Scientia Pharmaceutica

Non-steroidal anti-inflammatory drugs (NSAIDs) are one of the oldest and most widely used groups of drugs nowadays. However, the problem of searching for and creating new NSAIDs remains open, primarily due to the risks owing to their short- and long-term use. In this context, triazole-azepine hybrid molecules are attractive and prospective objects for the rational design of novel potential NSAIDs. In the present work studies of 3-aryl-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepines as potential non-steroidal anti-inflammatory agents are reported. Evaluation of drug-like properties for all tested triazole-azepine hybrids was performed in silico using SwissADME. The screening of analgesic and anti-inflammatory activities was performed in vivo using acid-induced writhing and carrageenin-induced hind paw oedema models in mice. Derivatives with activity levels more potent compared with reference drugs ketorolac and diclofenac sodium were identified. Preliminary SAR was performed based on the screening results. Full article

Etifoxine is an anxiolytic drug with a dual mechanism of action. In contrast to conventional benzodiazepine anxiolytics, which induce cognitive dysfunction and myorelaxation, no memory impairment nor a decrease in motor activity is observed with etifoxine. This study aims to evaluate the effects of etifoxine on locomotor activity and passive learning in rats with diazepam-induced memory deficit. Male Wistar rats were treated intraperitoneally for 7 days with: (1) saline; (2) diazepam 2.5 mg/kg bw or (3) diazepam 2.5 mg/kg bw and etifoxine in a dose of 50 mg/kg bw. Activity cage test was used for evaluation of locomotor activity, and step-through and step-down tests were performed to study the passive learning. Etifoxine increased the number of horizontal movements on the 7th and 14th days of the experiment. The drug exhibits anti-amnesic effect in a model of diazepam-induced anterograde amnesia by enhancing long-term memory in passive learning tests. The data obtained suggest that etifoxine can reduce the benzodiazepine-induced cognitive deficit. Moreover, such a combination can alleviate the negative influence of benzodiazepines on locomotor activity. However, additional studies are necessary to translate these results into clinical practice. Full article

The Zingiber montanum herbal compress remedy is a type of herbal medicine that can be used as an alternative treatment for improving pain symptoms. This study aimed to evaluate the clinical efficacy of a Z. montanum herbal compress remedy for pain relief. PubMed, Scopus, ScienceDirect, and Thai databases were systematically searched for relevant articles published from inception to December 2022. Only randomized clinical trials (RCTs) wherein the efficacy of the Z. montanum remedy was compared to that of a placebo or non-steroidal anti-inflammatory drugs (NSAIDs) were included. Six RCTs with a total of 812 patients were included in the analysis. The efficacy of the Z. montanum remedy had a significantly decreased pain score compared to the placebo (SMD = −0.63; 95% CI = −1.20, −0.06; I² = 90%), but there was no significant difference when compared to NSAIDs (SMD = −0.61; 95% CI = −1.41, 0.81; I² = 73%). Moreover, the efficacy of the Z. montanum remedy in terms of the flexibility score (SMD = 0.59; 95% CI −0.56, 1.74; I² = 86.0%) and quality of life (SMD = 0.34; 95% CI −0.38, 1.05; I² = 81.0%) was similar to that of the placebo. This meta-analysis demonstrates that the use of the Z. montanum herbal compress remedy significantly reduces the pain scores reported by patients. Full article

The aim of this study is to compare three different dissolution methods to assess the drug release from oral lyophilisates, based on interpolyelectrolyte complexes (IPECs). IPECs were prepared by mixing solutions of a linear polymer, Eudragit^® EPO, with a polymer with a cross-linked structure, Noveon^® AA-1 or Carbopol^® 10 Ultrez (in ratios of 1:2 and 1:1, respectively). Metformin or metronidazole were used as model drugs to achieve a systemic or local effect. A comparative assessment of the drug release kinetics was carried out using artificial saliva and three different set-ups: a paddle stirrer (USP apparatus 2), a flow cell (USP apparatus 4) and a Franz diffusion cell. The results demonstrated that oral lyophilisates disintegrated within 1 min. In the case of metformin, the drug release was completed in about 90 min independently of the set-up. The static conditions in the Franz diffusion cell and USP apparatus 2 permitted the aggregation of the IPEC; therefore, the release profiles show a significant difference compared to the USP apparatus 4. Full article

