Changes In Drug Concentration Research Articles

In Situ Imaging of Subcutaneous Drug Delivery Systems Using Microspatially Offset Low-Frequency Raman Spectroscopy.

The noninvasive in situ monitoring of the status of drug retention and implant integrity of subcutaneous implants would allow optimization of therapy and avoid periods of subtherapeutic delivery kinetics. A proof-of principle study was conducted to determine the use of microspatially offset low-frequency Raman spectroscopy (micro-SOLFRS) for nonintrusive in situ analysis of subcutaneous drug delivery systems. Caffeine was used as the model drug, and it was embedded in a circular-shape Soluplus matrix via vacuum compression molding. For the exploratory analysis, prototype implants were positioned underneath skin tissue samples, and various caffeine concentrations (1-50% w/w) and micro-SOLFRS displacement settings (Δz = 0-8 mm) were tested from the pseudo three-dimensional (3D)-imaging perspective. This format allowed the optimization of real-time micro-SOLFRS analysis of implants through skin tissue that was embedded in an agarose hydrogel. Notably, this analytical approach allowed the temporal and spatial erosion of the implant and solid-state transformations of caffeine to be distinguished. The spectrometric results correlated with complementary high-performance liquid chromatography (HPLC) determination of changes in drug concentration, illustrating drug dissipation/diffusion characteristics. The discovered capability of micro-SOLFRS for in situ measurements of drugs and implants makes it attractive for biomedical diagnostics that, ultimately, could result in development of a new point-of-care technology.

Changes in Psychotropic Drug Concentrations Across the Menstrual Cycle: A Pilot Study.

The escalating prescription of psychopharmacological medications to women of reproductive age underscores the growing significance of sex-specific variations in pharmacotherapy. Despite this, clinical trials have largely overlooked these differences. Preliminary data indicate sex-specific variations in the neurobiology of affective disorders and in the metabolism, pharmacodynamics, and kinetics of therapeutic drugs. This underscores the imperative for a more nuanced exploration of menstrual cycle-dependent fluctuations in psychotropic drugs. This pilot study aimed to investigate drug and hormone fluctuations in female patients with affective disorders, aiming to enhance comprehension of the interplay between cycle-related hormone fluctuations and pharmacokinetics. The ultimate goal is to facilitate more effective and safer pharmacological therapy in the future. Blood samples were collected from 27 patients and 27 age-matched control participants at 3 distinct time points (early follicular phase, ovulation, and late luteal phase) during each menstrual cycle. Depressive and manic symptoms were assessed, and hormone concentrations were measured in the entire sample, while drug concentrations were assessed solely in the affective disorder sample using mass spectrometry. Significant variations in drug concentration were observed throughout the menstrual cycle for bupropion, with a trend toward altered concentration for venlafaxine. Moreover, notable differences in hormone concentrations were identified between patients and controls, even after accounting for the impact of contraceptive use, diagnoses, and medication. This pilot study reinforces previously reported data, underscoring the significance of sex-specific pharmacological therapy approaches. It provides further evidence supporting the interaction among sex hormones, drugs, and symptoms of affective disorders.

Real-Time Measurement of Antiglaucoma Drugs in Porcine Eyes Using Boron-Doped Diamond Microelectrodes.

The primary treatment for glaucoma, the most common cause of intermediate vision impairment, involves administering ocular hypotensive drugs in the form of topical eye drops. Observing real-time changes in the drugs that pass through the cornea and reach the anterior chamber of the eye is crucial for improving and developing safe, reliable, and effective medical treatments. Traditional methods for measuring temporal changes in drug concentrations in the aqueous humor employ separation analyzers such as LC-MS/MS. However, this technique requires multiple measurements on the eyes of various test subjects to track changes over time with a high temporal resolution. To address this issue, we have developed a measurement method that employs boron-doped diamond (BDD) microelectrodes to monitor real-time drug concentrations in the anterior chamber of the eye. First, we confirmed the electrochemical reactivity of 13 antiglaucoma drugs in a phosphate buffer solution with a pH of 7.4. Next, we optimized the method for continuous measurement of timolol maleate (TIM), a sympathetic beta-receptor antagonist, and generated calibration curves for each BDD microelectrode using aqueous humor collected from enucleated porcine eyes. We successfully demonstrated the continuous ex vivo monitoring of TIM concentrations in the anterior chambers of these enucleated porcine eyes. The results indicate that changes in intracameral TIM concentrations can be monitored through electrochemical measurements using BDD microelectrodes. This technique holds promise for future advancements in optimizing glaucoma treatment and drug administration strategies.

