Technique / Pharmacology and Toxicology

Pharmacology is the study of how drugs interact with living organisms to produce a change in function. Toxicology (from the Greek words toxicos and logos) is the study of the adverse effects of chemicals on living organisms.

Neonatal drug dosing needs to be based on the physiological characteristics of the newborn and the pharmacokinetic parameters of the drug. Size-related changes can in part be modelled based on allometry and relates to the observation that metabolic rate relates to weight by a kg 0.75 trend. Until adult metabolic activity has been reached, ontogeny, i.e. isoenzyme-specific maturation and maturation of renal clearance also contributes to drug metabolism, making isoenzyme-specific documentation of maturation necessary. Changes in body composition and ontogeny are most prominent in neonates. The body fat content (/kg) is markedly lower and the body water content (/kg) is markedly higher in neonates.These findings have an impact on the distribution volume of both lipophilic and hydrophilic drugs. Drugs are cleared either by metabolism or elimination.While the first is mainly hepatic, the second route is mainly renal. Both hepatic metabolism and renal clearance display maturation in early life although other covariables (e.g. polymorphisms, co-administration of drugs, first pass metabolism, disease characteristics) further contribute to the interindividual variability in drug disposition. Documentation of these maturational processes based on in vivo 'case' studies is of value since these drug-specific observations can subsequently be extrapolated to other drugs which are either already being prescribed or even considered for use in neonates by the introduction of these observations in 'generic physiologically-based pharmacokinetic' models.

The Kv7 potassium channel family encompasses five members (from Kv7.1 to Kv7.5) having distinct expression pattern and functional role. Although Kv7.1 is prevalently expressed in the cardiac muscle, Kv7.2, Kv7.3, Kv7.4, and Kv7.5 are expressed in neural tissue. Mutations in Kv7.2 and/or Kv7.3 genes are responsible for an autosomal-dominant epilepsy of the newborn defined as benign familial neonatal seizures (BFNS), whereas defects in the Kv7.4 gene have been found in families affected by a rare form of nonsyndromic autosomal-dominant hearing loss (DFNA2). Compounds acting as direct activators of neuronal channels formed by Kv7 subunits have been approved for clinical use as analgesics or are in advanced stages of clinical evaluation as anticonvulsants; in addition to these indications, solid preclinical studies reveal their potential usefulness in other diseases characterized by neuronal hyperexcitability. In the present work, we will summarize the available evidence providing proof-of-principles that neuronal Kv7 channels are highly attractive pharmacological targets, review the molecular basis of their peculiar pharmacological sensitivity, introduce some newly synthesized I(KM) openers showing improved pharmacokinetic or pharmacodynamic properties compared to older congeners, and discuss the potential novel therapeutic application of neuronal Kv7 channels in diseases additional to epilepsy.