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Background Amlodipine is a widely used antihypertensive agent for the treatment of paediatric hypertension, but the commercially available tablets are not suitable to treat young patients, who need lower, flexible dosages and a liquid formulation. Objective To determine the pharmacokinetic properties of amlodipine and the acceptability of a standardised, extemporaneous oral solution. Method A newly developed liquid formulation of amlodipine was administered to hypertensive children between the age of 6 months and 11 years. Using a limited sampling strategy, population PK analysis was performed using nonlinear mixed effects modelling. Results Nine children, with a median age of 2.9 years (IQR 1.8-8.4), receiving stable amlodipine therapy in a median dose of 0.15 mg kg -1  day -1 (IQR 0.11-0.18), were switched to study medication. The population pharmacokinetic model was able to accurately predict the clearance of amlodipine in the study population. Based on the final model, clearance was reduced by 31.2% (RSE: 10%) in females. Patient reported outcomes on taste from a five-point hedonic scale were available for five patients, who scored the taste from positive to slightly negative. Conclusion The results from the PK study and the acceptability assessment show that the amlodipine oral solution presented in this study offers an appropriate treatment option for young children.

Introduction: Amlodipine is an antihypertensive agent recommended for the management of hypertension in children and adolescents. The commercially available tablets of 5 and 10mg do not provide the necessary flexibility in dosing needed for treating children. Our goal was to develop a pediatric oral solution of amlodipine, using a robust manufacturing process suitable for ex-tempora and larger scale production., Methods: The parameters API and preservative content, related substances, appearance and pH were studied under four different storage conditions. Samples were analyzed up to 12months. Microbiological quality was studied in an 18-week in-use test based on a two-times daily dosing schedule., Results: The stability of the formulation was influenced by storage conditions and composition. A formulation containing amlodipine besylate, sucrose syrup and methyl paraben remained physically stable for 12months at 4°C with no loss of amlodipine content. Related substances increased during the study but remained below 0.5%. In-use stability was proven up to 18weeks., Discussion: Storage under refrigerated conditions was necessary to prevent precipitation and to obtain an acceptable shelf-life. In conclusion, we have developed and validated an amlodipine oral solution, suitable for the pediatric population. This liquid formulation is preferred over manipulated commercial dosage forms or non-standardized extemporaneously compounded formulations., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Objective: Determine the definitive position of ketanserin and dihydralazine for treatment of severe hypertension in pregnancy., Study Design: A single centre double blind randomized controlled trial was performed at the obstetrical tertiary high care unit of the University Medical Centre in Rotterdam, the Netherlands. Women with severe hypertension in pregnancy (diastolic blood pressure (DBP)≥110mmHg), and significant proteinuria (≥300mg/24h), and gestational age≤32 weeks were eligible for the study. All patients (n=30) received two infusions (double dummy technique): one contained the active ingredient (ketanserin or dihydralazine), the other was used for placebo. Nicardipine was used as rescue medication. The main outcome measures were persistent severe hypertension (DBP>100mmHg>120min) despite maximum dosage of study medication and prolongation of pregnancy., Results: Dihydralazine was significantly more effective in lowering blood pressure than ketanserin. No significant difference in prolongation of pregnancy was seen between the two groups. After 30 inclusions, the study was stopped because of the high rate of persistent hypertension using ketanserin and the high rate of maternal side effects using dihydralazine and the apparent succesful use of the rescue drug nicardipine., Conclusions: Our results do not support the use of either dihydralazine or ketanserin for the treatment of severe hypertension in pregnancy. Future research is needed to compare nicardipine with other antihypertensive drugs currently in use for treatment of severe hypertension in pregnancy., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Objective: To describe the pharmacokinetics and exposure of oral sildenafil (SIL) in neonates (2-5 kg) with pulmonary hypertension (PH)., Design: We included 11 neonates (body weight 2-5 kg, postnatal age 2-121 days) who received SIL and extracorporeal membrane oxygenation (ECMO) treatment for PH. SIL capsules were given via a nasogastric tube. Blood samples were collected via a pre-existing arterial line to quantify SIL and metabolite plasma levels (219 samples). Non-linear mixed effects modelling was used to describe SIL and desmethylsildenafil (DMS) pharmacokinetics., Results: A one-compartment model was suitable for SIL and DMS. Interpatient and intrapatient variability for clearance at 100% bioavailability were 87% and 27% (SIL) and 62% and 26% (DMS). Patient weight, postnatal age and post-ECMO time did not explain variability. Concomitant fluconazole use was associated with a 47% reduction in SIL clearance. The exposure expressed as average plasma concentration area under the curve over 24 h (AUC(24 (SIL+DMS))) ranged from 625 to 13 579 ng/h/ml. An oral dose of 4.2 mg/kg/24 h would lead to a median AUC(24 (SIL+DMS)) of 2650 ng/h/ml equivalent to 20 mg three times a day in adults. Interpatient variability was large, with a simulated AUC(24 (SIL+DMS)) range (10th and 90th percentiles) of 1000-8000 ng/h/ml., Conclusions: SIL pharmacokinetics are highly variable in post-ECMO neonates and infants. In a median patient, the current dose regimen of 0.5-2.0 mg/kg four times a day leads to an exposure comparable to the recommended adult dose of 20 mg four times a day. Careful dose titration, based on efficacy and the occurrence of hypotension, remains necessary. Follow-up research should include appropriate pharmacodynamic endpoints, with a population pharmacokinetic/pharmacodynamic analysis to assign a suitable exposure window or target concentration.

