Administration Of Single Dose Research Articles

Zigakibart demonstrates clinical safety and efficacy in a Phase 1/2 trial of healthy volunteers and patients with IgA nephropathy.

Zigakibart demonstrates clinical safety and efficacy in a Phase 1/2 trial of healthy volunteers and patients with IgA nephropathy.

Efficacy and safety results of a multi-center phase I study of utidelone capsule, a novel oral microtubule inhibitor, in advanced solid tumor patients.

3030 Background: Utidelone is a novel microtubule inhibitor, whose injectable formulation (UTD1) has been approved for advanced breast cancer in China since 2021. Attempts to develop oral microtubule inhibitor have not made significant progress; no oral microtubule inhibitors have been approved in the United States to date. Utidelone is insusceptible to P-glycoprotein-mediated efflux, thereby optimizing it for oral administration on an intermittent schedule. Utidelone capsule (UTD2) can significantly improve medication compliance and the convenience of clinical application. This is the first-in-human study of UTD2, and the trial has been completed with final results presented here. Methods: Eligible patients were aged ≥18, with an ECOG PS of 0-1, life expectancy ≥12weeks, pathologically confirmed advanced solid tumor refractory to prior standard therapies. Patients were treated with UTD2 monotherapy. The starting dose was 5-day 25 mg/m 2 /d for 2 patients, with planned escalation to 5-day 50, 75, 100 mg/m 2 /d and 7-day 70 mg/m 2 /d for 2, 6, 3 and 2 patients, repectively in a 21-day cycle. The primary objective was to determine DLT and the MTD. Secondary objectives included efficacy, PK profile and RP2D. Results: 18 advanced solid tumor patients were enrolled (3 didn’t complete DLT observation) with median age of 60.8 years (range 29.0-81.0), 9 females and 9 males. All patients had received prior treatment in advanced settings with maximal 9 lines. Two DLTs of Grade 3 and Grade 4 diarrhea occurred, one at 5-day 100 mg/m 2 /d and one at 7-day 70 mg/m 2 /d. Considering the total dose per cycle for both cohorts were similar, the MTD was determined to be 5-day 75 mg/m 2 /d via SMC. 11 patients were evaluated for efficacy with an outcome of 1 CR (ovarian cancer), 1 PR (ovarian cancer), 7 SD (testicular Sertoli cell tumor, NSCLC*2, pancreatic adenocarcinoma*2, appendiceal adenocarcinoma and soft tissue sarcoma), with the longest DoT of 12 cycles. The ORR was 18.2% and the CBR was 81.8%. PK results showed that the characteristics of utidelone were consistent with a two-compartment model. Compared to single-dose administration, there was no accumulation of utidelone in plasma upon multi-dose. The most frequent TEAEs were Grade 1/2, including diarrhea, fatigue, nausea, peripheral sensory neuropathy, vomiting, and decreased appetite (≥20% incidence rate), which recovered with supportive treatments. The ≥Grade 3 TRAE included diarrhea (27.8%) and fatigue (5.6%). Conclusions: This completed study demonstrates encouraging anti-tumor activity with manageable safety of UTD2 in patients with heavily pre-treated advanced solid tumors. The results support continuing development of UTD2 for the upcoming phase II/III studies for gastric and ovarian cancers. Clinical trial information: NCT05681000 .

Bioequivalence and Safety of Bilastine 20 mg Administered in Three Eight-Hourly Dose Versus a Single Daily Dose: A Randomized Two-Treatment, Two-Period, Cross-Over Comparative Study.

