Naunyn Schmiedebergs Arch. Pharmacol. [JOURNAL]
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200 papers
Multidisciplinary management of headache in developmental age: effects on school performance, quality of life, and therapeutic perspectives.
Ferrara F, De Berardinis F
Naunyn Schmiedebergs Arch Pharmacol · 2026 May · PMID 42209735 · Publisher ↗
Primary headaches represent a major public health burden in the pediatric population, with a prevalence exceeding 60%. They significantly impair quality of life, school attendance, and family dynamics, often manifesting...
Primary headaches represent a major public health burden in the pediatric population, with a prevalence exceeding 60%. They significantly impair quality of life, school attendance, and family dynamics, often manifesting as a complex biopsychosocial condition. This review provides a comprehensive update on the epidemiology, clinical classification, and comorbidities of pediatric primary headaches, offering a critical analysis of current diagnostic pathways and evolving therapeutic strategies. We examined recent literature, ICHD-3 classification criteria, and international consensus guidelines (AAN/AHS), focusing on the pathophysiology, neuro-psychiatric associations, and evidence-based management of migraine and tension-type headache in developmental age. Clinical evidence highlights a significant bidirectional comorbidity between headaches and neurodevelopmental disorders (ADHD, learning disabilities) as well as mood disorders (anxiety, depression), likely mediated by shared neurotransmitter dysregulation. Diagnosis remains fundamentally clinical, relying on history taking and "red flag" exclusion to rule out secondary etiologies. Regarding management, the therapeutic paradigm has shifted towards a "bio-behavioral first" approach, following evidence of high placebo response rates in prophylaxis trials (CHAMP study). While NSAIDs and triptans remain the cornerstone of acute care, emerging anti-CGRP therapies represent a promising frontier for refractory cases. Effective management of pediatric headache requires a multidisciplinary approach. The integration of lifestyle modifications, behavioral interventions (CBT, biofeedback), and judicious pharmacotherapy is superior to single-modality treatments in reducing disability, improving global functioning, and preventing chronification.
Pristimerin enhances erastin-induced ferroptosis in AML cells via the ATF3/SLC7A11 axis.
Chen S, Zhong L, Liu L … +8 more , Ke Z, Zhao Y, Wan P, Zhang Y, Liao Y, Deng Y, Yu L, Liu B
Naunyn Schmiedebergs Arch Pharmacol · 2026 May · PMID 42209734 · Publisher ↗
Acute myeloid leukemia (AML) is a highly aggressive hematologic malignancy predominantly seen in adults, with chemotherapy remaining the primary modality for its clinical management. Nevertheless, the efficacy of chemoth...
Acute myeloid leukemia (AML) is a highly aggressive hematologic malignancy predominantly seen in adults, with chemotherapy remaining the primary modality for its clinical management. Nevertheless, the efficacy of chemotherapy is often compromised by issues such as drug resistance, toxicity, and long-term adverse effects, particularly in refractory and relapsed patients. Natural products have historically served as a vital source for the development of anti-cancer agents. In this study, we examined the therapeutic potential of pristimerin (PM), a natural bioactive compound derived from the Malvaceae and Portulacaceae families, against acute myeloid leukemia and explored its underlying mechanisms. Our findings indicate that PM effectively suppressed AML cell proliferation, triggered apoptosis, and arrested the cell cycle at the G0/G1 phase. Furthermore, PM was found to enhance erastin-induced ferroptosis via modulation of the ATF3/SLC7A11 axis, characterized by increased iron (Fe) content, elevated malondialdehyde (MDA) levels, and decreased glutathione (GSH) levels. Mechanistically, PM augmented erastin-induced ferroptosis by regulating the expression of ATF3/SLC7A11, and knockdown of ATF3 significantly attenuated the ferroptosis effect. In conclusion, our results elucidate a previously uncharacterized role of PM in erastin-induced ferroptosis through the modulation of the ATF3/SLC7A11 pathway, indicating its potential as a naturally sourced therapeutic strategy for refractory and relapsed AML.
Combination treatment with mitoxantrone and doxorubicin induces multidrug resistance in Ewing Sarcoma CDX reporter xenografts.
Reddy K, Ramanathan S, Ayyadurai P … +3 more , Rajasekaran RR, Murhekar K, Ramachandran B
Naunyn Schmiedebergs Arch Pharmacol · 2026 May · PMID 42207282 · Publisher ↗
Ewing Sarcoma (ES) is an aggressive malignancy with limited treatment options in advanced disease. This study aimed to identify efficacious therapeutic candidates from FDA-approved drugs via in silico screening and evalu...
Ewing Sarcoma (ES) is an aggressive malignancy with limited treatment options in advanced disease. This study aimed to identify efficacious therapeutic candidates from FDA-approved drugs via in silico screening and evaluate the potential of the top candidate, mitoxantrone (Mito), alone and in combination with standard-of-care doxorubicin (Doxo). In silico screening was performed against an ES-specific molecular expression profile. Mito was validated in ES in vitro cellular models, and combination effects with Doxo were assessed by cytotoxicity assays. In vivo efficacy was evaluated in ES cell-line-derived xenograft (CDX) reporter models, with MDR1 (ABCB1) expression quantified across treatment arms to assess multidrug resistance. Mito demonstrated significant in vitro cytotoxicity, and Mito + Doxo produced an additive effect. However, in vivo CDX models showed no significant tumor response improvement with combination treatment relative to monotherapies. Combination-treated xenografts showed increased tumorigenicity, while monotherapy arms showed significant antitumor efficacy. MDR1 expression was markedly elevated in combination-treated tumors, indicating an acquired multidrug-resistant phenotype. This study reveals a critical in vitro and in vivo discordance and suggests that Mito + Doxo co-administration may paradoxically induce multidrug resistance, abrogating backbone chemotherapy efficacy. These findings urge caution in preclinical combination strategies involving standard-of-care agents and underscore the need for further investigation prior to clinical translation in ES.
