Therapeutic drug monitoring of fenfluramine in clinical practice: Pharmacokinetic variability and impact of concomitant antiseizure medications.

OBJECTIVE: This study was undertaken to determine the plasma concentration and pharmacokinetic variability of fenfluramine (FFA) and its main active metabolite norfenfluramine (norFFA) in relation to the prevalence of adverse effects in patients with refractory epilepsy treated with FFA. In addition, the interaction with concomitant antiseizure medications including stiripentol (STP) is studied. METHODS: Patients were recruited at our center from two open-label sources, an investigator-initiated observational study and an international multicenter extension study. Venous blood samples were collected between June 2015 and December 2020. Plasma FFA and norFFA concentrations were determined by liquid chromatography tandem spectrometric analysis. Clinical data were collected retrospectively. Intrapatient coefficient of variation was calculated for all patients with at least three samples. Interpatient variability was calculated based on the concentration to weight-adjusted dose ratio (C/D) of all patients. RESULTS: We collected 321 samples from 61 patients (49 with Dravet syndrome, seven with Lennox-Gastaut syndrome, and five with a developmental and epileptic encephalopathy). With a mean daily dose of .33 mg/kg/day (SD = ±.16), the median FFA plasma concentration was 41.4 µg/L (range = 5.1-712.5) and median norFFA concentration 28.1 µg/L (range = 2.6-149.6). The FFA plasma concentration was linearly related to the daily dose (p < .001) and norFFA levels (p < .001). The C/D of FFA increased with age (p < .001). Median FFA C/D was 428% higher (p < .001), norFFA C/D 83% lower (p < .001), and norFFA/FFA 23% lower (p < .001) in patients treated with STP comedication. Higher FFA concentration was associated with fatigue (p = .001) and somnolence (p < .001), but not anorexia (p = .0619) or reduction in seizure frequency (p = .772). Gender and other ASMs were not associated with significant variations in (nor)FFA C/D ratio. SIGNIFICANCE: Most FFA levels are in the lower range (<50 µg/L), although a high interpatient and intrapatient variability is present. In combination with STP, the dose of FFA should be reduced.

Tolerogenic Dendritic Cells Induce Apoptosis-Independent T Cell Hyporesponsiveness of SARS-CoV-2-Specific T Cells in an Antigen-Specific Manner.

Although the global pandemic caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is still ongoing, there are currently no specific and highly efficient drugs for COVID-19 available, particularly in severe cases. Recent findings demonstrate that severe COVID-19 disease that requires hospitalization is associated with the hyperactivation of CD4+ and CD8+ T cell subsets. In this study, we aimed to counteract this high inflammatory state by inducing T-cell hyporesponsiveness in a SARS-CoV-2-specific manner using tolerogenic dendritic cells (tolDC). In vitro-activated SARS-CoV-2-specific T cells were isolated and stimulated with SARS-CoV-2 peptide-loaded monocyte-derived tolDC or with SARS-CoV-2 peptide-loaded conventional (conv) DC. We demonstrate a significant decrease in the number of interferon (IFN)-γ spot-forming cells when SARS-CoV-2-specific T cells were stimulated with tolDC as compared to stimulation with convDC. Importantly, this IFN-γ downmodulation in SARS-CoV-2-specific T cells was antigen-specific, since T cells retain their capacity to respond to an unrelated antigen and are not mediated by T cell deletion. Altogether, we have demonstrated that SARS-CoV-2 peptide-pulsed tolDC induces SARS-CoV-2-specific T cell hyporesponsiveness in an antigen-specific manner as compared to stimulation with SARS-CoV-2-specific convDC. These observations underline the clinical potential of tolDC to correct the immunological imbalance in the critically ill.

Partial Inhibition of Glycolysis Reduces Atherogenesis Independent of Intraplaque Neovascularization in Mice.