Antihistamines are an essential treatment option for cough and upper respiratory symptoms. Bilastine is a 2nd-generation antihistamine which is approved as a 20 mg once daily dose. The objective of the current study is to compare the oral bioavailability of bilastine administered thrice daily as a triple combination syrup of test product bilastine + dextromethorphan hydrobromide + phenylephrine hydrochloride (3.3 mg + 10 mg +5 mg)/5 mL and a reference product of single-dose administration of 2.5 mg/mL (bilastine 2.5 mg) in healthy, adult, male human subjects under fed condition. This was an open-label, balanced, randomized, two-treatment, two-period, cross-over comparative bioavailability study. Patients were administered 10 mL of three 8-hourly doses of the triple combination test product and once daily dose of the reference product (syrup containing bilastine 2.5 mg). A 7-day washout period was implemented between doses. Blood samples were collected to assess the oral bioavailability of the test and reference products. Each subject received both treatments, serving as their own control, eliminating the need for a separate control group. Blood samples were collected pre-dose and at various intervals post-dose to determine plasma concentrations of bilastine using LC-MS/MS (Liquid Chromatography-Mass Spectrometry/Mass Spectrometry. Primary pharmacokinetic parameters were analyzed for bioequivalence using SAS version 9.4. A total of 34 subjects out of 36 enrolled, successfully completed the study, and were analyzed. The geometric mean ratios of test versus reference product for the areas under the curve (AUC0-t and AUC0-∞ ) were 88.42% (84.15-92.91%) and 98.06% (93.63-102.69%), respectively, which are within the bioequivalence acceptance limits of 80.00-125.00%. Our study concluded that the test product, bilastine + dextromethorphan hydrobromide + phenylephrine hydrochloride syrup (3.3 mg + 10 mg + 5 mg)/5 mL, and the reference product, bilastine solution 2.5 mg/mL, are bioequivalent with respect to the extent of absorption and were well tolerated.

Hepatoprotective Effect of <I>Ipomoea cairica</I> Leaf Extract against Acetaminophen Hepatotoxic Effect in Rats viz antioxidant and anti-inflammatory activities

Background: Acetaminophen is one of the over-the-counter drugs commonly used by humans as a pain reliever. While it is generally safe at a prescribed dose, misuse and overdose of the drug make it one of the substances linked to liver damage. Ipomoea cairica is one of the medicinal plants reported to be an alternative source of treatment and prevention of toxic effects of chemicals against organ function. This study evaluated the hepatoprotective effect of I. cairica leaf extract against the hepatotoxic effect of acetaminophen in rats. Methods: Thirty-five male Wistar rats were randomly divided into five groups of seven rats each. I: Normal control; II: orally administered 2000 mg/kg of acetaminophen (ACET); III: orally administered 100 mg/kg Methanolic extract of I. cairica (MEIC) for 14 days before single dose administration of ACET; IV: orally administered 250 mg/kg of MEIC for 14 consecutive days before single dose administration of ACET V: orally administered 250 mg/kg of MEIC for 14 consecutive days. Animals were sacrificed 24 hours after the last administration. Blood was collected and processed for markers of lipidaemia and hepatic function. The liver was excised and processed for antioxidant, oxidative stress, and pro-inflammatory activities Results: The results showed that ACET (group II) caused a significant increase in the concentration of serum total cholesterol (TC), triglyceride (TG), and low-density lipoprotein (LDL). In contrast, the concentration of HDL was significantly reduced when compared to the rats in the control group. Pretreatment with MEIC at a higher dose was able to prevent the production of malondialdehyde(MDA) and phosphatidylserine (PC) as well as glutathione (GSH) levels. MEIC also prevented the depletion of SOD and CAT activities by ACET. In addition, ACE overdose elevated the activities of NADPH oxidoreductases, xanthine oxidases, and MPO. However, administration of the two doses of MEIC was able to reverse all the toxic effects of acetaminophen on hepatic tissues. Conclusion: The results provided scientific proof of the potential of I. cairica to protect against hepatotoxicity that can be linked to the antioxidant and anti-inflammatory activity of the plant.

GDF8 and activin A are the key negative regulators of muscle mass in postmenopausal females: a randomized phase I trial

