Dose Range Research Articles

Improvement of both human and animal memory by synergy between fructooligosaccharide and L‐theanine function establishing a safe and effective food supplement

AbstractAging is classically associated with a decline of cognitive abilities, especially in relation to memory. While the development of potential treatments for neurodegenerative diseases has been in sharp focus, mild cognitive impairment (MCI), a form of age‐related memory loss, in the absence of severe functional impairment, a condition experienced by many healthy adults, has received relatively little attention. Advances in this space would make significant contributions to the goal of healthy aging and may also help promote cognitive performance across the wider population. The individual action of either fructooligosaccharide (FOS) or L‐theanine, both natural plant‐derived molecules, has been tentatively linked with improvements in cognition, but our understanding remains far from complete. We therefore determined the effect of different dose combinations of FOS and L‐theanine (termed MT‐01/GBL‐Memory1) in mice against FOS and L‐theanine monotherapy. FOS and L‐theanine were found to synergistically enhance murine memory in our animal tests at a dose of 100 mg/kg (coefficient of drug interaction (CDI) < 1). In a subsequent human trial, we demonstrated that MT‐01 improved the memory of healthy adults after 1 month of consumption. Our results suggest that a combination of FOS and L‐theanine synergistically enhances murine memory within a specific dose range. We show that this plant natural product regimen also improves human memory in a population of healthy adults. MT‐01 therefore represents a novel, safe, and effective dietary supplement to promote human memory and cognition.

Use of anticoagulant drugs for hospitalised patients: A multicentre study

Background: Anticoagulants are indicated for several types of diseases with progression related to coagulation. Patients administered this drug need to be evaluated by the pharmacist regarding its effectiveness and possible side effects. Objective: This research aimed to analyse the profile use of anticoagulants among patients at Yogyakarta Hospital. Method: This research was a multicentre study conducted retrospectively using the medical records of inpatients who received anticoagulants. Result: Among a total of 486 respondents, the majority were male (63.58%), and the adult age category (18-59 years) was 55.76%. Most anticoagulants were used in cases of cardiovascular disease, diagnosed with NSTEMI as much as 20.21%. The most used anticoagulant drug was heparin (48.9%), followed by fondaparinux (34.3%) and enoxaparin (16.8%). The most duration of anticoagulant use was one to four days (73.02%) with the dose range being 200-1000 units/day. Conclusion: Heparin was the anticoagulant widely used in patients with NSTEMI. Although the elderly were the group most at risk of ADR due to anticoagulants, most of these drugs were precisely taken by adults, who also required serious attention. Further research is needed to provide a more comprehensive approach to anticoagulant therapy.

The Role of Ferrate (VI) in the Pretreatment of Algal Cells and Algal Organic Matters: A Review

Algal blooms are caused by excessive levels of nitrogen, phosphorus, and other plant nutrients in water. Algae and algal organic matter (AOM) pose a great threat to the quality of drinking water. This manuscript offers a systematic review of algal removal by ferrate (Fe(VI)) oxidation, including the conditions for the removal of different algae by Fe(VI) and the factors affecting the removal efficiency. On this basis, the oxidation and coagulation mechanisms of algae removal by Fe(VI) are discussed. Then, the review introduces the process combining Fe(VI) pre-oxidation with aluminum sulfate action. The addition of aluminum sulfate can further enhance the coagulation effect and reduce the formation of disinfection byproducts (DBPs) in the subsequent chlorination process by effectively removing AOM, which is recognized as a precursor of DBPs. In addition, recent studies on the combined application of Fe(VI) and Fe(II) are also reviewed. In a reasonable dose range, the synergistic effect of Fe(VI) and Fe(II) can significantly improve the removal of algae and algal toxins. Finally, this review provides a comprehensive evaluation of the applicability of Fe(VI) in removing algal material, offers guidance for the harmless treatment of algae with Fe(VI), and identifies future research questions.

Performance assessment and economic aspects for water reclamation from UASB reactor effluent: Influence of coagulant type and membrane pore size

ABSTRACT This paper investigates the influence of coagulant type in coagulation, flocculation and sedimentation processes and membrane pore size on the performance and economic aspects of water reclamation from UASB reactor effluent. The methodology involved laboratory-scale experiments using two different coagulant types (a modified tannin coagulant, TANm, and a polyaluminum chloride, PACl) and membrane filtration tests with microfiltration (MF) and ultrafiltration (UF). Compared to PACl, TANm had a smaller effect on the pH, consumed less alkalinity, and generated less sludge. However, PACl was more efficient in removing turbidity (89–97%), organic matter (70–72%), and phosphorus within the dosage range of 25 to 100 mg.L−1. Both membranes achieved high removal rates for turbidity and organic matter. Despite the higher flux decay, the MF system could have higher operating flux and lower fouling resistance. The operating costs were higher for the C/F systems, which was attributed to the cost of coagulants and sludge disposal. The system with MF membranes had a lower total cost, and the estimated payback period for the investment was between 0.73 to 0.24 years, based on the values charged for reuse water. This information can be used to optimize the design and operation of UASB-based water reclamation systems.

