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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.

Remdesivir has displayed pharmacological activity against SARS-CoV-2. However, no pharmacometabolomics (PM) or correlation analysis with pharmacokinetics (PK) was revealed. Rats were intravenously administered remdesivir, and a series of blood samples were collected before and after treatment. Comprehensive metabolomics profile and PK were investigated and quantitated simultaneously using our previous reliable HPLC-MS/MS method. Both longitudinal and transversal metabolic analyses were conducted, and the correlation between PM and PK parameters was evaluated using Pearson’s correlation analysis and the PLS model. Multivariate statistical analysis was employed for discovering candidate biomarkers which predicted drug exposure or toxicity of remdesivir. The prominent metabolic profile variation was observed between pre- and posttreatment, and significant changes were found in 65 metabolites. A total of 15 metabolites—12 carnitines, one N-acetyl-D-glucosamine, one allantoin, and one corticosterone—were significantly correlated with the concentration of Nuc (active metabolite of remdesivir). Adenosine, spermine, guanosine, sn-glycero-3-phosphocholine, and l-homoserine may be considered potential biomarkers for predicting drug exposure or toxicity. This study is the first attempt to apply PM and PK to study remdesivir response/toxicity, and the identified candidate biomarkers might be used to predict the AUC and Cmax, indicating capability of discriminating good or poor responders. Currently, this study originally offers considerable evidence to metabolite reprogramming of remdesivir and sheds light on precision therapy development in fighting COVID-19.

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: nondifferential misclassification, differential misclassification (misclassifications dependent on an unmeasured risk factor doubling the outcome risk), and nondifferential misclassification in a comparative effectiveness study (RRA and RRB both 2.0 compared to nonuse, RRA-B 1.0). Results For the scenarios with nondifferential misclassification, 25% nonadherence or 25% uncaptured exposure changed the RR from 2.0 to 1.75, and 1.95, respectively. Applying different proportions of nonadherence 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 nonadherence 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 nonadherence 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.

Human immunodeficiency virus (HIV) infection remains one of the most severe problems for humanity, particularly due to the development of HIV resistance. To evaluate an association between viral sequence data and drug combinations and to estimate an effect of a particular drug combination on the treatment results, collection of the most representative drug combinations used to cure HIV and the biological data on amino acid sequences of HIV proteins is essential. We have created a new, freely available web database containing 1,651 amino acid sequences of HIV structural proteins [reverse transcriptase (RT), protease (PR), integrase (IN), and envelope protein (ENV)], treatment history information, and CD4+ cell count and viral load data available by the user’s query. Additionally, the biological data on new HIV sequences and treatment data can be stored in the database by any user followed by an expert’s verification. The database is available on the web at http://www.way2drug.com/rhivdb.

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/ )

Characterizing long‐term prescription data is challenging due to the time‐varying nature of drug use. Conventional approaches summarize time‐varying data into categorical variables based on simple measures, such as cumulative dose, while ignoring patterns of use. The loss of information can lead to misclassification and biased estimates of the exposure‐outcome association. We introduce a classification method to characterize longitudinal prescription data with an unsupervised machine learning algorithm. We used administrative databases covering virtually all 1.3 million residents of Manitoba and explicitly designed features to describe the average dose, proportion of days covered (PDC), dose change, and dose variability, and clustered the resulting feature space using K‐means clustering. We applied this method to metformin use in diabetes patients. We identified 27,786 metformin users and showed that the feature distributions of their metformin use are stable for varying the lengths of follow‐up and that these distributions have clear interpretations. We found six distinct metformin user groups: patients with intermittent use, decreasing dose, increasing dose, high dose, and two medium dose groups (one with stable dose and one with highly variable use). Patients in the varying and decreasing dose groups had a higher chance of progression of diabetes than other patients. The method presented in this paper allows for characterization of drug use into distinct and clinically relevant groups in a way that cannot be obtained from merely classifying use by quantiles of overall use., Distinction between stable and varying patterns of metformin use.