Evolutionary pressures to protect against food scarcity likely resulted in highly-conserved pathways designed to minimize energy expenditure, one of which involves the minimization of muscle mass; these mechanisms may be counter-productive in a modern world suffering from obesity and sarcopenia. Growth differentiation factor 8 (GDF8)/myostatin, acting via ActRIIA/B receptors, is the best-characterized negative regulator of muscle mass, leading to therapeutic efforts to augment muscle growth by blocking GDF8 or ActRIIA/B. ActRIIA/B blockade approximately doubles the muscle increase of GDF8 blockade, and as ActRIIA/B responds to multiple other TGFβ-family members, this implies other ligands might also regulate muscle mass. Previously, we suggested that activin A (ActA) is the key second negative regulator acting via ActRIIA/B, as blockade of both GDF8 and ActA in mice/monkeys matches the muscle growth of ActRIIA/B blockade. Here, we extend these observations to humans in a two-part, randomized, placebo-controlled Phase 1 trial (www.clinicaltrials.gov, NCT02943239) conducted at two sites in New Zealand. Eligible subjects included healthy postmenopausal females aged 45–70 years and males aged 35–60 years not intending to father children, with a body mass index of 18–32 kg/m2. Part I tested single-dose administration of anti-GDF8 alone, anti-ActA alone, several dose combinations of anti-GDF8 + anti-ActA, or placebo in healthy postmenopausal females; part II tested multiple-dose administration of anti-ActA alone or placebo in healthy postmenopausal females, combination anti-GDF8 + anti-ActA or placebo in healthy postmenopausal females, and anti-ActA alone or placebo in healthy males. The primary outcome measure was the incidence and severity of treatment-emergent adverse events through week 16 for the single-dose part of the study and through week 40 for the multiple-dose part of the study. Secondary endpoints included percent and absolute change in thigh muscle volume, percent and absolute change in total and regional body composition, pharmacokinetic profiles of the GDF8 and ActA mAbs in serum over time, changes in serum total GDF8 and total ActA levels over time, and the presence of anti-drug antibodies against the GDF8 mAb or the ActA mAb. Magnetic resonance imaging was used to quantitate changes in thigh muscle volume and dual x-ray absorptiometry was used to quantitate changes in regional body composition (total lean mass, appendicular lean body mass, android fat mass, and total fat mass). A total of 82 subjects were enrolled (48 in the single-dose part and 34 in the multiple-dose part of the study). Baseline demographic and clinical characteristics were generally balanced across the single- and multiple-dose parts of the study. Combining GDF8 and ActA blocking antibodies led to greater muscle growth than either antibody alone; increases in muscle were accompanied by reductions in fat. The observed clinical effects on muscle and fat paralleled mAb exposure in serum. The combination was generally well tolerated, and no subjects tested positive for anti-drug antibodies post-treatment. These results suggest that GDF8 and ActA are the dominant negative regulators of muscle mass in humans, and that combined blockade may be a promising therapeutic approach in muscle atrophy and obesity settings.

A surface lipoprotein on Pasteurella multocida binds complement factor I to promote immune evasion.

Pasteurella multocida is the leading cause of wound infections in humans following animals' bites or scratches. This bacterium is also commonly found in the respiratory tract of many mammals and can cause serious diseases resulting in the rapid death of infected animals, especially cattle. To prevent these infections in cattle, a subunit-based vaccine utilizing the surface lipoprotein PmSLP was developed and showed remarkable protection with a single dose administration. Here, we report that PmSLP binds host complement factor I (FI) and facilitates cleavage of complement components C3b and C4b independently of any cofactors (e.g., FH, C4BP), thereby allowing the pathogen to evade host defence. Cryo-EM structure of PmSLP bound to FI reveals that PmSLP stimulates FI enzymatic activity by stabilizing the catalytic domain. This is the first time that a bacterial protein has been shown to directly activate FI independent of complement cofactors and target all arms of the complement cascade.

Bioequivalence and Food Effect Assessment of Two Fixed-Dose Combination Formulations of Telmisartan-Hydrochlorothiazide Tablets in Chinese Healthy Subjects.

This study assessed the bioequivalence and food effect of two fixed-dose combination (FDC) formulations of telmisartan-hydrochlorothiazide tablets (telmisartan 40 mg, hydrochlorothiazide 12.5 mg) in healthy Chinese subjects. Seventy-two subjects were enrolled and divided into fasted and fed cohorts in a single-center, randomized, open-label, single-dose, three-period, three-sequence, and crossover study. The pharmacokinetic characteristics of telmisartan and hydrochlorothiazide, including Cmax and AUC, were compared after subjects received single oral doses of telmisartan-hydrochlorothiazide tablets using a validated LC-MS/MS method. Safety and tolerability of treatments were monitored. Pharmacokinetic profiles of two FDC telmisartan-hydrochlorothiazide tablets were comparable after single-dose administration. 90% CI of geometric mean ratios (GMRs) of AUC0-t, AUC0-∞, and Cmax of telmisartan and hydrochlorothiazide of two FDC formulations fell within the predefined bioequivalence range of 80.0%-125.0% under both fasted and fed conditions. Administration with food had significant effects on telmisartan pharmacokinetic parameters but a slight impact on hydrochlorothiazide. Notably, Cmax and AUC of telmisartan were significantly decreased by 39.6%-43.7% in the fed versus fasted conditions. Safety assessments revealed all treatments were safe and well tolerated. Two telmisartan-hydrochlorothiazide FDC formulations were bioequivalent in healthy Chinese subjects in both fasted and fed states. All treatments were well tolerated.