Pharmacokinetics and pharmacodynamics of perfluoropropane after intra-venous bolus injection of perflutren lipid microsphere injection (DEFINITY®) in healthy Chinese volunteers

Background and objectiveDefinity is an ultrasound contrast agent consisting of phospholipids-encapsulated perfluoropropane (PFP), also known as perflutren, microspheres, which is initially designed to enhance echocardiographic ultrasound images. With no pharmacologic action, Definity can increase the backscatter of ultrasound resulting enhanced ultrasound signals. The objective of this study was to determine the pharmacokinetics (PKs), Pharmacodynamics (PDs) and safety of Definity in healthy male and female Chinese volunteers.MethodsA simple GC-MS method was developed and applied to simultaneously quantify PFP both in human whole blood and in expired air using Perfluorobutane (PFB) as internal standard. Meanwhile, the blood microbubble Doppler intensities were continuously monitored as companion PDs by a Doppler ultrasonography system using a non-imaging method.ResultsAfter intravenous infusion of 10 µL/kg of PFP within 30 seconds, the mean AUClast of the pharmacokinetic analysis set was 0.000653 (uL/mL)*min, the average AUC∞ was 0.001051 (uL/mL)*min. The main coefficient of variation of parameters were within 30%. In this trial, the blood drug concentration of female subjects was lower than that of males. Female Cmax, AUClast and AUC∞ were lower than males’, Tmax and t1/2 was close to males’, Vss and CL were slightly higher than males’. The concentration of PFP in the expired air of the subject reached the maximum value 1–2 min after administration and the PFP accumulation curve in the expired air began to become flat at 9.5–11 min after administration. The PFP in the expired air at the last sampling point of most subjects was still measurable. The results of the analysis showed that female subjects had slightly more and faster PFP excretion via the lungs than males. The change of blood drug concentration in this trial was related to the change process of Doppler signal intensity. The trend of the two was close, but the peak time of blood drug concentration was slightly delayed compared with the peak time of the Doppler signal intensity. The results showed that female tmax−pd, t10 was earlier than male, and women have lower AUCpd than men.ConclusionThe pharmacokinetics and pharmacodynamics of Definity in blood and expired air were systematically evaluated for the first time in this study. The PK/PD analysis results of this trial showed that the change of blood concentration was related to the change process of Doppler signal intensity, the trend of the two was close and expired air are the main excretion pathways of Definity. Definity was well tolerated by all subjects in the trial.Trial registrationThis study was registered on 08 December 2017 at the Chinese Clinical Trial Registry (CTR20171087).

Physiologically Based Pharmacokinetic Modeling in Neonates: Current Status and Future Perspectives.

Rational drug use in special populations is a clinical problem that doctors and pharma-cists must consider seriously. Neonates are the most physiologically immature and vulnerable to drug dosing. There is a pronounced difference in the anatomical and physiological profiles be-tween neonates and older people, affecting the absorption, distribution, metabolism, and excretion of drugs in vivo, ultimately leading to changes in drug concentration. Thus, dose adjustments in neonates are necessary to achieve adequate therapeutic concentrations and avoid drug toxicity. Over the past few decades, modeling and simulation techniques, especially physiologically based pharmacokinetic (PBPK) modeling, have been increasingly used in pediatric drug development and clinical therapy. This rigorously designed and verified model can effectively compensate for the deficiencies of clinical trials in neonates, provide a valuable reference for clinical research design, and even replace some clinical trials to predict drug plasma concentrations in newborns. This review introduces previous findings regarding age-dependent physiological changes and pathological factors affecting neonatal pharmacokinetics, along with their research means. The application of PBPK modeling in neonatal pharmacokinetic studies of various medications is also reviewed. Based on this, we propose future perspectives on neonatal PBPK modeling and hope for its broader application.

Simultaneous Prediction Method for Intestinal Absorption and Metabolism Using the Mini-Ussing Chamber System.

