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The article presents the discussion on nurses playing a key role in administering medications. Topics include understanding of pharmacology for general practices nurses (GPNs) and advanced nurse practitioners (ANPs) in primary care; and medicinal drugs such as those used for prevention and treatment, non-medicinal drugs, such as those used for recreational purposes.

Different approaches to the implementation of photocatalytic elimination of urea in aqueous solutions are considered. The main advantages and drawbacks of the photocatalytic method as compared with existing methods for dialysate regeneration are presented. The potential for using the photocatalytic method for urea elimination in wearable artificial blood purification devices is described. [ABSTRACT FROM AUTHOR]

Background: Chinese herbal medicine (CHM) is characterized by "multi-compounds, multi-targets and multipathway", which has advanced benefits for preventing and treating complex diseases, but there still exists unsolved issues, mainly include unclear material basis and underlying mechanism of prescription. Integrated pharmacology is a hot cross research area based on system biology, mathematics and poly-pharmacology. It can systematically and comprehensively investigate the therapeutic reaction of compounds or drugs on pathogenic genes network, and is especially suitable for the study of complex CHM systems. Intracerebral Hemorrhage (ICH) is one of the main causes of death among Chinese residents, which is characterized with high mortality and high disability rate. In recent years, the treatment of ICH by CHM has been deeply researched. Xue Fu Zhu Yu Decoction (XFZYD), one of the commonly used prescriptions in treating ICH at clinic level, has not been clear about its mechanism. Methods: Here, we established a strategy, which based on compounds-targets, pathogenetic genes, network analysis and node importance calculation. Using this strategy, the core compounds group (CCG) of XFZYD was predicted and validated by in vitro experiments. The molecular mechanism of XFZYD in treating ICH was deduced based on CCG and their targets. Results: The results show that the CCG with 43 compounds predicted by this model is highly consistent with the corresponding Compound-Target (C-T) network in terms of gene coverage, enriched pathway coverage and accumulated contribution of key nodes at 89.49%, 88.72% and 90.11%, respectively, which confirmed the reliability and accuracy of the effective compound group optimization and mechanism speculation strategy proposed by us. Conclusions: Our strategy of optimizing the effective compound groups and inferring the mechanism provides a strategic reference for explaining the optimization and inferring the molecular mechanism of prescriptions in treating complex diseases of CHM. [ABSTRACT FROM AUTHOR]

The role of individual cytochrome P450 (CYPs) responsible for the drug metabolism can be determined through their chemical inhibition. During the pandemic, dexamethasone and remdesivir with omeprazole were used for the treatment of COVID-19, while Ibuprofen was taken to treat the symptoms of fever and headache. This study aimed to examine the potency of ibuprofen remdesivir, and omeprazole as inhibitors of cytochrome P450s using rat liver microsomes in vitro. Dexamethasone a corticosteroid, sometimes used to reduce the body's immune response in the treatment of COVID-19, was used as a probe substrate and the three inhibitors were added to the incubation system at different concentrations and analysed by a validated High Performance Liquid Chromatography (HPLC) method. The CYP3A2 isoenzyme is responsible for dexamethasone metabolism in vitro. The results showed that ibuprofen acts as a non-competitive inhibitor for CYP3A2 activity with Ki = 224.981 ± 1.854 µM and IC50 = 230.552 ± 2.020 µM, although remdesivir showed a mixed inhibition pattern with a Ki = 22.504 ± 0.008 µM and IC50 = 45.007 ± 0.016 µM. Additionally, omeprazole uncompetitively inhibits dexamethasone metabolism by the CYP3A2 enzyme activity with a Ki = 39.175 ± 0.230 µM and IC50 = 78.351 ± 0.460 µM. These results suggest that the tested inhibitors would not exert a significant effect on the CYP3A2 isoenzyme responsible for the co-administered dexamethasone drug's metabolism in vivo. [ABSTRACT FROM AUTHOR]

Sulopenem (formerly known as CP-70,429, and CP-65,207 when a component of a racemic mixture with its R isomer) is an intravenous and oral penem that possesses in vitro activity against fluoroquinolone-resistant, extended spectrum β-lactamases (ESBL)-producing, multidrug-resistant (MDR) Enterobacterales. Sulopenem is being developed to treat patients with uncomplicated and complicated urinary tract infections (UTIs) as well as intra-abdominal infections. This review will focus mainly on its use in UTIs. The chemical structure of sulopenem shares properties of penicillins, cephalosporins, and carbapenems. Sulopenem is available as an oral prodrug formulation, sulopenem etzadroxil, which is hydrolyzed by intestinal esterases, resulting in active sulopenem. In early studies, the S isomer of CP-65,207, later developed as sulopenem, demonstrated greater absorption, higher drug concentrations in the urine, and increased stability against the renal enzyme dehydropeptidase-1 compared with the R isomer, which set the stage for its further development as a UTI antimicrobial. Sulopenem is active against both Gram-negative and Gram-positive microorganisms. Sulopenem's β-lactam ring alkylates the serine residues of penicillin-binding protein (PBP), which inhibits peptidoglycan cross-linking. Due to its ionization and low molecular weight, sulopenem passes through outer membrane proteins to reach PBPs of Gram-negative bacteria. While sulopenem activity is unaffected by many β-lactamases, resistance arises from alterations in PBPs (e.g., methicillin-resistant Staphylococcus aureus [MRSA]), expression of carbapenemases (e.g., carbapenemase-producing Enterobacterales and in Stenotrophomonas maltophilia), reduction in the expression of outer membrane proteins (e.g., some Klebsiella spp.), and the presence of efflux pumps (e.g., MexAB-OprM in Pseudomonas aeruginosa), or a combination of these mechanisms. In vitro studies have reported that sulopenem demonstrates greater activity than meropenem and ertapenem against Enterococcus faecalis, Listeria monocytogenes, methicillin-susceptible S. aureus (MSSA), and Staphylococcus epidermidis, as well as similar activity to carbapenems against Streptococcus agalactiae, Streptococcus pneumoniae, and Streptococcus pyogenes. With some exceptions, sulopenem activity against Gram-negative aerobes was less than ertapenem and meropenem but greater than imipenem. Sulopenem activity against Escherichia coli carrying ESBL, CTX-M, or Amp-C enzymes, or demonstrating MDR phenotypes, as well as against ESBL-producing Klebsiella pneumoniae, was nearly identical to ertapenem and meropenem and greater than imipenem. Sulopenem exhibited identical or slightly greater activity than imipenem against many Gram-positive and Gram-negative anaerobes, including Bacteroides fragilis. The pharmacokinetics of intravenous sulopenem appear similar to carbapenems such as imipenem-cilastatin, meropenem, and doripenem. In healthy subjects, reported volumes of distribution (Vd) ranged from 15.8 to 27.6 L, total drug clearances (CLT) of 18.9–24.9 L/h, protein binding of approximately 10%, and elimination half-lives (t½) of 0.88–1.03 h. The estimated renal clearance (CLR) of sulopenem is 8.0–10.6 L/h, with 35.5% ± 6.7% of a 1000 mg dose recovered unchanged in the urine. An ester prodrug, sulopenem etzadroxil, has been developed for oral administration. Initial investigations reported a variable oral bioavailability of 20–34% under fasted conditions, however subsequent work showed that bioavailability is significantly improved by administering sulopenem with food to increase its oral absorption or with probenecid to reduce its renal tubular secretion. Food consumption increases the area under the curve (AUC) of oral sulopenem (500 mg twice daily) by 23.6% when administered alone and 62% when administered with 500 mg of probenecid. Like carbapenems, sulopenem demonstrates bactericidal activity that is associated with the percentage of time that free concentrations exceed the MIC (%f T > MIC). In animal models, bacteriostasis was associated with %f T > MICs ranging from 8.6 to 17%, whereas 2-log10 kill was seen at values ranging from 12 to 28%. No pharmacodynamic targets have been documented for suppression of resistance. Sulopenem concentrations in urine are variable, ranging from 21.8 to 420.0 mg/L (median 84.4 mg/L) in fasted subjects and 28.8 to 609.0 mg/L (median 87.3 mg/L) in those who were fed. Sulopenem has been compared with carbapenems and cephalosporins in guinea pig and murine systemic and lung infection animal models. Studied pathogens included Acinetobacter calcoaceticus, B. fragilis, Citrobacter freundii, Enterobacter cloacae, E. coli, K. pneumoniae, Proteus vulgaris, and Serratia marcescens. These studies reported that overall, sulopenem was non-inferior to carbapenems but appeared to be superior to cephalosporins. A phase III clinical trial (SURE-1) reported that sulopenem was not non-inferior to ciprofloxacin in women infected with fluoroquinolone-susceptible pathogens, due to a higher rate of asymptomatic bacteriuria in sulopenem-treated patients at the test-of-cure visit. However, the researchers reported superiority of sulopenem etzadroxil/probenecid over ciprofloxacin for the treatment of uncomplicated UTIs in women infected with fluoroquinolone/non-susceptible pathogens, and non-inferiority in all patients with a positive urine culture. A phase III clinical trial (SURE-2) compared intravenous sulopenem followed by oral sulopenem etzadroxil/probenecid with ertapenem in the treatment of complicated UTIs. No difference in overall success was noted at the end of therapy. However, intravenous sulopenem followed by oral sulopenem etzadroxil was not non-inferior to ertapenem followed by oral stepdown therapy in overall success at test-of-cure due to a higher rate of asymptomatic bacteriuria in the sulopenem arm. After a meeting with the US FDA, Iterum stated that they are currently evaluating the optimal design for an additional phase III uncomplicated UTI study to be conducted prior to the potential resubmission of the New Drug Application (NDA). It is unclear at this time whether Iterum intends to apply for EMA or Japanese regulatory approval. The safety and tolerability of sulopenem has been reported in various phase I pharmacokinetic studies and phase III clinical trials. Sulopenem (intravenous and oral) appears to be well tolerated in healthy subjects, with and without the coadministration of probenecid, with few serious drug-related treatment-emergent adverse events (TEAEs) reported to date. Reported TEAEs affecting ≥1% of patients were (from most to least common) diarrhea, nausea, headache, vomiting and dizziness. Discontinuation rates were low and were not different than comparator agents. Sulopenem administered orally and/or intravenously represents a potentially well tolerated and effective option for treating uncomplicated and complicated UTIs, especially in patients with documented or highly suspected antimicrobial pathogens to commonly used agents (e.g. fluoroquinolone-resistant E. coli), and in patients with documented microbiological or clinical failure or patients who demonstrate intolerance/adverse effects to first-line agents. This agent will likely be used orally in the outpatient setting, and intravenously followed by oral stepdown in the hospital setting. Sulopenem also allows for oral stepdown therapy in the hospital setting from intravenous non-sulopenem therapy. More clinical data are required to fully assess the clinical efficacy and safety of sulopenem, especially in patients with complicated UTIs caused by resistant pathogens such as ESBL-producing, Amp-C, MDR E. coli. Antimicrobial stewardship programs will need to create guidelines for when this oral and intravenous penem should be used. [ABSTRACT FROM AUTHOR]

