Human Dose Research Articles

Preclinical safety and efficacy evaluation of the intrathecal transplantation of GMP-grade human umbilical cord mesenchymal stem cells for ischemic stroke

Intrathecal administration of human umbilical cord mesenchymal stem cells may be a promising approach for the treatment of stroke, but its safety, effectiveness, and mechanism remain to be elucidated. In this study, good manufacturing practice–grade human umbilical cord mesenchymal stem cells (5 × 105 and 1 × 106 cells) and saline were administered by cerebellomedullary cistern injection 72 hours after stroke induced by middle cerebral artery occlusion in rats. The results showed (1) no significant difference in mortality or general conditions among the three groups. There was no abnormal differentiation or tumor formation in various organs of rats in any group. (2) Compared with saline-treated animals, those treated with human umbilical cord mesenchymal stem cells showed significant functional recovery and reduced infarct volume, with no significant differences between different human umbilical cord mesenchymal stem cell doses. (3) Human umbilical cord mesenchymal stem cells were found in the ischemic brain after 14 and 28 days of follow-up, and the number of positive cells significantly decreased over time. (4) Neuronal nuclei expression in the human umbilical cord mesenchymal stem cell group was greater than that in the saline group, while glial fibrillary acidic protein and ionized calcium binding adaptor molecule 1 expression levels decreased. (5) Human umbilical cord mesenchymal stem cell treatment increased the number of CD31+ microvessels and doublecortin-positive cells after ischemic stroke. Human umbilical cord mesenchymal stem cells also upregulated the expression of CD31+/Ki67+. (6) At 14 days after intrathecal administration, brain-derived neurotrophic factor expression in the peri-infarct area and the concentrations of brain-derived neurotrophic factor in the cerebrospinal fluid in both human umbilical cord mesenchymal stem cell groups were significantly greater than those in the saline group and persisted until the 28th day. Taken together, these results indicate that the intrathecal administration of human umbilical cord mesenchymal stem cells via cerebellomedullary cistern injection is safe and effective for the treatment of ischemic stroke in rats. The mechanisms may include alleviating the local inflammatory response in the peri-infarct region, promoting neurogenesis and angiogenesis, and enhancing the production of neurotrophic factors.

Development of a pharmacokinetic/pharmacodynamic evaluation model for osteomyelitis and usefulness of tedizolid as an alternative to vancomycin against MRSA osteomyelitis.

This study aimed to develop a suitable osteomyelitis model for pharmacokinetic/pharmacodynamic (PK/PD) evaluation and to investigate the target PK/PD values of vancomycin and tedizolid against methicillin-resistant Staphylococcus aureus (MRSA) osteomyelitis. An osteomyelitis model was established by implanting an MRSA-exposed sterilized suture in the tibia of normal mice and mice with cyclophosphamide-induced neutropenia. The suitability of the osteomyelitis mouse model for PK/PD evaluation was assessed using vancomycin as an indicator. The target PK/PD values for tedizolid were determined using this model. In neutropenic mice, to achieve a static effect and 1 log10 kill against MRSA, the ratios of the area under the free drug concentration-time curve for 24h to the minimum inhibitory concentration (fAUC24/MIC) of vancomycin were 91.29 and 430.03, respectively, confirming the validity of the osteomyelitis model for PK/PD evaluation. In immunocompetent mice, the target fAUC24/MIC values of tedizolid for achieving a static effect and 1 log10 kill against MRSA were 2.40 and 49.20, respectively. Additionally, only a 0.28 log10 kill was achieved in neutropenic mice with 20 times the human equivalent dose of tedizolid. In patients with restored immunity, tedizolid can potentially be used as an alternative to intravenous vancomycin therapy.

Prediction of First-in-Human Dose of Chimeric Antigen Receptor-T (CAR-T) Cells from Mice.

