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Background There is inconsistency between many guidelines in the recommended dose reduction of renally cleared antibiotics in patients with impaired renal function. Objectives This systematic review summarizes the available evidence on the adequacy of the recommended dose reduction in terms of achieving sufficient antibiotic drug exposure or pharmacokinetic/pharmacodynamic target attainment after treatment with these reduced doses. Data sources We systematically searched Ovid Medline and Embase from inception (respectively 1946 and 1947) through July 2019. Study eligibility criteria All studies reporting antibiotic drug exposure and/or pharmacokinetic/pharmacodynamic (PK/PD) target attainment after dose reduction of antibiotics in patients with impaired renal function. Participants Adult patients with or without infections. Interventions Administration of reduced doses of antibiotics (orally, intravenously or intramuscularly). Methods The reduced dose was considered adequate when the most relevant parameters of drug exposure or PK/PD target attainment in patients with impaired renal function were within a range of 80% to 125% of that patients with adequate renal function receiving a regular dose (reference) or when PK/PD target attainment was attained in at least 90% of the patients with impaired renal function, regardless of the lack of a reference group. Results Twenty-seven of the 4202 identified studies were included. The quality of 15 of 27 studies was fair, and most studies were of β-lactams (12/27). Best evidence was available for meropenem: four studies were included, of which two studies were of good quality. Drug exposure for meropenem is 158% to 286% higher in patients with impaired renal function receiving reduced doses compared to patients with adequate renal function receiving regular doses. For all other antibiotics, a maximum of one good-quality study could be identified. Conclusions No good-quality evidence on the recommended dose reduction of renally cleared antibiotics in patients with impaired renal function is present, with the exception of meropenem.

The most sensitive indicators of the functional state of the kidneys are the glomerular filtration rate and the level of creatinine in the blood, which is practically independent of extrarenal factors and does not lend itself to significant daily fluctuations. The search for new possibilities of correcting drug exposure on the course of acute pyelonephritis and concomitant diabetes mellitus seems to be promising in order to prevent the development of pathomorphological changes in functional renal disorders. Evaluation of the effectiveness of etiotropic drug exposure to drugs and their combination with the pathogenetic effect on the creatinine content in blood plasma and urine and its clearance in acute pyelonephritis and concomitant diabetes mellitus type I and II in the experimental conditions was the aim of our study. The obtained experimental data revealed a more pronounced increase in creatinine in blood plasma compared with its content in urine: in blood plasma by 83.6 % and in urine by 25.1 %, respectively, in relation to the norm, which indicates a significant decrease in glomerular level filtering. The clearance of cretinin in acute pyelonephritis was reduced by 15.2 %, and with concomitant diabetes mellitus, more distinct changes were observed, for type II diabetes there was a decrease of 27.3 %, and for type I diabetes by 36.4 % in relation to normal. The use of etiotropic exposure for type I and II diabetes contributed to a moderate improvement in this indicator, and the use of ethiopathogenetic effects caused a significant increase in creatinine clearance, the level of which differed from normal only by 9.1 % in type II diabetes and by 15.2 % with type I diabetes. Etio-pathogenetic drug intervention has led to the prevention and deterrence of nephrosclerotic changes, which should be associated with the complex effect of antibacterial, membrane-protective and metabolism correcting effects.

This study examines the lifetime prevalence of illicit drug use and illicit drug exposure in disadvantaged ("Roma") and more affluent neighborhoods in Czechia. The results of a survey among populations of both types of neighborhoods suggest no statistically significant difference between the two in terms of the overall lifetime prevalence of illicit drug use; however, lifetime prevalence of methamphetamine use proved higher in disadvantaged neighborhoods. The population of disadvantaged neighborhoods has also lower chances to use LSD during their lifetime. Further differences were identified in drug exposure, with the population of more affluent neighborhoods being more frequently exposed to illicit drugs than the population of disadvantaged neighborhoods. The predictors of drug use and drug exposure were partially different for both populations. In the disadvantaged population, drug use was revealed, among other predictors, to be associated with housing conditions.

BACKGROUND: Drug exposure assessment based on dispensing data can be misclassified when patients do not adhere to their therapy or when information about over-the-counter drugs is not captured in the study database. Previous research has considered hypothetical sensitivity and specificity values, whereas this study aims to assess the impact of literature-based real values of exposure misclassification. METHODS: A synthetic cohort study was constructed based on the proportion of exposure theoretically captured in a database (range 0.5-1.0) and the level of adherence (0.5-1.0). Three scenarios were explored: non-differential misclassification, differential misclassification (misclassifications dependent on an unmeasured risk factor doubling the outcome risk), and non-differential misclassification in a comparative effectiveness study (RRA and RRB both 2.0 compared to non-use, RRA-B 1.0). RESULTS: For the scenarios with non-differential misclassification, 25% non-adherence or 25% uncaptured exposure changed the RR from 2.0 to 1.75 and 1.95, respectively. Applying different proportions of non-adherence or uncaptured use (20% vs 40%) for subgroups with and without the risk factor, an RR of 0.95 was observed in the absence of a true effect (i.e., true RR = 1). In the comparative effectiveness study, no effect on RR was seen for different proportions of uncaptured exposure; however, different levels of non-adherence for the drugs (20% vs 40%) led to an underestimation of RRA-B (0.89). DISCUSSION: All scenarios led to biased estimates, but the magnitude of the bias differed across scenarios. When testing the robustness of findings of pharmacoepidemiologic studies, we recommend using realistic values of non-adherence and uncaptured exposure based on real-world data.

Aims Rituximab is standard care in a number of lymphoma subtypes, including follicular lymphoma (FL), although many patients are resistant to rituximab, or develop resistance with repeated treatment, and a high proportion relapse. Obinutuzumab is a novel anti-CD20 monoclonal antibody with improved efficacy over rituximab. It is approved for previously untreated chronic lymphocytic leukaemia (CLL), and for use with bendamustine in patients with rituximab-relapsed/refractory FL. Methods Using a previously described population pharmacokinetic (PK) model of obinutuzumab in patients with non-Hodgkin lymphoma and CLL, we conducted an exposure-response analysis using data from 6 clinical trials in patients with CD20+ B-cell malignancies (CLL11, GADOLIN, GATHER, GAUDI, GAUGUIN and GAUSS) to describe the PK properties of obinutuzumab, identify covariates influencing exposure, and explore how exposure affects safety, efficacy and pharmacodynamics. Results A 2-compartment model with linear and time-dependent clearance described obinutuzumab PK. Disease type and subtype, body weight, baseline tumour size, and sex had the largest effects on PK. Obinutuzumab exposure was not associated with occurrence or severity of adverse events, but higher exposure appeared to be associated with greater efficacy, particularly longer progression-free survival. However, in multivariate Cox regression analysis, progression-free survival benefit in the obinutuzumab plus bendamustine arm was independent of exposure. Conclusion The updated population PK model reported here accurately describes the PK of obinutuzumab patients with non-Hodgkin lymphoma and CLL. The selected obinutuzumab dosing regimen offers clinical benefit in a majority of rituximab-refractory FL patients treated with bendamustine, irrespective of variability in exposure, whilst minimising adverse events.

International audience; Pharmacoepidemiology is the study of interactions between drugs and human populations, investigating, in real conditions of life, benefits, risks and use of drugs. Pharmacoepidemiology applies to drugs and their pharmacological evaluations, the different methods also used in epidemiology to assess in real conditions of life, benefits, risks and use of drugs. Pharmacoepidemiologic studies are ad-hoc studies or studies on databases. Specific methods exist to measure drug exposure, as well as indicators of compliance and misuse of drugs. Various designs for descriptive and explanatory studies exist, in a context in which a growing proportion of studies are carried out using medico-administrative data. The limits traditionally affecting the study designs are modified in this context, almost any design selected for the conduct of a study from these databases then deriving from a cohort in whom the information has been recorded prospectively and exhaustively.

Trial data support an absence of an exposure–survival relationship for pembrolizumab. As these relationships remain unexamined in a real‐world setting, we determined them in metastatic melanoma prospectively in an observational study. Translational objectives included identifying biomarkers of progressive disease (PD). Checkpoint blockade naïve patients receiving 2 mg/kg Q3W pembrolizumab had pharmacokinetic and clinical outcome data collected. Trough, a valid surrogate for drug exposure, was assessed using ELISA. T‐cell exhaustion and chemokine markers were determined using flow cytometry. Geometric means of exposures and biomarkers were tested against objective response groups using one‐way ANOVA. The cohort was split by the median into high versus low pembrolizumab exposure groups. Kaplan–Meier progression‐free survival (PFS) and overall survival (OS) curves were estimated for high versus low exposure, compared using the log rank test. The high pembrolizumab exposure group (n = 14) experienced substantially longer median OS (not reached vs. 48 months, p = .014), than the low exposure group (n = 14). A similar positive exposure PFS relationship was found (median not reached vs. 48 months, p = .045). The frequency of TIM‐3 expression on CD4+ T cells was significantly higher in PD (mean 27.8%) than complete response (CR) (13.38%, p = .01) and partial response (12.4%, p = .05). There was a near doubling of CXCR6 and TIM‐3 co‐expression on CD4+ T cells in PD (mean 23.3%) versus CR (mean 11.4, p = .003) and partial response (9.8%, p = .0001). We describe positive exposure‐PFS and exposure‐OS relationships for pembrolizumab in metastatic melanoma. TIM‐3, alongside co‐expression of CXCR6 and TIM‐3 on circulating CD4+ T cells are potential bio markers of treatment failure., Low pembrolizumab exposure is associated with inferior overall survival in metastatic melanoma. ​

Recognize that delayed hypersensitivity reactions to sulfonamides may present as urticated plaques with hyperpigmentation and purpura for which a diagnosis of urticarial vasculitis should be considered.