OBJECTIVE: Intraplaque neovascularization is an important feature of unstable human atherosclerotic plaques. However, its impact on plaque formation and stability is poorly studied. Because proliferating endothelial cells generate up to 85% of their ATP from glycolysis, we investigated whether pharmacological inhibition of glycolytic flux by the small-molecule 3PO (3-[3-pyridinyl]-1-[4-pyridinyl]-2-propen-1-one) could have beneficial effects on plaque formation and composition. Approach and Results: ApoE-/- (apolipoprotein E deficient) mice treated with 3PO (50 µg/g, ip; 4×/wk, 4 weeks) showed a metabolic switch toward ketone body formation. Treatment of ApoE-/-Fbn1C1039G+/- mice with 3PO (50 µg/g, ip) either after 4 (preventive, twice/wk, 10 weeks) or 16 weeks of Western diet (curative, 4×/wk, 4 weeks) inhibited intraplaque neovascularization by 50% and 38%, respectively. Plaque formation was significantly reduced in all 3PO-treated animals. This effect was independent of intraplaque neovascularization. In vitro experiments showed that 3PO favors an anti-inflammatory M2 macrophage subtype and suppresses an M1 proinflammatory phenotype. Moreover, 3PO induced autophagy, which in turn impaired NF-κB (nuclear factor-kappa B) signaling and inhibited TNF-α (tumor necrosis factor-alpha)-mediated VCAM-1 (vascular cell adhesion molecule-1) and ICAM-1 (intercellular adhesion molecule-1) upregulation. Consistently, a preventive 3PO regimen reduced endothelial VCAM-1 expression in vivo. Furthermore, 3PO improved cardiac function in ApoE-/-Fbn1C1039G+/- mice after 10 weeks of treatment. CONCLUSIONS: Partial inhibition of glycolysis restrained intraplaque angiogenesis without affecting plaque composition. However, less plaques were formed, which was accompanied by downregulation of endothelial adhesion molecules-an event that depends on autophagy induction. Inhibition of coronary plaque formation by 3PO resulted in an overall improved cardiac function.

The 13C glucose breath test accurately identifies insulin resistance in people with type 1 diabetes.

OBJECTIVE: This study investigated whether the delta-over-baseline of exhaled 13CO2 (Δ13CO2), generated from a 13C glucose breath test (13C-GBT), measured insulin resistance (IR) in people with type 1 diabetes, using the hyperinsulinemic-euglycemic clamp (HEC) as reference method. Secondary objective was to compare the 13C-GBT with the estimated glucose disposal rate (eGDR). METHODS: A 40 mU/m2/min HEC and two separate 13C-GBTs (euglycemic with insulin bolus and hyperglycemic without bolus) were consecutively performed in 44 adults with type 1 diabetes with varying body compositions. eGDR was calculated based on HbA1c, presence of hypertension and waist circumference. RESULTS: Mean M-value was 5.9 ± 3.1 mg/kg/min, mean euglycemic Δ13CO2 was 6.4 ± 2.1 δ‰, while median eGDR was 5.9 [4.3 - 9.8] mg/kg/min. The hyperglycemic Δ13CO2 did not correlate with the M-value, while the euglycemic Δ13CO2 and the M-value correlated strongly (r = 0.74, p < 0.001). Correlation between M-value and eGDR was more moderate (Spearman's rho = 0.63, p < 0.001). Linear regression showed an association between Δ13CO2 and M-value, adjusted for age, sex and HbA1c (adjusted R² = 0.52, B = 1.16, 95% CI 0.80 - 1.52, p < 0.001). The AUROC for Δ13CO2 to identify subjects with IR (M-value < 4.9 mg/kg/min) was 0.81 (95% CI 0.68 - 0.94, p < 0.001). The optimal cut-off for Δ13CO2 to identify subjects with IR was ≤ 5.8 δ‰. CONCLUSIONS: Under euglycemic conditions, the 13C-GBT accurately identified individuals with type 1 diabetes and concurrent IR, suggesting its potential as a valuable non-invasive index.

