Low Plasma Concentrations Research Articles

Physiological Confounders of Blood‐Based Alzheimer’s Disease Biomarkers in Middle‐Aged Asymptomatic Individuals

AbstractBackgroundBlood‐based biomarkers represent a promising tool for Alzheimer’s disease (AD) clinical diagnosis and patient management. However, the identification of physiological factors that may influence their concentration levels in plasma is fundamental to warrant their clinical use, but more data is needed on whether such possible confounders result in clinically relevant changes. Here, we aim to identify physiological confounders of blood‐based AD biomarkers in a middle‐aged asymptomatic population.MethodThe Progression of Early Subclinical Atherosclerosis (PESA) study is a longitudinal study following >4000 asymptomatic middle‐aged individuals. This study included 537 PESA participants, 370 of them with follow‐up data 4.7±0.6 years later. The concentrations of Aβ40, Aβ42, p‐tau181, GFAP and NFL in plasma were quantified using the Simoa pTau‐181 V2 and Neurology 4‐Plex E Advantage Kits. Potential confounders were also measured and included body mass index (BMI), as a proxy of blood volume; creatinine, as of kidney function; and aspartate (AST) and alanine aminotransferase (ALT), as of liver function. Stepwise regression was used to determine which confounders (predictors) are associated with plasma biomarkers (outcomes), adjusting for age, sex and APOE, both cross‐sectionally and in annual change rates (p<0.05). Participants were classified into normal and abnormal, based on standard cut‐off values for all potential confounders. Between‐group differences in plasma biomarkers were sought, and the abnormal group’s fold‐change was calculated.ResultThe studied sample had a mean age of 50.4±4.3 years, 441 were males and 88 APOE‐ε4 carriers (Figure 1). All blood‐based biomarkers but Aβ42/40 were negatively correlated with BMI and positively correlated with creatinine (Figure 2). ALT and AST were associated with Aβ40, Aβ42 and p‐tau181 but with opposite effects. Increases in BMI were associated with a decline in NFL and GFAP, while an increase in AST with a decline in amyloid and tau accumulation in plasma. Abnormally high BMI was associated with lower biomarker plasma concentrations, except for in Aβ42/40, with a maximum fold‐change of ‐12% for GFAP (Figure 3).ConclusionBMI, kidney and liver function are associated with plasma brain biomarkers levels in asymptomatic middle‐aged individuals. However, the magnitude of their effect is minor, with limited impact for their clinical applicability in individual patients.

Non-therapeutic plasma levels in individuals utilizing curcumin supplements in daily life

IntroductionThe spice curcumin and its metabolites are widely used by cancer patients but have not shown proven health benefits in clinical studies, likely due to low plasma concentrations after oral intake. However, public interest in curcumin continues to grow, and companies claim enhanced absorption in their formulations. This study aims to determine if daily oral intake of curcumin leads to sufficient plasma concentrations for health effects. The study was registered in the Dutch Clinical Trial Register with ID NL5931.MethodsWe used a validated HPLC-MS/MS method to measure curcumin and its metabolites in 47 individuals using their own curcumin formulations. Questionnaires assessed other supplement and medication use. Plasma samples were collected before and 1.5 h after intake, analyzing curcumin and metabolite levels with and without β-glucuronidase pretreatment to measure conjugated and unconjugated forms.ResultsPlasma concentrations of curcumin, demethoxycurcumin, bisdemethoxycurcumin and tetrahydrocurcumin, ranged between 1.0 and 18.6 ng/mL. Adding β-glucuronidase resulted in an increase of unconjugated curcumin plasma levels to 25.4 ng/mL; however still significantly below (1000-fold) a plasma concentration that is expected to have a beneficial health effect. The use of adjuvants like piperine did not result in higher curcumin plasma concentrations.DiscussionOur study shows that using oral curcumin supplements still does not result in therapeutic plasma levels. Health care practitioners need to be critical toward the claimed beneficial systemic health effects of current curcumin supplement use by their patients.Clinical Trial Registrationhttps://onderzoekmetmensen.nl/en/trial/25480, NL5931.