Pharmacological repurposing of cilostazol to attenuate the progression of pulmonary fibrosis: efficacy validation via integrated network pharmacology and in vivo experimentation.
Misar PL, Otari KV, Pande VV … +1 more , Ige PP
Naunyn Schmiedebergs Arch Pharmacol · 2026 May · PMID 42207281 · Publisher ↗
Pulmonary fibrosis is a severe, chronic, and often lethal interstitial lung disease characterized by a destructive cycle of alveolar injury and inflammation, culminating in irreversible lung scarring. Its complex and mul...
Pulmonary fibrosis is a severe, chronic, and often lethal interstitial lung disease characterized by a destructive cycle of alveolar injury and inflammation, culminating in irreversible lung scarring. Its complex and multifactorial pathogenesis contributes to a poor prognosis and susceptibility to recurrent lung damage. This study employed an integrated network pharmacology and molecular docking approach to investigate the therapeutic repurposing of cilostazol for pulmonary fibrosis. Cilostazol was selected as a highly promising candidate owing to its broad pharmacological profile, encompassing anti-inflammatory, antioxidant, antiapoptotic, and antifibrotic properties. Network pharmacology analysis identified 10 potential targets of cilostazol, of which eight emerged as key network regulators: phosphodiesterase 3 (PDE3), PIK3CA, PTK2, RPS6KB1, VEGFR, F2-thrombin, ULK3 kinase, and PI3K delta. Molecular docking demonstrated that cilostazol binds to these profibrotic and fibrotic target proteins with binding affinities comparable to those of established experimental inhibitors. Experimental validation was performed using a bleomycin (BLM)-induced rat model of pulmonary fibrosis, incorporating histopathological and biochemical analyses of lung tissue and bronchoalveolar lavage fluid. Cilostazol exhibited significant antioxidant activity by reducing lipid peroxidation and restoring antioxidant enzyme levels. It exerted anti-inflammatory effects by downregulating proinflammatory cytokines (TNF-α, NO, and IL-6) and inflammatory markers (CRP, LDH, and MPO). Furthermore, cilostazol attenuated key indicators of fibrosis progression, including KL-6 and endothelin-1, alongside fibrotic markers such as TGF-β, α-SMA, and collagen I and III. At the molecular level, it significantly reduced the mRNA expression of fibrosis-associated genes, including TGF-β, fibronectin, α-SMA, collagen I, and MMP-7. Collectively, these findings demonstrate that cilostazol confers significant protection against bleomycin-induced pulmonary fibrosis through the targeted inhibition of the TGF-β/Smad, PI3K/AKT, and Wnt/β-catenin signaling cascades, highlighting its potential as a viable repurposed therapeutic strategy for inflammation-driven pulmonary fibrosis.
Integrated experimental and network pharmacology analyses reveal inhibitory effects of albiflorin on renal cell carcinoma cells.
Meng K, Zhang Y, Ma L … +5 more , Chen Z, Qian H, Sun Z, Jia X, Liu M
Naunyn Schmiedebergs Arch Pharmacol · 2026 May · PMID 42201344 · Publisher ↗
Renal cell carcinoma (RCC) remains a clinically challenging malignancy because of its marked molecular heterogeneity and the limited long-term efficacy of current systemic therapies. Albiflorin, a major bioactive constit...
Renal cell carcinoma (RCC) remains a clinically challenging malignancy because of its marked molecular heterogeneity and the limited long-term efficacy of current systemic therapies. Albiflorin, a major bioactive constituent of Paeonia lactiflora, has been reported to possess anti-inflammatory, antioxidant, and cytoprotective activities, whereas its potential role in RCC remains unclear. In the present study, the anti-RCC activity of albiflorin was investigated by integrating in vitro experiments, network pharmacology, and molecular docking, and experimental validation. CCK-8 assays showed that albiflorin reduced the viability of 786-O and A498 cells in a concentration-dependent manner, with lower IC50 values in RCC cells than in HK-2 cells. EdU incorporation and wound-healing assays further demonstrated that albiflorin suppressed RCC cell proliferation and migration. Albiflorin-related targets were collected from SuperPred and SwissTargetPrediction, while RCC-related targets were obtained from the KICH, KIRC, and KIRP datasets in TCGA. Sixty-four overlapping targets were identified. GO and KEGG enrichment analyses indicated that these targets were mainly associated with signal transduction, apoptosis, migration, angiogenesis, and cancer-related pathways, including MAPK, PI3K-Akt, Ras, and calcium signaling. Candidate target screening identified EGFR, MMP9, and FGF2 as representative candidate targets. Molecular docking supported the potential binding of albiflorin to EGFR and MMP9. RT-qPCR showed that albiflorin reduced MMP9 and FGF2 mRNA expression, whereas EGFR mRNA was not markedly altered. Western blotting showed decreased EGFR and ERK phosphorylation, and EGF stimulation partially restored EGFR/MAPK signaling activation in albiflorin-treated RCC cells. These findings suggest that albiflorin inhibits RCC cell viability, proliferation, and migration, partly through suppression of EGFR/MAPK signaling and regulation of tumor progression-related molecules.