A new multiplex analysis of glucosylsphingosine and globotriaosylsphingosine in dried blood spots by tandem mass spectrometry.

Background: Gaucher's and Fabry's disease are two of the most common treatable lysosomal storage diseases, and have a wide spectrum of clinical symptoms. Early detection is important, because timely initiation of treatments can improve the disease status and prevent complications. However disease manifestations develop in childhood, diagnosis is delayed until adulthood partly due to the limitations of the currently used diagnostic pathway. The aim of this research is to develop and validate a multiplex assay and defining reference ranges, which do not exist at this moment, to improve and facilitate the entire diagnostic work up and enable treatment in an earlier stage of disease. Methods and findings: Biomarkers glucosylsphingosine (GlcSph) and globotriaosylsphingosine (Lyso-Gb3) were detected and quantified using LC-MS/MS on dried blood spots. We developed an improved and new extraction method that allowed to measure GlcSph and Lyso-Gb3 in a multiplex analytical platform. After validation of the method, samples of 1480 individuals with normal enzymatic activity were collected to determine age and gender-related reference ranges.Our combination method showed a good linearity, precision, accuracy and limit of quantification with lack of carry-over following the specific international CLSI guidelines. The suggested protocol is robust, efficient, sensitive, specific, comprehensive and relatively cheap in order to accelerate the diagnostic process for both lysosomal storage diseases. The samples, with normal enzymatic activity, defined statistical relevant and clinical correct reference ranges for each specific age group by gender. Conclusion: We report a multiplex LC-MS/MS method and relevant reference ranges that are appropriate for the targeted screening, diagnosis and follow-up of Fabry and Gaucher disease.

Does the Tacrolimus Trough Level Adequately Predict Drug Exposure in Patients Requiring a High Tacrolimus Dose?

Tacrolimus (Tac) has a narrow therapeutic range. Dosing is generally targeted at Tac trough levels (C 0), notwithstanding conflicting reports on the correlation between Tac C 0 and systemic exposure measured by the area-under-the-concentration-over-time curve (AUC). The Tac dose required to meet the target C 0 varies highly among patients. We hypothesized that patients requiring a relatively high Tac dose for a certain C 0 may show a higher AUC. Methods: We retrospectively analyzed data from 53 patients in which a 24-h Tac AUC24 estimation was performed at our center. Patients were divided into those taking a low (≤0.15 mg/kg) or high (>0.15 mg/kg) once-daily Tac dose. Multiple linear regression models were used to investigate if the association between C 0 and AUC24 changes according to dose level. Results: Despite the large difference in mean Tac dose between the low- and high-dose group (7 versus 17 mg/d), C 0 levels were similar. However, the mean AUC24 was substantially higher in the high-dose group (320 ± 96 h·µg/L versus 255 ± 81 h·µg/L, P < 0.001). This difference remained significant after adjusting for age and race. For a same C 0, every 0.01 mg/kg increase in Tac dose resulted in an AUC24 increase of 3.59 h·µg/L. Conclusions: This study challenges the general belief that C 0 levels are sufficiently reliable to estimate systemic drug exposure. We demonstrated that patients requiring a relatively high Tac dose to attain therapeutic C 0 levels have higher drug exposure and could therefore potentially be overdosed.

Serum concentrations of local anesthetics after unilateral interpectoral-pectoserratus plane block in breast cancer surgery: a pharmacokinetic study.