In this study, six scaling methods were evaluated for the prediction of FIH dose for CAR-T cells. The methods were body weight-based fixed exponents such as 1.0 and 0.75, human equivalent dose (HED) using exponents 0.33, two modified HED methods such as using total animal dose (in place of per kg basis) and body surface area in place of body weight using total animal dose with exponent 0.33 and a physiological factor derived from physiological parameters. The FIH doses of six CAR-T cells were predicted in this study. The predicted human doses were compared with the recommended human dose by the US-FDA for four CAR-T cell products, and the literature data were used for the remaining two CAR-T cells. The results indicated that the two modified HED methods and physiological factor are the best and reliable methods for the prediction of FIH dose for CAR-T cells. The proposed methods are simple and accurate in their predictive power and can be used on a spreadsheet.

OA07 Upadacitinib exposure during pregnancy in seronegative Rheumatoid arthritis

Abstract Introduction Targeted therapies have become increasingly prevalent in the management of rheumatoid arthritis (RA), with Janus kinase inhibitors (JAK inhibitors) gaining traction in clinical practice. Upadacitinib, a selective JAK1 inhibitor, is widely used for its efficacy in controlling RA. However, preclinical studies have demonstrated teratogenic effects associated with JAK inhibitors, raising concerns about their safety during pregnancy. Given the limited data on human exposure, current guidelines recommend the immediate discontinuation of JAK inhibitors upon pregnancy detection. This case report details an instance of Upadacitinib exposure during pregnancy. Case description A 36-year-old woman was diagnosed with seronegative RA in January 2020. Her medical history is otherwise unremarkable. She has two children, aged four and two, both of whom were born after uneventful pregnancies. She has no history of spontaneous abortions. At the time of her RA diagnosis, the patient was considering pregnancy and was initially started on sulfasalazine. However, due to the development of a rash, her treatment was switched to certolizumab injections. Despite this treatment, she exhibited only a partial response with ongoing disease activity, leading to a change to etanercept in August 2021. When etanercept proved ineffective, adalimumab was considered in January 2022. Unfortunately, her response to adalimumab was limited. Consequently, she was started on Upadacitinib in July 2022. The patient responded well to Upadacitinib, achieving remission with normal inflammatory markers. In April 2024, the patient reported being six weeks pregnant while on Upadacitinib. Upon confirmation of her pregnancy, Upadacitinib was discontinued at approximately four weeks of gestational age. The parents were informed about the potential risks of teratogenicity. After a detailed discussion with the high-risk pregnancy team, who provided reassurance, the patient decided to continue the pregnancy. She was subsequently started on certolizumab. Unfortunately, the patient experienced a miscarriage at 11 weeks of gestation. Discussion Currently, there are no published human studies available in the literature regarding the effects of upadacitinib during pregnancy. It is crucial to encourage adequate contraception for women of childbearing potential and to verify a negative pregnancy status before initiating therapy. Women with reproductive potential should be advised to use effective contraception during upadacitinib therapy and for at least four weeks after discontinuation. If a patient becomes pregnant while on the drug, they should be informed of the potential risks to the foetus. According to the 2019 product information on upadacitinib, animal studies have shown that the drug, when administered at exposures equal to or greater than approximately 1.6 to 15 times the maximum recommended human dose, resulted in dose-related increases in skeletal and cardiovascular malformations, increased post-implantation loss, and decreased foetal body weights. There are no controlled data on upadacitinib use during human pregnancy, and it is unknown whether the drug can cause foetal harm or adversely affect reproductive capacity in humans. Data about pregnancy while on upadacitinib is limited. There are some unpublished data from the clinical trials and it was noted most of the patients had live births without congenital anomaly. Spontaneous abortions, elective terminations and ectopic pregnancies were among the other outcomes noted. Key learning points • Due to issues such as primary or secondary treatment failures, hypersensitivity reactions, and adverse events, patients often require sequential trials of different agents in management of Rheumatoid Arthritis (RA). Janus kinase inhibitors (JAK inhibitors) have shown remarkable efficacy in managing RA over the last decade. Despite their widespread use, there is limited literature on the safety of upadacitinib exposure during pregnancy in humans. Most of the available data come from unexpected pregnancies documented during clinical trials. • Animal studies indicate that upadacitinib can be harmful to a developing foetus. Furthermore, data suggest that women with RA who experience increased disease activity are at a heightened risk for adverse pregnancy outcomes, including preterm delivery, low birth weight, and infants who are small for gestational age. • It is crucial to emphasize pregnancy contraindications during follow-up appointments for patients on these medications. Access to a medical obstetrician team is invaluable in managing such cases. • While some case reports have documented positive pregnancy outcomes with other JAK inhibitors, such as tofacitinib and baricitinib, there remains a significant gap in knowledge regarding upadacitinib. This case report adds to the limited data on the potential risks associated with upadacitinib exposure during pregnancy. Comprehensive and targeted studies are necessary to better understand the safety of this class of drugs during pregnancy and lactation.