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.

Cytostatic drugs used in cancer therapy were evaluated for their capacity to inhibit Echinococcus multilocularis metacestode growth and proliferation. Metacestode tissues were exposed in vitro to docetaxel, doxorubicin, navelbine, paclitaxel, and vorinostat for 1 week, then incubated in drug-free culture, and thereafter metacestodes were injected into the peritoneum of Meriones unguiculatus. Magnetic resonance imaging (MRI) and simultaneous positron emission tomography (PET) were applied to monitor in vivo growth of drug-exposed E. multilocularis in Meriones. At 3 month p.i., docetaxel (at 10 μM, 5 μM and 2 μM) inhibited in vivo growth and proliferation of E. multilocularis, and at 5 months p.i., only in the 2 μM docetaxel exposure group 0.3 cm 3 of parasite tissue was found. With paclitaxel and navelbine the in vivo growth of metacestodes was suppressed until 3 months p.i., thereafter, parasite tissues enlarged up to 3 cm 3 in both groups. E. multilocularis tissues of more than 10 g developed in Meriones injected with metacestodes which were previously exposed in vitro to doxorubicin, navelbine, paclitaxel or vorinostat. In Meriones infected with metacestodes previously exposed to docetaxel, the in vivo grown parasite tissues weighted 0.2 g. In vitro cultured E. multilocularis metacestodes exposed to docetaxel did not produce vesicles until 7 weeks post drug exposure, while metacestodes exposed to doxorubicin, navelbine and vorinostat proliferated continuously. In summary, docetaxel, and less efficaciously paclitaxel, inhibited in vivo and in vitro parasite growth and proliferation, and these observations suggest further experimental studies with selected drug combinations which may translate into new treatment options against alveolar echinococcosis.

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.

Tyramine, formed by the decarboxylation of tyrosine, is a natural constituent of numerous food products. As an indirect sympathomimetic, it can have potentially dangerous hypertensive effects. In vitro data indicated that the pharmacokinetics of tyramine possibly depend on the organic cation transporter OCT1 genotype and on the CYP2D6 genotype. Since tyramine is a prototypic substrate of monoamine oxidase A (MAO-A), genetic polymorphisms in MAO-A may also be relevant. The aims of this study were to identify to what extent the interindividual variation in pharmacokinetics and pharmacodynamics of tyramine is determined by genetic polymorphisms in OCT1, CYP2D6, and MAO-A. Beyond that, we wanted to evaluate tyramine as probe drug for the in vivo activity of MAO-A and OCT1. Therefore, the pharmacokinetics, pharmacodynamics, and pharmacogenetics of tyramine were studied in 88 healthy volunteers after oral administration of a 400 mg dose. We observed a strong interindividual variation in systemic tyramine exposure, with a mean AUC of 3.74 min*µg/ml and a high mean CL/F ratio of 107 l/min. On average, as much as 76.8% of the dose was recovered in urine in form of the MAO-catalysed metabolite 4-hydroxyphenylacetic acid (4-HPAA), confirming that oxidative deamination by MAO-A is the quantitatively most relevant metabolic pathway. Systemic exposure of 4-HPAA varied only up to 3-fold, indicating no strong heritable variation in peripheral MAO-A activity. Systolic blood pressure increased by more than 10 mmHg in 71% of the volunteers and correlated strongly with systemic tyramine concentration. In less than 10% of participants, individually variable blood pressure peaks by >40 mmHg above baseline were observed at tyramine concentrations of >60 µg/l. Unexpectedly, the functionally relevant polymorphisms in OCT1 and CYP2D6, including the CYP2D6 poor and ultra-rapid metaboliser genotypes, did not significantly affect tyramine pharmacokinetics or pharmacodynamics. Also, the MOA-A genotypes, which had been associated in several earlier studies with neuropsychiatric phenotypes, had no significant effects on tyramine pharmacokinetics or its metabolism to 4-HPAA. Thus, variation in tyramine pharmacokinetics and pharmacodynamics is not explained by obvious genomic variation, and human tyramine metabolism did not indicate the existence of ultra-low or -high MAO-A activity. Open-Access-Publikationsfonds 2019 peerReviewed

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.