Influence of gamma radiation treatment on microbial contamination, quality indicators and anthocyanin content in dark raisins

One of the most promising and gentle methods for reducing the number of microorganisms in food and agricultural raw materials is treatment with ionizing radiation. The work aimed to evaluate the effect of antimicrobial treatment with gamma radiation on quality indicators and anthocyanin content in dark raisins. The object of the study was dark raisins produced in Uzbekistan. The studied samples were analyzed according to quality indicators (organoleptic, moisture, color) and microbiological indicators (total microbial contamination, yeast content, mold, and coliform bacteria). The main groups of microorganisms isolated from the surface of raisins were also identified using MALDI-TOF mass spectrometry. The anthocyanin content of the samples was measured by pH differential spectroscopy. Studies have shown that when dark raisins are irradiated in the dose range from 1.5 to 9 kGy, there is a significant decrease in the number of main sanitary-indicative microorganisms. It has been established that the optimal dose for suppressing microflora is 4-6 kGy. Microbial contamination of raisins is mainly caused by molds of the genera Mucor, Rhizopus, and Aspergillus and yeasts of the genera Candida and Phomopsis. As a result of treatment with ionizing radiation, a decrease in the content of anthocyanins by 1.5-2 times was noted. At the same time, no changes in the color, taste, and presentation of raisins were established. Treatment of dark varieties of raisins with gamma radiation can be recommended as an alternative to chemical treatment.

Noninvasive release of tendons using MRI guided focused ultrasound: a hybrid therapy using long-pulse focused ultrasound followed by thermal ablation

Introduction Magnetic Resonance-guided Focused Ultrasound (MRgFUS) thermal ablation is an effective noninvasive ultrasonic therapy to disrupt in vivo porcine tendon but is prone to inducing skin burns. We evaluated the safety profile of a novel hybrid protocol that minimizes thermal spread by combining long-pulse focused ultrasound followed by thermal ablation. Methods In-vivo Achilles tendons (hybrid N = 15, thermal ablation alone N = 21) from 15 to 20 kg Yorkshire pigs were randomly assigned to 6 treatment groups in two studies. The first (N = 21) was ablation (600, 900, or 1200 J). The second (N = 15) was hybrid: pulsed FUS (13.5 MPa peak negative pressure) followed by ablation (600, 900, or 1200 J). Measurements of ankle range of motion, tendon temperature, thermal dose (240 CEM43), and assessment of skin burn were performed in both groups. Results Rupture was comparable between the two protocols: 1/5 (20%), 5/5 (100%) and 5/5 (100%) for hybrid protocol, compared to 2/7 (29%), 6/7 (86%) and 7/7 (100%) for the ablation-only protocol with energies of 600, 900, and 1200 J, respectively. The hybrid protocol produced lower maximum temperatures, smaller areas of thermal dose, fewer thermal injuries to the skin, and fewer full-thickness skin burns. The standard deviation for the area of thermal injury was also smaller for the hybrid protocol, suggesting greater predictability. Conclusion This study demonstrated a hybrid MRgFUS protocol combining long-pulse FUS followed by thermal ablation to be noninferior and safer than an ablation-only protocol for extracorporeal in-vivo tendon rupture for future clinical application for noninvasive release of contracted tendon.

Cenobamate Plasma Levels in Patients with Epilepsy: Correlation with Efficacy and Tolerability?

