Naunyn Schmiedebergs Arch. Pharmacol. [JOURNAL]
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200 papers
Impact of cannabis, benzodiazepines, and methamphetamine use on inflammatory and hepatic biomarkers in Benin City, Nigeria: a case-control study.
Usman-Onoruvie VO, Dele-Ochie PE, Adejumo BIG … +14 more , Oyakhire FO, Akhaumere EO, Odionyenma UC, Dimkpa U, Madompoyil B, Etinosa OB, Aneke GC, Abdulkadir UI, Obasuyi GE, Aiyesoro FO, Efenarhua S, Esezobor KI, Olaniyan MF, Odegbemi OB
Naunyn Schmiedebergs Arch Pharmacol · 2026 May · PMID 42183857 · Publisher ↗
Cannabis (tetrahydrocannabinol, THC), benzodiazepines (BZO), and methamphetamine (MET) exert diverse pharmacodynamic effects on hepatic metabolism and immune signaling pathways. While experimental studies suggest that th...
Cannabis (tetrahydrocannabinol, THC), benzodiazepines (BZO), and methamphetamine (MET) exert diverse pharmacodynamic effects on hepatic metabolism and immune signaling pathways. While experimental studies suggest that these agents modulate cytochrome P450 activity, oxidative stress pathways, and cytokine production, comparative clinical data particularly in African populations remain limited. This study investigated the association between single and polysubstance use and alterations in hepatic and inflammatory biomarkers. In a case-control design, 83 adults (19-59 years) from Benin City, Nigeria, were categorized as controls (n = 20) or users of THC only (n = 27), THC/BZO (n = 12), THC/MET (n = 10), BZO/MET (n = 5), or THC/BZO/MET (n = 9). Substance exposure was confirmed by urine immunochromatographic screening. Plasma levels of aspartate aminotransferase (AST, U/L), alanine aminotransferase (ALT, U/L), alkaline phosphatase (ALP, U/L), gamma-glutamyl transferase (GGT, U/L), total bilirubin (mg/dL), direct bilirubin (mg/dL), interleukin-6 (IL-6, pg/mL), and interleukin-10 (IL-10, pg/mL) were measured using standardized biochemical and ELISA methods. Group differences were assessed using ANOVA with Bonferroni correction. AST levels were significantly elevated in the THC-only (79.07 ± 59.60 U/L) and THC/BZO (73.58 ± 46.11 U/L) groups compared with controls (36.90 ± 11.05 U/L; p = 0.002 and p = 0.027, respectively). ALT was higher in the THC/MET group (54.30 ± 51.15 U/L) versus controls (33.60 ± 12.31 U/L; p = 0.037). IL-6 concentrations were significantly reduced in THC-only, THC/BZO, and THC/BZO/MET users compared with controls (p = 0.002), an unexpected finding discussed further below, whereas IL-10 showed no significant intergroup differences. Cannabis, benzodiazepine, and methamphetamine exposure particularly in combination is associated with biochemical patterns consistent with subclinical hepatocellular and cholestatic stress, alongside selective modulation of IL-6-mediated inflammatory signaling. These findings support pharmacologically plausible interactions affecting hepatic metabolism and immune regulation and warrant longitudinal investigation to clarify mechanistic pathways and reversibility.
Disruption of upstream ox-LDL signaling and HSP90-mediated NLRP3 stability protects against experimental steatohepatitis.
Karam A, Abdelhamid AM, Saber S
Naunyn Schmiedebergs Arch Pharmacol · 2026 May · PMID 42183856 · Publisher ↗
Metabolic dysfunction-associated steatohepatitis (MASH), the progressive inflammatory form of metabolic dysfunction-associated steatotic liver disease (MASLD), involves interconnected metabolic, inflammatory, and fibroge...
Metabolic dysfunction-associated steatohepatitis (MASH), the progressive inflammatory form of metabolic dysfunction-associated steatotic liver disease (MASLD), involves interconnected metabolic, inflammatory, and fibrogenic pathways unlikely to respond fully to single-target therapies. This study investigated the therapeutic potential of combining alvespimycin (ALV), an HSP90 inhibitor, with fluvastatin (FLU), a lipid-lowering agent, in a thioacetamide (TAA)-augmented high-fat diet rat model of MASH, hereafter referred to as the NASH model in keeping with established preclinical nomenclature. Disease induction caused marked hepatocellular injury, dyslipidemia, oxidative imbalance, inflammasome activation, pyroptosis, and fibrosis. Monotherapy with either ALV or FLU improved selected parameters, but each exerted incomplete effects. In contrast, combined ALV + FLU therapy produced coordinated protection, normalizing liver enzymes, improving lipid profile, restoring antioxidant capacity, and significantly reducing inflammatory and fibrogenic mediators including TNF-α, IL-1β, IL-18, TGF-β1, and hydroxyproline. Western blot analysis further showed that dual therapy markedly suppressed HSP90, NLRP3, caspase-1, NTGSDMD, and p-SMAD2/3. Mechanistically, the combination targets two distinct but converging levels of inflammasome regulation: FLU reduces ox-LDL, a key upstream activator of NLRP3, whereas ALV destabilizes the client protein NLRP3 by inhibiting its molecular chaperone HSP90. This dual-level interruption of the ox-LDL-NLRP3-caspase-1-IL-1β/IL-18 axis explains the superior anti-inflammatory, anti-pyroptotic, and antifibrotic efficacy of the combination. Exploratory HSA and Bliss analyses supported positive combination effects across oxidative, inflammatory, and fibrotic endpoints. Collectively, these findings suggest that ALV + FLU may represent a mechanistically rational, multitarget strategy capable of attenuating several hallmarks of MASH pathogenesis. Further studies are warranted to evaluate the translational potential of this combinatorial regimen for MASLD/MASH management.