Population pharmacokinetic model of rifampicin for personalized tuberculosis pharmacotherapy: Effects of SLCO1B1 polymorphisms on drug exposure

Rifampicin (RIF) exhibits high pharmacokinetic (PK) variability among individuals; a low plasma concentration might result in unfavorable treatment outcomes and drug resistance. This study evaluated the contributions of non- and genetic factors to the interindividual variability of RIF exposure, then suggested initial doses for patients with different weight bands. This multicenter prospective cohort study in Korea analyzed demographic and clinical data, the solute carrier organic anion transporter family member 1B1 (SLCO1B1) genotypes, and RIF concentrations. Population PK modeling and simulations were conducted using nonlinear mixed-effect modeling. In total, 879 tuberculosis (TB) patients were divided into a training dataset (510 patients) and a test dataset (359 patients). A one-compartment model with allometric scaling for effect of body size best described the RIF PKs. The apparent clearance (CL/F) was 16.6% higher among patients in the SLCO1B1 rs4149056 wild-type group than among patients in variant group, significantly decreasing RIF exposure in the wild-type group. The developed model showed better predictive performance compared with previously reported models. We also suggested that patients with body weights of <40 kg, 40-55 kg, 55-70 kg, and >70 kg patients receive RIF doses of 450, 600, 750, and 1050 mg/day, respectively. Total body weight and SLCO1B1 rs4149056 genotypes were the most significant covariates that affected RIF CL/F variability in Korean TB patients. We suggest initial doses of RIF based on World Health Organization weight-band classifications. The model may be implemented in treatment monitoring for TB patients.

Comparative retrospective review of perioperative analgesia using ultrasound-guided programmed intermittent erector spinae plane block for video-assisted thoracoscopic lobectomy

BackgroundThe retrospective cohort study was conducted to estimate the opioid-sparing anesthesia and limited side-effects with ultrasound (US)-guided ESPB using programmed intermittent bolus (PIB) or continuous infusion (CI) and standard opioid-based anesthesia in patients undergoing video-assisted thoracoscopic lobectomy (VATS).MethodsPatients underwent VATS were stratified into either control group or one of the two ESPB groups in a 1:2:2 ratio depending on whether PIB was implemented or not. The primary endpoint was intra- and post-operative opioids consumption over the first 48 h following surgery.ResultsA total of 180 cases were included in the analysis. Cumulative perioperative opioid administration was found to be significantly different between PIB, CI and control group (both p < 0.001), and between PIB and CI group (p = 0.028). More specifically, the mean was 305.30 ± 51.35 mg, 339.68 ± 56.07 mg and 468.91 ± 79.84 mg in PIB, CI and control group. NRS scores at rest across all postoperative times were comparable in two ESPB groups, while significantly lower than control group, however, scores during exercising at postoperative 3, 6, 12 h were significantly lower in PIB group as compared to CI group. A wider anesthetized dermatomes with PIB was observed at 6, 24 and 48 h as opposed to the CI. The mean of levobupivacaine plasma concentration was significantly lower for PIB at postoperative 0.5, 12, 24 and 48 h after initiation than CI. However, local anesthetic toxicity was not observed in any of the two ESPB groups.ConclusionsWhen US-guided ESPB using PIB was performed preoperatively, it contributed to the minimization of intra- and post-operative opioid consumption due to better analgesia with a wider anesthetic dermatome opposed to conventional CI, whereas, it was also associated with lower risk of local anesthetic toxicity because of lower plasma concentration of levobupivacaine.

Hyperglucagonaemia and amino acid alterations in individuals with type 2 diabetes and non-alcoholic fatty liver disease.

Hyperglucagonaemia contributes to the pathophysiology in type 2 diabetes (T2D), but the mechanisms behind the inappropriate glucagon secretion are not fully understood. Glucagon and amino acids are regulated in a feedback loop referred to as the liver-α cell axis. Individuals with non-alcoholic fatty liver disease (NAFLD) appear to be glucagon resistant, disrupting the liver-α cell axis resulting in hyperglucagonaemia and hyperaminoacidaemia. We investigated the associations between circulating glucagon, amino acids, and liver fat content in a cohort of individuals with T2D. We included 110 individuals with T2D in this cross-sectional study. Liver fat content was quantified using 1H magnetic resonance spectroscopy (MRS). Associations between liver fat content and plasma glucagon and amino acids, respectively, were estimated in multivariate linear regression analyses. Individuals with NAFLD (n = 52) had higher plasma glucagon concentrations than individuals without NAFLD (n = 58). The positive association between plasma glucagon concentrations and liver fat content was confirmed in the multivariable regression analyses. Plasma concentrations of isoleucine and glutamate were increased, and glycine and serine concentrations were decreased in individuals with NAFLD. Concentrations of other amino acids were similar between individuals with and without NAFLD, and no clear association was seen between liver fat content and amino acids in the regression analyses. MRS-diagnosed NAFLD in T2D is associated with hyperglucagonaemia and elevated plasma concentrations of isoleucine and glutamate and low plasma concentrations of glycine and serine. Whether NAFLD and glucagon resistance per se induce these changes remains to be elucidated.