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.

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.

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: 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.

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.

This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Antiretroviral treatment history and past HIV-1 genotypes have been shown to be useful predictors for the success of antiretroviral therapy. However, this information may be unavailable or inaccurate, particularly for patients with multiple treatment lines often attending different clinics. We trained statistical models for predicting drug exposure from current HIV-1 genotype. These models were trained on 63,742 HIV-1 nucleotide sequences derived from patients with known therapeutic history, and on 6,836 genotype-phenotype pairs (GPPs). The mean performance regarding prediction of drug exposure on two test sets was 0.78 and 0.76 (ROC-AUC), respectively. The mean correlation to phenotypic resistance in GPPs was 0.51 (PhenoSense) and 0.46 (Antivirogram). Performance on prediction of therapy-success on two test sets based on genetic susceptibility scores was 0.71 and 0.63 (ROC-AUC), respectively. Compared to geno2pheno[resistance], our novel models display a similar or superior performance. Our models are freely available on the internet via www.geno2pheno.org. They can be used for inferring which drug compounds have previously been used by an HIV-1-infected patient, for predicting drug resistance, and for selecting an optimal antiretroviral therapy. Our data-driven models can be periodically retrained without expert intervention as clinical HIV-1 databases are updated and therefore reduce our dependency on hard-to-obtain GPPs. info:eu-repo/semantics/publishedVersion

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 paper examines the relationship between plasma concentration of antidepressant and both clinical response and adverse effects in treatment-resistant depressed adolescents. Adolescents (n = 334) with major depression who had not responded to a selective serotonin reuptake inhibitor (SSRI) were randomized to 1 of 4 treatments: switch to another SSRI (fluoxetine, citalopram, or paroxetine), switch to venlafaxine, switch to SSRI plus cognitive behavior therapy, or switch to venlafaxine plus cognitive behavior therapy. Adolescents who did not improve by 6 weeks had their dose increased. Plasma concentrations of medication and metabolites were measured at 6 weeks in 244 participants and at 12 weeks in 204 participants. Adolescents treated with citalopram whose plasma concentration was equal to or greater than the geometric mean (GM) showed a higher response rate compared to those with less than the GM, with parallel but nonsignificant findings for fluoxetine. A dose increase of citalopram or fluoxetine at week 6 was most likely to result in response when it led to a change in concentration from less than the GM at 6 weeks to the GM or greater at week 12. Plasma levels of paroxetine, venlafaxine, or O-desmethylvenlafaxine were not related to clinical response. Exposure was associated with more cardiovascular and dermatologic side effects in those receiving venlafaxine. Antidepressant concentration may be useful in optimizing treatment for depressed adolescents receiving fluoxetine or citalopram.

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.

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

In a previous study, we detected unexpectedly high levels of acquired antibiotic resistance in commensal Escherichia coli isolates from a remote Guaraní Indian (Bolivia) community with very low levels of antibiotic exposure and limited exchanges with the exterior. Here we analyzed the structure of the resistant E. coli population from that community and the resistance mechanisms. The E. coli population (113 isolates from 72 inhabitants) showed a high degree of genetic heterogeneity, as evidenced by phylogenetic grouping (77% group A, 10% group B1, 8% group D, 5% group B2) and genotyping by randomly amplified polymorphic DNA (RAPD) analysis (44 different RAPD types). The acquired resistance genes were always of the same types as those found in antibiotic-exposed settings [ bla TEM , bla PSE-1 , catI , cmlA6 , tet (A), tet (B), dfrA1 , dfrA7 , dfrA8 , dfrA17 , sul1 , sul2 , aphA1 , aadA1 , aadA2 , aadA5 , aadB , and sat-1 ]. Class 1 and class 2 integrons were found in 12% and 4% of the isolates, respectively, and harbored arrays of gene cassettes similar to those already described. The cotransferability of multiple-resistance traits was observed from selected isolates and was found to be associated with resistance conjugative plasmids of the F, P, and N types. Overall, these data suggest that the resistance observed in this remote community is likely the consequence of the dissemination of resistant bacteria and resistance genes from antibiotic-exposed settings (rather than of an independent in situ selection) which involved both the clonal expansion of resistant strains and the horizontal transfer/recombination of mobile genetic elements harboring resistance genes.

