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Objective Many patients with Essure® devices request the removal of these implants due to persistent adverse effects. The pathophysiology remains unknown, but a corrosion of the implants in the in-vivo environment leading to metal ion release may be suspected. The implants consist of polyester fibers, nickel-titanium alloy and other metals including chromium. The purpose of this study is to deliver the first results on the concentrations of nickel and chromium (two potential toxic metal elements) in peritoneal fluid and in the fallopian tube tissue during laparoscopic removal of Essure®. Study design In this prospective observational study conducted in a French academic research hospital (University hospital of Lyon), nickel and chromium concentrations were determined in the fallopian tube tissue and peritoneal liquid from symptomatic patients with Essure® by Inductively Coupled Plasma Mass Spectrometry (ICP-MS) analysis in a PerkinElmer NexION 350. Results Significant metal element concentrations were showed in the peritoneal fluid. There was also a differential concentration in the fallopian tube tissue with higher concentration close to the implant then lower at a distance from this implant. There was a correlation between the concentrations of the two metals. Conclusion The presence of nickel and chromium in the fallopian tube tissue and the peritoneal fluid raises the question of a possible relationship between the symptoms attributed to Essure® implants and the dissemination of potential toxic metals due to galvanic corrosion of the devices.

Background Chronic kidney disease (CKD) after lung transplantation (LT) is underestimated. The aim of the present study was to measure the loss of glomerular filtration rate (GFR) 1 year after LT and to identify the risk factors for developing Stage ≥3 CKD. Methods LT patients in the University Hospital of Lyon had a pre- and post-transplantation measurement of their GFR (mGFR), and GFR was also estimated using the Chronic Kidney Disease Epidemiology Collaboration equation. Results During the study period, 111 patients were lung transplant candidates, of which 91 had a pre-transplantation mGFR, and 29 had a mGFR at 1 year after LT. Six patients underwent maintenance haemodialysis after transplantation. Mean mGFR was 106 mL/min/1.73 m2 before LT and 58 mL/min/1.73 m2 1 year after LT (P Conclusion The present study underlines the value of mGFR in the pre-LT stage and found major renal function loss after LT, and consequently two-thirds of patients have Stage ≥3 CKD at 1 year. All patients with a pre-LT mGFR

There are growing concerns about dolutegravir (DTG)-related neuropsychiatric adverse events and about differences in the characteristics of people living with HIV infection (PLWH) potentially associated with higher risks of said side effects. Several studies have shown that DTG was stopped more frequently among women, older PLWH, and PLWH who initiated abacavir (ABC) at the same time. This study aimed to clarify the factors affecting the pharmacokinetics (PKs) of DTG in a real-life cohort of PLWH using a population PK approach.The model-building strategy was based on a previously published model developed from premarketing trials (1-compartment model with first-order absorption and a lag time). Sparse therapeutic drug monitoring data were obtained from a real-life cohort of 279 PLWH, and population PK analysis was performed using Monolix software. A stepwise covariate model-building strategy was used to evaluate any relevant effects of age, body weight, gender, total bilirubin, smoking status, formulations of DTG, morning versus evening dosing, backbone therapy, and other comedications including CYP/UGT inducers/inhibitors.For a typical 70-kg PLWH, the apparent clearance (CL/F) and apparent volume of distribution (V/F) were 0.748 L/h and 14.6 L, respectively. Of the demographic factors evaluated, body weight was a significant covariate for CL/F and for V/F. Smokers had a 17% higher CL/F relative to nonsmokers. Both strong enzyme inhibitors (eg, atazanavir) and inducers (eg, rifampicin) had marked effects on DTG exposure, with potential clinical implications. Ritonavir-boosted darunavir was found to moderately increase clearance of DTG by 23%. No significant effect of ABC-based backbone therapy was observed on the PK parameters of DTG.Our results did not support the hypothesis that ABC, by competing with the DTG metabolic pathway, may significantly increase DTG exposure leading to potential drug toxicity.

