ALBERT

Description: Introduction: Bioactive encapsulation and drug delivery systems have already found their way to the market as efficient therapeutics to combat infections, viral diseases and different types of cancer. The fields of food fortification, nutraceutical supplementation and cosmeceuticals have also been getting the benefit of encapsulation technologies. Aim: Successful formulation of such therapeutic and nutraceutical compounds requires thorough analysis and assessment of certain characteristics including particle number and surface area without the need to employ sophisticated analytical techniques. Solution: Here we present simple mathematical formulas and equations used in the research and development of drug delivery and controlled release systems employed for bioactive encapsulation and targeting the sites of infection and cancer in vitro and in vivo. Systems covered in this entry include lipidic vesicles, polymeric capsules, metallic particles as well as surfactant- and tocopherol-based micro- and nanocarriers.

Description: Studies on potential treatments of Coronavirus Disease 2019 (COVID-19) are important to improve the global situation in the face of the pandemic. This review proposes lithium as a potential drug to treat COVID-19. Our hypothesis states that lithium can suppress NOD-like receptor family pyrin domain containing-3 (NLRP3) inflammasome activity, inhibit cell death, and exhibit immunomodulation via membrane depolarization. Our hypothesis was formulated after finding consistent correlations between these actions and membrane depolarization induced by lithium. Eventually, lithium could serve to mitigate the NLRP3-mediated cytokine storm, which is allegedly reported to be the inciting event of a series of retrogressive events associated with mortality from COVID-19. It could also inhibit cell death and modulate the immune system to attenuate its release, clear the virus from the body, and interrupt the cycle of immune-system dysregulation. Therefore, these effects are presumed to improve the morbidity and mortality of COVID-19 patients. As the numbers of COVID-19 cases and deaths continue to rise exponentially without a clear consensus on potential therapeutic agents, urgent conduction of preclinical and clinical studies to prove the efficacy and safety of lithium is reasonable.

Description: Background: Even though, Pseudomonas aeruginosa is a common cause of hospital-acquired infections, treatment is challenging because of decreasing rates of susceptibility to many broad-spectrum antibiotics. Methods: Consumption data of eight broad spectrum antimicrobial agents and resistance rates of P. aeruginosa were collected for 48 consecutive months. Autoregressive integrated moving average (ARIMA) and transfer functions models were used to develop relationships between antibiotic use and resistance. Results: Positive correlations between P. aeruginosa resistance and uses of ciprofloxacin (p 〈 0.001), meropenem (p 〈 0.001), and cefepime (p = 0.005) were identified. Transfer function models showed the quantified effect of each of these antibiotics on resistance. Regarding levofloxacin, ceftazidime, piperacillin/tazobactam and imipenem, no significant relationships were found. For ceftazidime and levofloxacin, this was probably due to their low consumption, while for imipenem the reason can possibly be ascribed to the already high established P. aeruginosa resistance in the hospital. Conclusion: In the hospital setting, the effect of antimicrobial agents’ consumption on the susceptibility epidemiology of P. aeruginosa differs significantly for each one of them. In this study, the role of precedent use of meropenem, cefepime and ciprofloxacin was quantified in the development of P. aeruginosa resistance.

Description: Considering the importance of the cutaneous tissue investigation and the need for the development of new protocols to non-invasively establish the safety and efficacy of dermocosmetics and topical products, we aimed at developing an HPLC-TBARS-EVSC (high performance liquid chromatography–thiobarbituric acid reactive species–ex vivo stratum corneum) assay for the lipid peroxidation measurement on subjects’ stratum corneum (SC) obtained by tape stripping; additionally, we applied the HPLC-TBARS-EVSC assay in an emulsified sunscreen system containing ethylhexyl triazone and bemotrizinol as UV filters. HPLC analysis was performed in isocratic mode with 35% methanol/65% phosphate buffer (pH 7.0) as the mobile phase. The diode detector was set at 532 nm to quantify the malondialdehyde (MDA)-TBA adduct. An ex vivo tape stripping method was applied in 10 volunteers in three pre-defined regions of the volar forearms: the control; the irradiated; and the site containing the sunscreen (2.0 mg·cm−2). Ten adhesive tapes per region were used for SC removal. An exclusive ex vivo protocol to measure SC lipid peroxidation was preliminarily developed with linearity and selectivity. The protocol suggested the use of an artificial irradiation dose (5506 KJ·m−2) to improve the assay response from the SC. The sunscreen system had a significative decrease in SC lipoperoxidative damage compared to the control. Our protocol can aid in the efficacy establishment of anti-UV and antioxidant agents, for instance, in studies that aim at elucidating the level of SC lipid peroxidation and even in carrying out baseline investigations characterizing different ethnicities and genders.

Description: Asenapine maleate is an antipsychotic drug that is indicated in the treatment of schizophrenia and bipolar disorders. It has low aqueous solubility and high permeability (Class II drug) and undergoes an extensive first pass effect. These problems result in low oral bioavailability ( 0.9998) and accurate and precise. An ANOVA test indicated that calibration curves run on different days did not differ significantly. It was sensitive (lower limit of quantitation (LLOQ) = 25.03 ng/mL), specific (the co-formers did not interfere with the determination of the drug), and robust to small changes in the mobile phase (pH, composition, and flow rate). The in vitro release of asenapine maleate from the co-crystals and the physical mixture was much enhanced when compared to the in vitro dissolution of the unprocessed drug. In conclusion, the developed and validated RP-HPLC method met the acceptance criteria and was applied successfully in evaluating the in vitro release of the drug.

