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The ABCG2 membrane transporter affects bioavailability and milk secretion of xenobiotics and natural compounds, including vitamins such as riboflavin. We aimed to characterize the in vitro and in vivo interaction of ABCG2 with lumichrome, the main photodegradation product of riboflavin, which has proven in vitro anti-cancer activity and a therapeutical role in antibacterial photodynamic therapy as an efficient photosensitizer. Using MDCK-II polarized cells overexpressing murine Abcg2 and human ABCG2 we found that lumichrome was efficiently transported by both variants. After lumichrome administration to wild-type and Abcg2-/- mice, plasma AUC20–120 min was 1.8-fold higher in Abcg2-/- mice compared with wild-type mice. The liver and testis from Abcg2-/- mice showed significantly higher lumichrome levels compared with wild-type, whereas lumichrome accumulation in small intestine content of wild-type mice was 2.7-fold higher than in Abcg2-/- counterparts. Finally, a 4.1-fold-higher lumichrome accumulation in milk of wild-type versus Abcg2-/- mice was found. Globally, our results show that ABCG2 plays a crucial role in plasma levels, tissue distribution and milk secretion of lumichrome potentially conditioning its biological activity. [ABSTRACT FROM AUTHOR]

Importance and objective: Self-reported caffeine consumption has been widely used in research while it may be subject to bias. We sought to investigate the associations between self-reported caffeine consumption and plasma levels of caffeine and its two main metabolites (paraxanthine and theophylline) in the community. Methods: Data from two population-based studies (SKIPOGH1 and 2 (N = 1246) and CoLaus|PsyCoLaus (N = 4461)) conducted in Switzerland were used. Self-reported caffeine consumption was assessed using questionnaires. Plasma levels of caffeine and its metabolites were quantified by ultra-high performance liquid chromatography coupled to a tandem quadrupole mass spectrometer. Results: In both studies, mean log plasma levels of caffeine and its two metabolites were over 6.48 (plasma levels = 652 ng/ml) when no caffeine consumption was reported. Subsequently, nonlinear associations between log plasma levels and self-reported caffeine consumption were observed in SKIPOGH, with a change of the slope at 3–5 cups of espresso per day in SKIPOGH1 but not SKIPOGH2. In CoLaus|PsyCoLaus, increased daily consumption of caffeinated beverages was associated with increased log plasma levels with a change of the slope at 3 cups. In both studies, declared caffeine consumption higher than 3–5 cups per day was not associated with higher plasma levels of caffeine and its metabolites. Conclusion: Self-reports of no or low caffeine consumption and consumption of more than 3–5 cups of coffee should be interpreted with caution, with possible under- or over-estimation. Quantifying plasma levels of caffeine and its metabolites may contribute to a better estimation of caffeine intake. [ABSTRACT FROM AUTHOR]

Objective: Cenobamate is approved by the European Medicine Agency for the treatment of adult patients with epilepsy (PWEs) with ongoing focal-onset seizures despite appropriate treatment with at least two established antiseizure medications. Pivotal trials and post-marketing real-world observational studies suggest high efficacy with unusually high seizure-free rates. The authors sought to investigate the plasma levels of cenobamate under steady-state conditions in seizure-free versus non-responding PWEs, and in PWEs who experienced adverse events versus those who did not. Methods: Blood samples were collected from adult PWEs who were treated with adjunct cenobamate under steady-state conditions. Daily doses, concomitant medications, efficacy, and tolerability were assessed. The plasma cenobamate levels of seizure-free versus non-responding PWEs and between PWEs with and those without clinical adverse events were compared. Results: Samples from 101 PWEs were included. Thirty-six PWEs were seizure-free and 65 were non-responders. In 31 PWEs, adverse events were apparent, whereas in the remaining 70, no tolerability issues were reported. A linear correlation was found between the daily doses (range: 100 mg–400 mg) and the plasma levels (3.8 mg/L–54.6 mg/L). Neither the daily doses nor the plasma levels differed significantly between the investigated subgroups. The main reason for this result was that the individual therapeutic ranges varied widely: seizure freedom and adverse effects were observed alongside low doses and plasma levels in some PWEs. Conversely, there were examples of PWEs who did not respond or who reported no tolerability issues at high doses or plasma levels. Conclusions: To evaluate the individual therapeutic range and to better understand the influence of other drugs in cases where concomitant medications are used, the therapeutic drug monitoring of cenobamate may be useful. A general therapeutic range cannot be defined. [ABSTRACT FROM AUTHOR]

Opioid use disorder (OUD) is a chronic neurobehavioral ailment and is prevalent in pregnancy. OUD is commonly treated with methadone or buprenorphine (BUP). Pregnancy is known to alter the pharmacokinetics of drugs and may lead to changes in drug exposure and response. A simple, specific, and sensitive analytical method for measuring the parent drug and its metabolites is valuable for assessing the impact of pregnancy on drug exposure. A new liquid chromatography–tandem mass spectrometric method that utilized a simple protein precipitation procedure for sample preparation and four deuterated internal standards for quantification was developed and validated for BUP and its major metabolites (norbuprenorphine [NBUP], buprenorphine‐glucuronide [BUP‐G], and norbuprenorphine‐glucuronide [NBUP‐G]) in human plasma. The standard curve was linear over the concentration range of 0.05–100 ng/mL for BUP and NBUP, and 0.1–200 ng/mL for BUP‐G and NBUP‐G. Intra‐ and inter‐day bias and precision were within ±15% of nominal values for all the analytes. Quality controls assessed at four levels showed high recovery consistently for all the analytes with minimal matrix effect. Adequate analyte stability was observed at various laboratory conditions tested. Overall, the developed method is simple, sensitive, accurate and reproducible, and was successfully applied for the quantification of BUP and its metabolites in plasma samples collected from pregnant women in a clinical study assessing BUP exposure during OUD treatment. [ABSTRACT FROM AUTHOR]

Oxytocin is a reproductive hormone implicated in the process of parturition and widely used during labor. Oxytocin is produced within the supraoptic nucleus and paraventricular nucleus of the hypothalamus and released from the posterior pituitary lobe into the circulation. Oxytocin is released in pulses with increasing frequency and amplitude in the first and second stages of labor, with a few pulses released in the third stage of labor. During labor, the fetus exerts pressure on the cervix of the uterus, which activates a feedforward reflex—the Ferguson reflex—which releases oxytocin. When myometrial contractions activate sympathetic nerves, it decreases oxytocin release. When oxytocin binds to specific myometrial oxytocin receptors, it induces myometrial contractions. High levels of circulating estrogen at term make the receptors more sensitive. In addition, oxytocin stimulates prostaglandin synthesis and release in the decidua and chorioamniotic membranes by activating a specific type of oxytocin receptor. Prostaglandins contribute to cervical ripening and uterine contractility in labor. The oxytocin system in the brain has been implicated in decreasing maternal levels of fear, pain, and stress, and oxytocin release and function during labor are stimulated by a social support. Moreover, studies suggest, but have not yet proven, that labor may be associated with long-term, behavioral and physiological adaptations in the mother and infant, possibly involving epigenetic modulation of oxytocin production and release and the oxytocin receptor. In addition, infusions of synthetic oxytocin are used to induce and augment labor. Oxytocin may be administered according to different dose regimens at increasing rates from 1 to 3 mIU/min to a maximal rate of 36 mIU/min at 15- to 40-minute intervals. The total amount of synthetic oxytocin given during labor can be 5 to 10 IU, but lower and higher amounts of oxytocin may also be given. High-dose infusions of oxytocin may shorten the duration of labor by up to 2 hours compared with no infusion of oxytocin; however, it does not lower the frequency of cesarean delivery. When synthetic oxytocin is administered, the plasma concentration of oxytocin increases in a dose-dependent way: at infusion rates of 20 to 30 mIU/min, plasma oxytocin concentration increases approximately 2- to 3-fold above the basal level. Synthetic oxytocin administered at recommended dose levels is not likely to cross the placenta or maternal blood-brain barrier. Synthetic oxytocin should be administered with caution as high levels may induce tachystole and uterine overstimulation, with potentially negative consequences for the fetus and possibly the mother. Of note, 5 to 10 IU of synthetic oxytocin is often routinely given as an intravenous or intramuscular bolus administration after delivery to induce uterine contractility, which, in turn, induces uterine separation of the placenta and prevents postpartum hemorrhage. Furthermore, it promotes the expulsion of the placenta. [ABSTRACT FROM AUTHOR]

