Gabapentin is effective for treating post-herpetic neuralgia and neuropathic pain by stabilizing nerve activity through blocking calcium channels and reducing neurotransmitter release. Gabapentin is available in immediate-release (IR) and extended-release (ER) formulations. A comparative bioavailability study was conducted between Gabapentin ER 600 mg tablets once-daily (OD) (Gabantin® GRS) [Test (T)] (manufactured by Sun Pharmaceuticals Industries Limited), and Gabapentin Tablets 600 mg OD (Gralise®) [Reference (R)] (distributed by Almatica Pharma LLC) in healthy human male adults under fed conditions. In this open-label, balanced, randomized, crossover study each subject received a 600 mg single dose of either T or R in Period 1, followed by crossover treatment in Period 2, with a washout period of 12 days in-between. Pharmacokinetic parameters, including Cmax, AUC0-t, and AUC0₋∞, were assessed. Safety was monitored through treatment-emergent adverse events (AEs). All 24 enrolled subjects completed the study. The test formulation demonstrated comparable pharmacokinetic profile to the reference product, meeting the criteria for bioequivalence within acceptable limits (0.80–1.25). The percentage ratio for T vs R product was 0.9171 (90
High-altitude illness (HAI) poses health risks to individuals at high altitudes, and acetazolamide (ACZ) is the only Food and Drug Administration (FDA)-approved prophylactic drug. Conventional immediate-release (IR) tablets and extended-release (ER) capsules do not simultaneously provide early drug availability and prolonged coverage. This study aimed to develop a biphasic-release ACZ tablet-in-tablet (ACZ-TIT) formulation as a proof-of-concept oral dosage form integrating IR and ER. ACZ–excipient compatibility was assessed using Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), and powder X-ray diffraction (PXRD), and solubility was evaluated in physiologically relevant media. Formulation optimization was performed via single-factor studies and response surface methodology (RSM). Quality control included weight, hardness, friability, content, and related substances. In vitro dissolution studies were conducted, and drug release kinetics were analyzed using multiple models. No new incompatibility signals were observed between ACZ and the selected excipients, and only small solubility differences were found across the tested media. ACZ-TIT showed a biphasic-release profile, with 25.3
Background and Objectives Neuroendocrine tumors are a rare and heterogeneous group of neoplasms that frequently cause carcinoid syndrome, characterized by diarrhea, flushing, and carcinoid heart disease. A recent therapy for carcinoid syndrome involves inhibition of tryptophan hydroxylase, the rate-limiting enzyme in serotonin synthesis, using telotristat ethyl. Telotristat has demonstrated clinical control of carcinoid syndrome; however, its potential antitumoral effects remain unclear. This study aimed to evaluate the antitumor activity of telotristat ethyl alone and in combination with everolimus in neuroendocrine tumor models. Methods Cell viability was assessed in three neuroendocrine tumor cell lines of pancreatic (BON-1, QGP-1) and intestinal (HROC57) origin following treatment with telotristat ethyl. Combination treatments with telotristat ethyl and everolimus or other antitumoral agents were evaluated for effects on cell viability, apoptosis, and cell cycle distribution. In vivo efficacy was examined in nude mice bearing BON-1-derived xenografts treated with telotristat ethyl, everolimus, or the combination. Tumor growth, toxicity, proliferation (Ki67), and apoptosis (active caspase-3) were analyzed. Results Telotristat ethyl reduced cell viability in all three neuroendocrine tumor cell lines. Combination with everolimus, but not with other antitumoral treatments, synergistically decreased cell viability, induced apoptosis, and reduced the proportion of cells in the G2/M phase. In nude mice bearing BON-1 xenografts, combined treatment with telotristat ethyl and everolimus arrested tumor growth without signs of toxicity compared with single treatments. At the end of treatment, tumors from combination-treated mice showed a reduction in proliferation (Ki67) comparable to single-treated groups and an increase in apoptosis as indicated by active caspase-3. Conclusions Telotristat ethyl exhibits antitumoral activity in neuroendocrine tumor models in vivo. Moreover, the combination of telotristat ethyl and everolimus, two therapies already used in clinical practice, may represent a safe and effective therapeutic strategy for neuroendocrine tumors.
