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Guided by a computational docking analysis, about 30 Food and Drug Administration/European Medicines Agency (FDA/EMA)-approved small-molecule medicines were characterized on their inhibition of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease (Mpro). Of these small molecules tested, six displayed a concentration that inhibits response by 50% (IC50) value below 100 μM in inhibiting Mpro, and, importantly, three, that is, pimozide, ebastine, and bepridil, are basic molecules that potentiate dual functions by both raising endosomal pH to interfere with SARS-CoV-2 entry into the human cell host and inhibiting Mpro in infected cells. A live virus-based modified microneutralization assay revealed that bepridil possesses significant anti–SARS-CoV-2 activity in both Vero E6 and A459/ACE2 cells in a dose-dependent manner with low micromolar effective concentration, 50% (EC50) values. Therefore, the current study urges serious considerations of using bepridil in COVID-19 clinical tests.

Bepridil is a commonly used medication for arrhythmia and heart failure. It primarily exerts hemodynamic effects by inhibiting Na + /K + movement and regulating the Na + /Ca 2+ exchange. In comparison to other Ca 2+ inhibitors, bepridil has a long half-life and a complex pharmacology. Additionally, it is widely used in antiviral research and the treatment of various diseases. However, the toxicity of this compound and its other possible effects on embryonic development are unknown. In this study, we investigated the toxicity of bepridil on rat myocardial H9c2 cells. After treatment with bepridil, the cells became overloaded with Ca 2+ and entered a state of cytoplasmic vacuolization and nuclear abnormality. Bepridil treatment resulted in several morphological abnormalities in zebrafish embryo models, including pericardium enlargement, yolk sac swelling, and growth stunting. The hemodynamic effects on fetal development resulted in abnormal cardiovascular circulation and myocardial weakness. After inhibiting the Ca 2+ transmembrane, the liver of zebrafish larvae also displayed an ectopic and deficient spatial location. Additionally, the results of the RNA-seq analysis revealed the detailed gene expression profiles and metabolic responses to bepridil treatment in zebrafish embryonic development. Taken together, our study provides an important evaluation of antiarrhythmic agents for clinical use in prenatal heart patients.

Long QT syndrome (LQTS) is a disorder of the heart's electrical activity that infrequently causes severe ventricular arrhythmias such as a type of ventricular tachycardia called torsade de pointes (TdP) and ventricular fibrillation, which can be fatal. There have been no previous reports on the time-to-onset for LQTS based on data from spontaneous reporting systems. The aim of this study was to assess the time-to-onset of LQTS according to drug treatment. We analyzed the association between 113 drugs in 37 therapeutic categories and LQTS including TdP using data obtained from the Japanese Adverse Drug Event Report database. For signal detection, we used the reporting odds ratio (ROR). Furthermore, we analyzed the time-to-onset data and assessed the hazard type using the Weibull shape parameter. The RORs (95% confidence interval) for bepridil, amiodarone, pilsicainide, nilotinib, disopyramide, arsenic trioxide, clarithromycin, cibenzoline, donepezil, famotidine, sulpiride, and nifekalant were 174.4 (148.6-204.6), 17.3 (14.7-20.4), 52.0 (43.4-62.4), 13.9 (11.5-16.7), 69.3 (55.3-86.8), 54.2 (43.2-68.0), 4.7 (3.8-5.8), 19.9 (15.9-25.0), 8.1 (6.5-10.1), 3.2 (2.5-4.1), 7.1 (5.5-9.2), and 254.8 (168.5-385.4), respectively. The medians and quartiles of time-to-onset for aprindine (oral) and bepridil were 20.0 (11.0-35.8) and 18.0 (6.0-43.0) days, respectively. The lower 95% confidence interval of the shape parameter β of bepridil was over 1 and the hazard was considered to increase over time.Our study indicated that the pattern of LQTS onset might differ among drugs. Based on these results, careful long-term observation is recommended, especially for specific drugs such as bepridil and aprindine. This information may be useful for the prevention of sudden death following LQTS and for efficient therapeutic planning.

