Dose Range Research Articles

Reciprocal and non-reciprocal effects of clinically relevant SETBP1 protein dosage changes.

Many genes in the human genome encode proteins that are dosage sensitive, meaning they require protein levels within a narrow range to properly execute function. To investigate if clinically relevant variation in protein levels impacts the same downstream pathways in human disease, we generated cell models of two SETBP1 syndromes: Schinzel-Giedion Syndrome (SGS) and SETBP1 haploinsufficiency disease (SHD), where SGS is caused by too much protein, and SHD is caused by not enough SETBP1. Using patient and sex-matched healthy first-degree relatives from both SGS and SHD SETBP1 cases, we assessed how SETBP1 protein dosage affects downstream pathways in human forebrain progenitor cells. We find that extremes of SETBP1 protein dose reciprocally influence important signalling molecules such as AKT, suggesting that the SETBP1 protein operates within a narrow dosage range and that extreme doses are detrimental. We identified SETBP1 nuclear bodies as interacting with the nuclear lamina and suggest that SETBP1 may organize higher order chromatin structure via links to the nuclear envelope. SETBP1 protein doses may exert significant influence on global gene expression patterns via these SETBP1 nuclear bodies. This work provides evidence for the importance of SETBP1 protein dose in human brain development, with implications for two neurodevelopmental disorders.

Interleukin-10 exhibit dose-dependent effects on macrophage phenotypes and cardiac remodeling after myocardial infarction

IntroductionInterleukin-10 (IL-10) is a potent immunomodulatory cytokine widely explored as a therapeutic agent for diseases, including myocardial infarction (MI). High-dose IL-10 treatment may not achieve expected outcomes, raising the question of whether IL-10 has dose-dependency, or even uncharted side-effects from overdosing. We hypothesized that IL-10 has dose-dependent effects on macrophage (Mφ) phenotypic transition and cardiac remodeling after MI.MethodsUsing RAW264.7 monocyte models, we examined whether administering differential doses of exogenous IL-10 (0–1,000 ng/mL) perturbs classic M1 (pro-inflammatory) and M2 (anti-inflammatory) phenotypes of polarized Mφ or even alters the phenotypic transition of prospective M1 and M2 polarization. We then investigated the impact of single intramyocardial IL-10 administration on cardiac function, structure, and inflammation post-MI, using a mouse MI model.ResultsCompared with 0-ng/mL control, 250-ng/mL IL-10 had the strongest overall effects in decreasing M1 and increasing M2 phenotypes on polarized Mφ while ≥500-ng/mL IL-10 dampened M1 polarization and augmented native IL-10 secretion more effectively than low doses in vitro. Echocardiography revealed that the 250-ng group had consistently higher contractile function and lower left ventricular (LV) dilatation than the saline control over 6 weeks while ≥1,000-ng groups exhibited transient lower LV ejection fraction at 5 days post-MI in vivo. Moreover, different doses of IL-10 differentially modulated myocardial gene expression, phagocytic cell infiltration at the infarct, LV fibrosis, and revascularization post-MI, with some, but not all, doses exerting beneficial effects.DiscussionOur study suggested that IL-10 has an effective dose range on Mφ phenotypes, and intramyocardial IL-10 treatment may trigger cardioprotective or unwanted effects post-MI in a dose-dependent manner.

Analysis of Departures from Linearity in the Dose Response for Japanese Atomic Bomb Survivor Solid Cancer Mortality and Cancer Incidence Data and Assessment of Low-Dose Extrapolation Factors.