Many evaluation tools for predicting human absorption are well-known for using cultured cell lines such as Caco-2, MDCK, and so on. Since the combinatorial chemistry and high throughput screening system, pharmacological assay, and pharmaceutical profiling assay are mainstays of drug development, PAMPA has been used to evaluate human drug absorption. In addition, cultured cell lines from iPS cells have been attracting attention because they morphologically resemble human intestinal tissues. In this review, we used human intestinal tissues to estimate human intestinal absorption and metabolism. The Ussing chamber uses human intestinal tissues to directly assay a drug candidate's permeability and determine the electrophysiological parameters such as potential differences (PD), short circuit current (Isc), and resistance (R). Thus, it is an attractive tool for elucidating human intestinal permeability and metabolism. We have presented a novel prediction method for intestinal absorption and metabolism by utilizing a mini-Ussing chamber using human intestinal tissues and animal intestinal tissues, based on the transport index (TI). The TI value was calculated by taking the change in drug concentrations on the apical side due to precipitation and the total amounts accumulated in the tissue (Tcorr) and transported to the basal side (Xcorr). The drug absorbability in rank order, as well as the fraction of dose absorbed (Fa) in humans, was predicted, and the intestinal metabolism of dogs and rats was also predicted, although it was not quantitative. However, the metabolites formation index (MFI) values, which are included in the TI values, can predict the evaluation of intestinal metabolism and absorption by using ketoconazole. Therefore, the mini-Ussing chamber, equipped with human and animal intestinal tissues, would be an ultimate method to predict intestinal absorption and metabolism simultaneously.

Time- and Temperature-Dependent Postmortem ?9-Tetrahydrocannabinol Concentration Changes in Rabbits following Controlled Inhaled Cannabis Administration.

Postmortem redistribution (PMR), a well-known phenomenon in forensic toxicology, can result in substantial changes in drug concentrations after death, depending on the chemical characteristics of the drug, blood collection site, storage conditions of the body and postmortem interval (PMI). Limited PMR data are available for Δ9-tetrahydrocannabinol (THC), the primary psychoactive component in Cannabis sativa. PMR was evaluated after controlled cannabis inhalation via a smoking machine and exposure chamber in New Zealand white rabbits. Necropsies were performed on five control rabbits immediately after euthanasia, whereas 27 others were stored at room temperature (21°C) or refrigerated conditions (4°C) until necropsy at 2, 6, 16, 24 or 36 h after death. THC and its phase I and glucuronidated phase II metabolites were quantified in blood, vitreous humor, urine, bile and tissues by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Under refrigerated temperature, heart blood THC concentrations significantly increased at PMI 2 h in rabbits, whereas peripheral blood THC concentrations showed a significant increase at PMI 16 h. Central:peripheral blood and liver:peripheral blood ratios for THC ranged from 0.13 to 4.1 and 0.28 to 8.9, respectively. Lung revealed the highest THC concentrations, while brain and liver exhibited the most stable THC concentrations over time. This report contributes much needed data to our understanding of postmortem THC behavior and can aid toxicologists in the interpretation of THC concentrations in medicolegal death investigations.

B-315 Investigation Into Extraction Procedure Substitution in the Abbott Architect i2000 Tacrolimus, Sirolimus, and Cyclosporine Assays