Introduction: Secondary hyperoxalemia is a multifactorial disease that affects several organs and tissues in patients with native or transplanted kidneys. Plasma oxalate may increase during renal failure because it is cleared from the body by the kidneys. However, there is scarce evidence about the association between glomerular filtration rate and plasma oxalate, especially in the early stages of chronic kidney disease (CKD). Methods: A case series focuses on the description of variations in clinical presentation. A pilot study was conducted using a cross-sectional analysis with 72 subjects. The glomerular filtration rate (GFR) and plasma oxalate levels were measured for all patients. Results: Median (IQR) GFR was 70.50 [39.0; 91.0] mL/min/1.73 m2. Plasma oxalate was < 5.0 µmol/L in all patients with a GFR > 30 mL/min/1.73m2. Among the 14 patients with severe CKD (GFR < 30 mL/min/1.73 m2) only 4 patients showed a slightly increased plasma oxalate level (between 6 and 12 µmol/L). Conclusion: In non-primary hyperoxaluria, plasma oxalate concentration increases when GFR < 30mL/min/1.73 m2 and, in our opinion, values greater than 5 µmol/L with a GFR > 30 mL/min/1.73 m2 are suggestive of primary hyperoxaluria. Further studies are necessary to confirm plasma oxalate increase in patients with low GFR levels (< 30mL/min/1.73 m2). RESUMO Introdução: A hiperoxalemia secundária é uma doença multifatorial que afeta vários órgãos e tecidos em pacientes com rins nativos ou transplantados. O oxalato plasmático pode aumentar durante a insuficiência renal porque é eliminado do corpo pelos rins. No entanto, há evidências escassas sobre a associação entre taxa de filtração glomerular e oxalato plasmático, especialmente nos estágios iniciais da doença renal crônica (DRC). Métodos: uma casuística centrada na descrição das variações na apresentação clínica. Foi realizado um estudo piloto a partir da análise transversal com 72 indivíduos. As taxas de filtração glomerular (TFG) e os níveis plasmáticos de oxalato foram medidos para todos os pacientes. Resultados: A TFG mediana (IIQ) foi de 70,50 [39,0; 91,0] mL/min/1,73 m2. O nível plasmático de oxalato foi < 5,0 µmol/L em todos os pacientes com TFG > 30 mL/min/1,73 m2. Entre os 14 pacientes com DRC grave (TFG < 30 mL/min/1,73 m2), apenas quatro apresentaram ligeiro aumento do nível plasmático de oxalato (entre 6 e 12 µmol/L). Conclusão: Na hiperoxalúria não primária, a concentração plasmática de oxalato aumenta quando TFG < 30 mL/min/1,73 m2 e, em nossa opinião, valores superiores a 5 µmol/L com TFG > 30 mL/min/1,73 m2 sugerem presença de hiperoxalúria primária. Estudos adicionais são necessários para confirmar o aumento do oxalato plasmático em pacientes com níveis baixos de TFG (< 30 mL/min/1,73 m2).

Objective Dolutegravir (DTG), a highly effective second-generation HIV integrase inhibitor with high genetic barrier to resistance, has shown excellent tolerability and safety profiles in clinical trials. However, some patients may experience neurological or psychiatric adverse effects leading to DTG discontinuation. Case report This report describes a case of 29-year-old woman who developed neurological adverse events after starting the DTG-based antiretroviral therapy. Serum DTG concentrations were supratherapeutic which has required a dosing interval adjustment. The findings of this case report suggest that Therapeutic Drug Monitoring might be useful in individuals expressing unusual DTG pharmacokinetics.

Background Wilson’s disease (WD) is a rare autosomal-recessive, inherited disorder caused by a mutation in the copper-transporting gene ATP7B affecting the liver and nervous system. About 30% of patients with WD may initially present with psychiatric symptoms, and diagnosis can be difficult to establish. The objectives of the present preliminary study were [1] to evaluate the relevance of serum copper (Cu) and ceruloplasmin (Cp) measures in hospitalized patients with psychiatric disorders; and [2] to identify possible mutations in the ATP7B gene in patients with abnormal biological copper profile. Methods All psychiatric patients who participated in this study were hospitalized in Saint-Jean de Dieu Hospital (Lyon, France). Cp was measured by immunoturbidimetry and serum Cu by inductively coupled plasma-optical emission spectrometry. When Cp and serum Cu levels were inferior to, respectively, 0.18 g/L and 0.88 mg/L in combination with atypical psychiatric presentations, complete clinical examinations were performed by multidisciplinary physicians specialized in WD. In addition, mutation detection in the ATP7B gene was performed. Results A total of 269 patients completed the study. (1) 51 cases (19%) showed both decreased Cp and Cu concentrations. (2) Molecular genetic tests were performed in 29 patients, and one ATP7B mutation (heterozygous state) was found in four patients. We identified three different missense mutations: p.His1069Gln, c.3207C>A (exon 14), p.Pro1379Ser, c.4135C>T (exon 21) and p.Thr1434Met, c.4301C>T (exon 21). No pathogenic mutation on either ATP7B allele was detected. Conclusion Results of Cp and/or serum Cu concentrations below the normal limits are common in patients with psychiatric disorders and nonrelevant and/or informative for the WD diagnosis. WD diagnosis is based on a combination of clinical and biological arguments. Psychiatric patients with suspicion of WD should be evaluated in a reference center. Trial registration CPP Lyon Sud-Est IVNo 10/044, CNIL No DR-2011-470, Afssaps No B100832-40 and CCTIRS No 10.612 bis, registered 8 June 2010

