Blood Drug Concentration Research Articles

Drug-impaired driving and traffic collisions: Study on a cross section of the Italian population.

The present study focuses on the association between road accidents and the presence of drugs of abuse markers in the biological fluids of the drivers. Biological fluids collected from 1236 drivers involved in road accidents (54 fatal and 1182 non-fatal crashes) in the Rome area were analyzed for alcohol and psychotropic drugs, as required by judicial authorities. The substance most frequently detected was alcohol (in 19% of non-fatal and 32% of fatal crashes), followed by cannabinoids (12% of non-fatal crashes) and cocaine (9% of non-fatal and 20% of fatal crashes). The results obtained for cocaine and cannabinoids in blood and urine were compared. We observed the absence or low concentrations of the active drug in blood (cocaine was often below 5ng/ml and THC below 1ng/ml), whereas urinary concentrations of metabolites were generally high (benzoylecgonine 250-above 5000 ng/ml, THCCOOH 15-270 ng/ml). The risk of being involved in a road accident if cocaine or cannabis markers were present in the urine specimens was evaluated compared to a control population. The odds ratios calculated, being 8.13 for cannabis and 5.32 for cocaine, suggest a strong association between the presence of these drugs in the urine of drivers and traffic accidents, regardless of their presence in blood samples. The present data suggest that the chance of being involved in a road accident is higher than in the control population even if the subject is no longer "under the influence" of cannabis or cocaine at the time of the accident.

Evaluation of serum and rapid serum separator collection tubes for therapeutic drug assays

Appropriate specimen collection and storage is essential to preserve sample integrity and ensure accurate test results. The default collection containers for blood drug concentrations are tubes without gel separators to avoid possible drug adsorption. However, routine chemistry tests are generally collected in gel separator tubes due to their convenient transport and processing; collection of an additional gel-free tube is often required for drug measurements.Citrated whole blood was pooled, spiked with drug, and transferred to three tubes (red, SST gold, RST orange) containing calcium chloride. Blood was allowed to clot, centrifuged and stored at ambient temperature (24 h) or refrigerated (7 days). At defined times, serum drug concentrations were determined (Roche cobas c502). Based on these results, specimen collection requirements were updated to allow serum separator tubes for 17 assays.Of the 21 assays evaluated, 18 displayed acceptable stability in both gel-containing tubes (acetaminophen, amikacin, carbamazepine, digoxin, ethanol, gentamicin, lamotrigine, levetiracetam, lithium, methotrexate, phenobarbital, phenytoin, salicylate, theophylline, tobramycin, valproic acid, vancomycin, voriconazole). Three drugs displayed strong decreases in measured concentrations after storage in one or both gel-containing tubes (total tricyclics, lidocaine, and free phenytoin). Following adoption of gel-containing tubes, 94% of the five most frequently ordered drug monitoring tests in the Emergency Department were collected in serum separator tubes.Evaluation of the stability and accuracy of commonly monitored drugs revealed that the majority were not affected by exposure to gel separator material under conditions similar to outpatient clinic storage, courier transport, and laboratory storage. Expanding the collection requirements for appropriate drugs to include gel separator tubes decreases the number of specimens drawn and the complexity of laboratory workflows.

Interchangeability between Generic and Reference Products: Limits of Average Bioequivalence Methodology.

Marketing authorisation of generic drugs is based on a demonstration of the "average" bioequivalence (ABE), with acceptance limits of 0.8-1.25 for the 90% confidence interval (CI) of the ratio (generic versus reference) of geometric means of exposure (whole blood, serum or plasma drug concentration). However, when interchangeability of reference by one generic is considered during treatment of a given patient, such methodology cannot guarantee the lack of therapeutic impact especially for drugs with narrow therapeutic index. This review article describes the basis and limits of ABE methodology, and the adaptations that have been proposed by regulatory agencies. For highly variable drugs, given their large therapeutic margin, regulatory agencies even allow widening of the bioequivalence acceptance limits. For drugs with a narrow therapeutic index, the average bioequivalence methodology has been amended differently by regulatory agencies. The European Medicine Agency only requires the narrowing of the ABE acceptance limits to the 0.9-1.10 range. The US Food and Drug Administration (FDA) has proposed to narrow the ABE acceptance limits according to the reference within-subject variance. The FDA requires a fully replicate cross-over study (with four periods) which allows one to compare the within-subject variance between generic and reference drug, and to detect any subject-by-formulation interaction. Indeed, any within-subject variance difference or subject by formulation interactionis an obstacle to interchangeability at the individual level. These amendments for the ABE do not fundamentally change the fact that individual ratios of exposure (generic/reference) will vary to a larger extent than the ratio of their means. For these reasons, since true individual bioequivalence studies cannot be performed for practical reasons and statistical issues, one can suggest that, in addition to the usual average bioequivalence criteria, the limits of the 95% confidence interval of the individual generic/reference exposure ratios could be used to allow interchangeability during treatment (at least for narrow therapeutic index drugs). Limit values of such CI for interchangeability acceptance should be scaled to the therapeutic margin of the reference drug. Regulatory agencies could conduct calculations based on real datasets of bioequivalence studies to determine if such criteria could be acceptable to allow interchangeability.