Systemic treatment options for soft tissue sarcomas (STSs) have remained unchanged despite the need for novel drug candidates to improve STS outcomes. Drug repurposing involves the application of clinical drugs to different diseases, reducing development time, and cost. It has also become a fast and effective way to identify drug candidates. The present study used a computational method to screen three drug-gene interaction databases for novel drug candidates for the treatment of several common STS histologic subtypes through drug repurposing. STS survival-associated genes were generated by conducting a univariate cox regression analysis using The Cancer Genome Atlas survival data. These genes were then applied to three databases (the Connectivity Map, the Drug Gene Interaction Database and the L1000 Fireworks Display) to identify drug candidates for STS treatment. Additionally, pathway analysis and molecular docking were conducted to evaluate the molecular mechanisms of the candidate drug. Bepridil was identified as a potential candidate for several STS histologic subtype treatments by overlapping the screening results from three drug-gene interaction databases. The pathway analysis with the Kyoto Encyclopedia of Genes and Genomes predicted that Bepridil may target CRK, fibroblast growth factor receptor 4 (FGFR4), laminin subunit β1 (LAMB1), phosphoinositide-3-kinase regulatory subunit 2 (PIK3R2), WNT5A, cluster of differentiation 47 (CD47), elastase, neutrophil expressed (ELANE), 15-hydroxyprostaglandin dehydrogenase (HPGD) and protein kinase cβ (PRKCB) to suppress STS development. Further molecular docking simulation suggested a relatively stable binding selectivity between Bepridil and eight proteins (CRK, FGFR4, LAMB1, PIK3R2, CD47, ELANE, HPGD, and PRKCB). In conclusion, a computational method was used to identify Bepridil as a potential candidate for the treatment of several common STS histologic subtypes. Experimental validation of these in silico results is necessary before clinical translation can occur.

No therapeutics are approved for the treatment of filovirus infections. Bepridil, a calcium channel blocker developed for treating angina, was identified as a potent inhibitor of filoviruses in vitro, including Ebola and Marburg viruses, and Ebola virus in vivo. We evaluated the efficacy of bepridil in a lethal mouse model of Marburg virus disease. A dose of 12 mg/kg bepridil once or twice daily resulted in 80% or 90% survival, respectively. These data confirm bepridil's broad-spectrum anti-filovirus activity warranting further investigation of bepridil, or improved compounds with a similar mechanism, as a pan-filovirus therapeutic agent.

NOTCH1 PEST domain mutations are often seen in hematopoietic malignancies, including T-cell acute lymphoblastic leukemia (T-ALL), chronic lymphocytic leukemia (CLL), splenic marginal zone lymphoma (SMZL), mantle cell lymphoma (MCL), and diffuse large B-cell lymphoma (DLBCL). These mutations play a key role in the development and progression of lymphoproliferative tumors by increasing the Notch signaling and, consequently, promoting cell proliferation, survival, migration, and suppressing apoptosis. There is currently no specific treatment available for cancers caused by NOTCH1 PEST domain mutations. However, several NOTCH1 inhibitors are in development. Among these, inhibition of the Sarco-endoplasmic Ca[sup.2+]-ATPase (SERCA) showed a greater effect in NOTCH1-mutated tumors compared to the wild-type ones. One example is CAD204520, a benzimidazole derivative active in T-ALL cells harboring NOTCH1 mutations. In this study, we preclinically assessed the effect of CAD204520 in CLL and MCL models and showed that NOTCH1 PEST domain mutations sensitize cells to the anti-leukemic activity mediated by CAD204520. Additionally, we tested the potential of CAD204520 in combination with the current first-line treatment of CLL, venetoclax, and ibrutinib. CAD204520 enhanced the synergistic effect of this treatment regimen only in samples harboring the NOTCH1 PEST domain mutations, thus supporting a role for Notch inhibition in these tumors. In summary, our work provides strong support for the development of CAD204520 as a novel therapeutic approach also in chronic lymphoproliferative disorders carrying NOTCH1 PEST domain mutations, emerging as a promising molecule for combination treatment in this aggressive subset of patients.