Purpose: This study aims to examine the effect of ileal transposition (IT) on plasma levels of the total antioxidant status (TAS), total oxidant status (TOS), Oxidative Stress Index (OSI), Superoxide dismutase (SOD), Nicotinamide adenine dinucleotide phosphate oxidase (NOX), Catalase (CAT), Reduced Glutathione (GSH) in both rats with Metabolic syndrome (MetS) and healthy controls. Materials and Methods: In the MetS model, newborn male Wistar albino rats were given MSG (4 g/mg) on days 0, 2, 4, 6, 8, and 10. The control group was injected only saline. In the 5th month, sham and IT animals underwent selected surgery. 2 months after surgery TOS, TAS, OSI, SOD, NOX, CAT, and GSH levels were assessed in the plasma. Results: IT procedure significantly increased SOD and CAT levels in MetS + IT group when compared to the MetS group (SOD; MetS 1.75 ± 0.04, MetS+IT 2.1 ± 0.15, CAT; MetS 32.02 ± 1.73, MetS+IT 41.64 ± 1.18,). As expected, while GSH levels was increased in MetS+IT rats compared to MetS rats, but the difference was not significant (MetS 243.31 ± 6.36, MetS+IT 269.76 ± 9.17). The NOX activity was significantly lower in MetS+IT group than MetS and MetS+S groups (MetS 610.35 ± 26.25, MetS+IT 348.86 ± 14.12). Conclusion: These data revealed the healing effect of IT surgery against oxidative stress associated with MetS. The available data endorses IT surgery as an effective strategy to reduce oxidative damage in rats with MetS by modulating systemic oxidant and antioxidant responses. [ABSTRACT FROM AUTHOR]

OLNP-06 is ginger extract product standardized to higher amount of total gingerols formulated with proprietary Aqueosome technology. The safety and efficacy of OLNP-06 were evaluated in a randomized, double blind, placebo controlled, parallel group comparative clinical study in subjects with functional dyspepsia (FD). Significant improvements in clinical endpoints were observed during the trial along with excellent safety profile. Fifty subjects aged between 18 and 55 years suffering from FD as per ROME III criteria were enrolled into the study. They were randomized into two treatment groups, one group received OLNP-06, 200 mg twice daily and other group received placebo 200 mg twice daily. The primary efficacy end point was global assessment of overall treatment efficacy (OTE). Secondary efficacy endpoints were elimination rate of three major symptoms (postprandial fullness, upper abdominal bloating and early satiation) and elimination rate for each individual symptom scores. Biochemical and hematological parameters including urine analysis were performed to evaluate the safety of OLNP-06. Out of 50 subjects, 48subjects completed the study. Total 79% of the subjects receiving OLNP-06 and 21% of the subjects receiving placebo (p <.05) were classified as responders according to the assessment of OTE. Elimination rate (score 0) of postprandial fullness, upper abdominal bloating and early satiation was 64% in subjects receiving ONLP-06 compared with 13% in the placebo group (p <.05). OLNP-06 was found to be safe and well tolerated as there was no incidence of treatment-related AE's. Supplementation of OLNP-06 for 4 weeks significantly reduced dyspeptic symptoms in subjects suffering from FD. Trial Registration: Clinical Trial Registry-India, CTRI/2019/09/021019, Registered on 2 Sep 2019. [ABSTRACT FROM AUTHOR]

The article presents the discussion on the use of animal models in research. Topics include regulatory agencies recommended testing drugs and other chemicals in two different animal species; role of animals, insulin, penicillin, and the polio vaccine being discovered; and differing greatly from single cells cultured in a plastic dish or mice, dogs, or any other animal used for scientific experiments.

Hypothetical and experimental models of unbound fraction have been proposed to facilitate predicting the hepatic clearance (CL H ) of drugs from values of intrinsic clearance for the unbound drug (CL int-in vitro-unbound ) and the well-stirred model (WSM). The hypothetical model (fu -adjusted ) is adjusting the unbound fractions determined in plasma in vitro to estimate the maximum unbound fractions at the hepatocytes if each drug-protein complex in plasma becomes fully dissociated at the membrane by any albumin (ALB)-facilitated hepatic uptake mechanism. The model of fu -adjusted is also adjusting the unbound fraction for a pH gradient effect across the membrane. Alternatively, the new experimental model (fu -dynamic ) measures the unbound fractions resulting to the dynamic dissociation kinetics from proteins in the presence of plasma and a liver enzyme in an in vitro assay. The objective of this study was to conduct an in-depth analysis of previous CL H predictions made with these unbound fractions in a companion manuscript. Furthermore, a new dataset on transporter substrates was also included in this study. Finally, the physiological basis of fu -adjusted has been redefined to extend its applicability with more drugs. In this case, there are lower concentrations of binding proteins in liver versus plasma that could also explain the higher unbound fractions for that organ. The outcomes associated to additional analyses pointed out that fu -adjusted , again, generally provided the most accurate predictions of CL H because fu -dynamic has generated superior biases of underpredictions or overpredictions. For slowly metabolized drugs bound to ALB, fu -dynamic was definitively less accurate than fu -adjusted . For other drug properties, fu -dynamic fared better but it was still not generally more accurate than fu -adjusted . Furthermore, experimental values of fu -dynamic were sometimes incoherent. For example, drugs bound to alpha-acid glycoprotein (AGP) did not follow the principle of fu -dynamic (i.e., values of fu -dynamic did not correlate with values of CL int-in vitro-unbound ) by contrast to those drugs bound to ALB. Therefore, the current experimental setting for fu -dynamic might be unsuitable in some circumstances. Overall, this study confirmed that calculated values of fu -adjusted were as accurate as experimental values of fu -dynamic and can even be more accurate. A guidance on which unbound fraction to use in the WSM is also provided., (Copyright © 2024 American Pharmacists Association. Published by Elsevier Inc. All rights reserved.)