Fatal concentrations of antidepressants and antipsychotics in post-mortem blood

The objective was to compare the summary statistics for fatal antidepressant and antipsychotic drug concentrations mined by different approaches from post-mortem (PM) toxicological data. Reference concentrations of drugs play a major part in the interpretation of PM toxicology results. However, PM drug concentrations are not necessarily the same as those at the time of death, and consequently standard tables of clinical plasma concentration data are of limited value. Compilations of PM concentrations collected from literature sources are often heterogeneous in terms of the sampling site, the analytical methods used, and the number of cases involved. However, there are also published summary statistics for drug concentrations in PM femoral venous blood, based on extensive databases from centralized laboratories with well-established and high-quality working practices. The present study establishes concentration distributions for a number of antidepressant and antipsychotic drugs, specified as a principal finding in fatal poisoning (principal finding approach). These levels are then compared with those obtained using two previous approaches: according to the all-causes-of-death (Ketola RA, Drug Test Anal, 2019, 11, 1326–1337) or according to the grouped causes of death, aka “the Druid approach”, where the reference information is subdivided into poisonings by one specific substance only, multi-substance poisonings and non-poisoning controls (Reis M, J Anal Toxicol, 2007, 31, 254-264; Söderberg C, Forensic Sci Int, 2016, 266, 91-101). Summary statistics for fatal antidepressant and antipsychotic drug concentrations in PM femoral venous blood were generated according to the principal drug finding. In most cases, also other drugs were implicated in the cause of death. The data were mined between 2000–2020 from the national PM toxicology database, maintained by the Finnish Institute for Health and Welfare, in which all results of the toxicological analyses in medico-legal investigations and information from the respective death certificates are collected. From this material, those antidepressant and antipsychotic drugs that had been quantitatively analysed at least 10 times were selected. Concentration percentiles (10th, 50th, 90th, 95th, 97.5th) were calculated for 16 different antidepressant ( N = 1999) and for 7 different antipsychotic drugs ( N = 1134), defined as principal findings of fatal poisoning by forensic pathologists. For instance, for the antidepressant amitriptyline the respective concentrations were 0.66, 2.0, 8.3, 13 and 25 mg/L, and for the antipsychotic levomepromazine (methotrimeprazine) 0.40, 1.5, 5.3, 10 and 16 mg/L. A comparison with other data mining approaches will be presented in visual form. A clear correspondence was found between, for example, the 90th percentile concentration level of the present principal finding approach and the 97.5th percentile concentration level of the all-causes-of-death approach. Similarly, a correspondence was found between, for example, the median concentration level of the present principal finding approach and the median concentration level of the multi-substance poisoning group in the Druid approach. The novel data presented in this study followed by a systematic comparison with data from previous studies helps rationalize the use of reference concentrations from various sources in the interpretation of potential poisoning deaths. Further data mining for additional drugs will be markedly easier in the principal finding approach than in the Druid approach, provided that the principal findings are specified in advance in the database as is in our case. Despite the proven usefulness of reference concentrations, interpretation must always be made on a case-by-case basis, taking into account e.g. background information, autopsy findings, and substance interactions. A forensic toxicologist must have the evidence-based PM concentration information at his or her disposal when assisting a forensic pathologist in determining the cause of death or being called to testify in court.