INTRODUCTION: The ultrasound-guided interpectoral-pectoserratus plane block is a fascial plane block for superficial surgery of the anterolateral chest wall. This technique involves injecting a relatively large volume of local anesthetics (typically 30 mL of 0.25%-0.50%, ie, 75-150 mg ropivacaine) underneath the major and minor pectoral muscles of the anterior thoracic wall. There is a potential risk of toxic serum concentrations of local anesthetics due to systemic absorption. METHODS: 22 patients scheduled for elective unilateral breast cancer surgery were included in this study. All surgery was performed with general anesthesia and an ultrasound-guided interpectoral-pectoserratus plane block with 2.5 mg/kg ropivacaine. Ten venous blood samples were collected at 0 (two samples) 10, 20, 30, 45, 60, 90 and 120 min and at 4 hours after performing the block. Free and total ropivacaine levels were measured at each time point. Albumin and alpha-1-acid-glycoprotein were measured to monitor shifts between the free and bound fraction of ropivacaine. RESULTS: Samples of 20 patients were analyzed. The mean dose of ropivacaine was 172.8 (22.5) mg. In 50% of the patients, the potentially toxic threshold of 0.15 µg/mL free ropivacaine concentration was exceeded. Mean peak serum concentration occurred at 20 min postinjection. CONCLUSIONS: This pharmacokinetic study demonstrated that a 2.5 mg/kg ropivacaine interpectoral-pectoserratus plane block may result in exceeding the threshold for local anesthetic systemic toxicity.

Belgian rare diseases plan in clinical pathology: identification of key biochemical diagnostic tests and establishment of reference laboratories and financing conditions.

BACKGROUND: One objective of the Belgian Rare Diseases plan is to improve patients' management using phenotypic tests and, more specifically, the access to those tests by identifying the biochemical analyses used for rare diseases, developing new financing conditions and establishing reference laboratories. METHODS: A feasibility study was performed from May 2015 until August 2016 in order to select the financeable biochemical analyses, and, among them, those that should be performed by reference laboratories. This selection was based on an inventory of analyses used for rare diseases and a survey addressed to the Belgian laboratories of clinical pathology (investigating the annual analytical costs, volumes, turnaround times and the tests unavailable in Belgium and outsourced abroad). A proposal of financeable analyses, financing modalities, reference laboratories' scope and budget estimation was developed and submitted to the Belgian healthcare authorities. After its approval in December 2016, the implementation phase took place from January 2017 until December 2019. RESULTS: In 2019, new reimbursement conditions have been published for 46 analyses and eighteen reference laboratories have been recognized. Collaborations have also been developed with 5 foreign laboratories in order to organize the outsourcing and financing of 9 analyses unavailable in Belgium. CONCLUSIONS: In the context of clinical pathology and rare diseases, this initiative enabled to identify unreimbursed analyses and to meet the most crucial financial needs. It also contributed to improve patients' management by establishing Belgian reference laboratories and foreign referral laboratories for highly-specific analyses and a permanent surveillance, quality and financing framework for those tests.

Non-Alcoholic Steatohepatitis Decreases Microsomal Liver Function in the Absence of Fibrosis.

The incidence of non-alcoholic fatty liver disease (NAFLD) is rising across the globe, with the presence of steatohepatitis leading to a more aggressive clinical course. Currently, the diagnosis of non-alcoholic steatohepatitis (NASH) is based on histology, though with the high prevalence of NAFLD, a non-invasive method is needed. The 13C-aminopyrine breath test (ABT) evaluates the microsomal liver function and could be a potential candidate. We aimed to evaluate a potential change in liver function in NASH patients and to evaluate the diagnostic power of ABT to detect NASH. We performed a retrospective analysis on patients suspected of NAFLD who underwent a liver biopsy and ABT. 440 patients were included. ABT did not decrease in patients with isolated liver steatosis but decreased significantly in the presence of NASH without fibrosis and decreased even further with the presence of significant fibrosis. The predictive power of ABT as a single test for NASH was low but improved in combination with ALT and ultrasonographic steatosis. We conclude that microsomal liver function of patients with NASH is significantly decreased, even in the absence of fibrosis. The ABT is thus a valuable tool in assessing the presence of NASH; and could be used as a supplementary diagnostic tool in clinical practice.

Evaluation of vilazodone for the treatment of depressive and anxiety disorders.