Perianal fistulizing Crohn’s disease (PFCD) is a severe and complex manifestation associated with high morbidity and limited treatment durability. Ustekinumab is a monoclonal antibody targeting the interleukin-12/23 pathway, which is involved in the pathogenesis of PFCD. Evidence from post hoc analyses and real-world studies has shown the therapeutic potential of ustekinumab in both anti-tumor necrosis factor-experienced and selected biologic-naïve patients with PFCD. Preliminary evidence has indicated that the treatment effect may be improved when used in combination with surgical interventions such as seton placement or sphincter-preserving procedures. Adjunctive antibiotics during induction and early monitoring of clinical and radiologic response may further enhance outcomes. While ustekinumab is increasingly being incorporated into multidisciplinary PFCD management, prospective fistula-specific trials are needed to clarify its optimal positioning. Future research should also focus on predictive biomarkers and treatment algorithms to support personalized and durable care.
Non-small cell lung cancer (NSCLC) remains a leading cause of cancer-related mortality. While EGFR tyrosine kinase inhibitors (EGFR-TKIs) have improved survival, acquired resistance mediated by tumor hypoxia and HIF-1α stabilization often leads to treatment failure. This study investigated the regulatory role of HIF-1α in NSCLC drug resistance and evaluated a combined therapeutic strategy to overcome EGFR-TKI resistance. HIF-1α expression and downstream targets were assessed in H1975 and A549 cell lines using RT-qPCR and Western blot. Functional assays, including cell proliferation, apoptosis, invasion, lactate production, and ROS measurements, were performed following HIF-1α siRNA transfection and/or erlotinib treatment. Bioinformatics analyses of public datasets evaluated clinical relevance and pathway enrichment. HIF-1α knockdown inhibited glycolysis, reduced lactate production, and alleviated hypoxia-induced oxidative stress. Combined treatment with HIF-1α siRNA and erlotinib synergistically suppressed cell proliferation, induced apoptosis, and inhibited invasion more effectively than single-agent treatments. Mechanistically, EGFR signaling positively regulated HIF-1α stability via the PI3K/AKT and MEK/ERK pathways. Bioinformatics confirmed that high HIF-1α expression correlates with poor prognosis in NSCLC patients. Targeting HIF-1α disrupts metabolic reprogramming and hypoxia adaptation, thereby enhancing erlotinib efficacy. This combined approach highlights the therapeutic potential of HIF-1α inhibition as a novel strategy to overcome EGFR-TKI resistance in NSCLC.
Viloxazine, which has been used to treat depression and attention-deficit/hyperactivity disorder (ADHD), has been termed a moderate-affinity, selective norepinephrine reuptake inhibitor based on high selectivity for norepinephrine relative to serotonin and dopamine transporters. However, accumulated research suggests a more complex mechanism of action, based on studies showing activity at serotonin 5-HT2C, 5-HT2B, and 5-HT7 receptors, as well as findings that viloxazine increases extracellular serotonin (along with norepinephrine and dopamine) in the rat prefrontal cortex. This in vitro pharmacology study aimed to replicate and expand prior experiments to better characterize viloxazine’s affinity for and activity at the norepinephrine transporter (NET) and individual serotonin receptors and to clarify how these effects contribute to the mechanism of action. Using in vitro binding competition and functional assays and ex vivo receptor occupancy studies in rats, we assessed viloxazine activity at human NET isoforms and 5-HT2C, 5-HT2B, and 5-HT7 receptors relative to clinically relevant unbound viloxazine plasma concentrations (0.4–3.6 μM). Viloxazine showed moderate binding affinity for NET (inhibition constant [Ki] = 0.13 µM) and 5-HT2C (Ki = 0.66 µM), 5-HT2B (Ki = 0.83 µM), and 5-HT7 (Ki = 1.90 µM) receptors. In vitro functional studies showed viloxazine acted as a NET inhibitor, 5-HT2C partial agonist, and 5-HT2B and 5-HT7 antagonist. At clinically relevant concentrations, viloxazine could potentially occupy nearly 95