Abstract 12564: Safety, Pharmacokinetics, and Lipid Lowering Effects of the Oral, Liver-Targeted Liver X Receptor (LXR) Inverse Agonist TLC-2716 in Healthy Volunteers

Background: The liver X receptors are oxysterol-activated nuclear hormone receptors that regulate cholesterol homeostasis and de novo lipogenesis. TLC-2716 is an oral, liver-targeted inverse agonist of LXRα/β in development for severe hypertriglyceridemia (SHTG) and NASH. Methods: In this randomized, double-blind, placebo (PBO)-controlled Phase 1 study (NCT05483998), healthy subjects (n=8/2 TLC-2716 vs PBO/cohort) received single ascending doses (SAD) of TLC-2716 (0.5, 2, 6, 12, or 20 mg) or multiple ascending doses (MAD) QD for 14 days (0.5, 2, 6, or 12 mg) while fed or 6 mg fasted. Safety, PK, serum lipid parameters by NMR LipoProfile ® , and gene expression in PBMCs were evaluated. Results: The proportion of subjects with adverse events (AEs) was 60% with PBO and 13-50% with TLC-2716 in the SAD cohorts (n=50), and 40% and 13-88%, respectively, in the MAD cohorts (n=50). All AEs were mild except an unrelated, Grade 2 thrombophlebitis in a subject on TLC-2716 2 mg. TLC-2716 was rapidly absorbed (T max 2-4h) with a short steady-state half-life (T 1/2 ~1.5-2.5h) and low maximal plasma concentrations (C max &lt;7 ng/mL), consistent with rapid hepatic uptake. With fed dosing, TLC-2716 AUC and C max increased less than dose proportionally and were 25-50% lower on Day 14 vs Day 1. With fasted dosing, exposures were similar on Days 1 and 14 and ~3-fold higher than with fed dosing. Significant, dose-dependent reductions in serum triglycerides, total and LDL-C, total and small LDL particles, and TG/HDL-C ratio—but not HDL-C—were observed with TLC-2716 ( Figure ). Lipid reductions were greatest in subjects with higher baseline values. TLC-2716 did not impact LXR target gene expression (e.g., reverse cholesterol transporters ABCA1 , ABCG1 ) in PBMCs, supporting its liver-targeted profile. Conclusion: The liver-targeted LXR inverse agonist TLC-2716 was well tolerated and caused significant lipid lowering in healthy subjects, supporting its evaluation in patients with SHTG and NASH.

Quantification of nine bufadienolides of Shexiang Tongxin Dropping Pills in rat plasma and tissues using UPLC-MS/MS and its application to healthy and ischemia-reperfusion rats pharmacokinetic studies

Shexiang Tongxin Dropping Pill (STDP) is a well-known compound preparation used in traditional Chinese medicine for treating cardiovascular diseases. Bufadienolides are the major active compounds of toad venom and are the key to the seven medicinal herbs that comprise STDP. In this study, a reliable and sensitive high-performance liquid chromatography-tandem mass spectrometry method was developed and validated for the quantitative determination of nine bufadienolides (bufalin, gamabufotalin, resibufogenin, marinobufagin, arenobufagin, desacetylcinobufagin, telocinobufagin, hellebrigenin, and hellebrigenol) in rat plasma and tissues (heart and liver). The chromatography column used was a Waters ACQUITY UPLC HSS-T3 column with gradient elution using mobile phase consisting of acetonitrile–water (0.1% formic acid added) at a flow rate of 0.25 mL/min. This method passed the methodological validation of plasma and tissues and was successfully applied to pharmacokinetic and tissue distribution studies after oral administration of STDP in healthy and ischemia-reperfusion (I/R) rats. This indicated that most bufadienolides were well absorbed and quickly distributed in the heart and liver. The area-under-the-curve (AUC)(0−t) of most analytes increased in a dose-dependent manner. Moreover, most of the tested components showed lower plasma and higher tissue concentrations in I/R rats than in healthy rats. The above results on the oral pharmacokinetics and tissue distribution may be helpful for the clinical application of STDP.