Objective: Cenobamate is approved by the European Medicine Agency for the treatment of adult patients with epilepsy (PWEs) with ongoing focal-onset seizures despite appropriate treatment with at least two established antiseizure medications. Pivotal trials and post-marketing real-world observational studies suggest high efficacy with unusually high seizure-free rates. The authors sought to investigate the plasma levels of cenobamate under steady-state conditions in seizure-free versus non-responding PWEs, and in PWEs who experienced adverse events versus those who did not. Methods: Blood samples were collected from adult PWEs who were treated with adjunct cenobamate under steady-state conditions. Daily doses, concomitant medications, efficacy, and tolerability were assessed. The plasma cenobamate levels of seizure-free versus non-responding PWEs and between PWEs with and those without clinical adverse events were compared. Results: Samples from 101 PWEs were included. Thirty-six PWEs were seizure-free and 65 were non-responders. In 31 PWEs, adverse events were apparent, whereas in the remaining 70, no tolerability issues were reported. A linear correlation was found between the daily doses (range: 100 mg–400 mg) and the plasma levels (3.8 mg/L–54.6 mg/L). Neither the daily doses nor the plasma levels differed significantly between the investigated subgroups. The main reason for this result was that the individual therapeutic ranges varied widely: seizure freedom and adverse effects were observed alongside low doses and plasma levels in some PWEs. Conversely, there were examples of PWEs who did not respond or who reported no tolerability issues at high doses or plasma levels. Conclusions: To evaluate the individual therapeutic range and to better understand the influence of other drugs in cases where concomitant medications are used, the therapeutic drug monitoring of cenobamate may be useful. A general therapeutic range cannot be defined.

Usability of sand samples in TL Radiation Dosimetry.

This study investigated natural sand thermoluminescence (TL) response as a possible option for retrospective high-dose gamma dosimetry. The natural sand under investigation was collected from six locations with selection criteria for sampling sites covering the highest probability of exposure to unexpected radiation on the Egyptian coast. Dose-response, glow curve, chemical composition, linearity, and fading rate for different sand samples were studied. Energy Dispersive X-ray Spectroscopy (EDX) analysis revealed differences in chemical composition among the various geological sites, leading to variations in TL glow curve intensity. Sand samples collected from Ras Sedr, Taba, Suez, and Enshas showed similar TL patterns, although with different TL intensities. Beach sands of Matrouh and North Coastal with a high calcite content did not show a clear linear response to the TL technique, in the dose range of 10Gy up to 30kGy. The results show that most sand samples are suitable as a radiation dosimeter at accidental levels of exposure. It is proposed here that for high-dose gamma dosimetry with doses ranging from 3 to 10kGy, a single calibration factor might be enough for TL measurements using sand samples. However, proper calibration might allow dose assessment for doses even up to 30kGy. Most of the investigated sand samples had nearly stable fading rates after seven days of storage. The Ras Sedr sands sample was the most reliable for retrospective dose reconstruction.

Exploring the Association Between Isotretinoin and Sexual Dysfunction: A Comprehensive Scoping Review.

The potential link between isotretinoin and sexual dysfunction has been reported in various studies. However, such an association has not been explored within the context of a literature review until now. To evaluate the methodology and quality of studies investigating this association, and to examine the definitions of sexual dysfunction used. A scoping review approach was used to identify peer-reviewed research articles. The search terms used were: "isotretinoin", "sexual dysfunction", "erectile dysfunction", "ejaculatory disorders" "decreased libido", "female sexual interest", "female arousal disorder", "libido", "pelvic pain", "dyspareunia", "orgasmic disorder", "impotence", "ovaries", "fertility" and "menstrual irregularity". 54 peer-reviewed manuscripts consisting of 8 animal studies and 46 human studies consisting of 2,420 patients were included. Of the studies in humans, there were 18 case reports/case series, 2 case-controls, 4 cross-sectional studies, 6 longitudinal studies, 3 pharmacovigilance reports and 13 cohort studies. The most frequently observed dose range of isotretinoin was 0.5-1.0mg/kg/day usually for a duration of 1-6 months. More than half of the studies (54%, n=25) reported a beneficial or neutral effect of isotretinoin on sexual function. The majority of studies (89%, n = 41) were categorized as Oxford evidenced-based-medicine level 4. This scoping review revealed very weak evidence supporting a link between isotretinoin and sexual dysfunction. Notably, the diverse definitions of sexual dysfunction pose a significant challenge for comparative analysis. The authors advocate for a standardized definition of sexual dysfunction and a framework for determining causality in order to contribute to a more comprehensive understanding of the relationship between isotretinoin and sexual dysfunction.