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.

Mechanistic target of rapamycin (mTOR) is a conserved serine/threonine kinase important in cell proliferation, growth and protein translation. Rapamycin, a well-known anti-cancer agent and immunosuppressant drug, inhibits mTOR activity in different taxa including zebrafish. In the present study, the effect of rapamycin exposure on the transcriptome of a zebrafish fibroblast cell line, ZF4, was investigated. Microarray analysis demonstrated that rapamycin treatment modulated a large set of genes with varying functions including protein synthesis, assembly of mitochondrial and proteasomal machinery, cell cycle, metabolism and oxidative phosphorylation in ZF4 cells. A mild however, coordinated reduction in the expression of proteasomal and mitochondrial ribosomal subunits was detected, while the expression of numerous ribosomal subunits increased. Meta-analysis of heterogeneous mouse rapamycin microarray datasets enabled the comparison of zebrafish and mouse pathways modulated by rapamycin, using Kyoto Encyclopedia of Genes and Genomes and Gene Ontology pathway analysis. The analyses demonstrated a high degree of functional conservation between zebrafish and mice in response to rapamycin. In addition, rapamycin treatment resulted in a marked dose-dependent reduction in body size and pigmentation in zebrafish embryos. The present study is the first, to the best of our knowledge, to evaluate the conservation of rapamycin-modulated functional pathways between zebrafish and mice, in addition to the dose-dependent growth curves of zebrafish embryos upon rapamycin exposure.

