Scientia Pharmaceutica

The potential therapeutic benefit of transdermal delivery systems for some active pharmaceutical ingredients (APIs) has been well-established for decades within the scientific community. However, together with the clinical efficacy, there is the need for an evaluation of the stability of such APIs in bases with known transdermal capabilities, which is necessary to provide the compounding pharmacist with confidence when providing transdermal products. In this study, the stability of danazol, metformin HCl, and resveratrol as individual ingredients, as well as metformin HCl, resveratrol, and Vitamin D3 in combinations at bracketed high and low concentrations, were evaluated over a period of 6 months, using a ready-to-use transdermal vehicle for compounding pharmacies (Pentravan^® or Pentravan^® Plus). The five formulations tested (F1: Danazol 50 mg/g + Miodesin^TM 85 mg/g in Pentravan^®, F2: Metformin HCl 200 mg/g in Pentravan^®, F3: Resveratrol 200 mg/g in Pentravan^®, F4: Metformin HCl 100 mg/g + Resveratrol 100 mg/g + Vitamin D3 5000 IU in Pentravan^®, and F5: Metformin HCl 200 mg/g + Resveratrol 200 mg/g + Vitamin D3 5000 IU in Pentravan^® Plus) presented a beyond-use date of at least 6 months, presenting high convenience for the compounding pharmacies. Full article

Knowledge within the field of phytochemistry research has accelerated at a tremendous speed. The excess of literature reports featuring plants of high ethnopharmacological importance, in combination with our interest in the Asteraceae family and traditional medicine, led us to acknowledge the value of the Achillea L. genus. In a broad context, the various Achillea species are used around the globe for the prevention and treatment of different diseases, including gastrointestinal problems, haemorrhages, pneumonia, rheumatic pains, diuresis, inflammation, infections, and wounds, as well as menstrual and gynaecologic abnormalities. The present review aims to provide and summarize the recent literature (2011–2021) on the phytochemistry of the Achillea genus. In parallel, this study attempts to bridge the reports on the traditional uses with modern pharmacological data. Research articles that focused on secondary metabolites, traditional uses and pharmacological activities were collected from various scientific databases such as Pubmed, ScienceDirect, Reaxys and Google Scholar. This study revealed the presence of 141 phytochemicals, while 24 traditionally used Achillea spp. were discussed in comparison to current data with an experimental basis. Full article

The rapid development in bacterial resistance to many groups of known antibiotics forces the researchers to discover antibacterial drug candidates with previously unknown mechanisms of action, one of the most relevant being the inhibition of tRNA (Guanine37-N1)-methyltransferase (TrmD). The discovery of selective TrmD inhibitors in the series of carboxamide derivatives of thienopyrimidines became a background for further modification of the similar structures aimed at the development of promising antibacterial agents. As part of this research, we carried out the construction of heterocyclic hybrids bearing the moieties of thieno[2,3-d]pyrimidine and benzimidazole starting from 3,5-dimethyl-4-oxo-2-thioxo-1H-thieno[2,3-d]pyrimidine-6-carboxylic acid, which was used as the pivotal intermediate. The hybrid molecule of 6-(1H-benzimidazol-2-yl)-3,5-dimethyl-2-thioxo-1H-thieno[2,3-d]pyrimidin-4-one prepared via condensation of the carboxylic acid with ortho-phenylenediamine was further alkylated with aryl/hetaryl chloroacetamides and benzyl chloride to produce the series of S-alkyl derivatives. The results of molecular docking studies for the obtained series of S-alkyl benzimidazole-thienopyrimidines showed their high affinity to the TrmD isolated from the P. aeruginosa. The results of antimicrobial activity screening revealed the antimicrobial properties for all of the studied molecules against both Gram-positive and Gram-negative bacteria and the Candida albicans fungal strain. The highest antimicrobial activity was determined for 2-{[6-(1H-benzimidazol-2-yl)-3,5-dimethyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidin-2-yl]thio}-N-(4-isopropylphenyl)acetamide, which also had the highest affinity to the TrmD inhibitor’s binding site according to the docking studies results. Full article