Catalpol and tetramethylpyrazine relieve Alzheimer's disease by facilitating AQP4 protein expression and polarized distribution in hippocampal astrocytes via inducing the STAT3-mediated UCHL1 expression.
Deng C, Zhu M, Yuan J … +3 more , Yin T, Chen H, Meng S
Naunyn Schmiedebergs Arch Pharmacol · 2026 May · PMID 42178415 · Publisher ↗
Alzheimer's disease (AD) is a prevalent neurodegenerative disorder leading to dementia. This study investigated the effects of catalpol and tetramethylpyrazine (CT) on AD. AD mice were treated with CT, TGN020, 6RK73, and...
Alzheimer's disease (AD) is a prevalent neurodegenerative disorder leading to dementia. This study investigated the effects of catalpol and tetramethylpyrazine (CT) on AD. AD mice were treated with CT, TGN020, 6RK73, and Stattic. The Morris water maze task was employed to assess spatial learning and memory. Histological staining was used to evaluate hippocampal neuronal damage, Aβ1-40 clearance, and AQP4 protein distribution in the hippocampus. An AD cell model was established by inducing Aβ1-42 in mouse astrocytes, followed by CT, 6RK73, and Stattic treatments. UCHL1 siRNA was transfected into astrocytes, and ubiquitination analysis was conducted. Gene expression was assessed via qRT-PCR and Western blot. CT improved spatial learning and memory in AD mice, mitigated hippocampal neuronal damage, enhanced Aβ1-40 clearance, increased UCHL1 and p-STAT3/STAT3 expression, and promoted AQP4 protein expression and its polarized distribution in the hippocampus. The improvement in spatial learning, memory, and hippocampal neuronal damage was diminished by TGN020. 6RK73 inhibited CT-induced AQP4 expression and its polarized distribution in hippocampal astrocytes. Stattic counteracted CT-induced upregulation of UCHL1 in the hippocampus. UCHL1 facilitated AQP4 deubiquitination. Silencing UCHL1 or treating with 6RK73 blocked CT-induced AQP4 expression and its polarized distribution in Aβ1-42-treated astrocytes. Stattic abolished CT-induced UCHL1 expression in Aβ1-42-treated astrocytes. CT likely promotes STAT3 phosphorylation, enhancing UCHL1 expression, which in turn facilitates AQP4 expression and its polarized distribution in hippocampal astrocytes, providing therapeutic benefits in AD. These findings suggest CT as a potential therapeutic agent for AD.
Metagenomic surveillance identifies a high-risk antibiotic resistance profile in community wastewater: a pilot study from Pakistan.
Khan I, Naeem I, Ali S … +3 more , Gulbin M, Iqbal A, Shafiq M
Naunyn Schmiedebergs Arch Pharmacol · 2026 May · PMID 42176043 · Publisher ↗
Environmental antimicrobial resistance surveillance in low- and middle-income countries (LMICs) faces critical data gaps, particularly in Pakistan, where approximately 90% of municipal wastewater is discharged untreated....
Environmental antimicrobial resistance surveillance in low- and middle-income countries (LMICs) faces critical data gaps, particularly in Pakistan, where approximately 90% of municipal wastewater is discharged untreated. In the absence of systematic monitoring in regions like Khyber Pakhtunkhwa, we conducted a pilot shotgun metagenomic sequencing study on two strategically selected community wastewater sites in Mardan. To translate complex metagenomic data into actionable public health intelligence, we developed the Antibiotic Resistance Risk Index (ARRI), a novel framework integrating antibiotic resistance gene (ARG) proportional abundance, pathogen taxonomic expansion, and WHO priority weighting. Our analysis revealed that the urban site (MCW2) exhibited a "critical" resistance profile, characterized by a 54% increase in ARG allelic richness (628 unique variants) despite a 19.9% decline in total relative ARG abundance. Taxonomic compositional changes consistent with an aerobic shift, including a 34-fold decline in Thermodesulfobacteria and a 46% increase in Pseudomonadota, were observed alongside an increased proportion of WHO priority pathogens, including Acinetobacter baumannii, Pseudomonas aeruginosa, and Escherichia coli. This site served as a reservoir for last-resort resistance determinants, including bla, bla, bla, and mcr, which emerged exclusively in the urban drainage environment. The resistome contained 159 ARG families and 26 MGE types. Network analysis showed that 90.8% of ARG-MGE pairs exhibited coordinated increase in relative abundance, with all carbapenemase-linked pairs showing parallel trends. Consequently, ARRI scores escalated from 8.7 (moderate risk) to 34.2 (critical risk) at the urban site. These findings reveal the environmental circulation of hospital-associated resistance through decentralized sanitation infrastructure, representing a convergence of hospital-associated and community resistance profiles in LMIC settings. This study demonstrates that risk-weighted surveillance enables high-resolution, actionable AMR monitoring, providing a baseline methodology for environmental AMR surveillance in resource-limited settings.
Pharmacology through the lens of bibliometrics: global trends, research hotspots, and collaborations (2015-2026).
Kumar N
Naunyn Schmiedebergs Arch Pharmacol · 2026 May · PMID 42176042 · Publisher ↗
The current study conducts extensive bibliometric analysis of pharmacology bibliometric publications worldwide during 2015-April 15, 2026. The objective of this study was to explore publication trends, contributors, and...