Background and Objective: CYP450 (CYP) phenotyping involves quantifying an individual's plasma clearance of CYP-specific probe drugs, as a proxy for in vivo CYP enzyme activity. It is increasingly applied to study alterations in CYP enzyme activity under various (patho)physiological conditions, such as inflammation, obesity, or pregnancy. The phenotyping approach assumes that changes in plasma clearance of probe drugs are driven by changes in CYP enzyme activity. However, plasma clearance is also influenced by protein binding, blood-to-plasma ratio, and hepatic blood flow, all of which may change under (patho)physiological conditions., Methods: Using a physiologically based pharmacokinetic (PBPK) workflow, we aimed to evaluate whether the plasma clearance of commonly used CYP probe drugs is indeed directly proportional to alterations in CYP enzyme activity (sensitivity), and to what extent alterations in protein binding, blood-to-plasma ratio, and hepatic blood flow observed under (patho)physiological conditions impact plasma clearance (specificity)., Results: Plasma clearance of CYP probe drugs is sensitive to alterations in CYP enzyme activity, since alterations in intrinsic clearance between - 90% and + 150% resulted in near-proportional changes in plasma clearance, except for midazolam in the case of > 50% CYP3A4 induction. However, plasma clearance also changed near-proportionally with alterations in the unbound drug fraction, diminishing probe specificity. This was particularly relevant for high protein-bound probe drugs, as alterations in plasma protein binding resulted in larger relative changes in the unbound drug fraction. Alterations in the blood-to-plasma ratio and hepatic blood flow of ± 50% resulted in plasma clearance changes of less than ± 16%, meaning they limitedly impacted plasma clearance of CYP probe drugs, except for midazolam. In order to correct for the impact of non-metabolic determinants on probe drug plasma clearance, an R script was developed to calculate how much the CYP enzyme activity is actually altered under (patho)physiological conditions, when alterations in the unbound drug fraction, blood-to-plasma ratio, and/or hepatic blood flow also impact probe drug plasma clearance., Conclusions: As plasma protein binding can change under (patho)physiological conditions, alterations in unbound drug fraction should be accounted for when using CYP probe drug plasma clearance as a proxy for CYP enzyme activity in patient populations. The tool developed in this study can support researchers in determining alterations in CYP enzyme activity in patients with (patho)physiological conditions., Competing Interests: Declarations Funding No sources of funding were received for this work. Conflict of interest Laura M. de Jong, Marinda van de Kreeke, Mariam Ahmadi, Jesse J. Swen, Catherijne A.J. Knibbe, J.G. Coen van Hasselt, Martijn L. Manson, and Elke H.J. Krekels have declared no conflicts of interest/competing interests for this work. Data availability Available upon request. Ethics approval Not applicable. Consent to participate Not applicable. Consent for publication Not applicable. Code availability Available upon request. Author contributions LMJ, MA, MLM, and EHJK designed the research; LMJ, MK, MA, and EHJK performed the research. All authors contributed to interpreting the results, and all authors wrote the manuscript., (© 2024. The Author(s).)

Abstract: Nuclear industry workers exposed to uranium aerosols may risk kidney damage and radiation-induced cancer. This warrants the need for well-established dose and risk assessments, which can be greatly improved by using material-specific absorption parameters in the ICRP Human Respiratory Tract Model. The present study focuses on the evaluation of the slow dissolution rate ( s s , d -1 ), a parameter that is difficult to quantify with in vitro dissolution studies, especially for more insoluble uranium compounds. A long-term follow-up of urinary excretion after the cessation of chronic inhalation exposure can provide a better estimate of the slow-rate dissolution. In this study, two workers, previously working for >20 y at a nuclear fuel fabrication plant, provided urine samples regularly for up to 6 y. One individual had worked at the pelletizing workshop with the known presence of uranium dioxide (UO 2 ) and triuranium octoxide (U 3 O 8 ). The second individual worked at the conversion workshop where multiple compounds, including uranium hexafluoride (UF 6 ), uranium dioxide (UO 2 ), ammonium uranyl carbonate, and AUC [UO 2 CO 3 ·2(NH 4 ) 2 CO 3 ], are present. Data on uranium concentration in urine during working years were also available for both workers. The daily excretion of uranium by urine was characterized by applying non-linear least square regression fitting to the urinary data. Material-specific parameters, such as the activity median aerodynamic diameter (AMAD), the respiratory tract absorption parameters, rapid fraction ( f r ,), rapid dissolution rate ( s r , d -1 ), and slow dissolution rate ( s s , d -1 ) and alimentary tract transfer factor ( f A ) acquired from previous work along with default absorption types, were applied to urine data, and the goodness of fit was evaluated. Thereafter intake estimates and dose calculations were performed. For the ex-pelletizing worker, a one-compartment model with a clearance half-time of 662 ± 100 d ( s s = 0.0010 d -1 ) best represented the urinary data. For the ex-conversion worker, a two-compartment model with a major [93% of the initial urinary excretion (A 0 )] fast compartment with a clearance half-time of 1.3 ± 0.4 d ( s r = 0.5 d -1 ) and a minor (7% of A 0 ) slow compartment with a half-time of 394 ± 241 d ( s s = 0.002 d -1 ) provided the best fit. The results from the data-fitting of urinary data to biokinetic models for the ex-conversion worker demonstrated that in vitro derived experimental parameters (AMAD = 20 μm, f r = 0.32, s r = 27 d -1 , s s = 0.0008 d -1 , f A = 0.005) from our previous work best represented the urinary data. This resulted in an estimated intake rate of 0.66 Bq d -1 . The results from the data-fitting of urinary data to biokinetic models for the ex-pelletizing worker indicated that the experimental parameters (AMAD = 10 μm and 20 μm, f r = 0.008, s r = 12 d -1 , f A = 0.00019) from our previous dissolution studies with the slow rate parameter step-wise optimized to urine-data ( s s = 0.0008 d -1 ) gave the best fit. This resulted in an estimated intake rate of 5 Bq d -1 . Experimental parameters derived from in vitro dissolution studies provided the best fit for the subject retired from work at the conversion workshop, where inhalation exposure to a mix of soluble (e.g., AUC, UF 6 ) and relatively insoluble aerosol (e.g., UO 2 ) can be assumed. For the subject retired from work at the pelletizing workshop, which involved exposure to relatively insoluble aerosols (UO 2 and U 3 O 8 ), a considerably higher s s than obtained in dissolution studies provided a better representation of the urinary data and was comparable to reported s s values for UO 2 and U 3 O 8 in other studies. This implies that in vitro dissolution studies of insoluble material can be uncertain. When evaluating the results from the retrospective fitting of urine data, it is evident that the urine samples acquired after cessation of exposure provide less fluctuation. Long-term follow-up of uranium excretion after cessation of exposure is a good alternative for determining absorption parameters and can be considered the most viable way for determining the slow rate for more insoluble material., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Health Physics Society.)