AIMS: To compare the pharmacokinetics, distribution and efficacy (pharmacodynamic response) of intraruminal ivermectin (IVM) and moxidectin (MXD) administered at 0.2 and 0.4 mg/kg to naturally nematode-infected lambs, and to determine the ex vivo accumulation of these anthelmintics by Haemonchus contortus. METHODS: Romney Marsh lambs, naturally infected with IVM-resistant H. contortus, were allocated to treatment groups based on faecal nematode egg counts. They received 0.2 or 0.4 mg/kg IVM or MXD (n=10 per group), or no treatment (Control; n=6), on Day 0. Samples from four animals from each treatment group, including abomasal parasites, were obtained on Day 1. Plasma samples were also collected from Day 0 to 14, and a faecal egg count reduction test (FECRT) and a controlled efficacy trial were carried out on Day 14. Concentrations of IVM and MXD in plasma, in abomasal and intestinal tissues and in H. contortus were evaluated by high-performance liquid chromatography. Additionally, the ex vivo drug accumulation of IVM and MXD by H. contortus was determined. RESULTS: Peak plasma concentrations and the area under the concentration vs. time curve for both IVM and MXD were higher for 0.4 than 0.2 mg/kg treatments (p95% for both treatments, and efficacy against H. contortus was 85.1% and 98.1% for 0.2 and 0.4 mg/kg, respectively. The ex vivo accumulation of IVM and MXD in H. contortus was directly related to the drug concentration present in the environment and was influenced by the duration of exposure. CONCLUSION: Administration of IVM and MXD at 0.4 compared with 0.2 mg/kg accounted for enhanced drug exposure in the target tissues, as well as higher drug concentrations within resistant nematodes. The current work is a further contribution to the evaluation of the relationship between drug efficacy and basic pharmacological issues in the presence of resistant parasite populations. Fil: Lloberas, Maria Mercedes. Instituto Nacional de Tecnología Agropecuaria. Centro Regional Buenos Aires Sur. Estación Experimental Agropecuaria Balcarce. Agencia de Extensión Rural Balcarce; Argentina Fil: Alvarez, Luis Ignacio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tandil. Centro de Investigación Veterinaria de Tandil. Universidad Nacional del Centro de la Provincia de Buenos Aires. Centro de Investigación Veterinaria de Tandil. Provincia de Buenos Aires. Gobernación. Comision de Investigaciones Científicas. Centro de Investigación Veterinaria de Tandil; Argentina Fil: Entrocasso, Carlos Miguel. Instituto Nacional de Tecnología Agropecuaria. Centro Regional Buenos Aires Sur. Estación Experimental Agropecuaria Balcarce. Agencia de Extensión Rural Balcarce; Argentina Fil: Ballent, Mariana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tandil. Centro de Investigación Veterinaria de Tandil. Universidad Nacional del Centro de la Provincia de Buenos Aires. Centro de Investigación Veterinaria de Tandil. Provincia de Buenos Aires. Gobernación. Comision de Investigaciones Científicas. Centro de Investigación Veterinaria de Tandil; Argentina Fil: Virkel, Guillermo Leon. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tandil. Centro de Investigación Veterinaria de Tandil. Universidad Nacional del Centro de la Provincia de Buenos Aires. Centro de Investigación Veterinaria de Tandil. Provincia de Buenos Aires. Gobernación. Comision de Investigaciones Científicas. Centro de Investigación Veterinaria de Tandil; Argentina Fil: Luque, Sonia Elisabet. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tandil. Centro de Investigación Veterinaria de Tandil. Universidad Nacional del Centro de la Provincia de Buenos Aires. Centro de Investigación Veterinaria de Tandil. Provincia de Buenos Aires. Gobernación. Comision de Investigaciones Científicas. Centro de Investigación Veterinaria de Tandil; Argentina Fil: Lanusse, Carlos Edmundo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tandil. Centro de Investigación Veterinaria de Tandil. Universidad Nacional del Centro de la Provincia de Buenos Aires. Centro de Investigación Veterinaria de Tandil. Provincia de Buenos Aires. Gobernación. Comision de Investigaciones Científicas. Centro de Investigación Veterinaria de Tandil; Argentina Fil: Lifschitz, Adrian Luis. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tandil. Centro de Investigación Veterinaria de Tandil. Universidad Nacional del Centro de la Provincia de Buenos Aires. Centro de Investigación Veterinaria de Tandil. Provincia de Buenos Aires. Gobernación. Comision de Investigaciones Científicas. Centro de Investigación Veterinaria de Tandil; Argentina

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).

Selective N3-adenine methylation represents a novel strategy for tumors with a phenotype of poor responsiveness to a number of anticancer agents currently used in the clinic. Resistance to N3-methyl-adenine-inducing agents, such as MeOSO2(CH2)(2)-lexitropsin (Me-Lex), is due to high levels of N-methylpurine glycosylase (MPG). However, tumor cells with high MPG activity can be rendered susceptible to Me-Lex using poly(ADP-ribose) polymerase-1 (PARP-1) inhibitors. Purpose: To evaluate the potential toxicity of Me-Lex, used as single agent or combined with PARP-1 inhibitors, in normal peripheral blood lymphocytes (PBL). Methods: PBL either resting or activated with phytohemagglutinin (PHA), obtained from healthy donors, were treated with graded concentrations of Me-Lex with or without PARP-1 inhibitor (3-aminobenzamide, AB, or NU1025, NU). MPG activity, apoptosis and sister chromatid exchanges (SCE) were evaluated. Results: (a) Me-Lex was cytotoxic mainly in PHA-activated PBL with low MPG activity; (b) combincd treatment with Me-Lex and AB induced apoptotic effects as early as 24 h after drug exposure both in non-stimulated and PHA-activated PBL. When concentrations of PARP-I inhibitors (25 muM NU and 4 mM AB) that produced a twofold increase in Me-Lex cytotoxicity in tumor cells were compared, NU induced a less-pronounced increase in apoptosis in PBL treated with Me-Lex; (c) Me-Lex at concentrations that allowed cytogenetic analysis did not induce a significant number of SCE; (d) PARP-1 inhibitors provoked a dose-dependent increase in SCE, but 25 muM NU was devoid of genotoxic effects and did not significantly increase SCE in PBL treated with Me-Lex. Conclusions: Me-Lex showed preferential cytotoxicity against mitogen-activated PBL. Our results also indicated that for each PARP-1 inhibitor it is necessary to define the concentration devoid of genotoxic effects in normal cells, but still capable of enhancing the efficacy of DNA-damaging agents in tumor cells.