The current study conducts extensive bibliometric analysis of pharmacology bibliometric publications worldwide during 2015-April 15, 2026. The objective of this study was to explore publication trends, contributors, and research hotspots. The search process was conducted using the Scopus database, with analysis being performed using the VOSviewer software. In total, 1014 articles were selected out of 1242 studies. The yearly publication count has risen significantly from 23 in 2015 to 280 in 2025, representing approximately 12 times more publications, while total citation count amounted to 14,984 citations, with a maximum citation count of 3922 in 2025. Geographical distribution demonstrated China as the leading producer with 419 publications, while the second and third places belong to the USA (104) and India (96). However, the USA leads in terms of collaboration intensity. Journals with the highest number of published papers include Frontiers in Pharmacology, with 43 articles and 786 citations. The keyword co-occurrence analysis reveals the presence of key topics such as drug therapy, oxidative stress, inflammation, and bibliometric analysis. Emerging topics include artificial intelligence and machine learning. The results of collaboration network analysis show growing globalization trends, although regional differences remain significant.
Short-term actions of arsenic trioxide on metabolic fluxes in the isolated perfused rat liver.
de Queiroz Eskuarek Melo NM, Peralta RM, Bracht L … +1 more , Bracht A
Naunyn Schmiedebergs Arch Pharmacol · 2026 May · PMID 42176041 · Publisher ↗
Arsenic trioxide has recently been approved for the treatment of acute promyelocytic leukemia, but it is also a highly toxic compound. The purpose of the present work was to obtain a general view about the acute effects...
Arsenic trioxide has recently been approved for the treatment of acute promyelocytic leukemia, but it is also a highly toxic compound. The purpose of the present work was to obtain a general view about the acute effects of arsenic trioxide on liver metabolism using the isolated perfused rat liver, a system that preserves microcirculation and cell polarity. Hepatic lactate and alanine gluconeogenesis were inhibited by arsenic trioxide with IC values of 21.7 and 21.4 µM, respectively. Oxygen uptake was inhibited only at concentrations above the IC value for gluconeogenesis inhibition. In addition to the carbon fluxes derived from alanine metabolism, arsenic trioxide also inhibited nitrogen detoxification (urea production) with an IC of 47.9 µM. Glycolysis from endogenous glycogen was stimulated at concentrations of up to 25 µM. Fructose metabolism was also affected: transformation into glucose was inhibited and fructolysis was stimulated. Glycerol metabolism was not modified. The ATP levels were not significantly diminished, but arsenic trioxide inhibited pyruvate carboxylase and phosphoenolpyruvate carboxykinase, phenomena that seem to be the main cause for gluconeogenesis inhibition. The acute effects of arsenic trioxide described herein are likely to contribute significantly to the general toxicity of the compound especially when combined with the reported long-term induction of exacerbated reactive oxygen species (ROS) production. When using the compound as a therapeutic agent, extreme care must be taken to avoid even mild overdosing as harmful and therapeutic levels for acute promyelocytic leukemia treatment are in fact relatively close to each other.
Development and characterization of a reserpine-induced mouse model of depression: An integrated in-vivo and in-silico approach.
Gautam K, Prasad S, Singh P
Naunyn Schmiedebergs Arch Pharmacol · 2026 May · PMID 42174108 · Publisher ↗
Depression is a complex neuropsychiatric disorder characterized by affective, cognitive, and somatic dysfunctions, yet its pathophysiology remains poorly understood. Reliable preclinical models are essential for elucidat...
Depression is a complex neuropsychiatric disorder characterized by affective, cognitive, and somatic dysfunctions, yet its pathophysiology remains poorly understood. Reliable preclinical models are essential for elucidating disease mechanisms and identifying therapeutic alternatives. The present study aimed to develop and characterize a reserpine-induced mouse model of depression using an integrated in-vivo and in-silico approach. Adult male Swiss mice (8-12 weeks) received oral reserpine (0.75 mg/kg BW/day) for 14 consecutive days. Behavioral assessments revealed significant reductions in food intake, body weight, and sucrose preference, alongside increased immobility time and impaired spatial memory. Biochemical analyses demonstrated elevated oxidative stress markers and diminished antioxidant enzyme activity in brain tissue. Neurochemical profiling confirmed significant depletion of key monoamines (serotonin, dopamine, norepinephrine, and histamine), increased acetylcholinesterase activity, and elevated serum corticosterone and liver enzymes (ALT and AST). Genotoxic and apoptotic evaluations indicated substantial DNA damage, increased apoptosis, and reduced cell viability. Histopathological observations further confirmed neurodegenerative changes and disrupted neuronal architecture in critical brain regions associated with mood and cognition, indicating compromised neuroplasticity. Complementary, molecular docking studies further demonstrated strong binding affinities of reserpine with key molecular targets involved in oxidative stress and neurotransmission, providing a mechanistic support for the observed pathophysiological changes. Overall, the present study establishes a robust and multidimensional model that captures behavioral, biochemical, and structural aspects of depression. The integration of experimental and computational approaches highlights the model's utility for advancing mechanistic insights and facilitating the development of novel antidepressant strategies.
Deleterious in vitro effects of ammonia and accumulated urea cycle amino acids on leukocyte DNA: assessment of the antioxidant effects of N-acetylcysteine and L-carnitine.
Lopes FF, Faverzani JL, Dos Reis BG … +8 more , Böttcher AK, Tedesco LMB, Altenhofen S, Dos Santos LS, Schreiner GE, Manfredini V, Wajner M, Vargas CR
Naunyn Schmiedebergs Arch Pharmacol · 2026 May · PMID 42171752 · Publisher ↗
The urea cycle is essential for ammonia detoxification. Deficiencies in this pathway cause urea cycle disorders (UCDs), characterized by hyperammonemia and severe systemic and neurological manifestations. While ammonia t...