International consensus supports the development of standardized protocols for measured glomerular filtration rate (mGFR) to facilitate the integration of mGFR testing in both clinical and research settings. To this end, the European Kidney Function Consortium convened an international group of experts with relevant experience in mGFR. The working group performed an extensive literature search to inform the development of recommendations for mGFR determination using 1-compartment plasma clearance models and iohexol as the exogenous filtration marker. Iohexol was selected as it is non-radio labeled, inexpensive, and safe, can be assayed at a central laboratory, and the other commonly used non-radio-labeled tracers have been (inulin) or are soon to be (iothalamate) discontinued. A plasma clearance model was selected over urine clearance as it requires no urine collection. A 1 compartment was preferred to 2 compartments as it requires fewer samples. The recommendations are based on published evidence complemented by expert opinion. The consensus paper covers practical advice for patients and health professionals, preparation, administration, and safety aspects of iohexol, laboratory analysis, blood sample collection and sampling times using both multiple and single-sample protocols, description of the mGFR mathematical calculations, as well as implementation strategies. Supplementary materials include patient and provider information sheets, standard operating procedures, a study protocol template, and support for mGFR calculation., (Copyright © 2024 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Purpose: The CYP2D6 gene exhibits significant polymorphism, contributing to variability in responses to drugs metabolized by CYP2D6. While CYP2D6*2 and CYP2D6*35 are presently designated as alleles encoding normal metabolism, this classification is based on moderate level evidence. Additionally, the role of the formerly called "enhancer" single nucleotide polymorphism (SNP) rs5758550 is unclear. In this study, the impacts of CYP2D6*2, CYP2D6*35 and rs5758550 on CYP2D6 activity were investigated using risperidone clearance as CYP2D6 activity marker., Methods: A joint parent-metabolite population pharmacokinetic model was used to describe 1,565 serum concentration measurements of risperidone and 9-hydroxyrisperidone in 512 subjects. Risperidone population clearance was modeled as the sum of a CYP2D6-independent clearance term and the partial clearances contributed from each individually expressed CYP2D6 allele or haplotype. In addition to the well-characterized CYP2D6 alleles (*3-*6, *9, *10 and *41), *2, *35 and two haplotypes assigned as CYP2D6*2-rs5758550G and CYP2D6*2-rs5758550A were evaluated., Results: Each evaluated CYP2D6 allele was associated with significantly lower risperidone clearance than the reference normal function allele CYP2D6*1 (p < 0.001). Further, rs5758550 differentiated the effect of CYP2D6*2 (p = 0.005). The haplotype-specific clearances for CYP2D6*2-rs5758550A, CYP2D6*2-rs5758550G and CYP2D6*35 were estimated to 30%, 66% and 57%, respectively, relative to the clearance for CYP2D6*1. Notably, rs5758550 is in high linkage disequilibrium (R 2  > 0.85) with at least 24 other SNPs and cannot be assigned as a functional SNP., Conclusion: CYP2D6*2 and CYP2D6*35 encode reduced risperidone clearance, and the extent of reduction for CYP2D6*2 is differentiated by rs5758550. Genotyping of these haplotypes might improve the precision of genotype-guided prediction of CYP2D6-mediated clearance., (© 2024. The Author(s).)

Lenacapavir (LEN), a long-acting injectable, is the first approved human immunodeficiency virus type 1 capsid inhibitor and one of a few Food and Drug Administration-approved drugs that exhibit atropisomerism. LEN exists as a mixture of two class 2 atropisomers that interconvert at a fast rate (half-life < 2 hours) with a ratio that is stable over time and unaffected by enzymes or binding to proteins in plasma. LEN exhibits low systemic clearance (CL) in nonclinical species and humans; however, in all species, the observed CL was higher than the in vitro predicted CL. The volume of distribution was moderate in nonclinical species and consistent with the tissue distribution observed by whole-body autoradiography in rats. LEN does not distribute to brain, consistent with being a P-glycoprotein (P-gp) substrate. Mechanistic drug disposition studies with [ 14 C]LEN in intravenously dosed bile duct-cannulated rats and dogs showed a substantial amount of unchanged LEN (31%-60% of dose) excreted in feces, indicating that intestinal excretion (IE) was a major clearance pathway for LEN in both species. Coadministration of oral elacridar, a P-gp inhibitor, in rats decreased CL and IE of LEN. Renal excretion was < 1% of dose in both species. In plasma, almost all radioactivity was unchanged LEN. Low levels of metabolites in excreta included LEN conjugates with glutathione, pentose, and glucuronic acid, which were consistent with metabolites formed in vitro in H μ rel hepatocyte cocultures and those observed in human. Our studies highlight the importance of IE for efflux substrates that are highly metabolically stable compounds with slow elimination rates. SIGNIFICANCE STATEMENT: LEN is a long-acting injectable that exists as conformationally stable atropisomers. Due to an atropisomeric interconversion rate that significantly exceeds the in vivo elimination rate, the atropisomer ratio of LEN remains constant in circulation. The disposition of LEN highlights that intestinal excretion has a substantial part in the elimination of compounds that are metabolically highly stable and efflux transporter substrates., (Copyright © 2024 by The Author(s).)

Hepatic clearance ( CL H ) prediction is a critical parameter to estimate human dose. However, CL H underpredictions are common, especially for slowly metabolized drugs, and may be attributable to drug properties that pose challenges for conventional in vitro absorption, distribution, metabolism, and elimination (ADME) assays, resulting in nonvalid data, which prevents in vitro to in vivo extrapolation and CL H predictions. Other processes, including hepatocyte and biliary distribution via transporters, can also play significant roles in CL H Recent advances in understanding the interplay of metabolism and drug transport for clearance processes have aided in developing the extended clearance model. In this study, we demonstrate proof of concept of a novel two-step assay enabling the measurement of multiple kinetic parameters from a single experiment in plated human primary hepatocytes with and without transporter and cytochrome P450 inhibitors-the hepatocyte uptake and loss assay (HUpLA). HUpLA accurately predicted the CL H of eight of the nine drugs (within twofold of the observed CL H ). Distribution clearances were within threefold of observed literature values in standard uptake and efflux assays. In comparison, the conventional suspension hepatocyte stability assay poorly predicted the CL H The CL H of only two drugs was predicted within twofold of the observed CL H Therefore, HUpLA is advantageous by enabling the measurement of enzymatic and transport processes concurrently within the same system, alleviating the need for applying scaling factors independently. The use of primary human hepatocytes enables physiologically relevant exploration of transporter-enzyme interplay. Most importantly, HUpLA shows promise as a sensitive measure for low-turnover drugs. Further evaluation across different drug characteristics is needed to demonstrate method robustness. SIGNIFICANCE STATEMENT: The hepatocyte uptake and loss assay involves measuring four commonly derived in vitro hepatic clearance endpoints. Since endpoints are generated within a single test system, it blunts experimental error originating from assays otherwise conducted independently. A key advantage is the concept of removing drug-containing media following intracellular drug loading, enabling the measurement of drug reappearance rate in media as well as the measurement of loss of total drug in the test system unencumbered by background quantities of drug in media otherwise present in a conventional assay., (Copyright © 2024 by The American Society for Pharmacology and Experimental Therapeutics.)

Ritlecitinib is an oral once-daily irreversible inhibitor of Janus kinase 3 and tyrosine-protein kinase family being developed for the treatment of moderate-to-severe alopecia areata. This study examined the disposition of ritlecitinib in male participants following oral and intravenous administration using accelerator mass spectroscopy methodology to estimate pharmacokinetic parameters and characterize metabolite profiles. The results indicated ritlecitinib had a systemic clearance of 43.7 L/h, a steady state volume of distribution of 73.8 L, extent of absorption of 89%, time to maximum plasma concentration of ∼0.5 hours, and absolute oral bioavailability of 64%. An observed long terminal half-life of total radioactivity was primarily attributed to ritlecitinib binding to plasma albumin. Ritlecitinib was the main circulating drug species in plasma (∼30%), with one major pharmacologically inactive cysteine conjugated metabolite (M2) at >10%. Oxidative metabolism (fractional clearance 0.47) and glutathione-related conjugation (fractional clearance 0.24) were the primary routes of elimination for ritlecitinib with the greatest disposition of radioactivity shown in the urine (∼71%). In vitro phenotyping indicated ritlecitinib cytochrome P450 (CYP) fraction of metabolism assignments of 0.29 for CYP3A, 0.09 for CYP2C8, 0.07 for CYP1A2, and 0.02 for CYP2C9. In vitro phenotyping in recombinant human glutathione S-transferases indicated ritlecitinib was turned over by a number of cytosolic and microsomal enzyme isoforms. SIGNIFICANCE STATEMENT: This study provides a detailed understanding of the disposition and metabolism of ritlecitinib, a JAK3 and TEC family kinase inhibitor for alopecia areata in humans, as well as characterization of clearance pathways and pharmacokinetics of ritlecitinib and its metabolites. As an AMS-based ADME study design, we have expanded on reporting the standard ADME endpoints, providing key pharmacokinetic parameters, such as clearance, volume of distribution, and bioavailability, allowing for a more comprehensive understanding of drug disposition., (Copyright © 2024 by The American Society for Pharmacology and Experimental Therapeutics.)

Over the last decade, it has become evident that cerebrospinal fluid (CSF) plays a pivotal role in brain solute clearance through perivascular pathways and interactions between the brain and meningeal lymphatic vessels. Whereas most of this fundamental knowledge was gained from rodent models, human brain clearance imaging has provided important insights into the human system and highlighted the existence of important interspecies differences. Current gold standard techniques for human brain clearance imaging involve the injection of gadolinium-based contrast agents and monitoring their distribution and clearance over a period from a few hours up to 2 days. With both intrathecal and intravenous injections being used, which each have their own specific routes of distribution and thus clearance of contrast agent, a clear understanding of the kinetics associated with both approaches, and especially the differences between them, is needed to properly interpret the results. Because it is known that intrathecally injected contrast agent reaches the blood, albeit in small concentrations, and that similarly some of the intravenously injected agent can be detected in CSF, both pathways are connected and will, in theory, reach the same compartments. However, because of clear differences in relative enhancement patterns, both injection approaches will result in varying sensitivities for assessment of different subparts of the brain clearance system. In this opinion review article, the "EU Joint Programme - Neurodegenerative Disease Research (JPND)" consortium on human brain clearance imaging provides an overview of contrast agent pharmacokinetics in vivo following intrathecal and intravenous injections and what typical concentrations and concentration-time curves should be expected. This can be the basis for optimizing and interpreting contrast-enhanced MRI for brain clearance imaging. Furthermore, this can shed light on how molecules may exchange between blood, brain, and CSF., (© 2024 The Authors. NMR in Biomedicine published by John Wiley & Sons Ltd.)