Chemotherapy-induced diminished murine ovarian reserve model and impact of low-dose chemotherapy on fertility.

Chemotherapy-induced diminished murine ovarian reserve model and impact of low-dose chemotherapy on fertility.

Polysaccharide profile, acute toxicity and bile secretion effects of the choleretic herbal preparation 'Safroart herbal tea'

The aim. The aim of this study was to determine the polysaccharide composition of the choleretic collection "Safroart herbal tea", focusing on the identification of key carbohydrate fractions and their monosaccharide composition, as well as to evaluate its acute toxicity and choleretic activity. This investigation contributes to understanding the biochemical and pharmacological properties underlying the plant's therapeutic effects. Materials and methods. The herbal collection was subjected to sequential extraction to isolate its polysaccharides, which were fractionated into water-soluble polysaccharides (WSPS), pectin substances (PS), and hemicelluloses (HMC). These fractions were analyzed using paper chromatography, gas chromatography (GC), and infrared (IR) spectroscopy. For pharmacological evaluation, acute toxicity was assessed in mice using a single-dose administration protocol, and the choleretic effect was studied in rats by measuring bile secretion over a 4-hour period following administration of a 10 % aqueous infusion. Results. Alcohol-soluble sugars, including sucrose and fructose, were identified. WSPS were primarily composed of glucose, galactose, and arabinose, while PS and HMC contained rhamnose, arabinose, and xylose. IR spectroscopy confirmed the structural features of the fractions. The herbal collection was classified as practically non-toxic (LD₅₀ > 4000 mg/kg). In vivo studies revealed a 27.4 % increase in bile secretion in treated rats compared to controls, confirming a significant choleretic effect. Conclusions.‘Safroart herbal tea’ contains a complex mixture of polysaccharides with distinct monosaccharide profiles and demonstrates both safety and choleretic efficacy in experimental models. These findings support its potential use as a natural hepatobiliary remedy and contribute to the phytochemical and pharmacological understanding of its therapeutic action

Potent Cross-neutralizing Antibodies Reveal Vulnerabilities of Henipavirus Fusion Glycoprotein.

Hendra and Nipah viruses (HNVs), zoonotic paramyxoviruses with >50% case fatality rates, cause fatal encephalitis and respiratory disease, yet lack approved therapies. Here, nine rhesus-derived monoclonal antibodies (mAbs) targeting the fusion glycoprotein (F) prefusion conformation are developed. Four mAbs exhibit first-rate cross-neutralization against HNVs, with two showing synergistic potency when combined with attachment glycoprotein (G)-specific mAbs. Single-dose administration of mAbs confers robust protection against lethal Nipah virus challenge in hamsters. Structural insights reveal that 8 of the 9 potent mAbs adopt a human IGHV4-59-like framework with protruding CDRH3 loops, forming pushpin-shaped paratopes that stabilize the prefusion F-trimer by occupying vulnerable interprotomer cavities. Systematic mutational profiling identifies 14 prefusion-locking residues within the F ectodomain, classified as i) structural linchpins governing fusogenicity or ii) immunodominant hotspots targeted by cross-neutralizing mAbs. This work delivers promising therapeutic candidates against HNVs and provides blueprints for the rational design of antibodies and vaccines targeting viral fusion machinery.

Impact of intraoperative ketorolac on postoperative pain in children undergoing adenotonsillectomy: a double blind, placebo-control trial.

