Estradiol and weight are covariates of paracetamol clearance in young women.

AIM: Paracetamol clearance differs between pregnant and non-pregnant women and between women with or without specific oral contraceptives (OCs). However, an association between female sex hormones and paracetamol clearance has never been explored. METHODS: In total, 49 women at delivery, 8 female control subjects without OC use, historical data of 14 women taking OCs, and 15 postpartum observations with and without OCs were pooled to explore covariates of paracetamol clearance. All received a single intravenous 2-gram paracetamol dose, and blood samples were collected up to 6 h after dosing. High-performance liquid chromatography was used to quantify paracetamol. The area under the curve to time infinity (AUC0-∞) was determined and clearance (l/h·m(2)) was calculated by dose/ AUC0-∞. In addition, estradiol and progesterone were quantified by ELISA with electro-chemiluminescence. RESULTS: Median paracetamol clearance at delivery was significantly higher when compared to postpartum or non-pregnant women (11.9 vs. 6.42 and 8.4 l/h·m(2), at least p < 0.05), while an association between paracetamol clearance and estradiol was observed (R = 0.494, p < 0.0001). In non-pregnant subjects, there was no impact of OC exposure on paracetamol clearance. Multiple regression revealed a linear association (Radj = 0.41, p < 0.001) between paracetamol clearance and weight (p = 0.0462) and estradiol (p < 0.0001). CONCLUSION: Estradiol and weight in part explain the variation in paracetamol clearance in young women.

Pharmacokinetics of a loading dose of intravenous paracetamol post caesarean delivery.

BACKGROUND: The postpartum period affects drug disposition, but data of intravenous paracetamol loading dose pharmacokinetics immediately following caesarean delivery have not yet been reported. METHODS: Immediately following caesarean delivery, women received a 2-g loading dose of intravenous paracetamol. Plasma samples were collected at 1, 2, 4 and 6 h. Individual pharmacokinetics were calculated assuming a linear one-compartment model with instantaneous input and first-order output. Data were reported using median and range. RESULTS: Twenty-eight patients undergoing caesarean delivery were recruited (age 31.5 [20-42] years, weight 79 [57-110] kg, body surface area 1.9 [1.5-2.4]m(2)). Median paracetamol plasma concentrations after 1, 2, 4 and 6 h were 22.5, 15.25, 7.9, and 3.9 mg/L respectively. Paracetamol clearance was 20.3 (11.8-62.8) L/h or 10.9 (7-23.8)L/hm(2), distribution volume 58.3 (42.9-156) L or 0.72 (0.52-1.56) L/kg. CONCLUSION: Pharmacokinetics of intravenous paracetamol have been estimated following caesarean delivery. Although limited to a loading dose shortly after surgery, the results are clinically relevant since this is the first description in this patient population. These data provide evidence on which to base further integrated pharmacokinetic/pharmacodynamic studies in peripartum analgesia.

Transplacental transfer of anthracyclines, vinblastine, and 4-hydroxy-cyclophosphamide in a baboon model.

OBJECTIVE: The paucity of data on the fetal effects of prenatal exposure to chemotherapy prompted us to study transplacental transport of chemotherapeutic agents. METHODS: Fluorouracil-epirubicin-cyclophosphamide (FEC) and doxorubicin-bleomycin-vinblastine-dacarbazine (ABVD) were administered to pregnant baboons. At predefined time points over the first 25 h after drug administration, fetal and maternal blood samples, amniotic fluid (AF), urine, fetal and maternal tissues, and cerebrospinal fluid (CSF) were collected. High-performance liquid chromatography (HPLC) and liquid chromatography-mass spectrometry (LC-MS) were used for bioanalysis of doxorubicin, epirubicin, vinblastine, and cyclophosphamide. RESULTS: In nine baboons, at a median gestational age of 139 days (range, 93-169), FEC 100% (n = 2), FEC 200% (n=1), ABVD 100% (n = 5), and ABVD 200% (n = 1) were administered. The obtained ratios of fetal/maternal drug concentration in the different simultaneously collected samples were used as a measure for transplacental transfer. Fetal plasma concentrations of doxorubicin and epirubicin averaged 7.5 ± 3.2% (n = 6) and 4.0 ± 1.6% (n = 8) of maternal concentrations, respectively. Fetal tissues contained 6.3 ± 7.9% and 8.7 ± 8.1% of maternal tissue concentrations for doxorubicin and epirubicin, respectively. Vinblastine concentrations in fetal plasma averaged 18.5 ± 15.5% (n=9) of maternal concentrations. Anthracyclines and vinblastine were neither detectable in maternal nor in fetal brain/CSF. 4-Hydroxy-cyclophosphamide concentrations in fetal plasma and CSF averaged 25.1 ± 6.3% (n = 3) and 63.0% (n = 1) of the maternal concentrations, respectively. CONCLUSION: This study shows limited fetal exposure after maternal administration of doxorubicin, epirubicin, vinblastine, and 4-hydroxy-cyclophosphamide.