Extraordinary variance in meta-analysis of venom toxicity of 160 most lethal ophidians and guidelines for estimating human lethal dose range

Background: This is the first meta-analysis to characterize intra-ophidian-species variation in whole venom. Being the largest possible meta-analysis at this time, it encompasses all known records of animal lethality studies over the past 100 years. These results were not artifacts of resistant test-animal species and showed orders of magnitude beyond the 1.6 logs (40-fold change) range of lethal dose documented in the literature between amphibians, lizards, and mice. Methods: A total of 1003 lethal dose study results for 160 of the most lethal venomous ophidian species in the world were analyzed. Results: LDLo was not different from LD50 across studies, indicating the true range of toxicity is probably larger. The belief that, for the route of inoculation, IC < IV < IP < IM < SC was well supported (R2 = 0.90). However, 5% of ICs were the highest dose, and 7% of SC inoculations were the lowest dose. Within the mouse test species, for one route of inoculation, the widest LD range was 2.96 logs (917-fold change, N = 20). Within mouse species, for multiple routes of inoculation, the widest LD range was 3.6 logs (4,150-fold change, N = 20). The strongest correlation for the range of lethal dose results was the number of studies (R2 = 0.56), followed by the number of test-animal species (R2 = 0.55) and then the number of routes of inoculation (R2 = 0.43). Conclusion: Scientists working with humans should use combined LDLo and LD50 meta-datasets for all data and calculate mean, median, minimum, range, and standard deviation as shown in the supplement spreadsheet, and the equations we provide. Standard deviation multiples may provide the desired safety for experimenters. For estimating the LD50 range and minimum lethal dose for species with little data, we recommend curating a meta-dataset of related snakes, and computational research to strengthen this estimation.

An Insight of Plant Source, Toxicological Profile, and Pharmacological Activities of Iridoid Loganic Acid: A ComprehensiveReview.

This study evaluates the pharmacological effects of iridoid glucoside loganic acid, a plant constituent with diverse properties, based on literature, and explores the underlying cellular mechanisms for treating several ailments. Data were collected from reliable electronic databases, including PubMed, Scopus, Web of Science, and Google Scholar, etc. The results demonstrated the anti-inflammatory, anti-oxidant, and other protective effects of loganic acid on metabolic diseases and disorders such as atherosclerosis, diabetes, and obesity, in addition to its osteoprotective and anticancer properties. The antioxidant activity of loganic acid demonstrates its capacity to protect cells from oxidative damage and mitigates inflammation by reducing the activity of inflammatory cytokines involving TNF-α and IL-6, substantially upregulating the expression of PPAR-γ/α, and decreasing the clinical signs of inflammation-related conditions related to hypertriglyceridemia and atherosclerosis. Meanwhile, loganic acid inhibits bone loss, exhibits osteoprotective properties by increasing mRNA expression levels of bone synthesizing genes such as Alpl, Bglap, and Sp7, and significantly increases osteoblastic proliferation in preosteoblast cells. Loganic acid is an anti-metastatic drug that reduces MnSOD expression, inhibits EMT and metastasis, and prevents cellular migration, proliferation, and invasion in hepatocellular carcinoma cells. However, additional clinical trials are required to assess its safety, efficacy, and human dose.

