Dose Range Research Articles

The impact of different strategies for modeling associations between medications at low doses and health outcomes: a simulation study and practical application to postpartum opioid use.

Pharmacoepidemiological studies commonly examine the association between drug dose and adverse health outcomes. In situations where no safe dose exists, the choice of modeling strategy can lead to identification of an apparent safe low dose range in the presence of a non-linear relationship or due to the modeling strategy forcing a linear relationship through a dose of 0. We conducted a simulation study to assess the performance of several regression approaches to model the drug dose-response curve at low doses in a setting where no safe range exists, including the use of a (1) linear dose term, (2) categorical dose term, and (3) natural cubic spline terms. Additionally, we introduce and apply an expansion of prior work related to modeling dose-response curves at low and infrequently used doses in the setting of no safe dose ("spike-at-zero" and "slab-and-spline"). Furthermore, we demonstrate and empirically assess the use of these regression strategies in a practical scenario examining the association between the dose of the initial postpartum opioid prescribed after vaginal delivery and the subsequent total dose of opioids prescribed in the entire postpartum period among a cohort of opioid-naïve women with a vaginal delivery enrolled in a State Medicaid program (2007-2014).

First-in-human study to assess the safety, tolerability, and pharmacokinetics of intravenous SHPL-49 following single- and multiple-ascending-dose administration in healthy adults

SHPL-49 is an innovative glycoside derivative that is synthesized by structural modifications of salidroside，demonstrating therapeutic effects on animal models of ischemia in pre-clinical experiments. A phase I, single-center, randomized, double-blind, placebo-controlled, single and multiple dose administration study of SHPL-49 was conducted in healthy Chinese volunteers. In single-ascending-dose (SAD) study, 32 subjects randomized 6:2 to receive SHPL-49 (30 mg, 75 mg, 150 mg, 300 mg) or placebo with 30 minutes infusion. In multiple-ascending-dose (MAD) study, subjects were randomized 6:2 to receive SHPL-49 (75 mg, 150 mg, 300 mg) or placebo with 30 minutes infusion every 8 h for 7 days. Safety evaluations were conducted throughout the studies. Plasma and urine concentrations of SHPL-49 were detected and its metabolites were identified. Pharmacokinetic parameters were calculated using noncompartmental methods. SHPL-49 was generally safe and well-tolerated at single ascending doses (30–300 mg) and multiple ascending doses (75–300 mg). All adverse events were mild and resolved without any intervention. No serious adverse events were reported. In the SAD study, SHPL-49 exhibited dose-proportional plasma pharmacokinetics, with peak plasma concentration (Cmax) ranging from 673.83 to 6275.00 ng/mL, area under the plasma concentration-time curve (AUC0–t) ranging from 338.57 to 3732.67 h·ng/mL, and elimination half-life (t1/2) ranging from 0.49 to 0.67 h. In the MAD, the exposure was also dose-proportional and there was no significant accumulation following multiple dosing. Four metabolites were identified in urine and plasma. SHPL-49 shows a favorable pharmacokinetic, safety, and tolerability profile in healthy Chinese volunteers following a single- and multiple-ascending- dose administration in this study. For future therapeutic investigations, it is recommended to administer SHPL-49 intravenously at 8-hour intervals with a dosage range of 150–300 mg.

Structural, optical and thermoluminescence properties of amazonite

This study presents an analysis of the structural and thermoluminescence properties of amazonite, a feldspar species. The characterization was done using X-ray diffraction (XRD), X-ray fluorescence (XRF), optical spectroscopy, and vibrational spectroscopies such as Raman and Fourier Transform Infrared (FTIR). The sample exhibits a partial (Al, Si) ordenation, and contains an albite phase in addition to microcline. FTIR and Raman indicated the presence of water and OH– vibration modes. Optical absorption measurements highlighted the influence of the hydroxyl groups as catalyst for Pb transitions, contributing to the coloration of amazonite. Thermoluminescence (TL) studies were performed within a dose range from 0.1 to 10 Gy using a built-in beta source (90Sr/90Y; delivering 10 mGy/s), showing seven TL glow peaks based on non-first kinetic order. The sample exhibited a linear dose–response, with TL signals proving to be both repeatable and reproducible (CV ∼ 2%). Fading analysis showed the first two TL peaks disappear after 16 days of dark storage. Thermal quenching behavior was investigated under various heating rates, demonstrating a decrease in luminescence efficiency with increasing heating rates. Additionally, the activation energies were determined using different methods, and the amazonite TL glow curve presented activation energies values within 0.7 to 2 eV.