Abstract Background Tacrolimus, cyclosporine, and sirolimus are commonly used immunosuppressive drugs with narrow therapeutic windows requiring consistent monitoring to avoid drug toxicity. The Abbott Architect i2000 tacrolimus, sirolimus, and cyclosporine assays each require a pre-analytical whole blood lysing extraction step prior to analysis on the i2000. This extraction is largely manual, requiring the combination of an extraction reagent with the patient sample, followed by an incubation and centrifugation/pelleting steps, after which, the resulting supernatant is assayed for drug concentration. Each assay has its own unique extraction reagent and incubation steps, albeit all three procedures are quite similar. A clinician-requested investigation into a questionably elevated tacrolimus level led us to investigate the effect of substituting extraction reagents and procedures between the three assays. In this study, we investigated the effect of substituting extraction procedures and reagents on assayed immunosuppressive drug values between the Abbott tacrolimus, sirolimus, and cyclosporine immunoassays. Methods Whole blood was obtained from three patients who had previously had either their tacrolimus, sirolimus, or cyclosporine level assayed within the normal therapeutic range. For each patient, the cyclosporine, tacrolimus, or sirolimus level was re-assayed in triplicate, with the substitution of the other two assay’s extraction procedures performed prior to analysis. Such as: tacrolimus extraction was performed, then assayed for sirolimus or cyclosporine. This procedure was repeated for all three drugs and extraction procedures, affording 9 trials in total. The procedure was repeated with three samples obtained from patients with no measurable immunosuppressive drug levels. Additionally, cross-reactivity in the assay extraction reagents was assessed by measuring, in triplicate, immunosuppressive drug concentration on each extraction reagent without the addition of patient whole blood. Results Analysis in patients undergoing immunosuppressive drug therapy afforded the following changes in assayed drug concentration: Tacrolimus substituting sirolimus, cyclosporine extractions, 5.60 to 8.13, 8.47 ng/mL; sirolimus substituting cyclosporine, tacrolimus extractions 13.63 to 4.60, 8.07 ng/mL; cyclosporine substituting sirolimus, tacrolimus extractions 274.6 to 391.3, 757.30 ng/mL. Analysis in patients with no measurable drug content resulted in no change in assayed drug concentration with exception of tacrolimus, in which tacrolimus substituting sirolimus, cyclosporine extractions afforded <1.50 to 4.40, 4.00 ng/mL. Cross-reactivity trials yielded the following drug concentrations: tacrolimus precipitant: tacrolimus: >30.00, cyclosporine: >1500, sirolimus: 5.97 ng/mL; cyclosporine precipitant: cyclosporine: >1500, tacrolimus: 7.13, sirolimus 1.53 ng/mL; sirolimus precipitant: sirolimus: 5.00, tacrolimus: 8.67, cyclosporine: <25.00 ng/mL. Conclusions The use of incorrect extraction reagents and procedures resulted in both increased and decreased assayed immunosuppressive drug concentrations. These changes in drug concentration were observed in both samples containing, and not containing, immunosuppressive drugs. Significant cross-reactivity was observed in all three assay extraction reagents resulting inappropriately elevated assayed drug concentrations in all three assays. This highlights the need for comprehensive technologist training and effective pre-analytical workflows to prevent errors, such as reagent substitution, from occurring. This study has clinical implications into investigations of spurious immunosuppressive drug values, and substitution of assay extraction reagents and procedures should be investigated when performing root cause analysis into incorrectly reported immunosuppressive drug concentrations.

Influence of electric pulse characteristics on the cellular internalization of chemotherapeutic drugs and cell survival fraction in electroporated and vasoconstricted cancer tissues using boundary element techniques.

Electroporation has emerged as a suitable technique to induce the pore formation in the cell membrane of cancer tissues, facilitating the cellular internalization of chemotherapeutic drugs. An adequate selection of the electric pulse characteristics is crucial to guarantee the efficiency of this technique, minimizing the adverse effects. In the present work, the dual reciprocity boundary element method (DR-BEM) is applied for the simulation of drug transport in the extracellular and intracellular space of cancer tissues subjected to the application of controlled electric pulses, using a continuum tumour cord approach, and considering both the electro-permeabilization and vasoconstriction phenomena. The developed DR-BEM algorithm is validated with numerical and experimental results previously published, obtaining a satisfactory accuracy and convergence. Using the DR-BEM code, a study about the influence of the magnitude of electric field (E) and pulse spacing (dpulses) on the time behavior and spatial distribution of the internalized drug, as well as on the cell survival fraction, is carried out. In general, the change of drug concentration, drug exposure and cell survival fraction with the parameters E and dpulses is ruled by two important factors: the balance between the electro-permeabilization and vasoconstriction phenomena, and the relative importance of the sources of cell death (electric pulses and drug cytotoxicity); these two factors, in turn, significantly depend on the reversible and irreversible thresholds considered for the electric field.