Objectives: To explore the association between drug exposure and SARS-CoV-2 prognosis among elderly people living in long-term care facilities (LTC) Design: We carried out a cross-sectional study among old people living in LTC that had a proven SARS-CoV-2 infection, including socio-demographic data, comorbidities and drug intake at the moment of the diagnosis. The study was focused on ACE2 inhibitors, ARA-II blockers, inhaled bronchodilators, oral corti-coids, platelet antiaggregants, oral anti-coagulants, statins and Vitamin D. Results: 1 306 individuals were included, with a mean age of 86.7 years, and 72.3% were females. The case fatality rate was 24.4%. Among the studied exposures platelet antiaggregants were the most preva-lent (24.7%). After adjusting for propensity score, the intake of inhaled corticoids (OR 0.73; p = 0.03) and statins (OR 0.65; p = 0.03) were found to be protective factors of death, whereas ACE2 inhibitor showed an almost significant association (OR 0.73, p = 0.07). Conclusions: Considering the high prevalence of drug intake among elderly people, drug exposure may be an important Covid-19 disease modifier in LTC residents and should be considered when exploring prognostic risk factors associated to Covid-19. (c) 2021 The Author(s). Published by Elsevier Ltd on behalf of International Society for Infectious Diseases. This is an open access article under the CC BY-NC-ND license ( http://creativecommons.org/licenses/by-nc-nd/4.0/ )

Background Cerebrovascular disorders have occurred more frequently in some Central Nervous System (CNS) disorders, such as epilepsy. Some CNS drugs have been associated with increased stroke risk. Our aim was to estimate the risk of ischaemic stroke in patients exposed to antiepileptic drugs (AED). Methods Population-based matched case-control study using SIDIAP database, based in electronic health records from primary healthcare from Catalonia, Spain. Cases were those patients with a registered diagnosis of first stroke during 2009–2014. Up to 10 controls were selected for each case and matched by sex, age, and geographic area and without a prior diagnosis of stroke. We considered global drug exposure to AED, past and current exposure and exposure in monotherapy to each AED. Results 2,865 cases and 19,406 controls were exposed to AED during the study period. Global exposure to levetiracetam [(ORadj3.3, CI95 % 2.8-4.0)], phenytoin [ORadj1.5, CI95 % 1.2–41.9)], and valproic acid [(ORadj 1.3, CI95 % 1.1–1.6)], showed significantly association to ischaemic stroke that was also maintained with current exposure of levetiracetam [ORadj4.1, CI95 % 3.3–5.2)] and valproic acid [ORadj1.4, CI95 % 1.1–1.9)]. Current levetiracetam monotherapy showed a very high risk of ischaemic stroke [(ORadj 5.1, CI95 % 3.7–6.9)]. Conclusions Drugs used for other conditions than epilepsy (pregabalin, gabapentin) were the most used AED and both did not show a risk. Levetiracetam shows a risk for stroke even when assessed in current monotherapy. The lack of data regarding the link with diagnosis and severity in our study makes it necessary to conduct further studies to confirm or dismiss our results, focussing on levetiracetam.

Despite increasing knowledge of the biologic drivers of central nervous system tumors, most targeted agents trialed to date have not shown activity against these tumors in clinical trials. To effectively treat central nervous system tumors, an active drug must achieve and maintain an effective exposure at the tumor site for a long enough period of time to exert its intended effect. However, this is difficult to assess and achieve due to the constraints of drug delivery to the central nervous system. To address this complex problem, an understanding of pharmacokinetic principles is necessary. Pharmacokinetics is classically described as the quantitative study of drug absorption, distribution, metabolism, and elimination. The innate chemical properties of a drug, its administration (dose, route and schedule), and host factors all influence these four key pharmacokinetic phases. The central nervous system adds a level of complexity to standard plasma pharmacokinetics as it is a coupled drug compartment. This review will discuss special considerations of pharmacokinetics in the context of therapeutic development for central nervous system tumors.

Publisher's version (útgefin grein), Purpose: Exposure definitions vary across pharmacoepidemiological studies. Therefore, transparent reporting of exposure definitions is important for interpretation of published study results. We aimed to assess the quality of reporting of exposure to identify where improvement may be needed. Method: We systematically reviewed observational pharmacoepidemiological studies that used routinely collected health data, published in 2017 in six pharmacoepidemiological journals. Reporting of exposure was scored using 11 items of the ISPE-ISPOR guideline on reporting of pharmacoepidemiological studies. Results: Of the 91 studies included, all studies reported the type of exposure (100%), while most reported the exposure risk window (85%) and the exposure assessment window (98%). Operationalization of the exposure window was described infrequently: 16% (14/90) of the studies explicitly reported the presence or absence of an induction period if applicable, 11% (5/47), and 35% (17/49) reported how stockpiling and gaps between exposure episodes were handled, respectively, and 35% (17/49) explicitly mentioned the exposure extension. Switching/add-on was reported in 62% (50/81). How switching between drugs was dealt with and specific drug codes were reported in 52 (57%) and 24 (26%) studies, respectively. Conclusion: Publications of pharmacoepidemiological studies frequently reported the type of exposure, the exposure risk window, and the exposure assessment window. However, more details on exposure assessment are needed, especially when it concerns the operationalization of the exposure risk window (eg, the presence or absence of an induction period or exposure extension, handling of stockpiling and gaps, and specific codes), to allow for correct interpretation, reproducibility, and assessment of validity., RHHG was funded by the Netherlands Organization for Scientific Research (ZonMW‐Vidi project 917.16.430) and an LUMC fellowship.

AimsMicroRNAs (miRNAs) may be useful biomarkers of rejection and allograft outcome in kidney transplantation. Elevated urinary CXCL10 levels have been associated with acute rejection (AR) and may predict allograft failure. We examined the correlation of miRNA, CXCL10 levels and immunosuppressive drug exposure with AR and graft function in kidney transplant recipients. MethodsEighty de novo kidney transplant recipients were recruited from four European centres. All patients received tacrolimus, mycophenolate mofetil, and methylprednisolone. Urinary pellet expression of miR-142-3p, miR-210-3p and miR-155-5p was assessed by quantitative real-time polymerase chain reaction and urinary CXCL10 levels by enzyme-linked immunosorbent assay at the 1(st) week and the 1(st), 2(nd), 3(rd) and 6(th) months post-transplantation. ResultsEight patients experienced AR. Before and during AR, patients showed a significant increase of urinary miR-142-3p, miR-155-5p and CXCL10 levels and a decrease of miR-210-3p levels. Receiver operating characteristic curve analysis showed that miR-155-5p (area under the curve=0.875; P=0.046) and CXCL10 (area under the curve=0.865; P=0.029) had excellent capacity to discriminate between rejectors and nonrejectors. The optimal cut-off values for the prognosis of AR were 0.51, with 85% sensitivity and 86% specificity for miR-155-5p and 84.73pgml(-1), with 84% sensitivity and 80% specificity for CXCL10. miR-155-5p and CXCL10 levels correlated with glomerular filtration rate. Levels of both biomarkers normalized after recovery of graft function. ConclusionsThe regular early post-transplantation monitoring of urinary miR-155-5p and CXCL10 can help in the prognosis of AR and graft dysfunction. Large prospective randomized multicentre trials are warranted to refine our cut-off values and validate the clinical usefulness of these biomarkers.

AIM: The PLANET trials showed that atorvastatin 80 mg but not rosuvastatin at either 10 or 40 mg reduced urinary protein to creatinine ratio (UPCR) at similar effects on LDL-cholesterol. However, individual changes in both UPCR and LDL-cholesterol during treatment with these statins varied widely between patients. This inter-individual variability could not be explained by patients' physical or biochemical characteristics. We assessed whether the plasma concentrations of both statins were associated with LDL-cholesterol and UPCR response.MATERIALS AND METHODS: The PLANET trials randomized patients with a UPCR of 500-5000 mg/g and fasting LDL-cholesterol >2.33 mmol/l to a 52-week treatment with atorvastatin 80 mg, rosuvastatin 10 mg or 40 mg. For the current analysis, patients with available samples at week 52 and treatment compliance >80% by pill count were included (N = 295). The main outcome measurements were percentage change in UPCR and absolute change in LDL-cholesterol (delta LDL) from baseline to week 52.RESULTS: Median (interquartile range) plasma concentration at week 52 for atorvastatin 80 mg was 3.9 ng/ml (IQR: 2.1 to 8.7), for rosuvastatin 10 mg 1.0 ng/ml (IQR: 0.7 to 2.0) and for rosuvastatin 40 mg 3.5 ng/ml (IQR: 2.0 to 6.8). Higher plasma concentration of statin was associated with larger LDL-cholesterol reductions at week 52 [rosuvastatin r = -0.40 (P CONCLUSIONS: Individual variation in plasma concentrations of rosuvastatin and atorvastatin was associated with LDL-cholesterol changes in patients. The individual variation in UPCR change was not associated with the plasma concentration of both statins. This article is protected by copyright. All rights reserved.

