BACKGROUND We evaluated the clinical effectiveness of variable courses of paracetamol

BACKGROUND We evaluated the clinical effectiveness of variable courses of paracetamol on patent ductus arteriosus (PDA) closure and examined its effect on the term and preterm murine ductus arteriosus (DA). infants (= 5). The PDA became less significant and eventually closed in six LCOP infants (= 7). PDA closure was achieved in eight IVP infants (= 9). On pressure myograph paracetamol induced a concentration-dependent constriction of the term mouse DA up to 30% of baseline (< 0.01) but required >1 μmol/l. Indomethacin induced greater DA constriction and suppression of prostaglandin synthesis (< 0.05). CONCLUSION The clinical efficacy of paracetamol on PDA closure may depend on the duration of treatment and the mode of administration. Paracetamol is less potent than indomethacin for constriction of the mouse DA evaluation of the dose-responsiveness of paracetamol in the term and preterm murine ductus arteriosus (DA) (phase II). RESULTS Human Study A total of 21 infants were included in the study; specifically 5 infants received a short course of oral paracetamol (SCOP) 7 received a long course of oral paracetamol (LCOP) and 9 infants received a course Rabbit polyclonal to ALDH3B2. of intravenous paracetamol (IVP) (Table 1). The PDA remained open in all neonates who received SCOP. There was neither clinical improvement nor change in the echocardiography markers of hemodynamic significance following treatment (Table 2). All infants eventually required PDA ligation. Seven infants received a LCOP URB754 (LCOP group Table 1). Following a 7-d course PDA closure was achieved in one patient and there was a reduction of ductal diameter and an improvement of the echocardiography markers of PDA significance in five infants (Table 2). All six infants demonstrated clinical improvement and were successfully weaned from respiratory support. There was no response to treatment in one infant who required PDA ligation. Table 1 Individual patient characteristics and response to paracetamol treatment Table 2 Echocardiography characteristics before and after treatment of the groups Nine infants received IVP treatment (IVP group). Of these five achieved immediate PDA closure and three infants demonstrated a significant reduction of PDA diameter (Table 2). Subsequent PDA closure was achieved in the three infants prior to discharge without any need for further intervention. The remaining infant had a nonsignificant PDA on discharge. Two infants died during their hospital stay due to unrelated causes (pulmonary hypoplasia and cystic periventricular leukomalacia). None of the deaths occurred during paracetamol therapy. None of the infants in the cohort had elevated liver enzyme or developed liver toxicity. None of the PDAs successfully closed following LCOP or IVP reopened URB754 after treatment. Study The isolated mouse DA is more sensitive to indomethacin than paracetamol Exposure to paracetamol did not produce a significant change in the diameter of the preterm DA. Indomethacin caused a small but significant constriction of the ductus with increasing concentration (Figure 2a). In contrast indomethacin produced marked constriction of the isolated mouse ductus at term gestation with complete closure of the vessel lumen at the highest concentrations studied (Figure 2b). Paracetamol also caused significant concentration-dependent constriction of the term ductus. The magnitude of paracetamol-induced constriction was less than half of indomethacin-induced constriction at each concentration. lumen closure was not observed in paracetamol treated vessels. Figure 2 Response of the ductus arteriosus to paracetamol and indomethacin. The isolated ductus of preterm mice (a) displayed URB754 limited response to increasing concentrations of paracetamol (black squares = 12) whereas indomethacin (white circles = … Indomethacin inhibits ductus-specific prostaglandin production Due to the limited quantity of preterm ductus URB754 tissue and because isolated preterm vessels had only URB754 modest response to inhibitors (Figure 2a) only the excised ductus of term gestation mice was assayed for URB754 prostaglandin synthesis. We observed significant reduction in 6-keto prostaglandin F1α (PGF1α) the stable metabolite of prostacyclin (PGI2) and prostaglandin E2 (PGE2) in response to indomethacin treatment (Figure 3). A reduced trend in prostaglandin (PG) synthesis was noted in.