Flucloxacillin instantly decreases serum levels of valproic acid: A case report.

Valproic acid (VPA) is used for epilepsy and bipolar disorder. It has near-complete bioavailability and is primarily metabolized by glucuronosyltransferases and mitochondrial oxidation. This case highlights a 79-year-old male with bipolar disorder on VPA therapy that started with flucloxacillin for Staphylococcus aureus bacteraemia and exhibited significantly reduced VPA serum levels. During hospitalization, flucloxacillin treatment correlated with a sharp decline of 75% in VPA total serum levels, a novel drug-drug interaction not previously reported. Nonadherence and absorption issues of VPA were ruled out, confirming flucloxacillin's role in reducing VPA levels. Because free-fraction serum levels of VPA remained within therapeutic range (5-25 mg/L) and our patient's bipolar disorder remained stable at 1000 mg twice daily, a dose increase was not necessary. Previous reports described cytochrome P450 enzyme induction as the mechanism of flucloxacillin lowering serum levels of immunosuppressants and antimycotics. Because only 10% of VPA is metabolized by cytochrome P450 enzymes, this is not plausible for this case. The proposed mechanism for the VPA-flucloxacillin drug-drug interaction is flucloxacillin as inducer of glucuronosyltransferase enzymes via the pregnane X receptor pathway, accelerating VPA metabolism. Because this case showed that free-fraction serum levels remained within therapeutic range, it underscores the need for free-fraction VPA monitoring in bipolar disorder and flucloxacillin therapy. When VPA is used for epilepsy, it is advised to consider alternative antibiotics to avoid this interaction.

Quality of Lactation Studies Investigating Antidepressants.

Introduction: The aim of this study was to determine the quality of lactation studies investigating antidepressants in breast milk according to the Food and Drug Administration (FDA) draft guidelines and the article by Begg et al., 2002, published in the official journal of the International Lactation Consultant Association (ILCA). Materials and Methods: We used PubMed and LactMed® for the literature search. Furthermore, cross references were searched for additional studies. Results: A total number of 60 articles were included for review. For selective serotonin reuptake inhibitors and venlafaxine, only two studies correctly assessed the absolute infant dose and milk to plasma ratio; one sertraline and one fluoxetine study. Of all tricyclic antidepressants, one study for amitriptyline and one for nortriptyline assessed these endpoints correctly. We found a lack of information on breast milk sampling methods in many studies. Concentrations needed for the calculations were based on single measurements instead of at least five measurements during one dose interval, and the relative infant dose was not normalized by maternal weight, or an average maternal weight of 70 kg was used as a standard. Discussion: We conclude that the quality of the current literature on this topic does not meet the standards of the FDA. Studies of higher quality are needed to determine the extent of drug transfer to breast milk for antidepressants, so an adequate recommendation about use of these drugs during lactation can be given.

The quality of lactation studies including antipsychotics.

THE AIM OF THE STUDY: The aim of this study is to determine the quality of lactation studies that investigated antipsychotics in breast milk according to the Food and Drug Administration (FDA) and International Lactation Consultant Association (ILCA) draft guidelines. MATERIALS AND METHODS: We used the draft FDA and ILCA guidelines to review the quality of articles including antipsychotic use during breastfeeding. We used PubMed and Lactmed for the literature search. Furthermore, cross references were searched for additional studies. RESULTS: Of the 51 studies, only one olanzapine and one quetiapine study calculated the milk to plasma ratio (M:P ratio), the Absolute Infant Dose (AID), and the Relative Infant Dose (RID) correctly. In the remaining studies, at least one of the three endpoints was not determined properly. No correct endpoints were calculated in studies containing chlorpromazine, chlorprothixene, clozapine, haloperidol, sulpiride, trifluoperazine, ziprasidone, zonisamide, and zuclopenthixol. This review investigated that there was a lack of information on the sampling methods of breast milk. Furthermore, the concentrations needed for the calculations of the three endpoints were mainly based on single measurements instead of at least five measurements during one dose interval. In many studies, the RID was not calculated correctly due to the fact that the RID was not normalized by the maternal weight or an average maternal weight of 70 kg was used as a standard. CONCLUSION: Except for two studies, most studies about the safety of antipsychotic use during lactation did not meet the criteria of the draft FDA and ILCA guidelines. Further research is mandatory to assess the safety of using antipsychotics while breastfeeding.

Influence of bariatric surgery on the use of medication.