Description: Malignant melanoma is the major cause of skin cancer-related deaths. Surgery in combination with radiotherapy, immunotherapy or chemotherapy is used to eradicate cancer cells, however, this treatment option is limited by the tolerance of the surrounding healthy tissue. The extracts from Galenia africana have been shown to possess anti-cancer flavonoid compounds and can be a safer and cost-effective alternative treatment. The study aimed to compare the anti-proliferative effects of G. africana on human skin cells (HaCaT) and human malignant melanoma cells (A375). The cells were exposed to various concentrations of the G. africana extract at different times. In vitro assays were employed to determine cell viability and cytotoxicity. Hoechst 33342 staining was performed to observe the nuclear changes, including apoptosis. G. africana significantly reduced the cell viability of the A375 cells in a dose and time-dependent manner, while having no effect on the HaCaT cells. The A375 cells displayed nuclear condensation, brightly stained nuclei and nuclear fragmentation indicative of apoptosis. This suggests a clinical rationale for the use of G. africana as a potential anti-melanoma agent offering efficacy and low toxicity. This study provides new insights for future work on investigating the utilization of G. africana in malignant melanoma treatment.

Description: Our main target and concept was to develop a method for the determination of the most prescribed antilipemic drug, atorvastatin, together with its related substances, with a single sample preparation and during a single chromatographic run, in the shortest possible period of time, with the lowest possible mobile phase consumption. A new rapid, simple chromatographic method for the determination of atorvastatin and its main specified impurities was developed, using different chromatographic columns. With this new concept of a mobile phase and a powerful core–shell, or a superficially porous silica-based column, satisfactory results for targeted parameters, such as critical peak resolution, run time length, and column backpressure, were achieved. The analysis is performed within a run duration of less than 15 min, which is about six times shorter than the official European Pharmacopoeia method. The chromatogram performances suggests that the method limit of quantification (LOQ) can be about 7 times lower, and the limit of detection (LOD) about 20 times lower, using an injection volume of only 2 µl. This was confirmed by the performed method validation in accordance with the International Conference on Harmonization (ICH) guideline for the validation of analytical procedures Q2(R1), where the selectivity, linearity, accuracy, precision, limit of quantification, and limit of detection were tested and confirmed.

Description: Bacteria have acquired resistance against almost all antibiotics because of the misuse of antibacterial agents and long periods of treatment. Antimicrobial peptides (AMPs) are one of the most encouraging candidates to solve this problem, as they possess high prokaryotic selectivity, and affect the bacteria by a unique mode of action. Novel cyclic undecapeptides (QNRNFYFNRNQ and QNRNFHFNRNQ) and their linear counterparts were investigated for their antibacterial activity against virulent strains. The minimal inhibitory concentration (MIC) values showed that tyrosine and histidine AMPs have promising antibacterial activity against virulent bacteria. The MIC values against the P. aeruginosa PA14, E. coli O157:H7 CR3, S. aureus 209P, and B. subtilis ATCC 6633 bacterial strains were evaluated for the cyclic peptide containing tyrosine, and their values were 6.25, 12.5, 12.5, and 12.5 µM, respectively. Meanwhile, for the linear form, they were 9.3, 12.5, 12.5, and 12.5 µM, respectively. The cyclic-peptide–containing histidines’ MIC values were 6.25, 3.1, 6.25, and 3.1 µM, respectively. Meanwhile, for the linear form, they were 3.1, 3.1, 3.1, and 6.25 µM, respectively. The antibacterial activities of the new AMPs were compared with that of gentamicin sulfate, and showed relatively higher potencies. Time-inhibition studies demonstrated the rapid antibacterial effects of the novel AMPs, which were more likely to be concentration-dependent, rather than time-dependent. At double the MIC concentration, all of the tested peptides exhibited relatively stable antibacterial effects up to 24 h, especially the peptides containing tyrosine, which showed an improved antibacterial effect.

Description: 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% CapryolTM 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.

Description: 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.

Description: 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.

Description: (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.

Description: 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 () 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 () and the experimentally measured . 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.

Description: 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.

Description: 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.

Description: 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.

Description: Sphenopalatine ganglion (SPG) stimulation has been shown to reversibly alter blood-brain barrier (BBB) permeability. It is widely used for the treatment of cluster headaches in Europe and is well tolerated in humans. The therapeutic potential for SPG stimulation in other central nervous system (CNS) diseases has yet to be explored. Glioblastoma Multiforme (GBM) remains one of the most difficult primary CNS neoplasms to treat, with an average survival of approximately 18 months at the time of diagnosis. Since 2004, the gold standard of treatment for GBM in the United States includes surgery followed by treatment with temozolomide (TMZ) and radiation. We sought to determine if SPG stimulation could increase chemotherapy concentrations in rodent brains with an intact BBB. Here, we show a statistically significant (p = 0.0006), five-fold upregulation of TMZ crossing the BBB and reaching brain parenchyma in rats receiving low-frequency (LF, 10 Hz) SPG stimulation. All the measurements were performed using a highly sensitive liquid chromatography mass spectrometry (LCMS) method that was developed for quantitation of TMZ in plasma and brain tissue. Our treatment paradigm shows novel delivery route by which we could more effectively and safely deliver TMZ in a targeted manner, to minimize systemic toxicity and maximize action at the target tissue.