The urea cycle is essential for ammonia detoxification. Deficiencies in this pathway cause urea cycle disorders (UCDs), characterized by hyperammonemia and severe systemic and neurological manifestations. While ammonia toxicity is well established, the contribution of urea cycle altered amino acids that accumulate in specific UCDs to cellular stress and DNA damage-associated responses remains poorly understood. This study investigated the DNA damage effects of ornithine (1 mM), homocitrulline (0.5 mM), citrulline (1 mM), and arginine (1 mM), alone and combined with ammonia (1 mM), in human peripheral leukocytes, as well as the protective effects of N-acetylcysteine (1 mM) and L-carnitine (60 µM). DNA damage was evaluated using the comet assay and statistically analyzed. All treatments induced significant DNA damage compared with controls. When tested individually at pathophysiologically relevant concentrations, urea cycle-related metabolites produced measurable increases in DNA damage, with citrulline and arginine inducing damage comparable to ammonia. Homocitrulline also caused DNA damage, to a lesser extent, while ornithine induced the lowest levels among isolated treatments. Combined exposure to ammonia and amino acids markedly increased DNA damage levels compared with isolated conditions, emphasizing the impact of metabolic imbalance in UCDs. The highest DNA damage indices were observed with ornithine and homocitrulline in the presence of ammonia, indicating potential synergistic interactions. L-carnitine significantly reduced DNA damage in all experimental conditions. N-acetylcysteine also reduced DNA damage effects in most combinations, except for ornithine with ammonia. Overall, these findings demonstrate that both isolated and combined UCD-related metabolites are associated with increased DNA damage under hyperammonemic conditions and support antioxidant strategies as potential complementary approaches to mitigate genomic stress in UCDs.
Ceramide signaling in non-small-cell lung cancer: from dysregulation to targeted therapy.
Patil DN, Yadav KS
Naunyn Schmiedebergs Arch Pharmacol · 2026 May · PMID 42171751 · Publisher ↗
Non-small-cell lung cancer (NSCLC) continues to exhibit high mortality largely due to adaptive resistance and metabolic plasticity. Among lipid signaling pathways, ceramide metabolism has emerged as a critical determinan...
Non-small-cell lung cancer (NSCLC) continues to exhibit high mortality largely due to adaptive resistance and metabolic plasticity. Among lipid signaling pathways, ceramide metabolism has emerged as a critical determinant of tumor cell death. Ceramide functions as a stress-responsive lipid mediator that promotes apoptosis, growth arrest, and immunogenic cell death. In NSCLC, however, ceramide signaling is persistently attenuated through enhanced degradation, diversion toward sphingosine-1-phosphate and glycosphingolipid synthesis, and altered intracellular trafficking. This metabolic shift suppresses apoptotic signaling, sustains oncogenic pathways, remodels the tumor microenvironment, and contributes to resistance across chemotherapy, targeted therapy, radiation, and immunotherapy. Unlike mutation-driven resistance, ceramide suppression represents a dynamic metabolic adaptation shared across heterogeneous tumors. Restoring ceramide-centered stress signaling therefore offers a unified strategy to lower apoptotic thresholds and re-sensitize resistant tumors. This review synthesizes mechanistic insights into ceramide dysregulation in NSCLC and examines therapeutic strategies aimed at re-establishing ceramide dominance, including enzyme inhibition, combination-based sensitization, nanocarrier-mediated delivery, and lung-targeted platforms. Finally, a precision framework incorporating lipidomic profiling and biomarker-guided stratification is proposed to facilitate clinical translation. Targeting ceramide metabolism may represent a metabolically informed adjunctive approach to enhance therapeutic durability in NSCLC.
Advancing PCOS drug development: multi-omics discovery of key targets and repurposable compounds.
Xiao Z, Zhang X, Zhang Y … +6 more , Liu J, Zheng X, Lai R, Yang H, Wu J, Yang J
Naunyn Schmiedebergs Arch Pharmacol · 2026 May · PMID 42171750 · Publisher ↗
Polycystic ovary syndrome (PCOS) is a prevalent endocrine disorder in reproductive-age women, characterized by limited therapeutic options that address its underlying mechanisms. This study aimed to identify novel drugga...
Polycystic ovary syndrome (PCOS) is a prevalent endocrine disorder in reproductive-age women, characterized by limited therapeutic options that address its underlying mechanisms. This study aimed to identify novel druggable protein targets for PCOS using a multi-omics integrative approach. Proteome-wide association studies (PWAS)-Mendelian randomization (MR) and summary-based MR (SMR) analyses were performed on large-scale plasma proteomics data from deCODE and UK Biobank cohorts, integrated with PCOS genome-wide association study (GWAS) summary statistics to screen for causal associations. Validation and prioritization involved Bayesian colocalization, transcriptome-wide association studies (TWAS), methylome-wide association studies (MWAS), and Gene Expression Omnibus (GEO) differential expression analysis. Biological mechanisms, druggability, and potential side effects were evaluated through protein-protein interaction networks, Gene Ontology/Kyoto Encyclopedia of Genes and Genomes enrichment, single-cell expression profiling, drug prediction via DSigDB, molecular docking, and MR-phenome-wide association studies (PheWAS). Fifty-seven candidate proteins were nominally associated with PCOS risk. FSHB met the stringent high-colocalization criterion (PPH4 > 0.8), whereas THOP1, CAMKK1, PDLIM4, and ERBB4 met the broader colocalization criterion (PPH3 + PPH4 > 0.8). After robustness filtering, ERBB4 was retained as a secondary candidate, and THOP1, FSHB, CAMKK1, and PDLIM4 were prioritized as tier 1 targets, with pathway analyses implicating lysosomal and MAPK-related processes. Drug predictions identified compounds such as Triciribine and 1,3,5(10)-Estratriene-2,3-diol-17-one, demonstrating favorable docking affinities (e.g., - 9.7 kcal/mol for FSHB). MR-PheWAS indicated limited side effects for most targets, except for FSHB-associated reproductive risks. These findings offer robust evidence for prioritized therapeutic targets, facilitating advancements in precision medicine and drug development for PCOS.