Postoperative pain control following adenotonsillectomy in the pediatric population poses a great challenge to care providers. Multi-modal pain management regimes including NSAIDs such as intraoperative ketorolac usage has been purposed for many years. However, the effectiveness of ketorolac to reduce post-tonsillectomy pain and opioid-related side effects is controversial. The study was to evaluate the opioid-sparing effect of an intraoperative intravenous single dose of ketorolac in children undergoing adenotonsillectomy. We also assessed the effectiveness of perioperative ketorolac on alleviating the common adverse effects of opioid usage. With IRB approval, a total of 142 pediatric patients aged between 3 and 12years undergoing elective adenotonsillectomy were randomized to receive either placebo or 0.5mg/kg ketorolac intraoperatively with other pain management remaining the same. The primary outcomes were postoperative pain scores and postoperative rescue pain medication usage. Common postoperative anesthesia-related complications such as nausea, vomiting and postoperative rebleeding were assessed. We found that ketorolac usage decreased the overall postoperative pain scores significantly (Max FLACC score 4.3 ± 2.6 for ketorolac vs. 5.9 ± 3.0 for placebo). However, intraoperative single-dose ketorolac administration did not reduce postoperative rescue opioid usage, nor decrease the rates of postoperative nausea and vomiting. We did not observe significant postoperative bleeding or other complications associated with ketorolac usage. While intraoperative ketorolac usage reduces the overall postoperative pain score, it does not decrease the postoperative opioid consumption in our current practice regime. Ketorolac may be a good multi-modal pain management adjunct without increased postoperative complications such as rebleeding.

Abstract 7302: A Novel Therapeutic Approach : New Drug Candidate with are potent and safe next-generation multi-target immune checkpoint inhibitor

Abstract Immune checkpoint inhibitors play a crucial role in current cancer treatments, serving as promising therapeutic options across various cancer types. In particular, PD-L1/PD-1 immune checkpoint inhibitors have been at the forefront of this field. However, recent concerns have been raised regarding the risk-benefit ratio of treatment based on PD-L1 expression levels, prompting the need for the development of immune checkpoint therapies that demonstrate high efficacy regardless of whether PD-L1 expression is high or low. Cellemedy’s T-sphaera platform based multi-target immune checkpoint inhibitors that simultaneously act on multiple immune targets, regardless of target expression levels. This platform offers several advantages: 1) it introduces biologically active domains that exhibit therapeutic effects, 2) it demonstrates high avidity based on protein structural characteristics, 3) it inherently possesses a cancer-T cell engaging effect when introducing multi-targets, and 4) being human protein-based results in reduced immune-related side effects, contributing to a favorable safety profile and therapeutic index. Cellemedy’s multi-target immune checkpoint inhibitors exhibit target-specific cytotoxicity against melanoma cancer cell line. In a non-human toxicity study, those compounds were well tolerated during repeated dosing, providing evidence of a superior safety profile without noticeable side effects. Furthermore, we verified strong efficacy in in vivo studies through T/NK cell engagement and high target avidity following a single-dose administration. Rapid and durable anti-tumor responses have been observed in vivo models. In summary, Cellemedy’s T-sphaera is promising multi-target immune checkpoint inhibitor platform that can be designed for various target, not only immune checkpoint blockade but also other tumor receptors, aiming at multiple cancers. Citation Format: Bo-Ram Lee, Seon-Boon Lee, Chul Joo Yoon, Hyunju Hwang, Sunho Jung, Joon Heo, Kyung-Mi Lee, H. Chris Kim. A Novel Therapeutic Approach : New Drug Candidate with are potent and safe next-generation multi-target immune checkpoint inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 7302.

