Pharmacokinetics and clinical efficacy of indomethacin in premature infants with patent ductus arteriosus

Despite a considerable amount of investigation, controversy continues concerning the use of indomethacin in inducing the closure of patent ductus arteriosus. This controversy may be attributable to differences in dosage, route of administration, postnatal age at treatment and the variable pharmacokinetics of the drug in premature infants. The pharmacokinetics and clinical efficacy of i.v. administered indomethacin in five premature infants with PDA were evaluated. There was considerable intersubject variability in the half life of elimination (63.1 +/- 38 h). This variability was mainly due to clearance (0.0086 +/- 0.0069 l/h/kg) rather than to distribution volume variability (0.54 +/- 0.27 l/kg). A reduction of half life was observed after the second dose, probably due to a maturation process. A permanent closure of the ductus was obtained in two patients after the first dose and in two patients after the second dose. The side-effects observed in our infants were transient and no long-term complication was attributable to this drug.     

Pharmacokinetics of oral ibuprofen in premature infants

Patent ductus arteriosus (PDA) is a frequent complication in premature infants. So far, intravenous indomethacin is the standard mode of medical therapy in such patients but carries a risk of frequently occurring side effects. Ibuprofen, another nonsteroidal anti-inflammatory drug, has also been shown to be efficacious in closing ductus with lesser adverse effects after parenteral administration. However, limited data are available on the pharmacokinetics of intravenous ibuprofen in this population. Nonavailability of parenteral preparation and lack of information regarding pharmacokinetic disposition of ibuprofen in this subgroup of the population led the authors to conduct this pharmacokinetic study with oral ibuprofen. Twenty premature infants with a gestational age of 30.45 +/- 0.33 weeks and a birth weight of 1262.5 +/- 55.4 g (values given as mean +/- SEM) admitted to the neonatal unit were enrolled in this study. Ibuprofen was administered in a single oral dose of 10 mg/kg between 4 and 72 hours postnatally, and blood samples were collected through an indwelling vascular catheter at time 0 and 1, 2, 4, 8, 12, and 24 hours. Ibuprofen plasma concentrations were assayed by high-performance liquid chromatography. There was a large interindividual variability observed for plasma concentrations, elimination half-life (t1/2) (15.72 +/- 3.76 h), and area under the plasma concentration-time curve (AUC0-infinity) (402.60 +/- 79.67 micrograms.h/mL) in these babies. Variables such as gestational age, birth weight, and sex did not affect ibuprofen pharmacokinetics significantly (p > 0.05). Moreover, no correlation could be found between elimination half-life and gestational age (r = 0.02). Ibuprofen pharmacokinetics showed a wide variability in premature infants. The results of the present study warrant revising the oral dosage schedule to achieve comparable plasma concentrations of ibuprofen associated with successful closure of ductus, as reported in earlier studies.     

Comparative evaluation for the use of oral ibuprofen and intravenous indomethacin in Korean infants with patent ductus

Ductus arteriosus is a normal connecting blood vessel between the pulmonary artery and aorta in the fetus. However, if the ductus arteriosus is not closed and maintained as the open state even after 72 h of the birth, this is called a patent ductus arteriosus (PDA). Intravenous indomethacin is the conventional treatment for PDA in immature infants, but remains controversial in mature infants. The purpose of this study was to compare intravenous indomethacin and oral ibuprofen with regard to efficacy and safety for treatment of PDA. 78 neonates treated for PDA were included and classified into immature (n = 49) and mature (n = 29) groups. Ductal closure occurred in immature infants treated with indomethacin (74.1%) and ibuprofen (90.9%). Ductal closure occurred in mature infants treated with indomethacin (66.7%) and ibuprofen (92.9%). Platelet counts were increased in immature infants treated with ibuprofen (p = 0.027). Hyponatremia occurred in immature infants treated with ibuprofen (p = 0.002) and in both groups of mature infants (p = 0.001 for both groups). Serum creatinine values were lowered in mature infants treated with ibuprofen (p = 0.032). Bleeding occurred in 5 immature infants treated with indomethacin. Administration of furosemide for urine output was more frequent in the mature groups than in the immature group. In conclusion, oral ibuprofen was as effective as intravenous indomethacin in the immature groups and more effective in the mature groups. Adverse effects of oral ibuprofen were less severe than intravenous indomethacin.     