Radiophotoluminescence response of LiF:Mg,Ti pellets irradiated with clinical proton beams in the 70–200 MeV energy range

Lithium fluoride doped with Mg and Ti (LiF:Mg,Ti) has been used for several decades as thermoluminescent dosimeter material, but recently also its radiophotoluminescence has been investigated for applications in dosimetry. In this work, LiF:Mg,Ti pellets (TLD-100) were irradiated in a water phantom at CNAO (Pavia, Italy) with therapeutic proton beams at five energies from 70 to 200 MeV in the dose range from 2 to 20 Gy. After irradiation, their visible radiophotoluminescence spectra were measured in controlled conditions and the spectrally-integrated red emission response of radiation-induced color centers has been investigated. The radiophotoluminescence signal, excited by a 445 nm continuous wave laser, was integrated within a 50 nm-wide band around the emission peak of the F2 color centers, located around 670 nm in LiF. The spectrally-integrated signal of the samples irradiated at the energy of 147.7 MeV exhibited a linear dependence with dose. Moreover, this radiophotoluminescence response appears independent from Linear Energy Transfer in the range from 0.8 to 1.6 keV/μm in all the samples irradiated at the dose of 5 Gy. Such independence was found up to 10.3 keV/μm in samples irradiated within two spread out Bragg peaks made of 36 energy components in the entire investigated proton energy range. The radiophotoluminescence response of the TLD-100 pellets was compared to that of nominally-pure LiF crystals irradiated in the same conditions, which show a similar behavior. The results are encouraging for the exploitation of TLD-100 pellets as passive solid-state radiophotoluminescent dosimeters for proton therapy.

Safety, tolerability, and pharmacokinetics of the novel RdRp inhibitor SHEN26 against SARS-CoV-2: a randomized, placebo-controlled, double-blind phase I study in healthy subjects

ABSTRACT Background SHEN26, an oral broad-spectrum antiviral drug, possesses potent preclinical activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and has a favorable safety profile. Methods We report safety, tolerability, and pharmacokinetic data from a randomized, double-blind, placebo-controlled phase I study of SHEN26. Eighty-six healthy subjects were enrolled in the three studies: a single ascending-dose study (SAD), a multiple ascending-dose study (MAD), and a food-effect study (FE). Results In the SAD trial, the maximum observed plasma concentration (Cmax) and area under the curve (AUC) of the SHEN26 rapid metabolite SHEN26-69-0 increased approximately dose-proportionally in the 50–400 mg fasting dose range. In the 800 mg dose group, standard meals increased the Cmax and AUC of SHEN26-69-0. In the MAD trial, the accumulation ratios of Cmax and AUC indicated slight accumulation upon repeated SHEN26 dosing. In the FE trial, a high-fat meal prolonged the time to maximum plasma concentration (Tmax) and increased the Cmax and AUC of SHEN26-69-0 compared with fasting administration. Most treatment-related adverse events were mild and resolved without treatment. Conclusion SHEN26 demonstrated satisfactory safety and tolerability in healthy subjects, which supports the continued study of SHEN26 against SARS-CoV-2. Trial Registration The trial is registered in ClinicalTrials.gov (CT. gov identifier: NCT05504746).

Tailor-Made Doses of Pharmaceuticals by Tunable Modular Design: A Case Study on Tapering Antidepressant Medication.

An abrupt cessation of antidepressant medication can be challenging due to the appearance of withdrawal symptoms. A slow hyperbolic tapering of an antidepressant, such as citalopram hydrobromide (CHB), can mitigate the withdrawal syndrome. However, there are no viable dosage forms on the market to implement the tapering scheme. A solution using a tunable modular design (TMD) approach to produce flexible and accurate doses of CHB is proposed. This design consists of two parts: 1) a module with a fixed amount of preloaded CHB in a freeze-dried polymer matrix, and 2) fine-tuning the CHB dose by inkjet printing. A noncontact food-grade printer, used for the first time for printing pharmaceuticals, is modified to allow for accurate printing of the highly concentrated CHB ink on the porous CHB-free or CHB-preloaded modules. The produced modules with submilligram precision are bench-marked with commercially available CHB tablets that are manually divided. The TMD covers the entire range of doses needed for the tapering (0.5-23.8mg). The greatest variance is 13% and 88% when comparing the TMD and self-tapering, respectively. Self-tapering is proven inaccurate and showcases the need for the TMD to make available accurate and personalized doses to wean off treatment with CHB.