A bispecific antibody NXT007 exerts a hemostatic activity in hemophilia A monkeys enough to keep a nonhemophilic state

BackgroundEmicizumab, a factor (F) VIIIa-function mimetic bispecific antibody (BsAb) to FIXa and FX, has become an indispensable treatment option for people with hemophilia A (PwHA). However, a small proportion of PwHA still experience bleeds even under emicizumab prophylaxis, as observed in the long-term outcomes of clinical studies. A more potent BsAb may be desirable for such patients. ObjectivesTo identify a potent BsAb to FIXa and FX, NXT007, surpassing emicizumab by in vitro and in vivo evaluation. MethodsNew pairs of light chains for emicizumab’s heavy chains were screened from phage libraries, and subsequent antibody optimization was performed. For in vitro evaluation, thrombin generation assays were performed with hemophilia A plasma. In vivo hemostatic activity was evaluated in a nonhuman primate model of acquired hemophilia A. ResultsNXT007 exhibited an in vitro thrombin generation activity comparable to the international standard activity of FVIII (100 IU/dL), much higher than emicizumab, when triggered by tissue factor. NXT007 also demonstrated a potent in vivo hemostatic activity at approximately 30-fold lower plasma concentrations than emicizumab’s historical data. In terms of dose shift between NXT007 and emicizumab, the in vitro and in vivo results were concordant. Regarding pharmacokinetics, NXT007 showed lower in vivo clearance than those shown by typical monoclonal antibodies, suggesting that the Fc engineering to enhance FcRn binding worked well. ConclusionNXT007, a potent BsAb, was successfully created. Nonclinical results suggest that NXT007 would have a potential to keep a nonhemophilic range of coagulation potential in PwHA or to realize more convenient dosing regimens than emicizumab.

Albumin and fibrinogen synthesis rates in advanced chronic liver disease.

Synthesis of plasma proteins is an important function of the liver that has sparsely been investigated by modern techniques in patients with advanced chronic liver disease (CLD). Twenty-eight well-characterized patients with CLD under evaluation for liver transplantation were included. Albumin and fibrinogen synthesis rates were measured by the flooding dose technique using stable isotope labelled phenylalanine. Transcapillary escape rate of albumin and plasma volume were assessed by radio-iodinated human serum albumin. The absolute albumin synthesis rates were low (65 mg/kg/day, range 32-203), and associated with impaired liver function, as reflected by the risk-scores Child-Pugh (p = 0.025) and Model for End-stage Liver Disease rs = -0.62, p=0.0005. The fibrinogen synthesis rate (12.8 mg/kg/day, range 2.4-52.9) was also negatively associated with liver function. The synthesis rates of albumin and fibrinogen were positively correlated. Plasma volume was high (51 ± 9 mL/kg body weight), which contributed to an almost normal intravascular albumin mass despite low plasma concentration. Autoimmune inflammatory etiologies to CLD were associated with higher fibrinogen synthesis. De novo synthesis rates of albumin and fibrinogen in advanced chronic liver failure were negatively correlated to prognostic scores of liver disease. Albumin synthesis rate was low and associated with both liver failure and autoimmune inflammation, while fibrinogen synthesis was often normal and positively associated with chronic inflammation. This is different from acute inflammatory states in which both albumin and fibrinogen synthesis rates are high.

Towards optimization of ceftazidime dosing in obese ICU patients: the end of the 'one-size-fits-all' approach?

Ceftazidime is commonly used as a key antibiotic against Pseudomonas aeruginosa in critically ill patients. ICU patients have severely altered and variable antibiotic pharmacokinetics, resulting in lower antimicrobial concentrations and potentially poor outcome. Several factors, including obesity and renal function, may influence pharmacokinetics. Thus, the objective of the study was to evaluate the impact of obesity and renal function on ceftazidime plasma concentrations and dosing regimen in ICU patients. All consecutive adult patients from six ICUs, treated with continuous ceftazidime infusion and under therapeutic drug monitoring evaluation, were included. Obesity was defined as BMI ≥30 kg/m². Glomerular filtration rate (GFR) was estimated by the Chronic Kidney Disease Epidemiology Collaboration formula. The ceftazidime recommended target for plasma concentrations was between 35 and 80 mg/L. A total of 98 patients (45 obese), with an average weight of 90 (±25) kg, were included. Mean GFR was 84.1 (±40.4) mL/min/1.73 m2. Recommended ceftazidime plasma concentrations were achieved for only 48.0% of patients, with median dosing regimen of 6 g/day. Obese patients had lower ceftazidime plasma concentrations compared with non-obese patients (37.8 versus 56.3 mg/L; P = 0.0042) despite similar dosing regimens (5.83 g/day versus 5.52 g/day, P = 0.2529). Almost all augmented renal clearance patients were underdosed despite ceftazidime dosing of 6.6 (±0.8) g/day. Weight-based ceftazidime dosing seemed to attenuate such obesity-related discrepancies, regardless of GFR. Obese ICU patients required significantly greater ceftazidime doses to achieve the target range. A tailored dosing regimen may be considered based on weight and GFR. Future prospective studies should be performed to confirm this individualized dosing approach.