Androgen deprivation therapy (ADT) remains the primary treatment for advanced prostate cancer. However, most patients relapse within 18–24 months, progressing to castration-resistant prostate cancer (CRPC) which is currently incurable. Our preliminary studies identified the arylpiperazine derivative NAF19 as a promising therapeutic agent against prostate cancer, though its precise mechanisms remained unclear. This study aims to systematically evaluate the antitumor effects of NAF19 in prostate cancer cells and elucidate its molecular mechanisms, with a focus on its multi‑target inhibition of the AR/AR‑Vs signaling pathway and key survival pathways. To evaluate the effects of NAF19 on prostate cancer cell growth, we treated a panel of prostate cancer cell lines (LNCaP, C4-2, 22Rv1, DU145, and PC-3) representing both androgen-sensitive and castration-resistant phenotypes (including AR-expressing and AR-null subtypes) with varying concentrations of NAF19 for 72 h. Cell viability and sensitivity were subsequently assessed using the CCK-8 assay. In LNCaP and 22Rv1 cells, we further performed qRT-PCR to analyze the mRNA expression levels of AR/AR-Vs and their downstream target genes (PSA and UBE2C), flow cytometry to determine cell cycle distribution, and western blotting to examine the levels of cleaved PARP, antiapoptotic Bcl-2 family proteins, phosphorylated AKT (at Ser473 and Thr308), phosphorylated ERK, phosphorylated S6, as well as total AR and AR-V7. To assess the impact of NAF19 on tumor cell metastatic potential and proliferation, transwell migration and invasion assays, along with EdU incorporation assays, were conducted. Furthermore, a luciferase reporter assay was carried out to evaluate the transcriptional activity of the androgen receptor (AR). NAF19 exhibited growth-inhibitory effects across all five prostate cancer cell lines. It significantly suppressed AR/AR-Vs downstream gene expression, induced G1-phase cell cycle arrest in 22Rv1 cells, and reduced anti-apoptotic Mcl-1 protein levels while activating apoptosis. NAF19 dose-dependently induced PARP cleavage; NAF19 significantly reduced the phosphorylation levels of AKT (at T308 and S473 sites), ERK, and S6. Functional assays confirmed marked suppression of migration, invasion, and proliferation in NAF19-treated cells. The novel arylpiperazine derivative NAF19 exerts multi-targeted antitumor effects by concurrently inhibiting AR/AR-Vs signaling pathways and activating apoptotic cascades, thereby potently suppressing the migratory, invasive, and proliferative capacities of prostate cancer cells.
Iclepertin, a selective GlyT1 inhibitor undergoes metabolism mainly via hepatic CYP3A4, with only a small fraction undergoing urinary excretion. Patients with kidney or liver problems can have reduced CYP3A4 levels or activity, which may affect the levels of iclepertin in the blood and, in turn, its safety. Here, we present the results of two studies investigating the safety and pharmacokinetics of iclepertin in participants with various degrees of renal or hepatic impairment. In these two phase I, open-label, non-randomised, parallel studies, a single oral dose of iclepertin 10 mg was administered to participants with mild, moderate or severe renal impairment or mild or moderate hepatic impairment, together with healthy matched participants (based on age, sex, weight and race [only for renal impairment]; n = 8 for each impairment group. Primary and secondary endpoints included maximum plasma concentration (Cmax) and exposure metrics (area under the concentration-time curve [AUC]) of iclepertin. Safety was also assessed (adverse events [AEs]). In the renal impairment study (N = 36), exposure of iclepertin was minimally affected by renal impairment across trial groups except for the severe renal impairment group, which showed increased iclepertin exposure (AUC0–tz and AUC0–∞ geometric mean ratio impaired versus matched participants [90