Absence of correlation between risk factors for endometrial cancer and the presence of tamoxifen-associated endometrial polyps in postmenopausal patients with breast cancer.

In order to investigate the presence of established risk factors for endometrial carcinoma in postmenopausal patients with breast cancer and with tamoxifen-associated endometrial polyps we compared a group of 25 patients with tamoxifen-associated endometrial polyps with 25 tamoxifen-treated patients without endometrial polyps. No significant differences were found between both groups of patients in age, parity, time after breast cancer and after menopause, duration and daily and total cumulative dose of tamoxifen intake, body mass index and serum levels of luteinising hormone (LH), follicle-stimulating hormone (FSH), oestradiol (E2), progesterone, sex hormone-binding globulin (SHBG), tamoxifen and CA125. So far there is no evidence that these polyps are premalignant lesions.

Effect of montelukast on the pharmacokinetics and pharmacodynamics of warfarin in healthy volunteers.

Montelukast, a cysteinyl leukotriene receptor antagonist, is being developed for the treatment of asthma and related diseases. This study was designed to evaluate whether montelukast at clinically used dosage levels would interfere with the anticoagulant effect of warfarin. In a two-period, double-blind, randomized crossover study, 12 healthy male subjects received a single oral dose of 30 mg warfarin on the 7th day of a 12-day treatment with montelukast, 10 mg daily by mouth, or a placebo. Montelukast had no significant effect on the area under the plasma concentration-time curves and peak plasma concentrations of either R- or S-warfarin. However, slight but statistically significant decreases in time to peak concentration of both warfarin enantiomers and in elimination half-life of the less potent R-warfarin were observed in the presence of montelukast. These changes were not considered as clinically relevant. Montelukast had no significant effect on the anticoagulant effect of warfarin, as assessed by the international normalized ratio (INR) for prothrombin time (AUC0-144 and INR maximum). The results of this study suggest that a clinically important interaction between these drugs is unlikely to occur in patients requiring concomitant administration of both drugs.

Increase in antioxidant capacity of plasma during propofol anesthesia.

We have examined the effect of total intravenous anesthesia (TIVA) using a continuous propofol infusion on the antioxidant capacity of plasma in 18 neurosurgical patients who required cerebrospinal fluid shunting. Patients were premedicated with hydroxyzine, alprazolam, and atropine. Anesthesia was induced intravenously with propofol 1.5 mg kg-1 and sufentanil 0.15-0.3 microgram kg-1. Tracheal intubation was facilitated with atracurium 0.5 mg kg-1. Anesthesia was maintained with a continuous propofol infusion at an increasing rate from 6 to 12 mg kg-1 h-1 under controlled ventilation (FiO2 = 0.4 in air). In all patients, arterial blood samples were drawn before induction of anesthesia and during surgery for measurement of blood propofol concentration and plasma antioxidant capacity, which was assessed as the ability to inhibit lipid peroxidation. Lipid peroxidation was induced in vitro by exposing a linoleic acid microemulsion to hemoglobin-generated oxoferryl radicals, and assessed by ultraweak chemiluminescence in the absence (control) and the presence of the plasma samples. The antioxidant capacity of plasma, measured by the inhibition of light emission and expressed as a percentage of control, increased significantly from 39.8 +/- 2% (mean +/- SEM) to 44.7 +/- 2.4% during anesthesia (Wilcoxon test, p < 0.001). No correlation was observed between this increased resistance to lipid peroxidation and blood propofol concentrations (Spearman test, r = 0.07, NS). We conclude that the capacity of plasma to inhibit lipid peroxidation increases in patients during TIVA maintained with a continuous propofol infusion.

Acute bronchodilation with an intravenously administered leukotriene D4 antagonist, MK-679.

Descriptive studies suggest an association between the release of the cysteinyl leukotrienes and clinical asthma. To help clarify this association, we tested the hypothesis that an intravenous infusion of a potent and specific investigational LTD4 receptor antagonist, MK-679, would cause rapid bronchodilation. In a three-period, randomized, double-blind, crossover study, single doses of MK-679, 125 and 500 mg, and placebo were given intravenously by bolus infusion to nine patients with moderate, stable asthma (FEV1 40 to 80% predicted) on individual study days separated by a week. Spirometry was preformed predose and at intervals for as long as 8 h postdosing; blood samples for MK-679 concentrations were drawn over this time. Fifteen minutes after the end of infusion, the FEV1 percent change from baseline increased a mean of 15.8 +/- 15.7 and 7.8 +/- 11.6% with the 500- and 125-mg doses, respectively, compared with a mean decrease of 2.6 +/- 6.2% with placebo (p = 0.01, overall; p = 0.003, 500 mg versus placebo). The mean end-of-infusion MK-679 plasma concentrations were 86.2 +/- 13.9 and 19.9 +/- 2.7 micrograms/ml for the 500- and 125-mg doses, respectively. MK-679 was well-tolerated, with no significant adverse experiences observed. We conclude that a single, intravenously administered, bolus infusion of MK-679 causes bronchodilation in patients with moderate, stable asthma.