The potential of integrating stereotactic ablative radiotherapy techniques with hyperfractionation for lung cancer.

Limited literature exists on the feasibility and effectiveness of integrating stereotactic ablative radiotherapy (SABR) techniques with hyperfractionated regimens for patients with lung cancer. This study aims to assess whether the SABR technique with hyperfractionation can potentially reduce lung toxicity. We utilized the linear-quadratic model to find the optimal fraction to maximize the tumor biological equivalent dose (BED) to normal-tissue BED ratio. Validation was performed by comparing the SABR plans with 50 Gy/5 fractions and hyperfractionationed plans with 88.8 Gy/74 fractions with the same tumor BED and planning criteria for 10 patients with early-stage lung cancer. Mean lung BED, Lyman-Kutcher-Burman (LKB) normal tissue complication probability (NTCP), critical volume (CV) criteria (volume below BED of 22.92 and 25.65 Gy, and mean BED for lowest 1000 and 1500 cc) and the percentage of the lung receiving 20Gy or more (V20) were compared using the Wilcoxon signed-rank test. The transition point occurs when the tumor-to-normal tissue ratio (TNR) of the physical dose equals the TNR of α/β in the BED dose-volume histogram of the lung. Compared with the hypofractionated regimen, the hyperfractionated regimen is superior in the dose range above but inferior below the transition point. The hyperfractionated regimen showed a lower mean lung BED (6.40 Gy vs. 7.73 Gy) and NTCP (3.50% vs. 4.21%), with inferior results concerning CV criteria and higher V20 (7.37% vs. 7.03%) in comparison with the hypofractionated regimen (p < 0.01 for all). The hyperfractionated regimen has an advantage in the high-dose region of the lung but a disadvantage in the low-dose region. Further research is needed to determine the superiority between hypo- and hyperfractionation.

Effect of Ca co-doping on gamma-stimulated luminescence of Lu2SiO5:Ce

In order to estimate the stability of the light output of the scintillation detector, the Lu2SiO5:Ce scintillation crystals, additionally doped with Ca2+ ions at concentrations of 0 ÷ 0.4 at%, were studied. The spectra of optical absorption, gamma-luminescence, thermal luminescence, dose and temperature dependences of luminescence were measured. Gamma-luminescence in the dose range 10 - 5·107 Gy was recorded using 60Co gamma-source at the temperature range of 310–460 K. In contrast to the initial sample (non-doped with Ca), in the sample doped with 0.1 at% of Ca, an increase in the luminescence intensity was observed in the range of 390–425 nm, but further with an increase in the concentration of Ca (0.3–0.4 at%), the intensity of this band decreased to the initial level (undoped). At Ca concentrations of 0.3 and 0.4 at%, the intensity of the Ce1 center band remains practically unchanged up to a dose of 5·107 Gy. LSO crystals doped with Ce 0.1 at% and co-doped with Ca 0.1 at% can be recommended as a scintillation detector up to a gamma-dose of 105 Gy at room temperature.

Population pharmacokinetics of TLD-1, a novel liposomal doxorubicin, in a phase I trial.

TLD-1 is a novel pegylated liposomal doxorubicin (PLD) formulation aiming to optimise the PLD efficacy-toxicity ratio. We aimed to characterise TLD-1's population pharmacokinetics using non-compartmental analysis and nonlinear mixed-effects modelling. The PK of TLD-1 was analysed by performing a non-compartmental analysis of longitudinal doxorubicin plasma concentration measurements obtained from a clinical trial in 30 patients with advanced solid tumours across a 4.5-fold dose range. Furthermore, a joint parent-metabolite PK model of doxorubicinentrapped, doxorubicinfree, and metabolite doxorubicinol was developed. Interindividual and interoccasion variability around the typical PK parameters and potential covariates to explain parts of this variability were explored. Medians standard deviations of dose-normalised doxorubicinentrapped+free Cmax and AUC0-∞ were 0.342 0.134mg/L and 40.1 18.9mg·h/L, respectively. The median half-life (95h) was 23.5h longer than the half-life of currently marketed PLD. The novel joint parent-metabolite model comprised a one-compartment model with linear release (doxorubicinentrapped), a two-compartment model with linear elimination (doxorubicinfree), and a one-compartment model with linear elimination for doxorubicinol. Body surface area on the volumes of distribution for free doxorubicin was the only significant covariate. The population PK of TLD-1, including its release and main metabolite, were successfully characterised using non-compartmental and compartmental analyses. Based on its long half-life, TLD-1 presents a promising candidate for further clinical development. The PK characteristics form the basis to investigate TLD-1 exposure-response (i.e., clinical efficacy) and exposure-toxicity relationships in the future. Once such relationships have been established, the developed population PK model can be further used in model-informed precision dosing strategies. ClinicalTrials.gov-NCT03387917-January 2, 2018.