Yerba-mate contains in its composition a high concentration of phenolic compounds. This class of secondary metabolites exhibits strong values of molar absorptivity on ultraviolet and visible wavelengths. This study evaluated the effect of yerba-mate extracts on the in vitro solar protection factor (SPF) value of sunscreen formulations. The sunscreen formulations were prepared to have non-ionic lotion as a basis and yerba-mate extract and/or avobenzone as active agents. The SPF and resveratrol protective effect of the formulations were determined by UV-vis spectrometry. A synergic effect between the yerba-mate extract and avobenzone on the SPF was found. Yerba-mate extract at 5% improved the SPF of the avobenzone 5% formulation from 28.46 ± 5.45 to 40.48 ± 0.84. Yerba-mate extract at 5% avoided resveratrol degradation by ultraviolet radiation. At this same concentration, avobenzone produced a smaller effect than yerba-mate extracts in resveratrol protection. The formulations with yerba-mate + avobenzone presented smaller changes in pH values during 12 days of storage. The spreadability profile of yerba-mate and avobenzone formulations was similar to the profile of avobenzone formulations. The results reported here show the suitability of the yerba-mate extract use in photoprotective formulations, highlighting their in vitro effect and opening possibilities for new investigations exploring this property. Full article

Our main target was to develop methods for the quality control of the tablet «ramipril» according to the indicators of «Quantitative determination», «Impurities» and «Dissolution». New, precise, accurate and green HPLC methods were developed for the determination of ramipril and its impurities in tablets. The separation was accomplished using a diode array detector at 210 nm with an isocratic and gradient mobile phase consisting of a 0.2 g/L solution of sodium hexanesulfonate (pH 2.7) and the acetonitrile and chromatographic columns Acclaim 120 C18 and Inertsil ODS-3. The developed method was validated in accordance with ICH guidelines. The analysis of impurities was performed within a run duration of less than 25 min, which is about a two times shorter than that of the official Ph. Eur. method. The analysis of ramipril in tablets was performed with a run duration of less than 4.5 min, which is about three times shorter than that of the official USP method. The developed methods were successfully applied for the quality control of the tablet «ramipril» according to the indicators of «Quantitative determination», «Impurities» and «Dissolution». In addition, they proved its superiority over the reported methods in terms of greenness using different assessment tools. Full article

Skin inflammation occurs as an immune response to various stimuli such as ultraviolet light, irritants, or any type of skin barrier injury. Finding safe and effective drugs to combat skin inflammation remains a research challenge. Ethical and legal considerations in animal testing encourage the development of in vitro and ex vivo models for the detection of skin inflammation. This report presents an updated review of non-animal study models available for screening drugs with anti-inflammatory potential. It includes a description of the basic methods used to inhibit protein denaturation and red blood cell membrane stability. Three in vitro inhibition assay methods for enzymes relevant to the skin inflammatory process are then described. The development of cell culture models is described: relatively simple and easy-to-produce two-dimensional (2D) skin cell cultures that allow assessment of response to a given stimulus, three-dimensional (3D) cell cultures that better mimic human skin physiology by more accurately replicating mechanical and chemical signals, and vascularized 3D skin models with dynamic perfusion and microfluidic devices known as skin on a chip. Finally, ex vivo skin models are presented that could more accurately represent human skin in terms of structure, cell signaling mechanisms, and absorption effects. Although the current development of models without the use of animals is promising, improvements and refinements are needed to make the models more suitable as screening platforms for topical anti-inflammatory drugs. Full article

Carnosol is a natural diterpene present in Rosmarinus officinalis L. (rosemary) with anti-tumor and anti-inflammatory properties. Despite its importance, the pharmacological mechanisms underlying the interactions between carnosol and human targets are still unclear. The goal was to identify plausible human target for carnosol and the network pharmacology. Rosemary was analyzed using HPLC-QTOF-MS/MS. Potential carnosol targets were identified using docking and a public database (CTD). Carnosol was screened against 708 human proteins using AutoDock Vina, and affinity values were used as prioritization criteria. The targets set was uploaded to WebGestalt to obtain Gene Ontology (GO) and KEGG pathway enrichment analysis. HPLC-QTOF-MS/MS analyses allowed the tentative annotation of nine chemicals, with carnosol being the most ionized. There were 53 plausible targets for carnosol, with 20 identified using virtual screening, including Hsp90α (−10.9 kcal/mol), AKR1C3 (−10.4 kcal/mol), and Hsp90β (−10.4 kcal/mol), and 33 identified from CTD. The potential targets for carnosol identified with PPI and molecular docking were HSP90AA1, MAPK1, MAPK3, CAT, JUN, AHR, and CASP3. GO terms and KEGG pathways analysis found that carnosol is closely related to infection (Chagas, influenza A, toxoplasmosis, and pertussis) and inflammation (IL-17 and TNF signaling pathway and Th-17 cell differentiation). These results demonstrated that carnosol may induce an immuno-inflammatory response. Full article