Elucidating the molecular mechanisms linking bisphenol A to breast cancer: an integrated study of bioinformatics, machine learning, and molecular docking.
Bu X, Ma J, Liu Q … +4 more , Li T, Gao C, Li W, Luo Z
Naunyn Schmiedebergs Arch Pharmacol · 2026 May · PMID 42201343 · Publisher ↗
Bisphenol A (BPA) is a prevalent environmental endocrine disruptor linked to breast cancer. However, the precise molecular mechanisms and core therapeutic targets remain to be fully elucidated. This study employed an int...
Bisphenol A (BPA) is a prevalent environmental endocrine disruptor linked to breast cancer. However, the precise molecular mechanisms and core therapeutic targets remain to be fully elucidated. This study employed an integrative multi-omics approach to explore the potential mechanism of BPA-associated breast cancer. We integrated multiple transcriptomic datasets from the Gene Expression Omnibus (GEO) database and identified intersection targets between BPA and breast cancer through differential expression analysis, WGCNA, and multi-source database predictions (ChEMBL, PharmMapper, SEA). Pathway enrichment analyses revealed that these targets are predominantly involved in key signaling cascades, such as MAPK and PI3K/Akt. To identify robust biomarkers, we constructed a diagnostic model using machine learning algorithms and prioritized core genes via SHapley Additive exPlanations (SHAP) value analysis. Five core genes (EGFR, PPARG, MMP12, ADRB2, and KIF11) were identified, all of which demonstrated high diagnostic accuracy (AUC > 0.7) in validation sets. Subsequent molecular docking and molecular dynamics simulations predicted that BPA exhibits strong binding affinity (binding energy < - 5 kcal/mol) to these core proteins. Collectively, our findings suggest that BPA may promote breast cancer progression by modulating these core targets and interfering with the MAPK/PI3K/Akt pathways. This study provides a data-driven theoretical basis for elucidating the molecular link between BPA and breast cancer, proposing potential biomarkers that warrant further investigation for clinical diagnosis and intervention.
Neuroprotective effects of luteolin against aluminum-induced brain injury via chelation and antioxidant pathways.
Aydın Ş, Dalkılınç E, Özdemir S … +3 more , Küçükler S, Çomaklı S, Adıgüzel A
Naunyn Schmiedebergs Arch Pharmacol · 2026 May · PMID 42201342 · Publisher ↗
Aluminum (Al) is a widespread environmental neurotoxin linked to several neurodegenerative conditions through oxidative stress, inflammation, and apoptosis. Because it is present in food, water, pharmaceuticals, and cons...
Aluminum (Al) is a widespread environmental neurotoxin linked to several neurodegenerative conditions through oxidative stress, inflammation, and apoptosis. Because it is present in food, water, pharmaceuticals, and consumer products, chronic exposure is nearly unavoidable and poses a public health concern. Luteolin (LUT), a natural flavone with antioxidant, anti-inflammatory, and metal-chelating properties, has emerged as a potential neuroprotective agent. This study investigated the protective effects of LUT against aluminum chloride (AlCl)-induced neurotoxicity in rats. Sprague-Dawley rats received AlCl (4.2 mg/kg, i.p.) alone or together with LUT (25 or 50 mg/kg, p.o.) for 30 days. Behavioral performance was evaluated using novel object recognition and open-field tests. ICP-MS was employed to quantify brain Al levels, and complementary analyses were conducted to assess oxidative stress, neuroinflammation, apoptosis-related gene expression, neuroplasticity markers (BDNF, c-Fos), and cholinergic function (AChE). AlCl exposure significantly increased brain Al accumulation and induced oxidative stress, inflammation, apoptosis, and behavioral deficits. Although LUT co-treatment led to an apparent increase in total brain Al, this rise is likely attributable to the formation of Al-LUT complexes. This interpretation is supported by the marked reduction in Al-induced oxidative stress, apoptosis, and inflammation, accompanied by improved behavioral outcomes. This evaluation reveals that LUT provides protection in an environmental Al neurotoxicity model, offering insights beyond classical Alzheimer's disease contexts. Although its antioxidant and anti-inflammatory effects are well documented, evidence for its efficacy against environmentally induced Al neurotoxicity is still lacking.
Dihydroxyflavones as potential therapeutic agents against inflammation and renal injury via p38 MAP kinase inhibition: an in silico and experimental study.
Naqvi F, Jabeen A, Shafiq M … +2 more , Faizi S, Ul-Haq Z
Naunyn Schmiedebergs Arch Pharmacol · 2026 May · PMID 42189167 · Publisher ↗
Nephrotoxicity poses a significant clinical challenge, contributing to renal complications and increased mortality, thus necessitating novel therapeutics with superior efficacy and safety. Our study addresses this need b...