Description: Drugs are the most widely used therapeutic tool for treatment of diseases. However, misuse can lead to an adverse drug event (ADE) in susceptible individuals such as those that are severely obese. This study aimed to describe the frequency of ADEs, the associations of ADEs with anatomical therapeutic chemical classes and their respective frequency, estimate the prevalence of ADEs, and analyse factors associated with ADE in adults with severe obesity. Cross-sectional analysis of baseline data from a randomized clinical trial in the central-western region of Brazil. A total of 150 individuals aged 18–65 years with a Body Mass Index of 35 kg/m2 were included. The outcome variable was the presence of ADE and the explanatory variables were socio-demographic factors, lifestyle, health, and medication use. ADEs were associated with use of drugs for the digestive tract and metabolism (p 〈 0.001) and the cardiovascular system (p 〈 0.001). The prevalence of ADEs was 32.67% (n = 49) and associated with the age range 40 to 49 years (p = 0.033), diabetes (p = 0.004), multimorbidities ≥ 4 (p = 0.009), self-medication (0.031), and presence of potential drug interactions (0.017). The prevalence of ADEs was high and was associated with drugs commonly used in treatment of obesity-related morbidities and self-medication. The introduction of a pharmacist to multi-professional teams can improve medication safety for severely obese patients.

Description: Carpobrotus edulis, formerly known as Mesembryanthemum edule L, belongs to the Aizoaceae family of plants. It is a facultative halophytic invasive medicinal and edible succulent plant that is native to South Africa and is distributed worldwide. Hitherto, this plant appears to be mainly known for its ornamental use in decorations, soil stabilization, and erosion control, and not for its many potential medicinal and nutritional benefits, thus suggesting its underutilization. This review presents cogent and comprehensive information on the distribution, ethnomedicinal use, phytochemistry, pharmacology, toxicology, and nutritional value of Carpobrotus edulis and provides the rationale for further pharmacognostic research that will validate its many folkloric medicinal and nutraceutical claims, and promote its standardization into a commercially available product. The reported traditional use of this plant for the treatment of sinusitis, diarrhoea, tuberculosis, infantile eczema, fungal and bacterial infections, oral and vaginal thrush, high blood pressure, diabetes, wound infections, spider and tick bites, sore throat as well as mouth infections are well documented. Its therapeutic activities such as anti-proliferative, antioxidant, antifungal, antibacterial, antidiabetic, anti-inflammatory, cytotoxicity, and nutritional value have also been reported to be attributable to the array of phytoconstituents present in the plant. These have promoted renewed research interests into this valuable medicinal plant with a view to repositioning and expanding its uses from the current predominantly ornamental and environmental management role to include phytotherapeutical applications through scientific validation studies that will improve its value for the drug discovery process as well as its contribution to food security.

Description: In the present work, the hydrolytic stability of new memantine analogues modified with amino acids, at different pH corresponding to the human biological liquids and organs, was evaluated. Memantine is an uncompetitive N-methyl-d-aspartate receptor antagonist with low-to moderate-affinity. In addition, it is the first representative of a novel class of Alzheimer’s disease (AD) medications acting on the glutamatergic system by blocking N-methyl-D-aspartate receptors. Generally, prodrugs are compounds aiming to improve stability of active fragment and to facilitate transportation across the cell membranes or lipid barriers. The investigated series of prodrugs include modified memantine with the following amino acids: alanine, β-alanine, glycine, phenylalanine, and valine. Hydrolytic stability was determined at two different pH values 2.0 and 7.4 at 37 °C, similar to those in the human stomach and blood plasma. Specially developed UV-VIS spectrophotometric method for quantification of the concentrations of unchanged compounds was applied in the kinetic studies. Val-MEM is the most stable in neutral medium and at 37 °C compound with t1/2 = 50.2 h. The compound Phe-MEM has also very good hydrolytic stability with t1/2 = 29.6 h. The order of other compounds is: Val-MEM ≫ Phe-MEM ≫ Ala-MEM ≈ Val-MEM 〉 β-Ala-MEM. Ala-MEM and Gly-MEM are the most stable compounds at acid condition with almost identical values for t1/2 = 17.8 h and t1/2 = 16.3 h, respectively. The stability of tested compounds in acid conditions are relatively less than in neutral one. They are ordered as follows: Ala-MEM ≈ Gly-MEM 〉 Val-MEM ≈ Phe-MEM ≈ β-Ala-MEM. All compounds have relatively good hydrolytic stability of more than 10 h at both neutral and acid conditions, which is quite enough in order to pass in the blood circulation and to be used as a potential antimicrobial agent.

Description: Although cyclophosphamide (CP) has been used successfully in the clinic for over 50 years, it has so far not been possible to elucidate the mechanism of action and to use it for improvement. This was not possible because the basis of the mechanism of action of CP, which was found by lucky coincidence, is apoptosis, the discovery of which was honored with the Nobel Prize only in 2002. Another reason was that results from cell culture experiments were used to elucidate the mechanism of action, ignoring the fact that in vivo metabolism differs from in vitro conditions. In vitro, toxic acrolein is formed during the formation of the cytotoxic metabolite phosphoreamidemustard (PAM), whereas in vivo proapoptotic hydroxypropanal (HPA) is formed. The CP metabolites formed in sequence 4-hydroxycyclophosphamide (OHCP) are the main cause of toxicity, aldophosphamide (ALDO) is the pharmacologically active metabolite and HPA amplifies the cytotoxic apoptosis initiated by DNA alkylation by PAM. It is shown that toxicity is drastically reduced but anti-tumor activity strongly increased by the formation of ALDO bypassing OHCP. Furthermore, it is shown that the anti-tumor activity against advanced solid P388 tumors that grow on CD2F1 mice is increased by orders of magnitude if DNA damage caused by a modified PAM is poorly repairable.