Abstract PO5-03-11: Ultra-low dose nivolumab added to dose-dense, cisplatin-based neoadjuvant chemotherapy in locally advanced, borderline operable triple negative breast cancer: A matched case-control study

Abstract Background In India, the majority of patients with triple negative breast cancer(TNBC) present with locally advanced and often inoperable disease due to lack of screening, awareness, and social stigma. This makes pathological complete response(pCR) after neoadjuvant chemotherapy(NAC) less likely, leading to early recurrence and poor survival outcomes. Immune checkpoint inhibitors(ICI) in addition to platinum agents have improved both pCR and disease-free survival(DFS). However, these are accessible only to a very small proportion(< 3%) of patients in LMICs due to exorbitant costs. The activity and cost-effectiveness of low dose ICI has been demonstrated in head and neck. The efficacy of low dose ICI in the neoadjuvant setting for TNBC has not been studied. We examined our outcomes with ultra-low dose nivolumab(< 0.6 mg/kg every 2 weeks) added to NAC for locally advanced and borderline operable TNBC. Methods A retrospective analysis of 132 patients with TNBC who received NAC with the ddDCEP regimen(Docetaxel 75mg/m2 and Cyclophosphamide 600 mg/m2 alternating with Epirubicin 90mg/m2 and Cisplatin 60mg/m2 every 2 weeks for 8 cycles) or ddDCEP plus low dose nivolumab(< 0.6mg/kg/2 weeks) and underwent mastectomy at our centre between 2018-2023 was carried out. 105 and 27 patients received ddDCEP alone and ddDCEP + low dose nivolumab respectively. Using rigorous exact matching, 26 matched pairs(52 patients) were obtained based on tumour grade and AJCC TNM stage. pCR in the surgical specimen was the principal outcome assessed. Survival data, adverse events and cost were also analysed. Results The median age of cases and controls was 42 and 40 years respectively. Tumour histology was ductal carcinoma most patients. Across both groups the stage distribution was the same with nearly 85% stage III(IA 3.8%;IIB 7.7%; IIIA 23.1%;IIIB 43.2%;IIIC 19.2%). 92% of cases and 85% of controls had node positive disease. 62% of cases and 46% of controls had T4 disease. At a median follow up of 9 months, there were no recurrences or deaths among the cases. The most common immune mediated adverse event was hypothyroidism seen in 11.5% of cases. The rates of grade 3/4 anaemia, thrombocytopenia and febrile neutropenia were approximately 38%, 10% and 3.8% across cases and controls respectively. The median dose of nivolumab was 0.27mg/kg/2weeks as opposed to the approved dose of 3mg/kg/2weeks for most indications. The range of doses varied from 0.07 to 0.58mg/kg/2weeks. In the overall cohort, the addition of nivolumab did not have any apparent effect on the pCR rates which were identical at 42.3% in both cases and controls. However, there was a positive correlation between the total dose of nivolumab/kg(body weight) and the likelihood of pCR(coefficient 0.34; p-value 0.046). Patients who received higher than the median dose of nivolumab had a significantly higher likelihood of attaining pCR than those who received lower doses (69.2% pCR vs.15.4%;p-value 0.015). The cost of nivolumab at 0.6 mg/kg for 4 doses is approximately USD2000 compared to USD34400 for 8 doses of pembrolizumab in the neoadjuvant component of the KEYNOTE-522 regimen. Conclusion In this cohort with locally advanced/inoperable TNBC, the addition of ultra-low dose nivolumab did not improve pCR overall compared to a matched control set who did not receive ICI. However, in the subset of patients who received between 0.27-0.58 mg/kg/2weeks, the pCR rates were significantly higher at 69%. This presents a promising and cost-effective approach for TNBC management in LMICs. This effect needs verification in larger phase II/III trials. Table. Citation Format: Zachariah Thomas, Josh Georgy, Ashish Singh, Anjana Joel, Divya Thumaty, Ajoy John, Jerryes Wisely, Grace Rebekah, Elanthenral Sigamani, Anish Cherian, Deepak Abraham, Paul Jacob, Rajesh Balakrishnan, Patricia Solomon, Selvamani Backianathan, Raju Chacko. Ultra-low dose nivolumab added to dose-dense, cisplatin-based neoadjuvant chemotherapy in locally advanced, borderline operable triple negative breast cancer: A matched case-control study [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-03-11.

