Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0029713 (immaturity)
 4,335 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Aspirin is the most commonly used analgesic and antiinflammatory agent. In this study, at physiological concentrations, it profoundly inhibited CD40, CD80, CD86, and MHC class II expression on murine, GM-CSF + IL-4 stimulated, bone marrow-derived myeloid dendritic cells (DC). CD11c and MHC class I expression were unaffected. The inhibitory action was dose dependent and was evident at concentrations higher than those necessary to inhibit PG synthesis. Experiments with indomethacin revealed that the effects of aspirin on DC maturation were cyclooxygenase independent. Nuclear extracts of purified, aspirin-treated DC revealed a decreased NF-kappaB DNA-binding activity, whereas Ab supershift analysis indicated that aspirin targeted primarily NF-kappaB p50. Unexpectedly, aspirin promoted the generation of CD11c+ DC, due to apparent suppression of granulocyte development. The morphological and ultrastructural appearance of aspirin-treated cells was consistent with immaturity. Aspirin-treated DC were highly efficient at Ag capture, via both mannose receptor-mediated endocytosis and macropinocytosis. By contrast, they were poor stimulators of naive allogeneic T cell proliferation and induced lower levels of IL-2 in responding T cells. They also exhibited impaired IL-12 expression and did not produce IL-10 after LPS stimulation. Assessment of the in vivo function of aspirin-treated DC, pulsed with the hapten trinitrobenzenesulfonic acid, revealed an inability to induce normal cell-mediated contact hypersensitivity, despite the ability of the cells to migrate to T cell areas of draining lymphoid tissue. These data provide new insight into the immunopharmacology of aspirin and suggest a novel approach to the manipulation of DC for therapeutic application.
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PMID:Aspirin inhibits in vitro maturation and in vivo immunostimulatory function of murine myeloid dendritic cells. 1139 Apr 49

Patent ductus arteriosus (PDA) is a common complication in preterm infants. An intravenous (IV) cyclooxygenase (COX) inhibitor is the pharmacotherapy of choice. Concerns over adverse effects associated with the traditional treatment, IV indomethacin, have led to the investigation of other COX inhibitors to assist closure of PDA. IV ibuprofen lysine is a COX inhibitor that demonstrates similar efficacy to indomethacin with few adverse effects. In addition, IV ibuprofen lysine does not cause reductions in cerebral, renal, and mesenteric blood flow that can be seen with indomethacin, and thus ibuprofen therapy is not associated with reduced renal function. Ibuprofen is primarily metabolized by cytochrome P450 (CYP) 2C9. The immaturity of neonatal biotransformation pathways has a pronounced effect on the pharmacokinetic parameters of ibuprofen, particularly because CYP2C9 enzyme activity is known to be very low at birth and to increase rapidly over the first several days of life. Ibuprofen is highly bound to albumin, raising concern that ibuprofen may displace bilirubin and subsequently increase free bilirubin concentrations. However, the ibuprofen concentrations achieved with approved dosing with IV ibuprofen lysine are lower than those expected to result in displacement of bilirubin and related adverse effects. Factors such as gestational age and CYP2C9 polymorphism may affect ibuprofen metabolism and therefore optimal dosing, but further clinical investigation is needed in these areas. Other areas for future investigation include prolonged dosing regimens, prophylactic administration, and alternate indications. At the approved dose, IV ibuprofen lysine is a safe, effective pharmacologic agent to promote closure of PDAs in preterm infants.
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PMID:Pharmacologic, pharmacodynamic, and pharmacokinetic considerations with intravenous Ibuprofen lysine. 2305 51