Description: The coronavirus disease 2019 (COVID-19) pandemic is a major global threat. With no effective antiviral drugs, the repurposing of many currently available drugs has been considered. One such drug is ivermectin, an FDA-approved antiparasitic agent that has been shown to exhibit antiviral activity against a broad range of viruses. Recent studies have suggested that ivermectin inhibits the replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), thus suggesting its potential for use against COVID-19. This review has summarized the evidence derived from docking and modeling analysis, in vitro and in vivo studies, and results from new investigational drug protocols, as well as clinical trials, if available, which will be effective in supporting the prospective use of ivermectin as an alternative treatment for COVID-19.

Description: Essential oils are volatile fragrance liquids extracted from plants, and their compound annual growth rate is expected to expand to 8.6% from 2019 to 2025, according to Grand View Research. Essential oils have several domains of application, such as in the food and beverage industry, in cosmetics, as well as for medicinal use. In this study, Michelia alba essential oil was extracted from leaves and was rich in linalool components as found in lavender and jasmine oil. The effects of inhaling michelia oil on human brainwaves still need to be elucidated. Ten male and ten female subjects were recruited. Thirty-two-channel electroencephalography was recorded. The raw data were spectrally analyzed for slow alpha, fast alpha, low beta, mid beta, and high beta activities. The results demonstrate that michelia leaf oil could reduce the alertness level observed by beta wave decrease and fast alpha wave activity increase. The inhalation of pure linalool showed virtually identical responses as the michelia oil inhalation. In conclusion, the sedative effects of michelia oil inhalation might originate from its major linalool component.

Description: A derivative series of 3,4-dimethoxy-β-nitrostyrene was synthesized through nitroaldol reaction, including a new compound of 3,4-ethylenedioxy-β-bromo-β-nitrostyrene. The antimicrobial activity effect of 3,4-alkyloxy modification of β-nitrostyrene was investigated. A molecular docking study was also performed to obtain information about their interactions with protein tyrosine phosphatase 1B (PTP1B). The active residues of cysteine-215 and arginine-221 of PTP1B play a key role in signaling pathways that regulate various microorganism cell functions. It also acts as a negative regulator in signaling pathways of insulin that are involved in type 2 diabetes and other metabolic diseases. These derivatives exhibited potential antifungal activity. The studied compounds were also had potential as fragments to be PTP1B inhibitors by interacting with serine-216 and arginine-221 residues, according to their molecular docking. 3,4-Ethylenedioxy-β-methyl-β-nitrostyrene was the most successful potential candidate as a PTP1B inhibitor. However, further research is needed to investigate their potential for medicinal use.

Description: The aim of this study is to investigate the Thymus vulgaris essential oil (TVEO) as an antifungal agent in aromatherapy and/or as an active ingredient in the prevention or management of topical inflammatory diseases. The chemical composition of TVEO was determined with gas chromatography and revealed the presence of 25 compounds. Carvacrol was found to be the major component (56.8%). Antifungal action of TVEO was determined in vitro by using different methods. By the disc diffusion method, TVEO showed more potent antifungal activity against Candida strains than the positive control. The diameter of inhibition zone (DIZ) varied from 34 to 60 mm for Candida yeasts. Significantly higher antifungal activity was observed in the vapor phase at lower quantities. Candida albicans and C. parapsilosis were the most susceptible strains to the oil vapor with DIZ varying from 35 to 90 mm. The minimum inhibitory concentrations (MIC) of yeast were determined with an agar dilution method and revealed that MIC varied from 0.3 to 0.15 µL/mL for yeast species. The topical anti-inflammatory potential of TVEO was also explored in vivo with the croton oil-induced ear edema assay. TVEO exhibited a potent anti-inflammatory effect at all doses (100, 10 and 2 mg/kg), which were statistically similar (p 〉 0.05) to the positive control. This activity was also confirmed at the cellular level with histopathology analysis. Our results suggest the potential application of this carvacrol-rich TVEO in the prevention and management of fungal infections and topical inflammation and deserve further investigation for clinical applications. Furthermore, while the mode of action remains mainly undetermined and should be studied.

Description: Mangosteen, or Garcinia mangostana L., has merged as an emerging fruit to be investigated due to its active compounds, especially xanthone derivatives such as α -mangostin (AM), γ-mangostin (GM), and gartanin (GT). These compounds had been reported to exert some pharmacological activities, such as antioxidant and anti-inflammatory, therefore, the development of an analytical method capable of quantifying these compounds should be investigated. The aim of this study was to determine the correlation between FTIR spectra and HPLC chromatogram, combined with chemometrics for quantitative analysis of ethanolic extract of mangosteen. The ethanolic extract of mangosteen pericarp was prepared using the maceration technique, and the obtained extract was subjected to measurement using instruments of FTIR spectrophotometer at wavenumbers of 4000–650 cm−1 and HPLC, using a PDA detector at 281 nm. The data acquired were subjected to chemometrics analysis of partial least square (PLS) and principal component regression (PCR). The result showed that the wavenumber regions of 3700–2700 cm−1 offered a reliable method for quantitative analysis of GM with coefficient of determination (R2) 0.9573 in calibration and 0.8134 in validation models, along with RMSEC value of 0.0487% and RMSEP value 0.120%. FTIR spectra using the second derivatives at wavenumber 3700–663 cm−1 with coefficient of determination (R2) 〉0.99 in calibration and validation models, along with the lowest RMSEC value and RMSEP value, were used for quantitative analysis of GT and AM, respectively. It can be concluded that FTIR spectra combined with multivariate are accurate and precise for the analysis of xanthones.