Taxadiene synthase (TDS) is the rate-limiting enzyme of Taxol biosynthesis that cyclizes the geranylgeranyl pyrophosphate into taxadiene. Attenuating Taxol productivity by fungi is the main challenge impeding its industrial application; it is possible that silencing the expression of TDS is the most noticeable genomic feature associated with Taxol-biosynthetic abolishing in fungi. As such, the characterization of TDS with unique biochemical properties and autonomous expression that is independent of transcriptional factors from the host is the main challenge. Thus, the objective of this study was to kinetically characterize TDS from endophytic bacteria isolated from different plants harboring Taxol-producing endophytic fungi. Among the recovered 23 isolates, Bacillus koreensis and Stenotrophomonas maltophilia achieved the highest TDS activity. Upon using the Plackett–Burman design, the TDS productivity achieved by B. koreensis (18.1 µmol/mg/min) and S. maltophilia (14.6 µmol/mg/min) increased by ~2.2-fold over the control. The enzyme was purified by gel-filtration and ion-exchange chromatography with ~15 overall folds and with molecular subunit structure 65 and 80 kDa from B. koreensis and S. maltophilia, respectively. The chemical identity of taxadiene was authenticated from the GC-MS analyses, which provided the same mass fragmentation pattern of authentic taxadiene. The tds gene was screened by PCR with nested primers of the conservative active site domains, and the amplicons were sequenced, displaying a higher similarity with tds from T. baccata and T. brevifolia. The highest TDS activity by both bacterial isolates was recorded at 37–40 °C. The Apo-TDSs retained ~50% of its initial holoenzyme activities, ensuring their metalloproteinic identity. The activity of purified TDS was completely restored upon the addition of Mg²⁺, confirming the identity of Mg²⁺ as a cofactor. The TDS activity was dramatically reduced upon the addition of DTNB and MBTH, ensuring the implementation of cysteine-reactive thiols and ammonia groups on their active site domains. This is the first report exploring the autonomous robust expression TDS from B. koreensis and S. maltophilia with a higher affinity to cyclize GGPP into taxadiene, which could be a novel platform for taxadiene production as intermediary metabolites of Taxol biosynthesis. Full article

The algae Kappaphycus alvarezii is considered an important raw material for industrial practices, producing high economic value of various derived products. However, the quality of this commodity, which can be indicated by the level of phenolic compounds, may vary due to growth factors, including cultivation sites. An analytical UV-Vis spectrophotometry method coupled with chemometrics was proposed to standardize the red alga based on the content of phenolic compounds. The correlation between the UV-Vis spectra and UPLC–PDA results, combined with a multivariate calibration of the K. alvarezii extracts, was analyzed. The extracts were prepared using an ultrasound-based technique and subsequently subjected to UV-Vis spectral measurements at 200–800 nm and UPLC–PDA at 260 and 330 nm. Chemometric techniques and partial least squares (PLS) were applied to the acquired data to build a reliable analysis of the phenolics in the K. alvarezii extracts. The result showed that the wavelength combination of 200–450 and 600–690 nm provided a valid method for quantitative analysis of the studied phenolics that belong to hydroxybenzoic acid, hydroxycinnamic acid, and flavonoid with a coefficient of regression (R²) > 0.96 in the calibration and validation models, along with an RMSEC and RMSEP value < 8%. The method was then employed to characterize the K. alvarezii samples from 13 different cultivation areas. Principal component analysis (PCA) generated principal components that produced a clear distribution among the samples of K. alvarezii based on phenolic compounds corresponding to the geographical origin. Full article

Causes of the progression of periodontitis such as an imbalance between the immune response by the host by the release of inflammatory mediators in the response of the oral pathogenic dysbiotic biofilm have been identified. New insights on specific cell signaling pathways that appear during periodontitis have attracted the attention of researchers in the study of new personalised approaches for the treatment of periodontitis. The gold standard of non-surgical therapy of periodontitis involves the removal of supra and subgingival biofilm through professional scaling and root planing (SRP) and oral hygiene instructions. In order to improve periodontal clinical outcomes and overcome the limitations of traditional SRP, additional adjuvants have been developed in recent decades, including local or systemic antibiotics, antiseptics, probiotics, anti-inflammatory and anti-resorptive drugs and host modulation therapies. This review is aimed to update the current and recent evolution of therapies of management of periodontitis based on the adjunctive and target therapies. Moreover, we discuss the advances in host modulation of periodontitis and the impact of targeting epigenetic mechanisms approaches for a personalised therapeutic success in the management of periodontitis. In conclusion, the future goal in periodontology will be to combine and personalise the periodontal treatments to the colonising microbial profile and to the specific response of the individual patient. Full article