Although leukemia in the Japanese atomic bomb survivor data has long exhibited upward curvature, until recently this appeared not to be the case for solid cancer. It has been suggested that the recently observed upward curvature in the dose response for the Japanese atomic bomb survivor solid cancer mortality data may be accounted for by flattening of the dose response in the moderate dose range (0.3-0.7 Gy). To investigate this, the latest version available of the solid cancer mortality and incidence datasets (with follow-up over the years 1950-2003 and 1958-2009 respectively) for the Life Span Study cohort of atomic bomb survivors were used to assess possible departures from linearity in the moderate dose range. Linear-spline models were fitted, also up to 6th order polynomial models in dose (higher order polynomials tended not to converge). The organ dose used for all solid cancers was weighted dose to the colon. There are modest indications of departures from linearity for the mortality data, whether using polynomial or linear-spline models. Use of the Akaike information criterion (AIC) suggests that the optimal model for the mortality data is given by a 5th order polynomial in dose. There is borderline significant (P = 0.071) indication of improvement provided by a linear-spline model in the mortality data. The low-dose extrapolation factor (LDEF), which measures the degree of overestimation of low-dose linear slope by the linear slope fitted over some specified dose range, is generally between 1.1-2.0 depending on the dose range, with upper confidence limits that sometimes exceed 10; although LDEF < 1 for the lowest dose range (<0.5 Gy), there are substantial uncertainties, with an upper confidence limit that exceeds 1.6. There are generally only modest indications of departures from linearity for the solid cancer incidence data, whether using polynomial or linear-spline models. In contrast to the mortality data, there are much weaker indications of improvement in fit provided by higher order polynomials, and only weak indications (P > 0.2) of improvement provided by linear-spline models. Nevertheless, use of AIC suggests that the optimal model for the incidence data is given by a 3rd order polynomial. LDEF evaluated over various dose ranges is generally between 1.2-1.4 with upper confidence limits that generally exceed 1.6; although LDEF < 1 for the lowest dose range (<0.5 Gy), there are substantial uncertainties, with an upper confidence limit that substantially exceeds 2.0. In summary, the evidence we have presented for higher order powers than the second in the dose response is not overwhelmingly strong, and is to some extent dependent on dose range. A feature of the dose response, which is reflected in the higher-order polynomials fitted to the data, is a leveling off or even a downturn in the response at doses >2 Gy. The linear-quadratic model is very widely used for modeling of dose response, and has been widely used in radiotherapy oncology applications as part of treatment planning. There is a theoretical basis for this model, based on the two-target model, although the data used to validate this has been mainly in vitro; there may be more complicated interactions than are implied by a two-target model, but the contributions made by these, which would contribute to higher order (than quadratic) powers of dose, may not be very pronounced over moderate ranges of dose.

Association of caffeine intake and sleep duration with bone mineral density: a cross-sectional study from National Health and Nutrition Examination Survey between 2011 and 2018

ObjectiveThe association between sleep duration, caffeine intake, and bone mineral density (BMD) is not well understood, with previous studies providing controversial results. This study explores the associations among caffeine intake, sleep duration, and BMD.MethodsData were sourced from the National Health and Nutrition Examination Survey (NHANES) from 2011 to 2018, including 13,457 participants who self-reported sleep duration and caffeine intake, with BMD measured via dual X-ray absorptiometry. Multivariable linear regression models, adjusted for confounders, were used alongside restricted cubic splines to examine dose-response association.ResultsOf all participants, 6821 (50.7%) were males and 6636 were females (49.3%). The mean caffeine intake and sleep duration were 93.4 mg/day and 7.19 h, respectively. RCS results showed that BMD increased with the increase in caffeine intake, especially in the low dose range of 0-200 mg/day. The dose-response association between sleep duration and BMD showed that sleep durations of 0–6 h may promote the increase of BMD, but after sleep durations greater than 6 h, BMD decreases. After adjustment for potential confounders, compared to the lowest referent quartile, individuals with caffeine intake in quartiles 2, 3, and 4 had a positive correlation with BMD (0.62 95% CI: 0.24–1.37; 0.51 95% CI: 0.22–1.13; 0.75 95% CI: 0.41–1.46; P for trend < 0.05). In covariate-adjusted linear regression models, compared with those sleeping 6 h or less per night, the difference in BMD among those sleeping 6–7 h, 7–8 h, and 8–14.5 h per night were 1.81 (95% CI: 0.4122.71), 1.25 (95% CI: 0.55–2.93), and 0.87 (95% CI: 0.38–1.69). Associations of caffeine intake, sleep duration, and BMD stratified by sex and age failed to reach statistical significance.ConclusionsAssociation might exist between the consumption of caffeine, sleep duration, and BMD; however, when stratified by sex and age, the association did not reach statistical significance.