Riociguat, a first-in-class soluble guanylate cyclase stimulator, is approved for the treatment of pulmonary arterial hypertension (PAH), a serious potential complication of human immunodeficiency virus (HIV) infection. This open-label study investigated the pharmacokinetic drug–drug interaction potential of antiretroviral therapies on riociguat exposure in HIV-infected adults. HIV-infected adults without PAH on stable antiretroviral regimens (efavirenz/emtricitabine/tenofovir disoproxil, emtricitabine/rilpivirine/tenofovir disoproxil, elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil, abacavir/dolutegravir/lamivudine, or a ritonavir-boosted triple regimen) for ≥ 6 weeks received a single riociguat dose (0.5 mg). Riociguat pharmacokinetics and safety were assessed; pharmacokinetics was compared with historical healthy volunteer data. Of 41 participants treated (n = 8 in each arm, except n = 9 in the ritonavir-boosted triple regimen arm), 40 were included in the pharmacokinetic analyses. Riociguat median t max was 1.00–1.27 h, with comparable maximum concentration (C max ) across the five background antiretroviral groups. Riociguat exposure was highest with abacavir/dolutegravir/lamivudine, followed by elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil > emtricitabine/rilpivirine/tenofovir disoproxil > ritonavir-boosted triple regimen > efavirenz/emtricitabine/tenofovir disoproxil; riociguat area under the plasma concentration versus time curve (AUC) was approximately threefold higher with abacavir/dolutegravir/lamivudine than efavirenz/emtricitabine/tenofovir disoproxil. Compared with historical data, riociguat exposure in HIV-infected adults was similar when co-administered with efavirenz/emtricitabine/tenofovir disoproxil, slightly increased when administered with ritonavir-boosted triple regimen and increased by approximately threefold when administered with abacavir/dolutegravir/lamivudine. Riociguat was well tolerated, with no new safety findings. Riociguat was well tolerated in adults with HIV on stable background antiretroviral therapy although an apparent increase in AUC of riociguat was observed in patients receiving abacavir/dolutegravir/lamivudine. Patients should be monitored closely during riociguat initiation and dose adjustment for signs and symptoms of hypotension.

Cysticercosis is a parasitic disease that frequently involves the human central nervous system (CNS), and current treatment options are limited. Oxfendazole, a veterinary medicine belonging to the benzimidazole family of anthelmintic drugs, has demonstrated substantial activity against the tissue stages of Taenia solium and has potential to be developed as an effective therapy for neurocysticercosis. To accelerate the transition of oxfendazole from veterinary to human use, the pharmacokinetics, safety, and tolerability of oxfendazole were evaluated in healthy volunteers in this phase 1 first-in-human (FIH) study. Seventy subjects were randomly assigned to receive a single oral dose of oxfendazole (0.5, 1, 3, 7.5, 15, 30, or 60 mg oxfendazole/kg body weight) or placebo and were followed for 14 days. Blood and urine samples were collected, and the concentrations of oxfendazole were measured using a validated ultraperformance liquid chromatography mass spectrometry method. The pharmacokinetic parameters of oxfendazole were estimated using noncompartmental analysis. Oxfendazole was rapidly absorbed with a mean plasma half-life ranging from 8.5 to 11 h. The renal excretion of oxfendazole was minimal. Oxfendazole exhibited significant nonlinear pharmacokinetics with less than dose-proportional increases in exposure after single oral doses of 0.5 mg/kg to 60 mg/kg. This nonlinearity of oxfendazole is likely due to the dose-dependent decrease in bioavailability that is caused by its low solubility. Oxfendazole was found to be well tolerated in this study at different escalating doses without any serious adverse events (AEs) or deaths. There were no significant differences in the distributions of hematology, biochemistry, or urine parameters between oxfendazole and placebo recipients. (This study has been registered at ClinicalTrials.gov under identifier NCT02234570.).

Contains fulltext : 202694.pdf (Publisher’s version ) (Open Access) OBJECTIVE: To compare assessment of early pregnancy medication exposure using three methods of data collection. METHODS: Serum samples were obtained from 752 women participating in the PRegnancy and Infant DEvelopment (PRIDE) Study before gestational week 17. For 52 women using medication at the date of blood sampling according to Web-based questionnaires or pharmacy records, we analysed serum samples using untargeted liquid chromatography time-of-flight spectrometry. RESULTS: Medication was detected in 18 serum samples (35%). Medications taken orally for chronic conditions reported in the questionnaire were detected in serum and vice versa. Pharmacy records did not identify additional exposed women, but missed exposure in 5 women mainly due to unavailability. We observed substantial discordance between the three methods for inhaled medication, dermatological preparations, and medications for short-term use, which went often undetected in serum. CONCLUSIONS: It remains challenging to assess medication use in large-scale studies as no 'gold standard' is currently available.

To evaluate criteria driving retreatment with ranibizumab in Italian patients with myopic choroidal neovascularization (mCNV). OLIMPIC was a 12-month, phase IIIb, open-label study. Patients with active mCNV were treated with ranibizumab 0.5 mg according to the European label. The study assessed local criteria in Italy driving retreatment decisions with ranibizumab; and the efficacy, safety, and tolerability of ranibizumab. The mean (standard deviation [SD]) age of treated patients (N = 200) was 61.8 (12.7) years; range 22–85 years. The multivariate regression model indicated that presence of active leakage (odds ratio [OR] 95% confidence interval [CI]: 11.30 [1.03–124.14]), presence of intraretinal fluid (OR [95%CI]: 28.21 [1.55–513.73]), and an improvement in best-corrected visual acuity (BCVA) from baseline

Arctium lappa (burdock) is the most popular daily edible vegetable in China and Japan because of its general health tonic effects. Previous studies focused on the beneficial role of Arctigenin but neglected its potential side-effects and toxicities. In the present study, the sub-chronic toxicity profile of Arctigenin following 28 days of consecutive exposure was investigated in rats. The results showed that during the drug exposure period, Arctigenin-12 mg/kg administration resulted in focal necrosis and lymphocytes infiltration of heart ventricular septal muscle cells. In the kidney cortical zone, the renal tubular epithelial cells were swollen, mineralized, and lymphocyte infiltrated. In the liver, the partial hepatocyte cytoplasm showed vacuolation and fatty changes, focal necrosis, and interstitial lymphocyte infiltration. In the rats that underwent 36 mg/kg/day administration, there was bilateral testis and epididymis atrophy. In the lung and primary bronchus, erythrocytes and edema fluid were observed. Changes of proestrus or estrus were observed in the uterus, cervix, and vagina intimal epithelial cells. Lymphocytic focal infiltration occurred in the prostate mesenchyme. The high dosage of Arctigenin only decreased the body weight at day 4. At the end of the recovery period, histopathological changes were irreversible, even after withdrawal of the drug for 28 days. Focal necrosis still existed in the heart ventricular septal muscle cells and hepatocytes. Lymphocyte infiltrations were observed in the heart, renal cortex, hepatocyte, and pancreas exocrine gland. Meanwhile, atrophy occurred in the testicles and pancreas. In addition, in the Arctigenin-12 mg/kg group, creatinine (CREA) and brain weight were both significantly increased. The toxicokinetical study demonstrated that Arctigenin accumulated in the organs of rats. The food consumption, hematological, and biochemical parameters were not associated with the above results. These contradictory results might result from the lesions induced by Arctigenin, which were not sufficiently serious to change the parameters. These results suggest that Arctium lappa should be consumed daily with caution because of the potential toxicity induced by Arctigenin. According to all results, the lowest observed adverse effect level (LOAEL) was induced by 12 mg/kg daily exposure to Arctigenin, and the No-observed-adverse-effect-level (NOAEL) should be lower than 12 mg/kg.

Background Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a serious life-treating condition characterized by skin eruption, fever, haematologic abnormalities, and multi-organ involvement that can be fatal if unrecognized, especially in patients with liver failure. Diagnosis may be difficult because it is rarely described in children and can mimic many different conditions. Case presentation We report two cases of DRESS syndrome due to prolonged antibiotic treatment in young children in whom recovery occurred following different therapeutic approaches. A previously healthy 5-year-old boy had been receiving intravenous vancomycin for right wrist and left elbow osteomyelitis and developed DRESS syndrome on day 30. The patient achieved a complete resolution of all symptoms with pulse methylprednisolone followed by oral prednisone. A 4-year-old girl with cystic fibrosis, pancreatic insufficiency, chronic pulmonary colonization by Gram-positive bacteria admitted for pulmonary exacerbation was treated with intravenous piperacillin-tazobactam and tobramycin. After 14 days of treatment, she developed DRESS syndrome: antibiotic treatment was therefore stopped, and without any further therapy, a progressive resolution of the patient’s clinical features was observed within 7 days, while the normalization of laboratory abnormalities was achieved at 14 days. Conclusions Our cases highlight that paediatricians should be aware of the clinical presentations of and therapeutic approaches for DRESS syndrome, especially in children receiving long-term antibiotic treatment. The removal of the offending drug is crucial and may be the only life-saving measure. In more aggressive cases, corticosteroid or other immunosuppressive drugs should be considered to achieve the best outcome.