Abstract PO4-04-11: Exposure–response analyses of GO39932: a Phase Ia/b study of giredestrant in estrogen receptor-positive, HER2-negative, locally advanced or metastatic breast cancer

Abstract BACKGROUND Giredestrant (GIR) is a highly potent, nonsteroidal, oral, selective estrogen receptor antagonist and degrader (SERD). The Phase Ia/b GO39932 study (NCT03332797) investigated GIR ± palbociclib (palbo) and ± a luteinizing hormone-releasing hormone agonist for patients with ER-positive, HER2-negative, locally advanced or metastatic breast cancer who had disease progression on prior endocrine therapies. In the single-agent dose-escalation stage, patients received 10, 30, 90, or 250 mg of once-daily (QD) GIR. In the dose-expansion stage, patients received 30, 100, or 250 mg of QD GIR. Safety and tolerability of 100 mg GIR + 125 mg palbo was also explored in the dose-escalation and -expansion stages. Results showed that GIR was well tolerated and potentially clinically active as a single agent and in combination with palbo, including in patients with ESR1-mutated tumors. To inform the selection of the clinical dose for GIR late-stage development based on risk–benefit considerations, exposure–response (E–R) analyses for efficacy and safety endpoints were conducted using single-agent GIR data. METHODS Exposure metrics included maximum concentration at steady state and area under the concentration–time curve at steady state. The association between the exposure metrics and efficacy endpoints (objective response rate [ORR] and clinical benefit rate [CBR]) or safety endpoints (all adverse events [AEs], Grade ≥ 3 AEs, selected AEs of interest [sAEIs], including all-grade hepatotoxicity, and bradycardia) were evaluated. RESULTS Data cutoff was September 17, 2021. A total of 111 patients were enrolled in the single-agent GIR cohort. Of these 111 patients, 107 were pharmacokinetic-evaluable and included in the analysis. ORR in patients with measurable disease at baseline was 20% (16/81 patients) and CBR was 49% (54/111). No significant associations were observed between exposure and ORR or CBR, including in patients with ESR1-mutated tumors and those with no mutation detected (p > 0.05). There were 92/107 patients (86%) with AEs of any grade, overall. Seventy-two (67%) had sAEIs, 19 (18%) experienced hepatotoxicity (all events were reported as liver function test abnormalities), 11 (10%) had bradycardia, and 20 (19%) had Grade ≥ 3 AEs. Increasing exposure did not significantly increase the incidence of all AEs, Grade ≥ 3 AEs, sAEIs, or bradycardia at the dose range of 10 to 250 mg (p > 0.05). For hepatotoxicity, the analysis suggested that higher exposure may lead to a higher probability of events (p = 0.0065); however, at the clinically relevant exposure range for the 30 mg dose, the incidence of hepatotoxicity was low and the predicted exposures were at the shallower slope of the relationship. CONCLUSIONS Single-agent GIR did not exhibit a significant association between exposure and efficacy endpoints at a dose range of 10 to 250 mg, regardless of ESR1 mutation status, indicating that the efficacy of GIR might have reached a plateau at low dose levels. At the clinically relevant exposure range of the 30 mg dose, GIR exposure was not associated with an appreciable increase in the incidence of AEs. The Phase Ia/b study design and subsequent E–R results enabled dose selection to be based on risk–benefit considerations, rather than the traditional maximum tolerated dose paradigm, in line with the United States Food and Drug Administration’s oncology dose optimization recommendations. The E–R results also indicate that GIR may have a relevant wide therapeutic window. Overall, these data support the 30 mg clinical dose of GIR that was selected, with a favorable risk–benefit profile, for further clinical studies. Citation Format: Komal Jhaveri, Yi Ting (Kayla) Lien, Nicholas Turner, Elgene Lim, Maureen Cannon, Richard Anziano, Jurgen Langenhorst, Kenta Yoshida, Vikram Malhi, Mary Gates, Jennifer Eng-Wong, Chunze Li, Mona Shah, Pablo Perez-Moreno, Jiajie Yu, Aditya Bardia. Exposure–response analyses of GO39932: a Phase Ia/b study of giredestrant in estrogen receptor-positive, HER2-negative, locally advanced or metastatic breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-04-11.

Changes in the structural and functional state of the thyroid gland of small mammals when exposed to low-intensity chronic radiation.

The study gives a morphofunctional assessment of the state of the thyroid gland of tundra voles (Microtus oeconomus Pall.) in conditions of an increased radiation background (the Ukhta district of the Komi Republic (Russia) and the 30-km zone of the Chernobyl NPP), as well as in an experiment with chronic external gamma irradiation in the low dose range. The work summarizes the experience of more than 35 years of field and laboratory research. The authors have noted the high sensitivity of the thyroid gland to chronic radiation against the general irradiation of the organism both in natural conditions and in the experiment. The repeatability of the observed effects in voles from natural populations and the comparability of some effects with the morphological changes occurring in animals after exposure to ionizing radiation in the experiment indicates the radiation nature of these effects. The tundra voles living in conditions of increased radiation background have been identified for a greater variety of morphological rearrangements in the thyroid parenchyma than the experimental animals. The complex and ambiguous nature of the thyroid gland responses to radiation exposure indicates the possibility of a significant increase in the risk of negative effects of ionizing radiation in contrast with the expected results of biological effects' extrapolation from high to low doses.

