Pharmacokinetics of Gabapentin during Delivery, in the Neonatal Period, and Lactation: Does a Fetal Accumulation Occur during Pregnancy?

Summary: Purpose: To study the pharmacokinetics of gabapentin (GBP) during delivery, lactation, and in the neonatal period. Methods: GBP concentrations in plasma and breast milk were determined with high-performance liquid chromatography in samples from six women treated with GBP and in their offspring. Blood samples were obtained at delivery from mothers, from the umbilical cord, and from the newborns on three occasions during 2 days after delivery. GBP concentration also was determined in breast milk and in blood collected from five of the mothers and suckling infants 2 weeks to 3 months after birth. Results: The umbilical cord/maternal plasma concentration ratios ranged from 1.3 to 2.1 (mean, 1.7). GBP plasma concentrations in the neonates declined with an estimated half-life of 14 h. Mean GBP plasma concentrations in the infants were 27% of the cord plasma levels (range, 12-36%) 24 h postpartum. The mean milk/maternal plasma concentration ratio was 1.0 (range, 0.7-1.3) from 2 weeks to 3 months. The infant dose of GBP was estimated to 0.2-1.3 mg/kg/day, equivalent to 1.3-3.8% of the weight-normalized dose received by the mother. The plasma concentrations in the breast-fed infants were ∼12% of the mother's plasma levels, but no adverse effects were observed. Conclusions: Our limited observations suggest an active transplacental transport of GBP, with accumulation in the fetus as a consequence. We suggest that this could be by the specific L-type amino acid transporter 1 (LAT-1), which is expressed in the placenta. Newborns seem to have a slightly lower capacity to eliminate GBP than do adults. Transfer of GBP to breast milk is extensive, but plasma concentrations appear to be low in suckling infants. No adverse effects were observed in the newborn. Although more data are needed, our observations suggest that breastfeeding in conjunction with GBP treatment is safe

GRADE equity guidelines 3: considering health equity in GRADE guideline development: rating the certainty of synthesized evidence

Objectives: The aim of this paper is to describe a conceptual framework for how to consider health equity in the Grading Recommendations Assessment and Development Evidence (GRADE) guideline development process. Study Design and Setting: Consensus-based guidance developed by the GRADE working group members and other methodologists. Results: We developed consensus-based guidance to help address health equity when rating the certainty of synthesized evidence (i.e., quality of evidence). When health inequity is determined to be a concern by stakeholders, we propose five methods for explicitly assessing health equity: (1) include health equity as an outcome; (2) consider patient-important outcomes relevant to health equity; (3) assess differences in the relative effect size of the treatment; (4) assess differences in baseline risk and the differing impacts on absolute effects; and (5) assess indirectness of evidence to disadvantaged populations and/or settings. Conclusion: The most important priority for research on health inequity and guidelines is to identify and document examples where health equity has been considered explicitly in guidelines. Although there is a weak scientific evidence base for assessing health equity, this should not discourage the explicit consideration of how guidelines and recommendations affect the most vulnerable members of society

ApoB100-LDL Acts as a Metabolic Signal from Liver to Peripheral Fat Causing Inhibition of Lipolysis in Adipocytes

International audienceBACKGROUND: Free fatty acids released from adipose tissue affect the synthesis of apolipoprotein B-containing lipoproteins and glucose metabolism in the liver. Whether there also exists a reciprocal metabolic arm affecting energy metabolism in white adipose tissue is unknown. METHODS AND FINDINGS: We investigated the effects of apoB-containing lipoproteins on catecholamine-induced lipolysis in adipocytes from subcutaneous fat cells of obese but otherwise healthy men, fat pads from mice with plasma lipoproteins containing high or intermediate levels of apoB100 or no apoB100, primary cultured adipocytes, and 3T3-L1 cells. In subcutaneous fat cells, the rate of lipolysis was inversely related to plasma apoB levels. In human primary adipocytes, LDL inhibited lipolysis in a concentration-dependent fashion. In contrast, VLDL had no effect. Lipolysis was increased in fat pads from mice lacking plasma apoB100, reduced in apoB100-only mice, and intermediate in wild-type mice. Mice lacking apoB100 also had higher oxygen consumption and lipid oxidation. In 3T3-L1 cells, apoB100-containing lipoproteins inhibited lipolysis in a dose-dependent fashion, but lipoproteins containing apoB48 had no effect. ApoB100-LDL mediated inhibition of lipolysis was abolished in fat pads of mice deficient in the LDL receptor (Ldlr(-/-)Apob(100/100)). CONCLUSIONS: Our results show that the binding of apoB100-LDL to adipocytes via the LDL receptor inhibits intracellular noradrenaline-induced lipolysis in adipocytes. Thus, apoB100-LDL is a novel signaling molecule from the liver to peripheral fat deposits that may be an important link between atherogenic dyslipidemias and facets of the metabolic syndrome

Topiramate Kinetics during Delivery, Lactation, and in the Neonate: Preliminary Observations