Ketamine in DUID cases in the greater Cologne area. A case series

Cases of ketamine consumption in driving under the influence of drugs (DUID) were evaluated with regard to recorded psychomotor impairments and possible co-consumption of drugs of abuse or other substances. Ketamine is a substance that is used e.g. as an anaesthetic or for analgesics in medical treatment. Due to its dissociative effects, ketamine abuse has increased in the past years leading to several drug-impaired driving cases. According to literature, ketamine plasma concentrations above 50 ng/mL are associated with significant psychomotor impairments, whereby mind-altering effects can be expected at plasma concentrations of ketamine between 50 and 200 ng/mL. They seem to be concentration dependent. The most commonly described impairments comprise a slurred speech, drowsiness, confusion and vomiting as well as lack of coordination and dystonia, blurred vision or visual field narrowing, dissociation, referential thinking, euphoria, depersonalization and anxiety. Moreover, pupil dilatation, a lack of convergence, horizontal gaze nystagmus, elevated pulse rate and failure of divided attention tests like walk-and-turn and one-leg stand test were observed. DUID cases from two institutes of legal medicine from the years 2021 to early 2022 were evaluated with regard to drug-impaired drivers who consumed ketamine. The cases were compared with regard to psychomotor impairments, salience in driving and co-consumption of drugs. Technical devices for the analyses of drug concentrations in blood were drug-dependent and therefore either performed by GC-MS/MS, LC-MS/MS or HPLC-DAD. Five cases of drivers (all male, between 21 and 44 years old) were collected. Ketamine consumption was admitted in two out of five cases. Indications for a medical application were not given in the other three cases without confessed consumption. Ketamine concentrations of approx. 165 ng/mL, 245 ng/mL, 610 ng/mL, 676 ng/mL and 3800 ng/mL were detected in the serum samples. Moreover, co-consumption of either one or multiple substances like cannabis ( n = 2), amphetamine ( n = 4), 3,4-methylenedioxymethamphetamine (MDMA) ( n = 1), cocaine ( n = 2) and clonazepam ( n = 1) could be ascertained in all cases. The recorded psychomotor impairments of the drivers comprised e.g. dilated pupils ( n = 2), missing or delayed pupil reactions ( n = 3), as well as aggressive behaviour ( n = 3), a slurred or decelerated speech ( n = 2), a delayed reaction ( n = 2), lack of concentration ( n = 2) or vertigo ( n = 3). The observed psychomotor impairments correlated with literature data. However, the assessment and differentiation of impairments with regard to ketamine consumption is aggravated due to co-consumption of other drugs of abuse or substances. In literature, co-consumption of e.g. alcohol, cannabis, MDMA, amphetamine, benzodiazepines or cocaine is also described when ketamine is abused, which is also in line with the collected data. The extremely high concentration of ketamine (approx. 3800 ng/mL) in one case from the present case series, might allow the supposition that the recorded impairments are most likely due to ketamine consumption, although cocaine and its metabolite benzoylecgonine (BE) were also detected in moderate concentrations (cocaine = 32 ng/mL, BE = 729 ng/mL) as well. However, a decent distinction of the impairments is not possible. The presented case series provides additional data on psychomotor impairments observed in DUID cases after the consumption of ketamine, although the results have to be regarded critically due to co-consumption of other substances and the limited case number. Nevertheless, correlation between existing literature data could be observed. Since the abuse of ketamine has increased in the past years, those data can support the assessment of cases, where ketamine abuse is in question.

Postmortem investigation of more than 100 consecutive autopsy cases in femoral blood, cardiac blood, brain tissue and muscle tissue