Epidemiological Studies of the Respiratory System in a Cohort of People Exposed to Chronic Radiation Exposure

Diseases of the respiratory system are leading in the structure of oncopathology in persons exposed to chronic radiation exposure in the low dose range. The objective of the work is characterize malignant neoplasms of the respiratory system in the Southern Urals Population Exposed to Radiation cohort over a long period of observation (71 years).Materials and methods. The South Urals Population Exposed to Radiation (SUPER) Cohort by accidents at the Mayak Production Association consists of 62 592 persons. We have detected 1023 cases of death from malignant neoplasms of respiratory system during the 71-year follow-up period. The total number of person-years at risk was 1 964 136. The study used a descriptive and analytical epidemiological method.Results. Deaths from malignant neoplasms of the respiratory system in the Southern Urals Population Exposed to Radiation cohort of the accidentally exposed population were registered in 898 men and 125 women. Mortality from respiratory cancer is significantly higher in men compared to women. The dependence of mortality growth on the age of initiation of exposure and its increase was revealed. Mortality is higher in the Russian ethnic group of the population compared with the ethnic group of Tatars and Bashkirs for all periods of observation, except for the period from 2016 to 2020. An increase in mortality from neoplasms of the respiratory system was revealed with an increase in the age reached and the age of initiation of exposure. The risk of mortality from of respiratory cancer is significantly higher in smokers.Conclusions. The study of oncopathology of respiratory tract in exposed people is undoubtedly of scientific and practical interest. The results can serve as a basis for development and improvement of preventive care programs for the affected population.

Meta-Analysis of the Input and Disposition of Various Dosage Forms of Methylprednisolone in Healthy Subjects Utilizing a Physiologically Based Pharmacokinetic Model.

The study quantitatively analyzes and compares the pharmacokinetics (PK) of methylprednisolone (MPL) in humans upon administration of various dosage forms. The PK parameters and profiles of MPL in healthy subjects were collected from 22 literature sources. A minimal physiologically based pharmacokinetic (mPBPK) model consisting of blood and two tissue (lumped liver and kidney, remainder) compartments with nonlinear tissue partitioning was applied to describe MPL disposition. Overall 18 plasma concentration profiles were well captured and 85% of PK parameters reasonably estimated. The clearance (CL) of MPL averaged 336mL/h/kg and appeared slightly nonlinear across a dosage range of 5 to 800mg, the distribution volume (Vd) averaged 1.17 L/kg, and the model predicted elimination half-life (t1/2) was 2.6h. Rapid prodrug conversion was found for intravenous MPL sodium succinate (MPSS) with a t1/2 of 1.7min, and followed by MPL phosphate (MPPS) 3.8min, MPL hemisuccinate (MPHS) 16min, and MPL suleptanate (MPSP) 2.9h. Their bioavailabilities (F) varied slightly from 60 to 73%. Intramuscular doses showed an absorption rate constant (ka) of 1.5h-1 for MPSS and 96h-1 for MPSP. Oral doses of 5 formulations were examined. Medrol exhibited greatest absorption with F of 74% and ka of 2.1h-1, while one generic product had F of 32.6%. This study demonstrated the utility of a mechanistic mPBPK disposition model for comparing MPL formation from various esters, absorption from several oral dose formulations, and modest variability across numerous PK studies in healthy humans.

Gafchromic Films as a Complementary In-field Dosimetric Tool to Monitor Low Photon Radiation Doses (≤50 mSv).

This study elucidated the radiation response characteristics of a Gafchromic radiochromic film subjected to low photon doses of ≤50 mSv, which corresponds to the annual whole body effective dose limit for radiation workers in Canada. Radiochromic films are investigated for possible use as a complementary tool for the Canadian Armed Forces that can be worn in addition to their existing personal dosimetry to quickly assess personal radiation dose received from radiological hazards without reliance on electronics. The films were exposed to varying photon energies emanating from x-ray generators and radioisotopes, specifically cesium-137, cobalt-60, and americium-241. The resultant radiation-induced film darkening was quantitatively assessed employing three analytical methodologies: net optical density analysis, UV/Visible spectroscopic analysis, and Fourier Transform Infrared spectroscopic analysis. Ideally, a film dosimeter necessitates a pronounced chromatic alteration and the capability to accurately quantify doses ≤50 mSv where net optical density analysis was identified as the optimal modality for interpreting the film darkening into a dose approximation. This new approach established a lower detection threshold of 7.6 mSv for the films when exposed to cesium-137 radiation. Notably, the film exhibited a linear dose response relationship in terms of net optical density; however, a photon energy-dependent variability was observed within the 0-100 mSv dose range. In conclusion, these Gafchromic radiochromic films present a promising candidate for military dosimetry applications. They offer a real-time, visual dose response that can be discerned by military personnel or analyzed using mobile spectroscopic instrumentation. Moreover, these films demonstrate proficiency in the accurate quantification of photon doses ≤50 mSv. Future investigations will evaluate the film's performance under heterogeneous and indeterminate radiation environments, as well as the impact of environmental conditions on the film's performance.