H-BN layered material: A new frontier in radiation dosimetry

This study explores the potential of hexagonal boron nitride (h-BN) nanostructures for dosimetry of diverse ionizing radiation. We focus on the crucial thermoluminescence (TL) properties of h-BN, including glow curve, dose-response, reproducibility, sensitivity, and fading, within the conventional framework of TL dosimetry. The h-BN powder samples were exposed to different ionizing radiations, including 60Co gamma-rays with a mean energy of 1.25 MeV, electrons (6 MeV), and photons (6 MV), at levels of dose familiar in radiotherapy ranging from 2 Gy to 15 Gy. The h-BN's effective atomic number of 6.25, similar to human tissue, opens up exciting possibilities for applications in medical imaging and dosimetry. Notably, h-BN demonstrates a linear response within the dose range of interest, showcasing excellent sensitivity, particularly at low doses and low photon energies. Additionally, h-BN samples exhibit remarkable reproducibility, with a standard deviation of less than 2.4%, albeit accompanied by significant fading. Regarding the trapping parameters underpinning the manifestation of the glow curves of the irradiated samples, use was made of the peak shape method with different models to estimate the order of kinetics (b), activation energy (E), and frequency factor (s) or escape probability and trap lifetime (τ). The data suggest that the TL glow peaks of the h-BN obey general-order kinetics. These findings underscore the transformative potential of h-BN layered material in advancing radiation dosimetry, particularly in medical physics fields. The inherent characteristics of h-BN, coupled with its effective atomic number, excellent linearity over a wide range of radiation doses especially for electron irradiation and better reproducibility, positioned it as a suitable tool for precise and reliable dose measurement in medical imaging and therapy, heralding a new frontier in radiation dosimetry.

Studying the toxicity and safety of the carbon mass of hemosorbent

In recent years, methods of extracorporeal detoxification using carbon materials have received due recognition and widespread development. Carbon materials for blood detoxification based on coal have firmly taken a dominant position among sorption materials. This is due, first of all, to the fact that carbon sorbents have wide possibilities for selecting the required physicochemical and structural sorption characteristics. It has been established that a single oral administration of biomass to rats at a dose of 75 mg/kg does not cause any signs of intoxication. At the same time, no animal deaths were recorded throughout the entire observation period. There were no gender differences in the sensitivity of rats to the action of the drug. Due to the lack of mortality in the dose range studied, the lethal doses of LD100 and LD50 could not be determined.

The morphophysiological and yield characteristics of biquinho amarelo pepper in response to bovine rumen residue and chicken litter in soil are dose dependent

In response to the growing demand for environmentally sustainable agricultural practices that enhance production efficiency, this study aimed to determine the optimal application rates of bovine rumen content (CBR) and chicken litter (CCL) as organic composts. Conducted in a controlled greenhouse environment, the research assessed the effects of various doses of these composts on soil chemical and microbiological properties and on the growth and productivity of yellow biquinho pepper (Capsicum chinense Jacq.). The results of this study confirm that organic composts improve soil health and increase the growth and productivity of yellow biquinho pepper. However, while CBR consistently enhances plant growth across a range of doses, CCL shows a dose-dependent response, with the highest fruit production achieved at an application rate of 73.92 Mg ha−1. Although this dose of CCL is beneficial for increasing yield, it also marks a threshold beyond which further increases may lead to negative effects such as nutrient saturation or salt accumulation, potentially resulting in soil toxicity. The study supports the use of CBR and CCL as effective soil conditioners and emphasizes the need to identify the optimal compost dose to efficiently harness the benefits of organic composts in sustainable agricultural practices.