The safety profile of lenalidomide, dexamethasone, daratumumab, and bortezomib combinations in multiple myeloma: a retrospective analysis of the FAERS database.
Li D, Xiao Q, Yu Z … +5 more , Zheng X, Hu X, He Y, Zhou J, Zheng X
Naunyn Schmiedebergs Arch Pharmacol · 2026 May · PMID 42171749 · Publisher ↗
The current study aimed to compare the real-world safety profiles of first-line multiple myeloma regimens-lenalidomide plus dexamethasone (Rd), bortezomib plus lenalidomide and dexamethasone (VRd), and daratumumab plus l...
The current study aimed to compare the real-world safety profiles of first-line multiple myeloma regimens-lenalidomide plus dexamethasone (Rd), bortezomib plus lenalidomide and dexamethasone (VRd), and daratumumab plus lenalidomide and dexamethasone (DRd)-using the FDA Adverse Event Reporting System (FAERS) database. A large-scale retrospective analysis was conducted on 54,243 cases from the FAERS database (2004-2025). Analytical methods included trend analysis, disproportionality analysis (using Bayesian Information Component and Reporting Odds Ratio), co-medication assessment for drug-drug interactions, and time-to-onset analysis with Weibull modeling. Trend analysis reveals a steady increase in DRd adoption since its introduction in 2016, contrasting with a decline in Rd reports after 2021 and a modest decrease in VRd cases after 2020, potentially reflecting the emergence of new therapeutic alternatives and growing safety concerns. Disproportionality analyses confirm significantly elevated signals for infections associated with DRd and neurological disorders linked to VRd across multiple subgroup analyses. Co-medication assessments suggested potential drug-drug interaction signals associated with increased reporting frequencies of these adverse events. Time-to-onset analysis indicates an earlier manifestation of infectious complications with DRd. The findings support the potential value of regimen-specific safety monitoring: proactive infection prophylaxis for DRd recipients and subcutaneous bortezomib with neurological surveillance for VRd patients. This real-world evidence complements clinical trials and guides personalized treatment strategies to optimize the risk-benefit balance in multiple myeloma management.
Agent-specific bleeding signatures in non-hypertensive versus hypertensive patients exposed to oral anticoagulants: a real-world pharmacovigilance study.
Feng Y, Liu HH, Li LC … +3 more , Mao KL, Niu XF, Hu J
Naunyn Schmiedebergs Arch Pharmacol · 2026 May · PMID 42171748 · Publisher ↗
Oral anticoagulants (OAC) are effective in thrombo-embolic disorders, but their real-world bleeding profiles in hypertensive versus non-hypertensive users remain unknown. This study provides an exploratory, real-world as...
Oral anticoagulants (OAC) are effective in thrombo-embolic disorders, but their real-world bleeding profiles in hypertensive versus non-hypertensive users remain unknown. This study provides an exploratory, real-world assessment of the population-level, agent-specific safety hierarchy of direct OAC (DOACs; apixaban, dabigatran, edoxaban, rivaroxaban) and warfarin. We queried the FAERS database (Q1 2004-Q2 2025) using four disproportionality methods, requiring concordant signals from all four algorithms (a high-specificity, lower-sensitivity approach), and stratified by hypertension status as defined by MedDRA-coded diagnosis terms. A clinical priority matrix (0-8) incorporating salience, reporting density, robustness, and fatality was then applied to tier bleeding events. Among non-hypertensive reporters (n = 101,469), rivaroxaban dominated case volume (50,676; 49.9%), a finding that primarily reflects its market dominance rather than a higher intrinsic risk. In descriptive reporting patterns, dabigatran showed the highest proportion of fatal outcomes among its cases (23.7%). In the much smaller hypertensive subset (n = 4,252), edoxaban (based on only 142 reports) showed a fatality proportion of 28.9%; however, this estimate is based on a small sample and is subject to instability ("small cell" bias), warranting cautious, hypothesis-generating interpretation only. Hypertension was associated with a shift in the anatomical signal pattern from gastrointestinal and vascular-malformation bleeding observed in non-hypertensive toward deep intracerebral, traumatic, and adrenal hemorrhages in OAC. Temporal occurrence revealed early-phase rivaroxaban predominance in both strata, whereas warfarin exhibited a delayed but sustained reporting tail beyond 360 days. Clinical priority scoring identified brain stem hemorrhage as the only universally tier-5 event across DOACs and cerebral microhemorrhage was flagged moderate only in rivaroxaban in non-hypertensive patients. Edoxaban further generated unique tier-5 signals for cerebellar and pulmonary alveolar bleeding in both strata, though these findings are based on small numbers and require replication. Hypertension appears to be a qualitative effect-modifier that reallocates the population burden of OAC-related hemorrhage and redirects bleeding topography in this spontaneous reporting dataset. Agent-specific, blood-pressure-adjusted risk algorithms warrant further investigation and could eventually inform future guidelines, but prospective validation is required before clinical implementation.
Critical analysis of withdrawn drug applications in marketing authorization procedures of the European Medicines Agency (EMA) 2006-2024.
Hitsch F, Seifert R
Naunyn Schmiedebergs Arch Pharmacol · 2026 May · PMID 42171747 · Publisher ↗
Withdrawn drug applications (WDAs) are drug approval applications withdrawn by the applicant before the European Medicines Agency (EMA) has made a final decision. To better understand the main reasons for the emergence o...