Cancer is a large group of diseases that can affect any organ or body tissue due to the abnormal cellular growth with the unknown reasons. Many of the existing chemotherapeutic agents are highly toxic with a low level of selectivity. Additionally, they lead to development of therapeutic resistance. Hence, the development of targeted chemotherapeutic agents with low side effects and high selectivity is required for cancer treatment. Quinazoline is a vital scaffold well-known to be linked with several biological activities. The anticancer activity is one of the prominent biological activities of this scaffold. Several established anticancer quinazolines work by different mechanisms on the various molecular targets. The aim of this review is to present different features of medicinal chemistry as drug design, structure activity relationship, and mode of action of some targeted anticancer quinazoline derivatives. It gives comprehensive attention on the chemotherapeutic activity of quinazolines in the viewpoint of drug discovery and its development. This review provides panoramic view to the medicinal chemists for supporting their efforts to design and synthesize novel quinazolines as targeted chemotherapeutic agents. Full article

This research sought to optimize the microwave-assisted extraction of Chatuphalathika as an herbal recipe maximizing the active compounds and the antioxidant activity by the Box–Behnken design. Three factors—microwave power, time, and cycle—were varied. Eight responses—extraction yield, total phenolic content, gallic acid content, corilagin content, chebulagic acid, chebulinic acid, IC₅₀ from DPPH assay, and IC₅₀ from FRAP assay—were monitored. Furthermore, cytotoxicity was evaluated to ensure the safety of the extract. After that, the optimized extract was compressed into tablets. The results showed that the optimal condition of the microwave-assisted extraction gave the simultaneous maximum extraction yield, total phenolic content, and antioxidant activity with a microwave power of 450 W for 30 s and 3 cycles. The extract obtained from the optimal condition exhibited a good safety profile although a concentration of 5 mg/mL was used. The optimized tablets were achieved when a compression force of 1500 psi and magnesium stearate of 1% were applied, and no sodium starch glycolate was added. In conclusion, the optimal green extraction method could be used for the extraction of the Chatuphalathika. Furthermore, the fabrication of Chatuphalathika tablets was successful, as the tablets had low friability with a short disintegration time. Full article

The wound healing potential of the aerial parts of Hypericum triquetrifolium Turra (Hypericaceae) was evaluated using an in vivo excision wound model in rats. Adult male Sprague Dawley rats were randomly assigned into seven groups; blank vehicles (olive oil and petroleum jelly), negative control, treatments [H. triquetrifolium ethanolic extract in petroleum jelly (5% and 10%) and H. triquetrifolium olive oil macerate (100 and 200 g/L)], and positive control (MEBO). Treatments were applied topically once daily until the wounds had completely healed. Wound areas and contraction rates were calculated, and full-thickness samples of the healed skin were collected for histopathological examination. H. triquetrifolium ointment (5%) showed the best wound healing activity with statistically significant differences when compared with the MEBO, petroleum jelly, and the negative control groups. Tissue sections were histopathologically examined in terms of re-epithelialization, granulation tissue development, collagen deposition, inflammatory cell infiltration, angiogenesis, and ulcer formation to support the in vivo excision wound model findings. H. triquetrifolium ointment (5%) showed the best histopathological scores in both re-epithelialization and ulcer formation. For quality control purposes, a high-performance liquid chromatography (HPLC) method was used to quantify key marker compounds in the extract, namely hypericin and rutin which showed a content of 0.64% and 4.46% (w/w), respectively. Based on the experimental results, H. triquetrifolium ointment (5%) exhibits remarkable wound healing properties at various stages of the wound healing process. Further investigations to prove its safety and efficacy in different types of wounds and to uncover its cellular mechanisms are warranted. Full article