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This research studies the dose–plasma level (PL) relationship of second-generation antipsychotics, together with the treatment outcomes achieved, in seriously ill people with schizophrenia. An observational, prospective, one-year follow-up study was carried out with patients (N = 68) with severe schizophrenia treated with paliperidone three-month (PP3M) or aripiprazole one-month (ARIM). Participants were divided into standard-dose or high-dose groups. PLs were divided into "standard PL" and "high PL" (above the therapeutic reference range, TRR) groups. The dose/PL relationship, and severity, hospitalizations, tolerability, compliance, and their relationship with doses and PLs were evaluated. There was no clear linear relationship between ARIM or PP3M doses and the PLs achieved. In half of the subjects, standard doses reached PLs above the TRR. The improvements in clinical outcomes (decrease in clinical severity and relapses) were related to high PLs, without worse treatment tolerability or adherence. All participants remained in the study, regardless of dose or PL. Clinical severity and hospitalizations decreased significantly more in those patients with high PLs. Considering the non-linear dose–PL relationship of ARIM and PP3M in people with severe schizophrenia, PLs above the TRR are linked to better treatment outcomes, without worse tolerability. The need in a notable number of cases for high doses to reach those effective PLs is highlighted. [ABSTRACT FROM AUTHOR]

Purpose: The transthyretin kinetic stabilizer tafamidis, used as a first-line therapy of amyloidosis patients, binds selectively to the transthyretin protein structure and thus prevents its dissociation. The limited information regarding tafamidis application in Glu89Gln amyloidosis patients imposed our research team to determine and evaluate its individual mean plasma levels and their biological variation. Methods: The present cohort study investigated Bulgarian amyloidosis patients, grouped by gender, age, and therapy duration. A total of sixty patients aged 40–75 years and therapy duration up to 9 years were included. A precise and accurate high-performance liquid chromatography method with ultraviolet detection was used for plasma concentration measurement. Results: Mean plasma concentrations were 5.13 ± 2.64 µmol/L and showed low intra-individual (18.50%) and high inter-individual variability (51.43%). No significant difference was observed between tafamidis plasma levels and therapy duration with p = 0.5941 (p < 0.05 considered significant), but a significant positive correlation was found between plasma concentration, gender, and age with obtained results about p-value 0.0001 and 0.0235, respectively. Conclusion: The summary results of the study showed differences that may be based on some specific clinical features of the Glu89Gln mutation. [ABSTRACT FROM AUTHOR]

Aims: By meta-analysing pooled studies and available individual participant data, we aim to provide new insight on olanzapine therapeutic drug monitoring in schizophrenia. Method: We conducted a computerized search of bibliographic databases (Pubmed, Cochrane library, Web of Science and PsycINFO) to identify studies that assessed the relationship between olanzapine plasma concentration and the change in patients’ clinical scores. We investigated this relationship with olanzapine plasma level 12h00 post-intake using a random-effects model. Results: 7 studies were included in the pooled data analysis (781 patients). We found no difference in oral dose between responders and non-responders but a significantly higher concentration of 4.50 µg/L in responders (p

Objectives: Imatinib is the first therapeutic option for the treatment of unresectable or metastatic gastrointestinal stromal tumours. Previous studies have shown an improvement in patient survival rates following the use of imatinib. Nevertheless, adequate plasma concentrations of imatinib are necessary to achieve such improvement in survival and limit the toxicity of the drug. This study aims to analyse the influence of imatinib plasma concentrations on efficacy and safety in the treatment of gastrointestinal stromal tumour. Materials and methods: This descriptive, multicentre study analysed plasma levels of imatinib in patients diagnosed with gastrointestinal stromal tumour in the period 2019–2020. An optimal therapeutic range of 750–1500 ng/mL was established for the patient stratification based on their minimum plasma concentrations measured at the steady state. Results: This study included 11 patients with metastatic disease in total, among whom only 54.5% (n = 6) had a minimum plasma concentrations measured at the steady state value within the therapeutic range. A median progression-free survival of 7.0 months was recorded for those patients with minimum plasma concentrations measured at the steady state < 750 ng/mL, while that median progression-free survival value remained unachieved for the group with minimum plasma concentrations measured at the steady state > 750 ng/mL (p = 0.005). The toxicity rate was 25% and 14.3% for patients with minimum plasma concentrations measured at the steady state > 1500 ng/mL and minimum plasma concentrations measured at the steady state ≤1500 ng/mL, respectively (p = 0.66). Conclusions: The present study aims to describe the correlation between the toxicity and effectiveness of imatinib as a function of minimum plasma concentrations measured at the steady state under routine clinical practice conditions. The results described here show the usefulness of imatinib plasma concentrations monitoring as part of the standard daily routine in our hospitals. [ABSTRACT FROM AUTHOR]

We assessed if there were any sex-related differences in the ability of nicotine to increase plasma corticosterone secretion after single or repeated nicotine administration. For single-dose studies, male and female mice were habituated to the test room for 1 h and injected with saline or nicotine (0.25 or 1 mg/kg, subcutaneously (s.c.)). In repeated-dosing studies, mice were injected with saline or nicotine (1 mg/kg, s.c.) once daily for six days, and, on day 7, received nicotine (1 mg/kg, s.c.). Mice were then euthanized 15 min later, and trunk blood was collected for the measurement of corticosterone, nicotine, and cotinine. Our results showed that saline or nicotine each significantly increased plasma corticosterone levels in both males and females, with a greater response in female mice. Plasma corticosterone levels were increased in male but not female mice after being treated repeatedly compared to single nicotine administration. The level of cotinine, a biomarker of nicotine use, was significantly higher in female than in male mice. Taken together, these novel findings suggest that female mice respond to nicotine and the stress of handling more than male mice and provide for the first-time quantitative data on male-female differences in nicotine-induced elevations of corticosterone and cotinine plasma levels.

BackgroundThe effectiveness of oral emtricitabine (FTC)/tenofovir (TFV) disoproxil fumarate-based HIV pre-exposure prophylaxis (PrEP) depends on adherence. Pharmacologic measures help interpret patterns and predictors of PrEP adherence.SettingWe analyzed data from the subsample of men who have sex with men enrolled in HPTN 067/ADAPT in Bangkok, Thailand, and Harlem, NY, U.S.MethodsAfter a 5-week directly observed therapy period, participants were randomized to daily, time-driven, or event-driven PrEP. Follow-up occurred at weeks 4, 12, and 24 after randomization. Plasma and hair FTC/TFV levels indicated short- and long-term PrEP use, respectively. Electronic pill bottle data (Wisepill) were collected weekly. Pearson correlation coefficients between PrEP use measures were calculated; linear mixed models assessed predictors of plasma and hair drug concentrations.ResultsAmong 350 participants (median age: 31 years, interquartile range: 25-38), 49.7% were from Harlem, half had less than college education, and 21% reported heavy alcohol use. In multivariable models, being enrolled in Harlem, being in non-daily arms, and having less than college education were associated with lower hair FTC/TFV concentrations; heavy alcohol use was associated with higher concentrations. Similar results were found for plasma concentrations by site and arm, but older age and greater number of sex partners were associated with higher concentrations. Hair and plasma FTC/TFV concentrations were moderately correlated with Wisepill data (r ≥ 0.29) across visits.ConclusionsIn HPTN067, plasma, hair, and Wisepill data correlated with one another and served as complementary adherence measures. Site, arm, education, age, alcohol, and sexual behavior influenced patterns of adherence.

Introduction: The addition of imatinib to the therapeutic arsenal for chronic myeloid leukaemia (CML) has changed the natural course of the disease, in such a way that it is now considered a chronic pathology. However, to achieve therapeutic success, it is necessary to reach adequate plasma concentrations to ensure efficacy and safety. In this study, we aimed to evaluate the plasma concentration of imatinib, analysing its influence on effectiveness and safety in patients with CML. Methods: We performed a descriptive, multicentre study in which imatinib plasma levels from patients diagnosed with CML between 2019–2020 were analysed. An optimal therapeutic range of 750–1500 ng/mL was established for the stratification of patients, according to their minimum plasma concentrations measured at steady state (Cssmin). Results: A total of 28 patients were included, of whom only 39.3% (n = 11) showed Cssmin within the therapeutic range. 100% of patients with Cssmin >750 ng/mL achieved an optimal molecular response, while only 50% of patients with Cssmin <750 ng/mL achieved an optimal molecular response (p = 0.0004). The toxicity rate was 36.4% for patients with Cssmin >1500 ng/mL and 5.9% for those with Cssmin <1500 ng/mL (p = 0.039). Conclusions: This study aimed to describe the correlation between the toxicity and effectiveness of imatinib according to its Cssmin in routine clinical practice conditions. Based on our findings, it would be certainly justified to monitor patient plasma concentrations of imatinib on a daily routine basis in our hospitals. [ABSTRACT FROM AUTHOR]

Ethambutol is considered to be safest first-line antitubercular drug, and patient acceptability is rather good in both intensive and continuation phase of the tuberculosis treatment with daily regimen. The important adverse effect associated with ethambutol is optic neuritis, resulting in loss of visual acuity, color vision, and field defects. The incidence of optic neuritis is generally directly proportional to the dose and duration of ethambutol therapy and rarely reported in a low standard dose. Here, we report a case of a 40-year-old female patient with complaints of progressive diminished vision (especially during day time) with a low daily dose (15 mg/kg/day) of ethambutol. She got diagnosed with cervical tuberculous lymphadenitis and was receiving isoniazid, rifampicin, ethambutol, and levofloxacin. In rare instances, ethambutol ocular toxicity may present with cecocentral scotoma. In rare instances, plasma levels are performed. An estimated plasma level of ethambutol was found to be in higher end (5.6 μg/ml) of the reported therapeutic range (2–6 μg/ml). Bilateral retrobulbar neuritis with cecocentral scotoma adverse effect due to ethambutol can be seen in plasma therapeutic range.