Modelling of reversible tissue electroporation and its thermal effects in drug delivery

Electroporation is a very useful tool for drug delivery into various diseased tissues of the human body. This technique helps to improve the clinical treatment by transferring drugs into the targeted cells rapidly. In electroporation, drug particles enter easily into the intracellular compartment through the temporarily permeabilized cell membrane due to the applied electric field. In this work, a mathematical model of drug delivery focusing on reversible tissue electroporation is presented. In addition, the thermal effects on the tissue, which is an outcome of Joule heating, are also considered. This model introduces a time-dependent mass transfer coefficient, which is significant to drug transport. Multiple pulses with low voltage are applied to reach sufficient drugs into the targeted cells. Based on the physical circumstances, a set of differential equations are considered and solved. The changes in drug concentration with different parameters (e.g., diffusion coefficient, drug permeability, pulse length, and pulse number) are analyzed. The model optimizes the electroporation parameters to uptake sufficient drugs into the cells with no thermal damage. This model can be used in clinical experiments to predict drug uptake into the infected cells by controlling the model parameters according to the nature of infections.

Preparation of chitosan-coated hollow tin dioxide nanoparticles and their application in improving the oral bioavailability of febuxostat

The aim of this study was to design a chitosan-coated hollow tin dioxide nanosphere (CS-HSn) for loading febuxostat (FEB) using an adsorption method to obtain a sustained-release system (CS-HSn-FEB) to improve the oral bioavailability of FEB. The morphological characteristics of hollow tin dioxide nanospheres (HSn) and CS-HSn were analyzed by transmission electron microscopy (TEM) and dynamic light scattering (DLS). The hemolysis test and CCK-8 test were used to assess the biosafety of HSn and CS-HSn. Powder X-ray diffraction (PXRD) and differential scanning thermal analysis (DSC) were performed on CS-HSn-FEB to analyze the drug presence status. The dissolution behavior and changes in plasma drug concentration of CS-HSn-FEB were evaluated in vitro and in vivo. Sections of intestinal tissues from SD rats were obtained to observe whether chitosan could increase the distribution of nanoparticles in the intestinal tissues. The results showed that FEB was present in CS-HSn in an amorphous state. Moreover, CS-HSn, with good biosafety, significantly improved the water solubility and oral absorption of FEB, indicating that CS-HSn has great potential to improve the intestinal absorption and oral bioavailability of insoluble drugs.

Assessment of the sensitivity of 2 H MR spectroscopy measurements of [2,3-2 H2 ]fumarate metabolism for detecting tumor cell death.

Imaging the metabolism of [2,3-2 H2 ]fumarate to produce malate can be used to detect tumor cell death post-treatment. Here, we assess the sensitivity of the technique for detecting cell death by lowering the concentration of injected [2,3-2 H2 ]fumarate and by varying the extent of tumor cell death through changes in drug concentration. Mice were implanted subcutaneously with human triple negative breast cancer cells (MDA-MB-231) and injected with 0.1, 0.3, and 0.5 g/kg [2,3-2 H2 ]fumarate before and after treatment with a multivalent TRAlL-R2 agonist (MEDI3039) at 0.1, 0.4, and 0.8 mg/kg. Tumor conversion of [2,3-2 H2 ]fumarate to [2,3-2 H2 ]malate was assessed from a series of 13 spatially localized 2 H MR spectra acquired over 65 min using a pulse-acquire sequence with a 2-ms BIR4 adiabatic excitation pulse. Tumors were then excised and stained for histopathological markers of cell death: cleaved caspase 3 (CC3) and DNA damage (terminal deoxynucleotidyl transferase dUTP nick end labeling [TUNEL]). The rate of malate production and the malate/fumarate ratio plateaued at tumor fumarate concentrations of 2 mM, which were obtained with injected [2,3-2 H2 ]fumarate concentrations of 0.3 g/kg and above. Tumor malate concentration and the malate/fumarate ratio increased linearly with the extent of cell death determined histologically. At an injected [2,3-2 H2 ]fumarate concentration of 0.3 g/kg, 20% CC3 staining corresponded to a malate concentration of 0.62 mM and a malate/fumarate ratio of 0.21. Extrapolation indicated that there would be no detectable malate at 0% CC3 staining. The use of low and nontoxic fumarate concentrations and the production of [2,3-2 H2 ]malate at concentrations that are within the range that can be detected clinically suggest this technique could translate to the clinic.