Several studies have reported that oral antibacterials, including ciprofloxacin, administered during mycophenolate mofetil therapy may reduce mycophenolic acid (the active drug moiety) exposure. To our knowledge, however, this effect has never been described with antibiotics administered by the parenteral route. We describe a 17-year-old female who received intravenous mycophenolate mofetil after bone marrow transplantation, with therapeutic drug monitoring performed during therapy. On day 2 of mycophenolate mofetil therapy, the mycophenolic acid area under the plasma concentration-time curve was 30.3 mg•hour/L. On day 8, although her mycophenolate mofetil dosage had remained unchanged, the mycophenolic acid area under the plasma concentration-time curve was unexpectedly lower at 10.7 mg•hour/L. A drug interaction was suspected. Three intravenous antiinfective drugs had been introduced after initial therapeutic drug monitoring had been performed—ciprofloxacin, trimethoprim-sulfamethoxazole, and caspofungin. The patient subsequently developed severe graft-versus-host disease during mycophenolate mofetil therapy and died. Use of the Horn drug interaction probability scale indicated a probable interaction between intravenous mycophenolate mofetil and intravenous ciprofloxacin in this patient. The available literature does not support the role of either trimethoprim-sulfamethoxazole or caspofungin in a drug interaction with mycophenolate mofetil. Published studies have shown that ciprofloxacin is partially excreted by transintestinal elimination after intravenous administration and that it may greatly reduce the levels of enterobacteria of gastrointestinal flora, which are responsible for mycophenolic acid enterohepatic recirculation. Clinicians should be aware that ciprofloxacin, even administered intravenously, may modify the pharmacokinetics of mycophenolate mofetil. Ciprofloxacin should be used with caution in patients receiving mycophenolate mofetil; if this antiinfective must be used, therapeutic drug monitoring should be performed to guide dosage adjustments.

Despite the increasing use of mycophenolate mofetil (MMF) in pediatric liver transplantation recipients, data on MMF pharmacokinetics in this population are relatively scattered. This pilot study was performed to explore whether recipient age-related factors, in conjunction with donor factors, can explain variability in mycophenolic acid (MPA) exposure. Thirty-four MPA pharmacokinetic profiles were performed in 20 stable pediatric liver transplantation recipients (median age, 12 years; range, 1-18 years; median delay after liver transplant, 88 months; range, 3-179 months). Ten children were converted to MMF; the others received MMF as a primary immunosuppressive regimen. MMF was used in combination with tacrolimus. Plasma MPA concentrations were analyzed samples collected at 0, 1, 3, and 6 hours after MMF administration using the enzyme multiplied immunotechnique immunoassay. The median MMF dose was 431 mg/m2 per day (range, 189-833 mg/m2 per day) leading to a median estimated MPA-AUC0-12h of 27 mg/h/L (range, 17-79 mg/h/L). Dose-normalized MPA-AUCs were characterized by high interpatient variability. Young children receiving a liver from a pediatric donor had lower MPA exposure compared with those receiving liver from an adult donor. No correlation was seen between MPA-C0 and MPA-AUC 0-6h in infants, whereas this correlation was significant but moderate in older children. The interpatient variability of MPA exposure observed with this pilot study is an argument for developing therapeutic drug monitoring-based dose adaptation strategies in pediatric liver transplantation recipients. A marked MPA underexposure was observed among young children receiving livers from pediatric donors, indicating that higher doses (mg/m2 of body surface area) might be required to reach the same MPA exposure as in adolescents.

International audience; BACKGROUND: In HIV infected patients, the impact of ribavirin (RBV) pharmacology on sustained virologic response (SVR) to hepatitis C virus (HCV) treatment has not been fully investigated. The objective of this study was to compare the early RBV plasma exposure between a population of HIV-HCV coinfected patients and an HCV monoinfected group. METHODS: Early RBV plasma exposure (expressed as Area Under the Curve (AUC) from 0 to 4 h) after a 600 mg first dose of RBV was measured in a population of HIV-HCV coinfected patients in comparison with an HCV monoinfected group. Peripheral blood samples were collected before the 600 mg RBV first dose (T0) to ensure no detectable baseline plasma RBV, and then 30 mn, 1, 2 and 4 hours after RBV intake (T0.5, T1, T2 and T4). RESULTS: Eighty-six patients with chronic hepatitis C entered the study among whom 23 (27%) were HIV-HCV coinfected. Coinfected patients had a significantly lower RBV-AUC(0-4h) (median: 1469 μg*h/L [range 936-3677]) compared with monoinfected patients (2030 μg*h/L [851-7700]; p = 0.018). This RBV under exposure in coinfected patients persisted after normalization of AUC to RBV dose per kilogram of body weight (182 μg*h/L [110-425] versus 271 μg*h/L [82-1091], p = 0.001). CONCLUSIONS: These results suggest that lower early bioavailability of RBV could be one of the reasons for lower SVR in HIV-HCV coinfected patients treated with pegylated interferon/RBV combination therapy. RBV plasma underexposure seems to be associated with the immunological status of the patients with lower AUC(0-4h) values observed in the more immunosuppressed coinfected patients.

We describe a case of a spurious increase in serum thyroid-stimulating hormone (TSH) attributed to a circulating human anti-mouse antibody (HAMA) in a two-site mouse monoclonal antibody-based assay. A 71-year-old woman on long-term levothyroxine therapy was referred for investigation of uveitis. Her serum TSH had been maintained within the usual reference interval for more than a decade. The initial TSH value by an immunometric method (assay A) on the Dimension RxL analyzer (Dade Behring) was 7.5 mIU/L (reference interval, 0.34–4.82 mIU/L). Because …