Evolution of the electrical characteristics of the ATLAS18 ITk strip sensors with HL-LHC radiation exposure range

The objective of the study is to evaluate the evolution of the performance of the new ATLAS Inner-Tracker (ITk) strip sensors as a function of radiation exposure, to ensure the proper operation of the upgraded detector during the lifetime of the High-Luminosity Large Hadron Collider (HL-LHC). Full-size ATLAS ITk Barrel Short-Strip (SS) sensors with final layout design, ATLAS18SS, have been irradiated with neutrons and gammas, to confirm the results obtained with prototypes and miniature sensors during the development phase. The irradiations cover a wide range of fluences and doses that ITk will experience, going from 1×1013 neq/cm2 and 0.49 Mrad, to 1.6×1015 neq/cm2 and 80 Mrad. The split irradiation enables a proper combination of fluence and dose values of the HL-LHC, including a 1.5 safety factor. A complete electrical characterization of the key sensor parameters before and after irradiation is presented, studying the leakage current, bulk capacitance, single-strip and inter-strip characteristics. The results confirm the fulfilment of the ATLAS specifications throughout the whole experiment. The study of a wide range of fluences and doses also allows to obtain detailed results, such as the frequency dependence of the bulk capacitance measurements for highly irradiated sensors, or the evolution of the punch-through protection and inter-strip resistance with radiation.

Thermoluminescence properties of Cr, Si, and Mg co-doped Al2O3 ceramics plates under X-ray irradiation

The thermoluminescence (TL) properties and precise dose distribution measurement capabilities of Cr, Si, and Mg co-doped Al2O3 ceramics (Al2O3:Cr,Si,Mg) plates were investigated under X-ray irradiation. The co-doping of Si and Mg significantly enhanced the TL sensitivity, approximately doubling it compared to conventional Al2O3:Cr plates, due to the creation of new trapping levels. The TL dose response was proportional in the dose range of 0.5 to 5 Gy, and off-axis ratio (OAR) measurements confirmed the high spatial resolution and accuracy of the plates to reproduce the radiation distributions. This study is the first to evaluate TL plates of this size (200 × 200 mm2) that utilize Al2O3 as the host material, and demonstrate their significant potential for radiotherapy dosimetry systems. This significant contribution highlights the potential of Al2O3:Cr,Si,Mg ceramic plates to transform dosimetry systems for radiotherapy by providing a combination of high sensitivity, spatial resolution, and robustness. The results of this study lay the groundwork for the development and practical application of large-area TL imaging devices in medical dose verification.

Therapeutic Potential of Oral Nalbuphine for the Treatment of Chronic Pain: A Literature Review

Typical opioids used for pain, including morphine, activate mu opioid receptors. Disadvantages of these drugs include their abuse potential, risk of respiratory depression, and the development of tolerance, dependance, and constipation. Nalbuphine is an injectable opioid agonist-antagonist analgesic with low abuse potential and a unique mechanism of action. Not only is its analgesic potency comparable to morphine within the typical dosing range, but it also has a low risk of clinically significant respiratory depression, and is generally considered much safer than morphine-like opioids. Nalbuphine is not commercially available as an oral product and as such, research on the efficacy of this formulation is limited. While oral nalbuphine has not been studied in chronic pain, the intention of this review is to extrapolate trial data to help determine whether nalbuphine would make a good candidate for use in chronic pain. Oral nalbuphine is effective for the treatment of acute pain and prolonged duration of its use in trials for chronic cough and uremic pruritus have established its safety. The most significant limitation to oral nalbuphine treatment appears to be the frequency of sedation and nausea. The safety and efficacy profile of oral nalbuphine make it a promising therapy option for chronic pain as an alternative to morphine-life opioids, but at this point trials are still needed to make a definitive conclusion.

Single and repeated-dose toxicity studies by intravaginal administration of Lactobacillus plantarum ATG-K2 powder in female rats.