Invention of VH-937, a Potent HIV-1 Maturation Inhibitor with the Potential for Infrequent Oral Dosing in Humans

Invention of VH-937, a Potent HIV-1 Maturation Inhibitor with the Potential for Infrequent Oral Dosing in Humans

Preclinical Assessment of the PI3Kα Selective Inhibitor Inavolisib and Prediction of Its Pharmacokinetics and Efficacious Dose in Human

1. Small molecule inhibitors of the PI3K pathway have been extensively investigated as potential anticancer agents. Among the effectors in this pathway, PI3Kα is the kinase most frequently associated with the development of tumors, through mutations and amplifications of the PIK3CA gene encoding the p110α catalytic subunit. 2. Inavolisib (GDC-0077) is a potent and PI3Kα-selective inhibitor that also specifically triggers the degradation of the mutant p110α protein. 3. We characterized inavolisib ADME properties in preclinical in vitro and in vivo studies, assessed its efficacy in the PIK3CA mutant KPL-4 breast cancer xenograft model, and predicted its pharmacokinetics and efficacious dose in humans. 4. Inavolisib had a moderate permeability (1.9•10−6 cm/s) in MDCK cells and was a P-gp and Bcrp1 substrate. It appeared metabolically stable in hepatocytes incubations from human and preclinical species. The systemic clearance was low in mouse, monkey and dog and high in rat. Oral bioavailability ranged from 57.5% to 100%. Inavolisib was efficacious in the KPL-4 sub-cutaneous xenograft model. 5. The PK/PD model parameters estimated from the efficacy study, combined with PBPK model-predicted human PK profiles, projected that a dose of 3 mg could lead to clinical response. Inavolisib is currently being tested in phase 3 trials.

Fluoride Ingestion Induces Formation of Unusual Macromolecular Complexes in Gut Lumen Which Retard Absorption of Essential Minerals and Trace Elements by Chelation.

This study investigates the impact of chronic fluoride exposure on the absorption of essential minerals in the gut and explores the mechanisms underlying mineral deficiencies due to fluoride ingestion. Male Wistar rats were randomly assigned to three groups: group 1 (G-1) served as the control (non-fluoride exposed), while group 2 (G-2) and group 3 (G-3) received human equivalent doses (HED) of fluoride (50 and 100ppm ad libitum, corresponding to 5 and 10ppm in humans, respectively) for 75days. Serum fluoride concentrations were measured, and the levels of essential minerals and trace elements in blood and stool were analyzed using ICP-MS. X-ray diffraction (XRD) analysis was performed on stool samples to identify chemical compounds. The chemical compounds and macromolecular complexes containing fluoride and essential minerals were identified and quantified using Match3 software. Results indicated that the blood concentrations of essential minerals were significantly lower (p ≤ 0.05) in the fluoride-exposed groups compared to the control, while excretion of essential elements in stool was significantly higher (p ≤ 0.05) in the fluoride-administered groups. XRD analysis revealed the formation of unusual macromolecular chemical complexes in the stool of fluoride-treated groups, with the types and concentrations of these compounds increasing with higher fluoride doses. The study concludes that fluoride in the stomach chelates minerals, reducing their absorption, and induces the formation of unusual high molecular weight macromolecular chelation complexes, which alter the chemical species in the gut and further impair the absorption of essential minerals.

Dose-fractionation studies of a Plasmodium phosphatidylinositol 4-kinase inhibitor in a humanized mouse model of malaria.

UCT594 is a 2-aminopyrazine carboxylic acid Plasmodium phosphatidylinositol 4-kinase inhibitor with potent asexual blood-stage activity, the potential for interrupting transmission, as well as liver-stage activities. Herein, we investigated pharmacokinetic/pharmacodynamic (PK/PD) relationships relative to blood-stage activity toward predicting the human dose. Dose-fractionation studies were conducted in the Plasmodium falciparum NSG mouse model to determine the PK/PD indices of UCT594, using the in vivo minimum parasiticidal concentration as a threshold. UCT594 demonstrated concentration-dependent killing in the P. falciparum-infected NSG mouse model. Using this data and the preclinical pharmacokinetic data led to a low predicted human dose of <50 mg. This makes UCT594 an attractive potential antimalarial drug.