Effect of duloxetine on changes in serum proinflammatory cytokine levels in patients with major depressive disorder

ObjectiveAccumulating evidence supports the idea that inflammation may contribute to the pathophysiology of major depressive disorder (MDD). Duloxetine, a serotonin-norepinephrine reuptake inhibitor, exhibits anti-inflammatory effects both in vitro and in vivo. In this study, we investigated the impact of duloxetine on changes in serum proinflammatory cytokine levels among individuals diagnosed with MDD.MethodsA cohort of 23 drug-naïve individuals diagnosed with MDD and 23 healthy controls were included in this study. The severity of depressive symptoms was evaluated using the 24-item Hamilton Depression Scale (HAMD-24). A panel of 7 proinflammatory cytokines, including interleukin-1β (IL-1β), IL-2, IL-6, IL-8, IL-12, tumor necrosis factor-α (TNF-α), and interferon-γ (IFN-γ), were quantified using multiplex Luminex assays. The levels of serum cytokines in healthy controls and patients with MDD were compared at baseline. All patients received duloxetine at a dosage range of 40–60 mg/day for a duration of 4 weeks. The HAMD-24 scores and serum cytokine levels were compared before and after duloxetine treatment.ResultsCompared with healthy controls, patients with MDD had significantly greater levels of IL-2, IL-6, IL-8, IL-12, TNF-α, and IFN-γ (P < 0.05). Moreover, there was a significant decrease in HAMD-24 scores observed pre- and post-treatment (t = 13.161, P < 0.001). Furthermore, after 4 weeks of treatment, the serum levels of IL-8 (t = 3.605, P = 0.002), IL-12 (t = 2.559, P = 0.018), and IFN-γ (t = 3.567, P = 0.002) decreased significantly. However, there were no significant differences in other cytokines, including IL-1β, IL-2, IL-6, and TNF-α, before and after treatment (P > 0.05).ConclusionsThese findings present compelling evidence, potentially for the first time, indicating that duloxetine treatment may effectively reduce the serum concentrations of IL-8, IL-12, and IFN-γ in individuals diagnosed with MDD. However, the precise mechanisms underlying this effect remain unclear and warrant further investigation.

Safety, tolerability, and pharmacokinetic of HY0721 in Chinese healthy subjects: A first-in-human randomized, double-blind, placebo-controlled dose escalation phase I study

BackgroundHY0721 is a novel inhibitor of sulfonylurea receptor 1–transient receptor potential melastatin 4 (SUR1-TRPM4) for the treatment of acute ischemic stroke. This study aimed to evaluate the safety, tolerability, and pharmacokinetic (PK) profiles of single and multiple intravenous administration of HY0721 in Chinese healthy subjects. MethodsThe study enrolled 48 and 30 healthy volunteers in the single-ascending dose (SAD) cohort (20, 60, 120, 240, and 320 mg) and multiple-ascending dose (MAD) cohort (60, 120, and 160 mg/bid), respectively, to receive the corresponding dosage of HY0721 or placebo. Safety monitoring included but was not limited to recording adverse events (AEs), vital signs, electrocardiograms, and laboratory tests. The blood samples were collected from subjects to determine the concentrations of HY0721 for PK evaluation. ResultsThe administration of HY0721 showed good safety and tolerability up to 320 mg in the SAD study and up to 160 mg twice daily in the MAD study. The most common AE was injection site reaction, and no AE led to discontinuation of administration or subject dropout. The exposures of HY0721 increased greater than dose proportional manner at the dosages of 20 to 320 mg in the SAD study. A linear PK profile was observed following multiple doses ranging from 60 to 160 mg twice daily, with no evidence of accumulation. Additionally, the human effective dose of HY0721 was estimated to be 120 mg. ConclusionThis study demonstrated the intravenous administration of HY0721 is safe and well-tolerated in Chinese healthy subjects and provided 60 to 160 mg b.i.d. as the recommended dosing range for further clinical trials. Trial registrationChinaDrugTrials.Org.cn; No. CTR20202604, 18 December 2020.

Nimbolide: A Potential Phytochemical Agent in Multimodal Pancreatic Cancer Therapies.