Abstract 2964: SCR-A002, a novel FGFR2b-targeting ADC for solid tumors

Abstract Background: FGFR2b (fibroblast growth factor receptor 2 IIIb), an isoform of transmembrane tyrosine kinase FGFR family, is overexpressed in various cancers, including gastric, esophageal, breast, hepatocellular, pancreatic, ovary, uterine, cervical, endometrial, lung, colorectal cancers. Bemarituzumab (FPA144) is an afucosylated humanized IgG1 monoclonal antibody targeting FGFR2b with enhanced ADCC activity, which had promising clinical efficacy in phase 2 study of FGFR2b-selected gastric or gastroesophageal junction adenocarcinoma. Simcere Zaiming has developed a potential first-in-class FGFR2b-targeting ADC (SCR-A002) at IND-enabling status, displaying significantly superior anti-tumor potency compared to Bemarituzumab. Methods: Using hybridoma technique, anti-FGFR2b antibody was generated from immunization of FGFR2b protein in mice. SCR-A002 was comprised of a humanized anti-FGFR2b IgG1 monoclonal antibody conjugated through a cleavable linker to proprietary TOPO1 inhibitor payload (DAR 8). Binding activity and cytotoxicity were assessed in FGFR2b+ tumor cell line. And anti-tumor efficacy was evaluated in several CDX and PDX models. Results: SCR-A002 specifically bound to FGFR2b on tumor cells and could be internalized, and the TOPO1 inhibitor could be cleaved intracellularly and then exhibited potent cytotoxicity to tumor cells. And tumor regression was achieved after single-dose administration of SCR-A002 in different FGFR2b expression level CDX and PDX models, even with big-size tumor or Bemarituzumab resistance. Conclusion: SCR-A002 showed remarkable anti-tumor efficacy in preclinical data, suggesting that SCR-A002 is expected to provide a new treatment option as single agent or combo with SoC for patients with FGFR2b-overexpressing solid tumor. Citation Format: Yayuan Fu, Yuanjie Ge, Xiaohui Shao, Qi Deng, Chunlei Xia, Renhong Tang. SCR-A002, a novel FGFR2b-targeting ADC for solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2964.

Abstract 4303: AZD2284: A novel, alpha-particle emitting radioconjugate targeting STEAP2 in metastatic castration-resistant prostate cancer

Abstract Background: AZD2284 is a novel, targeted alpha therapeutic directed against six-transmembrane epithelial antigen of prostate-2 (STEAP2), a receptor highly overexpressed in prostate cancer. AZD2284 is comprised of a humanized, STEAP2-targeting rodent cross-reactive IgG1 monoclonal antibody conjugated with a DOTA chelate and radiolabeled with the alpha-particle emitting radionuclide, actinium-225 [225Ac]. Leveraging high STEAP2 expression in prostate cancer and the high linear energy transfer of the alpha emitter, AZD2284 is presumed to deliver the radioisotope to targeted tumor cells, generating clustered DNA double strand breaks and other cellular damage that ultimately leads to cell death. Methods: Preclinical pharmacological assessments were conducted with the lutetium-177 [177Lu] labeled analog of AZD2284, FPI-2281. In vitro binding and internalization assays with FPI-2281 were performed in STEAP2-positive prostate cancer cell lines with varying levels of target expression. In vivo biodistribution and uptake were evaluated ex vivo across multiple timepoints following FPI-2281 administration to tumor-bearing cell-line derived xenograft (CDX) models. To assess the radiotherapeutic efficacy of AZD2284, a single dose was administered intravenously to prostate cancer CDX and patient-derived xenograft (PDX) models. Results: Binding and internalization studies demonstrated FPI-2281 effectively binds to the STEAP2-positive prostate cancer cell line models (LNCaP, C4-2, and 22Rv1) with over 30% cellular retention at 24 hours. Corresponding in vivo biodistribution profiles showed sustained tumor uptake in xenograft models, with peak tumor uptakes of 60% ID/g in the 22Rv1 model and 83% ID/g in the C4-2 model at 14 days, respectively, with limited normal organ uptake observed at all timepoints. AZD2284 elicited target- and dose-dependent anti-tumor efficacy and sustained tumor regressions in CDX and PDX models with varying levels of STEAP2 expression. Conclusions: In preclinical models, AZD2284 effectively binds to and internalizes in prostate cancer cells, thereby delivering the radioisotope, [225Ac]. Biodistribution studies confirm sustained tumor uptake of AZD2284 with low normal organ uptake. Single-dose administration of AZD2284 leads to durable anti-tumor efficacy in xenograft models. These data suggest AZD2284 is a promising therapeutic candidate in prostate cancer and support the initiation of clinical trials. Citation Format: Darlene Monlish, Brigitte Thériault, Mel Ehudin, Vanessa Muniz-Medina, Dewald van Dyk, Lisa Godfrey, Dipal Patel, William Turnbull, Liang Zhang, Moditha Nawinne, Teresa Collins, Kenneth Thress, Douglas Ferguson, Rajiv Bhalla, Nicolas Giraldo, Melody Handali, Jeong Min Han, Crystal Cheung, Asurayya Worrede, Clare Hoover, Sujiet Puthenveetil, Edward Rosfjord, Frank Comer, Elaine Hurt, Darshan Dalal, Christopher Leamon, John Valliant, Puja Sapra. AZD2284: A novel, alpha-particle emitting radioconjugate targeting STEAP2 in metastatic castration-resistant prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4303.