Description: The skin is constantly exposed to various environmental stresses, in particular to the damage caused by pollution and ultraviolet radiation (UV), and as a consequence, the horny extract can be negatively impacted by the harmful influence of some of its surface components. The mechanisms involved in the degradation processes promoted by UV radiation are driven by the direct absorption of radiation via cellular chromophores, the formation of excited states and the consequent chemical reactions, or even by the photosensitization mechanisms, in which UV light is absorbed by the sensitizers that are excited and their reactions promote the formation of reactive oxygen species (ROS). The mechanisms of polluting agents are not yet fully understood, however, they indicate that one of the main mechanisms involved is oxidative stress by lipid peroxidation, with the ability to promote damage to the composition of sebum, the quality of the stratum corneum and also, promote aging skin. Recent studies demonstrate the potential of antioxidant agents, with an emphasis on products of natural origin, which try to promote the maintenance of the physiological balance of the skin.

Description: Our previous study showed that water-soluble fiber from bengkoang (Pachyrizus erosus (L.) Urban) fiber extract (BFE) and bengkoang fiber fraction B (BFE-B) have phagocytic activity and modulation of cytokine production in vitro. The present study evaluates the immunomodulatory effects of water-soluble fibers BFE and BFE-B on male mice induced by hepatitis B vaccine. Thirty mice were divided into six groups and induced by hepatitis B vaccine intraperitoneally on days 7 and 14. The mice were then treated with BFE, BFE-B, levamisole, or sodium carboxymethyl cellulose for 18 days. At the end of the treatments (day 19), phagocytic activity, lymphocyte proliferation, spleen index, cytokine, and immunoglobulin G (IgG) production were determined. The results showed that the water-soluble fiber treatment could significantly increase phagocytic capacity, nitric oxide production, and spleen index. However, BFE-B could modulate tumor necrosis factor (TNF)-α and interleukin (IL)-10 secretion, BFE demonstrated no such effect on cytokine production. Lymphocyte proliferation assay revealed that treatment with 50 mg/kg body weight (BW) BFE and 50 mg/kg BW BFE-B could significantly enhance lymphocyte proliferation. Treatment with 25 and 50 mg/kg BW BFE-B stimulated IgG production. In conclusion, BFE and BFE-B similarly have immunomodulatory effects on innate immune responses. BFE-B further demonstrated immunomodulatory effects on adaptive immune responses.

Description: Breast cancer is one of the most common cancers worldwide, which makes it a very impactful malignancy in the society. Breast cancers can be classified through different systems based on the main tumor features and gene, protein, and cell receptors expression, which will determine the most advisable therapeutic course and expected outcomes. Multiple therapeutic options have already been proposed and implemented for breast cancer treatment. Nonetheless, their use and efficacy still greatly depend on the tumor classification, and treatments are commonly associated with invasiveness, pain, discomfort, severe side effects, and poor specificity. This has demanded an investment in the research of the mechanisms behind the disease progression, evolution, and associated risk factors, and on novel diagnostic and therapeutic techniques. However, advances in the understanding and assessment of breast cancer are dependent on the ability to mimic the properties and microenvironment of tumors in vivo, which can be achieved through experimentation on animal models. This review covers an overview of the main animal models used in breast cancer research, namely in vitro models, in vivo models, in silico models, and other models. For each model, the main characteristics, advantages, and challenges associated to their use are highlighted.

Description: The editorial team greatly appreciates the reviewers who have dedicated their considerable time and expertise to the journal’s rigorous editorial process over the past 12 months, regardless of whether the papers are finally published or not. [...]

Description: Cyclosporine is a potent immunosuppressive drug. It has a narrow therapeutic index, and therefore the measurement of cyclosporine’s blood concentration is essential to obtain optimal therapy. Measurement of the area under the blood concentration-time curve (AUC) is reflective of total drug exposure. However, for organ transplant patients, the measurement of AUC involves many problems and difficulties. Thus, it is more clinically acceptable to use a single blood sample as a surrogate index of total drug exposure. Fifty-four adults bone marrow transplant Iraqi patients were given cyclosporine every 12 h as prophylaxis using Neoral® oral solution. Steady-state blood concentrations were monitored for each patient at zero time and then at 1, 2, 3, 4, 6, 8, 10, and at 12 h post-dosing. Cyclosporine blood levels were determined by using AXSYM automated immuno-analyzer which is a fluorescence polarization immunoassay (FPIA). The present investigation demonstrated the best correlation between C2 and the corresponding AUC0–4h and AUC0–12h compared to other concentrations. After two months of cyclosporine therapy, no unexpected biochemical changes and adverse effects were registered. It is concluded from this study that a single blood sample obtained at 2 h post-dosing (C2) and possibly at 3 h post dosing (C3) are ideal surrogate indexes for reflecting total drug exposure, and therefore may be used in clinical practice for predicting therapeutic and toxic effects of cyclosporine.

Description: In 2017, a regulation referred to as “pharmacies for the pharmacists” was implemented in Poland, and Ukraine is going to implement a similar act of law. The study was to collect Ukrainian pharmacists’ opinions about the upcoming market regulation and to compare their views with opinions obtained from Polish pharmacists collected two years following the amendment of this legislation. The study was conducted in Poland and Ukraine using a self-designed questionnaire. Of 2162 questionnaires received, 2043 were included in the study (1623 from Ukraine and 420 from Poland). Ukrainian pharmacists (76.8%) feared that medicine prices would increase. Moreover, they presented concerns related to poorer access to pharmaceuticals and reduced turnovers of pharmacies. Two years after the market regulation, 55.23% of Polish pharmacists pointed out that none of the fears reported in Ukraine were observed in Poland. However, 33.10% revealed that market regulation led to “a reduction in the number of pharmacies”. Ukrainian pharmacists are afraid of community pharmacies’ regulation. Polish pharmacists, however, have not observed such problems during the two years following the market regulation. The only noticeable market change in Poland was the reduced number of pharmacies.