Nephrotoxicity poses a significant clinical challenge, contributing to renal complications and increased mortality, thus necessitating novel therapeutics with superior efficacy and safety. Our study addresses this need by evaluating flavone derivatives as potential modulators of p38-MAPK to tackle both inflammation and renal damage, using cell-based assays, cytotoxicity profiling, molecular docking, and ADME-T profiling. Notably, 3,6-dihydroxyflavone (3,6-DHF) and 3,7-dihydroxyflavone (3,7-DHF) demonstrated a significant reduction in KIM-1 mRNA expression in CCl-induced damaged renal epithelial cells while exhibiting no cytotoxic effects on Vero cells at therapeutic doses. Protein slot blot analyses revealed alteration in expression of total p38-MAPK, with 3,6-DHF exhibiting the strongest inhibitory effect. On the other hand, both DHFs effectively quenched reactive oxygen and nitrogen species from phagocytes, underscoring their anti-inflammatory properties. Molecular docking showed high binding affinity for p38-MAPK, with values of - 6.8 kcal/mol for 3,6-DHF and - 6.05 kcal/mol for 3,7-DHF, while ADME-T profiling revealed compliance with the Lipinski rule, good gastrointestinal absorption, and low toxicity risk. The findings suggest the promising anti-inflammatory and renoprotective properties of 3,6-DHF and 3,7-DHF, offering potential benefits for the treatment of nephropathies and associated inflammation. Future directions involve in vivo validation using nephrotoxicity models and preclinical optimization of these compounds for potential clinical application in treating renal disorders.
The synergistic efficacy of lupeol and enzalutamide potentiates anticancer activity, inducing apoptosis and cell cycle arrest in breast cancer cells.
Ali N, Alasiri G, Babu MA … +5 more , Singh TG, Alaseem AM, Quadri MSA, Tyagi Y, Bansal N
Naunyn Schmiedebergs Arch Pharmacol · 2026 May · PMID 42189166 · Publisher ↗
Breast cancer is a leading cause of cancer and death in women. There is an urgent need to explore medicinal compounds that can enhance therapeutic effectiveness while minimizing toxicity. The present study utilized lupeo...
Breast cancer is a leading cause of cancer and death in women. There is an urgent need to explore medicinal compounds that can enhance therapeutic effectiveness while minimizing toxicity. The present study utilized lupeol and enzalutamide combinations in luminal and triple-negative breast cancer cells to assess their efficacy on cell proliferation, apoptosis, and cell cycle progression. We performed a cell viability assay to investigate cytotoxicity using the spectrophotometric method. A combination index analysis was performed to determine synergistic dose drug combinations. Apoptosis and cell cycle analysis were performed using flow cytometry. The mRNA expression was analyzed by RT-PCR. Results indicate that lupeol + enzalutamide (Lup + Enz) significantly reduces cell viability in cancer cells compared to the treatment alone. The Caspase Glo assay revealed that Lup + Enz increased the activities of caspase 3/7 and 9 in the breast cancer cell line. Furthermore, Lup + Enz induces G1 phase arrest (≈75%) and promotes apoptosis (20%) in MCF-7 cells. mRNA expression suggests that Lup + Enz activates apoptotic mRNA expression (≈ 0.25 to threefold) in cancer cells. In conclusion, lupeol, in combination with enzalutamide, alters various hallmarks of breast cancer, like proliferation, apoptosis, and cell cycle arrest. Thus, lupeol may be a promising agent that enhances the outcomes of enzalutamide-based therapy. Further preclinical and clinical research is needed to validate the findings of this study.
Syringaldehyde inhibits NFκB-mediated inflammation and apoptosis and activates Nrf2/HO-1 signaling to reduce HCl/ethanol-induced gastric injury.
Yalinbas-Kaya B, Cesur S, Ince S
Naunyn Schmiedebergs Arch Pharmacol · 2026 May · PMID 42189165 · Publisher ↗
Syringaldehyde (SG) is a naturally derived phenolic aldehyde known for a range of biological activities. This study evaluated its protective potential against the chemically induced gastric injury model and investigated...
Syringaldehyde (SG) is a naturally derived phenolic aldehyde known for a range of biological activities. This study evaluated its protective potential against the chemically induced gastric injury model and investigated the underlying mechanisms involved. Acute gastric ulceration was induced in male Swiss albino mice by intragastric administration of a mixture of 0.3 M HCl and 70% ethanol. SG was orally administered at 25 and 50 mg/kg, and omeprazole (20 mg/kg) served as the reference anti-ulcer drug. HCl/ethanol exposure caused severe gastric mucosal injury characterized by increased lipid peroxidation, elevated levels of inflammatory mediators (IL-6, NFκB, iNOS, Cox-2, TNF-α, and IL-1β), and enhanced pro-apoptotic markers Bax and Cas-3. In parallel, antioxidant defense mechanisms were markedly impaired, as indicated by decreased GSH levels, reduced SOD and CAT activities, diminished mucosal protective mediators (PGE2 and NO), and downregulation of HO-1, Nrf2, and Bcl-2 expression. Treatment with SG significantly attenuated oxidative stress, gastric mucosal damage, and inflammatory responses, and modulated apoptosis-related markers. These protective effects were accompanied by restoration of antioxidant enzyme activities and increased levels of PGE2 and NO, together with upregulation of Nrf2/HO-1 expression. Overall, these results suggest that SG may exert gastroprotective effects against gastric injury through modulation of oxidative stress, inflammation, and apoptotic pathways.