Summary: Purpose: To study the pharmacokinetics of topiramate (TPM) during delivery, lactation, and in the neonate. Methods: TPM concentrations in plasma and breast milk were measured with fluorescence polarization immunoassay (FPIA) in five women with epilepsy treated with TPM during pregnancy and lactation. Blood samples were obtained at delivery from mothers, from the umbilical cord, and from the newborns on three occasions (24, 48, and 72 h) after delivery. Blood and breast milk also were collected from mothers 2 weeks, and 1 and 3 months postpartum. Blood samples also were drawn from the infants during breast-feeding. Three of the mother-infant pairs were studied both at delivery and during lactation; two contributed with data from delivery only. Results: The umbilical cord plasma/maternal plasma ratios were close to unity, suggesting extensive transplacental transfer of TPM. The mean milk/maternal plasma concentration ratio was 0.86 (range, 0.67-1.1) at 2-3 weeks after delivery. The milk/maternal plasma concentration ratios at sampling 1 and 3 months after delivery were similar (0.86 and 0.69, respectively). Two to 3 weeks after delivery, two of the breast-fed infants had detectable (>0.9 M) concentrations of TPM, although below the limit of quantification (2.8 M), and one had an undetectable concentration. Conclusions: Our limited data suggest free passage of TPM over the placenta and an extensive transfer into breast milk. Breast-fed infants had very low TPM concentrations, and no adverse effects were observed in the infants. Key Words: Epilepsy-Pregnancy-Topiramate-Pharmacokinetics-Breast milk. An increasing number of women of childbearing age are treated with the new antiepileptic drug (AED) topiramate (TPM), resulting in more pregnant women being exposed to the drug. Information on the pharmacokinetics during pregnancy and breast-feeding is a prerequisite for the optimal use of a drug in such situations. For TPM, however, such data have been lacking. TPM, which currently is approved as adjunctive therapy for the treatment of partial seizures, differs both structurally and pharmacologically from other classes of AEDs. TPM is a sulfamate-substituted monosaccharide D-fructose derivative. After oral administration, the absorption of TPM is rapid, and the bioavailability high (1,2). TPM has a low level of protein binding (9-17%), and its volume of distribution is 0.6 to 0.8 L/kg (1,3). The major route of elimination is renal. A small proportion is metabolized by hydrolysis, hydroxylation, and glucuronidation. The proportion metabolized increases markedly in patients concomitantly treated with enzymeinducing AEDs (3). Considering the growing number of women taking TPM while pregnant, this study set out to provide information on transplacental transfer of TPM, serum concentrations in the newborn, distribution in breast milk, and drug concentrations in the nursed infant. In view of the total lack of information at present, we considered it reasonable to publish preliminary observations based on our first five mother-child pairs. SUBJECTS AND METHODS Five women receiving TPM treatment during pregnancy and lactation were studied (their characteristics are given in 1157 Blood samples from the mothers and from the umbilical cords were collected at delivery. Capillary blood samples also were obtained by heel prick from the newborns on three occasions (24, 48, and 72 h) after delivery. Three mother-infant pairs were studied during lactation, 2-3 weeks after delivery. Two of those also contributed with data 1 month and 3 months after delivery, respectively. After 2-3 weeks, when breast-feeding was established, a blood sample was drawn from the mothers and the infants before the morning dose, ∼10-15 h after the last TPM dose to the mother. A sample of the milk also was taken at the same time. After completion of breastfeeding, the sampling procedure was repeated. The mothers were then allowed to take the morning dose of TPM. TPM concentrations in plasma and breast milk were measured with fluorescence polarization immunoassay (FPIA) (4-7). With this method, the range of quantification is 2.8-94 M, and the limit of detection, 0.9 M. The between-day coefficient of variation (CV) is 10% at 2.8 M and 6.3% at 72.3 M, and the within-run CV, 0.5% at 2.8 M and 1.2% at 72.3 M. In the range 1.2-2.8 M, the CV is 20-25%. Method validation also includes measurement of TPM in breast milk. The Institutional Review Board approved the study, and patients gave their informed consent. RESULTS Maternal and umbilical cord TPM plasma concentrations at delivery and plasma levels in the infants up to 72 h after birth are given in c Data missing. I. OHMAN ET AL. 1158 Epilepsia, Vol. 43, No. 10, 2002 At 4 weeks, the milk/plasma ratio was 0.69 in one mother, and 3 months after delivery, the ratio was 0.86 6 h after dose intake in another mother. Plasma concentrations in the breast-fed infants were <0.9 M and 2.1 M, respectively. CONCLUSION AND DISCUSSION It should be acknowledged that our results are based on observations from only five patients at delivery and from five neonates. No more than three mother-child pairs were studied during nursing on five occasions. Furthermore, in many of the samples, TPM concentrations were below the range of quantification of the method we used for analysis, so these preliminary observations must be interpreted with caution. Nevertheless, some conclusions can be drawn. First, our observations suggest a considerable transfer over the placenta because the ratio between the drug concentration in umbilical cord plasma and maternal plasma was close to one. Second, the newborns seemed to have a reasonable capacity to eliminate TPM. Although our data do not permit a precise calculation of clearance and plasma half-life of TPM, the elimination half-life in the neonate could be estimated to ∼24 h. This is close to the 20-30 h reported among adult healthy controls (8) and may seem surprising, considering the fact that TPM is eliminated mainly unchanged through the kidneys and that kidney function is not fully developed in neonates (9). However, four of five mothers also were taking carbamazepine (CBZ) during pregnancy. CBZ induces the metabolism of TPM (10), and it was previously shown that maternal intake of CBZ during pregnancy can induce fetal metabolism (11). Third, the passage of TPM into the breast milk was extensive, with similar TPM concentrations in milk and maternal plasma levels from 2 to 3 weeks up to 3 months after delivery. The intake of TPM of the infant was estimated to be ∼0.1-0.7 mg/kg/day. However, this figure represents a minimal exposure, because the sampling was done before maternal intake of the morning TPM dose. Despite this, measured plasma concentrations of TPM in the suckling infants were low-in one case even below the limit of detection. Although a therapeutic interval has as yet not been defined for TPM, anticonvulsant effects have been reported at 15-50 M (12-14), levels that are much higher than those observed in the nursed infants. It is therefore not surprising that no adverse effects were observed. In conclusion, our limited data suggest free passage of TPM over the placenta, and an extensive transfer into breast milk. The low plasma concentrations in the suckling infants (∼10-20% of the mother's plasma levels) and the lack of adverse effects indicate minimal risk associated with nursing; however, it is advisable to monitor nursed infants of mothers treated with TPM until more experience has been gained. Additional studies are needed to confirm our observations, and more sensitive analytic methods should be applied for accurate estimation of TPM kinetics in the newborn