A significant contributor to cancer-related death, pancreatic cancer (PC) has a terrible prognosis in general that has not altered over many years. Currently, it is extremely difficult to prevent disease or discover it early enough to initiate treatment. The major challenge in PC is acquired chemo-radio resistance, which makes it very difficult to manage. PC is a challenging malignancy to treat, and several major impediments significantly impact the effectiveness of its treatment. These obstacles primarily include chemoresistance, drug toxicity, and limited drug bioavailability. Phytochemicals can be used as an alternative to chemotherapeutic drugs, or they can augment the anticancer properties of the chemotherapeutic agents. Nimbolide (NL) is a prominent limonoid compound found in Azadirachta indica, and has garnered substantial attention as a phytochemical with anticancer potential. It has powerful antiproliferative effects on a variety of cancer cell lines and is effective as a chemotherapeutic in preclinical studies. The primary modes of action of NL include suppression of metastasis and angiogenesis, activation of apoptosis, anti-proliferation, and control of enzymes that metabolize carcinogens. Despite numerous pharmacodynamic (PD) investigations, NL is still in the early stages of the drug development process because no comprehensive pharmacokinetic (PK) studies or long-term toxicity studies. Preclinical PK and toxicological assessments should be conducted to establish an appropriate dosage range, ensuring the safety of NL for its application in initial human clinical trials. This review endeavors to provide a comprehensive summary of the current developmental stage of NL along with nanoparticles as a principal candidate for therapeutic purposes in PC.

Precision dose prediction for breast cancer patients undergoing IMRT: The Swin-UMamba-Channel Model

BackgroundRadiation therapy is one of the crucial treatment modalities for cancer. An excellent radiation therapy plan relies heavily on an outstanding dose distribution map, which is traditionally generated through repeated trials and adjustments by experienced physicists. However, this process is both time-consuming and labor-intensive, and it comes with a degree of subjectivity. Now, with the powerful capabilities of deep learning, we are able to predict dose distribution maps more accurately, effectively overcoming these challenges. MethodsIn this study, we propose a novel Swin-UMamba-Channel prediction model specifically designed for predicting the dose distribution of patients with left breast cancer undergoing radiotherapy after total mastectomy. This model integrates anatomical position information of organs and ray angle information, significantly enhancing prediction accuracy. Through iterative training of the generator (Swin-UMamba) and discriminator, the model can generate images that closely match the actual dose, assisting physicists in quickly creating DVH curves and shortening the treatment planning cycle. Our model exhibits excellent performance in terms of prediction accuracy, computational efficiency, and practicality, and its effectiveness has been further verified through comparative experiments with similar networks. ResultsThe results of the study indicate that our model can accurately predict the clinical dose of breast cancer patients undergoing intensity-modulated radiation therapy (IMRT). The predicted dose range is from 0 to 50 Gy, and compared with actual data, it shows a high accuracy with an average Dice similarity coefficient of 0.86. Specifically, the average dose change rate for the planning target volume ranges from 0.28 % to 1.515 %, while the average dose change rates for the right and left lungs are 2.113 % and 0.508 %, respectively. Notably, due to their small sizes, the heart and spinal cord exhibit relatively higher average dose change rates, reaching 3.208 % and 1.490 %, respectively. In comparison with similar dose studies, our model demonstrates superior performance. Additionally, our model possesses fewer parameters, lower computational complexity, and shorter processing time, further enhancing its practicality and efficiency. These findings provide strong evidence for the accuracy and reliability of our model in predicting doses, offering significant technical support for IMRT in breast cancer patients. ConclusionThis study presents a novel Swin-UMamba-Channel dose prediction model, and its results demonstrate its precise prediction of clinical doses for the target area of left breast cancer patients undergoing total mastectomy and IMRT. These remarkable achievements provide valuable reference data for subsequent plan optimization and quality control, paving a new path for the application of deep learning in the field of radiation therapy.

Dosimetric response of radiophotoluminescent glass detectors in a scanning pencil proton beam

The dose and linear energy transfer (LET) dependence of the radiophotoluminescence (RPL) response was evaluated for RPL glass detectors, taken from the environmental dosimeter type SC-1, using a clinical 100 MeV and 200 MeV scanning pencil proton beam. The measurements were performed at different positions along the Bragg curves. The fluence-averaged (LETf) and dose-averaged (LETd) LET at the positions of the detectors were calculated using two Monte Carlo codes (MCNP and PHITS). Before measurements in proton beams, the linearity of the dose response for the dose range of interest (up to 10 Gy) was checked and confirmed in a Co-60 gamma ray field, since the FGD-202 reader for SC-1 dosimeters is usually used for doses up to 1 Gy and we found no data for higher doses in the literature. For proton beams, the linear dose response was determined for the doses investigated from 0.5 Gy to 8.8 Gy. For the LET range, which corresponds to the LETd from 0.47 keV/μm to 4.70 keV/μm, a decrease in response with an increase in LET was observed.