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.].

[No abstract available]

Objective: To determine whether there is an increased risk of hip fracture associated with the use of proton pump inhibitors in a Mediterranean area after adjusting for other potential risk factors. Methods: Retrospective multicenter case-control study carried out in 6 primary health care centers in Catalonia, Spain. Cases were patients aged 50. years and over with a fragility hip fracture registered between January 2007 and December 2010, matched with 2 controls by sex and age. Data collected: use of proton pump inhibitors (type, dosage) in the 5. years previous to the hip fracture, socio-demographic data, body mass index, alcohol and tobacco consumption as well as health conditions and drugs associated with an increase risk of fragility hip fracture. Results: 358 cases were matched with 698 controls. The mean age was 82. years old in both groups. Women represented 77.1% in the case group and 76.9% in the control group. Crude association between proton pump inhibitors and hip fracture was 1.44 (95% CI, 1.09-1.89) and adjusted OR was 1.24 (95% CI, 0.93-1.65). No association was found with the continuous or discontinuous use of proton pump inhibitors, OR 1.17 (95% CI, 0.77-1.79), and OR of 1.16 (95% CI, 0.85-1.60) respectively. No association was found when restricting the analysis by sex, OR of 1.19 (95% CI, 0.27-5.14) or by age, younger or older than 80. years, OR of 0.72 (95% CI, 0.24-2.15). Conclusion: The use of proton pump inhibitors was not associated with an increased risk of hip fracture after adjusting for other risk factors in a Mediterranean area. This result suggests the existence of protective environmental factors linked to this southern area of Europe that eventually could compensate for the potential harm produced by proton pump inhibitors. © 2012 Elsevier Inc.

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

Ropivacaine has an optimal toxicity profile for epidural anesthesia in adults, but there are currently no studies concerning its pharmacokinetics during continuous infusion. The primary objective of this study was to evaluate the pharmacokinetics and safety of ropivacaine in adults during a 48-h continuous epidural infusion.We enrolled 43 adults (ASA I-II) scheduled for major abdominal or urologic surgery with postoperative continuous epidural analgesia with ropivacaine 0.2% (5 mL/h) and sufentanil 0.75 μg/mL for 48 h. Ropivacaine blood samples were collected during continuous epidural infusion before the bolus and 3, 6, 12, 24, 48, 54, 60 h after the bolus; plasma concentrations were measured on HPLC-UV. The concentration-time relationship of ropivacaine levels was analyzed using a population pharmacokinetic method based on a mixed-effect-model approach (P-PHARM software).Mean plasma concentration of ropivacaine at the end of epidural infusion (C(48 h)) was 1.69 μg/mL (0.21-3.8 μg/mL). Mean (range) C(max) was 1.82 μg/mL (0.61-4.0 μg/mL); the area under the plasma concentration curve, AUC ((0-60)), was 67.48 ± 30.60 μg·h/mL. Total plasma ropivacaine concentrations fell mainly within (84%) or below (12%) the range reported to be safe in adults (1.0-3.0 μg/mL). Only two patients (5%) reached ropivacaine plasma levels higher than 3 μg/mL, namely 3.8 and 4.0 μg/mL at 48 and 54 h, respectively. Total ropivacaine concentrations up to 4.0 μg/mL were tolerated during long-term epidural ropivacaine infusion. Mean clearance for total ropivacaine was 5.33 L/h. Age was the only covariable to significantly reduce clearance variability: CL (L/h)=15.04-0.148 × age (years). The volume of distribution (Vd) was 92.15 L. The infusion dosing period half-life (t(1/2,DP)=0.693 × Vd/CL) was 10.8 h.Exposure to ropivacaine during epidural infusion is highly variable. The apparent infusion dosing half-life t(1/2,DP) is the most appropriate parameter to predict drug accumulation upon epidural infusion since it appears to better reflect the interplay interference between volume distribution and absorption rate during the accumulation phase. Prediction of ropivacaine accumulation can be improved by considering patient age.