This is the accepted manuscript of this article.; International audience; Introduction: Acute liver injury (ALI) is a major reason for stopping drug development or removing drugs from the market. Hospitalisation for ALI is relatively rare for marketed drugs, justifying studies in large-scale databases such as the nationwide Système National des Données de Santé (SNDS) that covers 99% of the French population.Methods: SNDS was queried over 2010-2014 for all hospital admissions for acute toxic liver injuries not associated with a possible other cause, using a case-population approach. Exposures of interest were drugs dispensed from 7 to 60 days before date of admission. Individual drugs were analysed by their frequency (if ≥ 5 cases), and by the ratio of exposed cases to the number of exposed subjects and to exposed patient-time in the general population over the same time-frame.Results: Over 5 years, 4,807 cases of ALI were identified, mean age 54.5, 59% women, 76% exposed to at least one of 249 different drugs. Drugs most commonly identified were non-overdose paracetamol (31% of cases), esomeprazole or omeprazole (18%), phloroglucinol, domperidone, coamoxiclav, furosemide, atorvastatin (more than 250 cases each). When compared to population exposures, the highest per-person risks were observed with antimycobacterial antibiotics with 1 case for 1,000 or fewer users, followed by colestyramine and erythromycin (around 1/5,300), antiepileptic drugs, anticoagulants, anti-Alzheimer drugs (1/6,000 - 1/10,000 users). When a person-time approach is considered, the drugs with the highest per-tablet risk were still the antituberculosis drugs followed by a number of other antibiotics. Conclusions: This nationwide study describes drugs associated with ALI, according to absolute population burden, to per-patient and per-tablet risk. Some of these associations may be spurious, others causal, and others yet were unexpected. Systematic analysis of drug classes will look for outliers within each class that could raise signals of unexpected hepatic toxicity.

Background: Poor response to TB therapy might be attributable to subtherapeutic levels in drug-compliant patients. Pharmacokinetic parameters can be affected by comorbidities or the interaction of drugs with food. Objectives: This study aimed to determine the effect of food intake upon pharmacokinetics of rifampicin and isoniazid in a Peruvian population with TB. Methods: Rifampicin and isoniazid levels were analysed at 2, 4 and 6 h after drug intake in both fasting and non-fasting states using LC-MS methods. Results: Sixty patients participated in the study. The median rifampicin Cmax and AUC0–6 were higher during fasting than non-fasting: 7.02 versus 6.59 mg/L (P = 0.054) and 28.64 versus 24.31 mg·h/L (P = 0.002). There was a statistically significant delay overall of non-fasting Tmax compared with the fasting state Tmax (P = 0.005). In the multivariate analysis, besides the effect of fasting, Cmax for females was 20% higher than for males (P = 0.03). Concerning isoniazid, there were significant differences in the Cmax during non-fasting (median = 3.51 mg/L) compared with fasting (4.54 mg/L). The isoniazid dose received had an effect upon the isoniazid levels (1.26, P = 0.038). In the multivariate analysis, isoniazid exposure during fasting was found to be 14% higher than during non-fasting (CI = 1.02–1.28, P

Background: The purpose of this study was to assess the impact of bevacizumab alone and in combination with cytotoxic therapy on tumour vasculature in osteosarcoma (OS) using DCE-MRI. Methods: Six DCE-MRI and three 18F-FDG PET examinations were scheduled in 42 subjects with newly diagnosed OS to monitor the response to antiangiogenic therapy alone and in combination with cytotoxic therapy before definitive surgery (week 10). Serial DCE-MRI parameters (Ktrans, vp, and ve) were examined for correlation with FDG-PET (SUVmax) and association with drug exposure, and evaluated with clinical outcome. Results: Ktrans (P=0.041) and vp (P=0.001) significantly dropped from baseline at 24 h after the first dose of bevacizumab alone, but returned to baseline by 72 h. Greater exposure to bevacizumab was correlated with larger decreases in vp at day 5 (P=0.04) and week 10 (P=0.02). A lower Ktrans at week 10 was associated with greater percent necrosis (P=0.024) and longer event-free survival (P=0.034). Conclusions: This is the first study to demonstrate significant changes of the plasma volume fraction and vascular leakage in OS with bevacizumab alone. The combination of demonstrated associations between drug exposure and imaging metrics, and imaging metrics and patient survival during neoadjuvant therapy, provides a compelling rationale for larger studies using DCE-MRI to assess vascular effects of therapy in OS.

Background: Metformin, statin and aspirin use seem associated with decreased mortality in cancer patients, though, without adjusting for one another. Independent associations of these drugs with overall mortality after colorectal cancer (CRC) diagnosis within glucose-lowering drugs (GLDs) users were assessed.Methods: Patients starting GLDs before CRC diagnosis (1998–2011) were selected from the Eindhoven Cancer Registry linked with the PHARMO Database Network. The Cox regression model, with time since CRC diagnosis, included time-dependent variables of cumulative exposure to metformin, statins and aspirin after cancer diagnosis and time-dependent ever-never terms for drug exposure.Results: A total of 1043 patients used GLDs before CRC diagnosis; 666 (64%) used metformin, 639 (61%) used statins and 490 (47%) used aspirin after CRC diagnosis. Multivariable analyses revealed that longer cumulative exposure to metformin was not associated with overall mortality (HRCumulative exposure/6 months 1.02; 95% CI 0.97–1.07), whereas the favourable effect of statins increased with cumulative exposure (HRCumulative exposure/6 months 0.93; 95% CI 0.89–0.98). No association between aspirin use and overall mortality was seen (HRCumulative exposure/6 months 0.98; 95% CI 0.93–1.03).Conclusions: No independent association between cumulative exposure to metformin, aspirin and overall mortality was found. Cumulative exposure to statins after CRC diagnosis was associated with lower overall mortality, supporting a drug effect of statins among GLDs users.Keywords: diabetes; cancer; overall mortality; drug exposure

This study aimed to develop clinically feasible models of limited sampling strategy (LSS) for estimation of the area under the concentration–time curve (AUC 24h) for isoniazid, that could be applied easily in daily clinical practice for dosage adjustment in adult patients with tuberculosis. Isoniazid plasma concentrations ( n =1665) from 185 adult tuberculous patients were used for the development and validation of LSS models to estimate AUC 24h following administration of the standard 5 mg/kg dose of isoniazid. Population pharmacokinetic analysis for appropriate estimation of isoniazid pharmacokinetic parameters was performed in a modelling group ( n =100). The Bayesian estimates of AUC 24h (AUC ref ) obtained for each individual were used as the dependent variable in the regression analysis for the development of various LSS models. The LSS models were validated in a separate cohort ( n =85). Several three and four time point LSS models were built and tested. Model H (AUC 24h =-1.88 + 1.05 × C 1 + 0.78 × C 2 + 9.44 × C 5 ) and Model I (AUC 24h =-0.65 + 1.00 × C 1 + 1.94 × C 2 + 15.45 × C 9 ) had the best performances [adj- R 2 =0.93, median prediction error (MPE)=-0.20, root median squared prediction error (RMSE)=4.65 for Model H; adj- R 2 =0.96, MPE=-0.05 RMSE=3.56 for Model I]. The very high R 2 values (≥0.97) of these regression equations in the validation cohort confirmed their high reliability. These LSS models could be applied in the context of therapeutic drug monitoring programmes aiming to personalize isoniazid dosing regimens for adult patients with tuberculosis.

The heterogeneity in case–control studies on the associations between community-acquired pneumonia (CAP) and ACE-inhibitors (ACEi), statins, and proton pump inhibitors (PPI) hampers translation to clinical practice. Our objective is to explore sources of this heterogeneity by applying a common protocol in different data settings. We conducted ten case–control studies using data from five different health care databases. Databases varied on type of patients (hospitalised vs. GP), level of case validity, and mode of exposure ascertainment (prescription or dispensing based). Identified CAP patients and controls were matched on age, gender, and calendar year. Conditional logistic regression was used to calculate odds ratios (OR) for the associations between the drugs of interest and CAP. Associations were adjusted by a common set of potential confounders. Data of 38,742 cases and 118,019 controls were studied. Comparable patterns of variation between case–control studies were observed for ACEi, statins and PPI use and pneumonia risk with adjusted ORs varying from 1.04 to 1.49, 0.82 to 1.50 and 1.16 to 2.71, respectively. Overall, higher ORs were found for hospitalised CAP patients matched to population controls versus GP CAP patients matched to population controls. Prevalence of drug exposure was higher in dispensing data versus prescription data. We show that case–control selection and methods of exposure ascertainment induce bias that cannot be adjusted for and to a considerable extent explain the heterogeneity in results obtained in case–control studies on statins, ACEi and PPIs and CAP. The common protocol approach helps to better understand sources of variation in observational studies.

