Experimental Serotonin Syndrome: Effects of GABA-ergic Medications and 5-HT2-Antagonists

Serotonin syndrome (SS) is a potentially life-threatening adverse drug effect that occurs after an overdose or combined administration of two or more drugs that increase the serotonin levels. In humans, SS is represented by a triad of symptoms including mental status changes, neuromuscular hyperactivity and autonomic dysfunction. The manifestations of the syndrome observed in rodents resemble the symptoms of SS in humans. Theoretically, SS can occur as a result of stimulation of any of the seven families of the serotonin receptors. However, most data support the involvement of 5-HT1A and 5-HT2A receptors. A number of studies indicate the effectiveness of 5-HT2 antagonists and GABA-ergic agents in the treatment of the hyperthermia and other symptoms of SS in rats. Therefore, animal models of SS may help to further elucidate the mechanism of its development and the possibilities for its treatment.

Evaluating risk detection methods to uncover ontogenic-mediated adverse drug effect mechanisms in children

BackgroundIdentifying adverse drugs effects (ADEs) in children is essential for preventing disability and death from marketed drugs. At the same time, however, detection is challenging due to dynamic biological processes during growth and maturation, called ontogeny, that alter pharmacokinetics and pharmacodynamics. As a result, current data mining methodologies have been limited to event surveillance and have not focused on investigating adverse event mechanisms. There is an opportunity to design data mining methodologies to identify and evaluate drug event patterns within observational databases for ontogenic-mediated adverse event mechanisms. The first step of which is to establish statistical models that can identify temporal trends of adverse effects across childhood.ResultsUsing simulation, we evaluated a population stratification method (the proportional reporting ratio or PRR) and a population modeling method (the generalized additive model or GAM) to identify and quantify ADE risk at varying reporting rates and dynamics. We found that GAMs showed improved performance over the PRR in detecting dynamic drug event reporting across child developmental stages. Moreover, GAMs exhibited normally distributed and robust ADE risk estimation at all development stages by sharing information across child development stages.ConclusionsOur study underscores the opportunity for using population modeling techniques, which leverages drug event reporting across development stages, to identify adverse drug effect risk resulting from ontogenic mechanisms.

High Direct Bilirubin Associated With Levoffoxacin Use in a Neonate

Limited data exist regarding the use of fluoroquinolones in the neonatal population. Levofloxacin has some utility in this population because it is one of a very limited number of antibiotics with activity against Stenotrophomonas maltophilia. We describe the successful treatment of S maltophilia tracheitis in a premature neonate using levofloxacin 10 mg/kg every 24 hours and the subsequent unexpected sharp rise in the direct bilirubin. This case illustrates a previously unrecognized adverse drug effect associated with levofloxacin use in neonates.