Withdrawn drug applications (WDAs) are drug approval applications withdrawn by the applicant before the European Medicines Agency (EMA) has made a final decision. To better understand the main reasons for the emergence of WDAs, this study critically analyzes all WDAs in the period from 2006 to 2024. The data analysis is based on the 330 WDAs published by the EMA during the period mentioned above. Various parameters were analyzed, such as active substances, therapeutic subgroups and objections raised by the EMA. The most common therapeutic subgroups are antineoplastic agents (N = 80), followed by immunosuppressants (N = 23). Most drug approval applications are for initial approval (N = 244; 73.9%), supported by a single key clinical trial. In 77.3% (N = 255) of cases, the key clinical trials included a control arm (reference drug and/or placebo). In 69.7% (N = 230) of cases, no initial marketing authorization recommendation was made by the EMA's Committee for Medicinal Products for Human Use (CHMP). The most common reason for this was concerns about clinical efficacy (33.46%; N = 348), partly due to inadequate clinical trial design. A major reason for the accumulation of WDAs in the antineoplastic agents group is presumably the high demand for supply and the resulting economic potential of this drug group. The present analysis may contribute to the identification of obstacles and the resulting potential for optimization in the EMA's drug approval procedures.
Ginsenoside Rg3 attenuates fatigue by restoring autophagic homeostasis via the PI3K/AKT/mTOR pathway in ammonium chloride-induced C2C12 cells.
Liu H, Xiong R, Zhang S … +2 more , Zheng Q, Lai X
Naunyn Schmiedebergs Arch Pharmacol · 2026 May · PMID 42171746 · Publisher ↗
Fatigue is a widespread health problem, and abnormal autophagy in skeletal muscle cells is a key mechanism driving fatigue progression. The purpose of this study was to evaluate the effect of ginsenoside Rg3 (Rg3) on fat...
Fatigue is a widespread health problem, and abnormal autophagy in skeletal muscle cells is a key mechanism driving fatigue progression. The purpose of this study was to evaluate the effect of ginsenoside Rg3 (Rg3) on fatigue in ammonium chloride (NHCl)-induced C2C12 myoblasts cells and to elucidate its potential molecular mechanism. The potential anti-fatigue mechanism of Rg3 was predicted by network pharmacology and molecular dynamics simulations. C2C12 cells were treated with NHCl to construct an in vitro fatigue model and then treated with Rg3. CCK-8, live/dead staining, Giemsa staining, autolysosome staining, and Western blot were used to evaluate cell viability, myotube morphology, autophagic flow, and key protein expression. Network pharmacology analysis indicated that the anti-fatigue effect of Rg3 was associated with the PI3K/AKT/mTOR pathway-regulated autophagy. Molecular docking and molecular dynamics simulations confirmed that Rg3 binds strongly to PI3K. Cell experiments showed that Rg3 significantly attenuated cell death, myotube injury and abnormal autophagy in NHCl-induced C2C12 cells. Moreover, Rg3 effectively activated the PI3K/AKT/mTOR pathway. Our results indicated that the anti-fatigue effect of Rg3 may be associated with the attenuation of autophagy through activation of the PI3K/AKT/mTOR pathway. This provides a potential therapeutic candidate for fatigue intervention.
Duloxetine as a gut-brain axis modulator in irritable bowel syndrome: neuroimmune, microbiota, and pharmacogenomic perspectives.
Rejili M, Mustafa AM, Al-Kuraishy HM … +5 more , Hussein NR, Al-Maiahy TJ, Al-Gareeb AI, Albuhadily AK, Batiha GE
Naunyn Schmiedebergs Arch Pharmacol · 2026 May · PMID 42168405 · Publisher ↗
To provide an updated and integrative evaluation of duloxetine as a potential therapeutic agent for irritable bowel syndrome (IBS), with emphasis on its mechanisms of action across the gut-brain axis. The review addresse...
To provide an updated and integrative evaluation of duloxetine as a potential therapeutic agent for irritable bowel syndrome (IBS), with emphasis on its mechanisms of action across the gut-brain axis. The review addresses the key research question: Can duloxetine, beyond its antidepressant effects, modulate neuroimmune, microbial, and pharmacogenomic factors relevant to IBS, particularly pain-predominant subtypes? This narrative review provides a targeted synthesis of selected preclinical, clinical, and translational literature addressing duloxetine as a potential gut-brain axis modulator in irritable bowel syndrome. Evidence related to neuroimmune mechanisms, microbiota-related pathways, pharmacogenomic considerations, and clinical studies was narratively summarized. Evidence indicates that duloxetine modulates serotonergic and noradrenergic neurotransmission, decreases visceral hypersensitivity, and attenuates neuroinflammation via inhibition of microglial P2X4/NF-κB signaling. Duloxetine also shifts cytokine balance toward an anti-inflammatory profile (↑ IL-10, ↓ IL-6, ↓ TNF-α). Emerging data suggest additional benefits through modulation of gut microbiota composition, enhancement of short-chain fatty acid (SCFA) production, and improvement of intestinal barrier integrity. Pharmacogenomic factors, especially CYP2D6 and CYP1A2 polymorphisms, significantly influence duloxetine metabolism and therapeutic response. Compared with TCAs and SSRIs, duloxetine shows more favorable efficacy in relieving combined gastrointestinal and psychological symptoms with fewer sexual side effects. Duloxetine exhibits multifaceted actions that extend beyond mood regulation, positioning it as a promising but still investigational GBA-directed option dual-action therapy within the gut-brain axis framework. The collective findings support the need for biomarker-guided clinical trials incorporating microbiota profiling, cytokine signatures, and pharmacogenetic testing to validate duloxetine's role in precision-medicine-based IBS management.
Berberine reshapes gut microbiota and attenuates bone loss in estrogen-deficient osteoporosis via the gut-bone axis.