Aims: The selective endothelin (ET) A receptor antagonist atrasentan has been shown to lower albuminuria in North American and Asian patients with type 2 diabetes and nephropathy. As drug responses to many drugs may differ between North American and Asian populations, we assessed the influence of geographical region on the albuminuria and fluid retention response to atrasentan.Materials and methods: Two 12-week double-blind randomised controlled trials were performed with atrasentan 0.75 or 1.25 mg/d vs placebo in patients with type 2 diabetes and nephropathy. The efficacy endpoint was the percentage change in albuminuria. Bodyweight change, a proxy of fluid retention, was used as a safety endpoint. Pharmacodynamics were determined in Asians (N = 77) and North Americans (N = 134). Atrasentan plasma concentration was measured in 161 atrasentan-treated patients.Results: Mean albuminuria reduction in Asian, compared to North American, patients was, respectively, -34.4% vs -26.3% for 0.75 mg/d (P = .44) and -48.0% vs -28.9% for 1.25 mg/d (P = .035). Bodyweight gain did not differ between North American and Asian populations. Atrasentan plasma concentrations were higher in Asians compared to North Americans and correlated with albuminuria response (7.2% albuminuria reduction per doubling atrasentan concentration; P = .024). Body surface area (beta = -1.09 per m(2); P Conclusion: The higher exposure and albuminuria reduction of atrasentan in Asian patients is not associated with more fluid retention, suggesting that Asian patients are less sensitive to atrasentan-induced sodium retention.

Introduction About a decade ago, synthetic cannabinoids (SC) started to appear as recreational drugs on the new psychoactive substance (NPS) market. This report from the STRIDA project describes analytically confirmed intoxications involving MDMB-CHMICA (methyl-2-(1-(cyclohexylmethyl)-1H-indol-3-ylcarbonylamino)-3,3-dimethylbutanoate), a SC that was first detected in 2014. Study Design This is an observational case series of patients from Sweden with suspected NPS exposure presenting in emergency departments and intensive care units. The results of retrospective serum and urine toxicological analysis were compared with clinical signs reported during consultation with the Poisons Information Centre and retrieved from medical records. Methods Clinical and bioanalytical data in nine acute intoxications associated with MDMB-CHMICA during 2014–2015 are presented. The patients were aged 23–62 (median 34) years, and eight were men. MDMB-CHMICA (parent compound) was analytically confirmed in serum samples, using a liquid chromatography–high-resolution mass spectrometry multi-component method. Results Of the nine MDMB-CHMICA-positive patients, eight had a Poisoning Severity Score (PSS) of 2 or 3, and five were monitored in the intensive care unit and all patients survived. Development of seizures and deep unconsciousness were common features. All cases except one also tested positive for other NPS and/or classical psychoactive compounds, hampering the possibility to establish a causal relationship between drug and toxic symptoms. MDMB-CHMICA was also identified in seven drug materials donated by the patients. Conclusions The association with severe adverse reactions in nine acute analytically confirmed intoxication cases involving MDMB-CHMICA is consistent with other reports of serious toxicity linked to this substance, suggesting that MDMB-CHMICA might be a particularly harmful SC.

WOS: 000369571000002, PubMed ID: 26860463, Background: Staphylococcus aureus is one of the causes of both community and healthcare-associated bacteremia. The attributable mortality of S. aureus bacteremia (SAB) is still higher and predictors for mortality and clinical outcomes of this condition are need to be clarified. In this prospective observational study, we aimed to examine the predictive factors for mortality in patients with SAB in eight Turkish tertiary care hospitals. Methods: Adult patients with signs and symptoms of bacteremia with positive blood cultures for S. aureus were included. All data for episodes of SAB including demographics, clinical and laboratory findings, antibiotics, and outcome were recorded for a 3-year (2010-2012) period. Cox proportional hazard model with forward selection was used to assess the independent effect of risk factors on mortality. A 28-day mortality was the dependent variable in the Cox regression analysis. Results: A total of 255 episodes of SAB were enrolled. The median age of the patients was 59 years. Fifty-five percent of the episodes were considered as primary SAB and vascular catheter was the source of 42.1 %. Healthcare associated SAB was defined in 55.7 %. Blood cultures yielded methicillin-resistant S. aureus (MRSA) as a cause of SAB in 39.2 %. Initial empirical therapy was inappropriate in 28.2 %. Although overall mortality was observed in 52 (20.4 %), 28-day mortality rate was 15.3 %. Both the numbers of initial inappropriate empirical antibiotic treatment and the median hours to start an appropriate antibiotic between the cases of fatal outcome and survivors after fever onset were found to be similar (12/39 vs 60/216 and 6 vs 12 h, respectively; p > 0.05). High Charlson comorbidity index (CCI) score (p = 0.002), MRSA (p = 0.017), intensive care unit (ICU) admission (p < 0.001) and prior exposure to antibiotics (p = 0.002) all were significantly associated with mortality. The Cox analysis defined age [Hazard Ratio (HR) 1.03; p = 0.023], ICU admission (HR 6.9; p = 0.002), and high CCI score (HR 1.32; p = 0.002) as the independent predictive factors mortality. Conclusions: The results of this prospective study showed that age, ICU stay and high CCI score of a patient were the independent predictors of mortality and MRSA was also significantly associated with mortality in SAB.

This systematic review assessed the global impact and effectiveness of quadrivalent human papillomavirus (HPV) vaccination on HPV infection and disease in real-world settings over a decade of use. Substantial reductions in HPV 6/11/16/18 infection, anogenital warts, and cervical lesions have been achieved., Prophylactic human papillomavirus (HPV) vaccination programs constitute major public health initiatives worldwide. We assessed the global effect of quadrivalent HPV (4vHPV) vaccination on HPV infection and disease. PubMed and Embase were systematically searched for peer-reviewed articles from January 2007 through February 2016 to identify observational studies reporting the impact or effectiveness of 4vHPV vaccination on infection, anogenital warts, and cervical cancer or precancerous lesions. Over the last decade, the impact of HPV vaccination in real-world settings has become increasingly evident, especially among girls vaccinated before HPV exposure in countries with high vaccine uptake. Maximal reductions of approximately 90% for HPV 6/11/16/18 infection, approximately 90% for genital warts, approximately 45% for low-grade cytological cervical abnormalities, and approximately 85% for high-grade histologically proven cervical abnormalities have been reported. The full public health potential of HPV vaccination is not yet realized. HPV-related disease remains a significant source of morbidity and mortality in developing and developed nations, underscoring the need for HPV vaccination programs with high population coverage.

Contains fulltext : 172349.pdf (Publisher’s version ) (Open Access) BACKGROUND AND OBJECTIVES: Caspofungin is an echinocandin antifungal agent used as first-line therapy for the treatment of invasive candidiasis. The maintenance dose is adapted to body weight (BW) or liver function (Child-Pugh score B or C). We aimed to study the pharmacokinetics of caspofungin and assess pharmacokinetic target attainment for various dosing strategies. METHODS: Caspofungin pharmacokinetic data from 21 intensive care unit (ICU) patients was available. A population pharmacokinetic model was developed. Various dosing regimens (loading dose/maintenance dose) were simulated: licensed regimens (I) 70/50 mg (for BW 80 kg); and (II) 70/35 mg (for Child-Pugh score B); and adapted regimens (III) 100/50 mg (for Child-Pugh score B); (IV) 100/70 mg; and (V) 100/100 mg. Target attainment based on a preclinical pharmacokinetic target for Candida albicans was assessed for relevant minimal inhibitory concentrations (MICs). RESULTS: A two-compartment model best fitted the data. Clearance was 0.55 L/h and the apparent volumes of distribution in the central and peripheral compartments were 8.9 and 5.0 L, respectively. The median area under the plasma concentration-time curve from time zero to 24 h on day 14 for regimens I-V were 105, 65, 93, 130, and 186 mg.h/L, respectively. Pharmacokinetic target attainment was 100 % (MIC 0.03 microg/mL) irrespective of dosing regimen but decreased to (I) 47 %, (II) 14 %, (III) 36 %, (IV) 69 %, and (V) 94 % for MIC 0.125 microg/mL. CONCLUSION: The caspofungin maintenance dose should not be reduced in non-cirrhotic ICU patients based on the Child-Pugh score if this classification is driven by hypoalbuminemia as it results in significantly lower exposure. A higher maintenance dose of 70 mg in ICU patients results in target attainment of >90 % of the ICU patients with species with an MIC of up to 0.125 microg/mL.

Objectives Gastrointestinal side-effects caused by mycophenolic acid (MPA) are frequent in liver transplant recipients, and in these cases a switch from two to three daily doses is usually recommended. However, a limited sampling strategy for the estimation of MPA area under the curve from 0 to 8 hours (AUC(0–8h)) has not been made. Design and methods In 22 liver transplant patients who were administered MPA three times daily, the trapezoidal extrapolated MPA AUC(0–8h) values using a sampling time from 0 to 2 hours were calculated. Results A tentative therapeutic range for MPA AUC(0–8h) of about 20–40 μg.h/mL is proposed, and in the 13 patients with supratherapeutic values the total leukocyte blood count was significantly lower than in the 9 patients with AUC(0–8h) ≤ 40 μg.h/mL (P < 0.001). Significant negative correlations were found between the total leukocyte blood count and the MPA trough levels (r = −0.458; P < 0.05), AUC(0–8h) (r = −0.479; P < 0.05), and AUC(0–2h) (r = −0.437; P < 0.05). A significant correlation was found between the trapezoidal extrapolated AUC(0–8h) and trapezoidal AUC(0–2h) results (r = 0.850; P < 0.001). Conclusions The trapezoidal extrapolated AUC(0–8h), and possibly trapezoidal AUC(0–2h), may be useful for routine therapeutic MPA monitoring in liver transplant recipients in which the dosing frequency is increased from twice to three times a day.