Omega-3 Polyunsaturated Fatty Acid Levels in Maternal and Cord Plasma Are Associated with Maternal Socioeconomic Status.

Omega-3 (n-3) polyunsaturated fatty acids (PUFAs) play a crucial role in fetal growth and neurodevelopment, while omega-6 (n-6) PUFAs have been associated with adverse pregnancy outcomes. Previous studies have demonstrated that socioeconomic status (SES) influences dietary intake of n-3 and n-6 PUFAs, but few studies have evaluated the association between maternal and cord plasma biomarkers of PUFAs and socioeconomic markers. An IRB-approved study enrolled mother-infant pairs (n = 55) at the time of delivery. Maternal and cord plasma PUFA concentrations were analyzed using gas chromatography. Markers of SES were obtained from validated surveys and maternal medical records. Mann-Whitney U tests and linear regression models were utilized for statistical analysis. Maternal eicosapentaenoic acid (EPA) (p = 0.02), cord EPA (p = 0.04), and total cord n-3 PUFA concentrations (p = 0.04) were significantly higher in college-educated mothers vs. mothers with less than a college education after adjustment for relevant confounders. Insurance type and household income were not significantly associated with n-3 or n-6 PUFA plasma concentrations after adjustment. Our findings suggest that mothers with lower educational status may be at risk of lower plasma concentrations of n-3 PUFAs at delivery, which could confer increased susceptibility to adverse pregnancy and birth outcomes.

High-Dose Methylphenidate and Carboxylesterase 1 Genetic Variability in Patients With Attention-Deficit/Hyperactivity Disorder: A Case Series.

Methylphenidate (MPH) is widely used to reduce symptoms of attention-deficit/hyperactivity disorder. Methylphenidate is metabolized by the carboxylesterase 1 (CES1) enzyme. Some patients need a very high dose of MPH to reach desired clinical effects, without having adverse effects. This may be due to differences in MPH pharmacokinetics (PK), potentially caused by DNA variants in CES1 , the gene encoding the enzyme that metabolizes MPH. Here we describe 3 patients requiring high-dose MPH and investigated the CES1 gene. The 3 patients were using short-acting MPH in a dose of 180 to 640 mg instead of the maximum advised dose of around 100 mg MPH in the Netherlands. Plasma concentrations of MPH were determined at scheduled time points (day-curve). Methylphenidate plasma concentrations were used for PK analysis using an earlier published 2-compartment PK population model of MPH. Individual data of the 3 patients were compared with simulated population data, when equivalent doses were used. In addition, CES1 was genotyped (number of gene copies and single nucleotide polymorphisms) using real-time polymerase chain reaction. Pharmacokinetic analysis in all 3 patients showed lower plasma concentrations of MPH in comparison with the population data. The mean absorption time and volume of distribution of the central compartment were equal, but the elimination clearance was higher. However, CES1 genotyping revealed no variations that could explain a higher metabolism of MPH. In these 3 cases, we could not demonstrate a correlation between MPH clearance and known genetic variants of the CES1 gene.

Distribution pattern of UGT1A6 and UGT2B7 gene polymorphism and its impact on the pharmacokinetics of valproic acid and carbamazepine: Prospective genetic association study conducted in Pakistani patients with epilepsy