Retraction Note: Thymoquinone dose‑dependently attenuates myocardial injury induced by isoproterenol in rats via integrated modulations of oxidative stress, inflammation, apoptosis, autophagy, and fibrosis.
Farag MM, Khalifa AA, Elhadidy WF … +1 more , Rashad RM
Naunyn Schmiedebergs Arch Pharmacol · 2026 May · PMID 42185563 · Publisher ↗
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Quality by design based development and optimization of a thermoreversible in situ intranasal gel of zavegepant for nose to brain delivery in migraine therapy.
Pawar A, Balme V, Pandhare R … +4 more , Deshmukh V, Bhagat B, Belhekar S, Andhale V
Naunyn Schmiedebergs Arch Pharmacol · 2026 May · PMID 42185562 · Publisher ↗
This study aims to develop and optimize a thermoreversible in-situ nasal gel of Zavegepant for effective and rapid treatment of acute migraine, enhancing brain targeting and bioavailability while overcoming limitations o...
This study aims to develop and optimize a thermoreversible in-situ nasal gel of Zavegepant for effective and rapid treatment of acute migraine, enhancing brain targeting and bioavailability while overcoming limitations of oral formulations. A 3 full factorial design was employed to evaluate the effects of Pluronic F-127 (X₁) and xanthan gum (X₂) on gelation temperature (Y₁) and mucoadhesive strength (Y₂). Nine formulations (VF1-VF9) were developed and evaluated for physicochemical properties, gelation behavior, mucoadhesion, in-vitro drug release, ex vivo permeation, and in vivo anti-migraine efficacy using a nitroglycerin-induced migraine model in rats. Optimized batch VF2 containing 20% Pluronic F-127 and 0.2% xanthan gum showed a gelation temperature of 34.94 °C and mucoadhesive strength of 5812.2 dyne/cm with minimal prediction error (< 5%). VF2 exhibited sustained ex vivo drug release (83.67% at 8 h) and steady-state flux of 522.94 μg/cm/h. In vivo studies demonstrated significant improvement in locomotor activity, photophobia, and mechanical allodynia, with biochemical normalization of CGRP (41.16 pg/mg), MDA, NO, GSH, and SOD levels, comparable to sumatriptan. Stability over 3 months confirmed formulation robustness. The optimized thermosensitive nasal gel (VF2) of Zavegepant presents a promising, non-invasive strategy for acute migraine therapy with sustained drug release, enhanced mucosal retention, and putative CNS delivery via olfactory and trigeminal pathway. Its clinical potential lies in offering fast, localized treatment with fewer systemic side effects and improved patient compliance.
Management of diabetes mellitus-associated atherosclerosis via simvastatin-loaded novasomes.
Fouad AG, Belal A, Gushgari OY … +3 more , Bawaked RA, Al Shwail FA, El-Ela FIA
Naunyn Schmiedebergs Arch Pharmacol · 2026 May · PMID 42185561 · Publisher ↗
The impact of atherosclerosis on global healthcare systems is increasing rapidly. Understanding the complications arising from constricted and blocked arteries is essential for comprehending the full impact of atheroscle...
The impact of atherosclerosis on global healthcare systems is increasing rapidly. Understanding the complications arising from constricted and blocked arteries is essential for comprehending the full impact of atherosclerosis. Additionally, atherosclerosis is exacerbated by diabetes mellitus (DM). Simvastatin (SVS), an HMG-CoA reductase antagonist, is known to protect against DM-associated atherosclerosis due to its cardioprotective, antioxidant, and anti-inflammatory effects. However, SVS has limited efficacy due to its poor solubility, short half-life, hepatic metabolism, and low bioavailability. This study aimed to develop, evaluate, and enhance nasal SVS-loaded novasomes (SLNs) with a focus on efficacy, bioavailability, and solubility for the treatment of DM-associated atherosclerosis. The efficacy of an optimized SLN formulation was investigated in albino Wistar rats. The optimized SLN formulation demonstrated an increase in bioavailability of 8.23 times, permeation of 4.52 times, and a release of 3.88-fold. The nasal SLN was found to be superior in terms of CK-MB, LDH, HDL, LDL, cholesterol, triglycerides, glutathione, superoxide dismutase, and catalase. The effectiveness and safety of the nasal SLN were validated using histopathological and toxicity studies. These results suggest that nasal SLN delivery could be a potential treatment strategy for DM-associated atherosclerosis.
Central toxic effects of an antitumoral bufadienolide: In silico targets and in vivo findings.
de Sousa RWR, de Almeida AAC, da Silva Fernandes G … +12 more , de Lima Sousa RC, Souza RP, Lima LKF, de Andrade FDCP, Mendes AN, Monção Filho EDS, Chaves MH, Junior GMV, de Jesus Rodrigues D, Dittz D, Feitosa CM, Ferreira PMP
Naunyn Schmiedebergs Arch Pharmacol · 2026 May · PMID 42185560 · Publisher ↗
Marinobufagin (MBG), a cardiotonic steroid from Rhinella toads, exhibits potent antitumor activity. However, their involvement in the mammalian neurotoxicity remains unclear. Therefore, this study evaluated the systemic...
