that in cats with NNNMU-induced respiratory distress: PEEP causes decreases in systemic blood flow, lung compliance and systemic oxygen transport are not clear indicators of optimal PEEP level, and returning end-expiratory lung volume to normal FRC does not significantly reduce pulmonary resistance to gas flow.     

Atorvastatin induces associated reductions in platelet P-selectin, oxidized low-density lipoprotein, and interleukin-6 in patients with coronary artery diseases

The development and progression of atherosclerosis comprises various processes, such as endothelial dysfunction, chronic inflammation, thrombus formation, and lipid profile modification. Statins are 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors that have pleiotropic effects in addition to cholesterol-lowering properties. However, the mechanisms of these effects are not completely understood. Here, we investigated whether atorvastatin affects the levels of malondialdehyde-modified low-density lipoprotein (MDALDL), an oxidized LDL, the proinflammatory cytokine interleukin-6 (IL-6), or platelet P-selectin, a marker of platelet activation, relative to that of LDL cholesterol (LDL-C). Forty-eight patients with coronary artery disease and hyperlipidemia were separated into two groups that were administered with (atorvastatin group) or without (control group) atorvastatin. The baseline MDA-LDL level in all participants significantly correlated with LDL-C (r = 0.71, P < 0.01) and apolipoprotein B levels (r = 0.66, P < 0.01). Atorvastatin (10 mg/day) significantly reduced the LDL-C level within 4 weeks and persisted for a further 8 weeks of administration. Atorvastatin also reduced the MDA-LDL level within 4 weeks and further reduced it over the next 8 weeks. Platelet P-selectin expression did not change until 4 weeks of administration and then significantly decreased at 12 weeks, whereas the IL-6 level was gradually, but not significantly, reduced at 12 weeks. In contrast, none of these parameters significantly changed in the control group within these time frames. The reduction (%) in IL-6 between 4 and 12 weeks after atorvastatin administration significantly correlated with that of MDALDL and of platelet P-selectin (r = 0.65, P < 0.05 and r = 0.70, P < 0.05, respectively). These results suggested that the positive effects of atorvastatin on the LDL-C oxidation, platelet activation and inflammation that are involved in atherosclerotic processes are exerted in concert after lowering LDL-C.     

Health and functional status of adult recipients 1 year after allogeneic haematopoietic stem cell transplantation

Increasing numbers of patients are surviving after allogeneic haematopoietic stem cell transplantation (SCT). Among these patients, a number of late complications have been described but few data on the risk factors of these long-term effects of SCT are available. We report the analysis on 105 adult patients, surviving free of haematological disease at a median time of 15 months after SCT. At the time of screening, 52% had returned to work, general health status was normal in 67% and 47% were sexually active. Female patient gender odds ratio (OR) 2.9 (P = 0.01) and age > 25 years (OR = 3.2, P = 0.02) were associated with non-return to work. Decreased general status was associated with chronic graft-versus-host disease (GvHD) (OR = 3.2, P = 0.009) and irradiation (OR = 3.6, P = 0.004). Sexual inactivity was associated with younger age (OR = 7.0, P = 0.0002) and chronic GvHD (OR = 3.3, P = 0.006). Risk factors for altered pulmonary function tests included previous smoking habits, irradiation and chronic GvHD. Obstructive lung disease was associated with a previous history of asthma. Sicca syndrome and conjunctivitis were increased in patients with previous acute GvHD and cataracts were less frequent in patients with aplastic anaemia. Persistent impaired hair re-growth was less frequent in patients who received irradiation (OR = 0.18, P = 0.002) but increased in patients with previous acute GvHD (OR = 5.3, P = 0.007). Microalbuminuria was more frequent in irradiated patients (OR = 9.4, P = 0.05). Raised cholesterol was associated with age (OR = 20.8, P < 0.001), previous acute GvHD (OR = 4.7, P = 0.03), steroid use (OR = 6.3, P = 0.001) and familial hypercholesterolaemia (OR = 4.4, P = 0.04). Decreased bone density was associated with chronic GvHD (OR = 3.9, P = 0.001). Thus, using routine tests in adult patients we were able to detect significant numbers of-non-symptomatic complications enabling early treatment.     

The psychology of ‘regrettable substitutions’: examining consumer judgements of Bisphenol A and its alternatives

Bisphenol A is a chemical used to make certain types of plastics and is found in numerous consumer products. Because scientific studies have raised concerns about Bisphenol A’s potential impact on human health, it has been removed from some (but not all) products. What many consumers do not know, however, is that Bisphenol A is often replaced with other, less-studied chemicals whose health implications are virtually unknown. This type of situation is known as a potential ‘regrettable substitution’, because the substitute material might actually be worse than the material that it replaces. Regrettable substitutions are a common concern among policymakers, and they are a real-world manifestation of the tension that can exist between the desire to avoid risk (known possible consequences that might or might not occur) and ambiguity (second-order uncertainty), which is itself aversive. In this article, we examine how people make such trade-offs using the example of Bisphenol A. Using data from Study 1, we show that people have inconsistent preferences towards these alternatives and that choice is largely determined by irrelevant contextual factors such as the order in which the alternatives are evaluated. Using data from Study 2, we further demonstrate that when people are informed of the presence of substitute chemicals, labelling the alternative product as ‘free’ of Bisphenol A causes them to be significantly more likely to choose the alternative despite its ambiguity. We discuss the relevance of these findings for extant psychological theories as well as their implications for risk, policy and health communication.     

Health effects in the Flemish population in relation to low levels of mercury exposure: From organ to transcriptome level

Due to possible health risks, quantification of mercury accumulation in humans was included in the Flemish biomonitoring programmes FLEHS I (2002–2006) and FLEHS II (2007–2011). The general objective of FLEHS I was to assess regional exposure levels in order to link possible differences in these internal exposure levels to different types of local environmental pressure. Therefore, Hg and MMHg (methylmercury) were only measured in pooled blood samples per region and per age class. In FLEHS II, mercury concentrations were measured in hair of each participant. About 200 adolescents and 250 mothers (reference group) and two times 200 adolescents (2 hotspots) were screened. The main objectives of the FLEHS II study were: (1) to determine reference levels of mercury in hair for Flanders; (2) to assess relations between mercury exposure and possible sources like fish consumption; (3) to assess dose–effect relations between mercury exposure and health effect markers. The results showed that mercury concentrations in the Flemish population were rather low compared to other studies. Mercury levels in the Flemish populations were strongly related to the age of the participants and consumption of fish. Significant negative associations were observed between mercury in hair and asthma, having received breast feeding as a newborn, age at menarche in girls, allergy for animals and free testosterone levels. Significant correlations were also observed between mercury in hair and genes JAK2, ARID4A, Hist1HA4L (boys) and HLAdrb5, PIAS2, MANN1B1, GIT and ABCA1 (girls).