A Phase 1, randomized, double-blind, placebo-controlled, single- and multiple-dose escalation study to evaluate the safety and pharmacokinetics/pharmacodynamics of PF-06835375, a C-X-C chemokine receptor type 5 directed antibody, in patients with systemic lupus erythematosus or rheumatoid arthritis

BackgroundThe objective of this study was to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of PF‑06835375, a potent selective afucosyl immunoglobulin G1 antibody targeting C-X-C chemokine receptor type 5 (CXCR5) that potentially depletes B cells, follicular T helper (Tfh) cells, and circulating Tfh-like (cTfh) cells, in patients with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA).MethodsThis first-in-human, multicenter, double-blind, sponsor-open, placebo-controlled Phase 1 study recruited patients aged 18–70 years with SLE or RA. In Part A, patients received single doses of intravenous PF-06835375 (dose range: 0.03–6 mg) or placebo in six sequential single ascending dose (SAD) cohorts. In Part B, patients received repeat doses of subcutaneous PF-06835375 (dose range: 0.3–10 mg) or placebo on Days 1 and 29 in five multiple ascending dose (MAD) cohorts. Tetanus/Diphtheria (Td) and Meningococcal B (MenB/Trumenba™) vaccines were administered at Day 4 (Td and MenB) and Week 8 (MenB only) to assess PF-06835375 functional effects. Endpoints included treatment-emergent adverse events (TEAEs), pharmacokinetic parameters, pharmacodynamic effects on B and cTfh cells, and biomarker counts, vaccine response, and exploratory differential gene expression analysis. Safety, pharmacokinetic, and pharmacodynamic endpoints are summarized descriptively. The change from baseline of B and Tfh cell-specific genes over time was calculated using a prespecified mixed-effects model, with a false discovery rate < 0.05 considered statistically significant.ResultsIn total, 73 patients were treated (SAD cohorts: SLE, n = 17; RA, n = 14; MAD cohorts: SLE, n = 22; RA, n = 20). Mean age was 53.3 years. Sixty-two (84.9%) patients experienced TEAEs (placebo n = 17; PF-06835375 n = 45); most were mild or moderate. Three (9.7%) patients experienced serious adverse events. Mean t1/2 ranged from 3.4–121.4 h (SAD cohorts) and 162.0–234.0 h (MAD cohorts, Day 29). B and cTfh cell counts generally showed dose-dependent reductions across cohorts (range of mean maximum depletion: 67.3–99.3%/62.4–98.7% [SAD] and 91.1–99.6%/89.5–98.1% [MAD], respectively). B cell-related genes and pathways were significantly downregulated in patients treated with PF-06835375.ConclusionsThese data support further development of PF-06835375 to assess the clinical potential for B and Tfh cell depletion as a treatment for autoimmune diseases.Trial registrationClinicalTrials.gov identifier: NCT03334851.

Pharmacological characterization of sex differences in the effects of dopaminergic drugs on effort-based decision making in rats.

Motivational dysfunctions related to effort exertion are common in psychiatric disorders. Dopamine systems regulate exertion of effort and effort-based choice in humans and rodents. Previous rodent studies mainly employed male rats, and it is imperative to conduct studies in male and female rats. The present studies compared the effort-related effects of IP injections of the dopamine antagonists ecopipam and haloperidol, and the vesicular monoamine transport-2 inhibitor tetrabenazine (TBZ), in male and female rats using the fixed ratio 5/chow feeding choice task. Ecopipam (0.05-0.2mg/kg) and haloperidol (0.05-0.15mg/kg) induced a low-effort bias, decreasing lever pressing and increasing chow intake in males and females in the same dose range. With lever pressing, there was a modest but significant dose x sex interaction after ecopipam injection, but there was no significant interaction after administration of haloperidol. In the first study with TBZ (0.25-1.0mg/kg), there was a robust sex difference. TBZ shifted choice from lever pressing to chow intake in male rats, but was ineffective in females. In a second experiment, 2.0mg/kg affected choice behavior in both males and females. TBZ increased accumbens c-Fos immunoreactivity in a sex-dependent manner, with males significantly increasing at 1.0mg/kg, while females showed augmented immunoreactivity at 2.0mg/kg. The neural and behavioral effects of TBZ differed across sexes, emphasizing the importance of conducting studies in male and female rats. This research has implications for understanding the effort-related motivational dysfunctions seen in psychopathology.