Isolated perfused rat liver (IPRL) experiments have been used to answer clearance-related questions, including evaluating the impact of pathological and physiological processes on hepatic clearance ( CL H ). However, to date, IPRL data has not been evaluated for in vivo CL H prediction accuracy.In addition to a detailed overview of available IPRL literature, we present an in-depth analysis of the performance of IPRL in CL H prediction.While the entire dataset poorly predicted CL H (GAFE = 3.2; 64% within 3-fold), IPRL conducted under optimal experimental conditions, such as in the presence of plasma proteins and with a perfusion rate within 2-fold of physiological liver blood flow and corrected for unbound fraction in the presence of red blood cells, can accurately predict rat CL H (GAFE = 2.0; 78% within 3-fold). Careful consideration of experimental conditions is needed to allow proper data analysis.Further, isolated perfused liver experiments in other species, including human livers, may allow us to address the current in vitro - in vivo disconnects of hepatic metabolic clearance and improve our methodology for CL H predictions.

When a new molecular entity is predicted to exhibit high clearance in humans, pharmaceutical sponsors almost universally search for similar acting back-up compounds that will demonstrate low clearance. Here we show that, except for oral dosing, there can be marked advantages to developing and commercializing controlled release formulations of high clearance drugs, the expertise of readers of this journal. Our recent publications demonstrate that the universally held pharmacokinetic principle that drug delivery rate has no effect on measured drug clearance is not correct. Rather, we show that if clearance from the drug delivery site is markedly less than the iv bolus clearance of a drug, the in vivo drug clearance can be the drug delivery clearance controlled by the designed dosage form. This approach will be especially advantageous for high hepatic clearance drugs. These advantages include not being concerned with: a) saturable nonlinear kinetics, b) significant pharmacogenomic differences, c) drug-drug induction mechanisms, and d) in many cases drug-drug inhibition interactions. This is due to the ability of a drug sponsor to design clearance, independent of the pharmacokinetic characteristics for high clearance compounds, where clearance from the dosage form becomes the drug clearance from the patient. Recognition of this principle, as described here, results from our development of the use of Kirchhoff's Laws from physics to derive rate-defining clearance and rate constant elimination processes independent of differential equation derivations. The key message for readers of this journal is that high clearance drugs are potentially drugable through formulation design and should not be outright disregarded, since for such drugs the dose-corrected area under the curve can be increased if the release rate from the injection site is controlled and slow resulting in drug clearance from the body controlled by clearance from the dosage form. The concepts presented here describe previously unrecognized advantages of controlled release formulations., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

This article explores the use of Factor XI/XIa inhibitors in preventing venous thromboembolism (VTE). These inhibitors target a protein involved in blood clotting, and by inhibiting it, they can prevent the formation of dangerous blood clots associated with VTE. Various molecules, such as antisense oligonucleotides, monoclonal antibodies, and natural inhibitors, have been developed and studied as potential inhibitors. Clinical trials are currently underway to evaluate their effectiveness and safety in different clinical scenarios, such as VTE prevention in orthopedic surgery patients. While initial trials have shown promising results with low rates of bleeding, further research is needed to establish their efficacy compared to standard VTE prevention methods. Additionally, questions regarding regulatory approval, acceptance by clinicians and patients, and costs remain unanswered. [Extracted from the article]

ECMO/ECLS is now a days very common modality for saving patient life in ICU. ECMO is unphysiological circulation which hampers the multiorgan function. Direct impact by releasing of pro-inflammatory cytokinin leads to impact on the many organ homeostasis. The anaesthetist/intensivist must have enough knowledge of pKa/Pd and most importantly still we do not have ideal guidelines for drug dosing. [ABSTRACT FROM AUTHOR]

This research project determined the most effective training mean for lactate clearance using the subaerobic functional area in Olympic wrestling athletes of the freestyle modality. Eight Olympic wrestlers participated (age: 20.1±2.74 years), using a four-phase crossover study design, in which the athlete performed active recovery alternating each of the training means (Elliptical machine, treadmill, crank ergometer and stationary bicycle); lactate samples were taken 5 minutes after each bout and 15 minutes after finishing the active recovery. The elliptical machine presented the highest average efficiency, with 56.6%, followed by the treadmill with a 54.1% efficiency average; the repeated measures ANOVA F test evidenced differences among the means (p = .001). Likewise, differences were found when performing the post hoc comparisons of minimal significant difference, between the elliptical machine with respect to the crank ergometer (p = .001) and the stationary bicycle (p = .007), but they were not registered between the elliptical machine and the treadmill (p = .737). Of the means analyzed in this study, the highest efficiency in the process of blood lactate clearance during active recovery was evidenced by the elliptical machine and treadmill. Resumen. La presente investigación determinó el medio de entrenamiento más eficaz en el aclaramiento de lactato utilizando el área funcional subaeróbica en deportistas de lucha olímpica de la modalidad de libre. Participaron ocho luchadores olímpicos (edad: 20.1±2.74 años), utilizando un diseño de estudio cruzado de cuatro fases, en el que el deportista realizó la recuperación activa alternando cada uno de los medios de entrenamiento (Elíptica, banda trotadora, ergómetro de manivela y cicla estática); las muestras de lactato fueron tomadas a los 5 min finalizado cada combate y a los 15 min de terminar la recuperación activa. La elíptica presentó el mayor promedio de eficacia, con un 56.6%, seguido de la banda trotadora con un 54.1%; la prueba F de ANOVA de medidas repetidas evidenció diferencias entre los medios (p = .001). Asimismo, se encontraron diferencias al realizar las comparaciones post hoc de diferencia mínima significativa, entre la elíptica con respecto al ergómetro de manivela (p = .001) y la cicla estática (p = .007), pero no se registraron entre la elíptica y la banda trotadora (p = .737). De los medios analizados en este estudio, la mayor eficacia en el proceso de aclaramiento de lactato sanguíneo durante la recuperación activa, lo evidenciaron la elíptica y la banda trotadora.

Coronavirus disease 2019 (COVID-19) has become a new public health crisis threatening the world. Dysregulated immune responses are the most striking pathophysiological features of patients with severe COVID-19, which can result in multiple-organ failure and death. The cytochrome P450 (CYP) system is the most important drug metabolizing enzyme family, which plays a significant role in the metabolism of endogenous or exogenous substances. Endogenous CYPs participate in the biosynthesis or catabolism of endogenous substances, including steroids, vitamins, eicosanoids, and fatty acids, whilst xenobiotic CYPs are associated with the metabolism of environmental toxins, drugs, and carcinogens. CYP expression and activity are greatly affected by immune response. However, changes in CYP expression and/or function in COVID-19 and their impact on COVID-19 pathophysiology and the metabolism of therapeutic agents in COVID-19, remain unclear. In this analysis, we review current evidence predominantly in the following areas: firstly, the possible changes in CYP expression and/or function in COVID-19; secondly, the effects of CYPs on the metabolism of arachidonic acid, vitamins, and steroid hormones in COVID-19; and thirdly, the effects of CYPs on the metabolism of therapeutic COVID-19 drugs. [ABSTRACT FROM AUTHOR]