Description: 3-O-ethyl l-ascorbic acid (EA), an ether derivative of Vitamin C, is widely used in skincare formulations. Previously, we reported the effects of neat solvents on EA percutaneous absorption and observed that 0.6–7.5% of the applied EA was delivered through the skin over 24 h. In this work, we designed complex formulations using combinations of solvents that may act synergistically and examined their impact on EA permeation in porcine skin in vitro under finite dose conditions. Binary combinations of propylene glycol (PG) with propylene glycol monolaurate (PGML) were effective in enhancing skin permeation of EA compared with individual solvents (p 〈 0.05). Combining PGML with 1,2-hexanediol (HEX) did not result in significantly higher EA permeation compared with the neat solvents (p 〉 0.05). Addition of the volatile solvent isopropyl alcohol (IPA) to PG solutions also did not improve EA skin delivery compared with neat PG. Ternary solvent systems containing PG:PGML were subsequently prepared by the addition of a lipophilic solvent, either isopropyl myristate (IPM), medium-chain triglycerides (MCT) or isostearyl isostearate (ISIS). The optimum vehicle, PG:PGML:IPM, promoted up to 70.9% skin delivery of EA. The PG:PGML:ISIS vehicles also promoted EA permeation across the skin, but to a significantly lesser extent than the IPM-containing vehicles. No enhancement of EA delivery was noted for the PG:PGML:MCT mixtures. These results will inform the development of targeted formulations for EA in the future.

Description: Current antileishmanial drugs are toxic, expensive, and resistance to them has emerged. Several studies have focused on natural products as alternatives. In the present work, the chemical composition, in vitro antileishmanial activity, cytotoxicity effects, and the influence on mitochondrial function of the essential oil from Tagetes lucida Cav. was determined, as well its main compound estragole. Forty-nine compounds were detected in the oil by gas chromatography-mass spectrometry (GC-MS), of which estragole was the main constituent (97%). The oil showed inhibition of the promastigotes of L. tarentolae and L. amazonensis (IC50 = 61.4 and 118.8 µg/mL, respectively), decreased oxygen consumption of L. tarentolae, disrupted mitochondrial membrane potential in L. amazonensis, inhibitory activity on the intracellular amastigote of L. amazonensis (IC50 = 14.2 ± 1.6 µg/mL), and cytotoxicity values ranging from 80.8 to 156 µg/mL against murine macrophages and J774 cells. Estragole displayed higher activity on promastigotes (IC50 = 28.5 and 25.5 µg/mL, respectively), amastigotes (IC50 = 1.4 ± 0.1 µg/mL), and cytotoxicity values ranging from 20.6 to 14.5 µg/mL, respectively, while on mitochondria, it caused a decrease of the membrane potential but did not inhibit oxygen consumption. The potential antileishmanial activity of the essential oil from T. lucida and estragole makes these compounds favorable candidates for exploration in further studies.

Description: Age-related macular degeneration (AMD) will be responsible for the vision impairment of more than five million late-aged adults in the next 30 years. Current treatment includes frequent intravitreal injections of anti-vascular endothelial growth factor (VEGF) agents. However, there are methods of drug delivery that can decrease the frequency of intravitreal injections by sustaining drug release. MPEG-PCL ((methoxypoly(ethylene glycol) poly(caprolactone)) has been reported as biocompatible and biodegradable. Polymeric micelles of MPEG-PCL can be useful in efficiently delivering anti-VEGF drugs such as sunitinib to the posterior segment of the eye. In this study, the novel micellar formulation exhibited an average dynamic light scattering (DLS) particle size of 134.2 ± 2.3 nm with a zeta potential of −0.159 ± 0.07 mV. TEM imaging further confirmed the nanoscopic size of the micelles. A sunitinib malate (SM)-MPEG-PCL formulation exhibited a sustained release profile for up to seven days with an overall release percentage of 95.56 ± 2.7%. In addition to their miniscule size, the SM-MPEG-PCL formulation showed minimal cytotoxicity onto the ARPE-19 human retinal pigment epithelial cell line, reporting a percent viability of more than 88% for all concentrations tested at time intervals of 24 h. The SM-MPEG-PCL micelles also exhibited exceptional performance during an anti-VEGF ELISA that decreased the overall VEGF protein expression in the cells across a 24–72 h period. Furthermore, it can be concluded that this type of polymeric vehicle is a promising solution to symptoms caused by AMD and improving the management of those suffering from AMD.

Description: At the beginning of 2020, the world was swept with a wave of a new coronavirus disease, named COVID-19 by the World Health Organization (WHO 2). The causative agent of this infection is the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The data available on one of the promising therapeutic agents—nucleotide analog remdesivir (Gilead Sciences number GS-5734)—were evaluated. These data were concerned with remdesivir activation from the prodrug to the active molecule—triphosphate containing 1′-cyano group and modified nucleobase. This triphosphate competes with the natural substrate adenosine triphosphate. Additionally, its mechanisms of action based on RNA and proofreading exonuclease inhibition, leading to the delayed RNA chain termination of infected cells, and basic pharmacological data were assessed. Additionally, the analytical determination of remdesivir and its metabolites in cells and body liquids and also some data from remdesivir use in other RNA infections—such as Ebola, Nipah virus infection, and Middle East Respiratory Syndrome (MERS)—were summarized. More recent and more detailed data on the clinical use of remdesivir in COVID-19 were reported, showing the intensive efforts of clinicians and scientists to develop a cure for this new disease. Remdesivir as such represents one of the more promising alternatives for COVID-19 therapy, however the current understanding of this disease and the possible ways of dealing with it requires further investigation.