The exposure of reactive oxygen species is one of the aging triggers at cellular level. The antioxidants have been used as strategic efforts in overcoming the accumulation of ROS. Previous research using crude extracts of clove bud and leaves showed its potential as an antioxidant agent. However, no data were available regarding the antioxidant and antiaging activities of subsequent fractions of clove extracts. Therefore, this study aimed to analyze the antioxidant and antiaging activities of the n-hexane and ethanol fractions from clove bud and leaves. Antioxidant and antiaging activities were tested at the cellular level using the yeast model Schizosaccharomyces pombe. The highest flavonoid content was shown by clove leaf n-hexane fraction (25.6 mgQE·g⁻¹). However, ethanol fraction of clove bud (FEB) showed the highest antioxidant activity based on TBA and antiglycation assays. FEB (8 μg·mL⁻¹) and leaf ethanol fraction (FEL) (10 μg·mL⁻¹) were able to induce yeast tolerance against oxidative stress. In addition, FEB could induce mitochondrial activity and delay the G1 phase of the cell cycle. FEB was found to be rich in gallic acid and (15Z)-9,12,13-trihydroxy-15-octadecenoic. Based on the data, FEB shows the potential antiaging activity, which is promising for further development as biopharmaceutical product formulations. Full article

In this work, antiparasitic peptidomimetics inhibitors (PEP) of falcipain-3 (FP3) of Plasmodium falciparum (Pf) are proposed using structure-based and computer-aided molecular design. Beginning with the crystal structure of PfFP3-K11017 complex (PDB ID: 3BWK), three-dimensional (3D) models of FP3-PEPx complexes with known activities (${ \mathrm{IC}}_{50}^{\exp }$) were prepared by in situ modification, based on molecular mechanics and implicit solvation to compute Gibbs free energies (GFE) of inhibitor-FP3 complex formation. This resulted in a quantitative structure–activity relationships (QSAR) model based on a linear correlation between computed GFE (ΔΔG_com) and the experimentally measured ${ \mathrm{IC}}_{50}^{\exp }$. Apart from the structure-based relationship, a ligand-based quantitative pharmacophore model (PH4) of novel PEP analogues where substitutions were directed by comparative analysis of the active site interactions was derived using the proposed bound conformations of the PEPx. This provided structural information useful for the design of virtual combinatorial libraries (VL), which was virtually screened based on the 3D-QSAR PH4. The end results were predictive inhibitory activities falling within the low nanomolar concentration range. Full article

Nicotine is widely used in pharmaceutical industries, especially for smoking cessation in the form of transdermal patches. Nicotine gel in the patches has limitations from nicotine instability and high volatility. Thus, a nicotine preservation technique is needed. In this study, a nicotine encapsulation process using methyl-β-cyclodextrin (MβCD) is investigated and compared with β-cyclodextrin (βCD) to evaluate the preservation and skin permeation of nicotine. The M06-2X/6-31G(d,p) density functional theory calculations indicate a 1:1 host–guest molar ratio for the inclusion complex of nicotine with βCD and MβCD, which have been validated by experimental studies. The encapsulation efficiencies of βCD and MβCD to encapsulate nicotine are 59.96% and 63.76%, respectively. The preservation study of the inclusion complexes compared to pure nicotine shows a stability improvement of nicotine after being encapsulated. After 21 days, the percentages of the nicotine/βCD and nicotine/MβCD inclusion complexes that remain are 89.32% and 76.22%, while only 65.56% of pure nicotine remains. Besides the one-hour skin permeation tests, the amounts of nicotine permeated through pig skin from the nicotine/βCD and nicotine/MβCD inclusion complex gels are 14 and 10 times as much as the pure nicotine gel, respectively. Therefore, the encapsulation of nicotine with βCD and MβCD can be used to enhance the stability and skin permeation application of nicotine-containing products. Full article