Essential oils are potential therapeutics for coronavirus disease 2019 (COVID-19), in which some of the volatile compounds of essential oils have been well known for their broad antiviral activities. These therapeutic candidates have been shown to regulate the excessive secretion of pro-inflammatory cytokines, which underlies the pathogenesis of severe COVID-19. We aimed to identify molecular targets of essential oils in disrupting the cell entry and replication of SARS-CoV-2, hence being active as antivirals. Literature searches were performed on PubMed, Scopus, Scillit, and CaPlus/SciFinder (7 December 2022) with a truncated title implying the anti-SARS-CoV-2 activity of essential oil. Data were collected from the eligible studies and described narratively. Quality appraisal was performed on the included studies. A total of eight studies were included in this review; four of which used enzyme inhibition assay, one—pseudo-SARS-CoV-2 culture; two—whole SARS-CoV-2 culture; and one—ACE2-expressing cancer cells. Essential oils may prevent the SARS-CoV-2 infection by targeting its receptors on the cells (ACE2 and TMPRSS2). Menthol, 1,8-cineole, and camphor are among the volatile compounds which serve as potential ACE2 blockers. β-caryophyllene may selectively target the SARS-CoV-2 spike protein and inhibit viral entry. Other interactions with SARS-CoV-2 proteases and RdRp are observed based on molecular docking. In conclusion, essential oils could target proteins related to the SARS-CoV-2 entry and replication. Further studies with improved and uniform study designs should be carried out to optimize essential oils as COVID-19 therapies. Full article

This study aimed to elucidate the anti-inflammatory activity of C. tinctorius leaves by measuring inflammatory parameters such as nitric oxide (NO) production and mRNA expression of iNOS, interleukin-6 (IL-6), and IL-1β in lipopolysaccharide (LPS)-induced HaCaT cells. Further, the effect of C. tinctorius ethanol extract on the MAPKs/NF-κB signaling pathway was examined in HaCaT cells. The phytochemical profile of the ethanol extract of C. tinctorius leaves was determined using UPLC-QTOF-MS/MS. The results indicated that the ethanol extract of C. tinctorius effectively attenuated LPS-induced secretion of NO, IL-6, and IL-1β in HaCaT cells. Further, LPS-stimulated mRNA and protein expressions of iNOS were decreased by pre-treatment with C. tinctorius ethanol extract at the transcriptional level in HaCaT cells. Moreover, the ethanol extract of C. tinctorius suppressed NF-κB signaling in LPS-induced HaCaT cells. This suppression was mediated by MAPKs/NF-κB signaling, inhibiting the phosphorylation of p38 and p65 in HaCaT cells. However, there is no significant effect on the phosphorylation of JNK by the ethanol extract. The QTOF-MS/MS analysis revealed the identification of 27 components in the ethanol extract of C. tinctorius leaves. The data demonstrate that the ethanol extract of C. tinctorius leaves protects the LPS-induced HaCaT cells by inhibiting the expression of iNOS, IL-6, and IL-1β and suppressing the phosphorylation of the p38, p65, p-JNK via inactivation of MAPKs/NF-κB signaling pathway. These results demonstrate that C. tinctorius leaves may serve as a potential candidate to prevent inflammation-related diseases. Full article

Searching for new types of biological activities among preliminarily identified hit compounds is a key challenge in modern medicinal chemistry. In our study, a previously studied 3-[5-(1H-indol-3-ylmethylene)-4-oxo-2-thioxothiazolidin-3-yl]-propionic acid (Les-6614) was screened for antimicrobial, antifungal, anti-allergic, and antitumor activities. Moreover, cytotoxicity, molecular docking, and SwissAdme online target screening were accomplished. It was determined that the Les-6614 has slight antimicrobial and antitumor activity. However, the studied compound decreased IgE levels in sensitized guinea pigs by 33–86% and reduced IgA, IgM, IL-2, and TNF-α, indicating anti-inflammatory and anti-allergic aactivities. According to the SwissADME web tool, target predictions for Les-6614 potentially have an affinity for lysosomal protective protein, Thromboxane-A synthase, and PPARγ. The molecular docking confirmed that the studied 2-thioxo-4-thiazolidinone derivative showed good bonding with LLP and TXAS, leading to stable protein–ligand complexes. Additionally, Les-6614 is a potential PPARγ modulator, which is important in the pathogenesis of allergy, cancer, and cardiovascular diseases. Full article