Description: Several topical products have been developed to avoid the harmful effects from ultraviolet (UV) radiation, such as sunscreens. Research for actives from natural sources is increasing due to the fact that chemical filters could induce adverse events. The microalgae Botryococcus braunii has potential interest in cosmetic applications. Specialized literature reported that B. braunii aqueous extract induced a reduction in skin dehydration and collagen production and promoted antioxidant activity. This research aimed to produce B. braunii biomass and to investigate its contribution regarding photoprotection. Formulations containing B. braunii dry biomass, with or without UV filters into vehicles composed of an emulsifying polymer or a self-emulsifying base, were evaluated in vitro by means of photoprotective activity and photostability. B. braunii dry biomass did not provide adequate photoprotection efficacy; however, it was observed that the self-emulsifying base promoted better sun protection factor (SPF) in comparison with the emulsifying polymer.

Description: The objectives of this study were to prepare and characterize a novel piperine–succinic acid multicomponent crystal phase and to evaluate the improvement in the solubility and dissolution rate of piperine when prepared in the multicomponent crystal formation. The solid-state characterization of the novel multicomponent crystal was performed by powder X-ray diffraction (XRD), differential scanning calorimetry (DSC), and Fourier transform-infrared (FT-IR) spectroscopy. Solubility and dissolution rate profiles were evaluated in distilled water. The physical stability was evaluated under high relative humidity (75% and 100% RH). The determination of the single crystal X-ray diffraction structure revealed that this novel multicomponent crystal was a cocrystalline phase of piperine–succinic acid (2:1 molar ratio). The differential scanning calorimetry thermogram of the cocrystal showed a single and sharp endothermic peak at 110.49 °C. The cocrystal resulted in greater solubility and a faster dissolution rate of piperine than intact piperine. This improvement was a result of the formation of a channel structure in the cocrystal. In addition, the cocrystal was stable under a humid condition.

Description: Self-emulsifying drug delivery systems (SEDDSs) originated as an oral lipid-based drug delivery system with the sole purpose of improving delivery of highly lipophilic drugs. However, the revolutionary drug delivery possibilities presented by these uniquely simplified systems in terms of muco-adhesiveness and zeta-potential changing capacity lead the way forward to ground-breaking research. Contrarily, SEDDSs destined for topical/transdermal drug delivery have received limited attention. Therefore, this review is focused at utilising principles, established during development of oral SEDDSs, and tailoring them to fit evaluation strategies for an optimised topical/transdermal drug delivery vehicle. This includes a detailed discussion of how the authentic pseudo-ternary phase diagram is employed to predict phase behaviour to find the self-emulsification region most suitable for formulating topical/transdermal SEDDSs. Additionally, special attention is given to the manner of characterising oral SEDDSs compared to topical/transdermal SEDDSs, since absorption within the gastrointestinal tract and the multi-layered nature of the skin are two completely diverse drug delivery territories. Despite the advantages of the topical/transdermal drug administration route, certain challenges such as the relatively undiscovered field of skin metabolomics as well as the obstacles of choosing excipients wisely to establish skin penetration enhancement might prevail. Therefore, development of topical/transdermal SEDDSs might be more complicated than expected.

Description: Curcumin is a hydrophobic compound with good anti-proliferative, anti-oxidative, and anti-cancer properties but has poor bioavailability. Liquid crystals (LC) can accommodate both hydrophilic and hydrophobic drugs. The aim of this study was to formulate and evaluate a novel vaginal drug delivery system for cervical cancer using a curcumin LC system. The curcumin LC system was formulated using surfactant, glycerol, and water together with curcumin. Three types of surfactants were used to optimize the formulation, i.e., Tween 80, Cremphor EL, and Labrasol. The optimized formulations were subjected to physicochemical analysis, and their efficacy was evaluated in HeLa cells. The pH of the formulations was in the range of 3.91–4.39. Environmental scanning electron microscopy (ESEM) observations revealed spherical as well as hexagonal micelles. In vitro release of LC curcumin from vaginal simulated fluid (VSF, pH 4.5) showed a release from 20.47% to 87.25%. The IC50 of curcumin in HeLa cells was 22.5 μg/mL, while the IC25 and IC75 were 6.5 μg/mL and 35μg/mL, respectively. The cytotoxicity of the formulations was determined in comparison with liquid crystals without curcumin and pure curcumin by performing a t-test based on a significance level of p less than or equal to 0.05 (p ≤ 0.05). The curcumin LC system was able to release the required amount of drug and was effective against the cervical cancer cell line examined.

Description: To investigate combined effect of the anticancer drug cisplatin (CP) and the opiate analgesic morphine (MOR) on liver, rats were administered MOR (10 mg/kg/day i.p. for 10 days), with or without CP (7.5 mg/kg i.p. once at day 5 of the study). MOR or CP alone caused deterioration of liver function tests and induced damage to histological architecture of liver. In addition, each drug alone caused hepatic oxidative stress, as evident by significant increase of malondialdehyde and nitric oxide, as well as the significant decrease in GSH, catalase and SOD compared to control. Administration of either MOR or CP also caused liver inflammation, evident by the increase in the pro-inflammatory cytokines; TNF-α and IL-6. In addition, either MOR or CP induced liver apoptosis, as shown by significant increase in expression of the pro-apoptotic marker; caspase 3 compared to control. Either MOR or CP also caused up-regulation of the efflux transporter P-glycoprotein (P-gp). Combining MOR with CP caused deterioration in all parameters tested compared to CP alone. Thus, treatment with MOR worsened CP-induced hepatotoxicity through oxidative stress, inflammation and apoptosis mechanisms. In addition, both drugs contributed to the up-regulation of P-gp, which might be a new mechanism for their hepatotoxic effects.