Marinobufagin (MBG), a cardiotonic steroid from Rhinella toads, exhibits potent antitumor activity. However, their involvement in the mammalian neurotoxicity remains unclear. Therefore, this study evaluated the systemic (neuro)toxicological action of MBG to understand its central effects, particularly those associated with seizure-inducing activity. Initially, physicochemical, pharmacokinetic, and drug-likeness profiles and molecular docking with receptors/channels were investigated by in silico platforms. Next, the pro-convulsive action of MBG was investigated using pharmacological modulators for specific neurotransmission pathways and in vitro inhibitory activity of acetylcholinesterase was quantified. MBG has intestinal absorption and capacity to cross the blood-brain barrier (BBB), binds strongly to plasma proteins, and acts as an inhibitory substrate for the CYP3A4 enzyme. It was classified as a drug-like molecule according to Lipinski's rule and ineligible according to the Lead-like and World Drug Index criteria. Molecular docking emphasized the interaction of MBG with ictogenesis-related targets, confirmed by reduction of in vivo seizures and death of pretreated animals with pharmacological blockers for dopamine D2 and glutamate NMDA receptors and Na1.2 channels, mainly. It was shown that affinity of MBG for excitatory targets is essential for neuronal excitability and onset of seizures and that interaction with GABA receptors is involved in bufadienolide-induced lethality. The findings also suggest that MBG-induced seizures may involve in silico binding to NMDA receptors and interactions with key excitatory (Na1.2 channels and NMDA receptor) and inhibitory (GABA and D2 receptors) neuronal targets, contributing to altered neuronal excitability. Notably, it is the first report that characterized MBG-induced seizures and proposes it as a promising chemical option to understand ictogenesis and mechanism(s) of new anticonvulsive agents.
Clinical, demographic, and pharmacological predictors of medication adherence to disease-modifying therapies in multiple sclerosis: a multidimensional analysis of merged survey and claims data.
Thavarajasingam A, Fricke LM, Krauth C
Naunyn Schmiedebergs Arch Pharmacol · 2026 May · PMID 42185559 · Publisher ↗
Sustained adherence to disease-modifying therapies (DMTs) is essential for achieving therapeutic benefit in multiple sclerosis (MS). Despite the availability of effective agents, adherence has been reported as variable a...
Sustained adherence to disease-modifying therapies (DMTs) is essential for achieving therapeutic benefit in multiple sclerosis (MS). Despite the availability of effective agents, adherence has been reported as variable and often suboptimal in German cohorts, and the relative influence of clinical, demographic, and pharmacological factors remains insufficiently characterised. This study therefore examined predictors of objective adherence to DMTs in people with MS and the association between subjective and objective adherence. We analysed 795 people with MS (PwMS) receiving oral, subcutaneous, or intramuscular DMTs between October 2020 and September 2021. Objective adherence was measured using the Medication Possession Ratio (MPR), and subjective adherence using a visual analogue scale. Permutation-based multivariable analyses (PERMANOVA) were used to examine associations between predefined predictors and MPR. Objective adherence averaged 88.4% (SD 18.0). Subjective adherence was substantially higher, averaging 95.9% (SD 11.6; median 100%), with a pronounced ceiling effect. Therapy-related characteristics were the only consistent predictors of adherence. Oral agents and intramuscular interferon beta-1a achieved comparable adherence (p = 0.90), both exceeding that of subcutaneous therapies (both p < 0.001); within interferons, intramuscular exceeded subcutaneous administration (p = 0.002). Across active substances, glatiramer acetate showed the lowest adherence and teriflunomide, sphingosine-1-phosphate (S1P) receptor modulators, and dimethyl fumarate the highest (all p < 0.001 vs. glatiramer acetate). Demographic, including socioeconomic, and clinical characteristics, comprising age, sex, income, education, employment, MS subtype, disease duration, and disease activity, showed no measurable association with adherence. Subjective and objective adherence correlated only weakly (Spearman's ρ = 0.10; p = 0.005). Adherence patterns in MS were largely shaped by pharmacological and administration-related factors rather than by patient demographics or clinical profile. The weak correlation between subjective and objective measures supports complementing patient report with objective adherence indicators in routine care.
Protective effects of gastrodin against bisphenol A-induced dopaminergic dysregulation and cognitive impairment in rats.
Saifi MA, Javed M, Jindal G … +2 more , Agarwal N, Raisuddin S
Naunyn Schmiedebergs Arch Pharmacol · 2026 May · PMID 42185558 · Publisher ↗
Gastrodin (GAS) is a potent neuroprotective compound extracted from the traditional Chinese medicinal herb Gastrodia elata Blume. However, its role in mitigating bisphenol A (BPA)-induced dopaminergic dysfunction and cog...
