RESUMO
In 2009 we reported the fatal case of a toddler who had received codeine after adenotonsillectomy for obstructive sleep apnea syndrome. The child was an ultra-rapid metabolizer of cytochrome P4502D6 (CYP2D6). We now report 3 additional fatal or life-threatening cases from North America. In the 2 fatal cases, functional gene duplications encoding for CYP2D6 caused a significantly greater production of potent morphine from its parent drug, codeine. A severe case of respiratory depression in an extensive metabolizer is also noted. These cases demonstrate that analgesia with codeine or other opioids that use the CYP2D6 pathway after adenotonsillectomy may not be safe in young children with obstructive sleep apnea syndrome.
Assuntos
Adenoidectomia/mortalidade , Analgésicos Opioides/toxicidade , Codeína/toxicidade , Complicações Pós-Operatórias/induzido quimicamente , Complicações Pós-Operatórias/mortalidade , Apneia Obstrutiva do Sono/cirurgia , Tonsilectomia/mortalidade , Alelos , Analgésicos Opioides/administração & dosagem , Analgésicos Opioides/farmacocinética , Broncopneumonia/induzido quimicamente , Broncopneumonia/mortalidade , Pré-Escolar , Codeína/administração & dosagem , Codeína/farmacocinética , Citocromo P-450 CYP2D6/genética , Evolução Fatal , Feminino , Duplicação Gênica/genética , Genótipo , Humanos , Inativação Metabólica/genética , Masculino , Taxa de Depuração Metabólica/genética , Morfina/farmacocinética , Morfina/toxicidade , Fatores de RiscoRESUMO
Ifosfamide (IFO), which is used in the treatment of pediatric solid tumors, causes high rates of nephrotoxicity. N-acetylcysteine (NAC), an antidote for acetaminophen overdose, has been shown to prevent IFO-induced renal cell death and nephrotoxicity in both LLCPK-1 cells and a rat model. To facilitate the use of NAC in preventing IFO-induced nephrotoxicity in children, the authors compared the systemic exposure to NAC in children treated for acetaminophen overdose to the systemic exposure of the therapeutically effective rat model. The mean systemic exposure in the rat model was 18.72 mM·h (range, 9.92-30.02 mM·h), compared to the mean systemic exposure found in treated children (14.48 mM·h; range, 6.22-32.96 mM·h). They also report 2 pediatric cases in which NAC-attenuated acute renal failure associated with IFO when given concurrently with their chemotherapy treatment. Systemic exposure to NAC measured in 1 of these cases was comparable to that in the children treated for acetaminophen overdose. These results corroborate NAC's potential to protect against IFO-induced nephrotoxicity in children when used in its clinically approved dose schedule and supports a clinical trial in children.
