scholarly journals Development of a method for assessing the accumulation and metabolization of antidepressant drugs in zebrafish (Danio rerio) eleutheroembryos

2021 ◽  
Author(s):  
Noemí Molina-Fernández ◽  
Sandra Rainieri ◽  
Riansares Muñoz-Olivas ◽  
Paloma de Oro-Carretero ◽  
Jon Sanz-Landaluze
Keyword(s):  
Danio Rerio ◽  
Analytical Method ◽  
Extraction Method ◽  
Selective Serotonin Reuptake Inhibitors ◽  
Antidepressant Drugs ◽  
Compartment Model ◽  
First Order ◽  
Cleanup Procedure ◽  
Metabolic Transformation ◽  
Dispersive Spe

AbstractAntidepressant drugs are widely used for the treatment of common mental or other psychiatric disorders such as depression, which affect about 121 million people worldwide. This widespread use has contributed to the input of these pharmaceuticals and their metabolites into the environment. The aim of this work was to develop an analytical method to quantify the most widely used antidepressant drugs, selective serotonin reuptake inhibitors (SSRI), and their main metabolites in the environment. For this, a new and reliable miniaturized extraction method based on dispersive SPE cleanup procedure for extraction of SSRI followed by derivatization with n-heptafluorobutyrylimidazole, and detection by GC-MS was developed. The methodology, including a first-order one-compartment model, was then applied to a bioconcentration study in zebrafish (Danio rerio) eleutheroembryos. The results showed low bioaccumulation of these compounds; however, a biotransformation evidence of the parent compounds into their metabolites was observed after 6 h of exposure. These results indicate the need to integrate metabolic transformation rates to fully model and understand the bioaccumulation patterns of SSRI and their metabolites.

scholarly journals EPID-36. ANTIDEPRESSANT DRUG USE IN GLIOBLASTOMA PATIENTS: AN EPIDEMIOLOGICAL VIEW

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii86-ii86
Author(s):  
Dorothee Gramatzki ◽  
James Rogers ◽  
Marian Neidert ◽  
Caroline Hertler ◽  
Emilie Le Rhun ◽  
...  
Keyword(s):  
Overall Survival ◽  
Multivariate Analysis ◽  
Drug Use ◽  
Survival Data ◽  
Selective Serotonin Reuptake Inhibitors ◽  
Methylation Status ◽  
Antidepressant Drug ◽  
Antidepressant Drugs ◽  
Population Level ◽  
Disease Course

Abstract PURPOSE Antidepressant drugs have shown anti-tumor activity in preclinical glioblastoma studies. Antidepressant drug use, as well as its association with survival, in glioblastoma patients has not been well characterized on a population level. METHODS Patient characteristics, including the frequency of antidepressant drug use, were assessed in a glioblastoma cohort diagnosed in a 10-year time-frame between 2005 and 2014 in the Canton of Zurich, Switzerland. Cox proportional hazards regression models were applied for multivariate analysis. Kaplan-Meier survival curves were used to estimate overall survival data and the log-rank test was performed for comparisons. RESULTS Four hundred four patients with isocitrate dehydrogenase (IDH) wildtype glioblastoma were included in this study. Sixty-five patients (16.1%) took antidepressant drugs at some point during the disease course. Patients were most commonly prescribed selective serotonin reuptake inhibitors at any time (N=46, 70.8%). Nineteen patients (29.2%) were on antidepressant drugs at the time of their tumor diagnosis. No differences were observed in overall survival between those patients who had taken antidepressants at some point in their disease course and those who had not (p=0.356). These data were confirmed in a multivariate analysis including age, Karnofsky performance status, gender, extent of resection, O6-methylguanine DNA methyltransferase (MGMT) promoter methylation status, and first-line treatment as cofounders (p=0.315). Also, there was no association of use of drugs modulating voltage-dependent potassium channels (citalopram; escitalopram) with survival (p=0.639). CONCLUSIONS This signal-seeking study does not support the hypothesis that antidepressants have antitumor efficacy in glioblastoma on a population level.

scholarly journals Population Pharmacokinetic Analysis of Voriconazole and Anidulafungin in Adult Patients with Invasive Aspergillosis