Huang L, Liu X, Huang F … +2 more , Chen L, Yue J
Naunyn Schmiedebergs Arch Pharmacol · 2026 May · PMID 42168404 · Publisher ↗
Postmenopausal osteoporosis (PMO) is a metabolic bone disorder characterized by estrogen deficiency-induced bone loss, deterioration of bone microstructure, and increased fracture risk. Current therapeutic agents are lim...
Postmenopausal osteoporosis (PMO) is a metabolic bone disorder characterized by estrogen deficiency-induced bone loss, deterioration of bone microstructure, and increased fracture risk. Current therapeutic agents are limited in efficacy and may have adverse effects. Berberine, a traditional Chinese medicinal compound, exhibits multitarget regulatory potential. However, its mechanism of action in alleviating PMO through modulation of the gut microbiota remains unclear. The objectives of this study are to assess the potential of berberine in mitigating estrogen deficiency-induced osteoporosis through modulation of the gut microbiota and to elucidate its underlying mechanisms. An ovariectomy (OVX)-induced PMO mouse model was established and divided into control, model, and berberine-treated (100 mg/kg/day) groups. Bone microstructure was examined using micro-CT, gut microbiota composition was analyzed through 16S rRNA sequencing; inflammatory factors and bone metabolism markers were evaluated using immunofluorescence; western blotting, qRT-PCR, and serum cytokine levels were quantified using ELISA. Berberine effectively reversed the OVX-induced gut dysbiosis by restoring the diminished levels of norank_f_Muribaculaceae and mitigating the elevated abundance of Lachnospiraceae_NK4A136_group, norank_f_Lachnospiraceae, and Roseburia. This modulation led to the suppression of intestinal inflammation, evidenced by decreased expression of IL-1β, IL-6, IL-8, and TNF-α, and an enhancement in gut barrier integrity, as indicated by increased levels of occludin and ZO-1. These changes collectively reduced the translocation of LPS into circulation. Consequently, berberine attenuated systemic and local release of pro-inflammatory cytokines and the activation of osteoclasts, resulting in the amelioration of PMO. Berberine mitigates PMO by reshaping the gut microbiota, improving intestinal barrier function, and suppressing systemic inflammation, thereby inhibiting bone resorption and restoring bone metabolic balance. This study offers a novel microbiome-targeted therapeutic approach for PMO.
Edaravone dexborneol in acute ischemic stroke: a systematic review and meta-analysis of randomized trials with clinical and thrombectomy-specific subgroup analyses.
Tariq E, Ahmed H, Qazi TI … +18 more , Muhaimin A, Malik AA, Soomro J, Qureshi R, Murtaza Z, Khan SA, Komal W, Tanveer H, Ameer R, Mohammad M, Haider K, Khan MF, Khan HW, Mehmood Y, Batool A, Al-Badri SG, Khattak MH, Khan BW
Naunyn Schmiedebergs Arch Pharmacol · 2026 May · PMID 42165867 · Publisher ↗
Edaravone dexborneol (ED), a combination of edaravone and ( +)-borneol, offers antioxidant and anti-inflammatory neuroprotection in acute ischemic stroke (AIS). Prior meta-analyses were limited by small sample sizes, inc...
Edaravone dexborneol (ED), a combination of edaravone and ( +)-borneol, offers antioxidant and anti-inflammatory neuroprotection in acute ischemic stroke (AIS). Prior meta-analyses were limited by small sample sizes, inclusion of observational studies, and lack of subgroup evaluations. To assess the efficacy and safety of ED in AIS, including patients undergoing endovascular thrombectomy (EVT). We systematically reviewed randomized controlled trials (RCTs) up to February 2026 using PubMed, Embase, Scopus, Cochrane Library, and ClinicalTrials.gov. The primary outcome was excellent functional recovery (mRS 0-1 at 90 days). Secondary outcomes included mRS 0-2 and 3-6, NIHSS changes, mortality, hemorrhagic complications, cognitive and functional measures, and adverse events. Risk of bias and certainty of evidence were evaluated using RoB 2 and GRADE. Eight RCTs (n = 4,197) were included. ED significantly improved mRS 0-1 (RR = 1.14; 95% CI: 1.07-1.20) and mRS 0-2 (RR = 1.06; 95% CI: 1.02-1.11), reduced poor outcomes (mRS 3-6; RR = 0.87; 95% CI: 0.79-0.94) and hemorrhagic transformation (RR = 0.55; 95% CI: 0.38-0.81), without increasing adverse events or mortality. Subgroup analyses suggested benefits across most demographics, although effects on mRS 0-1 were less pronounced in EVT-only patients. ED appears to improve functional outcomes and reduce hemorrhagic complications in AIS, with a favorable safety profile. However, findings should be interpreted cautiously due to population and trial limitations, and further multicentre studies are needed to confirm efficacy, particularly in EVT and high-risk subgroups.
Integrating network pharmacology, molecular docking, machine learning, and experimental validation: puerarin improves sepsis-induced acute kidney injury via the Sirt1-Nrf2-HO-1 pathway.
Fang S, Liu J, Li W … +5 more , Chang Z, Han Y, Zhang C, Hu X, Chen Y
Naunyn Schmiedebergs Arch Pharmacol · 2026 May · PMID 42165866 · Publisher ↗
Acute kidney injury (AKI) associated with sepsis has a high clinical mortality rate, and there is a lack of effective therapeutic targets; uncontrolled oxidative stress and inflammatory responses are central pathological...