Linalool, a volatile terpene alcohol, is responsible for a characteristic aroma in food, beverages, and cosmetics. However, linalool’s low aqueous solubility and high volatility limit the applications and shelf life of linalool-containing products. Nanoencapsulation using beta-cyclodextrin (BCD), methyl-beta-cyclodextrin (MBCD) and hydroxypropyl-beta-cyclodextrin (HPBCD) was studied to improve the aqueous solubility and stability of linalool. Linalool has two enantiomers with distinct flavors and odors which affect product quality. The enantiomeric selectivity of the cyclodextrins (CDs) toward racemic linalool standard was evaluated. A computational simulation was performed to predict the conformations and interactions of the inclusion complexes. The 1:1 host-guest ratio from the computer simulation was implemented in the experimental study. Phase solubility study shows an improvement in linalool aqueous solubility after being encapsulated by CDs. The encapsulation efficiencies of linalool/BCD, linalool/MBCD, and linalool/HPBCD inclusion complexes are 66.30%, 51.38% and 32.31%, respectively. Nanoencapsulation by CDs can preserve linalool in the form of inclusion complexes compared to its free form. The amount of remaining linalool in linalool/BCD, linalool/MBCD, and linalool/HPBCD inclusion complexes are 89.57%, 87.07%, and 74.86%, respectively which are considerably larger than that of pure linalool (42.30%). CDs also show the enantiomeric selectivity toward (R)-linalool as evident from (R)-linalool percentage of 54.53% in the inclusion complex. Full article

Background: Nicotine is the active alkaloid in cigarettes. It was reported that tobacco smoking has many hazards; one of these hazards is the effect on the cognitive function of the prefrontal cortex. The aim of our study is to investigate the antioxidant effects of ginger, cinnamon oils, and their combination on morphological changes in the prefrontal cortex that were induced by nicotine. Materials and methods: Fifty adult male albino rats were divided into five groups: group I (control group), group II (nicotine), group III (nicotine + cinnamon), group IV (nicotine + ginger), and group V (nicotine + cinnamon + ginger). The coronal sections from the anterior part of the rat brain at the site of prefrontal cortex were examined by light microscope for (H&E and immunohistochemical staining with TNF-α and GFAP), while the ultrastructure morphology was examined by transmission electron microscopy. Levels of the oxidative stress markers (MDA, GSH) in the rats’ brain tissue homogenate were biochemically assessed. Results: Compared to the control group, the rats that were treated with nicotine (group II) showed a significant oxidative stress in the form of marked elevation of MDA and decrease in GSH, apoptotic changes especially in the pyramidal cells in the form of neuronal cell degeneration and pyknosis, and an elevation in the inflammatory marker TNF-α and GFAP expressions. These changes were observed to a lesser degree in rat group (III) and group (IV), while there was a marked improvement achieved by the combined usage of cinnamon and ginger oils, together compared to the nicotine group. Conclusions: Ginger and cinnamon are powerful antioxidants which ameliorate the degenerative and oxidative effects produced by nicotine on a rat’s prefrontal cortex. Full article

(1) Background: Topical antiglaucoma medications may alter the microcirculation in the optic nerve head. We aimed to evaluate the changes in retinal vessel density (VD) on optical coherence tomography angiography (OCTA) in patients with newly diagnosed normal-tension glaucoma (NTG) treated with a topical beta-blocker. (2) Methods: This study included 80 patients diagnosed with NTG not using systemic medication, who received topical carteolol treatment between December 2019 and November 2020. We studied the changes in the OCTA VD/signal strength index (SSI) after the 6-month treatment period and determined the predictive factors affecting the changes in VD/SSI. (3) Results: After the 6-month treatment period, the peripapillary VD increased in 40 patients but decreased in the other 40 patients. The univariate and multivariate analyses revealed that old age and hypertension were significant factors associated with a VD/SSI decrease after carteolol treatment. Moreover, high baseline peripapillary, superficial, and deep macular VDs were significantly associated with the VD decrease after carteolol treatment. (4) Conclusions: Carteolol treatment could increase or decrease the VD in patients with NTG. The baseline VD, age, and hypertension could affect these VD changes. Patients with NTG and higher baseline peripapillary or macular VD, older age, and hypertension are more likely to have a decreased VD after carteolol treatment. Full article