A Rationally Designed Sulfonium Lipoglycopeptide with Micelles Self-Assembly to Combat Multidrug Resistance via Dual Enhanced Cell Wall-Membrane Inhibition and T7SS Proteins Downregulation.

Multidrug-resistant Gram-positive superbugs pose a significant menace to global public health, urgently demanding the advent of novel antibiotics. In this study, three biphenyl sulfonium lipoglycopeptides derived from vancomycin were rationally designed and synthesized to combat such resistance. Among them, the most promising derivative, BD-V-2, exhibited outstanding in vitro activity against a diverse array of refractory strains. Notably, in two highly challenging lethal sepsis models induced by MRSA and VREm (vanA), BD-V-2 achieved complete protection of the infected mice with remarkably low single-dose administrations of merely 7 and 2.5 mg/kg, respectively, vividly demonstrating its potent in vivo efficacy. Furthermore, its in vivo pharmacokinetic profile and toxicity assessment indicated favorable druggability. Interestingly, BD-V-2 was found to impart a novel self-assembly property into micelles. In addition, independent and synergistic mechanisms of action targeting the bacterial membrane, via phosphatidylglycerol (PG) interaction, and cell wall, via two more binding sites on lipid II, respectively, interpeptide bridge and pyrophosphate motif, were elucidated. Astonishingly, BD-V-2 was capable of significantly downregulating the expression of the type VII secretion system proteins, uncovering an unprecedented antivirulence mechanism for glycopeptide antibiotics. Collectively, these findings unraveled the hitherto unknown roles of the sulfonium strategy and established BD-V-2 as a highly prospective candidate for future pharmaceutical development.

Topical and oral emodepside formulations for last-line treatment of multianthelmintic drug-resistant hookworms when given orally to dogs are not bioequivalent

Abstract Objective To evaluate the pharmacokinetics of emodepside in dogs following single-dose administration of the FDA-approved feline topical solution orally and topically and the European Medicines Agency–approved canine modified-release tablet orally and to assess the bioequivalence of the feline topical solution administered orally compared to the canine modified-release tablet. Methods This study was conducted in 3 phases, during which dogs received single doses of emodepside as the feline topical solution (1 mg/kg) orally, the canine modified-release tablet (1 mg/kg) orally, and the topical feline solution (3 mg/kg) topically. Plasma pharmacokinetic profiles were determined for 21 days postdose. Bioequivalence testing was conducted for orally administered emodepside. Results 7 healthy client-owned dogs (4 female and 3 male) were prospectively enrolled in this crossover study from May through August 2023. Oral administration of the feline topical solution resulted in markedly greater emodepside absorption than the modified-release tablet and was not bioequivalent. Emodepside plasma concentrations following topical administration of the FDA formulation were 36- to 122-fold lower than after oral administration. Conclusions The feline topical solution administered orally at 1 mg/kg is not bioequivalent to the canine modified-release tablet. Markedly higher absorption of the feline topical solution administered orally raises potential safety concerns for extralabel use in dogs to treat multianthelmintic drug-resistant hookworm infections. Poor absorption following topical administration suggests it may be unsuitable for treating multianthelmintic drug-resistant hookworm infections. Clinical Relevance These findings highlight potential emodepside toxicity risks with extralabel use of the FDA-approved topical feline product and help inform safe off-label use in dogs.

A phase 1, randomized, double-blind, placebo-controlled trial investigating the safety, tolerability, pharmacokinetics, and pharmacodynamics of KN056 (a recombinant human GLP-1 variant Fc fusion protein) in healthy Chinese participants