Establishing a Relationship between In Vitro Potency in Cell-Based Assays and Clinical Efficacious Concentrations for Approved GLP-1 Receptor Agonists.

Background: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) play an important role in the treatment of type 2 diabetes (T2D) and obesity. The relationship between efficacy and dosing regimen has been studied extensively for this class of molecules. However, a comprehensive analysis of the translation of in vitro data to in vivo efficacious exposure is still lacking. Methods: We collected clinical pharmacokinetics for five approved GLP-1RAs to enable the simulation of exposure profiles and compared published clinical efficacy endpoints (HbA1c and body weight) with in-house in vitro potency values generated in different cell-based assays. Additionally, we investigated the correlation with target coverage, expressed as a ratio between the steady state drug exposure and unbound potency, body weight, or HbA1c reduction in patients with T2D. Results: We found that the best correlation with in vivo efficacy was seen for in vitro potency data generated in cellular assays performed in the absence of any serum albumin or using ovalbumin. Residual variability was larger using in vitro potency data generated in endogenous cell lines or in the presence of human serum albumin. For the human receptor assay with no albumin, exposures above 100-fold in vitro EC50 resulted in >1.5% point HbA1c reduction, while a 5% BW reduction was related to approximately 3× higher exposures. A similar relationship was seen in the ovalbumin assay. Conclusions: Overall, the relationship established for in vitro potency and in vivo efficacy will help to increase confidence in human dose prediction and trial design for new GLP-1RAs in the discovery and early clinical phases.

Updated Risk Assessment of Cannabidiol in Foods Based on Benchmark Dose–Response Modeling

Cannabidiol (CBD), a non-psychotropic main component of the Cannabis plant, has been approved as a drug in the European Union (EU) under the name “Epidyolex”. However, its approval process as a food ingredient under the Novel Food Regulation was paused by the European Food Safety Authority (EFSA) due to a lack of safety data. Nevertheless, there is a growing, unregulated market in which CBD is advertised with various health claims and dosage instructions. Of particular concern is its toxic effect on the liver and possible reproductive toxicity in humans. Studies suitable for calculating the benchmark dose were identified from the available data. Animal studies yielded a benchmark dose lower confidence limit (BMDL) of 43 mg/kg bw/day, which translates into a safe human dose of approximately 15 mg/day. Only the Lowest-Observed-Adverse-Effect Level (LOAEL) of 4.3 mg/kg bw/day could be identified from the human data. This updated risk assessment confirmed a health-based guidance value (HBGV) of 10 mg/day based on human LOAEL. Despite the existing data gaps, preliminary regulation appears advisable because the current form of the gray CBD market is unacceptable from the standpoint of consumer safety and protection.

PBPK-based translation from preclinical species to humans for the full-size IgG therapeutic efalizumab.

