Lidwien M. Hanff

Intravenous use of the calcium-channel blocker nicardipine as second-line treatment in severe, early-onset pre-eclamptic patients.

Objective To evaluate the efficacy of intravenous administration of nicardipine as a second-line temporizing treatment in severe, early-onset, pre-eclamptic patients. Design An open, prospective, evaluation study. Setting A high-care obstetric ward in a tertiary care centre. Patients Twenty-seven early-onset, pre-eclamptic patients with a median gestational age of 27 weeks 1 day (range, 21 weeks 2 days–32 weeks 4 days) with treatment failure on standard intravenous antihypertensive drugs (ketanserin, dihydralazin or labetalol). Intervention Nicardipine infusion was started for temporizing management of pre-eclampsia at a dosage of 3 mg/h and was subsequently titrated according to blood pressure. Nicardipine treatment was continued for as long as the maternal and foetal conditions allowed. Main outcome measures The endpoints of the study were defined as the percentage of patients reaching the target diastolic intra-arterial blood pressure (< 100 mmHg or < 90 mmHg in Haemolysis, Elevated Liver Enzymes, Low Platelet Count syndrome patients) within 1 h after the start of treatment, and the number of days of prolongation of pregnancy under nicardipine treatment. Maternal and foetal side effects, foetal death and neonatal outcome were assessed. Results In all patients the target diastolic intra-arterial blood pressure was obtained within a median of 23 min (range, 5–60 min). Delivery was postponed for a median of 4.7 days (range, 1–26 days) using nicardipine treatment, in a maximum dosage ranging from 3 to 9 mg/h. Detailed haemodynamic parameters with corresponding nicardipine dosages were obtained in nine patients. In one-fifth of the patients, unwanted hypotensive periods were registered during treatment, manageable with dosage adaptation. Foetal well-being did not seem adversely affected. Conclusion This evaluation shows that nicardipine is a potent antihypertensive drug and can be used for temporizing management in severe, early-onset pre-eclampsia when other antihypertensive drugs have failed.

Functional reactivity of 5-ht receptors in human umbilical cord and maternal subcutaneous fat arteries after normotensive or pre-eclamptic pregnancy

Objective To investigate the functional reactivity of 5-hydroxytryptamine (serotonin; 5-HT) receptors in foetal umbilical cord arteries (UCA) and maternal subcutaneous fat resistance arteries (SFA) in normotensive and pre-eclamptic pregnancy. Design Study groups were divided based on the presence or absence of pre-eclampsia and the duration of gestation. Methods Segments of UCA and SFA were mounted in tissue baths and concentration–response curves to 5-HT and sumatriptan (5-HT1B/1D receptor agonist) were constructed in the absence or presence of ketanserin (5-HT2A receptor antagonist) or GR125743 (5-HT1B/1D receptor antagonist). Results Both 5-HT and sumatriptan contracted all UCA segments studied. The responses to 5-HT and the potency of ketanserin in UCA were not different between the study groups, indicating a similar profile of the 5-HT2A receptor. In contrast, the potencies of sumatriptan and GR125743 were significantly higher in normotensive full-term pregnancies than in normotensive pre-term pregnancies in UCA. The response to sumatriptan in UCA arteries was not significantly different between pre-eclamptic and normotensive pregnancies. However, the potency of both sumatriptan and GR125743 was positively correlated to the gestational age in the normotensive group, whereas this relationship was absent in the pre-eclamptic group. In SFA, responses to 5-HT and sumatriptan were not different between the pre-eclamptic patients and normotensive controls. Conclusions In both UCA and SFA, 5-HT1B/1D and 5-HT2A receptors mediate vasoconstriction. The sensitivity of 5-HT1B/1D receptors increases in the last trimester in the UCA in normal pregnancies, which seems to be expedited in pre-eclamptic patients. Further studies on 5-HT1B/ID receptors will thus give new insights into the foetal development and pathophysiology of pre-eclampsia.

Nicardipine in pre‐eclamptic patients: placental transfer and disposition in breast milk

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.

Ketanserin versus dihydralazine for the treatment of severe hypertension in early-onset preeclampsia: a double blind randomized controlled trial

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.

Efficiency of different systems for medication distribution in an academic children's hospital in the Netherlands

Background: In the Sophia Childrens Hospital, both a ward stock system and a decentralized, patient-orientated, ready-to-use drug distribution system (a ‘satellite pharmacy system’) exist. Hospital management considered expanding the concept of the satellite pharmacies. Little was known, however, about the efficiency of this drug distribution system, whereas there is increasing pressure to demonstrate the cost-effectiveness of pharmacy services.Objective: To analyze the efficiency of satellite pharmacies compared with other medication distribution systems.Methods: All medication orders and prepared doses were counted. The workload of the two current distribution systems was calculated using the direct time study method. Furthermore, the consequences of altering the distribution system were calculated by formulating nine variants in which certain activities surrounding the medication distribution were moved between nurses and pharmacy technicians. Moreover, we varied the degree of computerization of the medication order registration.Results: The required working hours are the largest in the variants in which nurses do the preparation of the drugs. Moving the distribution of some drug categories, such as ready-to-use drugs, prepared oral drugs, and prepared inhalation drugs, from pharmacy technicians to nurses appeared not to produce noticeable benefits compared with the current distribution system. Expanding the concept of the satellite pharmacies involves a small rise in total working hours compared with the current situation, but does not raise personnel costs. The largest cost savings can be achieved by introducing an on-line computerized physician order-entry system.Conclusions: The concept of satellite pharmacies offers an efficient distribution system for the Sophia Childrens Hospital.