2014 ◽  
Vol 58 (8) ◽  
pp. 4718-4726 ◽  
Author(s):  
Ping Liu ◽  
Diane R. Mould
Keyword(s):  
Invasive Aspergillosis ◽  
Area Under The Curve ◽  
Compartment Model ◽  
Population Pharmacokinetic Analysis ◽  
Institutional Review Boards ◽  
Pharmacokinetic Analysis ◽  
Population Pharmacokinetic ◽  
Parameter Estimates ◽  
First Order ◽  
Two Compartment Model

ABSTRACTTo assess the pharmacokinetics (PK) of voriconazole and anidulafungin in patients with invasive aspergillosis (IA) in comparison with other populations, sparse PK data were obtained for 305 adults from a prospective phase 3 study comparing voriconazole and anidulafungin in combination versus voriconazole monotherapy (voriconazole, 6 mg/kg intravenously [IV] every 12 h [q12h] for 24 h followed by 4 mg/kg IV q12h, switched to 300 mg orally q12h as appropriate; with placebo or anidulafungin IV, a 200-mg loading dose followed by 100 mg q24h). Voriconazole PK was described by a two-compartment model with first-order absorption and mixed linear and time-dependent nonlinear (Michaelis-Menten) elimination; anidulafungin PK was described by a two-compartment model with first-order elimination. For voriconazole, the normal inverse Wishart prior approach was implemented to stabilize the model. Compared to previous models, no new covariates were identified for voriconazole or anidulafungin. PK parameter estimates of voriconazole and anidulafungin are in agreement with those reported previously except for voriconazole clearance (the nonlinear clearance component became minimal). At a 4-mg/kg IV dose, voriconazole exposure tended to increase slightly as age, weight, or body mass index increased, but the difference was not considered clinically relevant. Estimated voriconazole exposures in IA patients at 4 mg/kg IV were higher than those reported for healthy adults (e.g., the average area under the curve over a 12-hour dosing interval [AUC0–12] at steady state was 46% higher); while it is not definitive, age and concomitant medications may impact this difference. Estimated anidulafungin exposures in IA patients were comparable to those reported for the general patient population. This study was approved by the appropriate institutional review boards or ethics committees and registered on ClinicalTrials.gov (NCT00531479).

scholarly journals Trends and Advances in Separation and Detection of SSRIs and SNRIs in Biological Matrices

2013 ◽  
Vol 2013 ◽  
pp. 1-15 ◽  
Author(s):  
Ruchita Das ◽  
Y. K. Agrawal
Keyword(s):  
Reuptake Inhibitor ◽  
Serotonin Reuptake ◽  
Selective Serotonin Reuptake Inhibitors ◽  
Date Rape ◽  
Antidepressant Drugs ◽  
Selective Serotonin ◽  
Biological Matrices ◽  
First Choice ◽  
Analytical Approaches ◽  
Norepinephrine Reuptake

Nowadays antidepressant drugs like selective serotonin reuptake inhibitors (SSRIs) and selective norepinephrine reuptake inhibitors (SNRIs) represent the first choice in the treatment of moderate to severe depressive illness, various phobias, and personality disorders. In spite of the therapeutic aspects, they often produce very severe and toxic effects in deliberate and accidental cases of poisoning. These are also considered as date-rape drugs used for drugged victims for raping or robbing. Therefore, in recent years, their analyses in different biological matrices for clinical and toxicological analysis purposes has been a target worthy of interest. Thus, the review focuses on recent advancements of various separation techniques like chromatography and electrophoresis that are concernd with the determination of selective serotonin reuptake inhibitor and selective norepinephrine reuptake inhibitor drugs and their metabolites in various biological matrices. In addition to this, a critical discussion on analytical approaches has also been incorporated, suggesting their applicability and limitations for further implementations. Thus, this paper will definitely help in the selection and development of proper analytical methodologies to achieve satisfactory results, better scientific understanding, and test interpretation.

scholarly journals O09 Drug delivery kinetics of intravenous gentamicin in a population of neonates