Animal models play a vital role in pharmaceutical research and development by supporting the planning and design of later clinical studies. To improve confidence and reliability of first in human dose estimates it is essential to assess the comparability of animal studies with the human situation. In the context of large molecules, it is particularly important to evaluate the cross-species-translatability of parameters related to neonatal fragment crystallizable receptor (FcRn) binding and target mediated drug disposition (TMDD), as they greatly influence distribution and disposition of proteins in the body of an organism. Plasma pharmacokinetic data of the therapeutic protein efalizumab were obtained from literature. Physiologically based pharmacokinetic (PBPK) models were built for three different species (rabbit, non-human primate (NHP), human). Target binding was included in the NHP and human models. The assumption of similar target turnover and target-binding in NHP and human was explored, to gain insights into how these parameters might be translated between species. Efalizumab PBPK models were successfully developed for three species and concentration-time-profiles could be described appropriately across different intravenously administered doses. The final NHP and human models feature a common set of parameters for target turnover and drug-target-complex internalization, as well as comparable target-binding parameters. Our analyses show that different parameter values for FcRn affinity are crucial to accurately describe the concentration-time profiles. Based on the available data in rabbits, NHP and humans, parameters for FcRn affinity cannot be translated between species, but parameters related to target mediated drug disposition can be translated from NHP to human. The inclusion of additional pharmacokinetic (PK) data including different efalizumab doses would further support and confirm our findings on identifying TMDD and, thus, binding kinetics of efalizumab in NHPs. Furthermore, we suggest that information on target expression and internalization rates could make it possible to develop comprehensive human PBPK models with minimal animal testing. In this project, we compared the pharmacokinetics of a therapeutic protein in rabbit, NHP and human using an open PBPK modeling platform (Open Systems Pharmacology Suite, http://www.open-systems-pharmacology.org). Our findings could support similar translatory studies for first in human dose predictions in the future.

Hot topic: Avian influenza subtype H5N1 in US dairy—A preliminary dairy foods perspective

In February and March of 2024, an unusual illness began affecting dairy herds primarily in Texas and neighboring states. The causative agent of this illness was ultimately confirmed in late March 2024 to be a strain of highly pathogenic avian influenza H5N1 belonging to clade 2.3.4.4b. In the months following the emergence of this viral disease in cattle, infections have spread to at least 191 herds in 13 states at the time of this writing in August 2024, primarily through cattle and human movement. Surprisingly, early examination of raw milk samples from clinically affected animals indicated that the virus had an affinity for the mammary tissue, and viral shedding into raw milk occurred at high levels, exceeding 108 log10 50% tissue culture infectious dose (TCID50) in some cases. These high viral loads coupled with evidence that farm cats who consumed raw milk from clinically ill animals were infected and exhibited high mortality rates, raised concerns about the safety of the US milk supply for human consumption. To date, 4 cow-associated human infections have been reported, all from farm employees with direct contact with infected animals. Several parameters ultimately affect the theoretical public health risk from consumption of dairy products manufactured from a milk supply containing H5N1, namely (1) initial viral load, (2) persistence of H5N1 in raw milk, (3) viral inactivation through processing practices including pasteurization, and (4) human susceptibility and infectious dose. In the short period since the emergence of this disease in dairy cattle in the United States, research has begun to answer these critical questions, although our knowledge is still quite limited at this time. Here we review the literature available from the current H5N1 outbreak in US dairy cattle, as well as selected relevant literature from previous research in other animal agriculture sectors, that affect our current understanding of the parameters associated with the food safety risk of this disease in the US dairy supply chain.

Trophic transfer of carbon-14 from algae to zebrafish lead its blending in biomolecules and dysregulating metabolism via isotope effect

Abstract Carbon-14 (C-14) has been a major contributor to the human radioactive exposure dose, as discharged into environment from nuclear industry in larger quantities compared to other radionuclides. This most abundant nuclide enters the biospheric lifecycle as organically bounded C-14 (OBC-14) and threatens to public health, yet it remains unknown how this low radiotoxic nuclide induces health risks via chemical effects, e.g. isotope effect. Via establishing trophic transfer model by algae (Scenedesmus obliquus), daphnia (Daphnia magna) and zebrafish (Danio Rerio), we show that, rapidly incorporation and transformation of inorganic C-14 by algae into OBC-14 enables the blending of C-14 in biomolecules of zebrafish. We find that internalized C-14 persistently retains in brain of zebrafish, impacting on DNA methylation and inducing neuropathology alteration. Global isotope tracing metabolomics with C-14 exposure further highlight the participation of C-14 in various critical metabolic pathways, including one-carbon metabolism and nucleotide metabolism. We thus characterize the kinetic isotope effects (KIEs) for 12C/14C in the critical reaction of this metabolism via kinetic experiments and density functional theory (DFT) computations, showing that the isotopically substitution of carbon in biochemicals regulate metabolism by disrupting reaction ratios via isotope effect. Our findings suggest that nuclear industry discharged inorganic C-14 can be biotransformed to be organically bounded with biomolecules to impact metabolisms via isotope effect, providing new insights on understanding the health risk of C-14 that supposed to be a low radiotoxic nuclide.