BackgroundEthnic variation is one of the important factors in clinical practice that may affect the pharmacokinetics of drugs. The present study aims to determine the distribution pattern of UGT1A6 and UGT2B7 gene polymorphism and its possible impact on the metabolism of valproic acid (VPA) and carbamazepine (CBZ) in patients with epilepsy from Khyber Pakhtunkhwa region of Pakistan. Methods: After the enrollment of targeted patients, blood was collected for genotype analysis through Sanger sequencing. Plasma concentrations of VPA and CBZ were determined by reversed-phase high-performance liquid chromatography (HPLC) at the follow-up visit of third month from the initiation of therapy. The drug plasma levels were correlated with different genotypes of UGT1A6 and UGT2B7 to determine the impact of genetic polymorphism on the drug metabolism. Results: Of the total 178 epileptic patients, 120 subjects were prescribed VPA monotherapy while 58 subjects were given CBZ monotherapy. The mean age of the subjects was recorded as 26.1 ± 13.5 years with a predominance of the male gender. Generalized tonic-clonic (GTC) was the most prevalent type of seizure (82%) followed by partial seizure. Genotype analysis revealed that the frequency of homozygous and heterozygous variants of the targeted UGT genes were exceptionally high in the Khyber Pakhtunkhwa population compared to the ethnic groups of other countries. In UGT1A6-A552C and UGT1A6-A541G, AC and AG were the most prevalent genotypes with respective frequencies of 43.2% and 41.1% whereas, in UGT2B7-T161C and UGT2B7-G211T, TC and GG were the most prevalent genotypes with respective frequencies of 42.7% and 99.4%. In the VPA-treated group, the homozygous and heterozygous variants of UGT1A6-A552C and UGT1A6-A541G were significantly associated with lower drug plasma concentrations (p < 0.05). However, none of the genotypes of UGT2B7-T161C revealed any significant association with VPA plasma concentration (p greater than 0.05). In the CBZ-treated group, UGT gene polymorphisms were not recognized to cause alteration in the drug plasma concentrations (p greater than 0.05). Conclusion: The genetic polymorphisms of UGT1A6, but not UGT2B7 significantly affected the plasma levels of valproic acid. The chosen SNPs did not reveal a role in determining the plasma levels of carbamazepine.

Discovery of the Potent and Selective Inhaled Janus Kinase 1 Inhibitor AZD4604 and Its Preclinical Characterization.

JAK-STAT cytokines are critical in regulating immunity. Persistent activation of JAK-STAT signaling pathways by cytokines drives chronic inflammatory diseases such as asthma. Herein, we report on the discovery of a highly JAK1-selective, ATP-competitive series of inhibitors having a 1000-fold selectivity over other JAK family members and the approach used to identify compounds suitable for inhaled administration. Ultimately, compound 16 was selected as the clinical candidate, and upon dry powder inhalation, we could demonstrate a high local concentration in the lung as well as low plasma concentrations, suggesting no systemic JAK1 target engagement. Compound 16 has progressed into clinical trials. Using 16, we found JAK1 inhibition to be more efficacious than JAK3 inhibition in IL-4-driven Th2 asthma.

Association between plasma rituximab concentration and the risk of major relapse in antineutrophil cytoplasmic antibody-associated vasculitides during rituximab maintenance therapy.

Interindividual variability in response to rituximab remains unexplored in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides. Rituximab pharmacokinetics (PK) and pharmacodynamics (PD) as well as genetic polymorphisms could contribute to variability. This ancillary study of the MAINRITSAN 2 trial aimed to explore the relationship between rituximab plasma concentration, genetic polymorphisms in PK/PD candidate genes, and clinical outcomes. Patients included in the MAINRITSAN2 trial (NCT01731561) were randomized to receive a 500 mg fixed-schedule RTX infusion or an individually-tailored regimen. Rituximab plasma concentrations at month 3 (CM3 ) were assessed. DNA samples (n=53) were genotyped for single nucleotide polymorphisms within 88 putative PK/PD candidate genes. The relationship between PK/PD outcomes and genetic variants was investigated using logistic linear regression in additive and recessive genetic models. One hundred and thirty-five patients were included. The frequency of underexposed patients (<4 μg/mL) in the fixed-schedule group was statistically lower compared to that in the tailored-infusion group (2.0% vs. 18.0%; p=0.02, respectively). Low RTX plasma concentration at 3 months (CM3 <4 μg/mL) was an independent risk factor for major relapse (odds ratio=6.56; 95% CI 1.26-34.09; p=0.025) at month 28 (M28). A sensitivity survival analysis also identified CM3 <4 μg/mL as an independent risk factor for major relapse (Hazard ratio [HR] = 4.81; 95% CI 1.56-14.82; p=0.006) and relapse (HR=2.70; 95% CI 1.02-7.15; p=0.046). STAT4 rs2278940 and PRKCA rs8076312 were significantly associated with CM3 but not with major relapse onset at M28. These results suggest that drug monitoring could be useful to individualize the schedule of rituximab administration within the maintenance phase. This article is protected by copyright. All rights reserved.