Drug concentrations in peripheral blood are most often used in interpretation of toxicological results in postmortem cases. However, peripheral blood is not always available or suitable for analysis, especially in advanced stages of decomposition. Therefore, other matrices than peripheral blood need to be investigated in order to reveal the cause of death. However, there is no obvious second choice. In this study, we analyzed postmortem femoral blood, cardiac blood, brain tissue and muscle tissue in order to investigate if drug concentrations in these alternative matrices were comparable to femoral blood and thereby useful for toxicological interpretation. A total of 104 consecutive autopsies where toxicological investigation was included were performed in a four-month period. Femoral blood ( n = 89), cardiac blood ( n = 85), brain tissue ( n = 91) and muscle tissue ( n = 104) were analyzed in all cases when available. Quantification of 69 common drugs and metabolites of toxicological interest was performed with four different multi-analyte methods all employing automated sample preparation and UHPLC MS/MS in MRM mode. In 104 autopsy cases, we were able to detect a total of 53 drugs and metabolites. Alternative matrix to femoral blood concentration ratios were calculated for 47 analytes for cardiac blood, 49 analytes for brain tissue and 50 analytes for muscle tissue, respectively. However, about half of the analytes were only detected in < 5 cases. Median ratios of analytes detected in ≥ 5 cases were determined to 0.59–1.9 (median = 1.1) for cardiac blood to femoral blood, 0.57–2.5 (median = 1.5) for brain tissue to femoral blood and 0.67–7.0 (median = 1.4) for muscle tissue to femoral blood. The largest deviation in ratios was observed for THC in muscle tissue. Here muscle tissue to femoral blood ratios varied from 2.3 to 20 with a median of 7.0 ( n = 10). It is, however, a well-known fact that quantitative analysis of THC in muscle tissue is challenging, which our data also support. We therefore recommend that THC in muscle tissue should be reported as “detected” instead of a concentration. Analysis of postmortem cardiac blood, brain tissue and muscle tissue revealed that concentrations were not directly comparable to those of femoral blood. However, 85% of the median ratios of alternative matrix to femoral blood of analytes detected in ≥ 5 cases, where in the range 0.5–2.0, and were therefore not markedly different. This demonstrates that interpretation of postmortem concentration in other matrices than femoral blood can be challenging and must be performed with caution.

MWCNTs-CTAB and HFs-Lac Nanocomposite-Modified Glassy Carbon Electrode for Rutin Determination.

Rutin is a flavonoid glycoside compound, which is mainly transported via the blood circulation system in the human body. The monitoring of the blood concentration of rutin is of great significance in many fields such as pharmacology and pharmacokinetics. In this work, a biosensor based on multi-walled carbon nanotubes (MWCNTs), cetyltrimethylammonium bromide (CTAB), hydroxyl fullerenes (HFs), and laccase (Lac) nanocomposite-modified glassy carbon electrodes was constructed. The modified materials were characterized with a transmission electron microscope (TEM), cyclic voltammograms (CV), and electrochemical impedance spectroscopy (EIS). CTAB is used to disperse MWCNTs and improve hydrophilicity and biocompatibility of MWCNTs, while the use of Lac can enhance the oxidation of catechol structure in rutin, thus significantly improving the sensitivity and selectivity of the modified electrode. Linear sweep voltammetry (LSV) studies showed that the determination linear ranges of rutin were 0.1 µmol L−1 to 2 µmol L−1 and 2 µmol L−1 to 11 µmol L−1, with the determination limits of 30 nmol L−1 and 95.5 nmol L−1, respectively. The proposed biosensor can be used to detect rutin tablets and serum samples with high recovery, which indicates a good accuracy of this method, and the results are consistent with those measured by the traditional ultra-high performance liquid chromatography (UHPLC) method. Hence, this biosensor has potential practical application value in rutin drug quality testing and clinical blood drug concentration monitoring.

Current Aspects of Pediatric Pharmacokinetics and Pharmacodynamics of Antimicrobials in Japan: Importance of the Promotion of Population PK/PD Analysis.

Pharmacologic knowledge is important for pediatricians conducting feasible pharmacokinetic or pharmacodynamic (PK/PD) studies or applying effective antimicrobial therapies in children. Because of the difficulties in conducting PK/PD studies in children, antimicrobial PK/PD data in children are still limited. To fill in the lack of knowledge, promotion of population PK/PD analysis, which allows us to handle sparse sampling data from individual patients, is important because it is considered a suitable methodology to conduct PK/PD studies in children with limited blood drug concentration data for PK/PD analysis. Population PK/PD analysis is also useful in the clinical setting to provide individualized optimal dosage for each patient with various conditions. Here we summarized the current aspects of pediatric PK/PD studies of antimicrobials in Japan from clinical and research perspectives, specifically focusing on the importance of population PK/PD analysis.