UGT2B10 is the Major UDP-Glucuronosyltransferase 2B Isoform Involved in the Metabolism of Lamotrigine and is Implicated in the Drug-Drug Interaction with Valproic Acid.

Lamotrigine is a phenyltriazine anticonvulsant that is primarily metabolized by phase II UDP-glucuronosyltransferases (UGT) to a quaternary N2-glucuronide, which accounts for ~ 90% of the excreted dose in humans. While there is consensus that UGT1A4 plays a predominant role in the formation of the N2-glucuronide, there is compelling evidence in the literature to suggest that the metabolism of lamotrigine is catalyzed by another UGT isoform. However, the exact identity of the UGT isoform that contribute to the formation of this glucuronide remains uncertain. In this study, we harnessed a robust reaction phenotyping strategy to delineate the identities and its associated fraction metabolized (fm) of the UGTs involved in lamotrigine N2-glucuronidation. Foremost, human recombinant UGT mapping experiments revealed that the N2-glucuronide is catalyzed by multiple UGT isoforms. (i.e., UGT1A1, 1A3, 1A4, 1A9, 2B4, 2B7, and 2B10). Thereafter, scaling the apparent intrinsic clearances obtained from the enzyme kinetic experiments with our in-house liver-derived relative expression factors (REF) and relative activity factors (RAF) revealed that, in addition to UGT1A4, UGT2B10 was involved in the N2-glucuronidation of lamotrigine. This was further confirmed via chemical inhibition in human liver microsomes with the UGT1A4-selective inhibitor hecogenin and the UGT2B10-selective inhibitor desloratadine. By integrating various orthogonal approaches (i.e., REF- and RAF-scaling, and chemical inhibition), we quantitatively determined that the fm for UGT1A4 and UGT2B10 ranged from 0.42 - 0.64 and 0.32 - 0.57, respectively. Finally, we also provided nascent evidence that the pharmacokinetic interaction between lamotrigine and valproic acid likely arose from the in vivo inhibition of its UGT2B10-mediated pathway.

Crossing the Chasm: How to Approach Translational Pharmacokinetic-Pharmacodynamic Modeling of Phage Dosing.

Effectively treating multidrug-resistant bacterial infections remains challenging due to the limited drug development pipeline and a scarcity of novel agents effective against these highly resistant pathogens. Bacteriophages (phages) are a potential addition to the antimicrobial treatment arsenal. Though, phages are currently being tested in clinical trials for antibiotic-resistant infections, phages lack a fundamental understanding of optimal dosing in humans. Rationally designed preclinical studies using in vitro and in vivo infection models, allow us to assess clinically relevant phage +/- antibiotic exposure (pharmacokinetics), the resulting treatment impact on the infecting pathogen (pharmacodynamics) and host immune response (immunodynamics). A mechanistic modeling framework allows us to integrate this knowledge gained from preclinical studies to develop predictive models. We reviewed recently published mathematical models based on in vitro and/or in vivo data that evaluate the effects of varying bacterial or phage densities, phage characteristics (burst size, adsorption rate), phage pharmacokinetics, phage-antibiotic combinations and host immune responses. In our review, we analyzed study designs and the data used to inform the development of these mechanistic models. Insights gained from model-based simulations were reviewed as they help identify crucial phage parameters for determining effective phage dosing. These efforts contribute to bridging the gap between phage therapy research and its clinical translation.