Improved arterial inflammation with high dose omega-3 fatty acids in patients with elevated lipoprotein(a): Selective effect of eicosapentaenoic acid?

Elevated lipoprotein(a) [Lp(a)] is a causal risk factor for atherosclerotic cardiovascular disease. However, there are no approved and effective treatments for lowering Lp(a) and the associated cardiovascular risks. Omega-3 fatty acids (ω-3FAs), primarily eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), have both triglyceride-lowering and anti-inflammatory properties. This pilot study investigated the effect of high dose ω-3FAs (3.6 g/day) on arterial inflammation in 12 patients with elevated Lp(a) (> 0.5 g/L) and stable coronary artery disease (CAD) receiving cholesterol-lowering treatment. Arterial inflammation was determined using 18F-fluorodexoyglucose positron emission tomography/computed tomography before and after 12-weeks intervention. ω-3FAs significantly lowered plasma concentrations of triglycerides (–17%, p < 0.01), Lp(a) (-5%, p < 0.01) as well as aortic maximum standardized uptake value (SUVmax) (–4%, p < 0.05). The reduction in SUVmax was significantly inversely associated with average on-treatment EPA (r = -0.750, p < 0.01), but not DHA and triglyceride, concentrations. In conclusion, high dose ω-3FAs decrease arterial inflammation in patients with elevated Lp(a) and stable CAD, which may involve a direct arterial effect of EPA.

DOAC plasma concentration upon hospital admission in a cohort of trauma patients. An observational real-life study.

Due to a better safety profile, direct oral anticoagulants (DOACs) are increasingly prescribed for prevention of thromboembolic events. However, little is known about DOAC plasma concentrations in trauma patients upon hospital admission. Thus, we investigated the frequency and extent of DOAC possible over- and underdosing in trauma patients upon hospital admission. In this single-center retrospective study, DOAC plasma concentrations of adult trauma patients were analyzed with specific calibrated anti-IIa (dabigatran) and anti-Xa (apixaban, edoxaban and rivaroxaban) tests within 4h after hospital admission. A total of 210 trauma patients, admitted between 2019 and 2022, were included in the analyses. Low DOAC levels < 30ng/mL were detected in 13.3% of the patients. In 7.1% of the patients, DOAC plasma levels ranged between 300-399ng/mL and further 7.1% exhibited plasma concentrations > 400ng/mL. The highest incidence of high to very high DOAC plasma concentration was observed for patients on rivaroxaban and dabigatran. A moderate correlation was observed between dabigatran plasma concentration and estimated glomerular filtration rate (rho = - 0.5338, p = 0.0003). For rivaroxaban no clear association between plasma concentration and liver or renal function could be detected. Patients on statins had significantly higher DOAC concentration in comparison with those not taking statins (153 (76-274) vs 108 (51-217) ng/mL, p = 0.046). The current study revealed that patients on dabigatran and rivaroxaban were prone to higher DOAC plasma levels upon hospital admission in comparison with apixaban and edoxaban. DOAC plasma level measurement in trauma patients might be warranted due to unpredictively low or high plasma concentrations. However, the clinical impact of altered plasma levels on both, bleeding and thromboembolic events, remains to be determined by future studies.

Association between polymorphisms of IL4, IL13, IL10, STAT6 and IFNG genes, cytokines and immunoglobulin E levels with high burden of Schistosoma mansoni in children from schistosomiasis endemic areas of Cameroon.

Eliminating schistosomiasis as a public health problem by 2030 requires a better understanding of the disease transmission, especially the asymmetric distribution of worm burden in individuals living and sharing the same environment. It is in this light that this study was designed to identify human genetic determinants associated with high burden of S. mansoni and also with the plasma concentrations of IgE and four cytokines in children from two schistosomiasis endemic areas of Cameroon. In school-aged children of schistosomiasis endemic areas of Makenene and Nom-Kandi of Cameroon, S. mansoni infections and their infection intensities were evaluated in urine and stool samples using respectively the Point-of-care Circulating Cathodic Antigen test (POC-CCA) and the Kato Katz (KK) test. Thereafter, blood samples were collected in children harbouring high burden of schistosome infections as well as in their parents and siblings. DNA extracts and plasma were obtained from blood. Polymorphisms at 14 loci of five genes were assessed using PCR-restriction fragment length polymorphism and amplification-refractory mutation system. The ELISA test enabled to determine the plasma concentrations of IgE, IL-13, IL-10, IL-4 and IFN-γ. The prevalence of S. mansoni infections was significantly higher (P<0.0001 for POC-CCA; P=0.001 for KK) in Makenene (48.6% for POC-CCA and 7.9% for KK) compared to Nom-Kandi (31% for POC-CCA and 4.3% for KK). The infection intensities were also higher (P<0.0001 for POC-CCA; P=0.001 for KK) in children from Makenene than those from Nom-Kandi. The allele C of SNP rs3024974 of STAT6 was associated with an increased risk of bearing high burden of S. mansoni both in the additive (p=0.009) and recessive model (p=0.01) while the allele C of SNP rs1800871 of IL10 was protective (p=0.0009) against high burden of S. mansoni. The alleles A of SNP rs2069739 of IL13 and G of SNP rs2243283 of IL4 were associated with an increased risk of having low plasma concentrations of IL-13 (P=0.04) and IL-10 (P=0.04), respectively. This study showed that host genetic polymorphisms may influence the outcome (high or low worm burden) of S. mansoni infections and also the plasma concentrations of some cytokines.