Evidence has implicated apoptosis as a mechanism underlying cell demise in diverse neurodegenerative diseases including Parkinson's disease (PD). Endogenous toxins and other stress signals activate the sphingomyelin pathway increasing the levels of ceramide, an important regulator of cell death.In the present paper we have analysed the contribution of PI3K/AKT-GSK3? and MAPK (ERK and JNK) pathways to cell death in a catecholaminergic cell line following exposure to C2-ceramide. We also explored the potential neuroprotective action of insulin-like growth factor-1 (IGF-1) and neurotrophin-3 (NT3).We demonstrated that C2-ceramide-induced cell death is associated to an early decrease in phosphorylation (inhibition) of PI3K/AKT and ERK, followed by phosphorylation (activation) of JNK and de-phosphorylation (activation) of glycogen synthase kinase-3 beta (GSK3?). NT3 and IGF-1 increased survival at early time points, but only IGF-1 is capable to attenuate C2-ceramide-mediated neuronal death, and this neuroprotection is associated to strong and permanent activation of AKT and inhibition of GSK3?. In conclusion, C2-ceramide initiates a series of events including an early inactivation of PI3K/AKT and ERK pathways followed by activation of JNK and activation of GSK3? and neuronal death, changes that are counteracted by IGF-1. © 2010 Elsevier Inc.

Treatment of human K-562-J leukemia cells for 1 h with the topoisomerase II-reactive drugs VP-16, VM-26, or mAMSA resulted in a dose-dependent inhibition of proliferation and in an increase in the percentage of cells staining positive for hemoglobin, a marker of erythroid differentiation. Staining for hemoglobin of up to about 60% of the cells was observed at 20 μM VP-16, 1 μM VM-26, and 8 μM mAMSA. Such treatment also caused a G2 M arrest in the cell cycle. Incubation of the cells with radiolabeled VP-16 indicated that the induced erythroid differentiation was not due to continuous cell exposure to a residual amount of the drug. VP-16-induced erythroid differentiation was also not affected by DNA, RNA, or protein synthesis inhibitors. Differentiation induction and the G2 M arrest evoked by VP-16, VM-26, and mAMSA were, however, reduced in the presence of novobiocin. Our results indicate that topo-reactive drugs that cause G2 M arrest in the K-562-J cell cycle can induce in these cells erythroid differentiation after a short and irreversible interaction with their target molecule(s). © 1992. 203 100 106 Manufacturers: bristol national cancer institute sigma, United States Cited By :20

Domoic acid (DA) is a neurotoxicant produced by Pseudo-nitzschia from diatomeae. Although the neurotoxic and genotoxic effects of DA have been well documented, the number of in vivo studies regarding the oxidative stress inducing effects of DA is quite limited. In this study, in vivo toxic effects of DA were investigated on fish Oreochromis niloticus (Fam: Cichlidae), using oxidative stress biomarkers. Fish were exposed to three different concentrations (1, 5 and 10 μg/g body weight) of DA via intraperitoneal injections and the tissues were sampled at 24, 48 and 72 h post-treatment. Changes in the level of lipid peroxidation, and activities of antioxidant enzymes such as superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), and glutathione reductase (GRd) were evaluated in liver and gill tissues. Our results revealed dose and time dependent increases in the oxidative stress parameters. It was also observed that the toxic effects were more pronounced in liver than in gill tissue.