Indomethacin disposition and indomethacin-induced platelet dysfunction in premature infants

Indomethacin failed to produce permanent ductal closure in any of four premature infants with patent ductus arteriosus to whom the drug was given. Indomethacin half-lives measured in two premature infants were 21 and 24 hours, respectively, much longer than in full-term newborns or adults. Platelet function, as measured by platelet aggregation, was grossly abnormal for two to four days after indomethacin administration, normal values returning only by the ninth and tenth days. Gastrointestinal bleeding and transient renal dysfunction occurred in one infant. Measurement of plasma indomethacin concentrations in sick, low-birthweight infants could help guide indomethacin dose and dosage interval, prevent drug accumulation, and reduce toxicity. Further studies of potential toxicity seem to be indicated before instituting widespread indomethacin administration for ductal closure in premature infants.     

The pharmacokinetics and metabolism of the anilide local anaesthetics in neonates

Summary The pharmacokinetics and metabolism of mepivacaine has been studied in premature neonates dosed subcutaneously and in healthy adults dosed intravenously. The pharmacokinetics of mepivacaine in four neonates (N) was compared with that in six adults (A). Newborns had a significantly longer terminal phase half-life than adults (N mean 8.69 h; A mean 3.17 h). Total plasma clearance normalized on body weight was significantly smaller in neonates (mean 2.34 ml/min/kg) than in adults (mean 5.47 ml/min/kg), as was the hepatic blood clearance (N mean 1.37 ml/min/kg; A mean 5.10 ml/min/kg). The renal plasma clearance, however, was significantly greater in neonates (mean 0.76 ml/min/kg) than adults (mean 0.20 ml/min/kg). There was an average six-fold increase in the fraction of the dose excreted unchanged in newborns (mean 43.3%) compared to adults (mean 7.1%) with acidified urine (pH 5.5–6.0). There was significantly more of the mono-N-demethylated metabolite of mepivacaine excreted by newborns (mean 11.4%) than by adults (mean 2.2%), but their capacity to carry out aromatic hydroxylation of mepivacaine was negligible. These results for mepivacaine were compared with those previously reported for lignocaine in premature infants. The immaturity of hepatic function appears to have diminished more profoundly the ability of premature infants to metabolize mepivacaine than lignocaine. These findings are discussed in terms of perfusion theory of hepatic drug elimination.     

Orogastric and intravenous indomethacin administration to very premature neonates with patent ductus arteriosus: population pharmacokinetics, absolute bioavailability, and treatment outcome

A population pharmacokinetic model was developed after administration of orogastric and/or intravenous indomethacin for the treatment of patent ductus arteriosus in preterm infants. Plasma indomethacin concentrations (n=227) were obtained from 90 preterm infants of median gestational age 27 weeks, mean postnatal age of 12 days, and a mean current weight (WT) of 1010 g. Infants received one to three courses of indomethacin (0.1 mg/kg per day for 6 days). A one-compartment model was fitted to the data to obtain estimates of clearance (CL), volume of distribution (V), absorption rate constant (Ka) and orogastric bioavailability (F), using NONMEM. Model robustness was assessed by bootstrapping with replacement (500 samples). The structural model was: CL (L/h)=0.0166 (WT / 0.936)1.54; V (L)=0.484 (WT / 0.936)1.41; F=0.986; Ka (h(-1))=0.786. The interindividual variability for CL and V was 57.7% and 45.6%, respectively. There remained considerable residual unexplained variability (45.4%). Mean (range) conditional estimates from individual infants for CL, V, and elimination half-life were 18.9 (4.7-45.5) mL/h/kg, 509 (191-1120) mL/kg, and 20.0 (12.0-37.3) hours, respectively. Complete ductus closure occurred in 67% of patients. Infants of lower gestational age or birth weight had less chance of successful ductal closure. There was no obvious dose-response relationship between systemic exposure to varying plasma indomethacin concentrations and ductus closure, which does not support individualized indomethacin dosing based on monitoring to a target plasma concentration.     