The glycopeptide antibiotic, vancomycin, has been in use for the treatment of serious Gram-positive infections such as methicillin-resistant Staphylococcus aureus (MRSA) infection for nearly 60 years, and therapeutic monitoring for drug safety is acknowledged as an important part of the management strategy when treating patients with this agent [Moellering, 2006; Levine, 2006]. Vancomycin is still the treatment of choice for treatment of MRSA infection, however some authors comment that its days of utility are in the twilight due to rising minimum inhibitory concentrations (MICs) of MRSA isolates, which necessitates such high dosing and drug exposure that the probability of toxicity becomes too great to use it [Van Hal et al. 2013; Patel et al. 2011]. Historically, both peak and trough concentrations have been used at times to monitor the safety of vancomycin [Rybak, 2006]. Peak concentrations, however, have been discarded as a monitoring method for vancomycin as they do not correlate with therapeutic efficacy or key safety concerns of nephrotoxicity [Saunders, 1994; Suzuki et al. 2012]. Trough concentrations have become the dominant method for monitoring vancomycin toxicity and efficacy in clinical practice today; however, the pharmacokinetic–pharmacodynamic (PKPD) index of the area under the concentration curve (AUC) to MIC ratio of the organism being treated is recommended for monitoring treatment efficacy in serious infection [Kullar et al. 2011; Li et al. 2012]. An AUC/MIC ratio of over 400 has been associated with greater clinical success and more rapid bacterial eradication compared with lower AUC/MIC ratios [Moise-Broder et al. 2004]. Trough concentrations up to 15 mg/liter have been reported to correlate with an AUC/MIC ratio of 400 or greater when the organism MIC is up to 1 mg/liter [Giuliano et al. 2010]. The US guidelines on the therapeutic monitoring of vancomycin, released some 5 years ago, were an important step forward in garnishing consensus in guiding practice for the efficacious and safe use of this antibiotic. These guidelines promote aggressive dosing of vancomycin to attain a trough target in the range of up to 15–20 mg/liter, concurring that concentrations greater than 15 mg/liter will achieve an AUC/MIC ratio greater than 400 when the organism MIC is up to 1 mg/liter [Rybak et al. 2009]. The advent of more aggressive vancomycin dosing has led to increased concerns about the safety of dosing regimens which aim to achieve trough concentrations greater than 15 mg/liter. A systematic review of higher dosing to achieve troughs of 15–20 mg/liter reported greater nephrotoxicity [odds ratio 2.67; 95% confidence interval (CI) 1.95–3.65] compared with trough concentrations less than 15 mg/liter [Van Hal et al. 2013]. Curiously, however, a systematic review and meta-analysis of vancomycin continuous infusions achieving targets of 20–30 mg/liter resulted in significantly less nephrotoxicity compared with dosing by intermittent infusion [Cataldo et al. 2012]. This anomaly poses the question as to whether trough concentrations really are a good surrogate marker for AUC and vancomycin exposure. A recently published paper by Neely and colleagues set out to determine this very question: Are trough concentrations an appropriate surrogate for AUC? Briefly, they performed PK/PD modelling on data from 47 adults with 569 vancomycin concentrations. AUCs were determined using Pmeterics (version 1.1.1, Laboratory of Applied Pharmacokinetics, University of Southern California; www.lapk.org), which employs a two-compartmental nonparametric model for vancomycin modelling and simulation. They found the AUC was underestimated by a mean of 23% (CI 11–33%, p = 0.0001), calculated from a model using trough concentration data alone compared with a full model incorporating peak and trough concentrations to determine AUC. When modelling was performed using the full model as a Bayesian prior and only incorporating trough concentrations, a 97% accuracy of AUC estimation was achieved (CI 93–102%, p = 0.23). Using Bayesian modelling they simulated over 5000 concentration–time profiles and found that in adult patients with normal renal function and an AUC of at least 400 mg⋅h/liter with an organism MIC of 1 mg/liter, some 60% are expected to have trough concentration below 15 mg/liter. Thus, dosing to achieve a trough over 15 mg/liter may lead to excessive vancomycin exposure and unnecessary risk of toxicity. Further, the authors propose that a 24 h AUC of 700 mg⋅h/liter represents a conservative upper limit of vancomycin exposure that is safe with minimal risk of nephrotoxity [Neely et al. 2014]. This assertion of a 24 h AUC 700 mg⋅h/liter as an upper limit for safe vancomycin exposure is supported by the US consensus guidelines [Rybak et al. 2009], and others [Patel et al. 2011; Avent et al. 2013], in that if the organism being treated has a higher MIC (i.e. ≥2 mg), maintaining an AUC/MIC ratio of at least 400 in patients with normal renal function will require such high drug exposure that treatment will not be viable due to the increased risk of nephrotoxicity. The study by Neely and colleagues suggests vancomycin trough concentrations alone are not a good surrogate for AUC. If computerized Bayesian modelling of vancomycin is performed to determine AUC, we may be able to achieve the desired therapeutic AUC/MIC targets with less aggressive dosing and reduced risk of toxicity. Arguments against computerized estimation of AUC are that it requires additional software, trained staff, new processes and logistics; however, these barriers have not been insurmountable as some hospitals have adopted computerized AUC monitoring of other agents such as aminoglycosides into routine clinical practice [Baysari et al. 2012]. Computerized software for AUC determination of vancomycin is freely available. A considerable amount of time and money is wasted in routine care with vancomycin treatment when inappropriately timed blood samples are collected. Morrison and colleagues analyzed nearly 2600 vancomycin serum samples over a 13-month period (Boston, MA, USA) and found that 41% of samples were drawn too early, which resulted in clinicians reducing, withholding or ceasing patients’ vancomycin doses in addition to reordering concentrations (29.2% versus 20.0%, p < 0.001) compared with concentrations taken at the appropriate time, that is, 1 h predose and at steady state [Morrison et al. 2012]. Such wasted resources could be redirected to education with regard to appropriate timing of sample collection and implementation of vancomycin monitoring using AUC computation. Monitoring of vancomycin concentrations has been demonstrated to reduce nephrotoxicity (odds ratio 0.25, 95% CI 0.13–0.48, p < 0.0001), defined as a rise in serum creatinine greater than 44 µmol/liter (5 mg/liter) or 50% increase in serum creatinine from baseline during vancomycin therapy compared with patients who do not receive vancomycin monitoring [Ye et al. 2013]. However, strategies to improve vancomycin dosing and attainment of target concentrations, such as implementation of clinical practice guidelines, are important [Phillips et al. 2013], as are electronic decision support tools [McCluggage et al. 2010]. Determining vancomycin exposure by computation of AUC may help us to truly individualize therapy and better manage toxicity risk, rather than relying on trough concentrations alone. Such a strategy may help to prolong the utility of vancomycin in the era of increasing antibiotic resistance.

To evaluate whether the routinely collected data in birth defect registries could be used to assess association between medications and risk for congenital anomalies an "exposed case-only" design was performed.Twelve registries provided 18,131 cases exposed to a medication during the first trimester of pregnancy and with at least one major malformation. Odds ratios for malformations associated with maternal use of selected medications were computed.Among seven most commonly used medications very few significant associations with malformations were identified. Among fourteen potentially teratogenic medications several strong associations were found, including valproic acid with spina bifida, and insulin (as proxy for diabetes) with several types of cardiac defects.Finding known associations provides assurance on the validity of this approach, whereas identifying new associations provides a signal to be followed by confirmatory studies. Through this activity, international networks of birth defect registries can contribute with limited resources to post-marketing surveillance of the teratogenicity of medications. (C) 2010 Elsevier Inc. All rights reserved.

Background: A severe and challenging complication in the treatment of hemophilia A is the development of inhibiting antibodies (inhibitors) directed towards factor VIII (FVIII). Inhibitors aggravate bleeding complications, disabilities and costs. The etiology of inhibitor development is incompletely understood. Objectives: In a large cohort study in patients with mild/moderate hemophilia A we evaluated the role of genotype and intensive FVIII exposure in inhibitor development. Patients/methods: Longitudinal clinical data from 138 mild/moderate hemophilia A patients were retrospectively collected from 1 January 1980 to 1 January 2008 and analyzed by multivariate analysis using Poisson regression. Results: Genotyping demonstrated the Arg593Cys missense mutation in 52 (38%) patients; the remaining 86 patients had 26 other missense mutations. Sixty-three (46%) patients received intensive FVIII concentrate administration, 41 of them for surgery. Ten patients (7%) developed inhibitors, eight of them carrying the Arg593Cys mutation. Compared with the other patients, those with the Arg593Cys mutation had a 10-fold increased risk of developing inhibitors (RR 10; 95% CI, 0.9-119).The other two inhibitor patients had the newly detected mutations Pro1761Gln and Glu2228Asp. In both these patients and in five patients with genotype Arg593Cys, inhibitors developed after intensive peri-operative use of FVIII concentrate (RR 186; 95% CI, 25-1403). In five of the 10 inhibitor patients FVIII was administered by continuous infusion during surgery (RR 13; 95% CI, 1.9-86). Conclusion: The Arg593Cys genotype and intensive peri-operative use of FVIII, especially when administered by continuous infusion, are associated with an increased risk for inhibitor development in mild/ moderate hemophilia A. © 2009 International Society on Thrombosis and Haemostasis.