2019 ◽  
Vol 104 (6) ◽  
pp. e4.2-e4
Author(s):  
G Salis ◽  
N Medlicott ◽  
D Reith
Keyword(s):  
Drug Delivery ◽  
Time Lag ◽  
Medical Science ◽  
Compartment Model ◽  
Pharmacokinetic Parameters ◽  
List Type ◽  
First Order ◽  
Model Drug ◽  
The Individual ◽  
Kinetics Of

BackgroundGentamicin is commonly used in the NICU setting and is often administered via long lines, which increases variability in the rate of administration. We aimed to model drug delivery pharmacokinetic parameters for intravenous gentamicin administered via umbilical venous catheters (UVCs).MethodsData was modelled from infusion simulations of gentamicin delivery using UVCs with a background flow rate of 0.5 ml/h.1 Different combinations of dose (2 mg, 5 mg) were given by bolus injection over 3–5 minutes, followed by a normal saline flush (1 ml, 2 ml). Gentamicin levels were measured at 5 minute intervals over an hour via high pressure liquid chromatography.Phoenix Certara (version 8.1) was used for modelling. An extravascular model with clearance removed was used to predict parameters: absorption constant (Ka), time lag (Tlag), and bioavailability (F). F was used to enable an estimate of the variability in dose administered. Different error models were tested to ascertain which best described the data.ResultsAn extravascular one compartment model with first order absorption and additive error best described the data. Estimates for the model with a 2 mg dose and 1 ml flush were Ka 0.34L/min, Tlag 1.28min, F 0.97, standard deviation (stdev) 0.14. For 2 mg, 2 ml flush, estimates were Ka 0.86L/min, Tlag 3.01min, F 0.87, stdev 0.01. For 5 mg, 1 ml flush, estimates were Ka 0.48L/min, Tlag 3.13min, F 1.03, stdev 0.12. For 5 mg, 2 ml flush, estimates were Ka 0.83L/min, Tlag 3.29min, F 1.09, stdev 0.02. For each model epsshrinkage and nshrinkage for Tlag and F were low, however nshrinkage for ka was 0.9999.ConclusionThis is the first known modelling of gentamicin delivery kinetics. The studies all had high nshrinkage for Ka, therefore the individual estimates of ka may be unreliable. Further studies with a higher number of replicates would provide more favourable data for estimating Ka.ReferenceLala AC ( 2016). Variability in neonatal gentamicin administration influencing drug delivery kinetics (Thesis, Master of Medical Science). University of Otago.Disclosure(s)No conflict of interest declared. Funding for research via the Freemasons Society of New Zealand.

scholarly journals Population Pharmacokinetics of Oseltamivir: Pediatrics through Geriatrics

2013 ◽  
Vol 57 (8) ◽  
pp. 3470-3477 ◽  
Author(s):  
Mohamed A. Kamal ◽  
Scott A. Van Wart ◽  
Craig R. Rayner ◽  
Vishak Subramoney ◽  
Daniel K. Reynolds ◽  
...  
Keyword(s):  
Steady State ◽  
Time Course ◽  
Demographic Data ◽  
Visual Predictive Check ◽  
Compartment Model ◽  
Plasma Drug ◽  
First Order ◽  
Drug Concentrations ◽  
Population Pk ◽  
The Impact

ABSTRACTOseltamivir is a potent inhibitor of influenza virus neuraminidase enzymes essential for viral replication. This study aimed to investigate the impact of covariates on pharmacokinetic (PK) variability of oseltamivir and its active metabolite form, oseltamivir carboxylate (OC). Dosing history, plasma drug concentrations, and demographic information were pooled from 13 clinical trials providing data for 390 healthy and infected subjects ranging in age from 1 to 78 years and given oseltamivir doses of 20 to 1,000 mg. Candidate population PK models simultaneously characterizing the time course of oseltamivir and OC in plasma were evaluated by using the NONMEM software program, and subject covariates were assessed using stepwise forward selection (α = 0.01) and backward elimination (α = 0.001). A two-compartment model with first-order absorption of oseltamivir and first-order conversion of oseltamivir to OC and a one-compartment model with first-order elimination of OC were utilized. Body weight when evaluated using a power function was a significant predictor of the apparent oseltamivir clearance and both apparent OC clearance (CLm/F) and central volume of distribution (Vcm/F). Creatinine clearance was a significant predictor of CLm/F, while Vcm/F also decreased linearly with age. A visual predictive check indicated that the final model described oseltamivir and OC concentrations in plasma adequately across dose regimens and subject covariate ranges. Concordance of population mean and individualpost hocpredictions of maximum concentration of drug at steady state (Cmax) and area under the plasma drug concentration-time curve from 0 to 24 h at steady state (AUC0–24) was high (r2= 0.81 and 0.71, respectively). In conclusion, a comprehensive population PK model was constructed to bridge the adult to pediatric oseltamivir PK data, allowing for reasonable estimation of the PK of OC using subject demographic data alone.

