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Over a 4-year period, 63 premature babies presenting with patent ductus arteriosus were treated with indomethacin at two different dosage levels (0.1 and 0.2 mg/kg). For all infants the permanent closure rate was 68% (56% with 0.1 mg/kg and 75% with 0.2 mg/kg - n.s.) and the positive response rate (i.e. permanent and transient closure) 84%. There was no difference between the two dosages in the incidence of side-effects, particularly on diuresis, and in mortality and morbidity rates; the overall mortality rate was 31%. Pharmacokinetic studies performed in 51 cases did not show any difference related to indomethacin dosage. The changes observed after 2 or 3 doses resulted from improvement in haemodynamics. This study confirms the effectiveness of indomethacin in the treatment of patent ductus arteriosus and suggests an advantage for the 0.2 mg/kg dose.

Indomethacin (I) pharmacokinetics was evaluated in 6 premature infants who received the drug for treatment of patent ductus arteriosus. Administered by oral or rectal route, I (0.2 mg/kg/24 h X 3) was promptly absorbed with peak plasma concentrations attained within 1 and 3 h. The elimination of I appeared to follow two compartment open model kinetics, with terminal plasma half-lives ranging from 30 to 90 h. Apparent plasma clearance values were between 0.076 and 0.335 ml/min/kg. Ductal closure was observed in 4 of the 6 infants. Data point to a possible relationship between therapeutic effects and I plasma concentrations.

The pharmacokinetic and pharmacodynamic effects of indomethacin were studied in 18 prematures with patent ductus arteriosus, treated either enterally (group I, n = 7), or intravenously (group II, n = 11). A definitive closure assessed by echocardiography was observed in 13 cases (72%), and it was only transient in 4 cases (21%). Assisted ventilation was discontinued between 1 and 6 days following therapy in 14 cases. In most cases, indomethacin induced a significant reduction of diuresis but the plasma creatinine level increased above 15 mg/l in 3 cases only. The elimination half life of indomethacin (t 1/2 beta), of 40.3 +/- 12.2 hours in group I and 33.9 +/- 11.7 hours in group II, is increased as compared with adults. The difference of the surface under the curve (AUC O leads to 24 h, ng.ml-1.h-1) between the infants who presented complete or transient closure, suggests a relationship between the biodisponibility of the drug and the effect on patent ductus arteriosus. Treatment with indomethacin is an interesting alternative to surgical ligation in prematures with patent ductus arteriosus. Because of its side effects, especially on the kidneys, it is recommended to use this treatment only in intensive care units. The intravenous route seems to be better than the enteral route.