Insufficient Sedation and Severe Side Effects after Fast Administration of Remifentanil during INSURE in Preterm Newborns.

Background: Neonatal intubation is stressful and should be performed with premedication. In the case of an INSURE (intubation/surfactant/extubation) procedure a short duration of action of the premedication used is needed to facilitate fast extubation. Given its pharmacological profile, remifentanil seems a suitable candidate. Objectives: The aim here was to evaluate the effect and side effects of remifentanil as a premedication for preterm neonates undergoing INSURE. Methods: A prospective, single-center study in a level III neonatal intensive care unit was conducted. The quality of sedation was assessed in preterm infants receiving remifentanil prior to intubation for the INSURE procedure. Intravenous remifentanil was administered quickly and followed by a saline flush in approximately 30 s. The quality of sedation was defined by a combination of adequate sedation score, good intubation conditions and absence of side effects. Results: The study was terminated after the inclusion of 14 patients because of the high rate of side effects and the poor intubation conditions. Adequate sedation was achieved in only 2 patients (14%). Six patients (43%) needed additional propofol to obtain adequate sedation. Chest wall rigidity occurred in 6 patients (43%). Conclusions: The rapid administration of remifentanil provides insufficient sedation and is associated with a high risk of chest wall rigidity in preterm neonates.

Ketanserin in pre-eclamptic patients: transplacental transmission and disposition in neonates

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.

The Effect of Maternal Ketanserin Treatment on Foetal 5-HT Receptor Function in Umbilical Cord Artery of Pre-Eclamptic Patients

Background: Maternal treatment with the 5-HT2A 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-HT2A and 5-HT1B/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-HT1B/1D receptor agonist sumatriptan were constructed in the absence or presence of the 5-HT2A receptor antagonist KT or the 5-HT1B/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-HT2A and 5-HT1B/1D receptors in the foetal tissue. No significant differences were found in maximum response (Emax)(expressed in percent of response on 100 mM KCl) or potency (pEC50) of 5-HT in both groups (Emax = 141 ± 7.7%, pEC50 = 7.67 ± 0.26 in KT-treated group and Emax = 162 ± 12.6%, pEC50 = 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 (pKb = 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 (Emax = 142 ± 16.2 and 140 ± 14.7%, respectively, pEC50 = 6.17 ± 0.37 and 6.41 ± 0.28 respectively, pKb 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-HT2A and 5-HT1B/1D receptors in the UCA.

Population pharmacokinetics of ketanserin in pre-eclamptic patients and its association with antihypertensive response.

Ketanserin is an antihypertensive drug that is increasingly being used parenterally in the treatment of pre‐eclampsia. Because of lack of efficacy in a substantial part of our pre‐eclamptic patients, we determined the plasma concentrations of ketanserin in 51 pre‐eclamptic patients. Population pharmacokinetic parameters were assessed using the iterative two‐stage Bayesian population procedure. The influence of individual pharmacokinetic parameters on antihypertensive response, expressed as the attainment of a diastolic blood pressure ≤90 mmHg using ketanserin treatment, was analysed. Almost all plasma concentrations of ketanserin were in or above the therapeutic range. The individual pharmacokinetics of ketanserin in pre‐eclamptic patients showed an accurate fit using a three‐compartment model. The pharmacokinetic parameters in our pre‐eclamptic population were a metabolic clearance (Clm) of 37.9 ± 10.86 L/h and volume of distribution (V1) of 0.544 ± 0.188 L/kg, which is comparable with data from healthy volunteers. Despite a considerable inter‐individual variation, no correlation was found between differences in pharmacokinetic parameters and antihypertensive response. We conclude that therapeutic plasma levels can be obtained in pre‐eclamptic patients with a fixed dosage schedule of ketanserin and differences in antihypertensive responses within a pre‐eclamptic population cannot be attributed to pharmacokinetic differences.

Formulating a poorly water soluble drug into an oral solution suitable for paediatric patients; lorazepam as a model drug

Introduction: Many drugs are unavailable in suitable oral paediatric dosage forms, and pharmacists often have to compound drugs to provide paediatric patients with an acceptable formulation in the right dose. Liquid formulations offer the advantage of dosing flexibility and ease of administration to young patients, but drug substances often show poor aqueous solubility. The objective of this work was to study different solvents and matrices to design a liquid formulation for poorly water soluble drugs, using lorazepam as model drug. Methods: Three different formulation strategies were explored to improve the solubility. Firstly, water‐soluble organic solvents were used to improve the aqueous solubility directly, secondly, ionic surfactants were used to solubilise the model drug, and thirdly, complexation of lorazepam with cyclodextrin was studied. Specific attention was paid to excipients, adequate taste correction and palatability. For the final formulation, physical and chemical stability and microbiological quality were assessed for 12 months. Results: An organic solvent based formulation, containing a mixture of polyethylene glycol and glycerol 85%, with a minimum amount of propylene glycol, proved to be physically and chemically stable. Development of the non‐ionic surfactants formulation was discontinued due to taste problems. The cyclodextrin formulations were physically stable, but lorazepam content declined to 90% within five months. The final formulation contained in volume concentration (%v/v) 87% glycerol, 10% polyethylene glycol 400 and 3% propylene glycol. Orange essence was the preferred taste corrector. The formulation remained stable for 12 months at 4 °C, with lorazepam content remaining > 95%. Related substances increased during the study period but remained below 2%. In‐use stability was proven up to 4 weeks. Conclusion: An organic solvent based oral formulation was shown to be superior to a non‐ionic surfactant based formulation or a cyclodextrin formulation. These results may help to formulate paediatric formulations of other poorly water soluble drugs, to aid pharmacy compounding. Graphical abstract Figure. No caption available.