Pharmacokinetics of furosemide in neonates

Summary The pharmacokinetics of furosemide was evaluated in 12 newborns who received the drug transplacentally, and in 21 neonates who received it directly for therapeutic reasons. In the first group, the apparent plasma half-lives ranged from 96 to 6.8 h with a significant inverse relationship (p<0.01) between the gestational age and the elimination rate. In two cases a clear effect on diuresis was also observed. In the neonates receiving the drug i.v. for therapeutic reasons, the elimination kinetics appeared to follow a two-compartment open model, with a significant difference in the therminal plasma half-life between premature (26.8±12.2 h) and full-term newborns (13.4±8.6 h). In this group no relationship was observed between elimination rate and either gestational or conceptional age. In the case of repeated administration, an increase in plasma clearance and reduction in t_1/2 β was noticed.     

Induction of microsomal enzyme activity by flupenthixol in chronic schizophrenics

The effect of long-term treatment with flupenthixol on hepatic microsomal enzyme activity was studied in 12 chronic schizophrenic outpatients who had been receiving two weekly maintenance doses for at least 6 months. Antipyrine half-life was measured in the 12 patients while they continued to receive the drug. Flupenthixol was then discontinued for 6 weeks and antipyrine half-life was repeated in 7 of the 12 patients. In the 12 patients the plasma antipyrine elimination half-life was 4–24 h (mean 9.73±1.61 h) when receiving flupenthixol and there was a significant negative correlation between antipyrine half-life and the dose of flupenthixol (r=0.582, P<0.05). In the seven patients to whom antipyrine was given on two occasions, antipyrine half-life was 7.33±1.07 h and 12.04±1.87 h on and off flupenthixol treatment respectively. The clearance significantly decreased when flupenthixol was discontinued, but there was no change in the apparent volume of distribution.     

An unreported complication of intravenously administered ibuprofen: gastrointestinal bleeding

Ibuprofen is used for the closure of ductus arteriosus either intravenously or enterally. Although intraventricular hemorrhage, necrotizing enterocolitis, bronchopulmonary dysplasia, transient renal failure, oliguria, hyponatremia and thrombocytopenia are reported complications during or after ibuprofen treatment, gastrointestinal bleeding, to our knowledge, has not been reported previously. We herein report a premature newborn, in whom ibuprofen was used intravenously for the closure of ductus arteriosus and gastrointestinal bleeding developed as a complication, and aim to discuss this rare adverse effect. In conclusion, we emphasize the importance of close follow-up of premature newborns during intravenous ibuprofen treatment considering also the other rare systemic side effects reported in the literature.     

布洛芬治疗早产儿动脉导管未闭失败的影响因素分析

目的：探究布洛芬治疗胎龄小于37周且出生体质量<1 500 g早产儿动脉导管未闭（PDA）失败的影响因素,寻找PDA布洛芬治疗失败的危险因素。方法：选取2017年1月30日至2019年3月30日于我院就诊的400例胎龄<37周且出生体质量<1 500 g的PDA早产儿,均接受布洛芬治疗和床旁心电图检查。根据动脉导管是否封闭分为动脉导管未封闭组和动脉导管封闭组,分析早产儿PDA治疗失败的影响因素。结果：400例PDA患儿在接受布洛芬治疗后,140例导管未封闭,治疗失败率为35.0%,导管封闭260例,封闭率为65.0%。动脉导管未封闭组胎龄小于动脉导管封闭组,出生体质量低于动脉导管封闭组,动脉导管两端压差、宫内窘迫、窒息史、合并感染、呼吸支持、新生儿临床危险指数评分、左心房与主动脉根部内径比高于动脉导管封闭组,首次治疗日龄大于动脉导管封闭组,差异有统计学意义（P<0.05）。多因素回归分析结果显示,出生体质量、呼吸窘迫综合征、新生儿临床危险指数评分、窒息史、动脉导管两端压差、呼吸支持、合并感染是布洛芬治疗PDA失败的独立影响因素。结论：出生体质量低、合并宫内窘迫、呼吸窘迫综合征、感染、动脉导管两端压差较大、呼吸支持、新生儿临床危险指数评分>5分是出生体质量小于1 500 g PDA早产儿布洛芬治疗失败的危险因素。     