Hair concentrations of anti-malarials in returned travellers-the HAIR study: Proof of principle analysis

BackgroundHair analysis to identify substance use is an established methodology. This could also be a method to monitor adherence to antimalarial drugs. We aimed to establish a methodology to determine hair concentrations of atovaquone, proguanil and mefloquine in travellers using chemoprophylaxis. MethodsA liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated for simultaneous analysis of the antimalarial drugs -atovaquone (ATQ), proguanil (PRO) and mefloquine (MQ), in human hair. The hair samples from five volunteers were used for this proof-of-concept analysis. Three volunteers were taking daily atovaquone/proguanil (ATQ/PRO) chemoprophylaxis and two volunteers were using weekly mefloquine (MQ) chemoprophylaxis. ResultsWith this proof-of-principle analysis, we could show that ATQ/PRO and MQ are integrated into the hair matrix. Chemoprophylaxis could be quantified with the established method. In hair segments, maximal concentrations of 3.0 ng/mL/20 mg hair proguanil, 1.3 ng/mL/20 mg hair atovaquone and 78.3 ng/mL/20 mg hair mefloquine were measured. Moreover, malaria drug concentration changes correlated with the time interval since finishing the chemoprophylaxis regimen. ConclusionsThe validated method was used successfully for the analysis of antimalarial-drug positive hair samples containing atovaquone, proguanil or mefloquine. This research shows that hair can be used for adherence monitoring of chemoprophylaxis and paves the way for larger studies and optimized procedures.

Assumptions Underlying Hepatic Clearance Models: Recognizing the Influence of Saturable Protein Binding on Driving Force Concentration and Discrimination Between Models of Hepatic Clearance.

One underlying assumption of hepatic clearance models is often underappreciated. Namely, plasma protein binding is assumed to be nonsaturable within a given drug concentration range, dependent only on protein concentration and equilibrium dissociation constant. However, in vitro hepatic clearance experiments often use low albumin concentrations that may be prone to saturation effects, especially for high-clearance compounds, where the drug concentration changes rapidly. Diazepam isolated perfused rat liver literature datasets collected at varying concentrations of albumin were used to evaluate the predictive utility of four hepatic clearance models (the well-stirred, parallel tube, dispersion, and modified well-stirred model) while both ignoring and accounting for potential impact of saturable protein binding on hepatic clearance model discrimination. In agreement with previous literature findings, analyses without accounting for saturable binding showed poor clearance prediction using all four hepatic clearance models. Here we show that accounting for saturable albumin binding improves clearance predictions across the four hepatic clearance models. Additionally, the well-stirred model best reconciles the difference between the predicted and observed clearance data, suggesting that the well-stirred model is an appropriate model to describe diazepam hepatic clearance when considering appropriate binding models. SIGNIFICANCE STATEMENT: Hepatic clearance models are vital for understanding clearance. Caveats in model discrimination and plasma protein binding have sparked an ongoing scientific discussion. This study expands the understanding of the underappreciated potential for saturable plasma protein binding. Fraction unbound must correspond to relevant driving force concentration. These considerations can improve clearance predictions and address hepatic clearance model disconnects. Importantly, even though hepatic clearance models are simple approximations of complex physiological processes, they are valuable tools for clinical clearance predictions.

Postmortem redistribution of cocaine and its metabolites, benzoylecgonine and ecgonine methyl ester in humans: Important variables that might be influencing the central blood / peripheral blood ratio