Wheatgrass is widely used in the alternative medicine, however, there is a lack of clinical evidence to support its efficacy. Although based on its chemical composition, data from animal experiments and clinical trials, the use of juice and extracts of Triticum shoots seems to be safe, clinical reports point out its potential interaction with oral anticoagulants. The aim of our study was to assess the interaction of wheatgrass with warfarin in rats and to assess its flavonoid content. Three groups of animals were treated orally with wheatgrass, warfarin, or the combination of wheatgrass and warfarin for five days. Clotting assays were performed using platelet-poor plasma. Prothrombin time was determined by optical and mechanical coagulometers. Flavonoid content of wheatgrass was measured by HPLC. The effect of wheatgrass on prothrombin time was not confirmed. Co-administration of wheatgrass and warfarin did not result in diminished anticoagulant activity. Low amount of flavonoids was detected in wheatgrass juice, the total flavonoid content was 0.467 mg/100 g lyophilized juice powder. The previously reported rutin, quercetin and apigenin was not detected by us. Our results do not confirm the probability of interaction of wheatgrass with oral anticoagulants. However, the low flavonoid content of wheatgrass does not support its use as an antioxidant. Full article

Pentagamavunon-1 (PGV-1), a potential chemopreventive agent with a strong cytotoxic effect, modulates prometaphase arrest. Improvement to get higher effectiveness of PGV-1 is a new challenge. A previous study reported that the natural compound, galangin, has antiproliferative activity against cancer cells with a lower cytotoxicity effect. This study aims to develop a combinatorial treatment of PGV-1 and galangin as an anticancer agent with higher effectiveness than a single agent. In this study, 4T1, a TNBC model cell, was treated with a combination of PGV-1 and galangin. As a result, PGV-1 and galangin showed a cytotoxic effect with IC50 values of 8 and 120 µM, respectively. Combining those chemicals has a synergistic impact, as shown by the combination index (CI) value of 1. Staining with the May Grunwald-Giemsa reagent indicated mitotic catastrophe evidence, characterized by micronuclear and multinucleated morphology. Moreover, the senescence percentage was higher than the single treatment. Furthermore, bioinformatics investigations showed that PGV-1 and galangin target CDK1, PLK1, and AURKB, overexpression proteins in TNBC that are essential in regulating cell cycle arrest. In conclusion, the combination of PGV-1 and galangin exhibit a synergistic effect and potential to be a chemotherapeutic drug by the mechanism of mitotic catastrophe and senescence induction. Full article

Reactive oxygen species (ROS) are related to several degenerative diseases. In this study, Acacia, a genus with many fast-growing species, was investigated to explore the many phytochemical compounds that are biologically active in processes dealing with ROS-related diseases. This study aimed to select extracts of Acacia heartwood on the basis of their pharmacological and phytochemical profiles and identify their bioactive compounds. Five methanolic extracts from Acacia heartwood were evaluated for their antioxidant activity using three different in vitro assays: toxicity toward Artemia salina and phenolic and polyphenolic content. Multivariate analysis was conducted to select two promising extracts and then their bioactive compounds were identified using liquid chromatography coupled with mass spectrometry. Acacia crassicarpa extracts showed the highest antioxidant activity, as well as phenolic and hydrolyzable tannin contents, but low toxicity. The A. mangium extract exhibited high flavonoid and condensed tannin content, whereas A. decurrrens had the highest toxicity with low antioxidant activity. Pearson’s correlation analysis demonstrated no correlation between antioxidant activity and toxicity. Moreover, the phytochemical profile exhibited an association with pharmacological parameters. Principal component analysis followed by cluster analysis divided the extracts into three clusters. Two heartwood extracts of A. crassicarpa and A. auriculiformis were chosen as the best extracts. Identification showed that these extracts were dominated by phenolic compounds, as well as anthraquinone and xanthone. Full article