PURPOSE: Bariatric surgery can influence the prevalence and incidence of comorbidities, as well as the pharmacokinetics of drugs. This might lead to changes in the use of drugs. This study aimed to assess the influence of bariatric surgery on the use of medication in patients before and after surgery, focusing on type, number of medications, and daily dosage. METHODS: In a retrospective and prospective observational study, drug dispensing data from pharmacies of patients undergoing their first bariatric surgery between January 2008 and September 2011 was collected. Dispensing data from 1 month before until 12 months after surgery was analyzed. Drugs were classified according to the WHO-ATC classification system. Dosages of drugs were compared using defined daily dose (DDD). RESULTS: Among 450 patients, 12 months after surgery, the mean number of drugs per patient for antidiabetics, drugs acting on the cardiovascular system, anti-inflammatory and antirheumatic drugs, and drugs for obstructed airway diseases decreased by, respectively, 71.3 % (95 % CI 57.2 to 85.4), 34.5 % (95 % CI 28.2 to 43.0), 45.5 % (95 % CI 13.3 to 72.6), and 33.1 % (95 % CI 15.3 to 53.2). Patients used lower median DDD of oral antidiabetics, beta-blocking agents, and lipid-modifying drugs. CONCLUSIONS: For some major drug classes 12 months after bariatric surgery, the use of drugs decreases in terms of mean number per patient. A reduction in dose intensity was observed for oral antidiabetics, beta-blocking agents, and lipid-modifying drugs. Dispensing data from pharmacies may provide detailed information on the use of medications by patients after bariatric surgery.

Sedimentary geology of the middle Carboniferous of the Donbas region (Dniepr-Donets Basin, Ukraine).

The Paleozoic Dniepr-Donets Basin in Belarus, Ukraine, and Russia forms a major hydrocarbon province. Although well- and seismic data have established a 20 km thick stratigraphy, field-studies of its sediments are scarce. The inverted Donbas segment (Ukraine) exposes the middle Carboniferous part of the basin's stratigraphy. Here, we provide detailed sedimentological data from 13 sections that cover 1.5 of the total of 5 km of the Bashkirian and Moscovian stages and assess the paleoenvironment and paleo-current directions. Middle Carboniferous deposition occurred in a shelf environment, with coal deposition, subordinate fluvial facies, and abundant lower and middle shoreface facies, comprising an intercalated package of potential source and reservoir rocks. Sedimentary facies indicate a paleodepth range from below storm wave base to near-coastal swamp environments. Sedimentation and subsidence were hence in pace, with subtle facies changes likely representing relative sea-level changes. Paleocurrent directions are remarkably consistently southeastward in time and space in the different sedimentary facies across the Donbas Fold Belt, illustrating a dominant sedimentary infill along the basin axis, with little basin margin influence. This suggests that the middle Carboniferous stratigraphy of the Dniepr-Donets basin to the northwest probably contains significant amounts of fluvial sandstones, important for assessing hydrocarbon reservoir potential.

Lactation studies of anticonvulsants: a quality review.

AIM: The aim of this review was to investigate the quality of the current literature on the transfer of anticonvulsants to breast milk to provide an overview of which anticonvulsants are in need of further research. METHODS: We reviewed the quality of the available lactation studies for 19 anticonvulsants against the guidelines of the Food and Drug Administration (FDA) and the International Lactation Consultant Association (ILCA). RESULTS: Except for one study on lamotrigine and one case report on gabapentin, no study on anticonvulsants had both the absolute infant dose (AID) and milk to plasma ratio (M : P) correctly assessed. Only one study on carbamazepine, phenytoin and vigabatrin was found that correctly assessed the AID. The main cause for this low number is the lack of essential details in published studies, since 25 of 62 studies were case reports, letters or abstracts. Other major shortcomings were the lack of information on sampling methods, the number of samples in a particular dose interval as well as the low number of study participants. CONCLUSION: The quality of the current literature on the transfer of anticonvulsants to breast milk is low, except for lamotrigine, which makes it hard to draw conclusions about the safety of the use of anticonvulsants during the lactation period. Therefore, further research is needed.

Plate tectonic controls on atmospheric CO2 levels since the Triassic.

Climate trends on timescales of 10s to 100s of millions of years are controlled by changes in solar luminosity, continent distribution, and atmosphere composition. Plate tectonics affect geography, but also atmosphere composition through volcanic degassing of CO2 at subduction zones and midocean ridges. So far, such degassing estimates were based on reconstructions of ocean floor production for the last 150 My and indirectly, through sea level inversion before 150 My. Here we quantitatively estimate CO2 degassing by reconstructing lithosphere subduction evolution, using recent advances in combining global plate reconstructions and present-day structure of the mantle. First, we estimate that since the Triassic (250-200 My) until the present, the total paleosubduction-zone length reached up to ∼200% of the present-day value. Comparing our subduction-zone lengths with previously reconstructed ocean-crust production rates over the past 140 My suggests average global subduction rates have been constant, ∼6 cm/y: Higher ocean-crust production is associated with longer total subduction length. We compute a strontium isotope record based on subduction-zone length, which agrees well with geological records supporting the validity of our approach: The total subduction-zone length is proportional to the summed arc and ridge volcanic CO2 production and thereby to global volcanic degassing at plate boundaries. We therefore use our degassing curve as input for the GEOCARBSULF model to estimate atmospheric CO2 levels since the Triassic. Our calculated CO2 levels for the mid Mesozoic differ from previous modeling results and are more consistent with available proxy data.