Characterization and HPLC Method Validation for Determination of Dopamine Hydrochloride in Prepared Nano Particles and Pharmacokinetic Application

The emotional control monoamines neurotransmitter catecholamine group of chemicals is dopamine. It has been described and recognized that a lack of dopamine containing neurons contributes to neurological issues, such as Parkinsonism. Due to the incapability of dopamine HCl to cross the blood brain barrier, the advanced novel drug delivery of dopamine HCl is performed in the form of nano structure lipid carrier system (NLC-DOPA) to bypass the blood brain barrier using intranasal route of administration with improved compliance bioavailability and less side effect. The NLC-DOPA was prepared by the high pressure homogenizer ultra-probe sonicator and characterized by the particle size analyzer, zeta potential, transmission electron microscopy (TEM) and X-Ray diffraction (XRD). The determination of dopamine hydrochloride in formulation was evaluated by drug entrapment efficiency further it is validated by analytical method development using high performance liquid chromatography (HPLC) with C18 ODS column and 0.05 M KH2PO4 buffer pH 2.5 and Methanol (90:10) along with retention time 4.872 min at 280 nm wavelength. The method was validated for dopamine HCl in formulation with linearity, precision and recovery analysis. The study was shown that method was easy, rapid, accurate, specific and precise for quality analysis of dopamine HCl in NLC-DOPA formulation. The validated method of HPLC was further used for the biological application in term of the pharmacokinetic study to find out the concentration of drug in blood as well as brain. The pharmacokinetic parameters were calculated with help of the software PK solver 2.0 to determine the maximum concentration (Cmax), Maximum time (Tmax), Elimination half life (t1/2), Area under the curve (AUC0-t), volume of distribution (Vz/F_obs) and Clearance (Cl/F_obs) of all groups of animals (n=3). The study showed that the NLC-DOPA was producing a sustained and controlled release in appropriate amount of drug through intranasal bypass delivery into brain.

Dual sustained-release PTMC/PCL porous microspheres for lipid-soluble drugs

It is still a considerable research challenge to design biodegradable drug delivery systems that efficiently transport lipid-soluble drugs with controlled release. In the present study, a microsphere delivery system, γ-cyclodextrin (γ-CD)/glutathione (GSH)-atorvastatin (AT) fibrous nanoparticles (γ-CD/GSH-AT FNs) loaded polytrimethylene carbonate (PTMC)/polycaprolactone (PCL) microspheres (PTMC/PCL/γ-CD/GSH-AT MPs), was constructed through an exquisite method. The results show that a large number of γ-CD/GSH-AT FNs can be encapsulated during the formation of microspheres and released in a controllable manner. Notably, the high dispersibility and drug loading of FNs can load with lipid-soluble drugs and protect the drugs from the solvent during microsphere preparation. FNs and MPs can achieve dual release. First, with the degradation of the microspheres, the encapsulated FNs were gradually released into the local microenvironment. Subsequently, the FNs began to dissolve and release the loaded AT over a period of more than 3 days. Therefore, the dual sustained-release drug delivery system can maintain the blood drug concentration for a longer time and reduce the number of administrations and the side effects of the drug. This study provides new ideas for the on-demand manufacture of controllable degradable drug delivery platforms to treat diseases.

Analysis of dried blood spots is a feasible alternative for detecting ephedrine in doping control.

Dried blood spot (DBS) testing allows fast, easy and minimally invasive collection of microvolumes of blood. In an anti-doping context, DBS testing has particular relevance for substances prohibited in-competition only such as ephedrine, which is currently detected by urine analysis, because DBS can add information about the blood drug concentrations during the in-competition period. Several collection methods and devices exist for DBS collection from different anatomical sites. Thus, agreements between concentrations of target analytes in DBS samples from different sampling sites, along with between DBS and those in conventional venous plasma samples, need to be evaluated. Herein, we collected matched upper-arm DBS, fingerprick DBS and venous plasma samples from eight healthy male subjects in an 8-h period following oral administrations of 20 mg ('low dose') and 60 mg ('high dose') of ephedrine. We show that the use of alternative sampling sites and matrices is a feasible possibility for ephedrine analysis in doping control. We observed very good agreement between collection sites and that specificity and sensitivity can be upheld despite use of an alternative collection site. However, potential concentration differences between DBS and venous plasma should be considered, and distinct threshold might be necessary if implementing both blood matrices in ephedrine analysis.