Boswellic acids (BAs) are the main bioactive compounds of frankincense, a natural resin obtained from the genus Boswellia. This study aimed to develop a self-nanoemulsifying delivery system (SNEDS) to improve the antimicrobial and antiproliferative activities of standardized frankincense extract (Fr-extract). Fr-extract was standardized, and BA content was quantified using the developed HPLC-UV method. Screening studies of excipients followed by formula optimization using a mixture simplex lattice design was employed. The optimized Fr-SENDS formulation was characterized. Furthermore, microbiological and antiproliferative assessments of the standardized Fr-extract and Fr-SNEDS were evaluated. Quantification demonstrated that the major constituent is 11-keto-boswellic acid (KBA) (16.25%) among BA content (44.96%). The optimized Fr-SENDS (composed of 5% Capryol^TM 90, 48.7% Gelucire^® 44/14 and 46.3% ethanol) showed spherical nanosized dispersions with DS, PDI, and zeta potential of 17.9 nm, 0.2, and −14.5 mV, respectively. Fr-SNEDS exhibited lower MIC and MBC values compared with Fr-extract against pathogens conjugated with lung cancer and was comparable to reference antimicrobials. Fr-SNEDS showed superior antiproliferative activity over Fr-extract, with IC₅₀ values of 20.49 and 109.5 μg mL⁻¹, respectively. In conclusion, the optimized Fr-SNEDS could be easily developed and manufactured at a low cost and the in vitro results support its use as a potential adjuvant oral therapy for lung cancer. Further in vivo studies could be continued to assess the therapeutic efficiency of the prepared system. Full article

Transmucosal drug delivery represents a promising noninvasive option when drugs are employed which have a low oral bioavailability like CBD. However, this concept can only be successful as long as the formulation provides sufficient buccal retention and mucosal penetration. In this study, mucoadhesive carrier systems were evaluated consisting of CBD-loaded silica (Aeroperl 300) carriers, mucoadhesive polymers (Hypromellose (HPMC), chitosan and carbomer) and propylene glycol as a penetration enhancer. Mucoadhesive effect, drug release and penetration ability were evaluated for each carrier system. The results show that the addition of HPMC and carbomer substantially improve mucoadhesion compared to pure CBD, with an increase of 16-fold and 20-fold, respectively. However, due to their strong swelling, HPMC and carbomer hinder the penetration of CBD and rely on co-administration of propylene glycol as an enhancer to achieve sufficient mucosal absorption. Chitosan, on the other hand, achieves an 8-fold increase in mucoadhesion and enhances the amount of CBD absorbed by three times compared to pure CBD. Thus, chitosan represents a promising polymer to combine both effects. Considering the results, the development of silica-based buccal drug delivery systems is a promising approach for the effective delivery of CBD. Full article

Periconia is filamentous fungi belonging to the Periconiaceae family, and over the last 50 years, the genus has shown interest in natural product exploration for pharmacological purposes. Therefore, this study aims to analyze the different species of Periconia containing natural products such as terpenoids, polyketides, cytochalasan, macrosphelides, cyclopentenes, aromatic compounds, and carbohydrates carbasugar derivates. The isolated compound of this kind, which was reported in 1969, consisted of polyketide derivatives and their structures and was determined by chemical reaction and spectroscopic methods. After some years, 77 compounds isolated from endophytic fungus Periconia were associated with eight plant species, 28 compounds from sea hare Aplysia kurodai, and ten from endolichenic fungi Parmelia sp. The potent pharmacological agents from this genus are periconicin A, which acts as an antimicrobial, pericochlorosin B as an anti-human immunodeficiency virus (HIV), peribysin D, and pericosine A as cytotoxic agents, and periconianone A as an anti-inflammatory agent. Furthermore, information about taxol and piperine from Periconia producing species was also provided. Therefore, this study supports discovering new drugs produced by the Periconia species and compares them for future drug development. Full article

Dimenhydrinate is an over-the-counter medication that is used to relieve nausea, vomiting, and vertigo caused by motion sickness. It has a short elimination half-life, possibly due to its first-pass metabolism. The current study aimed to prepare and evaluate new transdermal formulations of dimenhydrinate to prolong the drug’s release and improve its cutaneous permeation. First, the patches were fabricated and evaluated to determine their properties. The results were statistically investigated and considered significant at the p < 0.05 level. Additionally, the quantitative analysis of the drug-release data and kinetic modeling was performed by using the DDSolver software to decide the candidate formula dependably. The effect of the penetration enhancers on the permeability of dimenhydrinate from the selected patch was then studied ex vivo compared to the control sample, and the patch’s safety was evaluated in rabbits, using the skin-irritation test. Full article