IntroductionA big challenge in forensic toxicology is the correct interpretation of the results of quantitative analyses in postmortem cases. Postmortem drug concentrations not necessarily reflect the drug concentrations at the time of death, due to postmortem changes in drug concentrations caused by postmortem redistribution (PMR). Cardiac blood is more prone to PMR related concentration changes than peripheral blood. Because of this difference in susceptibility to PMR related concentration changes, the ratio of cardiac blood concentration/peripheral blood concentration (C/P) of a drug is an often-used marker of PMR. In this study, we investigated the relationship between different potentially significant variables and the C/P ratios of cocaine, benzoylecgonine (BE) and ecgonine methyl ester (EME) in humans. The aim was to elucidate the mechanisms involved in PMR of these substances and potentially provide guidelines aiding forensic toxicologists in the interpretation of postmortem quantitative results of cocaine and its metabolites. To differentiate between postmortem concentration changes due to redistribution versus degradation of cocaine, the relationships between these variables and metabolite/cocaine ratios were investigated as well. MethodToxicological results of all postmortem cases that were positive for cocaine, BE and/or EME investigated by the Netherlands Forensic Institute between January 1st 2010 and July 31st 2020 were reviewed. The C/P ratios, BE/cocaine ratios and EME/cocaine ratios were determined for all selected cases. Cocaine, BE and/or EME were quantified in both femoral blood and cardiac blood in a total of 148 cases. Ratios were compared between subgroups by performing either a Mann-Whitney U test or a Kruskal-Wallis test followed by post-hoc Mann-Whitney U test. ResultsA statistically significant difference in C/P ratio of EME was observed between trauma and non-trauma cases with median C/P ratios of 2.03 and 1.57, respectively (p value=0.001). A statistically significant difference in EME/cocaine ratio was observed between the BMI subgroups 18.5 – 25.0 kg/m2 and> 25 kg/m2 with median EME/cocaine ratios of 3.79 and 1.58, respectively (p-value<0.001). ConclusionPostmortem cocaine concentrations should be interpreted with caution, considering the occurrence of both PMR and postmortem degradation. When interpreting postmortem toxicological results in cocaine-related fatalities, it might prove useful to take the above-mentioned variables into account.

Pharmacokinetic Consideration to Formulate Sustained Release Drugs: Understanding the Controlled Drug Diffusion through the Body Compartment of the Systemic Circulation and Tissue Medium-A Caputo Model

The aim of this study is to provide an overview of various models to study drug diffusion for a sustained period into and within the human body. Emphasized the mathematical compartment models using fractional derivative (Caputo model) approach to investigate the change in sustained drug concentration in different compartments of the human body system through the oral route or the intravenous route. Law of mass action, first-order kinetics, and Fick's perfusion principle were used to develop mathematical compartment models representing sustained drug diffusion throughout the human body. To adequately predict the sustained drug diffusion into various compartments of the human body, consider fractional derivative (Caputo model) to investigate the rate of concentration changing depending upon the change in the order of fractional differentiation in all the possible compartments of the body, i.e., systemic circulation and tissue compartments. Also, assigned a numerical parameter value to the rate of drug flow in different compartments to estimate the drug concentration. Results were calculated and figures were depicted by using MATLAB software (version R2020a). Illustrated graphical effects of change in concentration rate by assuming various intermediate values according to the fractional derivative (Caputo model). The resultant graphical representation concludes that considering the order of the differential equation values, the drug concentration varies depending upon its rate of constants in compartments concerning time. Considering the initial case for rough estimation where the body is indicated as a whole compartment, following division of the body into two model compartments. Whereas, the model I represents stomach, liver, and systemic blood, and model II consider arterial blood, liver tissue, and venous blood.

Genetic and physiological factors predisposing to individual selective serotonine reuptake inhibitors exposure during pregnancy and breast feeding

Anxiety and depression are very common during pregnancy. Post-partum period may frequently be complicated by more pro found depression due to hormonal changes, which may lead to fatal consequences for both — the mother and the child. The most commonly prescribed group of drugs for ambulatory patient care is the group of selective serotonine reuptake inhibitors (SSRIs). Absence of clinical trials where pregnant or breast-feeding women were among the participants has led to the situation when we can rule out effectiveness and safety of this drug class for pregnant and breastfeeding women based only on real-life studies. Current know ledge let us conclude that all individual group representatives have comparable efficacy and safety profile. The choice of a single agent to use may be difficult. In our paper we analyzed genetic and non-genetic factors, that may be important for individual pharmacokinetics of various SSRIs in order to reveal the most relevant for each group representative, and to determine those drugs with the most stable pharmacokinetic parameters in pregnancy. We also tried to define the drugs that may theoretically be more clinically reliable and safe for the fetus and the newborn. We considered such factors as expected changes in drug concentration during various periods in pregnancy, probable impact of pre-existing pharmacogenetic factors of individual drug exposure, potential for drug-drug interactions, and current knowledge about the extent of drug distribution in the blood of the newborns during breastfeeding

Comprehensive stability study of benzimidazole drug residues in standard solution, muscle and milk