INTRODUCTION: Major Depressive Disorder (MDD) and General Anxiety Disorder (GAD) significantly contribute to the global burden of disease. Vilazodone, a combined serotonin reuptake inhibitor and 5-HT1A partial agonist, is an approved therapy for the treatment of MDD and which has been further investigated for GAD. Areas covered: This article covers the pharmacokinetics and pharmacodynamics of vilazodone and provides an evaluation of the clinical usefulness of vilazodone for the treatment of MDD and anxiety disorders. A literature search was performed using PubMed/MEDLINE, Web of Science and the Cochrane Library. Expert opinion: Studies have shown that vilazodone is significantly superior to placebo. However, vilazodone cannot as yet be recommended as a first-line treatment option for MDD as it is unclear whether the drug's dual mechanism of action provides greater efficacy than prevailing treatment options. Moreover, more phase IV studies are needed to establish its efficacy and long-term safety in larger and more diverse populations. Although vilazodone may have an additional advantage for the treatment of anxiety symptoms in MDD, here also additional studies are required to confirm its efficacy over and above SSRI alternatives and other antidepressant treatments. Therefore, presently, vilazodone should be considered as a second- or third-line treatment option for MDD and GAD.

Analytical and clinical performance of three hand-held point-of-care creatinine analyzers for renal function measurements prior to contrast-enhanced imaging.

BACKGROUND: As iodine-based contrast can cause deterioration of renal function in patients with impaired kidney function, guidelines advise to measure creatinine and calculate estimated glomerular filtration (eGFR) prior to administration. Point-of-care (POC) devices seem an attractive alternative to central laboratory testing but uncertainty regarding analytical and clinical comparability remains. METHODS: This study compared three POC devices, i-STAT (Abbott), StatSensor (Nova) and epoc (Siemens) with a central laboratory method (enzymatic creatinine, Siemens Vista 1500 platform). 120 patients were included and underwent simultaneous finger prick capillary blood analysis on the StatSensor and heparine whole blood analysis on StatSensor, i-STAT and epoc. RESULTS: All POC devices generated results which showed considerable variability around the creatinine value of the reference standard, with StatSensor having the widest (-1,12-1,11 mg/dL) and epoc the tightest (-0,49-0,49 mg/dL) 95% limits of agreement. I-STAT showed the highest clinical concordance with the reference standard (Kappa: 0,94) and had the smallest average analytical error (6%) for creatinine and eGFR compared to the reference standard, meeting the predefined criteria of 8,87% and 10%, respectively. Epoc only met criteria for eGFR. StatSensor did not meet any of the criteria. CONCLUSIONS: I-STAT and epoc were, analytically and clinically, the most performant POC devices included in this study but showed to be less user-friendly. StatSensor did not meet any of the error criteria, neither for creatinine nor for eGFR measurements, and gave more clinical major classification errors. However, it proved to be more user-friendly compared to the other POC devices.

Fast analysis of decabrominated diphenyl ether using low-pressure gas chromatography-electron-capture negative ionization mass spectrometry.

This paper reports the applicability of low-pressure gas chromatography-mass spectrometry operated in electron-capture negative ionization mode (LP-GC-ECNI-MS) for the analysis of decabrominated diphenyl ether (BDE-209). Particular attention was paid to find optimal injector and oven conditions for minimal thermal degradation of BDE-209. The analytical characteristics were compared for LP-GC columns (10 m x 0.53 mm) with different film thicknesses (d(f) 0.15 microm versus 0.25microm) and for a conventional GC column (15 m x 0.25 mm, 0.10 microm d(f)). Short residence times (6.5 and 9.8 min) of BDE-209 were found for the LP-GC systems with 0.15 and 0.25microm d(f), respectively, resulting in a low elution temperature and minimal degradation. Additionally, baseline separation of 22 polybrominated diphenyl ether (PBDE) congeners (major components of PBDE technical mixtures) was possible in less than 12 min using the LP-GC-ECNI-MS system with 0.15microm d(f). The optimized method was applied for the determination of PBDEs in Belgian indoor dust samples. The obtained concentrations of BDE-209 (range 8-292 ng/g dry weight) were in the same range or lower than concentrations in dust from other European countries.