Gastrodin (GAS) is a potent neuroprotective compound extracted from the traditional Chinese medicinal herb Gastrodia elata Blume. However, its role in mitigating bisphenol A (BPA)-induced dopaminergic dysfunction and cognitive impairment remains insufficiently explored. Many studies have shown that BPA exposure causes neurodegeneration via mechanisms involving dopaminergic system dysfunction, oxidative stress, and neuroinflammation. Therefore, the present study aimed to investigate whether GAS mitigates the effects of BPA-induced cognitive impairment through neuroinflammation in a rat model. Weanling male Wistar rats exposed to BPA (50 µg/kg b.wt. × 30 days, po) were subsequently treated with GAS at two dose levels (30 and 60 mg/kg b.wt., ip × 7 days). After 24 h, neurobehavioral functions (Barnes maze and Y-maze tests), cresyl violet staining, and ultrastructural analysis were performed, demonstrating significant memory deficits and neuronal degeneration in BPA-exposed rats. In contrast, GAS treatment significantly improved memory impairment and reduced neuronal cell death in the prefrontal cortex (PFC). mRNA, protein, and immunohistochemical expression of inflammatory markers such as tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), (Iba-1), glial fibrillary acidic protein (GFAP), and nuclear factor kappa B-p65 (NFκB-p65) were significantly increased in BPA-treated rats, indicating enhanced glial activation and neuroinflammation, whereas GAS effectively attenuated these alterations. Additionally, dopaminergic markers such as tyrosine hydroxylase (TH), dopamine transporter-1/solute carrier family 6 member 3 (DAT-1/SLC6A3), and dopamine receptor D4 (DRD4) were significantly downregulated following BPA exposure and were restored by GAS treatment. Overall, findings suggested that GAS exerts protection against BPA-induced neurotoxicity by suppressing NF-κB-mediated neuroinflammatory response and modulating dopaminergic signaling, thereby improving cognitive and neuronal outcomes in the PFC.
Case report: Delayed onset rash, delirium, and cross allergic reactions caused by sequential administration of cefoperazone sulbactam, meropenem, and piperacillin tazobactam.
Zhang J, Gao K, Jiao H … +1 more , Zhu B
Naunyn Schmiedebergs Arch Pharmacol · 2026 May · PMID 42183861 · Publisher ↗
Elderly patients, due to the decline of physiological functions, coexistence of multiple diseases, and physiological decline in liver and kidney functions, experience significant changes in the pharmacokinetics and pharm...
Elderly patients, due to the decline of physiological functions, coexistence of multiple diseases, and physiological decline in liver and kidney functions, experience significant changes in the pharmacokinetics and pharmacodynamics of antibacterial drugs, with a markedly increased risk of adverse drug reactions. This article reports a case of a 91-year-old male patient who, due to a pulmonary infection and hip replacement surgery, successively used four β-lactam antibacterial drugs: ceftriaxone, cefoperazone-sulbactam, meropenem, and piperacillin-tazobactam. On the third day after switching to cefoperazone-sulbactam, the patient developed a delayed generalized rash (Naranjo score 6); on the fifth day of meropenem administration, delirium occurred (Naranjo score 6), which resolved after discontinuation of the drug; within 5 min of infusion of piperacillin-tazobactam, a rapid-onset generalized allergic reaction occurred (Naranjo score 7), suggesting cross-allergy mediated by homologous side-chain structures of the drugs. After multiple consultations with clinical pharmacists, and with timely discontinuation of the drugs and symptomatic treatment by the clinicians, all the patient's symptoms were relieved. This case indicates that elderly patients require strengthened individualized medication monitoring and high vigilance for cross-allergic reactions caused by homologous side-chain structures of β-lactam drugs. Full-process pharmaceutical supervision is key to ensuring the safe use of antibacterial drugs in elderly patients.
A randomized, open-label, three-period, cross-over, single intravenous or intramuscular dose, pharmacokinetics and bioequivalence study of vitamin K in healthy adults.
Li Y, Qi L, Wang Y … +3 more , Li Y, Zhong W, Wang X
Naunyn Schmiedebergs Arch Pharmacol · 2026 May · PMID 42183860 · Publisher ↗
This study aimed to evaluate the bioequivalence of Vitamin K (VK) injection produced by Hainan Brilliant Pharmaceutical Co., Ltd. compared to the original drug KONAKION®MM via intravenous (IV) administration and to evalu...
This study aimed to evaluate the bioequivalence of Vitamin K (VK) injection produced by Hainan Brilliant Pharmaceutical Co., Ltd. compared to the original drug KONAKION®MM via intravenous (IV) administration and to evaluate the pharmacokinetic (PK) characteristics and bioavailability of VK via intramuscular (IM) administration. A randomized, open-label, three-period, single-dose crossover study enrolled 34 subjects. Periods 1 and 2 involved a single 10 mg IV dose of test (T) or reference (R) formulation in crossover design, with a 9-day washout. In period 3, all received a 10 mg IM dose of T formulation. Blood concentrations of the E and Z isomers of VK were measured at 29 time points. Bioequivalence was determined if the 90% confidence intervals (CIs) of the geometric mean ratios (GMRs) of the peak concentration (C), the area under the concentration-time curve from time zero to the last measurable concentration (AUC) and the extrapolated area under the curve from time zero to infinity (AUC) after log transformation for VK E isomer fell within the 80.00-125.00% based on the data of period 1 and 2. The data of the third period was only to recognize the PK characteristics of VK via intramuscular administration. Safety assessments included vital signs and electrocardiograms (ECGs). After 10 mg single dose of intravenous administration of test formulation and reference formulation, the GMRs of C, AUC, and AUC for the VK E isomer were 96.79%, 106.45% and 106.54% (the 90% CIs were 92.32%-101.48%, 101.64%-111.49%, and 101.70%-111.61%, respectively). All values fell within the 80.00-125.00% equivalence margin, confirming bioequivalence between the two formulations. The bioavailability of intramuscular administration route was about 56%. Safety was favorable, with no serious adverse events (SAEs) or grade ≥ 3 AEs. The test VK injection is bioequivalent to KONAKION®MM when administered IV, supporting its generic approval, and demonstrated good safety in healthy Chinese subjects. Registry: chinadrugtrials.org, TRN: CTR20230319, Registration date: February 6, 2023.