Anaesthesia-free extracorporeal shock wave lithotripsy in patients with renal calculi.

Modern extracorporeal shock wave lithotripsy can be performed with combined ECG and respiratory triggered shock wave release. Disconnecting the ECG triggering increases the risk of ventricular arrhythmias, including potentially malignant ones. The aim of this study was to assess the relationship of any sympatho-adrenal excitation as a possible explanation for the occurrence of cardiac arrhythmia. Plasma catecholamine levels were assessed in 5 patients during and after 50 min of anaesthesia-free extracorporeal shock wave lithotripsy for the treatment of calculi in the upper pole of the left kidney. Venous blood sampling showed no significant increase in catecholamines (epinephrine, norepinephrine and dopamine) during or after treatment. The heart rate and arterial blood pressure were measured simultaneously and showed no significant increase when shock waves were released during ECG triggering. However, when disconnecting the ECG-triggering mode, the incidence of ventricular extrasystoles on Holter monitoring became more apparent during respiratory triggered shock wave release only, although there was no rise in plasma catecholamine levels. These data suggest that cardiac arrhythmias are related to direct and accidental mechanical stimulation of the heart rather than to any sympatho-adrenal discharge during shock wave release.

Influence of opioid antagonism on plasma catecholamines in pheochromocytoma patients.

The present study investigated whether in vivo endogenous opioids inhibit the secretory activity of pheochromocytomas and whether opioid antagonists may be useful in the diagnosis of pheochromocytoma. In six patients with pheochromocytoma in whom the diagnosis was histologically confirmed after surgery, mean intraarterial blood pressure (BP) increased by 45 mm Hg within 3 min after intravenous (i.v.) injection of 2 mg glucagon (95% confidence interval 23-68 mm Hg); heart rate (HR) remained unchanged, whereas plasma norepinephrine (NE) increased by 216% (31-658%) and plasma epinephrine (EPI) increased by 203% (37-571%). Although glucagon stimulation confirmed the secretory potential of the pheochromocytomas, opioid antagonism by a 10-mg i.v. bolus of naloxone produced no significant change in plasma NE and EPI concentrations or intraarterial pressure. The present study does not support the hypothesis that release of catecholamines from pheochromocytomas is inhibited by endogenous opioids. Use of opioid antagonists as a tool in the diagnosis of pheochromocytoma therefore cannot be recommended.

Comparison of cyclosporin A measurement in whole blood by six different methods.

In a multicentre trial, we analyzed and compared the cyclosporin concentrations in whole blood specimens (trough values) from renal and bone marrow transplant patients using six different methods: high-performance liquid chromatography (n-butyl reversed-phase column) as reference, and 5 immunoassay procedures using monoclonal specific or non-specific antibodies, or polyclonal antibodies, for measuring cyclosporin with and without its cross-reacting metabolites. Results obtained by the 2 specific RIAs show good correlations (r-values of 0.945 and 0.921) versus the HPLC method, with average assay ratios of: 1.52 for 3H-RIA/HPLC and 1.26 for 125I-RIA/HPLC. In contrast, ratios for non-specific immunoassay/HPLC show multiple-fold overestimations of cyclosporin with very wide variations: 4.58 for 3H-RIA/HPLC, 3.97 for 125I-RIA/HPLC and 3.87 for fluorescence polarization immunoassay (FPIA)/HPLC. These findings indicate 1) that the 'specific' 3H- and 125I-RIAs can be used for cyclosporin measurements in whole blood using normal therapeutic ranges established by HPLC, 2) that the important disparity and variable overestimations by 'non-specific' RIA or fluorescence polarization immunoassay, compared with HPLC, require adjustments in therapeutic ranges, and 3) that the available 'specific' and 'non-specific' immunoassays should enable establishment of within-house reference 'therapeutic/toxic' ranges for cyclosporin in individual centres, based on these 'specific' versus 'non-specific' assays.

Effect of aluminum hydroxide on diflunisal absorption.

1 The effect of aluminum hydroxide on the oral absorption of diflunisal was studied in healthy subjects. 2 Relative bioavailability of the oral diflunisal dose (500 mg) was estimated by comparison of the areas under plasma concentration versus time curves, and comparison of the amount of drug (unchanged + glucuronides) excreted in the urine. 3 From the AUC-method, a relative bioavailability of 0.60 was calculated. A similar value (F = 0.63) was obtained from the urinary excretion data. 4 The results indicate that co-administration of aluminum hydroxide reduces the bioavailability of oral diflusinal by about 40%.