ABSTRACT Background This randomized clinical pharmacology trial investigated the pharmacokinetics (PK), pharmacodynamics (PD), safety, and tolerability of KN056 following single-dose subcutaneous administration in healthy Chinese participants. Methods Thirty healthy male subjects were randomized to receive a single dose of KN056 (0.5, 1.0, 3.0, 6.0, or 12.0 mg) or placebo. PK and PD parameters, as well as safety and tolerability, were assessed. Results KN056 exposure increased proportionally with dose, with a half-life ranging from 141 to 188 hours. KN056 was well-tolerated, with gastrointestinal adverse events being the most common, particularly at the highest dose (12.0 mg). In the oral glucose tolerance test, KN056 dose-dependently decreased the AUC on the glucose versus time (gAUC) from baseline within 144 hours post-dosing. Specifically, the maximum reduction was 29.9% (occurring at the 72-hour mark). Body weight decreased within seven days of administration, correlating with dose levels, with a mean reduction of −1.68 kg in the 12.0 mg group; however, no significant change in body weight was observed by the end of the study. Conclusions KN056 demonstrated favorable PK, PD, and safety profiles in healthy Chinese participants, supporting its potential for once-weekly dosing.

Comparison between single bolus dose administration and continuous infusion of remimazolam for general anesthesia induction in non-cardiac surgery: a single-center prospective randomized controlled trial

BackgroundRemimazolam is a short-acting benzodiazepine anesthetic recommended for continuous infusion during anesthesia induction. However, the safety and efficacy of single bolus dose administration remain under investigation. This study compared continuous infusion with single bolus dose administration and assessed the safety of a single bolus dose administration.MethodsThe participants were randomly assigned into three groups based on the method of remimazolam administration the day before surgery: (1) continuous infusion group (continuous infusion at 12 mg/kg/h), (2) single bolus dose administration of 0.1 group (single administration of 0.1 mg/kg), or (3) single bolus dose administration of 0.2 group (single administration of 0.2 mg/kg). The time between drug administration and loss of consciousness was determined, and hemodynamic monitoring was performed.Results67 patients (continuous infusion group (n = 22), single bolus dose administration of 0.1 group (n = 22), and single bolus dose administration of 0.2 group (n = 23)) were included in the study. The different times to loss of consciousness were 88.2 ± 16.2 s, 59.5 ± 31.5 s, and 42.6 ± 11.4 s in the continuous infusion group, single bolus dose administration of 0.1 group, and single bolus dose administration of 0.2 group, respectively. No significant differences were observed in the incidence of adverse events between the groups. The results are presented as mean ± standard deviation (SD).ConclusionsSingle-dose remimazolam is a safe method for anesthesia induction, resulting in shorter time to loss of consciousness compared with continuous infusion, while maintaining a similar incidence of adverse events.Trial registrationjRCTs061230049, registered on 17/08/2023.

Single-dose oral administration of drug-loaded magnetic 3D-printed microbullets for eradication of Helicobacter pylori.

Infections of Helicobacter pylori (H. pylori) affect 42.1 % of the Chinese population and 43.1 % of the world population. H. pylori inhabits the mucous sublayer at the pylorus, leading to gastric ulcers, gastritis, and even cancer. Oral antibiotics are usually used to treat H. pylori infections, whereas traditional quadruple therapy has side effects including headaches, nausea, diarrhea, intestinal dysbacteriosis, antibiotic resistance, and repeat infections. Here, a drug-loaded magnetic microbullet was designed to realize long-term retention in the stomach for one-shot treatment for H. pylori infections. It comprises a hollow cylinder wherein eight microneedles homogenously distribute at the top and several round pores located at the bottom. It was three-dimensional (3D)-printed by stereolithography. A clarithromycin (CAM) ground mixture (CGM) was prepared to improve solubility. Enough CGM powders were filled into the cylinder, covered by a small round magnet, and sealed to form a CAM-loaded magnetic microbullet (CMMB). CAM continually released from CMMBs for >24 h. With outside magnetic guidance, an oral CMMB targeted the pylorus site and the microneedles immediately headed into the mucosa followed by long-term local drug release. The in vitro and in vivo safety of CMMBs was confirmed, where their swelling rates were low, and the oral CMMB was finally completely evacuated. An oral CMMB was administered to H. pylori-infected mice and maintained in the stomach for 36 h with magnetic guidance, and the successful eradication of H. pylori was confirmed after single-dose administration. Oral CMMBs are a convenient medication for the eradication of H. pylori.

A comprehensive evaluation of a bioanalytical technique for Encorafenib and Cetuximab combination Cancer therapy by LC-MS/MS and their pharmacokinetics in plasma.

A comprehensive evaluation of a bioanalytical technique for Encorafenib and Cetuximab combination Cancer therapy by LC-MS/MS and their pharmacokinetics in plasma.