The cytoskeletal protein tau is implicated in the pathogenesis of Alzheimer's disease which is characterized by intra-neuronal neurofibrillary tangles containing abnormally phosphorylated insoluble tau. Levels of soluble tau are elevated in the brain, the CSF, and the plasma of patients with Alzheimer's disease. To better understand the causes of these elevated levels of tau, we propose a three-compartment kinetic model (brain, CSF, and plasma). The model assumes that the synthesis of tau follows zero-order kinetics (uncorrelated with compartmental tau levels) and that the release, absorption, and clearance of tau is governed by first-order kinetics (linearly related to compartmental tau levels). Tau that is synthesized in the brain compartment can be released into the interstitial fluid, catabolized, or retained in neurofibrillary tangles. Tau released into the interstitial fluid can mix with the CSF and eventually drain to the plasma compartment. However, losses of tau in the drainage pathwaysmay be significant. The kineticmodel estimates half-life of tau in each compartment (552 h in the brain, 9.9 h in the CSF, and 10 h in the plasma). The kinetic model predicts that an increase in the neuronal tau synthesis rate or a decrease in tau catabolism rate best accounts for observed increases in tau levels in the brain, CSF, and plasma found in Alzheimer's disease. Furthermore, the model predicts that increases in brain half-life of tau in Alzheimer's disease should be attributed to decreased tau catabolism and not to increased tau synthesis. Most clearance of tau in the neuron occurs through catabolism rather than release to the CSF compartment. Additional experimental data would make ascertainment of the model parameters more precise. [ABSTRACT FROM AUTHOR]

Ethambutol is considered to be safest first-line antitubercular drug, and patient acceptability is rather good in both intensive and continuation phase of the tuberculosis treatment with daily regimen. The important adverse effect associated with ethambutol is optic neuritis, resulting in loss of visual acuity, color vision, and field defects. The incidence of optic neuritis is generally directly proportional to the dose and duration of ethambutol therapy and rarely reported in a low standard dose. Here, we report a case of a 40-year-old female patient with complaints of progressive diminished vision (especially during day time) with a low daily dose (15 mg/kg/day) of ethambutol. She got diagnosed with cervical tuberculous lymphadenitis and was receiving isoniazid, rifampicin, ethambutol, and levofloxacin. In rare instances, ethambutol ocular toxicity may present with cecocentral scotoma. In rare instances, plasma levels are performed. An estimated plasma level of ethambutol was found to be in higher end (5.6 μg/ml) of the reported therapeutic range (2–6 μg/ml). Bilateral retrobulbar neuritis with cecocentral scotoma adverse effect due to ethambutol can be seen in plasma therapeutic range. [ABSTRACT FROM AUTHOR]

Background: Progranulin (PGRN), also identified as Precursor cell-derived growth factor (PCDGF), is a glycoprotein that is expressed and released ubiquitously. PGRN is plays a crucial role in regulating cell proliferation, differentiation, and pathological pathways. PGRN overexpression has been noted in many cancers and plays an important role in wound healing. Surgery's impact on PGRN levels is unknown. The aim of this study was to assess the levels of plasma PGRN before during the first month after minimally invasive colorectal resection (MICR) for colorectal cancer (CRC) resection., Methods: CRC patients who were enrolled in a data/plasma bank approved by an Institutional Review Board and underwent MICR for whom adequate plasma samples were available were studied. Blood samples were obtained before surgery and at different time intervals after the operation and late samples were grouped into 7-day blocks and considered as single time points. PGRN levels (pg/mL) were determined in duplicate via ELISA and reported as median and 95% confidence interval (95% CI) values. The paired t -test was used for statistical analysis., Results: Preoperative and 1 or more late postoperative plasma sample were available for 93 MICR CRC patients. The distribution of cancer stages in the final analysis was: stage I accounted for 37% of cases, stage II for 27%, stage III for 32%, and stage IV for 4%. The median preoperative PGRN level was 50.69 pg/mL, 95% CI: 47.71-56.30, n=93. When compared to preoperative levels, significantly elevated (P<0.001) median levels (pg/mL) were noted on postoperative day (POD) 1 (64.78, 95% CI: 60.86-68.83, n=92), POD 3 (69.15, 95% CI: 66.43-74.32, n=85), POD 7-13 (63.93, 95% CI: 59.62-68.35, n=68), and POD 14-20 (68.19, 95% CI: 60.12-73.37, n=26), POD 21-27 (67.38, 95% CI: 60.30-76.65, n=20) and on POD 28-41 (75.13, 95% CI: 54.02-83.16, n=22; P<0.01)., Conclusions: Following surgery for CRC, plasma PGRN levels showed a significant increase compared to baseline levels, persisting for a duration of one month. This initial surge post-operation could potentially be attributed to the transient acute inflammatory response. The elevation observed in weeks 2 and 4 could potentially be attributed to the process of wound healing, as PGRN has been shown to enhance the accumulation of fibroblasts and facilitate angiogenesis within wounds. Additional investigation is warranted., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-24-114/coif). The authors have no conflicts of interest to declare., (2024 AME Publishing Company. All rights reserved.)

The cytoskeletal protein tau is implicated in the pathogenesis of Alzheimer's disease which is characterized by intra-neuronal neurofibrillary tangles containing abnormally phosphorylated insoluble tau. Levels of soluble tau are elevated in the brain, the CSF, and the plasma of patients with Alzheimer's disease. To better understand the causes of these elevated levels of tau, we propose a three-compartment kinetic model (brain, CSF, and plasma). The model assumes that the synthesis of tau follows zero-order kinetics (uncorrelated with compartmental tau levels) and that the release, absorption, and clearance of tau is governed by first-order kinetics (linearly related to compartmental tau levels). Tau that is synthesized in the brain compartment can be released into the interstitial fluid, catabolized, or retained in neurofibrillary tangles. Tau released into the interstitial fluid can mix with the CSF and eventually drain to the plasma compartment. However, losses of tau in the drainage pathways may be significant. The kinetic model estimates half-life of tau in each compartment (552 h in the brain, 9.9 h in the CSF, and 10 h in the plasma). The kinetic model predicts that an increase in the neuronal tau synthesis rate or a decrease in tau catabolism rate best accounts for observed increases in tau levels in the brain, CSF, and plasma found in Alzheimer's disease. Furthermore, the model predicts that increases in brain half-life of tau in Alzheimer's disease should be attributed to decreased tau catabolism and not to increased tau synthesis. Most clearance of tau in the neuron occurs through catabolism rather than release to the CSF compartment. Additional experimental data would make ascertainment of the model parameters more precise.