Effect of caffeine ingestion on time trial performance in cyclists: a systematic review and meta-analysis.

Caffeine, widely recognized as an ergogenic aid, has undergone extensive research, demonstrating its effectiveness to enhance endurance performance. However, there remains a significant gap in systematically evaluating its effects on time trial (TT) performance in cyclists. This meta-analysis aimed to determine the efficacy of caffeine ingestion to increase cycling TT performance in cyclists and to evaluate the optimal dosage range for maximum effect. A search of four databases was completed on 1 December 2023. The selected studies comprised crossover, placebo-controlled investigations into the effects of caffeine ingestion on cycling TT performance. Completion time (Time) and mean power output (MPO) were used as performance measures for TT. Meta-analyses were performed using a random-effects model to assess the standardized mean differences (SMD) in individual studies. Fifteen studies met the inclusion criteria for the meta-analyses. Subgroup analysis showed that moderate doses of caffeine intake (4-6 mg/kg) significantly improved cycling performance (SMD Time = -0.55, 95% confidence interval (CI) = -0.84 ~ -0.26, p < 0.01, I2 = 35%; SMD MPO = 0.44, 95% CI = 0.09 ~ 0.79, p < 0.05, I2 = 39%), while the effects of low doses (1-3 mg/kg) of caffeine were not significant (SMD Time = -0.34, 95% CI = -0.84 ~ 0.17, p = 0.19, I2 = 0%; SMD MPO = 0.31, 95% CI = -0.02 ~ 0.65, p = 0.07, I2 = 0%). A moderate dosage (4-6 mg/kg) of caffeine, identified as the optimal dose range, can significantly improve the time trial performance of cyclists, while a low dose (1-3 mg/kg) does not yield improvement. In addition, the improvements in completion time and mean power output resulting from a moderate dose of caffeine are essentially the same in cycling time trails.

Use of Syzygium aromaticum L. Fermented Plant Extract to Enhance Antioxidant Potential: Fermentation Kinetics

The concept of our research is related to the use of stems from S. aromaticum L. in the fermentation process in order to obtain new cosmetic raw materials with high antioxidant potential that are safe for human fibroblasts (HDFs) and keratinocytes (HaCaTs). This evaluation involves treating cell lines with different concentrations of fermented extracts to establish a noncytotoxic dose range. The focus was on evaluating antioxidant activity (AA), total polyphenol content (TPC), and lactic acid efficiency (LAe). For this purpose, the most favourable technological parameters of the fermentation process of stems were determined, including the type of microorganisms, initial sugar content, plant raw material content, and fermentation time. In the present study, lactic acid was obtained with maximum efficiency by stem fermentation in the presence of lactic acid bacteria (LAB) and molasses as a source of six-carbon sugars. In addition, fermentation kinetics was investigated, the essence of which was to identify the technological parameters that allow the highest values of the main functions describing the process (AA, TPC LAe). Two kinetic models were used to determine the kinetics of process function changes during fermentation. The most favourable fermentation conditions for maximum antioxidant activity (26.88 mmol Tx/L ± 0.19), total polyphenol content (5.96 mmol GA/L ± 0.19), and lactic acid efficiency (88% ± 1) were: type of microorganism L. rhamnosus MI-0272, initial sugar content 3.20%, plant raw material content 6.40%, and a fermentation time of 9 days. The values of chelating activity (ChA), AA, and TPC in the fermented stems increased more than two-fold compared to the non-fermented extracts. Reducing activity (RA) and LAe increased to 46.22 mmol Fe3+/L ± 0.29 and 88% ± 1, respectively. Of the kinetic models adopted, follow-up reaction equations and first-order equations best described the time-dependent changes taking place. This study shows that the process function values of AA and LAe are dependent on the LAB strain and the content of the plant material, and the rate of change of TPC may largely depend on the forms of phenolic compounds formed during fermentation.

A dose titration protocol for once-daily insulin glargine 300 U/mL for the treatment of diabetes mellitus in dogs.