Bioaccumulation of natural radionuclides in edible molluscs and associated risk from the Ashtamudi Estuary, situated in a high background natural radiation zone (HBNRA), Kerala, southwest coast of India

The study investigated various natural radionuclides, including 238U, 232Th, 210Po, and 210Pb, in edible molluscan species collected from different zones of the Ashtamudi estuary. Physicochemical and sedimentological factors played crucial roles in influencing the distribution of radionuclides in water and sediments. Notably, bivalve species, particularly those from the Cyrenidae family, exhibited significant bioaccumulation of 210Po (up to 432.8 Bq kg−1) and 210Pb (up to 121.3 Bq kg−1), with Zone VI recording the highest biological concentration factor (BCF) and biological sediment accumulation factor (BSAF). The calculated effective dose for humans consuming bivalve meat was moderate, falling above the lower end of the ICRP range of 1 mSv y−1 but well below the upper limit of 20 mSv y−1 for existing elevated radiation zones. The intake of radioactivity from some bivalves corresponded to a cancer risk of approximately 3.2 × 10−2 (total mortality + morbidity), exceeding the acceptable risk threshold reported by the USEPA. However, this level of exposure indicated that immediate action might not be necessary, especially if further dose reduction proved impractical, in line with the ICRP's approach to optimizing radiation protection.

Immunological properties of silica nanoparticles: a structure–activity relationship study

Silica nanoparticles are increasingly considered for drug delivery applications. These applications require an understanding of their biocompatibility, including their interactions with the immune system. However, systematic studies for silica nanoparticle immunological safety profiles are lacking. To fill this gap, we conducted an in vitro study investigating various aspects of silica nanoparticles’ interactions with blood and immune cells. Four types of silica nanoparticles with variations in size and porosity were studied. These included nonporous Stöber silica nanoparticles with average diameters of approximately 50 and 100 nm (SNP50 and SNP100), mesoporous silica nanoparticles of approximately 100 nm (Meso100), and hollow mesoporous silica nanoparticles of approximately 100 nm (HMSNP100) in diameter, respectively. The hematological compatibility was assessed using hemolysis, complement activation, platelet aggregation, and plasma coagulation assays. The effects of nanoparticles on immune cell function were studied using in vitro phagocytosis, chemotaxis, natural killer cell cytotoxicity, leukocyte proliferation, human lymphocyte activation, colony-forming unit granulocyte-macrophage, and leukocyte procoagulant activity assays. The in vitro findings suggest that at high concentrations, corresponding to the in vivo human dose of 40 mg/kg, silica nanoparticles demonstrated an array of immunotoxic effects that depended on their physicochemical properties. However, all types of silica nanoparticles studied were not immunotoxic at concentrations corresponding to lower doses (≤ 8 mg/kg) comparable to that of nanocarriers in other nanomedicines currently used in the clinic. These findings are promising for using silica nanoparticles for the systemic delivery of bioactive and imaging agents.

Discovery and Development of Highly Potent and Orally Bioavailable Nonpeptidic αvβ6 Integrin Inhibitors.

A series of 3-aryl((S)-3-fluoropyrrolidin-1-yl)butanoic acids were developed as potent orally bioavailable αvβ6 integrin inhibitors. Starting from a zwitterionic peptidomimetic series optimized for inhaled administration, the balancing of potency and passive permeability to achieve suitable oral agents through modification and exploration of aryl substituents and pKa of the central cyclic amine is described. (S)-4-((S)-3-Fluoro-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)-3-(3-(2-methoxyethoxy)phenyl)butanoic acid was found to have highly desirable oral pharmacokinetic profiles in rat, dog, and minipig, with low to moderate clearance (26%, 7%, and 18% liver blood flow, respectively), moderate volumes of distribution (3.6, 1.4, and 0.9 L/kg, respectively), high to complete oral bioavailabilities, high αvβ6 integrin potency of pIC50 of 8.0, and high solubility in physiological media (>2 mg/mL). Equating to the estimated human dose range of 10-75 mg b.i.d. to achieve 90% αvβ6 target engagement at Cmin, it was selected for further investigation as a potential therapeutic agent for the treatment of idiopathic pulmonary fibrosis.