Approval of Mycophenolate Mofetil for Prophylaxis of Organ Rejection in Pediatric Recipients of Heart or Liver Transplants: A Regulatory Perspective.

On June 6, 2022, the FDA expanded the indications for mycophenolate mofetil (MMF) to include the prophylaxis of organ rejection in combination with other immunosuppressants in pediatric recipients of allogeneic heart or liver transplants aged 3 months and older. The approved oral dosing regimen for these patients was a starting dose of 600 mg/m2 with titration up to a maximum of 900 mg/m2 twice daily. Data to support efficacy in pediatric patients were derived from established pharmacokinetic (PK) relationships across approved populations, a PK study in pediatric liver transplant recipients, and information from the Scientific Registry of Transplant Recipients database. Information supporting safety was based on comparing mycophenolic acid (MPA) exposure with that in pediatric kidney transplant recipients, the published literature, and post-marketing safety reports. Efficacy in pediatric patients was established based on extrapolation of efficacy from studies in adult liver, adult heart, and pediatric kidney transplant populations, and similarity in MPA exposure between pediatric and adult patients. Review of the data supported an oral dosing regimen for pediatric heart transplant and liver transplant recipients consisting of a starting dose of 600 mg/m2 up to a maximum of 900 mg/m2 b.i.d. A dosage range for MMF is recommended recognizing that the MMF dose may be modified in clinical practice for myriad factors. The dosage recommendations in the labeling for pediatric liver and pediatric heart transplant patients are intended to permit individualized dosing based on clinical assessment of these factors.

A Meta-analysis of probiotic interventions to mitigate ruminal methane emissions in cattle: implications for sustainable livestock farming

In recent years, the significant impact of ruminants on methane emissions has garnered international attention. While dietary strategies have been implemented to solve this issue, probiotics gained the attention of researchers due to their sustainability. However, it is challenging to ascertain their effectiveness as an extensive range of strains and doses have been reported in the literature. Hence, the objective of this experiment was to perform a meta-analysis of probiotic interventions aiming to reduce ruminal methane emissions from cattle. From 362 articles retrieved from scientific databases, 85 articles were assessed independently by 2 reviewers, and 20 articles representing 49 comparisons were found eligible for meta-analysis. In each study, data such as mean, standard deviation, and sample sizes of both the control and probiotic intervention groups were extracted. The outcomes of interest were methane emission, methane yield, and methane intensity. For the meta-analysis, effect sizes were pooled using a fixed effect or a random effect model depending on the heterogeneity. Afterward, sensitivity analyses were conducted to confirm the robustness of the findings. Overall pooled standardized mean differences (SMD) with their confidence intervals (CIs) did not detect significant differences in methane emission (SMD = -0.04; 95% CI = -0.18 to 0.11; p = 0.632), methane yield (SMD = -0.08; 95% CI = -0.24 to 0.07; p = 0.291), and methane intensity (SMD = -0.22; 95% CI = -0.50 to 0.07; p = 0.129) between cattle supplemented with probiotics and the control group. However, subgroup analyses revealed that multiple-strain bacterial probiotics (SMD = -0.36; 95% CI = -0.62 to -0.11; p = 0.005), specifically the combination of bacteria involved in reductive acetogenesis and propionate production (SMD = -0.71; 95% CI = -1.04 to -0.36; p = 0.001), emerged as better interventions. Likewise, crossbreeds (SMD = -0.48; 95% CI = -0.78 to -0.18; p = 0.001) exhibited a more favorable response to the treatments. Furthermore, meta-regression demonstrated that longer periods of supplementation led to significant reductions in methane emissions (p = 0.001), yield (p = 0.032), and intensity (p = 0.012) effect sizes. Overall, the results of the current study suggest that cattle responses to probiotic interventions are highly dependent on the probiotic category. Therefore, extended trials performed with probiotics containing multiple bacterial strains are showing the most promising results. Ideally, further trials focusing on the use of probiotics to reduce ruminal methane in cattle should be conducted to complete the available literature.