In purpose-bred dogs, insulin glargine 300 U/mL (IGla300) has long duration of action, peakless time-action profile, and low potency, making it suitable for use as a basal insulin. To evaluate IGla300 in client-owned diabetic dogs monitored using a flash glucose monitoring system (FGMS). Ninety-five client-owned diabetic dogs, newly diagnosed or previously treated with other insulin formulations, with or without concurrent diseases. Prospective multi-institutional study. Clinical signs and standardized assessment of FGMS data, using treatment and monitoring guidelines established a priori, guided dose adjustments and categorization into levels of glycemic control. The initial IGla300 dose was 0.5 U/Kg q24h for newly diagnosed dogs and (median dose [range]) 0.8 U/Kg (0.2-2.5) q24h for all dogs. Glycemic control was classified as good or excellent in 87/95 (92%) dogs. The IGla300 was administered q24h (1.9 U/kg [0.2-5.2]) and q12h (1.9 U/kg/day [0.6-5.0]) in 56/95 (59%) and 39/95 (41%) dogs, respectively. Meal-time bolus injections were added in 5 dogs (0.5 U/kg/injection [0.3-1.0]). Clinical hypoglycemia occurred in 6/95 (6%) dogs. Dogs without concurrent diseases were more likely to receive IGla300 q24h than dogs with concurrent diseases (72% vs 50%, respectively; P = .04). Insulin glargine 300 U/mL can be considered a suitable therapeutic option for once-daily administration in diabetic dogs. Clinicians should be aware of the low potency and wide dose range of IGla300. In some dogs, twice-daily administration with or without meal-time bolus injections may be necessary to achieve glycemic control. Monitoring with FGMS is essential for dose titration of IGla300.

Phase I study of TQB3728 tablets, an oral inhibitor of apoptosis proteins in patients with advanced solid tumor.

e13104 Background: Apoptosis proteins are frequently upregulated in human cancers and are associated with resistance to therapeutic agents and poor outcomes. TQB3728 antagonizes the function of inhibitor of apoptosis proteins (IAPs), thereby inhibiting NF-кB signaling pathways and promoting cancer cell death. This first-in-human study aims to evaluate the maximum-tolerated dose (MTD), safety, pharmacokinetics, pharmacodynamics, and antitumor activity of TQB3728 in patients with advanced solid tumors after the failure of standard therapy. Methods: This study combined an accelerated dose titration design with a 3+3 dose escalation design. Three dosage schedules were explored. First of all, TQB3728 was given orally once a week, on a 28-day cycle (DS1). The starting dose of 25mg was escalated by 100% in a single patient until the third dose, then diverted to a 3+3 dose escalation design. The other two dosage schedules were TQB3728 given once daily on days 1-14 every 3 weeks (DS2) and daily every 4 weeks (DS3). The primary endpoint was safety, maximum tolerated or maximum administered dose (MTD), and the secondary endpoints were pharmacokinetics, pharmacodynamics, and tumor response per RECIST v1.1. Results: As of Dec 15, 2023, 23 patients (pts) received at least one dose of TQB3728 (dose range, 25 to 600mg). Based on the pharmacokinetics and safety of DS1, then DS2 (dose range, 100 to 200mg) and DS3 (dose range, 100 to 200mg) were investigated. The median follow-up period was 8.5m (range, 0.5 to 25m). No dose-limited toxicity and cytokine release syndrome were observed. The main treatment-related adverse events (TRAEs) were nausea (56.5%), lymphopenia (56.5%), dizziness (39.1%), hypersomnia (34.8%), increased aspartate aminotransferase (30.4%), increased alanine aminotransferase (26.1%), vomiting (26.1%), anemia (21.7%), decreased appetite (21.7%), and grade≥3 TRAE were lymphopenia (8.7%), anemia (4.4%). As for DS1, the average Tmax and t1/2 were 2 h and 9.6 h, respectively. The exposure did not increase with the dose above 150mg. Moreover, the average Tmax was about 2.3 h and 0.8 h, and t1/2 was 6.6 h and 7 h in DS2 and DS3, respectively. There was no significant accumulation with continuous medication. Additionally, Plasma MCP-1 increased at 3-6h postdose at high dose; cIAP-1 levels in PBMCs were undetected. Two pts (8.7%) had stable disease &gt;6 weeks as the best treatment response. Conclusions: TQB3728 was well tolerated at doses up to 600mg but had limited anti-tumor activity in advanced solid tumor. According to the preliminary results, TQB3728 administered orally in combination with conventional chemo-radiotherapy is under exploration. Clinical trial information: NCT04523285 .