Simultaneous determination of bisphenol A, triclosan, and tetrabromobisphenol A in human serum using solid-phase extraction and gas chromatography-electron capture negative-ionization mass spectrometry.

This study aimed at optimizing and validating a sensitive method for simultaneous determination of bisphenol A (BPA), triclosan (TCS), and tetrabromobisphenol A (TBBPA) in human serum using solid-phase extraction (SPE) and gas chromatography coupled to electron-capture negative-ionization mass spectrometry (GC-ECNI/MS). Sample preparation involved denaturation of serum proteins with formic acid followed by SPE on an Oasis HLB cartridge. Fractionation was performed on Florisil from which the phenolic compounds were eluted with methanol-dichloromethane (DCM) (5:1, v/v). The phenolic fraction was further derivatized with pentafluoropropionic acid anhydride (30 min at 70 degrees C). Further liquid-liquid partitioning using hexane-DCM (4:1, v/v) and K(2)CO(3) 3% aqueous solution was used to eliminate excess reagent and acidic by-products formed during derivatization. The cleaned extract was injected into a GC-ECNI/MS system operated in selected ion monitoring mode. For thorough method validation, each step of the procedure was rigorously optimized. The method limits of quantitation for BPA, TCS, and TBBPA were 0.28 ng mL(-1), 0.09 ng mL(-1) and 0.05 ng mL(-1), respectively. Furthermore, the method was applied to 21 Belgian human serum samples. The median concentrations obtained for BPA (0.71 ng mL(-1)) and TCS (0.52 ng mL(-1)) in Belgian human serum samples were similar to previously reported data for human fluids. Slightly higher levels of TBBPA (0.08 ng mL(-1)) were found in Belgium samples compared to Norwegian serum.

Brominated flame retardants and polychlorinated biphenyls in fish from the river Scheldt, Belgium.

Levels of polybrominated diphenyl ethers (PBDEs), hexabromocyclododecanes (HBCDs), and polychlorinated biphenyls (PCBs) were measured in several fish species originating from the river Scheldt (Belgium). Five sampling locations were chosen in a highly industrialized area along the river, while two ponds in the vicinity of the river served as reference sites. The present study is a follow-up of a survey performed in 2000 which reported extremely high levels of PBDEs and HBCDs in eel (Anguilla anguilla) collected from the same region (Oudenaarde, Flanders). The sum of tri- to hepta-BDE congeners (2270+/-2260 ng/g lipid weight (lw), range 660-11500 ng/g lw) and total HBCDs (4500+/-3000 ng/g lw, range 390-12100 ng/g lw) were one order of magnitude higher than levels usually reported from freshwater systems, indicating the presence of point sources. In most samples, levels of total HBCDs were higher than those of PBDEs, probably due to the high density of factories using HBCD as an additive brominated flame retardant (BFR). The high values of HBCDs were confirmed by both gas- and liquid-chromatography-mass spectrometry. Although BFR levels were between the highest ever reported in freshwater ecosystems, PCBs could be detected at even higher concentrations (16000+/-14300 ng/g lw, range 3900-66600 ng/g lw), being among the highest levels recorded in Belgium. The inter-sampling site variation of PBDEs, HBCDs and PCBs was comparable. All locations presented similar PBDE congener profiles, with BDE 47 being the dominant congener, followed by BDE 100, BDE 99 and BDE 49, probably originating from the former use of the penta-BDE technical mixture. In order to estimate the impact of these point sources on human exposure, we further focussed on eels which showed a considerable decrease in the PBDE and HBCD levels between 2000 and 2006. Due to the wide span in concentrations between the different sampling locations, a variable contribution to the total human exposure through local eel consumption was estimated. The calculated daily intake ranged from 3 ng to 330 ng PBDEs/day for normal eel consumers, but was as high as 9800 ng PBDEs/day for anglers, which may be considered at risk.