Background: Calcitonin gene related peptide (CGRP) plays a key role in the pathophysiology of migraine and is therefore considered a potential biomarker for primary headache disorders. The challenge remaining is establishing standardized protocols for its assessment in various extracellular compartments and identifying pathological situations associated with an increase in CGRP. Methods: We performed longitudinal measurements of CGRP plasma levels in 30 volunteers with the diagnosis of episodic migraine with and without aura under controlled circumstances during an induced migraine attack under a hypoxic challenge. Blood samples were collected from a cubital vein and CGRP plasma levels measured using ELISA. Results: CGRP levels varied significantly between the subjects at baseline (15.48-1,889.31 pg/ml) but were neither associated with socio-demographic data nor with headache/migraine frequency or intensity collected before hypoxic exposure. CGRP levels during hypoxia fluctuated around baseline and increased with prolonged hypoxia but did not differ significantly in subjects with migraine or headache compared to those without. However, subjects experiencing migraine without aura showed significantly higher levels than those with aura. Ictal CGRP levels were increased in females, in subjects with a negative family history regarding headaches, in those older than 30 years of age or with a recent headache attack before the experiment (p < 0.05). Conclusion: CGRP plasma levels seemto be highly variable even at baseline inmigraine patients and increased during hypoxic challenge and migraine attacks. This is the first in human longitudinal measurement of peripheral CGRP levels during induced migraine attacks using a highly standardized protocol. [ABSTRACT FROM AUTHOR]

Background: The broad‐spectrum triazole isavuconazole is used for the treatment of invasive aspergillosis and mucormycosis. Data regarding human plasma concentrations in clinical routine of the drug are rare. Objectives: Plasma concentrations of isavuconazole were determined in critically ill ICU patients while considering different patients' characteristics. Methods: Retrospective analysis of isavuconazole plasma concentrations were obtained as part of routine therapeutic drug monitoring (TDM) of ICU patients with invasive aspergillosis or other fungal infections treated with isavuconazole. Plasma levels 0–4 h after last dosing were defined as peak levels (Cmax), those 20–28 h after last dosing as trough levels (Cmin). Results: Overall, 223 isavuconazole levels of 41 patients were analysed, divided into 141 peak levels and 82 trough levels. The overall median Cmax was 2.36 μg/ml (mean 2.43 μg/ml, range 0.41–7.79 μg/ml) and the overall median Cmin was 1.74 μg/ml (mean 1.77 μg/ml, range 0.24–4.96 μg/ml). In total, 31.7% of the Cmin values of the total cohort were below the plasma target concentrations of 1 μg/ml, defined as EUCAST antifungal clinical breakpoint for Aspergillus fumigatus. Both peak and trough plasma levels of isavuconazole were significantly lower among patients with a body mass index (BMI) ≥25. In addition, a significant correlation was observed between isavuconazole trough levels and sepsis‐related organ failure assessment (SOFA) score. Conclusions: This study shows that isavuconazole plasma concentrations vary in critical ill ICU patients. Significantly lower isavuconazole levels were associated with elevated BMI and higher SOFA score indicating a need of isavuconazole TDM in this specific patient population. [ABSTRACT FROM AUTHOR]

Clozapine is the gold standard for treatment-resistant schizophrenia. Serious and even life-threatening adverse effects, mostly granulocytopenia, myocarditis, and constipation, are of great clinical concern and constitute a barrier to prescribing clozapine, thus depriving many eligible patients of a lifesaving treatment option. Interestingly, clozapine presents variable pharmacokinetics affected by numerous parameters, leading to significant inter- and intra-individual variation. Therefore, therapeutic drug monitoring of plasma clozapine levels confers a significant benefit in everyday clinical practice by increasing the confidence of the prescribing doctor to the drug and the adherence of the patient to the treatment, mainly by ensuring effective treatment and limited dose-related side effects. In the present systematic review, we aimed at identifying how a full range of adverse effects relates to plasma clozapine levels, using the Jadad grading system for assessing the quality of the available clinical evidence. Our findings indicate that EEG slowing, obsessive-compulsive symptoms, heart rate variability, hyperinsulinemia, metabolic syndrome, and constipation correlate to plasma clozapine levels, whereas QTc, myocarditis, sudden death, leucopenia, neutropenia, sialorrhea, are rather unrelated. Rapid dose escalation at the initiation of treatment might contribute to the emergence of myocarditis, or leucopenia. Strategies for managing adverse effects are different in these conditions and are discussed accordingly. [ABSTRACT FROM AUTHOR]

BackgroundCalcitonin gene related peptide (CGRP) plays a key role in the pathophysiology of migraine and is therefore considered a potential biomarker for primary headache disorders. The challenge remaining is establishing standardized protocols for its assessment in various extracellular compartments and identifying pathological situations associated with an increase in CGRP.MethodsWe performed longitudinal measurements of CGRP plasma levels in 30 volunteers with the diagnosis of episodic migraine with and without aura under controlled circumstances during an induced migraine attack under a hypoxic challenge. Blood samples were collected from a cubital vein and CGRP plasma levels measured using ELISA.ResultsCGRP levels varied significantly between the subjects at baseline (15.48–1,889.31 pg/ml) but were neither associated with socio-demographic data nor with headache/migraine frequency or intensity collected before hypoxic exposure. CGRP levels during hypoxia fluctuated around baseline and increased with prolonged hypoxia but did not differ significantly in subjects with migraine or headache compared to those without. However, subjects experiencing migraine without aura showed significantly higher levels than those with aura. Ictal CGRP levels were increased in females, in subjects with a negative family history regarding headaches, in those older than 30 years of age or with a recent headache attack before the experiment (p < 0.05).ConclusionCGRP plasma levels seem to be highly variable even at baseline in migraine patients and increased during hypoxic challenge and migraine attacks. This is the first in human longitudinal measurement of peripheral CGRP levels during induced migraine attacks using a highly standardized protocol.

Abstract Introduction Apixaban, a direct factor Xa inhibitor, has been shown to be at least as safe and probably more effective than dalteparin for the treatment of cancer‐associated thrombosis (CAT) as reported in the ADAM‐VTE and Caravaggio studies, which included a low percentage of underweight patients. Lower‐weight–based dosing is supported by cancer‐specific studies such as half‐dose edoxaban in the Hokusai‐VTE cancer trial in individuals weighing 60 kg treated with apixaban 5 mg twice daily, patients weighing ≤60 kg also receiving apixaban 5 mg twice daily, and patients weighing ≤60 kg given half‐dose apixaban (2.5 mg twice daily). Apixaban plasma steady‐state trough levels were determined on a single occasion. Results Mean apixaban plasma trough levels were similar for patients weighing >60 kg on full‐dose apixaban to those weighing ≤60 kg taking 2.5 mg twice daily (mean, 109 ng/dL; 95% confidence interval [CI], 74‐145; standard deviation [SD]: 77.6; and mean,101 ng/dL, 95% CI, 67‐135; SD: 80, respectively). Mean values for low‐weight patients (≤60 kg) on the full 5 mg twice‐daily dosing tended to be higher (mean, 136 ng/dL; 95%CI, 70‐201; SD:114), without statistical significance (P = .22). Conclusions This study supports the rationale for studying weight‐based adjustments in apixaban dosing in prospective studies evaluating safety and efficacy of dose reduction in low‐weight patients with cancer.

24S‐hydroxycholesterol (i.e., cerebrosterol, 24S‐OH‐Chol) is the main form of cholesterol elimination from the brain. Liquid chromatography–tandem mass spectrometry methods were developed for the quantification of the total and unesterified/unbound fractions of 24S‐OH‐Chol, its monosulfate, monoglucuronide, and diconjugate derivatives (24S‐OH‐Chol‐3sulfate [3S], 24S‐OH‐Chol‐24glucuronide [24G] and 24S‐OH‐Chol‐3S, 24G, respectively) in human plasma. Linearity, precision, accuracy, and extraction recovery were validated within the typical physiological and pathological ranges of concentrations for each compound. The lower limit of quantifications was 2.00, 0.33, 0.26, and 0.74 ng/ml for 24S‐OH‐Chol, 24S‐OH‐Chol‐24G, 24S‐OH‐Chol‐3S, and 24‐OH‐Chol‐3S, 24G, respectively. Extraction recovery values in total and unbound plasma fractions were also analyzed in murine and monkey plasma and varied from 73% in mouse to 113% in cynomolgus monkey. The methods could rapidly (less than 7 min) quantify individual compounds with high sensitivity, accuracy (bias ≤15%), and reproducibility (coefficient of variation [CV] ≤ 17%). Their clinical applications were validated by measuring levels of the 4 compounds in samples from 20 noncholestatic donors, 5 cholestatic patients suffering from primary biliary cirrhosis, and 10 patients suffering from biliary stenosis. Results highlight the abundance of 24S‐OH‐Chol in the total fraction and the abundance of 24S‐OH‐Chol‐3S and 24G in the unbound ones. While the latter strongly accumulate in plasma fractions of cholestatic patients, levels of 24S‐OH‐Chol remained similar to those of healthy donors. Our results indicate that this approach is suitable for monitoring cerebrosterol and its conjugates in large‐scale clinical studies. [ABSTRACT FROM AUTHOR]