Pharmacokinetics and Pharmacodynamics of Standard Nerve Agent Medical Countermeasures in Göttingen Minipigs

Animal research continues to serve a critical role in the testing and development of medical countermeasures. The Göttingen minipig, developed for laboratory research, may provide many benefits for addressing research questions within chemical defense. Targeted development of the Göttingen minipig model could reduce reliance upon non-human primates, and improve study design, statistical power, and throughput to advance medical countermeasures for regulatory approval and fielding. In this vein, we completed foundational pharmacokinetics and physiological safety studies of intramuscularly administered atropine sulfate, pralidoxime chloride (2-PAM), and diazepam across a broad range of doses (1 to 6 autoinjector equivalent) using adult male Göttingen minipigs (n=11; n=4-8/study) surgically implanted with vascular access ports and telemetric devices to monitor cardiovascular, respiratory, arterial pressure, and temperature signals. Pharmacokinetic data were orderly and the concentration maximum mirrored available human data at comparably scaled doses clearly for atropine, moderately for 2-PAM, and poorly for diazepam. Time to peak concentration approximated 2, 7, and 20minutes for atropine, 2-PAM, and diazepam, respectively, and the elimination half-life of these drugs approximated 2hr (atropine), 3hr (2-PAM), and 8hr (diazepam). Atropine sulfate dose-dependently increased the magnitude and duration of tachycardia and decreased the PR and ST intervals (consistent with findings obtained from other species). Mild hypothermia was observed at the highest diazepam dose. Göttingen minipigs appear to provide a ready and appropriate large animal alternative to non-human primates, and further development and evaluation of novel nerve agent medical countermeasures and treatment strategies in this model are justified.

Enhancing starch functionality through synergistic modification via sequential treatments with cold plasma and electron beam irradiation

The impact of dual sequential modifications using radio-frequency (RF) plasma and electron beam irradiation (EBI) on starch properties was investigated and compared with single treatments within an irradiation dose range of 5–20 kGy. Regardless of sequence, dual treatments synergistically affected starch properties, increasing acidity, solubility, and paste clarity, while decreasing rheological features with increasing irradiation dose. The molecular weight distribution was also synergistically influenced. Amylopectin distribution broadened particularly below 10 kGy. Amylose narrowed its distribution across all irradiation doses. This was due to dominating EBI-induced degradation and molecular rearrangements from RF plasma. With the highest average radiation-chemical yield (G) and degradation rate constant (k) of (2.12 ± 0.14) × 10−6 mol·J−1 and (3.43 ± 0.23) × 10−4 kGy−1, respectively, upon RF plasma pre-treatment, amylose underwent random chain scission. In comparison to single treatments, dual modification caused minor alterations in spectral characteristics and crystal short-range order structure, along with increased granule aggregation and surface irregularities. The synergistic effect was dose-dependent, significant up to 10 kGy, irrespective of treatment sequence. The highest synergistic ratio was observed when RF plasma preceded irradiation, demonstrating the superior efficiency of plasma pre-treatment in combination with EBI. This synergy has the potential to lower costs and extend starch's technological uses by enhancing radiation sensitivity and reducing the irradiation dose.

Concentration-QTc modeling of sitravatinib in patients with advanced solid malignancies.

Sitravatinib (MGCD516) is an orally available, small molecule, tyrosine kinase inhibitor that has been evaluated in patients with advanced solid tumors. Concentration-corrected QT interval (QTc; C-QTc) modeling was undertaken, using 767 matched concentration-ECG observations from 187 patients across two clinical studies in patients with advanced solid malignancies, across a dose range of 10-200 mg, via a linear mixed-effects (LME) model. The effect on heart rate (HR)-corrected QT interval via Fridericia's correction method (QTcF) at the steady-state maximum concentration (Cmax,ss) for the sitravatinib proposed therapeutic dosing regimen (100 mg malate once daily [q.d.]) without and with relevant intrinsic and extrinsic factors were predicted. No significant changes in HR from baseline were observed. Hysteresis between sitravatinib plasma concentration and change in QTcF from baseline (ΔQTcF) was not observed. There was no significant relationship between sitravatinib plasma concentration and ΔQTcF. The final C-QTc model predicted a mean (90% confidence interval [CI]) ΔQTcF of 3.92 (1.95-5.89) ms and 2.94 (0.23-6.10) ms at the proposed therapeutic dosing regimen in patients with normal organ function (best case scenario) and patients with hepatic impairment (worst-case scenario), respectively. The upper bounds of the 90% CIs were below the regulatory threshold of concern of 10 ms. The results of the described C-QTc analysis, along with corroborating results from nonclinical safety pharmacology studies, indicate that sitravatinib has a low risk of QTc interval prolongation at the proposed therapeutic dose of 100 mg malate q.d.