Aromatase inhibitors alone or sequentially combined with tamoxifen in postmenopausal early breast cancer compared with tamoxifen or placebo - Meta-analyses on efficacy and adverse events based on randomized clinical trials

Tamoxifen (TAM) and aromatase inhibitors (AI) are adjuvant therapy options for postmenopausal women with estrogen receptor positive (ER+) breast cancer. This systematic review of seven randomized controlled studies comparing TAM and AI, and one study comparing extended therapy with an AI with placebo after about 5 years of tamoxifen, aims to assess long-term clinical efficacy and adverse events. The literature review was performed according to the principles of the Cochrane Collaboration. The search included common databases up to 2013-01-14. Studies of high or moderate quality were used for grading of evidence. Revman™ software was utilized for meta-analyses of published data. Disease free survival (DFS) and overall survival (OS) were improved with AI monotherapy compared to TAM with high and moderate quality of evidence respectively. Sequenced therapy with AI → TAM (or vice versa) improved DFS compared with TAM with moderate quality of evidence, but did not improve OS (low quality of evidence). However, if only studies on sequenced AI therapy with randomization before endocrine therapy were considered, no improvement of DFS could be found. Fractures are more frequently associated with AI whereas the risk of endometrial cancer and venous thromboembolism are higher with TAM. For cardiovascular events no difference was found between AI (mono- or sequenced therapy) and TAM, whereas sequenced therapy compared with AI had lower risk of cardiovascular events (moderate level of evidence). AIs are superior to TAM as adjuvant hormonal therapy for postmenopausal ER-positive breast cancer. TAM can be considered for individual patients due to the different toxicity profile compared with AI. Cardiovascular events related to AI treatment deserve further attention

Ruling out risks in medical research

In medical research, it is not unusual that risks are ruled out without any specification the exact risk that was ruled out. This makes it difficult to balance expected health benefits and risk of harm when choosing between alternative treatment options. International guidelines for reporting medical research results are sufficiently specific when it comes to establishing health benefits. However, there is a lack of standards for reporting on ruling out risks. We argue that transparency is needed, as in the case of non-inferiority trials. The Consolidated Standards of Reporting Trials and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statements should be revised accordingly

Economic Evaluation of Elective Cesarean Section on Maternal Request Compared With Planned Vaginal Birth—Application to Swedish Setting Using National Registry Data

Objectives: There is a lack of consensus around the definition of delivery by cesarean section (CS) on maternal request, and clinical practice varies across and within countries. Previous economic evaluations have focused on specific populations and selected complications. Our aim was to evaluate the cost-effectiveness of CS on maternal request compared with planned vaginal birth in a Swedish context, based on a systematic review of benefits and drawbacks and national registry data on costs. Methods: We used the results from a systematic literature review of somatic risks for long- and short-term complications for mother and child, in which certainty was rated low, moderate, or high using the Grading of Recommendations Assessment, Development and Evaluation. Swedish national registry data were used for healthcare costs of delivery and complications. Utilities for long-term complications were based on a focused literature review. We constructed a decision tree and conducted separate analyses for primi- and multiparous women. Costs and effects were discounted by 3% and the time horizon was varied between 1 and 20 years. Results: Planned vaginal birth leads to lower healthcare costs and somatic health gains compared with elective CS without medical indication over up to 20 years. Although there is uncertainty around, for example, quality-of-life effects, results remain stable across sensitivity analyses. Conclusions: CS on maternal request leads to increased hospitalization costs in a Swedish setting, taking into account short- and long-term consequences for both mother and child. Future research needs to study the psychological consequences related to different delivery methods, costs in outpatient care, and productivity losses