Safety and Pharmacokinetics of PSD502 in Healthy Chinese Male and Female Volunteers: Two Randomized, Double-Blind, Placebo-Controlled, Phase I Trials.

PSD502 is a metered-dose spray for premature ejaculation. The two trials aimed to evaluate the safety and pharmacokinetics of PSD502 in healthy Chinese male and female individuals. Two phase I, randomized, double-blind, placebo-controlled trials were conducted in men (Trial 1) and women (Trial 2). The participants were randomized 3:1 to receive PSD502 (7.5 mg of lidocaine and 2.5 mg of prilocaine per spray) or a placebo. For male individuals, a single dose (three sprays) once daily was applied to the glans penis for 21 days except for nine sprays (three doses) on days 7 and 14, 4 h apart for each dose. For female individuals, two sprays were applied to the vagina and one to the cervix once daily for 7 days. The primary endpoint was safety. Pharmacokinetics analysis was also performed. Twenty-four male and 24 female individuals were recruited. Treatment-emergent adverse events occurred in 38.9% (7/18) of male individuals and 66.7% (12/18) of female individuals in the PSD502 group, respectively. Both trials reported 50.0% (3/6) treatment-emergent adverse events for the placebo. No grade ≥ 3 treatment-emergent adverse events, serious adverse events, or treatment-emergent adverse events leading to early withdrawal or discontinuation occurred. After consecutive applications, lidocaine and prilocaine cleared rapidly in both trials. Plasma concentrations exhibited high inter-individual variability. The maximum plasma concentrations of active ingredients were far below the anticipated minimum toxic concentrations. The area under the plasma concentration-time curve of metabolites were ≤ 20% of the parent drugs. No clinically significant accumulations were observed in the two trials. PSD502 was well tolerated and showed low plasma concentrations in healthy Chinese male and female individuals.

Depressive symptoms, low-grade inflammation, and poor oral health prevents the success of nutritional guidance in older caregivers

The present study aimed to determine which factors prevents the success of nutritional interventions for older family caregivers (FCs), in the form of individually tailored nutritional guidance. The present study focuses on the intervention group of FCs (n=63) of a randomized controlled trial. Older FCs (≥60 years of age) receiving a care allowance for a home-living care recipient (≥65 years of age) were included in the present study, which focused on nutritional interventions via individually tailored nutritional guidance provided by a clinical nutritionist. The associations between changes in protein intake (3-day food record), Mini Nutritional Assessment (MNA) scores, and plasma albumin and prealbumin concentrations, as well as associated factors, for the 6-month intervention period were analyzed using generalized estimating equations. Intervention time, female sex, older age, higher net income, better hand grip strength, more teeth, and removable denture use were positively associated with an increase in protein intake. Fewer depressive symptoms were associated with a positive change in the MNA scores. Younger age, lower education level, lower body mass index (BMI), higher depressive symptoms, and fewer teeth were associated with an increase in plasma albumin concentration. Younger age, lower education, lower plasma concentration of high-sensitivity C-reactive protein at 6 months, lower Sense of Coherence (SOC)-13 score, fewer teeth, and absence of removable dentures were associated with an increase in plasma prealbumin concentration. Older female FCs with a higher income, better hand grip strength, lower education, and lower SOC benefited most from individually tailored nutritional guidance. Depressive symptoms, oral health, and low-grade inflammation should be considered when providing nutritional guidance to older FCs. ClinicalTrials.gov NCT04003493 (July 1, 2019).