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

BackgroundSmall intensive pharmacokinetic (PK) studies of medications in early-phase trials cannot identify the range of factors that influence drug exposure in heterogenous populations. We performed PK studies in large numbers of HIV-infected women on nonnucleoside reverse transcriptase inhibitors (NNRTIs) under conditions of actual use to assess patient characteristics that influence exposure and evaluated the relationship between exposure and response.MethodsTwo hundred twenty-five women on NNRTI-based antiretroviral regimens from the Women's Interagency HIV Study were enrolled into 12-hour or 24-hour PK studies. Extensive demographic, laboratory, and medication covariate data were collected before and during the visit to be used in multivariate models. Total NNRTI drug exposure was estimated by area under the concentration-time curves.ResultsHepatic inflammation and renal insufficiency were independently associated with increased nevirapine exposure in multivariate analysis: crack cocaine, high fat diets, and amenorrhea were associated with decreased levels (n = 106). Higher efavirenz exposure was seen with increased transaminase, albumin levels, and orange juice consumption; tenofovir use, increased weight, being African American, and amenorrhea were associated with decreased exposure (n = 119). With every 10-fold increase in nevirapine or efavirenz exposure, participants were 3.3 and 3.6 times likely to exhibit virologic suppression, respectively. Patients with higher drug exposure were also more likely to report side effects on therapy.ConclusionsOur study identifies and quantitates previously unrecognized factors modifying NNRTI exposure in the "real-world" setting. Comprehensive PK studies in representative populations are feasible and may ultimately lead to dose optimization strategies in patients at risk for failure or adverse events.

The acaricidal efficacy of ceramic tiles treated at field application rates with either spinosad (Mozkill (c) 120 SC, 0.01 g ai/m(2)), deltamethrin (Impotek Deltamethrin (c) EW, 0.01 g ai/m(2)), permethrin + esbiothrin (Chrysamed (c), 0.1 g ai/m(2)), chlorpyrifos-methyl (Chlortoks (c) EC 50, 0.2 g ai/m(2)) or a mixture of alpha-cypermethrin/tetramethrin/piperonyl butoxide (Ecorex Alfa (c) SE, 0.01 g ai/m(2)), against larval Rhipicephalus turanicus and Argas persicus ticks was determined in laboratory bioassays. All ticks were initially exposed to treated tiles for 15 min then removed to non-treated containers and mortality evaluated for 15 min, 1 h, 6 h, and 24 h postexposure. Generally, A. persicus proved to be the most susceptible of the two species to all treatments. The alpha-cypermethrin/tetramethrin/piperonyl butoxide mixture was the quickest acting acaricide against larval A. persicus where 100% mortality was observed 15 min postexposure. For the rest of the treatments complete mortality was obtained at 1 h except for permethrin/esbiothrin which occurred at 6 h postexposure. Complete mortality of larval R turanicus occurred to deltamethrin and spinosad at I h postexposure with all acaricides providing 100% control at 6 h except permethrin/esbiothrin which only achieved 92% control through the end of the study (i.e. 24 h). Our results showed that spinosad would be a useful addition in a tick control program as an alternative for pyrethroids and organic phosphorus acaricides against both tick species. Akdeniz Üniversitesi

Hospital infection due to multidrug-resistant Gram-positive bacteria may often represent a life-threatening challenge; thus, to appropriately combat them, clinicians should be confident and systematically apply several important pharmacodynamic concepts. The concept of 'correct antibiotic treatment' should include, in addition to an appropriate choice in terms of antimicrobial susceptibility, an appropriate dosage and administration schedule consistent with the pharmacodynamic principles. In the next few years, it is expected that some of the anti-Gram-positive antimicrobial agents that are currently under investigation will be added to the therapeutic armamentarium. However, optimization of the usage of old drugs still remains a clinical priority and a scientific challenge, whose dignity may be considered of similar importance to that of the assessment of the possible therapeutic role of the new compounds.