Datopotamab deruxtecan for endocrine-resistant HR-positive/HER2-negative breast cancer: biological rationale and clinical evidence.
Gumma B, Gumma L
Naunyn Schmiedebergs Arch Pharmacol · 2026 May · PMID 42183859 · Publisher ↗
Hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR-positive/HER2-negative) breast cancer is primarily managed with endocrine-based therapies; however, resistance to endocrine therapy and CDK4...
Hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR-positive/HER2-negative) breast cancer is primarily managed with endocrine-based therapies; however, resistance to endocrine therapy and CDK4/6 inhibitors commonly develops in advanced disease. Following treatment failure, therapeutic options are largely limited to sequential chemotherapy, which provides modest clinical benefit and is associated with cumulative toxicity. Antibody-drug conjugates (ADCs) targeting trophoblast cell surface antigen 2 (TROP-2) have emerged as a promising strategy for delivering cytotoxic agents selectively to tumor cells in endocrine-refractory disease. This narrative review summarizes current evidence on the biological rationale, pharmacologic characteristics, and clinical development of datopotamab deruxtecan (Dato-DXd), with emphasis on findings from the phase III TROPION-Breast01 trial and relevant translational studies. Datopotamab deruxtecan is a TROP-2-directed ADC that enables targeted delivery of a potent topoisomerase I inhibitor payload to tumor cells. In the TROPION-Breast01 trial, Dato-DXd demonstrated a statistically significant improvement in progression-free survival compared with investigator's choice chemotherapy in patients with endocrine-refractory HR-positive/HER2-negative metastatic breast cancer. Clinical activity was observed across heterogeneous TROP-2 expression, including in heavily pretreated patients and those with visceral disease. Hematologic toxicity was relatively limited, although interstitial lung disease remains an important safety consideration requiring proactive monitoring. Datopotamab deruxtecan represents a clinically meaningful therapeutic option based on the targeted delivery of cytotoxic chemotherapy for patients with endocrine-resistant HR-positive/HER2-negative breast cancer. Ongoing studies are required to define optimal treatment sequencing, combination strategies, and long-term safety outcomes.
Metformin-phytochemical combination therapy in metabolic dysfunction-associated steatotic liver disease: mechanistic insights and therapeutic potential.
Amri J, Karimpour A, Meshkani R
Naunyn Schmiedebergs Arch Pharmacol · 2026 May · PMID 42183858 · Publisher ↗
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a multifactorial metabolic disorder characterized by excessive hepatic lipid accumulation, insulin resistance, oxidative stress, and chronic inflammatio...
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a multifactorial metabolic disorder characterized by excessive hepatic lipid accumulation, insulin resistance, oxidative stress, and chronic inflammation. Its pathogenesis spans interconnected metabolic, inflammatory, and fibrotic pathways, limiting the efficacy of single-target therapeutic approaches. Metformin (MET), a first-line antidiabetic agent, improves hepatic lipid metabolism primarily through AMPK activation and enhanced fatty acid oxidation; however, its therapeutic impact on inflammatory and redox pathways remains limited, and its use is frequently associated with gastrointestinal adverse effects. In this context, phytochemicals-diverse plant-derived bioactive compounds with pleiotropic metabolic and antioxidant properties-have emerged as promising adjuncts to MET to achieve broader pathway coverage. For the first time, this comprehensive review evaluates preclinical in vivo evidence on metformin-phytochemical combination therapy in in vivo models of MASLD, with a specific focus on its mechanistic and therapeutic advantages over monotherapy. A comprehensive literature search was conducted using PubMed, Scopus, Web of Science, and Google Scholar. Only original preclinical in vivo studies evaluating the combination of metformin with an isolated phytochemical in animal models of MASLD were included. Data were extracted on compound identity, dosing regimens, experimental models, and metabolic, inflammatory, and signaling outcomes. Across eligible studies, metformin-phytochemical combinations consistently demonstrated superior efficacy compared with monotherapy in reducing hepatic steatosis, oxidative stress, and inflammatory mediators. Combinations involving berberine, chlorogenic acid, genistein, malvidin, morin, silymarin, and p-coumaric acid were associated with improved energy metabolism and fatty acid β-oxidation, alongside suppression of lipogenesis and fibrotic signaling. Additional benefits reported across studies included modulation of adipose tissue metabolism, enhancement of autophagy-related pathways, and favorable effects on gut-liver axis signaling, depending on the phytochemical class and experimental context. Overall, the preclinical in vivo evidence indicates that metformin-phytochemical cotherapy provides a multipathway modulatory framework integrating metabolic, anti-inflammatory, and antifibrotic effects. These findings support the translational potential of this combination strategy; however, well-designed clinical studies are required to assess pharmacokinetic compatibility, optimize dosing ratios, and determine its relevance in human MASLD.
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