Background: Combining antiangiogenic drugs with other chemotherapeutic drugs has been found to produce superior therapeutic outcomes and prevent drug resistance in a variety of cancers. Methods: Experimental assays such as the MTT assay, flow cytometry, western blotting, and qPCR have been used to evaluate the efficacy of combination therapy. Results: When compared to controls and monotherapies, the combination treatment of axitinib and idasanutlin demonstrated a substantial decrease in cell viability at lower doses, a significant decrease in migration, and a shift toward early and late apoptosis. This study examined major apoptotic, metastatic, and angiogenic factors, including MDM2, p21, BCL-2, BCL-XL, and MMP9, which have showed differential expressions at the protein and mRNA levels after combination. Axitinib and idasanutlin decreased tumorigenesis and migration in vitro in the MCF-7 cell line when compared to other chemotherapeutic medications. The suggested mechanisms of the antitumorigenic effect of the combination therapy may depend on its capacity to promote the production of apoptotic markers and reduce antiapoptotic markers. Conclusions: Treatments with axitinib and idasanutlin demonstrated effective therapeutic targeting of the primary angiogenic growth factor and, consequently, the pro-metastatic arbitrators. This will not only eliminate cancer cells but also stop other malignant processes and ultimately reduce the metastatic cascade. Full article

Paracetamol (acetaminophen, APAP) is known as a safe pain reliever; however, its negative effects on the central nervous system have gradually been reported. We examined alterations in learning and memory, and brain-derived neurotrophic factor (BDNF) expression in the frontal cortex and hippocampus at different durations of APAP treatment in rats. Novel object recognition (NOR) and Morris water maze (MWM) paradigms were used to assess learning and memory in rats fed with 200 mg/kg APAP at single-dose, 15-day or 30-day treatments. BDNF expression was evaluated through immunohistochemistry and Western blotting. The single-dose APAP treatment did not alter the NOR performance. However, deficits in the NOR and MWM capacities were detected in the rats with longer durations of APAP treatment. An analysis of BDNF expression revealed no significant change in BDNF expression in the single-dose APAP treatment, while rats given APAP for extended periods as treatment showed a significant decrement in this protein in the frontal cortex and hippocampus. Short-term APAP treatment has no effect on learning and memory, or BDNF expression; however, long-term APAP exposure causes cognitive impairment. The diminishment of the BDNF level in the frontal cortex and hippocampus due to the long period of treatment with APAP may at least in part be involved in altered learning and memory in rats. Full article

Funding is often a constraint when planning research, especially in countries where basic research is underfunded. Researchers must take into account these limitations, e.g., in relation to the selection of appropriate reagents, the source of which may affect the study’s final results. The aim of this article was to compare the results of bacteria susceptibility testing using three different sources of antimicrobial: the pure powder available from the supplier and two tablet formulations with different excipients. The chosen substance was furazidin (nitrofuran derivative). The susceptibility was tested on a group of 45 uropathogenic Enterobacterales using both microdilution and disk diffusion methods. The obtained results indicated that despite the relatively higher price, the powder appeared to be the best substance for scientific purposes, especially for quantitative determinations. Full article

Herein, we utilized several deep eutectic solvents (DES) that were based on hydrogen donors and hydrogen acceptors for their antibacterial application. These DES were tested for their bactericidal activities against Gram-positive (Streptococcus pyogenes, Bacillus cereus, Streptococcus pneumoniae, and methicillin-resistant Staphylococcus aureus) and Gram-negative (Escherichia coli K1, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Serratia marcescens) bacteria. Using lactate dehydrogenase assays, DES were evaluated for their cytopathic effects towards human cells. Results from antibacterial tests revealed that DES prepared from the combination of methyl-trioctylammonium chloride and glycerol (DES-4) and DES prepared form methyl-trioctylammonium chloride and fructose (DES-11) at a 2 µL dose showed broad-spectrum antibacterial behavior and had the highest bactericidal activity. Moreover, DES-4 showed 40% and 68% antibacterial activity against P. aeruginosa and E. coli K1, respectively. Similarly, DES-11 eliminated 65% and 61% E. coli K1 and P. aeruginosa, respectively. Among Gram-positive bacteria, DES-4 showed important antibacterial activity, inhibiting 75% of B. cereus and 51% of S. pneumoniae. Likewise, DES-11 depicted 70% B. cereus and 50% S. pneumoniae bactericidal effects. Finally, the DES showed limited cytotoxic properties against human cell lines with the exception of the DES prepared from Methyltrioctylammonium chloride and Citric acid (DES-10), which had 88% cytotoxic effects. These findings suggest that DES depict potent antibacterial efficacies and cause minimal damage to human cells. It can be concluded that the selected DES in this study could be utilized as valuable and novel antibacterial drugs against bacterial infections. In future work, the mechanisms for bactericides and the cytotoxicity effects of these DES will be investigated. Full article