Pharmacologic management of patent ductus arteriosus

The incidence, pathophysiology, and clinical findings of symptomatic patent ductus arteriosus (PDA) are reviewed, and the pharmacologic management of symptomatic PDA is discussed. Spontaneous closure of the ductus arteriosus (DA) usually occurs within four days after birth in most premature and full-term infants. The incidence of PDA is related to birth weight in premature infants and has been shown to decrease with an increase in birth weight. Clinical findings are reviewed. Prophylactic treatment in the first few hours after birth may not be needed in most premature infants. Treatment should be considered only if the ductus becomes symptomatic. Medical management consists of respiratory support, fluid restriction, diuretics, digoxin, and indomethacin. Respiratory support, fluid restriction, and diuretics are used as first-line treatment of symptomatic PDA. Digoxin cannot be recommended as part of first-line therapy, since its risks seem to outweigh the benefits in preterm infants. Indomethacin should be used only if other standard measures including fluid restriction and diuretic treatment fail. The mechanism of action, pharmacokinetics, adverse effects, and drug interactions of indomethacin are discussed. Symptomatic PDA can increase morbidity and mortality, especially in very low birth weight infants. Treatment of symptomatic PDA may decrease the morbidity associated with this condition.     

Pharmacokinetics of tocainide in patients with renal dysfunction and during haemodialysis

Summary The disposition of tocainide was studied in 15 patients with renal dysfunction. In 9 with total renal failure, the plasma half-life ranged from 16.6 to 42.7 h and total plasma clearance from 35 to 94 ml/min. The longest half-lives were found in 1 patient with cirrhosis, 3 taking the enzyme inhibitor allopurinol, and 1 on cimetidine. The mean half-life in the remaining patients was 22.3±4.8 h (±SD). During a 4 h haemodialysis, the half-life in the 9 patients decreased to 8.5±4.6 h, which was calculated to correspond to removal of 25±14% of the drug from the body. In 6 patients with impaired renal function (creatinine clearance 10–55 ml/min) the tocainide half-life ranged from 13.2 to 22.0 h and total plasma clearance from 72 to 122 ml/min. One patient was taking allopurinol and 1 dihydralazine, and the mean half-life in the others was 19.2±4.0 h. The apparent volume of distribution was similar to that found previously in healthy subjects. The results suggest that tocainide elimination is predictably reduced in patients with renal disease.     