Objective: Rapid relapses after successful withdrawal occur even in apparently motivated benzodiazepine (BZD)-dependent patients. Regardless of known personality or biological (re-adaptation) issues, the aim of this open-label, single-arm, seminaturalistic study was to search for any detoxification errors contributing to failures. Methods: The data came from 350 inpatients. Based on serum-BZD evolution criteria, the procedure was divided into four stages: substitution, accumulation, elimination and post-elimination observation. After switching the patients to a long-acting substitute (diazepam), to prevent data falsification due to unwanted overaccumulation, the doses were expeditiously reduced under laboratory feedback until accumulation stopped. With the start of effective elimination, the tapering rate slowed and was individually adjusted to the patient's current clinical state. The tracking of both serum-BZD concentration and the corresponding intensity of withdrawal symptoms was continued throughout the entire elimination phase, also following successful drug withdrawal. Detoxification was concluded only after the patient's post-elimination stabilization. Results: Regardless of various initial serum-BZD concentration levels and the customized dose-reduction rate, and despite the novel lab-driven actions preventing initial overaccumulation, elimination was systematically proven to be protracted and varied within the 2- to 95-day range after the final dose. Within this period, withdrawal syndrome culminated several times, with varying combinations of symptoms. The last crisis occurrence (typically 2–3 weeks after withdrawal) correlated with the final serum-BZD elimination. The factors that prolonged elimination and delayed the final crisis were patient age, duration of addiction, adjunct valproate medication and elimination stage start parameters growing with former overaccumulation. Conclusions: The low-concentration detoxification stage is critical for patients' confrontations with recurring withdrawal symptoms. Underestimated elimination time following drug withdrawal and premature conclusions of detoxification expose patients to unassisted withdrawal crises. Concentration tracking defines proper limits for medical assistance, preventing early relapses. [ABSTRACT FROM AUTHOR]

Hyperglucagonemia is a common observation in both obesity and type 2 diabetes, and the etiology is primarily thought to be hypersecretion of glucagon. We investigated whether altered elimination kinetics of glucagon could contribute to hyperglucagonemia in type 2 diabetes and obesity. Individuals with type 2 diabetes and preserved kidney function (eight with and eight without obesity) and matched control individuals (eight with and eight without obesity) were recruited. Each participant underwent a 1-h glucagon infusion (4 ng/kg/min), achieving steady-state plasma glucagon concentrations, followed by a 1-h washout period. Plasma levels, metabolic clearance rate (MCR), half-life (T1/2), and volume of distribution of glucagon were evaluated, and a pharmacokinetic model was constructed. Glucagon MCR and volume of distribution were significantly higher in the type 2 diabetes group compared with the control group, while no significant differences between the groups were found in glucagon T1/2. Individuals with obesity had neither a significantly decreased MCR, T1/2, nor volume of distribution of glucagon. In our pharmacokinetic model, glucagon MCR associated positivelywith fasting plasma glucose and negatively with body weight. In conclusion, our results suggest that impaired glucagon clearance is not a fundamental part of the hyperglucagonemia observed in obesity and type 2 diabetes. [ABSTRACT FROM AUTHOR]

Purpose: Mycophenolate mofetil (MMF), a mycophenolic acid (MPA) prodrug, is used to prevent graft-versus-host disease (GVHD) in hematopoietic stem cell transplantation (HSCT). Although previous studies have reported that enterohepatic circulation (EHC) of MPA, which is usually observed in MMF-treated patients, does not occur in HSCT patients, it is unclear what happens in haploidentical–HSCT (haplo-HSCT) patients, who are using post-transplant cyclophosphamide. This study was conducted to investigate MPA pharmacokinetics in haplo-HSCT patients. Methods: Seventeen haplo-HSCT patients, who received MMF for GVHD prophylaxis, were enrolled in this study. We collected blood samples on days 14 and 28, and plasma MPA concentrations were measured by high-performance liquid chromatography; pharmacokinetic parameters such as area under the curve (AUC), mean residence time (MRT), and apparent oral clearance (CL/F) were measured with moment analysis. We also evaluated EHC as AUC6-12h/AUC0-12h. Results: There was no significant difference in MPA pharmacokinetic parameters between days 14 and 28. There was also no difference between the pharmacokinetic parameter changes and diarrhea. Additionally, varying plasma MPA concentrations suggested that MPA EHC did not occur. Conclusion: In this study, we revealed the pharmacokinetics of MMF in Japanese haplo-HSCT recipients. Additionally, our study demonstrated that MPA EHC might not occur in Japanese haplo-HSCT recipients. [ABSTRACT FROM AUTHOR]

Burosumab is a fully human monoclonal antibody against fibroblast growth factor 23, which has been approved to treat X‐linked hypophosphatemia (XLH) in adult and pediatric patients. The present work describes the pharmacokinetics (PK) of burosumab and the pharmacokinetic‐pharmacodynamic (PK‐PD) relationship between burosumab and serum phosphorus in adult and pediatric patients with XLH. A total of 2844 measurable serum concentrations of burosumab and 6047 measurable serum concentrations of phosphorus in 277 subjects from 9 clinical studies were included in the population PK and PK‐PD modeling. The serum concentration of burosumab following a subcutaneous administration was well described by a population PK model comprising a first‐order absorption, 1‐compartmental distribution, and a linear elimination. The relationship between serum burosumab and serum phosphorus was adequately described by a sigmoid maximal efficacy model. Body weight was the only covariate associated with PK and PK‐PD parameters. No other intrinsic factors affected PK or PK‐PD relationship in adult and pediatric patients with XLH. Further simulations helped to guide the dosing regimen of burosumab in adult and pediatric patients with XLH including age groups with no clinical data. [ABSTRACT FROM AUTHOR]

Purpose: Hyperpolarized [1‐13C]pyruvate MRS can measure cardiac metabolism in vivo. We investigated whether [1‐13C]pyruvate MRS could predict left ventricular remodeling following myocardial infarction (MI), long‐term left ventricular effects of heart failure medication, and could identify responders to treatment. Methods: Thirty‐five rats were scanned with hyperpolarized [1‐13C]pyruvate MRS 3 days after MI or sham surgery. The animals were re‐examined after 30 days of therapy with β‐blockers and ACE‐inhibitors (active group, n = 12), placebo treatment (placebo group, n = 13) or no treatment (sham group, n = 10). Furthermore, heart tissue mitochondrial respiratory capacity was assessed by high‐resolution respirometry. Metabolic results were compared between groups, over time and correlated to functional MR data at each time point. Results: At 30 ± 0.5 days post MI, left ventricular ejection fraction (LVEF) differed between groups (sham, 77% ± 1%; placebo, 52% ± 3%; active, 63% ± 2%, P <.001). Cardiac metabolism, measured by both hyperpolarized [1‐13C]pyruvate MRS and respirometry, neither differed between groups nor between baseline and follow‐up. Three days post MI, low bicarbonate + CO2/pyruvate ratio was associated with low LVEF. At follow‐up, in the active group, a poor recovery of LVEF was associated with high bicarbonate + CO2/pyruvate ratio, as measured by hyperpolarized MRS. Conclusion: In a rat model of moderate heart failure, medical treatment improved function, but did not on average influence [1‐13C]pyruvate flux as measured by MRS; however, responders to heart failure medication had reduced capacity for carbohydrate metabolism. [ABSTRACT FROM AUTHOR]

Natural products are major molecules for drug discovery due to their structural diversity and their interaction with various biological targets, yet their clinical application is limited by poor water solubility or low lipophilicity, inappropriate molecular size, low dissolution rate and permeation, instability, high metabolic rate and rapid clearance. These issues can be solved by nanomedicine, by improving bioavailability and therapeutic efficacy. Here we review nanocarriers made of polymer or lipid constituents. Specifically, we describe the technological characteristics of each nanosystem, with examples of application to single natural constituents or plant extracts, and possible routes of administration. We report in vitro and in vivo studies and we conclude with the potential advantages of nanodelivery systems in terms of increased stability and solubility, improved biodistribution and efficacy, reduced adverse effects and toxicity. [ABSTRACT FROM AUTHOR]

BackgroundWe have investigated β3-adrenoceptor agonist mediated brown adipose tissue (BAT) activation using (18)F-FDG PET/CT in Zucker lean (ZL) and obese (ZF) rats.Methods(18)F-FDG was injected into ZL and ZF rats pretreated with saline or agonist CL316,243 for scans. (18)F-FDG metabolic activity was computed as standard uptake values.ResultsCL316,243 in ZL activated BAT up to 4-fold compared to saline, while ZF BAT was only up by 2 fold. The decreased activation was consistent with lower β3-adrenoceptor levels in ZF rats.ConclusionsThe genetically modified ZL and ZF rats may provide a useful rat model to evaluate the significance of β3-adrenoceptor agonist-induced BAT activation in obesity.