Ustekinumab during pregnancy and lactation: drug levels in maternal serum, cord blood, breast milk, and infant serum

BackgroundPatients with ulcerative colitis (UC) may be concerned about medication safety during preconception, pregnancy, and lactation, and they should be closely followed up to ensure that UC activity is controlled during the perinatal period. Reported information on the safety of ustekinumab during pregnancy and lactation is limited. In this case report, we examined the safety of ustekinumab in a fetus and breastfed infant with reference to drug concentrations in maternal serum, cord blood, breast milk, and infant serum.Case presentationA 36-year-old female who developed hematochezia and was diagnosed with ulcerative colitis at age 24 was pregnant with her first child. During pregnancy she was treated with subcutaneous bimonthly ustekinumab, at a dose of 90 mg, until 29 weeks of gestation. Her ulcerative colitis symptoms remained in remission. At 38 weeks of gestation she underwent cesarean section and delivered a healthy female infant weighing 3043 g and with no congenital malformations. The infant received routine vaccinations with no adverse events. Ustekinumab treatment was resumed at 7 weeks postpartum.The ustekinumab concentration in maternal serum at 12 days after injection (30.7 weeks of gestation) was 7968.5 ng/mL, and it decreased to 106.1 ng/mL at 114 days after the last dose. In cord blood, the ustekinumab concentration was 1131.2 ng/mL at 65 days after the last dose; this was 2.5 times higher than that in the maternal serum, which was consistent with a previous report. Ustekinumab was detected in infant serum collected at 71 days after the last maternal dose (299.0 ng/mL), with rapid elimination from the infant’s body. In breast milk, the maximum ustekinumab concentrations were 13.6 ng/mL at 9 days after the last maternal dose, respectively. The ratio of the calculated areas under the time-concentration curves of ustekinumab in breast milk and maternal serum was 0.0008 (257.1/327632.7), which was comparable with a previous human study.ConclusionThe placental transfer and breast milk secretion of ustekinumab in our case were comparable with previous reports. Use of ustekinumab during pregnancy and lactation was feasible in this case. Further research is needed to clarify the safety of ustekinumab during pregnancy and lactation.

New Insight Concerning Therapeutic Drug Monitoring-The Importance of the Concept of Psychonephrology.

Recently, the concept of psychonephrology was developed and has been recognized as a field of study that focuses on nephrology and mental health fields, such as psychiatry and psychosomatic medicine. Indeed, patients with chronic kidney disease frequently suffer from mental problems as the disease stage progresses. Most psychotropic drugs are hepatically metabolized, but some are unmetabolized and eliminated renally. However, renal disease may affect the pharmacokinetics of many psychotropic drugs, as the decreased renal function not only delays the urinary excretion of the drug and its metabolites but also alters various pharmacokinetic factors, such as protein-binding, enterohepatic circulation, and activity of drug-metabolizing enzymes. Therefore, when prescribing drug therapy for patients with both renal disease and mental issues, we should consider reducing the dosage of psychotropic drugs that are eliminated mainly via the kidney and also carefully monitor the blood drug concentrations of other drugs with a high extrarenal clearance, such as those that are largely metabolized in the liver. Furthermore, we should carefully consider the dialyzability of each psychotropic drug, as the dialyzability impacts the drug clearance in patients with end-stage renal failure undergoing dialysis. Therapeutic drug monitoring (TDM) may be a useful tool for adjusting the dosage of psychotropic drugs appropriately in patients with renal disease. We herein review the pharmacokinetic considerations for psychotropic drugs in patients with renal disease as well as those undergoing dialysis and offer new insight concerning TDM in the field of psychonephrology.

Dried Blood Spots as Matrix for Evaluation of Valproate Levels and the Immediate and Delayed Metabolomic Changes Induced by Single Valproate Dose Treatment

The immediate and delayed metabolic changes in rats treated with valproate (VPA), a drug used for the treatment of epilepsy, were profiled. An established approach using dried blood spots (DBS) as sample matrices for gas chromatography/mass spectrometry-based metabolomics profiling was modified using double solvents in the extraction of analytes. With the modified method, some of the previously undetectable metabolites were recovered and subtle differences in the metabolic changes upon exposure to a single dose of VPA between males and female rats were identified. In male rats, changes in 2-hydroxybutyric acid, pipecolic acid, tetratriacontane and stearic acid were found between the control and treatment groups at various time points from 2.5 h up to 24 h. In contrast, such differences were not observed in female rats, which could be caused by the vast inter-individual variations in metabolite levels within the female group. Based on the measured DBS drug concentrations, clearance and apparent volume of distribution of VPA were estimated and the values were found to be comparable to those estimated previously from full blood drug concentrations. The current study indicated that DBS is a powerful tool to monitor drug levels and metabolic changes in response to drug treatment.

Diagnostic Accuracy of Therapeutic Drug Monitoring During Tuberculosis Treatment.