Piracetam, a nootropic drug, is widely used for treating cognitive impairments. However, pharmacokinetic and bioequivalence data for piracetam formulations in the Chinese population are limited. This study was conducted to evaluate the pharmacokinetics and bioequivalence of a newly developed generic piracetam tablet compared with the reference product (Nootropyl®) in healthy Chinese participants under fasting and fed conditions. A randomized, open-label, single-dose, two-period, two-sequence crossover study was conducted in healthy Chinese participants under fasting and fed conditions. Healthy participants received a single oral dose of piracetam 800 mg as either the test or reference formulation, followed by a 7-day washout period. Plasma piracetam concentrations were determined using a validated high-performance liquid chromatography–tandem mass spectrometry method. Pharmacokinetic parameters, including maximum plasma concentration (Cmax), area under the plasma concentration–time curve from time zero to the last measurable concentration (AUC0–t), and area under the plasma concentration–time curve extrapolated to infinity (AUC0–∞), were calculated using non-compartmental analysis. Bioequivalence was assessed by calculating the 90
Lornoxicam (LOX) is a nonsteroidal anti-inflammatory drug used for pain management but requires frequent dosing due to its short half-life. This study aimed to develop a biphasic-release multiple-unit tablet (MUT) to achieve rapid and sustained LOX release with dose flexibility. LOX-loaded extended-release (ER) pellets were prepared by fluidized-bed coating of microcrystalline cellulose cores and optimized using a Box–Behnken design. The pellets were coated with Eudragit® RL/RS and combined with an immediate-release (IR) component to form MUTs by conventional tableting. Pellets and tablets were evaluated for physicochemical properties and in vitro drug release. Optimized ER pellets showed high drug-loading efficiency (92.2 ± 3
Therapeutic efficacy for malignancies and neurological disorders is fundamentally restricted by biological barriers, particularly the complex tumor microenvironment (TME) and selective blood–brain barrier (BBB). This review analyzes advanced drug delivery technologies engineered to overcome these obstacles. For TME penetration, stimuli-responsive nanocarriers enable spatiotemporally controlled drug release, while tumor-penetrating peptide functionalized nanoparticles enhance deep tumor diffusion; metal-organic frameworks further facilitate combinatorial therapy via microenvironment-triggered payload release. Regarding BBB transcendence, receptor-mediated transcytosis strategies significantly improve brain uptake, and physical-assisted approaches achieve localized barrier modulation. Bioinspired platforms—notably cell-membrane-coated nanoparticles and exosomes—demonstrate superior immune evasion and tissue-specific accumulation. Despite promising clinical progress exemplified by ANG1005 and focused ultrasound-assisted liposomal doxorubicin, translation challenges persist, including TME heterogeneity, scalable manufacturing complexities, and long-term biosafety. Future development prioritizes multifunctional theranostic systems integrating barrier-remodeling agents, artificial intelligence (AI)-optimized nanocarrier design, and sustainable manufacturing processes. Collectively, these innovations are transforming advanced drug delivery into a core therapeutic paradigm for intractable diseases.
Claudin18.2 (CLDN18.2) is a promising therapeutic target overexpressed in various tumor tissues. While CD3-engaging bispecific antibodies show great potential, their clinical application is often limited by poor efficacy in solid tumors and significant safety risks, such as cytokine release syndrome (CRS). The objective of this study was to comprehensively evaluate the preclinical anti-tumor efficacy, pharmacokinetics, tissue distribution, and safety profile of AHT-102, a novel Fc-free CLDN18.2 × CD3 bispecific antibody with a low-affinity CD3 arm, to determine its potential for clinical development. This study evaluated the anti-tumor efficacy of AHT-102 in CLDN18.2-positive gastric cancer mouse models (NUGC4-CLDN18.2). We further assessed its pharmacokinetic characteristics, quantitative tissue distribution using 125I-labeling, and long-term toxicity in human CD3EDG transgenic mice. AHT-102 (0.1, 0.3, and 1 mg/kg) demonstrated significant dose-dependent anti-tumor effects, with tumor weight inhibition reaching 51