BACKGROUND: The zone of stasis in burns is particularly vulnerable to progressive ischemia, making it a critical target for therapeutic interventions. Preventing damage in this zone is essential, as its viability can be preserved with adequate perfusion. Recognizing this, we aimed to investigate the systemic effects of nicardipine, a calcium channel blocker with vasodilatory properties, on the stasis zone in an experimentally induced burn model in rats. We hypothesized that nicardipine could mitigate ischemic progression in the stasis zone and thereby preserve tissue viability. METHODS: A total of 20 Wistar-Albino rats were included in this study and divided into two groups: a control group (n=10) and a treatment group (n=10). The experimental burn model described by Regas and Ehrlich was employed. Under anesthesia, a 1 * 2 cm metal comb, preheated in boiling water, was applied to the dorsal skin of the rats for 30 seconds to create burn wounds. No treatment was administered to the control group. The treatment group, however, received a daily systemic dose of nicardipine (5 mg/kg) via gastric lavage for three days. Wound healing was monitored daily using a digital camera for three consecutive days. One rat in the treatment group was excluded due to mortality. After three days, the burned areas were excised from the dorsal skin of all rats and subjected to histopathological examination. Additionally, photo analysis of the burn areas was conducted using data obtained from the digital images. RESULTS: N icardipine treatment significantly improved burn healing parameters in the stasis zone. Compared to the control group, the treatment group demonstrated lower scores for edema (0.78 vs. 2.80, p<0.05), congestion (0.22 vs. 2.80, p<0.05), inflammation (0.67 vs. 2.90, p <0.05), vascularization (0.11 vs. 2.70, p <0.05), and fibrosis (0.22 vs. 2.90, p <0.05). Quantitative measurements also revealed a significant reduction in necrosis zone thickness (1079.75 [micro]m vs. 2818.82 [micro]m, p <0.05) and necrosis area (249.33 [micro][m.sup.2] vs. 400.13 [micro][m.sup.2], p <0.05). These findings indicate that nicardipine effectively mitigates ischemic progression and promotes tissue recovery in burn injuries. CONCLUSION: Our experimental study demonstrated that nicardipine has the potential to prevent and treat damage in the burn stasis zone, suggesting its therapeutic role in burn injuries. Keywords: Burn; nicardipine; zone of stasis. AMAC: Yanik staz zonu, uzayan iskemiye karsi cok hassastir ve bu iskemiyi engellemek yanik tedavisinin bir hedefi haline gelmistir. Yanik staz zonundaki olasi hasari onlemek onemlidir, cunku bu bolgenin canliligi yeterli perfuzyon saglanirsa korunabilir. Calismamizda ratlarda deneysel olarak olusturulan bir yanik modelinde bir vazodilator ve kalsiyum kanal blokoru olan Nikardipin'in sistemik olarak uygulanmasinin yanik staz zonu uzerinde etkilerini arastirmayi amacladik. Nikardipin'in yanik staz zonundaki iskemik sureci aaltabilecegini ve boylece doku perfuzyonunu ve canliligini koruyabilecegini dusunduk. GEREC VE YONTEM: Calismaya toplam 20 Wistar-Albino rat dahil edildi. Ratlar 10 tanesi kontrol grubu 10 tanesi tedavi grubu olmak uzere 2 gruba ayrildi. Regas ve Ehrlich tarafindan tanimlanan deneysel yanik modeli kullanildi. Yanik yaralari olusturmak icin kaynar suda onceden isitilmis 1*2 cm'lik metal cubuklar, anestezi altindaki ratlarin sirt derisine 30 saniye boyunca uygulandi. Kontrol grubuna hicbir tedavi uygulanmazken, tedavi grubuna 3 gun boyunca gastrik lavaj yoluyla sistemik olarak 5 mg/kg dozunda Nikardipin verildi. Yara iyilesmesi 3 gun boyunca dijital kamera kullanilarak takip edildi. Tedavi grubundaki ratlardan biri exitus nedeniyle calismadan cikarildi. 3. Gunun sonunda ratlarin sirt derisi yanik alanlari dahil edilerek eksize edildi ve histopatolojik incelemeye gonderildi. Ek olarak, dijital goruntulerden elde edilen veriler kullanilarak yanik alanlarinin fotografik analizi yapildi. BULGULAR: Nikardipin tedavisi staz zonundaki yanik iyilesme parametrelerini onemli olcude iyilestirdi. Kontrol grubuyla karsilastirildiginda, tedavi grubu odem (0.78'e karsi 2.80, p <0.05), konjesyon (0.22'ye karsi 2.80, p <0.05), inflamasyon (0.67'ye karsi 2.90, p <0.05), vaskularizasyon (0.11'e karsi 2.70, p <0.05) ve fibrozis (0.22'ye karsi 2.90, p <0.05) icin daha dusuk skorlar gosterdi. Kantitatif olcumler ayrica nekroz bolgesi kalinliginda (1079.75 [micro]m'e karsi 2818.82 [micro]m, p <0.05) ve nekroz alaninda (249.33 [micro][m.sup.2]'ye karsi 400.13 [micro][m.sup.2], p <0.05) onemli bir azalma ortaya koydu. Bu bulgular, nikardipinin yanik yaralanmalarinda iskemik ilerlemeyi etkili bir sekilde azalttigini ve doku iyilesmesini destekledigini gostermektedir. SONUC: Ratlarda yapmis oldugumuz deneysel calisma, Nikardipin'in yanik staz zonundaki hasari onleme ve tedavi etme potansiyeline sahip oldugunu ve yanik yaralanmalarinda terapotik bir rol oynayabilecegini gostermektedir. Anahtar sozcukler: Nikardipin; staz zonu; yanik.