Acute kidney injury (AKI) associated with sepsis has a high clinical mortality rate, and there is a lack of effective therapeutic targets; uncontrolled oxidative stress and inflammatory responses are central pathological mechanisms. The Sirt1-Nrf2-HO-1 pathway plays a key role in renal antioxidant and anti-inflammatory protection. Although puerarin possesses anti-inflammatory and antioxidant activity, its specific molecular mechanisms for improving sepsis-induced AKI have not yet been fully elucidated. The aim of this study was to determine whether puerarin protects against sepsis-induced AKI by activating the Sirt1-Nrf2-HO-1 pathway and to establish a theoretical foundation for its clinical application. Using network pharmacology, we identified Sirt1, Nrf2, and HO-1 as key targets linked to oxidative stress and inflammation. Molecular docking suggested that puerarin binds well to all three proteins. In both cell and animal studies, we found that puerarin activates the Sirt1-Nrf2-HO-1 pathway, which in turn improves kidney function, reduces tissue damage, and lowers oxidative stress and inflammation. Our findings suggest that puerarin protects against sepsis-induced AKI by triggering the Sirt1-Nrf2-HO-1 pathway, pointing to this signaling axis as a possible target for treatment.
Molecular mechanisms underlaying fluoride-induced neurotoxicity: interplay of antioxidants and endoplasmic reticulum stress-mediated apoptotic pathways in rats.
Dahiru A, Nawaz I, Riaz SK … +5 more , Chaudry SS, Khan MJ, Huang Q, Abbas M, Eqani SAMAS
Naunyn Schmiedebergs Arch Pharmacol · 2026 May · PMID 42165865 · Publisher ↗
Fluoride is a naturally occurring compound widely present in soil, water, rocks and is essential to maintain the physiological function and structure of bones and teeth. However, chronic exposure to elevated fluoride lev...
Fluoride is a naturally occurring compound widely present in soil, water, rocks and is essential to maintain the physiological function and structure of bones and teeth. However, chronic exposure to elevated fluoride levels has been linked to adverse neurological effects. Despite its widespread environmental presence, the molecular mechanisms underlying fluoride-induced neurotoxicity remain incompletely understood. This study aimed to elucidate the effects of fluoride on oxidative stress, endoplasmic reticulum (ER) stress, apoptosis, and associated histopathological alterations in brain tissue. Forty Sprague-Dawley rats were randomly assigned to four groups (n = 10 per group; 5 male + 5 female) and administered sodium fluoride (NaF) in drinking water at concentrations of < 0.5 ppm (control), 50 ppm, 150 ppm, and 300 ppm for 90 consecutive days. The expression of antioxidant genes (SOD1 and GCLC), ER stress, and apoptosis-related genes (XBP1, GRP78, BCL-2, and BAX) was quantified using real-time quantitative PCR (RT-qPCR), and histopathological analysis of the brain tissues was performed. Fluoride exposure caused a dose-dependent downregulation of antioxidant and ER stress-related genes and concurrent upregulation of the pro-apoptotic genes. Histopathological analysis revealed structural damage in hippocampus and cerebral cortex, including neuronal shrinkage, vacuolization, and apoptotic features. These findings indicate that prolonged NaF exposure impairs antioxidant defenses, induces ER stress, and activates apoptotic pathways, thereby contributing to neuronal damage. This study provides mechanistic insights into fluoride-induced neurotoxicity and highlights the need for further research on potential therapeutic strategies targeting oxidative and ER stress pathways.
Comparative extracellular and intracellular anti-Mycobacterium tuberculosis activity of three tanshinones from Salvia miltiorrhiza and oral cryptotanshinone efficacy in mice.
Wang X, Zhu C, Zhang X … +7 more , Zhang C, Zhao J, Jia H, Zhao Y, Zhang L, Zhang Z, Pan L
Naunyn Schmiedebergs Arch Pharmacol · 2026 May · PMID 42165864 · Publisher ↗
Tuberculosis (TB) remains a major global health threat, particularly due to multidrug-resistant (MDR) Mycobacterium tuberculosis (M.tb). Although recent years have seen the introduction of new drugs and shorter regimens...
Tuberculosis (TB) remains a major global health threat, particularly due to multidrug-resistant (MDR) Mycobacterium tuberculosis (M.tb). Although recent years have seen the introduction of new drugs and shorter regimens for TB, additional chemical scaffolds with activity against drug-resistant and intracellular bacilli are still needed. Tanshinones from Salvia miltiorrhiza represent a natural product scaffold with potential anti-mycobacterial activity. We systematically compared three major tanshinones-Tanshinone I (TAN), Dihydrotanshinone I (DTI), and Cryptotanshinone (CTS)-against M.tb H37Rv and a panel of drug-resistant clinical isolates. Extracellular minimum inhibitory concentrations (MICs) were determined, and intracellular activity was evaluated in M.tb-infected THP-1 macrophages by colony-forming unit (CFU) enumeration after 48 h of treatment. CTS was further evaluated in an acute murine TB infection model via daily oral gavage (25 mg/kg/day) for 28 days starting 14 days post-infection. All three tanshinones inhibited extracellular growth of drug-sensitive and drug-resistant M.tb with MICs in the 5-20 μM range, with DTI showing the lowest extracellular MIC (5 μM). In infected THP-1 macrophages at 48 h, CTS (10 μM; 1 × MIC) reduced intracellular CFU by approximately 1.00 Log relative to vehicle. Under the same conditions, TAN reduced CFU by 0.14 Log at 10 μM (1 × MIC) and 0.52 Log at 20 μM (2 × MIC), whereas DTI showed minimal intracellular activity (0.17 Log reduction at 10 μM; 2 × MIC). In mice, oral CTS produced statistically significant reductions in bacterial burden in lungs and spleens and improved lung histopathology compared with vehicle control. Major tanshinones display measurable in vitro activity against drug-sensitive and drug-resistant M.tb, but their extracellular and intracellular profiles differ. CTS showed consistent activity across extracellular, intracellular, and in vivo assays, supporting further studies on mechanism of action, pharmacokinetic optimization, and evaluation in combination regimens.
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