Patients with tuberculosis (TB) coinfected with HIV are more likely to have low blood concentrations of the first‐line anti‐TB drugs (associated with poor outcomes). Therapeutic drug monitoring (TDM) is recommended for certain patient populations with TB at increased risk for a poor outcome. Our objective was to estimate the diagnostic accuracy of a 2‐hour TDM serum sample for the first‐line anti‐TB drugs among patients with HIV/TB and evaluate the information gained by an additional 6‐hour sample. We created a virtual (n = 1000) HIV/TB patient population and performed pharmacokinetic simulations using published population models for isoniazid, rifampin, pyrazinamide, and ethambutol. We performed receiver operating characteristic analysis to compare the diagnostic performance of a single 2‐hour serum sample with samples obtained at 2 and 6 hours after dosing. The sensitivity of a single 2‐hour serum concentration to identify patients with HIV/TB with adequate serum exposures was lowest for rifampin (54.9%; 95%CI, 50.79%‐59.41%) and highest for ethambutol (70.8%; 95%CI, 66.06%‐72.61%) for maximum concentration (Cmax) targets. Diagnostic accuracy of a single 2‐hour serum sample for the area under the concentration‐time curve (AUC) from time 0 to 24 hours target was highest for isoniazid (93%; 95%CI, 90.9%‐94.1%) and lowest for pyrazinamide (66.3%; 95%CI, 62.6%‐70.0%). In summary, the diagnostic performance of TDM for Cmax and AUC from time 0 to 24 hours targets demonstrated variability across the first‐line anti‐TB drugs. The addition of a 6‐hour serum sample led to the highest statistically significant improvement (P < .001) and highest increase in diagnostic accuracy (area under the receiver operating characteristic curve) for rifampin for Cmax and AUC. The other first‐line drugs had modest/negligible increases in diagnostic accuracy.

Risk factors for development of hematotoxicity in elderly patients treated with Linezolid

Objective: To analyze the clinical data, especially the occurrence of hematotoxicity, of hospitalized elderly patients who took Linezolid (LZD), and to further explore the related risk factors. Methods: Our study enrolled the elderly inpatients treated with linezolid at the Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School from January 2018 to September 2021. The hospital information system data were retrieved to retrospectively analyze the clinical characteristics of patients, particularly the clinical characteristics and related risk factors of patients who experienced hematotoxic reactions to LZD. Results: Of the 233 eligible cases included, 103 patients received empirical use of LZD (44.21%). The total effective rate was 76.39% (178/233). Among the 57 effective cases who received blood drug concentration monitoring, the trough concentration of LZD was high in 36.84 % (21/57) of elderly patients. Moreover, there were 15 patients with thrombocytopenia alone, 3 patients with decreased hemoglobin (HB) alone, and 3 patients with both thrombocytopenia and HB decrease. The patients who experienced hematotoxicity (developed a certain degree of hemoglobin decrease and/or thrombocytopenia) were more likely to be complicated with renal impairment (χ²=6.642, P=0.036), concomitantly using proton pump inhibitor (PPI) (χ²=4.566, P=0.033), and had a longer course of LZD treatment (P=0.041). There was no linear correlation between the trough concentration of LZD and glomerular filtration rate evaluated by Modification of Diet in Renal Disease Formula (eGFRMDRD) (R=0.226, P=0.136). Conclusions: The elderly patients, especially those with renal impairment, concomitant treatment with PPI, and a longer course of LZD treatment, exhibited a higher risk of hematotoxicity during LZD treatment. Hence, we should strengthen the protection of renal function, reduce drug interaction, and dynamically monitor the blood drug concentration of LZD to adjust its dose, thus implementing safer and more effective treatments.

Atomic Force Microscopy Application for the Measurement of Infliximab Concentration in Healthy Donors and Pediatric Patients with Inflammatory Bowel Disease.