Bacterial vaginosis (BV) isa microbial dysbiosis that shifts the paradigms of vaginal flora from lactobacilli to opportunistic pathogens. Globally, BV is treated with antibiotic therapy and recurrence rates are > 70% occurring within 6months due to antibiotic resistance against pathogenic bacteria. An incorporation of lactobacilli orally or intravaginally for the recolonization of healthy microbes in vagina is the suggested course of treatment. Although Lactobacilli are suggested as a novel therapeutic for women's BV, evaluation of safety and toxicity have not been well understood previously. Therefore, in this study, we aimed to evaluate the safety profile of Lactobacillus plantarum ATG-K2 in subacute intravaginal animal toxicity in Sprague-Dawley rats under OECD guidelines and GLP regulations. Toxicological assessments were performed in a single-dose toxicity study by intravaginal administration with local tolerance study, 1-week repeated-dose intravaginal toxicity dose range finding (DRF) study, and a 2-week repeated-dose intravaginal toxicity study with a 2-week recovery period. Studies were performed at dose 3-18 × 109CFU/head/day. No toxicological changes in clinical signs, body weight, water and food consumption, urinalysis, hematology, clinical biochemistry, gross findings, or histopathological examination were observed in intravaginal repeated-dose toxicity. And Lactobacillus plantarum ATG-K2 did not show any local tolerance at the same doses as the intravaginal repeated-dose toxicity study. In conclusion, the no-observed-adverse-effect level (NOAEL) of Lactobacillus plantarum ATG-K2 was 12 × 109CFU/head/day and no target organ was identified in female rats. Our findings are the first to suggest that Lactobacillus plantarum is safe for use as an intravaginal treatment with no adverse effects observed in toxicological testing and has potential for application as a therapeutic agent or for other biological uses.

Quantification of crisugabalin (HSK16149) in biological matrix by LC-MS/MS method: An application to rat pharmacokinetic and tissue distribution studies

Crisugabalin (HSK16149), a novel VGCC α2δ ligand, has been approved for the treatment of adult diabetic peripheral neuropathic pain (DPNP) and postherpetic neuralgia (PHN). In this study, an LC-MS/MS method was developed for the determination of crisugabalin in rat plasma and tissues homogenate. Samples were extracted by protein precipitation and separated on a Hypersil GOLD aQ column with methanol and 2 mM ammonium acetate in water containing 0.1 % formic acid as mobile phase. Crisugabalin and its internal standard HSK7891 were ionized by electrospray ionization source and detected by multiple reaction monitoring with transitions of m/z 210.9 → 134.4 and m/z 246.0 → 129.3. Over the range of 0.0100–10.0 μg/mL, the selectivity, linearity, precision and accuracy, matrix effect, stability, recovery and dilution integrity of crisugabalin were validated in rat plasma. Validation was also performed in rat liver homogenate at concentrations ranging from 0.0200-20.0 μg/g. The method was then successfully applied to determine the pharmacokinetics and tissue distribution of crisugabalin. In rats, orally administered crisugabalin was completely and rapidly absorbed with a peak time of about 0.57 h, and was mainly distributed to kidney, bladder and liver tissues. crisugabalin exhibited linear pharmacokinetics over the oral dose range of 3–30 mg/kg.

Preclinical pharmacokinetics, absolute bioavailability and dose proportionality evaluation of bioactive phytochemical Withanone in rats.

Withanone (WN), a bioactive phytochemical isolated from the medicinal herb Withania somnifera, has shown multiple pharmacological and therapeutic successes, including neuroprotective and anti-cancer activities. However, detailed pharmacokinetic (PK) properties of pure WN were not well defined. Pharmacokinetic (PK) characteristics, dose proportionality, and absolute bioavailability of pure WN were explored in rats using an efficient, reliable, and sensitive LC-MS/MS assay to address this gap. The method shows excellent linearity over 0.5-500ng/mL (r2≥0.99), is accurate, and requires less analysis time. A dose proportionality and absolute bioavailability of pure WN were determined in Sprague-Dawley (SD) rats through three ascending oral (10, 20, and 40mg/kg) and single intravenous (5mg/kg) PK studies. The peak concentration (Cmax) of WN was 60.53±20.33, 116.30±16.89, and 91.62±6.20ng/mL, corresponding to oral dosage of 10, 20, and 40mg/kg, respectively. WN shows poor systemic exposure upon oral administration, leading to low oral bioavailability (<15%). Additionally, the dose proportionality studies of WN revealed its saturable bioavailability and non-proportional systemic exposure over the dosage range of 10-40mg/kg in rats. The obtained PK findings of this study would be valuable for better understanding the pharmacological effects of WN, dose regimen optimization for future studies, and relevance for clinical reference to support its future development as a potential therapeutic molecule.