Polybrominated diphenyl ethers in domestic indoor dust from Canada, New Zealand, United Kingdom and United States.

Because of the similarities in European and North American dietary exposure, it has been suggested that the order of magnitude higher body burdens in North Americans may be due to international variations in exposure via ingestion of indoor dust. Furthermore, ingestion of indoor dust has been suggested as a possible source of PBDEs in the blood serum of New Zealanders. Hence, polybrominated diphenyl ethers (PBDEs) were measured in domestic indoor dust from: Amarillo/Austin, Texas, US; Birmingham, UK; Toronto, Canada; and Wellington, New Zealand. Concentrations of BDE 209 in two UK samples were - at 520,000 and 100,000 ng g(-1) - the highest ever recorded in a domestic (or office) indoor dust sample. Median concentrations in ng g(-1) were: in Canada 620 and 560 for Sigmatri-hexa-BDEs and BDE 209 respectively; in New Zealand 96, BDE 209 not determined; in the UK 59 and 2,800; and in the US 1600 and 1300. With respect to BDE 209, concentrations were in the order: UK approximately US>Canada. For Sigmatri-hexa-BDEs, the order of concentrations was US approximately Canada>>New Zealand approximately UK. Combined with principal component analysis of congener patterns, this suggests that, while North American dusts are contaminated by both Deca- and Penta-BDE commercial formulations, UK dusts are contaminated predominantly by Deca-BDE. The Octa-BDE formulation appears of minimal importance in accordance with available market demand figures. Despite the commercial formulations of PBDEs never having been manufactured in, nor imported into New Zealand, their presence in dusts from that country suggests international trade in PBDE-containing goods is an important pathway effecting their global distribution.

Polybrominated diphenyl ethers (PBDEs) and polychlorinated biphenyls (PCBs) in human liver and adipose tissue samples from Belgium.

Levels of polybrominated diphenyl ethers (PBDEs) and polychlorinated biphenyls (PCBs) were measured in paired human adipose tissue and liver samples (n=25) from Belgium. Average concentrations and standard deviation of sum PBDEs (congeners 28, 47, 99, 100, 153, 154 and 183) were 5.3+/-3.0 (range 1.4-13.2) and 3.6+/-2.1 (range 1.0-10.0)ng g(-1) lipid weight (lw) in adipose tissue and liver, respectively. These concentrations were similar to reported PBDE data from Belgium and were at the lower end of the concentration range reported elsewhere in the world. In both tissues under study, BDE 153 and BDE 47 were the most abundant PBDE congeners, contributing approximately 35% and 25% to the total PBDE content. Average concentrations and range of PCBs (sum of 23 congeners) were 490 (range 70-1130) and 380 (range 90-1140)ng g(-1)lw in adipose tissue and liver, respectively. No correlation between age and concentrations of PBDEs could be found (r=0.04), while PCB concentrations correlated significantly with age (r=0.62, p<0.01, for the sum PCBs; r=0.64, p<0.01 for PCB 153 alone). Factors, such as exposure pathways (food, dust and air), rates of bioaccumulation, metabolism and elimination, influence the concentrations of PBDEs differently than those of PCBs in humans.

Pharmacokinetic evaluation of the aripiprazole (once-monthly) injection for the treatment of bipolar disorder.

INTRODUCTION: Bipolar disorder is a severe, chronic psychiatric disorder with a need for long-term treatment. Patient nonadherence is frequent and poses a major problem in maintenance therapy. Aripiprazole once-monthly long-acting injectable (AOM LAI) is a recently US Food and Drug Administration-approved treatment option for maintenance therapy that could be of great value. Areas covered: This paper reviews the pharmacokinetic, efficacy and safety data for AOM LAI in bipolar disorder. Expert opinion: AOM LAI is a safe and efficacious treatment option in the maintenance therapy of bipolar I disorder. However, further research is still needed to determine the position of AOM LAI relative to other available treatment options.