Background Venlafaxine is a dual serotonin (5-HT) and norepinephrine reuptake inhibitor. The specific dose at which it begins to efficiently engage the norepinephrine transporter (NET) remained to be determined. Paroxetine is generally considered as a selective 5-HT reuptake inhibitor but exhibits some affinity for NET. Atomoxetine is a NET inhibitor but also has some affinity for the 5-HT reuptake transporter (SERT). Methods This study examined the effects of forced titration of venlafaxine from 75 to 300 mg/d, paroxetine from 20 to 50 mg/d, or atomoxetine from 25 to 80 mg/d in 32 patients with major depressive disorder. Inhibition of SERT was estimated using the depletion of whole-blood 5-HT. Inhibition of NET was assessed using the attenuation of the systolic blood pressure produced by i.v. injections of tyramine. Results All 3 medications significantly reduced 5-HT levels at the initiating regimens: venlafaxine and paroxetine by approximately 60% and atomoxetine by 16%. The 3 subsequent regimens of venlafaxine and paroxetine reduced 5-HT levels by over 90%, but the highest dose of atomoxetine only reached a 40% inhibition. Atomoxetine dose dependently inhibited the tyramine pressor response from the lowest dose, venlafaxine from 225 mg/d, and paroxetine left it unaltered throughout. Conclusion These results confirm that venlafaxine and paroxetine are potent SERT inhibitors over their usual therapeutic range but that venlafaxine starts inhibiting NET only at 225 mg/d, whereas paroxetine remains selective for SERT up to 50 mg/d. Atomoxetine dose dependently inhibits NET from a low dose but does not inhibit SERT to a clinically relevant degree. [ABSTRACT FROM AUTHOR]

Background: The antithrombotic effect of direct oral anticoagulants (DOAC) in specific clinical scenarios is difficult to assess. Objective: This study aimed to evaluate the effect of DOAC on thrombin generation (TG) in relation to their plasma level. Methods: Eighty patients newly started on anticoagulation were included, 20 patients for each DOAC—apixaban, edoxaban, rivaroxaban, and dabigatran. Plasma was sampled before DOAC (baseline), at plasma peak time, 6 and 12 hours after starting DOAC for quantification of drug levels and TG. Results: The baseline TG before DOAC intake showed inter‐individual variability. All DOACs significantly prolonged lag time (LT) and time to peak (TTP), but did not change endogenous thrombin potential (ETP). Anti‐Xa inhibitors but not dabigatran reduced thrombin peak, but the effect of apixaban at plasma peak was less pronounced (factor 1.6). LT and TTP prolongation of dabigatran was lower compared to anti‐Xa inhibitors. All DOACs showed a nonlinear dose‐response relationship, with the greatest antithrombotic effect at lower DOAC plasma levels. The inhibition of TG parameters between baseline and peak was parallel between individual patients but the coefficient of variation of TG was lower compared to drug levels. Conclusion: The antithrombotic effect at DOAC peak plasma level measured by TG depends on the patient‐specific baseline TG level and the drug‐specific inhibition by the particular DOAC. Although peak plasma levels have a high variability, the variation of TG is lower compared to drug levels. Therefore, TG assays may be superior to plasma levels in the assessment of the intensity of anticoagulation. [ABSTRACT FROM AUTHOR]

Vincenzo Russo,1 Andrea Paccone,2 Anna Rago,1 Valeria Maddaloni,3 Dario Iafusco,4 Riccardo Proietti,5 Umberto Atripaldi,3 Antonio D’Onofrio,1 Paolo Golino,1 Gerardo Nigro1 1Chair of Cardiology, University of Campania “Luigi Vanvitelli”- Monaldi Hospital, Naples, Italy; 2Chair of Cardiology, University of Bari “Aldo Moro”, Bari, Italy; 3Chemical Biochemistry Unit, Monaldi Hospital, Naples, Italy; 4Department of Pediatrics, University of Campania “Luigi Vanvitelli”, Naples, Italy; 5Chair of Cardiology, University of Padua, Padua, ItalyCorrespondence: Vincenzo RussoChair of Cardiology, University of Campania “Luigi Vanvitelli”-Monaldi Hospital, Via Leonardo Bianchi, Naples 80126, ItalyTel +39 0817062355Email v.p.russo@libero.itAbstract: We present the case of a 45-year-old man with atrial fibrillation and morbid obesity (weight 128 kg, height 168 cm, BMI 45.4) who was switched from Warfarin 5 mg once daily to Apixaban 5 mg twice daily because he did not achieve at least 60% of the time in therapeutic range. We performed serial determinations of apixaban plasma concentration (at 2, 6, 12, 24 hrs after intake) showing drug levels within reference range, even when the patient lose weight.Keywords: atrial fibrillation, obesity, non-vitamin k oral anticoagulant, plasma levels, apixaban, weight loss

Purpose: The understanding of the role of plasma antioxidant levels in male fertility in the USA is limited. In a secondary analysis of the Males, Antioxidants, and Infertility (MOXI) randomized clinical trial, we sought to determine whether serum levels of vitamin E (α-tocopherol), zinc, and selenium were correlated with semen parameters and couple fertility outcomes. Methods: This study is a secondary analysis of the MOXI clinical trial. The primary endpoints in this secondary analysis include semen parameters, and DNA fragmentation and clinical outcomes including pregnancy and live birth. Analyses were completed using Wilcoxon's rank-sum test and linear regression models. Results: At baseline, the analysis included plasma labs for vitamin E (n = 131), selenium (n = 124), and zinc (n = 128). All baseline plasma values were in the normal ranges. There was no association between selenium, zinc, or vitamin E levels and semen parameters or DNA fragmentation. Baseline antioxidant levels in the male partners did not predict pregnancy or live birth among all couples. Among those randomized to placebo, baseline male antioxidant levels did not differ between those couples with live birth and those that did not conceive or have a live birth. Conclusions: Among men attending fertility centers in the USA, who have sufficient plasma antioxidant levels of zinc, selenium, or vitamin E, no association was observed between vitamins and semen parameters or clinical outcomes in couples with male infertility. Higher levels of antioxidants among men with circulating antioxidants in the normal range do not appear to confer benefit on semen parameters or male fertility. [ABSTRACT FROM AUTHOR]

Background: Human Keratinocyte Growth Factor (KGF) is an FGF family protein produced by mesenchymal cells. KGF promotes epithelial cell proliferation, plays a role in wound healing and may also support tumor growth. It is expressed by some colorectal cancers (CRC). Surgery's impact on KGF levels is unknown. This study's purpose was to assess plasma KGF levels before and after minimally invasive colorectal resection (MICR) for CRC.Aim: To determine plasma KGF levels before and after minimally invasive colorectal resection surgery for cancer pathology.Method: CRC MICR patients (pts) in an IRB approved data/plasma bank were studied. Pre-operative (pre-op) and post-operative (post-op) plasma samples were taken/stored. Late samples were bundled into 7 day blocks and considered as single time points. KGF levels (pg/ml) were measured via ELISA (mean ± SD). The Wilcoxon paired t-test was used for statistical analysis.Results: Eighty MICR CRC patients (colon 61%; rectal 39%; mean age 65.8 ± 13.3) were studied. The mean incision length was 8.37 ± 3.9 and mean LOS 6.5 ± 2.6 days. The cancer stage breakdown was; I (23), II (26), III (27), and IV (4). The median pre-op KGF level was 17.1 (95 %CI: 14.6–19.4; n = 80); significantly elevated (p < 0.05) median levels (pg/ml) were noted on post-op day (POD) 1 (23.4 pg/ml; 95% CI: 21.4–25.9; n = 80), POD 3 (22.5 pg/ml; 95% CI: 20.7–25.9; n = 76), POD 7–13 (21.8 pg/ml; 95% CI: 17.7–25.4; n = 50), POD 14–20 (20.1 pg/ml; 95% CI: 17.1–23.9; n = 33), POD 21–27 (19.6 pg/ml; 95% CI: 15.2–24.9; n = 15) and on POD 28–34 (16.7 pg/ml; 95% CI: 14.0–25.8; n = 12).Conclusion: Plasma KGF levels were significantly elevated for 5 weeks after MICR for CRC. The etiology of these changes is unclear, surgical trauma related acute inflammatory response and wound healing process may play a role. These changes, may stimulate angiogenesis in residual tumor deposits after surgery.

Antipsychotic plasma levels have been extensively used in the assessment of poor treatment response, lack of adherence and adverse events in delusional disorder. It has not been used as an indicator of metabolizer status, to determine whether a delusional disorder patient is a poor, intermediate, or ultra-rapid metabolizer of antipsychotics. Pharmacogenetic probes are, of course, the right method for the latter task, but they are not readily available for clinical use. We report the case of a 46-year-old woman with delusional disorder who developed unexpected adverse effects to treatment with relatively low dose risperidone and poor symptomatic response. Blood level monitoring indicated high levels of risperidone and a high concentration-to-dose ratio, which suggested accumulation of unmetabolized risperidone. Paradoxically, extrapyramidal side effects increased when, after reducing the risperidone dose, 5 mg/day of aripiprazole was added. Consequently, the patient was switched to olanzapine 5 mg/day. Sertraline 150 mg/day was later added for comorbid depression. A complete symptomatic response was achieved. Although other factors may well have been at play, this sequence of events suggests that the patient was a slow metabolizer of CYP2D6, which metabolizes both risperidone and aripiprazole. With pharmacogenetic assessment not available, therapeutic drug monitoring helped clinicians decide on appropriate management.