The diagnostic work-up should include a thorough physical examination, including the pelvis, breasts, lymph nodes, skin and should limit unnecessary exposure to ionizing radiation. Fine needle aspiration, core needle or open excisional biopsies are safe to perform. Chest X-ray and mammography with abdominal shielding and ultrasonic examinations are the cornerstone of a basic staging, supplemented by MRI scans in the second/third trimesters when needed [IV, B]. In view of the theoretical risk of fetal heating/cavitation, first trimester MRI scans should be done sparingly and the potentially teratogenic gadolinium should not be administered [V, D]. Computerized tomography or radioisotope studies should be avoided. Minor staging procedures (spinal tap, bone marrow biopsy, endoscopies) are relatively safe to perform [IV, B].

Made available in DSpace on 2019-09-12T16:53:29Z (GMT). No. of bitstreams: 0 Previous issue date: 2009 Sleep bruxism (SB) is characterized by repetitive and coordinated mandible movements and non-functional teeth contacts during sleep time. Although the etiology of SB is controversial, the literature converges on its multifactorial origin. Occlusal factors, smoking, alcoholism, drug usage, stress, and anxiety have been described as SB trigger factors. Recent studies on this topic discussed the role of neurotransmitters on the development of SB. Thus, the purpose of this study was to detect and quantify the urinary levels of catecholamines, specifically of adrenaline, noradrenaline and dopamine, in subjects with SB and in control individuals. Urine from individuals with SB (n = 20) and without SB (n = 20) was subjected to liquid chromatography. The catecholamine data were compared by Mann-Whitney's test (p a parts per thousand currency sign 0.05). Our analysis showed higher levels of catecholamines in subjects with SB (adrenaline = 111.4 A mu g/24 h; noradrenaline = 261,5 A mu g/24 h; dopamine = 479.5 A mu g/24 h) than in control subjects (adrenaline = 35,0 A mu g/24 h; noradrenaline = 148,7 A mu g/24 h; dopamine = 201,7 A mu g/24 h). Statistical differences were found for the three catecholamines tested. It was concluded that individuals with SB have higher levels of urinary catecholamines. [Seraidarian, Paulo Isaias] Pontificia Univ Catolica Minas Gerais, Belo Horizonte, MG, Brazil [Cavalcanti, Bruno das Neves] Univ Ibirapuera, Sao Paulo, Brazil [Marchini, Leonardo] Univ Vale do Paraiba, BR-12244000 Sao Jose Dos Campos, SP, Brazil [Marchini, Leonardo] State Univ Sao Paulo UNESP, BR-12245000 Sao Jose Dos Campos, SP, Brazil [Seraidarian, Paula; Cavalcanti, Bruno das Neves; Marchini, Leonardo; Claro Neves, Ana Christina] Universidade de Taubaté (Unitau), BR-12020270 Taubat, SP, Brazil

Contains fulltext : 53153.pdf (Publisher’s version ) (Closed access) BACKGROUND: Nurses and other hospital workers are exposed to antineoplastic drugs during daily activities. Previous studies suggest that antineoplastic drugs at occupational exposure levels may be toxic to reproduction, but these studies are not consistent or conclusive. METHODS: Self-administered questionnaires were completed by 4393 exposed and nonexposed nurses employed between 1990 and 1997 (79% response). Questions were asked about pregnancy outcome, work-related exposures, and lifestyle. Exposure to antineoplastic drugs was estimated using task-based dermal exposure measurements and self-reported task frequencies. Time to pregnancy was modeled using survival analysis, and odds ratios (ORs) with 95% confidence intervals (CIs) were calculated for other reproductive outcomes using multiple logistic regression analysis. Associations were further explored by nonparametric regression modeling. RESULTS: Nurses highly exposed to antineoplastic drugs took longer to conceive than referent nurses (adjusted hazard ratio = 0.8; CI = 0.6-0.9). Exposure to antineoplastic drugs was associated with premature delivery (OR per unit increase in ln[exposure] = 1.08; CI = 1.00-1.17) and low birth weight (OR per unit increase in ln[exposure] = 1.11; 1.01-1.21). Penalized smoothed spline plots corroborated these log-linear relations. Spontaneous abortion, stillbirth, congenital anomalies, and sex of offspring appeared not to be related to exposure to antineoplastic drugs. CONCLUSION: Antineoplastic drugs may reduce fertility and increase poor neonatal outcomes among occupationally exposed oncology nurses.

Background Ketamine is a commonly used clinical anesthetic and a popular recreational drug. However, with the exception of studies about the nervous system, studies about the effect of early ketamine exposure on embryos are rare. Xenopus laevis is a commonly used vertebrate model for assessing teratogenicity. Therefore, we treated Xenopus embryos with ketamine to evaluate its teratogenicity on embryos. Methods Xenopus embryos were treated with ketamine from stages 8 to 21. Embryonic and cardiac morphology were analyzed using living embryo imaging and whole-mount RNA in situ hybridization (WMISH). Heart function was measured by heart rate and ventricular shortening fraction (VSF). The mRNA expression levels of several heart development-related genes were determined by reverse transcription quantitative polymerase chain reaction (RT-qPCR). The protein expression levels of XMLC2, phospho-histone H3 (pH3) and histone H3 were determined by western blot. Results Ketamine caused concentration-dependent increases in mortality and shortening of body length. At a dose of 0.5 mg/ml, ketamine exposure resulted in cardiac enlargement as the primary manifestation of several malformations: gut defects, a curved axis and shortened body length. Cardiac cells underwent increased proliferation. Moreover, the heart rate and ventricular shortening fraction were decreased, findings indicative of heart dysfunction. XMLC2 expression levels were down-regulated at stages 28, 32/33, 35/36 and 46. Conclusions Ketamine exposure during early development has teratogenic effects on Xenopus embryos. The heart enlargement and decreased VSF may result from the down-regulation of XMLC2 mRNA and protein levels. These findings provide new insight into the potential fetal defects induced by ketamine exposure during early pregnancy. Electronic supplementary material The online version of this article (doi:10.1186/s12871-016-0188-z) contains supplementary material, which is available to authorized users.

Evidence of an association between early pregnancy exposure to selective serotonin reuptake inhibitors (SSRI) and congenital heart defects (CHD) has contributed to recommendations to weigh benefits and risks carefully. The objective of this study was to determine the specificity of association between first trimester exposure to SSRIs and specific CHD and other congenital anomalies (CA) associated with SSRI exposure in the literature (signals). A population-based case-malformed control study was conducted in 12 EUROCAT CA registries covering 2.1 million births 1995-2009 including livebirths, fetal deaths from 20 weeks gestation and terminations of pregnancy for fetal anomaly. Babies/fetuses with specific CHD (n = 12,876) and non-CHD signal CA (n = 13,024), were compared with malformed controls whose diagnosed CA have not been associated with SSRI in the literature (n = 17,083). SSRI exposure in first trimester pregnancy was associated with CHD overall (OR adjusted for registry 1.41, 95 % CI 1.07-1.86, fluoxetine adjOR 1.43 95 % CI 0.85-2.40, paroxetine adjOR 1.53, 95 % CI 0.91-2.58) and with severe CHD (adjOR 1.56, 95 % CI 1.02-2.39), particularly Tetralogy of Fallot (adjOR 3.16, 95 % CI 1.52-6.58) and Ebstein's anomaly (adjOR 8.23, 95 % CI 2.92-23.16). Significant associations with SSRI exposure were also found for ano-rectal atresia/stenosis (adjOR 2.46, 95 % CI 1.06-5.68), gastroschisis (adjOR 2.42, 95 % CI 1.10-5.29), renal dysplasia (adjOR 3.01, 95 % CI 1.61-5.61), and clubfoot (adjOR 2.41, 95 % CI 1.59-3.65). These data support a teratogenic effect of SSRIs specific to certain anomalies, but cannot exclude confounding by indication or associated factors.

Efficacy of anidulafungin is driven by the area under the concentration-time curve (AUC)/MIC ratio. Determination of the anidulafungin AUC along with MIC values can therefore be useful. Since obtaining a full concentration-time curve to determine an AUC is not always feasible or appropriate, limited-sampling strategies may be useful in adequately estimating exposure. The objective of this study was to develop a model to predict the individual anidulafungin exposure in critically ill patients using limited-sampling strategies. Pharmacokinetic data were derived from 20 critically ill patients with invasive candidiasis treated with anidulafungin. These data were used to develop a two-compartment model in MW\Pharm using an iterative 2-stage Bayesian procedure. Limited-sampling strategies were subsequently investigated using two methods, a Bayesian analysis and a linear regression analysis. The best possible strategies for these two methods were evaluated by a Bland-Altman analysis for correlation of the predicted and observed AUC from 0 to 24 h (AUC 0–24 ) values. Anidulafungin exposure can be adequately estimated with the concentration from a single sample drawn 12 h after the start of the infusion either by linear regression ( R 2 = 0.99; bias, 0.05%; root mean square error [RMSE], 3%) or using a population pharmacokinetic model ( R 2 = 0.89; bias, −0.1%; RMSE, 9%) in critically ill patients and also in less severely ill patients, as reflected by healthy volunteers. Limited sampling can be advantageous for future studies evaluating the pharmacokinetics and pharmacodynamics of anidulafungin and for therapeutic drug monitoring in selected patients. (This study has been registered at ClinicalTrials.gov under registration no. NCT01047267.)