BackgroundThis first-in-human study evaluated AMG 208, a small-molecule MET inhibitor, in patients with advanced solid tumors.MethodsThree to nine patients were enrolled into one of seven AMG 208 dose cohorts (25, 50, 100, 150, 200, 300, and 400 mg). Patients received AMG 208 orally on days 1 and days 4-28 once daily. The primary objectives were to evaluate the safety, tolerability, pharmacokinetics, and maximum tolerated dose (MTD) of AMG 208.ResultsFifty-four patients were enrolled. Six dose-limiting toxicities were observed: grade 3 increased aspartate aminotransferase (200 mg), grade 3 thrombocytopenia (200 mg), grade 4 acute myocardial infarction (300 mg), grade 3 prolonged QT (300 mg), and two cases of grade 3 hypertension (400 mg). The MTD was not reached. The most frequent grade ≥3 treatment-related adverse event was anemia (n = 3) followed by hypertension, prolonged QT, and thrombocytopenia (two patients each). AMG 208 exposure increased linearly with dose; mean plasma half-life estimates were 21.4-68.7 hours. One complete response (prostate cancer) and three partial responses (two in prostate cancer, one in kidney cancer) were observed.ConclusionsIn this study, AMG 208 had manageable toxicities and showed evidence of antitumor activity, particularly in prostate cancer.

The pharmacokinetics and biodistribution of the (14) C-labeled actinide decorporation agent 3,4,3-LI(1,2-HOPO) were investigated in young adult Swiss Webster mice and Sprague Dawley rats, after intravenous, intraperitoneal, and oral dose administration. In all routes investigated, the radiolabeled compound was rapidly distributed to various tissues and organs of the body. In mice, the 24 h fecal elimination profiles suggested that the biliary route is the predominant route of elimination. In contrast, lower fecal excretion levels were observed in rats. Tissue uptake and retention of the compound did not differ significantly between sexes although some differences were observed in the excretion patterns over time. The male mice eliminated a greater percentage of (14) C through the renal pathway than the female mice after receiving an intravenous or intraperitoneal dose, while the opposite trend was seen in rats that received an intravenous dose. Metabolite profiling performed on selected rat samples demonstrated that a putative major metabolite of [(14) C]-3,4,3-LI(1,2-HOPO) is formed, accounting for approximately 10% of an administered oral dose. Finally, to improve its oral bioavailability, 3,4,3-LI(1,2-HOPO) was coformulated with a proprietary permeability enhancer, leading to a notable increase in oral bioavailability of the compound.

The pharmacokinetics and biodistribution of the (14) C-labeled actinide decorporation agent 3,4,3-LI(1,2-HOPO) were investigated in young adult Swiss Webster mice and Sprague Dawley rats, after intravenous, intraperitoneal, and oral dose administration. In all routes investigated, the radiolabeled compound was rapidly distributed to various tissues and organs of the body. In mice, the 24 h fecal elimination profiles suggested that the biliary route is the predominant route of elimination. In contrast, lower fecal excretion levels were observed in rats. Tissue uptake and retention of the compound did not differ significantly between sexes although some differences were observed in the excretion patterns over time. The male mice eliminated a greater percentage of (14) C through the renal pathway than the female mice after receiving an intravenous or intraperitoneal dose, while the opposite trend was seen in rats that received an intravenous dose. Metabolite profiling performed on selected rat samples demonstrated that a putative major metabolite of [(14) C]-3,4,3-LI(1,2-HOPO) is formed, accounting for approximately 10% of an administered oral dose. Finally, to improve its oral bioavailability, 3,4,3-LI(1,2-HOPO) was coformulated with a proprietary permeability enhancer, leading to a notable increase in oral bioavailability of the compound.

Gastric cancer (GC) is a typical heterogeneous malignant tumor, whose insensitivity to chemotherapy is a common cause of tumor recurrence and metastasis. There is no doubt regarding the effectiveness of adjuvant chemotherapy (ACT) for GC, but the population for whom it is indicated and the selection of specific options remain the focus of present research. The conventional pathological TNM prediction focuses on cancer cells to predict prognosis, while they do not provide sufficient prediction. Enhanced computed tomography (CT) scanning is a validated tool that assesses the involvement of careful identification of the tumor, lymph node involvement, and metastatic spread. Using the radiomics approach, we selected the least absolute shrinkage and selection operator (LASSO) Cox regression model to build a radiomics signature for predicting the overall survival (OS) and disease-free survival (DFS) of patients with complete postoperative gastric cancer and further identifying candidate benefits from ACT. The radiomics trait-associated genes captured clinically relevant molecular pathways and potential chemotherapeutic drug metabolism mechanisms. Our results of precise surrogates using radiogenomics can lead to additional benefit from adjuvant chemotherapy and then survival prediction in postoperative GC patients. [ABSTRACT FROM AUTHOR]

Introduction: Extracorporeal membrane oxygenation (ECMO) is a lifesaving support technology for potentially reversible neonatal cardiac and/or respiratory failure. Pharmacological consequences of ECMO-induced haemolysis in neonates are not well understood. Case report: We report a case report of a full-term neonate treated for congenital diaphragmatic hernia and sepsis with ECMO and with vancomycin. While the population elimination half-life of 7 h was estimated, fitting of the simulated population pharmacokinetic profile to truly observed drug concentration points resulted in the personalized value of 41 h. Discussion: The neonate developed ECMO-induced haemolysis with subsequent acute kidney injury resulting in prolonged drug elimination. Whole blood/serum ratio of 0.79 excluded possibility of direct increase of vancomycin serum concentration during haemolysis. Conclusion: Vancomycin elimination may be severely prolonged due to ECMO-induced haemolysis and acute kidney injury, while hypothesis of direct increase of vancomycin levels by releasing the drug from blood cells during haemolysis has been disproved. [ABSTRACT FROM AUTHOR]

Background: Plant extracts may help to improve glycemic control in individuals with poor glycemic control. However, few studies have been investigated in the prediabetes cohort, which is a high-risk condition for T2DM. Thus, this study aimed to investigate the acute effect of grape seed, rooibos tea, and olive leaf extracts on postprandial blood glucose and insulin in participants with prediabetes. Methods: An acute, single-blind, placebo-controlled, non-randomized, crossover study (ACTRN12617000837325) where placebo and extracts of grape seed, rooibos tea and olive leaf standardized for total antioxidant capacity were given separately during an oral glucose tolerance test to participants (n=19, five men and fourteen women, aged 65.0 ± 1.6 years, Body Mass Index (BMI) 27.3 ± 1.1 kg/m2) with prediabetes (Glycated hemoglobin A1c (HbA1c) 42 ± 1 mmol/mol). The primary outcome incremental area under the curve of glucose (iAUCglucose) was examined with other glycemic measures. Data was analyzed using linear mixed model for repeated measures. Secondary analysis was conducted by stratifying participants into either a healthier or less healthy subgroup based on the postprandial time to glucose and insulin peaks, with the less healthy subgroup experiencing delayed glucose and/or insulin peaks. Results: There were no overall significant changes to glucose and insulin measures between all plant extracts and placebo (p>0.05). Upon secondary analysis, all extracts affected glycemic responses in the less healthy subgroup. Compared to placebo, grape seed reduced plasma iAUCglucose (p=0.016, 21.9% reduction), 2 h postprandial glucose (2hPG) (p=0.034, 14.7% reduction) and metabolic clearance rate of glucose (MCRglucose) (p=0.016, 16.7% increase). It also improved insulin indices such as 2 h postprandial insulin (2hPI) (p=0.029, 22.4% reduction) and Stumvoll overall insulin sensitivity index (ISIoverall) (p=0.028, 15.0% increase). Rooibos tea extract significantly improved ß-cell function as demonstrated by the increased oral disposition index (DI) (p=0.031, 32.4% increase) compared to placebo. Olive leaf extract significantly increased incremental area under the curve of insulin (iAUCinsulin) (p=0.040, 16.7% increase). Conclusion: Grape seed, rooibos tea and olive leaf extracts demonstrated acute hypoglycemic benefits in adults with prediabetes and having less healthy metabolic profiles. A chronic study on the plant extracts is warranted to determine their longer-term impact on prediabetes. [ABSTRACT FROM AUTHOR]

This analysis compared the results from noncompartmental analysis and population pharmacokinetic (PopPK) predictions of exposure changes in patients with renal impairment (RI) for 27 new molecular entities (NMEs) approved between 2000 and 2015. Renal function was identified as a covariate in the final PopPK model for 17 NMEs. The final PopPK model was used to simulate (n = 1000 replicates/individual) the results of a dedicated PK study in subjects with renal impairment. For the majority of NMEs, concordance between observed, and predicted area under the curve (AUC) geometric mean ratio (GMR) was observed (ie, in 17, 11, and 11 NMEs for mild, moderate, and severe renal impairment groups, respectively, the observed and predicted AUC GMR were within the same fold of change). Inclusion of colinear covariates in the PopPK model appeared to be the major driver for the NMEs for which there was discordance. PopPK, when done properly, is a valuable tool for supporting labeling recommendations for subjects with renal impairment. [ABSTRACT FROM AUTHOR]