布洛芬与对乙酰氨基酚治疗早产儿症状性动脉导管未闭对患儿血浆和尿前列腺素E_2水平的影响

目的分析布洛芬与对乙酰氨基酚治疗早产儿症状性动脉导管未闭(sPDA)对患儿血浆和尿前列腺素E_2(PGE_2)水平的影响。方法纳入2014年7月至2016年12月我院出生的患有sPDA的84例早产儿作为观察对象。随机纳入42例给予布洛芬进行治疗(A组),另外42例给予对乙酰氨基酚治疗(B组)。对比两组治疗疗效,治疗前后血浆和尿PGE_2水平以及不良反应。结果两组患儿在各时段的关闭率以及总关闭率的组间差异均无统计学意义(P>0.05)。经治疗,两组患儿血浆PGE_2和尿PGE_2水平均较治疗前下降,与治疗前比较差异有统计学意义(P<0.05);A组下降程度稍大于B组,但组间差异均无统计学意义(P>0.05)。经治疗,两组患儿肝肾功能指标血肌酐(SCr)和丙氨酸氨基转移酶(ALT)水平均较治疗前略有上升(P>0.05),血小板(PLT)较治疗前有所下降,但差异无统计学意义(P>0.05);两组SCr、ALT及PLT水平比较差异无统计学意义(P>0.05)。B组高胆红素血症比例低于A组,组间差异有统计学意义(P<0.05),其他不良反应上,组间差异均无统计学意义(P>0.05)。结论布洛芬与对乙酰氨基酚的疗效相当,其对血浆PGE_2和尿PGE_2水平的影响略强于对乙酰氨基酚,但对乙酰氨基酚高胆红素血症的比例低于布洛芬。     

Pharmacokinetics of sotalol during pregnancy

Summary Sotalol, a beta-adrenoceptor blocking drug, was administered to 6 healthy pregnant volunteers between 32–36 weeks gestation and when at least 6 weeks post-partum. On both occasions, each volunteer was given sotalol 100 mg intravenously and 400 mg orally in randomised order with at least a 1 week washout period between. Plasma samples were analysed for sotalol using a fluorometric method and the pharmacokinetic profiles investigated. The systemic clearance of sotalol was significantly greater in the antenatal period (2.4±0.3 ml/min/kg) than in the post-natal phase (1.5±0.1 ml/min/kg). The apparent volume of distribution was similar in the two periods: the elimination half-life was 6.6±0.6h ante-natally and 9.3±0.7h post-natally after intravenous drug but the trend for faster elimination was not significant. The elimination half-life after oral administration (about 10h) and bioavailability (about 90%) were not altered significantly by pregnancy. It is suggested that the more rapid clearance of sotalol in pregnancy may be due to increases in renal plasma flow and glomerular filtration rate.     

布洛芬口服治疗新生儿呼吸窘迫综合症合并动脉导管未闭临床观察

目的：探讨布洛芬口服治疗新生儿呼吸窘迫综合症（NRDS）患儿发生动脉导管未闭（PDA）的有效性和安全性。方法：32例NRDS发生PDA的早产儿随机分成两组,一组口服布洛芬混悬液,另一组口服吲哚美辛,记录每天尿量、黄疸、消化道出血等情况．48h后再次予心脏彩色超声多谱勒检查。结果：总有效率两组比较无显著性差异;不良反应布洛芬组明显优于消炎痛组．有显著性差异。结论：布洛芬混悬液治疗早产儿PDA具有疗效好,不良反应少,临床应用限制较少的优点。     

Clinical pharmacokinetics of bezafibrate in patients with impaired renal function

Summary The pharmacokinetics of the new lipidlowering drug bezafibrate has been investigated in patients with impaired renal function and hyperlipoproteinaemia. 12 patients received a single oral dose of bezafibrate 300 mg. Plasma and urine samples were collected and bezafibrate was analyzed by gas chromatography. Eight of the patients had moderately impaired renal function, with a creatinine clearance between 20 and 40 ml/min; the mean plasma half-life of bezafibrate in them was 7.8±3.9 h (SD) and the plasma clearance was 0.03±0.02 l/kg · h. Three of the patients had a creatinine clearance>40 ml/min; in them the plasma half-life was shorter, 4.6±1.2 h, and the plasma clearance was higher, 0.06±0.01 l/kg · h. The slowest elimination of bezafibrate was found in a patient with a creatinine clearance of only 13 ml/min. This patient had a plasma half-life of 20.1 h, which is ten times longer than has been reported in healthy volunteers. Thus, when treating hyperlipoproteinaemia in patients with impaired renal function, the dosage of bezafibrate must be individualized because of its reduced renal elimination.     