S(+)‐ibuprofen (S‐IBU) and R(−)‐ibuprofen (R‐IBU) concentrations were measured in 16 neonates with patent ductus arteriosus during a cycle of therapy (three intravenous doses of 10–5–5 mg kg−1 at 24‐h intervals), at the end of the first infusion and 6, 24, 48, and 72 h later. Data were analyzed with a PK model that included enantiomer elimination rate constants and the R‐ to S‐IBU conversion rate constant. The T½ of S‐IBU in the newborn was much longer than in adults (41.8 vs. ≈2 h), whereas the T½ of R‐IBU appeared to be the same (2.3 h). The mean fraction of R‐ to S‐IBU conversion was much the same as in adults (0.41 vs. ≈0.60). S‐IBU concentrations measured 6 h after the first dose were higher than at the end of the infusion in 10 out of 16 cases, and in five cases, they remained higher even after 24 h. This behavior is unprecedented and may be attributable to a rapid R‐to‐S conversion overlapping with a slow S‐IBU elimination rate. In 13 of the 16 neonates, S‐IBU concentrations at 48 and/or 72 h were lower than expected, probably due to the rapid postnatal maturation of the newborn's liver metabolism. [ABSTRACT FROM AUTHOR]

By meta-analysing pooled studies and available individual participant data, we aim to provide new insight on olanzapine therapeutic drug monitoring in schizophrenia. We conducted a computerized search of bibliographic databases (Pubmed, Cochrane library, Web of Science and PsycINFO) to identify studies that assessed the relationship between olanzapine plasma concentration and the change in patients' clinical scores. We investigated this relationship with olanzapine plasma level 12h00 post-intake using a random-effects model. 7 studies were included in the pooled data analysis (781 patients). We found no difference in oral dose between responders and non-responders but a significantly higher concentration of 4.50 µg/L in responders (p < 0.01). Olanzapine concentration above the thresholds identified in each study was associated with response (odd ratio = 3.50, p = 0.0007). We identified that non-responder patients showed greater inter-individual variability than responders. In the individual data analysis (159 patients), we found no relationship between dose and clinical response but an association between plasma level and response in the shape of a parabolic curve. The Receiver Operating Characteristic curve found a threshold of 22.07 µg/L to identify responders (96% sensitivity, 86% specificity) and a threshold of 56.47 µg/L to identify a decreased probability of response. In contrast to oral dose, our work confirmed that plasma olanzapine levels are associated with clinical response and should therefore be used to optimise treatment. We determined a treatment response threshold of 22.07 µg/L and suggest that a concentration above the therapeutic window may result in a decreased response. [Display omitted] [ABSTRACT FROM AUTHOR]

Abstract Background Oxytocin is a key hormone in childbirth, and synthetic oxytocin is widely administered to induce or speed labour. Due to lack of synthetized knowledge, we conducted a systematic review of maternal plasma levels of oxytocin during physiological childbirth, and in response to infusions of synthetic oxytocin, if reported in the included studies. Methods An a priori protocol was designed and a systematic search was conducted in PubMed, CINAHL, and PsycINFO in October 2015. Search hits were screened on title and abstract after duplicates were removed (n = 4039), 69 articles were examined in full-text and 20 papers met inclusion criteria. As the articles differed in design and methodology used for analysis of oxytocin levels, a narrative synthesis was created and the material was categorised according to effects. Results Basal levels of oxytocin increased 3–4-fold during pregnancy. Pulses of oxytocin occurred with increasing frequency, duration, and amplitude, from late pregnancy through labour, reaching a maximum of 3 pulses/10 min towards the end of labour. There was a maximal 3- to 4-fold rise in oxytocin at birth. Oxytocin pulses also occurred in the third stage of labour associated with placental expulsion. Oxytocin peaks during labour did not correlate in time with individual uterine contractions, suggesting additional mechanisms in the control of contractions. Oxytocin levels were also raised in the cerebrospinal fluid during labour, indicating that oxytocin is released into the brain, as well as into the circulation. Oxytocin released into the brain induces beneficial adaptive effects during birth and postpartum. Oxytocin levels following infusion of synthetic oxytocin up to 10 mU/min were similar to oxytocin levels in physiological labour. Oxytocin levels doubled in response to doubling of the rate of infusion of synthetic oxytocin. Conclusions Plasma oxytocin levels increase gradually during pregnancy, and during the first and second stages of labour, with increasing size and frequency of pulses of oxytocin. A large pulse of oxytocin occurs with birth. Oxytocin in the circulation stimulates uterine contractions and oxytocin released within the brain influences maternal physiology and behaviour during birth. Oxytocin given as an infusion does not cross into the mother’s brain because of the blood brain barrier and does not influence brain function in the same way as oxytocin during normal labour does.

Clozapine is the gold standard for treatment-resistant schizophrenia. Serious and even life-threatening adverse effects, mostly granulocytopenia, myocarditis, and constipation, are of great clinical concern and constitute a barrier to prescribing clozapine, thus depriving many eligible patients of a lifesaving treatment option. Interestingly, clozapine presents variable pharmacokinetics affected by numerous parameters, leading to significant inter- and intra-individual variation. Therefore, therapeutic drug monitoring of plasma clozapine levels confers a significant benefit in everyday clinical practice by increasing the confidence of the prescribing doctor to the drug and the adherence of the patient to the treatment, mainly by ensuring effective treatment and limited dose-related side effects. In the present systematic review, we aimed at identifying how a full range of adverse effects relates to plasma clozapine levels, using the Jadad grading system for assessing the quality of the available clinical evidence. Our findings indicate that EEG slowing, obsessive-compulsive symptoms, heart rate variability, hyperinsulinemia, metabolic syndrome, and constipation correlate to plasma clozapine levels, whereas QTc, myocarditis, sudden death, leucopenia, neutropenia, sialorrhea, are rather unrelated. Rapid dose escalation at the initiation of treatment might contribute to the emergence of myocarditis, or leucopenia. Strategies for managing adverse effects are different in these conditions and are discussed accordingly.

Aims: Concern has been raised that treatment with angiotensin‐converting enzyme inhibitors and angiotensin receptor blockers may increase the expression of angiotensin‐converting enzyme 2 (ACE2), which acts as the entry receptor for SARS‐CoV‐2, and lead to an increased risk of death from SARS‐CoV‐2. We aimed to address this concern by evaluating the in vivo relationship of treatment with ACE inhibitors and angiotensin receptor blockers (ARB) with circulating plasma concentrations of ACE2 in a large cohort of patients with established cardiovascular disease (n = 1864) or cardiovascular risk factors (n = 2144) but without a history of heart failure. Methods and results: Angiotensin‐converting enzyme 2 was measured in 4008 patients (median age 68, 33% women, 31% on ACE‐inhibitors, 31% on ARB) using the SOMAscan proteomic platform (SomaLogic Inc, Colorado, USA). Plasma concentration of ACE2 was comparable in 1250 patients on ACE inhibitors (mean 5.99) versus patients without ACE inhibitors (mean 5.98, P = 0.54). Similarly, plasma concentration of ACE2 was comparable in 1260 patients on ARB (mean 5.99) versus patients without ARB (mean 5.98, P = 0.50). Plasma concentration of ACE2 was comparable in 2474 patients on either ACE inhibitors or ARB (mean 5.99) versus patients without ACE inhibitors or ARB (mean 5.98, P = 0.31). Multivariable quantile regression model analysis confirmed the lack of association between treatment with ACE inhibitors or ARB and ACE2 concentrations. Body mass index showed the only positive association with ACE2 plasma concentration (effect 0.015, 95% confidence interval 0.002 to 0.028, P = 0.024). Conclusions: In a large cohort of patients with established cardiovascular disease or cardiovascular risk factors but without heart failure, ACE inhibitors and ARB were not associated with higher plasma concentrations of ACE2. [ABSTRACT FROM AUTHOR]

