Transfer of parecoxib and its primary active metabolite valdecoxib via transitional breastmilk following intravenous parecoxib use after cesarean delivery: a comparison of naive pooled data analysis and nonlinear mixed-effects modeling.

BACKGROUND: Multimodal analgesia, including nonopioid analgesics, is usually used for several days after cesarean delivery. Because the breastfed infant receives transitional milk during this same period, it is important to know how much of a maternal analgesic drug is received by the infant. We designed this study to estimate infant exposure to parecoxib and its active metabolite valdecoxib (a cyclooxygenase-2 inhibitor) after a single IV maternal dose of parecoxib after cesarean delivery. METHODS: Forty women and their infants participated in the study. Parecoxib (40 mg) was administered IV at a mean of 41 hours after birth. Milk (4 samples) and plasma (1 sample) were collected from the women over the subsequent 24 hours and drug content was measured by liquid chromatography-tandem mass spectrometry. The infants were assessed the day after parecoxib dosing. Absolute (AID) and relative infant doses (RID) of both parecoxib and valdecoxib through milk were estimated by standard methods using the naïve pooled datasets, and where possible milk/plasma (M/P) concentration ratios were calculated. Nonlinear mixed-effects modeling was also used to fit the valdecoxib milk and plasma datasets to a compartmental model and to predict M/P, AID, and RID. RESULTS: M/P ratios (median [interquartile range; IQR]) were 0.5 (0.15 to 1.15) for parecoxib and 0.14 (0.11 to 0.18) for valdecoxib. Using the naïve pooled datasets, AID (drug concentration in milk×daily milk intake/kg) was 0.24 (0.05 to 1.85) µg/kg/day for parecoxib, and 1.82 (1.12 to 2.73) µg/kg/day, for valdecoxib. RID was 0.04 (0.01 to 0.43) % of the weight-adjusted maternal dose (one dose in 24 hours) for parecoxib and 0.47 (0.29 to 0.69) % for valdecoxib (as parecoxib equivalents). Compartmental modeling of valdecoxib alone produced a mean (interindividual variability) M/P of 0.149 (26%), median (IQR) AID of 1.47 (0.96 to 2.03) µg/kg/day, and median (IQR) RID of 0.39 (0.28 to 0.47) %. Neonatal neurologic and adaptive capacity scores (mean=34, 95% CI 33 to 35) were consistent with a normal expected score of 35. CONCLUSIONS: Both the naïve pooling of data and the modeling analyses gave similar results. The RID of both parecoxib and valdecoxib was low. We conclude that a single 40 mg IV dose of the cyclooxygenase-2 inhibitor parecoxib administered to lactating women after cesarean delivery is unlikely to cause adverse effects in breastfed infants.

Is there a role for isofurans and neuroprostanes in pre-eclampsia and normal pregnancy?

Pre-eclampsia is a complex disorder of pregnancy that adversely affects the mother and baby. Arachidonic acid and docosahexaenoic acid are essential for fetal development and can undergo free radical oxidation to F(2)-isoprostanes (F(2)-IsoPs) and isofurans (IsoFs); and F(4)-neuroprostanes (F(4)-NeuroPs), respectively. These metabolites may be relevant to pre-eclampsia and fetal development. We examined IsoFs, F(4)-NeuroPs, and F(2)-IsoPs in maternal plasma and cord blood plasma of 23 women with pre-eclampsia and 21 normal pregnancies. Women with pre-eclampsia had significantly elevated maternal IsoFs and F(4)-NeuroPs, but not F(2)-IsoPs. Cord blood F(4)-NeuroPs were elevated among neonates of women with pre-eclampsia. In women with pre-eclampsia, birth weight was predicted by gestation at delivery. The latter was also true in normal pregnancy, but birth weight was negatively related to maternal F(2)-IsoPs, IsoFs, and F(4)-NeuroPs. We have shown that in women with pre-eclampsia, IsoFs and F(4)-NeuroPs are elevated, and cord blood F(4)-NeuroPs are increased. The inverse relationship between maternal F(2)-IsoPs, IsoFs, and F(4)-NeuroPs and birth weight may be relevant as predictors of low birth weight in normal pregnancy. Future studies should examine whether these markers in maternal blood at early stages of pregnancy relate to subsequent maternal, fetal, and neonatal complications.

Management of postoperative nausea and vomiting: focus on palonosetron.

Postoperative nausea and vomiting (PONV) remains a significant problem in modern anesthetic practice, with an incidence in high-risk groups of up to 80%. In addition to being unpleasant and distressing for the patient, PONV has the potential to adversely affect patient and surgical outcomes. Advances in PONV prophylaxis over recent years include using non-pharmacological means to reduce baseline risk, a change to less emetogenic anesthetic techniques and the combination of multiple antiemetic drugs. The 5-hydroxytryptamine-3 (5-HT(3)) antagonists have proven a particularly valuable addition to the armamentarium against PONV. Palonosetron is a second-generation 5-HT(3) antagonist that has recently been approved for prophylaxis against PONV. It has unique structural, pharmacological and clinical properties that distinguish it from other agents in its class. This review summarizes current evidence on PONV prophylaxis, reviews the 5-HT(3) antagonists in particular and focuses on the established and future roles of palonosetron.