Objective: Type 2 diabetes (T2D) is one of the centenarian metabolic disorders and is considered as a stellar and leading health issue worldwide. According to the International Diabetes Federation (IDF) Diabetes Atlas and National Diabetes Statistics, the number of diabetic patients will increase at an exponential rate from 463 to 700 million by the year 2045. Thus, there is a great need for therapies targeting functions that can help in maintaining the homeostasis of glucose levels and improving insulin sensitivity. 5′ adenosine monophosphate-activated protein kinase (AMPK) activation, by various direct and indirect factors, might help to overcome the hurdles (like insulin resistance) associated with the conventional approach. Materials and results: A thorough review and analysis was conducted using various database including MEDLINE and EMBASE databases, with Google scholar using various keywords. This extensive review concluded that various drugs (plant-based, synthetic indirect/direct activators) are available, showing tremendous potential in maintaining the homeostasis of glucose and lipid metabolism, without causing insulin resistance, and improving insulin sensitivity. Moreover, these drugs have an effect against diabetes and are therapeutically beneficial in the treatment of diabetes-associated complications (neuropathy and nephropathy) via mechanism involving inhibition of nuclear translocation of SMAD4 (SMAD family member) expression and association with peripheral nociceptive neurons mediated by AMPK. Conclusion: From the available information, it may be concluded that various indirect/direct activators show tremendous potential in maintaining the homeostasis of glucose and lipid metabolism, without resulting in insulin resistance, and may improve insulin sensitivity, as well. Therefore, in a nut shell, it may be concluded that the regulation of APMK functions by various direct/indirect activators may bring promising results. These activators may emerge as a novel therapy in diabetes and its associated complications. [ABSTRACT FROM AUTHOR]

Continuous venovenous hemofiltration (CVVH) is a life‐sustaining procedure in patients with severe burns and acute kidney injury. Physiologic changes from burn injury and use of CVVH may alter imipenem pharmacokinetics (PK). We aimed to compare imipenem clearance (CL) in burn patients with and without CVVH, determine the effect of burn on imipenem volume of distribution (CVVH, n = 12; no CVVH, n = 11), in combination with previously published models. Model qualification was performed with standard diagnostics and comparing predicted PK parameters/time‐concentration profiles with those in the existing literature. Monte Carlo simulations were conducted to evaluate the probability of target attainment. A 2‐compartment model best described the data. Utilizing albumin as a covariate on volume parameters and leveraging the clearance model from prior literature, our model predicted imipenem central volume and CL within a 10% margin of error across healthy, renally impaired, and burn populations. We provide direct comparison of imipenem CL in burn patients with and without CVVH. Notably, there was no significant difference. Large imipenem Vd in patients with severe burns is likely explained by increased capillary permeability, for which serum albumin may be a reasonable surrogate. Dosing 500 mg every 6 hours is adequate for burn patients on renally dosed CVVH; however, suspicion of augmented renal clearance or patients placed on CVVH without renal impairment may necessitate dosing of 1000 mg every 6 hours. [ABSTRACT FROM AUTHOR]

Use of herbal medications and supplements has experienced immense growth over the last two decades, with retail sales in the USA exceeding $13 billion in 2021. Since the Dietary Supplement Health and Education Act (DSHEA) of 1994 reduced FDA oversight, these products have become less regulated. Data from 2012 shows 18% of U.S. adults used non-vitamin, non-mineral natural products. Prevalence varies regionally, with higher use in Western states. Among preoperative patients, the most commonly used herbal medications included garlic, ginseng, ginkgo, St. John's wort, and echinacea. However, 50–70% of surgical patients fail to disclose their use of herbal medications to their physicians, and most fail to discontinue them preoperatively. Since herbal medications can interact with anesthetic medications administered during surgery, the American Society of Anesthesiologists (ASA) and the American Association of Nurse Anesthetists (AANA) recommend stopping herbal medications 1–2 weeks before elective surgical procedures. Potential adverse drug effects related to preoperative use of herbal medications involve the coagulation system (e.g., increasing the risk of perioperative bleeding), the cardiovascular system (e.g., arrhythmias, hypotension, hypertension), the central nervous system (e.g., sedation, confusion, seizures), pulmonary (e.g., coughing, bronchospasm), renal (e.g., diuresis) and endocrine-metabolic (e.g., hepatic dysfunction, altered metabolism of anesthetic drugs). During the preoperative evaluation, anesthesiologists should inquire about the use of herbal medications to anticipate potential adverse drug interactions during the perioperative period. • This review article summarizes the pharmacologic effects and side effects of the most commonly used herbal medications. • Adverse side effects and potential drug interactions between herbal medications used by patients in the preoperative period. • This review provides anesthesia providers with a concise summary of the available pharmacologic data on herbal medications. • Limited scientific evidence in medical literature on herbal medication effects and dosages concerns anesthesia practitioners. • A lack of standardization in the manufacturing/marketing of herbal products also remains a concern for anesthesia providers. [ABSTRACT FROM AUTHOR]

Irritable bowel syndrome (IBS) patients exhibit significantly lower levels of serum selenium (Se) compared to healthy controls. This study integrates a prospective cohort analysis and animal experiments to investigate Se deficiency as a potential risk factor for IBS. Using data from the UK Biobank, a longitudinal analysis was conducted to explore the associations between dietary Se intake and the risk of incident IBS. In animal study, C57BL/6 mice were fed diets with normal (0.2 ppm) or low (0.02 ppm) Se levels to assess the impacts of Se deficiency on IBS symptoms. Furthermore, we performed 16 S rRNA sequencing, untargeted colonic fecal metabolomics analysis, and colon transcriptome profiling to uncover the regulatory mechanisms underlying Se deficiency-induced IBS. The analysis of UK Biobank data revealed a significant correlation between low dietary Se levels and an increased incidence of IBS. In the experimental study, a low Se diet induced IBS symptoms, evidenced by elevated abdominal withdrawal reflex scores, colon inflammation, and severe pathological damage to the colon. Additionally, the low Se diet caused disturbances in gut microbiota, characterized by an increase in Faecalibaculum and Helicobacter , and a decrease in Bifidobacterium and Akkermansia. Combined colonic fecal metabolomics and colon transcriptome analysis indicated that Se deficiency might trigger IBS through disruptions in pathways related to "bile excretion", "steroid hormone biosynthesis", "arachidonic acid metabolism", and "drug metabolism-cytochrome P450". These findings underscore the significant adverse effects of Se deficiency on IBS and suggest that Se supplementation should be considered for IBS patients. • UK Biobank data revealed an inverse correlation between diet Se and IBS incidence. • A low Se diet induced IBS symptoms in mice. • Four KEGG pathways were involved in the induction of IBS by low Se diet. [ABSTRACT FROM AUTHOR]

Background: Hepatitis C virus (HCV) is a major cause of chronic liver disease, with an estimated 170 million people infected worldwide. Treatment of hepatitis C virus has traditionally been difficult because of low rates of treatment success and high rates of treatment discontinuation due to side effects. Aim of the Work: The aim of this work is to study side effects of directly acting anti HCV drug (DAA) and its progression in metabolism of lipid profile, blood sugar level, and renal function. Patients and Methods: This case study had been carried out on 200 subjects presented to Department of Internal Medicine at Kobbri ELkobba hospital inpatient and outpatient clinics between March 2016 and September 2016. Results: sustained virological response (12 weeks) after end of the treatment in more than 90% of patients, Liver function parameters including albumin, bilirubin, and prothrombin time and liver enzymes Ast, Alt improved in the majority of patients during and after the end of therapy, but there is significant increase in urea level, serum creatinin and HbA1C. There is significant decrease in LDL and mild increase in TG level. Conclusion: Once-daily oral daclatasvir plus sofosbuvir with or without Ribavirin was associated with high rates of sustained virologic response among patients infected with HCV, including chronic cirrhotic patients and relapsers, successful treatment associated with Improvement of liver function parameters in the majority of patients, Increase in urea level, serum creatinin and HbA1C. There is significant decrease in LDL and mild increase in TG level. [ABSTRACT FROM AUTHOR]