High-dose methotrexate is a cornerstone agent in the chemotherapeutic treatment of patients with osteosarcoma. However, patients often develop methotrexate-induced toxicities. We aim to identify determinants of methotrexate-induced toxicities in osteosarcoma patients by investigating the relation between drug plasma levels, methotrexate-induced toxicities, and germline variants in genes related to drug absorption, distribution, metabolism, and elimination. A cohort of 114 osteosarcoma patients was genotyped for 1,931 variants in 231 genes using the Drug Metabolism Enzymes and Transporters Plus array. Methotrexate plasma levels and laboratory measurements during and after high-dose methotrexate treatment concerning renal function, liver damage, and myelopoiesis to reflect toxicity outcomes were obtained. One hundred and thirteen patients and a subset of 545 variants in 176 genes passed quality control checks. Methotrexate plasma levels showed associations with creatinine, alanine aminotransferase, and hemoglobin. Genetic variant rs3736599 in the 5’-untranslated region of SULT1E1 was associated with lower 48 hour methotrexate plasma levels [coef -0.313 (95% CI -0.459 – -0.167); p = 2.60 × 10-5]. Association with methotrexate-induced decreased thrombocyte counts was found for two intronic variants in CYP2B6 {rs4803418 [coef -0.187 (95% CI -0.275 – -0.099); p = 3.04 × 10-5] and rs4803419 [coef -0.186 (95% CI -0.278 – -0.093); p = 8.80 × 10-5]}. An association with increased thrombocyte counts was identified for the intronic variant rs4808326 in CYP4F8 [coef 0.193 (95% CI 0.099 – 0.287); p = 6.02 × 10-5]. Moreover, a secondary analysis with a binary approach using CTCAE toxicity criteria resulted in a nominal significant associations (p < 0.05) for two out of three variants (rs4803418 and rs4808326). This is the first study to identify genetic variants in SULT1E1, CYP2B6, and CYP4F8 to be associated with methotrexate pharmacokinetics and toxicities. Validation of these variants in an independent cohort and further functional investigation of variants in the identified genes is needed to determine if and how they affect methotrexate plasma levels and the development of methotrexate-induced toxicities.

We present the case of a 80-year-old man with atrial fibrillation, morbid obesity (weight 123 kg, height 167 cm, BMI 44.1), high clearance of creatinine and pharmacological polytherapy, in which the serial determinations of edoxaban plasma levels help us to choose the appropriate dose.

Abstract Background Ethnicity variation is one of the main factors that may affect drug response in clinical practice. As MTHFR gene affects different transcriptome and proteome which affect the clinical response of drugs. Purpose of the current study was to observe possible variations in plasma levels of carbamazepine monotherapy and seizures’ control in Pakhtun population of Khyber Pakhtunkhwa (KP) in the context of MTHFR (C677T and A1298C) gene polymorphisms. Methods Blood was collected from the epileptic patients treated with carbamazepine monotherapy for the first time following respective oral doses on its steady state concentration after 3 h of morning dose at 3rd and 6th month of the therapy. Plasma carbamazepine levels were determined using reverse phase high performance liquid chromatography after method validation. MTHFR (C677T, AA298C) gene was genotyped. Patients were followed on 3rd and 6th month of the therapy for monitoring of response to carbamazepine therapy. Results Following for 3rd and 6th month of duration of carbamazepine therapy, poor seizure controlled patients were more likely noticed in heterozygous variants (677CT and 1298 AC) of MTHFR gene (P 0.05) difference in the dose and plasma level of carbamazepine among different genotypes of MTHFR (C677T and A1298C) gene. Similarly, the difference in dose and plasma level of carbamazepine was not significant (P > 0.05) in the responder and non-responder people with epilepsy. Conclusion Our study suggests that heterozygous variants of MTHFR (C677T and A1298C) gene are associated with poor seizure control in Pakhtun population of KP despite the fact that plasma level of carbamazepine were found within the therapeutic range.

An increasing amount of data suggests a role of the eye vascular system and oxidative stress in glaucoma pathogenesis. Reports have suggested endothelin-1 (ET-1) and its receptor (ETR-A) as possible glaucoma biomarkers. This study explored the diagnostic and prognostic abilities of ET-1 and ETR-A plasma concentrations in primary open angle glaucoma (POAG). Seventy-five participants were divided into three groups: controls, early and advanced POAG stage, graded by a perimetric visual field test. All of them underwent a standard ophthalmological examination including optical coherence tomography. The statistical analysis showed a significant difference between the ET-1 values in the controls (4.88 ± 1.75 pg/mL) and the glaucoma patients, but lack of statistical significance in the glaucoma severity (early POAG: 6.33 ± 2.38 pg/mL and advanced POAG: 6.34 ± 1.56 pg/mL). The mean ETR-A values were significantly different between the three groups (controls 1209.28 ± 314.48 pg/mL, early POAG: 673.44 ± 283.02 pg/mL and advanced POAG: 992.28 ± 264.22 pg/mL). Two mathematical models were developed concerning the two perimetric indices (MD/PSD) and ETR-A in the early glaucoma group. ETR-A showed a very high diagnostic accuracy. Only ETR-A had significant diagnostic ability for advanced glaucoma after the comparison between the two glaucoma groups. Every 1 pg/mL increase in the ET-1 plasma concentration increased the possibility for early glaucoma changes by 2.124 times, whereas every 1 pg/mL increase in the ETR-A level decreased this possibility by 1%. Our results indicate that ET-1 and ETR-A could be two very good diagnostic parameters for early POAG changes.

High-dose methotrexate is a cornerstone agent in the chemotherapeutic treatment of patients with osteosarcoma. However, patients often develop methotrexate-induced toxicities. We aim to identify determinants of methotrexate-induced toxicities in osteosarcoma patients by investigating the relation between drug plasma levels, methotrexate-induced toxicities, and germline variants in genes related to drug absorption, distribution, metabolism, and elimination. A cohort of 114 osteosarcoma patients was genotyped for 1,931 variants in 231 genes using the Drug Metabolism Enzymes and Transporters Plus array. Methotrexate plasma levels and laboratory measurements during and after high-dose methotrexate treatment concerning renal function, liver damage, and myelopoiesis to reflect toxicity outcomes were obtained. One hundred and thirteen patients and a subset of 545 variants in 176 genes passed quality control checks. Methotrexate plasma levels showed associations with creatinine, alanine aminotransferase, and hemoglobin. Genetic variant rs3736599 in the 5'-untranslated region of SULT1E1 was associated with lower 48 hour methotrexate plasma levels [coef -0.313 (95% CI -0.459 – -0.167); p = 2.60 × 10-5]. Association with methotrexate-induced decreased thrombocyte counts was found for two intronic variants in CYP2B6 {rs4803418 [coef -0.187 (95% CI -0.275 – -0.099); p = 3.04 × 10-5] and rs4803419 [coef -0.186 (95% CI -0.278 – -0.093); p = 8.80 × 10-5]}. An association with increased thrombocyte counts was identified for the intronic variant rs4808326 in CYP4F8 [coef 0.193 (95% CI 0.099 – 0.287); p = 6.02 × 10-5]. Moreover, a secondary analysis with a binary approach using CTCAE toxicity criteria resulted in a nominal significant associations (p < 0.05) for two out of three variants (rs4803418 and rs4808326). This is the first study to identify genetic variants in SULT1E1, CYP2B6 , and CYP4F8 to be associated with methotrexate pharmacokinetics and toxicities. Validation of these variants in an independent cohort and further functional investigation of variants in the identified genes is needed to determine if and how they affect methotrexate plasma levels and the development of methotrexate-induced toxicities. [ABSTRACT FROM AUTHOR]

Background: Oral Factor Xa inhibitors for the prevention of stroke in atrial fibrillation require dose adjustment based on certain clinical criteria, but the off-label use of the reduced doses is common. Methods: Data from an observational registry including patients admitted with acute cerebral ischemia while taking oral Factor Xa inhibitors for atrial fibrillation between April 2016 and December 2018 were investigated. The dose regimen of the Xa inhibitor was classified as "appropriate", "underdosed" and "overdosed" in conformity with the European Medicines Agency labelling. The effect of underdosing on the functional factor Xa plasma level on admission, the clinical stroke severity and the functional outcome after 3 months were investigated. Results: 254 patients with cerebral ischemia while on Factor Xa inhibitors were included. The dose regimen of the Factor Xa inhibitor was appropriate in 166 patients (65%), underdosed in 67 patients (26%) and overdosed in 21 patients (8%). Underdosing was associated with female sex, diabetes mellitus and higher CHA2DS2–Vasc scores. Underdosing independently predicted lower anti-Xa plasma levels on admission [median 69.4 ng/ml (IQR 0.0–121.6) vs. 129.2 ng/ml (65.5–207.2); p < 0.001], was associated with higher NIHSS scores on admission [median 5 (IQR 1–10) vs. 3 (1–7); p = 0.041] and worse functional outcome after 3 months (favorable outcome 26.9% vs. 46.9%; p = 0.025). Conclusion: One in three patients with ischemic stroke during treatment with oral Xa inhibitors used inappropriate dose regimens. Underdosing was associated with lower functional plasma levels, higher clinical stroke severity and worse functional outcome. [ABSTRACT FROM AUTHOR]

