Practical recommendations for calcium channel antagonist poisoning.

Calcium channel antagonists (CCAs) are widely used for different cardiovascular disorders. At therapeutic doses, CCAs have a favourable side effect profile. However, in overdose, CCAs can cause serious complications, such as severe hypotension and bradycardia. Patients in whom a moderate to severe intoxication is anticipated should be observed in a monitored setting for at least 12 hours if an immediate-release formulation is ingested, and at least 24 hours when a sustained-release formulation (or amlodipine) is involved, even if the patient is asymptomatic. Initial treatment is aimed at gastrointestinal decontamination and general supportive care, i.e., fluid resuscitation and correction of metabolic acidosis and electrolyte disturbances. In moderate to severe CCA poisoning, a combined medical strategy might be indispensable, such as administration of vasopressors, intravenous calcium and hyperinsulinaemia/euglycaemia therapy. Especially hyperinsulinaemia/euglycaemia therapy is an important first-line treatment in CCA-overdosed patients in whom a large ingestion is suspected. High-dose insulin, in combination with glucose, seems to be most effective when used early in the intoxication phase, even when the patient shows hardly any haemodynamic instability. Intravenous lipid emulsion therapy should only be considered in patients with life-threatening cardiovascular toxicity, such as refractory shock, which is unresponsive to conventional therapies. When supportive and specific pharmacological measures fail to adequately reverse refractory conditions in CCA overdose, the use of extracorporeal life support should be considered. The efficacy of these pharmacological and non-pharmacological interventions generally advocated in CCA poisoning needs further in-depth mechanistic foundation, in order to improve individualised treatment of CCA-overdosed patients.

Ethylene glycol or methanol intoxication: which antidote should be used, fomepizole or ethanol?

Ethylene glycol (EG) and methanol poisoning can cause life-threatening complications. Toxicity of EG and methanol is related to the production of toxic metabolites by the enzyme alcohol dehydrogenase (ADH), which can lead to metabolic acidosis, renal failure (in EG poisoning), blindness (in methanol poisoning) and death. Therapy consists of general supportive care (e.g. intravenous fluids, correction of electrolytes and acidaemia), the use of antidotes and haemodialysis. Haemodialysis is considered a key element in the treatment of severe EG and methanol intoxication and is aimed at removing both the parent compound and its toxic metabolites, reducing the duration of antidotal treatment and shortening the hospital observation period. Currently, there are two antidotes used to block ADH-mediated metabolism of EG and methanol: ethanol and fomepizole. In this review, the advantages and disadvantages of both antidotes in terms of efficacy, safety and costs are discussed in order to help the physician to decide which antidote is appropriate in a specific clinical setting.

The olive oil antioxidant hydroxytyrosol efficiently protects against the oxidative stress-induced impairment of the NObullet response of isolated rat aorta.

The Mediterranean diet, which is abundant in antioxidants, is associated with a relatively low incidence of coronary heart disease. Olive oil and olives, which contain the antioxidants hydroxytyrosol, oleuropein, and tyrosol, are important components of this diet. In this study, the effects of oxidative stress on the nitric oxide radical (NO(*))-mediated relaxation of rat aorta and the protection by these antioxidants were determined. Cumene hydroperoxide (CHP) was used to mimic oxidative stress induced by lipid hydroperoxides, which is mediated by the formation of hydroxyl radicals (OH(*)). CHP (300 microM) impaired the NO(*)-mediated relaxation of rat aorta by the acetylcholine receptor agonist carbachol (P < 0.05). This was due to a reduction in NO(*) production. A diminished NO(*)-mediated relaxation disturbs the vascular tone and leads to a rise in blood pressure, which is a well-established risk factor for coronary heart disease. Hydroxytyrosol (10 microM) efficiently protected the aorta against the CHP-induced impairment of the NO(*)-mediated relaxation (P < 0.05). Oleuropein, tyrosol, and homovanillic alcohol, a major metabolite of hydroxytyrosol, did not show protection. Moreover, hydroxytyrosol was found to be a potent OH(*) scavenger, which can be attributed to its catechol moiety. Because of its amphiphilic characteristics (octanol-water partitioning coefficient = 1.1), hydroxytyrosol will readily cross membranes and provide protection in the cytosol and membranes, including the water-lipid interface. The present study provides a molecular basis for the contribution of hydroxytyrosol to the benefits of the Mediterranean diet.

[Podocyte dysfunction and proteinuria]. / Podocytdisfunctie en proteïnurie.

Podocytes play a central role in the pathogenesis of several glomerular diseases. In recent years, this has been revealed by molecular analysis of a number of rare hereditary renal diseases. Podocytes contain three domains: the domain bound to the glomerular basement membrane (GBM), the domain of the slit diaphragms and the apical domain. The slit diaphragms are situated basolaterally between the pedicles and form together with the GBM a mechanism for the selective filtration of blood to primary urine. The apical cell membrane forms a negatively charged layer which prevents adhesion to the adjacent cell membranes, thus keeping the slit diaphragms and urinary space open. Many podocyte diseases are characterised by foot process effacement, which causes the loss of slit diaphragms, and could lead to podocyte loss. Specific abnormalities have been discovered in the three domains of the podocyte to which a number of glomerular diseases can be attributed.