Patent ductus arteriosus in premature neonates

Persistent patency of the ductus arteriosus is a major cause of morbidity and mortality in premature infants. In infants born prior to 28 weeks of gestation, a haemodynamically significant patent ductus arteriosus (PDA) can cause cardiovascular instability, exacerbate respiratory distress syndrome, prolong the need for assisted ventilation and increase the risk of bronchopulmonary dysplasia, intraventricular haemorrhage, renal dysfunction, cerebral palsy and mortality. We review the pathophysiology, clinical features and assessment of haemodynamic significance, and provide a rigorous appraisal of the quality of evidence to support current medical and surgical management of PDA of prematurity. Cyclo-oxygenase inhibitors such as indomethacin and ibuprofen remain the mainstay of medical therapy for PDA, and can be used both for prophylaxis as well as for rescue therapy to achieve PDA closure. Surgical ligation is also effective and is used in infants who do not respond to medical management. Although both medical and surgical treatment have proven efficacy in closing the ductus, both modalities are associated with significant adverse effects. Because the ductus does undergo spontaneous closure in some premature infants, improved and early identification of infants most likely to develop a symptomatic PDA could help in directing treatment to the at-risk infants and allow others to receive expectant management.     

早产儿发生动脉导管未闭的影响因素分析

目的探讨早产儿发生动脉导管(DA)未闭(PDA)的影响因素,及PDA相关并发症发生情况。方法选取30例PDA早产儿作为研究组,同期出生的未发生PDA的42例早产儿作为对照组,根据患儿及产妇的临床资料,分析早产儿发生PDA的危险因素,并比较两组并发症(肺炎、颅内出血、心力衰竭)发生情况。结果产前吸氧、产前应用硫酸镁是早产儿发生PDA的保护因素,败血症、体重<1500 g是早产儿发生PDA的危险因素。研究组肺炎、颅内出血、心力衰竭发生率分别为26.67%、13.33%、23.33%,均高于对照组的7.14%、0、4.76%,差异均具有统计学意义(P<0.05)。结论产前吸氧、产前应用硫酸镁是早产儿发生PDA的保护因素,败血症、体重<1500 g是早产儿发生PDA的危险因素。PDA早产儿容易并发肺炎、颅内出血及心力衰竭。     

Disposition,Bioavailability, and Serum Protein Binding of Pentachlorophenol in the B6C3F1 Mouse

The toxicokinetics of pentachlorophenol (PCP) were studied in B6C3F1 mice, a strain in which PCP was previously found to be carcinogenic. In a crossover design, doses of 15 mg/kg were given intravenously (bolus) and orally (gastric intubation) to six animals. Concentrations of PCP in blood, urine, and feces were measured by capillary gas chromatography with electron-capture detection. After intravenous administration, the values of clearance and volume of distribution were 0.057 ± 0.007 L/hr/kg and 0.43 ± 0.06 L/kg, respectively. These two parameters exhibited low intermouse variability (coefficients of variation <14%). The elimination half-life was 5.2 ± 0.6 hr. After oral administration, the PCP peak plasma concentration (28 ± 7 µg/ml) occurred at 1.5 ± 0.5 hr and absorption was complete (bioavailability = 1.06 ± 0.09). The elimination half-life was 5.8 ± 0.6 hr. Only 8% of the PCP dose was excreted unchanged by the kidney. PCP was primarily recovered in urine as conjugates. A portion of the dose was recovered in urine as the mutagen, tetrachlorohydroquinone (5%) (TCHQ), and its conjugates (15%). For both PCP and TCHQ, sulfates accounted for 90% or more of the total conjugates (glucuronides and sulfates).     

口服吲哚美辛关闭早产儿动脉导管10例报告

目的:探讨口服剂型吲哚美辛能否关闭早产儿开放的动脉导管。方法:回顾性临床病例分析,胎龄<34周,在治疗原发疾病过程中心脏出现3～4级收缩期杂音、Yeh评分>3分和/或心脏彩超证实者纳入研究对象。结果:13例中10例获得成功,表现为杂音消失或明显减轻,临床症状改善,脉压差降低。结论:口服吲哚美辛可关闭早产儿开放的动脉导管。