Discriminative stimulus properties of α-ethyltryptamine (α-ET) in rats: α-ET-like effects of MDMA, MDA and aryl-monomethoxy substituted derivatives of α-ET.

Rationale α-ET (α-ethyltryptamine), a homolog of the classical hallucinogen α-methyltryptamine, was once prescribed clinically as an antidepressant. Classical psychedelic drugs are currently of interest as potential pharmacotherapy for psychiatric disorders. Objectives Drug discrimination was used to (a) determine if α-ET-like stimulus effects could be engendered by the prototypical phenylalkylamines MDMA ("Ecstasy") or MDA ("Love Drug") and (b) evaluate the α-ET-like stimulus effects of four synthesized aryl-substituted monomethoxy analogs of α-ET (4-OMe-, 5-OMe-, 6-OMe- and 7-OMe-α-ET). Methods Rats were trained to discriminate α-ET (2.5mg/kg) from saline using a two-lever operant task. Results The α-ET (ED50 = 1.04mg/kg) stimulus generalized to MDMA (ED50 = 0.72mg/kg) and MDA (ED50 = 0.48mg/kg). The four α-ET derivatives produced various results; 4-OMe α-ET yielded negligible (20% maximum) α-ET-like responding; 5-OMe α-ET occasioned a modest level (40% maximum) of α-ET-like substitution; 6-OMe α-ET (ED50 = 6.26mg/kg) generalized completely, but in a narrow dose range and in an inverted U-shaped manner; 7-OMe α-ET (ED50 = 2.78mg/kg) generalized completely. Conclusions α-ET stimulus effects are similar to those of MDMA, but appear more closely aligned to those of MDA and are produced by its stereoisomers which, when combined, exert MDA/MDMA-, hallucinogen- and some stimulant-like stimulus actions. Thus, α-ET exerts a complex (compound) stimulus and appears to be a tryptamine counterpart of these prototypic phenylalkylamines. The monomethoxy analogs of α-ET produced an assortment of α-ET-like outcomes such that future investigations of these agents will likely need to be performed on an individual basis; extrapolations of α-ET-like effects to these analogs should be done judiciously.

Tranexamic acid in hip and spine surgery for children with cerebral palsy — a PRISMA-compliant scoping review

Many children with cerebral palsy (CP) are frail and require major hip and/or spine surgeries associated with substantial blood loss. Tranexamic acid (TXA) is commonly used to reduce blood loss, but there is uncertainty around the optimal dose and timing of administration. There have been reviews in sub-populations and specific dosing regimens, but a broad overview of the available literature is lacking. The aim of this review was to map available evidence on TXA in hip and spine surgery for children with CP. Given the heterogeneous literature, a prospectively registered scoping review was conducted. Eligibility criteria were broad. Three screeners were involved, with the senior author consulted when disagreements were not resolved through discussion.Titles and abstracts of 14,609 records were screened, with 52 records included. Two additional records were obtained from grey literature and citation searching. Cohort studies (50.0%) were the most common. Most records (76.9%) were on spine surgery. TXA dose varied widely. Loading doses range from 5 to 100 mg/kg and intraoperative infusions from 1 to 10 mg/kg/h. Dose was not reported in 35.2% of records. Primary outcome measures included blood loss and transfusion requirements. TXA was generally reported to be safe. None of the included records reported postoperative TXA administration.While TXA is generally considered safe, there was mixed evidence on efficacy. Much of the evidence was drawn from studies in which TXA was used in patients at higher risk of bleeding or with reduced physiological reserve. There was no evidence for TXA being used postoperatively, when a large proportion of transfusions occur.

A Prospective, Single-Cohort, Open, Multi-Center, Observational Study of Sublingual Fentanyl for Breakthrough Cancer Pain: Effectiveness, Safety, and Tolerability in Korean Cancer Patients.