scholarly journals Population Pharmacokinetics of Nevirapine, Zidovudine, and Didanosine in Human Immunodeficiency Virus-Infected Patients

1999 ◽  
Vol 43 (1) ◽  
pp. 121-128 ◽  
Author(s):  
Xiao-Jian Zhou ◽  
Lewis B. Sheiner ◽  
Richard T. D’Aquila ◽  
Michael D. Hughes ◽  
Martin S. Hirsch ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Body Weight ◽  
Population Pharmacokinetics ◽  
Compartment Model ◽  
Volume Of Distribution ◽  
Zero Order ◽  
Triple Combination ◽  
Entire Study ◽  
First Order ◽  
Immunodeficiency Virus

ABSTRACT The population pharmacokinetics of nevirapine (NVP), zidovudine (ZDV), and didanosine (ddI) were evaluated in a total of 175 patients infected with human immunodeficiency virus randomized to receive either a double combination of ZDV plus ddI or a triple combination of NVP plus ZDV plus ddI as a substudy of the AIDS Clinical Trials Group Protocol 241. Levels (approximating 3.5 determinations/patient) of the three drugs in plasma were measured during 44 of a total 48 weeks of study treatment, and a set of potential covariates was available for nonlinear mixed-effect modeling analysis. A one-compartment model with zero-order input and first-order elimination was fitted to the NVP data. Individual oral clearance (CL) and volume of distribution (V) averaged 0.0533 liters/h/kg of body weight and 1.17 liters/kg, respectively. Gender was the only covariate which significantly correlated with the CL of NVP. ZDV and ddI data were described by a two-compartment model with zero-order input and first-order elimination. Individual mean oral CL,V SS (volume of distribution at steady state), and V of ZDV were 1.84 liters/h/kg and 6.68 and 2.67 liters/kg, respectively, with body weight and age as correlates of CL and body weight as a correlate of V SS. The average individual oral CL, V SS, andV of ddI were 1.64 liters/h/kg and 3.56 and 2.74 liters/kg, respectively, with body weight as a significant correlate of both CL and V SS. The relative bioavailability (F) of ZDV and ddI in the triple combination compared to that in the double combination was also evaluated. No significant effects of the combination regimens on the F of ddI were detected (F TRIPLE = 1.05 andF DOUBLE = 1 by definition), but theF of ZDV was markedly reduced by the triple combination, being only 67.7% of that of the double combination. Large (>50%) intraindividual variability was associated with both ZDV and ddI pharmacokinetics. Individual cumulative area under the plasma drug level-time curve of the three drugs was calculated for the entire study period as a measure of drug exposure based on the individual data and the final-model estimates of structural and statistical parameters.

The turnover of organic carbon and nitrogen in soil

1990 ◽  
Vol 329 (1255) ◽  
pp. 361-368 ◽  
Keyword(s):  
Plant Material ◽  
Field Experiments ◽  
Compartment Model ◽  
Soil Organic Nitrogen ◽  
Carbon And Nitrogen ◽  
First Order ◽  
Complex Process ◽  
Two Compartment Model ◽  
Term Field

Although the decomposition of plant material in soil is an extremely complex process, relatively simple models can give good fits to the decay process. Thus a two-compartment model gives a close representation, over the first few years, of the decay of 14 C-labelled plant material in soil. A model containing a single homogeneous humus compartment decomposing by a first-order process is surprisingly useful for soil organic nitrogen over periods measured in decades. More sophisticated multicompartmental models are now widely used to represent turnover in soil. One of these, the Rothamsted turnover model, is described in detail and shown to give a useful representation of data from the Rothamsted long-term field experiments.

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