The Ca super(2+)-sensor protein troponin C (TnC) exerts a key role in the regulation of muscle contraction, and constitutes a target for Ca super(2+) sensitizer compounds, such as bepridil, known to increase its apparent Ca super(2+) affinity. Moreover, bepridil has been reported to exert a differential effect in slow and fast skeletal muscle fibres, which express the slow/cardiac and fast TnC isoform, respectively. The role of the TnC isoform in establishing the differential effect of bepridil was assessed in slow soleus and fast tibialis rat skinned fibres, by extraction of endogenous TnC and consecutive reconstitution with either slow or fast recombinant TnC. A mutant (VG2), lacking the regulatory site II, was also used to distinguish the role of each regulatory site. Fast tibialis fibres reconstituted with cardiac TnC exhibited a typical slow bepridil reactivity, while slow soleus fibres reincorporated with fast TnC displayed a typically fast reactivity to bepridil. These results indicated that the differential effect of bepridil in slow and fast fibres is related to the TnC isoform predominantly expressed in a fibre. Experiments with the VG2 mutant demonstrated that BPD can achieve an increase in the Ca super(2+) affinity in the absence of a functional site II. Thus, site I was necessary for the BPD effect to be independent of the Ca super(2+) concentration. Moreover, the amplitude of the reinforcement in the Ca super(2+) affinity, induced by the binding of bepridil to the TnC molecule, is dependent on the number of functional regulatory sites, the larger affinity reinforcement being detected when only one regulatory site (either site I or II) is functional.

Herein, we report the synthesis of four new hybrid molecules between ketoprofen or 2-(3-benzoylphenyl)propanoic acid and N-containing heterocyclic compounds, such as piperidine, pyrrolidine, 1,2,3,4-tetrahydroquinoline, and 1,2,3,4-tetrahydroisoquinoline. The obtained hybrid compounds were fully characterized using [sup.1]H- and [sup.13]C-NMR, UV-Vis, and HRMS spectra. Detailed HRMS analysis is provided for all novel hybrid molecules. The compounds were assessed for their in vitro anti-inflammatory and antioxidant activity. The lipophilicity of the hybrids was determined, both theoretically (cLogP) and experimentally (R[sub.M]). The affinity of the compounds to the human serum albumin was assessed in silico by molecular docking study using two software, and the stability of the predicted complexes was evaluated by molecular dynamics study. All novel hybrids have shown very good HPSA activity, statistically close when compared to the reference—quercetin. The molecular docking confirmed the obtained in vitro results. Tetrahydroquinoline derivative 3c and tetrahydroisoquinoline derivative 3d have the highest affinity for albumin. They show stronger anti-inflammatory action than their predecessor, ketoprofen and the regularly used ibuprofen.