An increasing recognition has emerged of the complexities of the global health agenda-specifically, the collision of infections and noncommunicable diseases and the dual burden of over- and undernutrition. Of particular practical concern are both 1) the need for a better understanding of the bidirectional relations between nutritional status and the development and function of the immune and inflammatory response and 2) the specific impact of the inflammatory response on the selection, use, and interpretation of nutrient biomarkers. The goal of the Inflammation and Nutritional Science for Programs/Policies and Interpretation of Research Evidence (INSPIRE) is to provide guidance for those users represented by the global food and nutrition enterprise. These include researchers (bench and clinical), clinicians providing care/treatment, those developing and evaluating programs/interventions at scale, and those responsible for generating evidence-based policy. The INSPIRE process included convening 5 thematic working groups (WGs) charged with developing summary reports around the following issues: 1) basic overview of the interactions between nutrition, immune function, and the inflammatory response; 2) examination of the evidence regarding the impact of nutrition on immune function and inflammation; 3) evaluation of the impact of inflammation and clinical conditions (acute and chronic) on nutrition; 4) examination of existing and potential new approaches to account for the impact of inflammation on biomarker interpretation and use; and 5) the presentation of new approaches to the study of these relations. EachWGwas tasked with synthesizing a summary of the evidence for each of these topics and delineating the remaining gaps in our knowledge. This review consists of a summary of the INSPIRE workshop and the WG deliberations. © 2015 American Society for Nutrition.

The consensus of current international guidelines for the treatment of HIV infection is that data on therapeutic drug monitoring (TDM) of non-nucleoside reverse transcriptase inhibitors and protease inhibitors provide a framework for the implementation of TDM in certain defined scenarios in clinical practice. However, the utility of TDM is considered to be on an individual basis until more data are obtained from large clinical trials showing the benefit of TDM.In April 2004, a panel of experts met in Rome, Italy. This followed an inaugural meeting in Perugia, Italy, in October 2000, which resulted in the article published in AIDS 2002, 16(Suppl 1):S5–S37. The objectives of this second meeting were to review the questions surrounding TDM of antiretroviral drugs and discuss the clinical utility, current concerns and future prospects of drug concentration monitoring in the care of HIV-1-infected individuals.This report, which has been updated to include material published or presented at international conferences up to the end of September 2004, reviews pharmacokinetic and pharmacodynamic data and reports the issues discussed by the panel, offering advice to clinical care providers who may be currently, or are considering incorporating TDM into the routine care of their patients. In addition, the panel formulated a series of position statements that are relevant to the interpretation of current data and can aid the design of future clinical trials.Part 2 of this Special article, Therapeutic drug monitoring and drug–drug interactions involving antiretroviral drugs, will be published in Antiviral Therapy 10(4).

Background. Morbidity and mortality for critically ill patients with infections remains a global healthcare problem. We aimed to determine whether α-lactam antibiotic dosing in critically ill patients achieves concentrations associated with maximal activity and whether antibiotic concentrations affect patient outcome.Methods. This was a prospective, multinational pharmacokinetic point-prevalence study including 8 α-lactam antibiotics. Two blood samples were taken from each patient during a single dosing interval. The primary pharmacokinetic/pharmacodynamic targets were free antibiotic concentrations above the minimum inhibitory concentration (MIC) of the pathogen at both 50% (50% f TMIC) and 100% (100% f T MIC) of the dosing interval. We used skewed logistic regression to describe the effect of antibiotic exposure on patient outcome.Results. We included 384 patients (361 evaluable patients) across 68 hospitals. The median age was 61 (interquartile range [IQR], 48-73) years, the median Acute Physiology and Chronic Health Evaluation II score was 18 (IQR, 14-24), and 65% of patients were male. Of the 248 patients treated for infection, 16% did not achieve 50% f TMIC and these patients were 32% less likely to have a positive clinical outcome (odds ratio [OR], 0.68; P =. 009). Positive clinical outcome was associated with increasing 50% f TMIC and 100% f TMIC ratios (OR, 1.02 and 1.56, respectively; P

BACKGROUND: Venous thromboembolism (VTE) is a serious disorder that may be complicated by pulmonary embolism (PE). Case reports and observational studies published in the early 1950s suggested that antipsychotic (AP) drugs may represent a risk factor, while observational studies conducted in the last 3 decades have provided conflicting results. OBJECTIVE: The aim was to investigate whether AP drugs increase the risk of VTE and PE, and to ascertain the risk associated with first- and second-generation AP drugs and with exposure to individual drugs. DATA SOURCE: Relevant studies were located by searching MEDLINE, PubMed, EMBASE, PsychINFO, CINAHL and Scopus up to March 2013. Reference lists of relevant papers and previous review articles were hand searched for other relevant studies. STUDY SELECTION: Based on the titles and abstracts of 1,386 citations, we identified 30 potentially relevant studies. Of these, 17 studies were eligible for inclusion and were included in the meta-analysis. MAIN OUTCOMES AND MEASURES: The primary outcome measure of this meta-analysis was the occurrence of VTE or PE in individuals exposed to AP drugs in comparison with individuals unexposed or with past exposure to AP drugs. RESULTS: Antipsychotic exposure was associated with a significant increase in risk of developing VTE [odds ratio (OR) 1.54, 95% confidence interval (CI) 1.28-1.86, 11 studies]. Exposure to APs did not significantly increase the risk of PE (OR 4.90, 95% CI 0.77-30.98, three studies), but the overall estimate was highly heterogeneous and the CI included the possibility of substantial harm. Random-effects meta-analysis on the risk of VTE associated with exposure to first- (OR 1.74, 95% CI 1.28-2.37, six studies) and second-generation (OR 2.07, 95% CI 1.74-2.52, five studies) APs revealed an increased risk. Only a few studies provided data on individual drugs, and estimates of effect were very uncertain. CONCLUSIONS: Antipsychotic exposure in unselected patient populations may be associated with a 50% increase in the risk of developing VTE. However, between-study heterogeneity limits the confidence in this estimate. This increased risk similarly applies to first- and second-generation AP drugs.

Population pharmacokinetic-dynamic analysis was prospectively integrated in the clinical phase If programme of EO9 to determine the population pharmacokinetic profile in a larger population of patients, to estimate individual patient pharmacokinetic parameters, and to investigate relationships between drug exposure and clinical outcome. A sparse sampling method was developed, which involved three sampling times, and was implemented during course 1. A Bayesian algorithm was used to estimate individual pharmacokinetic parameters, In particular total plasma clearance (CL) of EO9 and area under the curve (AUC). In total, samples were collected of 85 (65%) of the patients. Pharmacokinetic evaluation was successful in 61 (72%) of the sampled patients. CL of EO9 showed substantial variability (median 5.08 l/min; range 2.67-6.42) and was of the same magnitude as in the phase I study where full pharmacokinetic profiles were used. No significant relationships were noticed between exposure parameters and safety, but overall limited toxicity was observed. No tumor responses were documented. Prospective implementation of large-scale population pharmacokinetic-dynamic analysis is feasible and may generate important findings, In particular when tumor responses and relevant toxicity are observed. [(C) 2001 Lippincott Williams & Wilkins.].

Purpose: The aim of this systematic review was to examine and compare differences in the way medication exposures are classified in studies using linked administrative data to investigate outcomes following medication use during pregnancy. This was undertaken with a focus on studies investigating specific neonatal outcomes following prenatal exposure to selective serotonin reuptake inhibitors (SSRIs). Conclusions: There is a need for greater focus on determining the most effective and accurate way of using linked administrative data to investigate outcomes following medication use during pregnancy in an effort to minimise potential biases. Methods: We searched Medline and Embase to identify studies that used linked administrative data to investigate specific neonatal outcomes (congenital malformations, birth weight, gestational age) following prenatal exposure to SSRIs. Results: Key factors such as dose, duration and timing of exposure were inconsistently addressed in the studies identified. In addition, there was a great deal of variability in the way medication exposures were classified and how women who stop taking their medication before or during early pregnancy are handled in analyses. Furthermore, there are issues in assuming how and when women who receive a dispensing for a medication actually take it during pregnancy. This creates a great deal of uncertainty around medication exposure during pregnancy in studies using linked administrative data, potentially resulting in biased risk estimates. Refereed/Peer-reviewed

Early-life exposure to bacterial endotoxins, such as lipopolysaccharides (LPS), can provide neuroprotection against experimental autoimmune encephalomyelitis (EAE) during adulthood, possibly through altering the responsiveness of the immune system. Here, we show that exposure of LPS to neonatal rats resulted in a sustained elevation of corticosterone level in urine when compared with saline-treated rats, and that the high level of urine corticosterone was maintained during the progression of EAE (P

Lung cancer in pregnancy is a rare situation; however, it is increasingly reported in the past two decades. The association might be more encountered in the coming years due to the rising trends of cigarette smoking among young women and tendency to delay pregnancy to later in life. We performed a literature search without any date or language restriction and identified 44 cases diagnosed and/or treated for lung cancer during the course of pregnancy. Patients had poor post-partum outcome with less than one-forth alive at 1 year following delivery. There was a high incidence of metastases to the products of conception reaching 26%. Eight patients were treated with systemic therapies during the course of gestation with normal fetal outcome and no evidence of fetal or placental metastases. Counseling of these patients is very important. Apart from the clinical conflict they pose, some ethical aspects should be taken in consideration. The poor maternal prognosis should be discussed and the patient's autonomy should be respected to decide whether she wants to keep the pregnancy or not. © 2009 Elsevier Ireland Ltd. All rights reserved. 67 3 251 256