To assess the safety risks to the fetus and neonate caused by maternal use of nicardipine in pre-eclamptic patients, we evaluated the placental transfer and the transfer to breast milk after maternal intravenous administration of nicardipine. In ten pre-eclamptic subjects, nicardipine concentrations of maternal blood (P) and both arterial and venous umbilical cord blood samples (Uarterial and Uvenous) were assessed, and the U/P ratio was calculated as an indication of placental transfer. We found a median transfer of 0.15 (Uarterial/P, range 0.05-0.22) and 0.17 (Uvenous/P, range 0.023-0.22). The highest umbilical cord concentration found after maternal dosage of 4.5 mg/hour was 18 ng/ml, which can be considered as subtherapeutic. Therefore, adverse fetal reactions caused by a direct pharmacological effect of nicardipine are unlikely to occur. Nicardipine levels were determined in 34 breast milk samples of seven women, and were found to be undetectable in 82% of the samples. In six breast milk samples of four different women, nicardipine levels (ranging from 5.1 to 18.5 ng/ml) were detectable during maternal nicardipine dosages ranging from 1 to 6.5 mg/hour. The maximum possible exposure of a neonate to nicardipine was calculated to be less than 300 ng/day, which is an insignificant fraction of therapeutic dosages used in neonates. In conclusion, the exposure of a fetus and neonate to nicardipine through placental transfer and disposition in breast milk expression is low.