The performance criteria of analytical methods and the necessity for stability analysis to provide the accuracy of the results of the analyzed samples are explained in European Commission Decision 2021/808/EC and the guidance document SANTE/2021/11312. Detection of time-dependent changes in drug concentrations during storage or transport and re-analysis of samples are crucial to obtain high-quality results and reliable data. In this way, it allows toxicologists to interpret the analytical results accurately in drug analyses. The aim of this study was comprehensively to investigate the stability of benzimidazoles (levamisole hydrochloride, albendazole, albendazole-sulfone, albendazole-2-amino sulfone, albendazole sulfoxide, oxfendazole, 5-hydroxythiabendazole, triclabendazole, ketotriclabendazole, thiabendazole, flubendazole, fenbendazole sulfone) in working solutions, muscle and milk samples. For this purpose, long-term stability was evaluated over 6 months and under four different storage conditions (4 °C, −20 °C, 20 °C light and 20 °C dark) in the matrix. The influences of three freeze-thaw cycles, autosampler stability, and 60 min storage at 40 °C were investigated for short-term stability. Simultaneously, the stability of the working solutions were established over 6 months and under five different conditions (4 °C, −20 °C, −80 °C, 20 °C light, and 20 °C dark). It was found that working solutions can be stored at −80 °C or −20 °C, and it is appropriate to prepare the standard working solution freshly once a month. Storage of milk at 4 °C is suitable for some analytes (ABZ-SO, FBZ-SO2, FLUBZ, ABZ, ABZ-NH2-SO2) whereas for the muscle almost all substances were stable only at −20 °C. Some freeze-thaw and short-term stability changes were detected.

Fractionalized mathematical models for drug diffusion

In this study, an effort is made to develop mathematical models that may be used to explain the distribution of drug administration in the human body after oral and intravenous administration of the drug. The diffusion process was utilized to create three models, applying Fick’s principle and the law of mass action. The Sumudu transform algorithm analyzes the rate of change of concentration in various compartments, such as blood and tissue medium. The general solution of drug concentration is demonstrated in the form of extended Mittag-Leffler function. The amount of drug that is contained in each compartment has been determined via the use of numerical parameters. The effect of the fractional parameter on the drug concentration is shown in graphical form. Using MAPLE software, graphs are created to highlight the change in drug concentration over time. The fractional model gives important and relevant inferences to infer new information about the medical field.

Nomogram predicting leukopenia in osteosarcoma after high-dose methotrexate chemotherapy.

Purpose: To explore the trends of plasma drug concentration changes after high-dose methotrexate (MTX) treatment of osteosarcoma (OS), analyse the risk factors for leukopenia (LP) after MTX treatment, and establish a LP prediction nomogram.Methods: A total of 35 OS patients at Tianjin Medical University Cancer Institute and Hospital between 2017 and 2021 were collected (the construction cohort). Another 12 OS patients between 2019 and 2021 in P.A. Hertsen Moscow Oncology Research Center were involved (the external validation cohort). Peripheral venous blood MTX concentration (CMTX) was monitored at 0h, 6h, 24h, 48h and 72h after MTX administration. The characteristics were collected: age, sex, body surface area, lesion site, pathological subtype, pathological fractures, American Joint Committee on Cancer (AJCC) clinical stage, MTX dose, tumour necrosis, Ki-67 index, erythrocyte count, haemoglobin count, white blood cell count, platelet count (PLT), alanine aminotransferase (ALT), aspartate aminotransferase (AST), bilirubin, albumin concentration, creatinine, alkaline phosphatase, and lactate dehydrogenase. Logistic regression analysis was used to determine the risk factors for LP occurrence. Significant factors were used to construct the prediction nomogram.Results: A total of 128 MTX chemotherapy cycles from 35 OS patients were included. Female, Ki-67>20%, CMTX>112μmol/L at 6h, PLT, and AST were risk factors for post-chemotherapy LP occurrence. The LP prediction nomogram was created and validated.Conclusions: Female, CMTX at 6h, Ki-67 index, AST and PLT before MTX treatment were risk factors for LP in OS patients who received MTX treatment. The established nomogram can guide personalized LP prediction in OS patients receiving MTX chemotherapy.