The present study evaluated the IL8-251 A/T polymorphism in samples from 74 patients with chronic hepatitis B (HBV), 100 patients with chronic hepatitis C (HCV), and 300 healthy donors (CG). The correlations of this polymorphism with plasma IL-8 and disease stage were calculated. Polymorphisms were identified by real-time PCR. IL-8 was measured by enzyme-linked immunosorbent assay. The IL8-251 A/T genotype was not associated with susceptibility to infection by HBV or HCV. The wild-type allele (A) was associated with higher levels of inflammation (p = 0.0464) and fibrosis scores (p = 0.0016) in the HBV group, representing an increased risk for increased inflammatory activity (OR = 1.84; p = 0.0464) and for high fibrosis scores (OR = 2.63; p = 0.0016). Viral load was higher in HBV patients with polymorphic genotypes (TA and TT) at the IL8-251 A/T polymorphism than in those with the wild-type genotype (p = 0.0272 and p = 0.0464, respectively). Plasma IL-8 was higher among patients infected with HBV or HCV than in the control group (p = 0.0445 and p = 0.0001, respectively). The polymorphic genotype was associated with lower IL-8 than the wild-type genotype in the HBV group (p = 0.0239) and the HCV group (p = 0.0372). The wild-type genotype for IL8-251 A/T and high IL-8 were associated with a worse prognosis for infections; therefore, they may contribute to viral persistence and the development of more severe forms of chronic viral liver diseases.

Background and Purpose Standard operating procedures (SOP) incorporating plasma levels of rivaroxaban might be helpful in selecting patients with acute ischemic stroke taking rivaroxaban suitable for IVthrombolysis (IVT) or endovascular treatment (EVT). Methods This was a single-center explorative analysis using data from the Novel-Oral-Anticoagulants-in-Stroke-Patients-registry (clinicaltrials.gov:NCT02353585) including acute stroke patients taking rivaroxaban (September 2012 to November 2016). The SOP included recommendation, consideration, and avoidance of IVT if rivaroxaban plasma levels were 100 ng/mL, respectively, measured with a calibrated anti-factor Xa assay. Patients with intracranial artery occlusion were recommended IVT+EVT or EVT alone if plasma levels were ≤100 ng/mL or >100 ng/mL, respectively. We evaluated the frequency of IVT/EVT, door-to-needle-time (DNT), and symptomatic intracranial or major extracranial hemorrhage. Results Among 114 acute stroke patients taking rivaroxaban, 68 were otherwise eligible for IVT/EVT of whom 63 had plasma levels measured (median age 81 years, median baseline National Institutes of Health Stroke Scale 6). Median rivaroxaban plasma level was 96 ng/mL (inter quartile range [IQR] 18‒259 ng/mL) and time since last intake 11 hours (IQR 4.5‒18.5 hours). Twenty-two patients (35%) received IVT/EVT (IVT n=15, IVT+EVT n=3, EVT n=4) based on SOP. Median DNT was 37 (IQR 30‒60) minutes. None of the 31 patients with plasma levels >100 ng/mL received IVT. Among 14 patients with plasma levels ≤100 ng/mL, the main reason to withhold IVT was minor stroke (n=10). No symptomatic intracranial or major extracranial bleeding occurred after treatment. Conclusions Determination of rivaroxaban plasma levels enabled IVT or EVT in one-third of patients taking rivaroxaban who would otherwise be ineligible for acute treatment. The absence of major bleeding in our pilot series justifies future studies of this approach.

Endothelin-1 (ET-1) is a potent vasoconstrictor and is considered to have a key role in the regulation of ocular perfusion and glaucoma pathogenesis. High ET-1 and ETA-receptor levels are reported in patients with primary open-angle glaucoma (POAG). We compared the mean plasma ET-1 and ETA-receptor concentration of controls and patients with early and advanced POAG stage, and assessed the correlation with the retinal nerve fibre layer (RNFL) thickness. The study included a total of 75 participants, aged 45–83 years: 25 (controls), 22 (early glaucoma) and 28 (advanced glaucoma). The plasma concentration of ET-1 and ETA-receptor was determined by enzyme-linked immunosorbent assay. The RNFL thickness was evaluated with spectral-domain optical coherence tomography. The mean ET-1 concentration was lower in the control group (4.88 ± 1.75 pg/mL) than in the early and advanced POAG group (6.33 ± 2.38 and 6.34 ± 1.56 pg/mL). Statistically significant difference was found between the mean ET-1 concentrations in controls and glaucoma patients (p = 0.029 – early glaucoma, p = 0.018 – advanced glaucoma), and no significant difference was observed between the two POAG groups (p = 0.998). The mean ETA-receptor concentration was highest in the control group (1209.28 ± 314.48 pg/mL) and the differences between the three groups were significant. Significant relationship was found only between ET-1 and RNFL. This study demonstrated the role of ET-1 in glaucoma pathogenesis based on the observed significant high ET-1 and ETA-receptor plasma levels in POAG patients. A new therapeutical approach needs to be considered in some patients.

Introduction The evaluation of plasma levels of antidepressants may improve the treatment outcome. The aim was to verify adherence and adequacy of administered doses of antidepressants among patients hospitalized for inadequate outpatient therapeutic response. Methods Selective serotonin reuptake inhibitors or venlafaxine plasma levels were assessed on the first day of hospitalization and after 3 days of controlled administration. The patients were considered adherent if the plasma level on admission was within the interval of the minimum and maximum plasma level on the fourth day, expanded by 30%. The adequacy of antidepressant doses used during the outpatient treatment was assessed by comparing the plasma level on the fourth day with the therapeutic reference range. Results Out of 83 patients, 52 (62.7%) were adherent. The plasma levels of antidepressants on the fourth day were found to be within the therapeutic reference range in 35 (43.2%) patients. The same number manifested levels below the therapeutic reference range. In 11 (13.6%) patients, the levels were higher than recommended. No significant difference in rate of adherence was found among individual antidepressants. Conclusion The results show that antidepressant nonresponders are frequently under-dosed or nonadherent. [ABSTRACT FROM AUTHOR]

Abstract This study used a comparative approach to gather clinical information to assess the effect of bovine somatotropin (bST) on follicular dynamics and ovulation in sheep and goats during an interovulatory cycle. The performance of general markers of ovarian function and specific features of follicular dynamics obtained by daily ultrasonography (US) were used to assess the hypothesis that bST, associated with supraphysiological levels of IGF-I, was able to disrupt the follicular dynamics and ovulation in Highlander ewes and Saanen goats. In Exp 1, 15 ewes and 14 goats were estrous-synchronized (P 4 -6 days + PGFα d-6) and then allocated to a bST-treated group (50 and 100 mg, Lactotropin®; n = 5 females each) and to an untreated control group (5 ewes and 4 goats) to assess the activity of bST through plasma IGF-I (RIA). In Exp 2, 12 animals from each species were synchronized. At day 6, they were divided into a bST-group (100 mg in sheep and 50 mg in goats, n = 6 each) and an untreated control group (n = 6 each). Starting at day 6 and up to 22 days after ovulation in sheep and 25 days in goats, each female was subjected to daily US (10 mHz probe) to assess follicular and luteal (CL) dynamics and ovulation. This included assessments of both general ovarian features and specific follicular wave features. Our results showed that bST increased plasma IGF-I by day 3 (p < 0.01) when compared to the control group. Moreover, these concentrations were maintained for at least 10 days in sheep and 10 days in goats before returning to pre-treatment concentrations. Increases in IGF-I after bST doses were similar in terms of a daily and total amount (P > 0.10). Results from Exp.2 indicate that in sheep, bST administration had a subtle inhibitory effect on follicular function. However, bST in goats had a stronger influence, extending the interovulatory cycle (P = 0,034), increasing the number of follicular waves during the period (P = 0.003), and reducing the functional potential of large follicles as measured by their lower follicular diameter (P = 0.02), duration of the follicle waves (P = 0.02), and persistence of follicles after reaching their maximum diameters (P = 0.04). In addition, untreated sheep and goats shared common patterns of terminal follicular development and ovulations characterized by overlapping between follicular waves and ovulations of follicles from different waves, features not seen in cattle. Highlights • bST-depot administration increased plasma concentrations of total IGF-I for 10 days in sheep and goats. • 50 and 100 mg of bST elicited similar IGF-I concentrations in both species. • bST had a subtle inhibitory influence on follicular function in sheep, expressed by an overall follicular underperformance. • The inhibitory influence in goats was stronger and expressed by a more extensive alteration on follicular performance. • Sheep and goat follicular dynamics exhibit overlapping between waves and ovulations of follicles from different cohorts. [ABSTRACT FROM AUTHOR]