Background: Maternal treatment with the 5-HT(2A) receptor antagonist ketanserin (KT) in pre-eclamptic patients is associated with a high placental transmission of KT, resulting in pharmacologically active levels of KT in the umbilical cord artery (UCA) and the neonate. Prolonged exposure to a 5-HT receptor antagonist may influence the functionality of foetal 5-HT receptors and compromise foetal development., Objective: To study whether exposure to KT influences the characteristics of foetal 5-HT receptors, functional studies were performed on 5-HT(2A) and 5-HT(1B/1D) receptors in UCA from pre-eclamptic patients treated with KT., Methods: UCAs were obtained, immediately after delivery, from pre-eclamptic patients (n = 7), treated antenatally with intravenous KT. Pre-eclamptic patients (n = 13), not treated with KT (non-KT), were included as a control group. Segments of UCA were prepared and mounted in tissue baths and isometric force changes were determined. Cumulative concentration response curves to 5-HT and to the 5-HT(1B/1D )receptor agonist sumatriptan were constructed in the absence or presence of the 5-HT(2A) receptor antagonist KT or the 5-HT(1B/1D) receptor antagonist GR125743, respectively., Results: All UCA segments showed contractile responses to both 5-HT and sumatriptan, and the concentration response curves showed a rightward shift with increasing concentrations of KT and GR125743, respectively, indicating the presence of functional 5-HT(2A) and 5-HT(1B/1D) receptors in the foetal tissue. No significant differences were found in maximum response (E(max))(expressed in percent of response on 100 mM KCl) or potency (pEC(50)) of 5-HT in both groups (E(max) = 141 +/- 7.7%, pEC(50) = 7.67 +/- 0.26 in KT-treated group and E(max) = 162 +/- 12.6%, pEC(50) = 7.69 +/- 0.14 in non-KT treated group, respectively). No significant differences were found in the potency of the antagonist KT in both study groups (pK(b) = 7.65 +/- 0.31 in KT group and 7.46 +/- 0.17 in non-KT group, respectively). Similarly, with sumatriptan, no significant differences were found between KT-treated patients and non-KT treated patients (E(max) = 142 +/- 16.2 and 140 +/- 14.7%, respectively, pEC(50) = 6.17 +/- 0.37 and 6.41 +/- 0.28 respectively, pK(b) of GR125743 = 7.83 +/- 0.48 and 8.43 +/- 0.29, respectively)., Conclusion: Foetal exposure to KT in pre-eclamptic patients does not seem to influence the functional characteristics of 5-HT(2A) and 5-HT(1B/1D) receptors in the UCA., ((c) 2007 S. Karger AG, Basel.)

Objective: To analyze the efficacy of intravenous ketanserin in controlling blood pressure of severe early-onset pre-eclamptic patients., Study Design: Pre-eclamptic patients (n=47) with a gestational age (GA) between 21 and 32 weeks were treated with intravenous ketanserin in a maximum dosage of 14 mg/h, to obtain a diastolic blood pressure of 90 mmHg or below. The number of patients reaching and maintaining target blood pressure was retrospectively assessed. Patient characteristics associated with an adequate or inadequate response to ketanserin treatment were identified., Results: With a maximum intravenous dosage of ketanserin, target blood pressure was not achieved in 15 (32%) patients. A high systolic blood pressure at the start of treatment was significantly (p=0.02) associated with failure of ketanserin treatment. The median period of ketanserin treatment in the responding group was 3 days (range 1-10 days). In 26 (55%) of initially successfully treated patients, additional antihypertensive drugs had to be added to maintain adequate blood pressure control., Conclusion: Intravenous ketanserin lacks antihypertensive efficacy in a substantial proportion of severe pre-eclamptic patients, despite high dosages. In patients who initially respond well to ketanserin treatment, additional antihypertensive treatment is often necessary to maintain adequate blood pressure control.

The aim of this prospective, observational study was to assess transplacental transmission of ketanserin, an antihypertensive drug used in pre-eclampsia, and to determine disposition and effects in the neonate after maternal ketanserin use. In 22 pregnant women with severe pre-eclampsia, admitted to the antenatal ward in the period 1999-2001, the ratio of drug levels in the umbilical cord to drug levels in maternal blood just before delivery was used as an indicator of placental transmission. Disposition of ketanserin was assessed using neonatal plasma concentrations of ketanserin in eight neonates after birth. A median placental transmission was found in the pre-eclamptic women of 0.95 (0.612-1.24) for ketanserin and for its metabolite, ketanserinol, of 0.60 (0.5-0.77). Pharmacologically relevant concentrations of ketanserin were found in the neonate after delivery. The elimination half-life of ketanserin in the neonate varied between 12.7 and 43.7 hours (median 19.3 hours) and of ketanserinol between 13.8 and 34.4 hours (median 18.7 hours). Despite the high placental transmission and disposition in the neonate, no apparent adverse effects in the neonates could be detected. In conclusion, a high placental transmission of ketanserin and its metabolite ketanserinol occurred after maternal treatment of pre-eclampsia with ketanserin and pharmacologically active concentrations of ketanserin are found in the neonate for a prolonged period after delivery.