The use of infliximab has completely changed the therapeutic landscape in inflammatory bowel disease. However, despite its proven efficacy to induce and maintain clinical remission, increasing evidence suggests that treatment failure may be associated with inadequate drug blood concentrations. The introduction of biosensors based on different nanostructured materials for the rapid quantification of drugs has been proposed for therapeutic drug monitoring. This study aimed to apply atomic force microscopy (AFM)-based nanoassay for the measurement of infliximab concentration in serum samples of healthy donors and pediatric IBD patients. This assay measured the height signal variation of a nanostructured gold surface covered with a self-assembled monolayer of alkanethiols. Inside this monolayer, we embedded the DNA conjugated with a tumor necrosis factor able to recognize the drug. The system was initially fine-tuned by testing known infliximab concentrations (0, 20, 30, 40, and 50 nM) in buffer and then spiking the same concentrations of infliximab into the sera of healthy donors, followed by testing pediatric IBD patients. A good correlation between height variation and drug concentration was found in the buffer in both healthy donors and pediatric IBD patients (p-value < 0.05), demonstrating the promising use of AFM nanoassay in TDM.

A Comparison of High Drug Concentrations in Impaired Driving and Postmortem Casework in Harris County, TX.

Drug-impaired driving is a growing public safety issue. Addressing impairment due to drugs other than ethanol can be challenging for forensic toxicologists as many factors need to be considered including the type of drug(s), drug-drug interaction, the dose(s) and the individual's physiological condition and drug use history. Interpretation of blood drug test results is additionally difficult as drug concentrations in impaired driving cases may overlap levels typically viewed as toxic. This study compares blood concentrations of drugs in impaired driving cases to those in postmortem cases in Houston, TX, from 2014 to 2020. Blood drug concentrations from driving while intoxicated (DWI) or driving under the influence of drugs (DUID) cases submitted to Houston Forensic Science Center (HFSC) and Harris County Institute of Forensic Sciences (HCIFS) were compared to postmortem blood test results from HCIFS. Eight DWI/DUID cases had drugs that exceeded impaired driving concentrations reported in the literature. These drugs included fentanyl (220 ng/mL), oxycodone (680 ng/mL), hydrocodone (310 and 490 ng/mL), clonazepam (330 ng/mL), methamphetamine (3,500 and 7,100 ng/mL) and tetrahydrocannabinol (THC) (160 ng/mL). For oxycodone and hydrocodone, the presented DWI/DUID cases exceeded 91% and 96% of postmortem concentrations, respectively. The 7,100 ng/mL methamphetamine DWI/DUID result was greater than 98% of postmortem cases. The presented DWI/DUID concentrations were higher than all but one postmortem case for clonazepam and higher than all postmortem cases for THC. This study demonstrates that extremely high drug concentrations in DWI/DUID casework blur the line between therapeutic/recreational and toxic concentrations.

A Novel Co-crystallization Technique to enhance the Physicochemical property of BCS Class-II drugs using Efavirenz as a model drug

Pharmaceutical co-crystallization, a novel technique, provides for alteration and tailoring of physicochemical properties of active pharmaceutical ingredients (API) notwithstanding maintaining the intrinsic activity of the drug molecule. In the present work, co-crystals of efavirenz (EFA) were prepared with selected conformers of GRAS (Generally Recognized as Safe) status wise salicylic acid (SA) and benzoic acid (BA) using solution crystallization method to improve its dissolution. The assembly of crystal structure was evaluated by means of fourier transformation infrared spectroscopy (FTIR), x-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), scanning electron microscopy (SEM) and nuclear magnetic resonance (NMR). Saturation solubility and in vitro dissolution studies were further employed to investigate co-crystals. Equilibrium solubility profile of EFA-SA and EFA-BA exhibits an enhancement of 1.60 and 1.29 folds of solubility of efavirenz co-crystals as compared to the pure drug. Pharmacokinetic study performed in rats showed AUC0-∞ for co-crystals formulation was higher (13.15±0.02µg hmL−1) than the pure drug suspension formulation 7.85±0.03µg hmL−1. Statistically, AUC0-t of the co-crystal formulation was significantly higher (p&lt;0.05) as compared to pure drug suspension formulation. Higher amount of drug concentration in blood indicated better systemic absorption of efavirenz from co-crystals formulation as compared to the pure drug suspension formulation.

A complete review on floating drug delivery system

The aim of writing this review on FDDS to focus on the system of floatation to attain gastric retention, or to attain desired concentration of drug in blood or tissues. Today’s condition focus on the formulation of the FDDS. Effervescent FDDS release carbon dioxide gas, thus decreases the density of the system and remain floatable in stomach for a longer period of time and released the drug at slowly conveniently in order to improve bioavailability of drug. The study summarizes the application of the system, factors that affect floating system, mechanism, advantages, disadvantages and preparation.