Fentanyl, a highly lipophilic opioid, was developed as a sublingual fentanyl tablet (SFT) for the management of breakthrough cancer pain (BTcP), and its efficacy and safety were confirmed in a randomized, controlled study. We investigated the effectiveness and safety of SFT administered to alleviate BTcP in a real-world setting. In this prospective, open, single-cohort study, conducted in 13 referral hospitals in South Korea, opioid-tolerant cancer patients receiving around-the-clock opioids for persistent cancer pain were enrolled if the individual had BTcP ≥ 1 episode/day during the preceding week. The primary outcome was the SFT titration success rate. Among 113 patients evaluated for effectiveness, 103 patients (91.2%) had a successful titration of SFT, with an effective dose range between 100 µg and 400 µg. The most frequent dose was 100 µg, administered to 65.0%, 72.1%, and 81.8% of the patients at Week 1, 4, and 12, respectively. The proportion of patients achieving the personalized pain goal assessed in the first week was 75.2%. The mean change in pain intensity measured with a numeric rating scale at 30 and 60 minutes after taking SFT was -2.57 and -3.62, respectively (p<0.0001 for both). The incidence rate of adverse events related to SFT among 133 patients included for safety evaluation was 9.0% (12/133), which included vomiting (3.0%), nausea (2.3%), and headache (1.5%). In a real-world setting, SFT provides rapid and effective analgesia in BTcP, even at the lowest dose (100 μg), and the safety profile was acceptable.

Research on Mechanical Properties of Cement Emulsified Asphalt Mortar Under the Influence of Water-to-Cement Ratios and Water-Reducing Agent

To understand the mechanical behavior of CRTS (China Railway Track System) II cement emulsified asphalt mortar (CA mortar), this study tested the compressive strength and flexural strength of CA mortar at different ages under varying water-to-cement ratios and dosages of water-reducing agent. Based on X-ray diffraction (XRD) and scanning electron microscopy (SEM) results, the hydration products and microstructure of CA mortar at different ages were analyzed. The main conclusions are as follows. As the water-to-cement ratio increases, the compressive strength and flexural strength of CA mortar generally exhibit a decreasing trend. The strength increases rapidly in the early stages, with the 7-day compressive strength reaching over 80% of the 28-day compressive strength, and the 7-day flexural strength reaching over 93% of the 28-day flexural strength. As the dosage of water-reducing agent increases, both the compressive strength and flexural strength of CA mortar first increase and then decrease, with a reasonable range of water-reducing agent dosage being between 0.2% and 1.0%, and 0.5% is most appropriate. The hydration reaction of CA mortar is nearly complete at 3 days, with the increase in ages, the cement hydration slows down due to the coating action of asphalt, and the strength no longer changes greatly. Hydration products are mainly Ettringite, which is the main source of strength of CA mortar. After the emulsified asphalt breaks, it adsorbs onto the hydration products and sand surfaces, gradually forming a continuous phase, which enhances the structural toughness of the CA mortar.

Development of a physiologically-based pharmacokinetic model for Ritonavir characterizing exposure and drug interaction potential at both acute and steady-state conditions.

Ritonavir (RTV) is a potent CYP3A inhibitor that is widely used as a pharmacokinetic (PK) enhancer to increase exposure to select protease inhibitors. However, as a strong and complex perpetrator of CYP3A interactions, RTV can also enhance the exposure of other co-administered CYP3A substrates, potentially causing toxicity. Therefore, the prediction of drug-drug interactions (DDIs) and estimation of dosing requirements for concomitantly administered drugs is imperative. In this study, we aimed to develop a physiologically-based PK (PBPK) model for RTV using the PK-sim® software platform. A total of 13 clinical PK studies of RTV covering a wide dose range (100 to 600 mg including both single and multiple dosing), and eight clinical DDI studies with RTV on CYP3A and P-gp substrates, including alprazolam, midazolam, rivaroxaban, clarithromycin, fluconazole, sildenafil, and digoxinwere used for the model development and evaluation. Chronopharmacokinetic differences (between morning vs. evening doses) and limitations in parameter estimation for biochemical processes of RTV from invitro studies were incorporated in the PBPK model. The final developed PBPK model predicted 100% of RTV AUClast and Cmax within a twofold dimension error. The geometric mean fold error (GMFE) from all PK datasets was 1.275 and 1.194, respectively. In addition, 97% of the DDI profiles were predicted with the DDI ratios within a twofold dimension error. The GMFE values from all DDI datasets were 1.297 and 1.212, respectively. Accordingly, this model could be applied to the prediction of DDI profiles of RTV and CYP3A substrates and used to estimate dosing requirements for concomitantly administered drugs.

