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Developmental Pharmacology - NIH Clinical Center - Americas 发育药理学NIH临床中心-美国
Developmental Pharmacology Scaling adult doses to infants based on body weight or surface area does not account for developmental changes that affect drug disposition or tissue/organ sensitivity. Frank Balis, M.D. February 22, 2007 Chloramphenicol Natural product of Streptomyces (1947) Inhibits protein synthesis (bacteriostatic) Eliminated by glucuronide conjugation (90%) and renal excretion (10%) Nursery infections treated with high doses Chloramphenicol in Infants 3320 gm infant, 44 week gestation Meconium stained, foul smelling, timing of ROM unknown Procaine penicillin (50,00 units) + chloramphenicol (250 mg) IM q8h - 230 mg/kg/day x 72 hr Day 4, gray color cold, moist skin Died at 106 hr, 8 hr after onset of vascular collapse Chloramphenicol in Premature Infants Gray Baby Syndrome Chloramphenicol Blood Levels Chloramphenicol Pharmacokinetics Repeated Administration Drug Use in Infants and Children Zidovudine in the Newborn Zidovudine in Newborns Prevention of HIV Transmission Ontogeny and Pharmacology Excretory organ (liver and kidneys) development has the greatest impact on drug disposition (pharmacokinetics) The most dramatic changes occur during the first days to months of life Anticipate age-related differences in drug disposition based on knowledge of ontogeny Effect of ontogeny on tissue/organ sensitivity to drugs (pharmacodynamics) is poorly studied Disease states may alter a drug’s PK/PD Renal Ontogeny Glomerular filtration rate Low at birth Full term newborn - 10-15 ml/min/m2 Premature - 5-10 ml/min/m2 GFR doubles by 1 week of age Adult values by 6-12 months of age Tubular function Secretory function impaired at birth Glomerulotubular imbalance Adult values by 1 year of age Glomerular Filtration Rate GFR in Infants Gentamicin in the Newborn Gentamicin Clearance Hepatic Ontogeny Phase 1 (oxidation, hydrolysis, reduction, demethylation) Activity low at birth Mature at variable rates Oxidative metabolism increases rapidly after birth Alcohol dehydrog
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