ET-26 is a novel etomidate analog with reduced adrenal suppression. This study evaluated its pharmacokinetics (PK), pharmacodynamics (PD), and safety in subjects with mild to moderate renal impairment. In this phase I trial, 24 subjects (normal renal function, mild renal impairment, moderate renal impairment; n = 8/group) received a single intravenous bolus ET-26 dose. PK parameters (Cmax, AUC0–∞, CL), urinary excretion, PD (time to unconsciousness, area under the curve [AUC] of the Bispectral Index [BIS]), and safety were assessed. Systemic exposure (AUC0–∞) differed by < 16 http://www.chinadrugtrials.org.cn/clinicaltrials.searchlistdetail.dhtml
Omadacycline is a novel tetracycline with a wide range of antibacterial activity. A comprehensive understanding of the factors influencing its metabolic processes is essential to optimize its therapeutic benefits and minimize any potential negative effects. It was found that the metabolism of omadacycline does not rely on UDP-glucosyltransferase or cytochrome P450 enzymes, which gives it a clear advantage in terms of drug interactions, bioavailability, and metabolic stability. The review offers a thorough analysis of the many elements influencing the pharmacokinetics of omadacycline, including its intrinsic properties, individual differences, dietary influences, and possible drug interactions. To achieve maximum efficacy and safety in clinical practice, a thorough understanding of the pharmacokinetic properties of omadacycline is essential, which helps to better customize dosing regimens and maximize therapeutic outcomes.
This phase I study was designed to evaluate the safety, tolerability, and pharmacokinetics of omecamtiv mecarbil with multiple oral doses at 25 mg twice daily, followed by titration to either 37.5 or 50 mg twice daily in healthy Chinese participants. Fifty healthy participants were enrolled and randomly assigned into three groups: Group A (20 subjects) received omecamtiv mecarbil 25 mg in period 1 and either 37.5 mg or 25 mg in period 2; Group B (20 subjects) received omecamtiv mecarbil 25 mg in period 1 and either 50 mg or 25 mg in period 2; and Group C (10 subjects) received a placebo in both periods. The pharmacokinetics of omecamtiv mecarbil were well characterized in healthy Chinese participants. Across all subgroups, the mean terminal elimination half-life ranged from 18.3 to 21.3 h. Mean accumulation ratios of area under the curve from time 0 to 12 h ranged from 4.54 to 5.01 in period 1 and 2. The mean maximum observed concentration/plasma concentration before dosing ratios varied between 1.23 and 1.31 on days 8 and 34 across subgroups. No subjects experienced serious adverse events. The most frequently reported adverse events were an increased blood creatine kinase levels (12.5
The emergence of severe acute respiratory syndrome coronavirus 2 variants against which sotrovimab has lower in vitro neutralisation activity has led to the exploration of higher (> 500-mg intravenous) doses. This study evaluated the safety, tolerability and pharmacokinetics of intravenous sotrovimab 3000 mg. We conducted a phase I, open-label, single-arm study in healthy adults. Participants were administered a single 3000-mg dose of intravenous sotrovimab (100 mg/mL) over 60 min (50 mg/min). Adverse events, serious adverse events and adverse events of special interest were assessed through week 35. Sotrovimab pharmacokinetics were evaluated through week 24. Of 100 participants enrolled, 98 received sotrovimab (median age 42.5 [range 18–64] years; 52
New coronavirus disease 2019 (COVID-19) therapeutics, including intramuscular (IM) formulations, may increase patient access. In COMET-TAIL, sotrovimab 500 mg IM was non-inferior to 500 mg intravenous (IV) in reducing the risk of COVID-19 progression; however, 250 mg IM was associated with more hospitalizations, despite similar viral load (VL) reductions to 500 mg IM. COMET-PEAK was a randomized, three-part study to assess safety, tolerability, and viral pharmacodynamics of sotrovimab in adults with early, mild-to-moderate COVID-19. Parts B/C evaluated sotrovimab 500-mg IV infusion versus 500-mg or 250-mg IM injection. The primary objective was to compare virologic response of sotrovimab IM versus IV (mean area under the curve from day 1 to day 8 [AUCD1–8] of severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2] VL); 90 https://classic.clinicaltrials.gov/ct2/show/NCT04779879 .