Tolerability, safety, and pharmacokinetics of GR1603 injection in healthy subjects: a randomized, double-blind, placebo-controlled single-dose escalation clinical trial

ABSTRACT Background GR1603 is a monoclonal antibody targeting the type I interferon receptor. The aim of this study was to evaluate the safety, tolerability, pharmacokinetics, immunogenicity and pharmacodynamics of GR1603 in healthy volunteers. Methods Healthy adults (≥18 years old) were enrolled in a placebo control, dose-escalation Phase I clinical trial receiving a single injectable dose of GR1603. Follow-up was 12 weeks. Adverse event (AE) profiles, vital signs, and blood samples were collected for assessment of safety, PK, and expression of type I interferon inducible genes. Results Of the 46 subjects, 44 completed treatment. In the experimental group of 34 subjects (mean age 26.6 years), 30 experienced treatment-emergent adverse events (TEAEs), with a total of 102 occurrences, resulting in an incidence rate of 88.2%. The most commonly reported drug-related AEs were upper respiratory tract infection (17.6%), all of which were ≤ grade 2. GR1603 exhibits non-linear PK in the dose range of 0.1 mg/kg to 9 mg/kg. All samples were negative for anti-drug antibodies before and after dosing. The degrees of IFN gene signature were significantly inhibited in the higher dose groups. Conclusion The safety/tolerability, PK and exploratory metrics observed in this study support further clinical development of GR1603. Clinical trial registration www.chictr.org.cn/searchproj.html identifier is ChiCTR2100045628.

Population Pharmacokinetics of Epcoritamab Following Subcutaneous Administration in Relapsed or Refractory B Cell Non-Hodgkin Lymphoma.

Epcoritamab is a CD3xCD20 bispecific antibody approved for the treatment of adults with different types of relapsed or refractory (R/R) B cell non-Hodgkin lymphoma (B-NHL) after ≥ 2 lines of systemic therapy. Here we report the first results from a population pharmacokinetic model-based analysis using data from 2 phase 1/2 clinical trials (EPCORE® NHL-1, NCT03625037 and EPCORE NHL-3, NCT04542824) evaluating epcoritamab in patients with R/R B-NHL. Plasma concentration-time data included 6819 quantifiable pharmacokinetic samples from 327 patients with R/R B-NHL. A wide range of subcutaneous epcoritamab doses, 0.004-60 mg, was explored, with most patients (n = 298) following the approved dosing regimen: step-up dose (SUD) 1 of 0.16 mg on cycle 1 day 1 and SUD 2 of 0.8 mg on cycle 1 day 8, followed by a full dose of 48 mg administered weekly during cycles 1-3, biweekly in cycles 4-9, and every 4 weeks thereafter. Each cycle lasted 28 days. The data were analyzed using nonlinear mixed-effects modeling. Quasisteady-state approximation of a two-compartment target-mediated drug disposition model with first-order absorption adequately characterized pharmacokinetics of epcoritamab following subcutaneous administration. After the first full dose and at the end of the weekly dosing regimen (end of cycle 3), the estimated median time to maximum concentration (tmax) was 4 and 2.3 days, respectively. Age and body weight were significant covariates on the pharmacokinetics of epcoritamab. The geometric mean (coefficient of variation [CV], %) of the apparent total volume of distribution was 25.6 L (82%) for patients with R/R large B cell lymphoma in EPCORE NHL-1. Epcoritamab elimination exhibited nonlinear characteristics, with exposure increasing more than proportionally over 1.5-48 mg doses. The geometric mean (CV%) values of apparent total clearance and terminal half-life were 0.53 L/day (40%) and 22 days (58%), respectively, at the end of cycle 3 for the 48 mg full dose. Clinical data analyses did not identify any association between assessed characteristics, including body weight or age, and clinical efficacy or safety. After accounting for body weight, no clinically significant differences in epcoritamab pharmacokinetics were observed for sex, race, renal or hepatic function, or other disease characteristics. Age was not found to significantly affect epcoritamab pharmacokinetic exposure. Antidrug antibodies developed in 4 (2.6%) of 156 evaluable patients treated with the approved 0.16/0.8/48 mg regimen. Antidrug antibody status did not affect epcoritamab pharmacokinetics. Epcoritamab pharmacokinetics in R/R B-NHL were well characterized by the population pharmacokinetic model. No dosage adjustments are recommended in subpopulations based on body weight, age, sex, race, mild-to-moderate renal impairment, or mild hepatic impairment. The risk of immunogenicity was low. These are the first published results of population pharmacokinetic modeling for epcoritamab.