Description: Here, we describe the synthesis and anticonvulsant activity of thiazole-bearing hybrids based on 2-imino-4-thiazolidinone and 2,4-dioxothiazolidine-5-carboxylic acid cores. The structure of target compounds was based on the following: (i) A combination of two thiazole cores; (ii) similarity to ralitolin’s structure; (iii) the compliance with structural requirements for the new anticonvulsants. Target compounds were synthesized via known approaches based on Knoenavegel reaction, alkylation reaction, and one-pot three-component reaction. Anticonvulsant properties of compounds were evaluated in two different models—pentylenetetrazole-induced seizures and maximal electroshock seizure tests. Among the tested compounds 5Z-(3-nitrobenzylidene)-2-(thiazol-2-ylimino)-thiazolidin-4-one Ib, 2-[2,4-dioxo-5-(thiazol-2- ylcarbamoylmethyl)-thiazolidin-3-yl]-N-(2-trifluoromethylphenyl)acetamide IId and (2,4-dioxo-5- (thiazol-2-ylcarbamoylmethylene)-thiazolidin-3-yl)acetic acid ethyl ester IIj showed excellent anticonvulsant activity in both models. The directions of compounds modification based on SAR aspects were discussed. The results of the study provide a basis for further study of the anticonvulsant properties of selected thiazole-thiazolidinones.

Description: The therapeutic effect of a drug depends on the method of effective delivery of the active ingredient to the site(s) of the pharmacological target area [...]

Description: In order to identify new regularities of the “structure–analgesic activity” relationship in the series of 2,1-benzothiazine derivatives, the synthesis of methyl 4-hydroxy-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxylate and a group of its analogs substituted in the benzene moiety of the molecule, as well as their mono-and diammonium salts, was performed with tris(hydroxymethyl)aminomethane. The algorithm was proposed; it allows for uniquely solving the question of the nature of the substituent and its true position in the benzothiazine core based on the complex use of NMR (1H and 13C) and mass spectrometry data. Using single-crystal X-ray diffraction analysis it was proven that salt formation first passes through the cyclic sulfamide group and only then through the 4-hydroxyl group, and is always accompanied by a significant conformational rearrangement of the molecule. Based on the results of pharmacological tests it was found that modification of the benzene moiety of the molecule can be used as a method for enhancing the analgesic properties of the class of compounds studied. The presence of a substitute in position 7 is particularly effective, regardless of its nature. A comparative analysis of the analgesic activity of the initial esters and their mono- and diammonium salts convincingly showed that the common belief about a direct relationship between the solubility of a substance and the level of its biological effect is not always true. As it turned out, increasing the solubility in water can lead to a variety of consequences: From a significant increase in analgesia to its complete elimination. It was suggested that the analgesic activity of the compounds studied is determined not by solubility, but by the molecular conformations formed during their obtainment.

Description: The aim of this research was the comparative study of the amino acids content in the dry extracts of Iridaceae plants of Ukrainian flora: Juno bucharica leaves and corms, Gladiolus hybrid Zefir leaves, Iris hungarica and Iris variegata rhizomes, and Crocus sativus stigmas, flowers, leaves and corms. A gas chromatography–mass spectrometry (GC–MS) method has been used. Separation of amino acids in the samples was carried out using a Shimadzu GC-MS-QP2010 equipped with an Rxi-5ms (Restek Corporation capillary column (30 m long, 0.25 mm outer diameter and 0.25 µm) with a liquid stationary phase (5% diphenyl and 95% polysiloxane) after derivatization with N-(t-butyldimethylsilyl)-N109 methyltrifluoroacetamide (MTBSTFA) reagent. The results obtained have shown that extracts from the aerial parts of plants investigated have a higher amino acid content and more diverse composition than the underground organs. Experimental data showed that Crocus leaves and Juno leaves extracts contain the highest general content of amino acids—31.99 mg/g and 14.65 mg/g respectively. All samples showed a high content of L-pyroglutamic acid (0.33–12.35 mg/g). Moreover, Crocus leaves and Juno leaves extracts had the most suitable amino acids composition and are prospective for further pharmacological studies.

Description: Curcumin is a dietary compound with accrued evidence of antiviral activity. Poor solubility and permeation renders curcumin a good applicant for incorporation into proniosomes. The intent of this study was to formulate curcumin proniosomal gel for topical application and the evaluation of its in-vitro, ex-vivo activities against Herpes Simplex virus type 1 (HSV-1), as well as molecular docking studies on HSV-1 thymidine kinase proteins. Coacervation phase separation tactic, using 23 full factorial design, was used in the preparation of different proniosomes. Cytotoxicity of the selected formulae (F4 and F8) was evaluated on the Vero cell line. Optimal formulae (F4 and F8) showed entrapment efficiency of 97.15 ± 2.47% and 95.85 ± 2.9%, vesicle size of 173.7 ± 2.26 nm and 206.15 ± 4.17 nm and percentages curcumin released after 3 h of 51.9 ± 1.4% and 50.5 ± 1.1%, respectively. Ex-vivo permeation studies demonstrated that the optimal formulae markedly improved the dermal curcumin delivery. Curcumin proniosomal gel formulae exhibited 85.4% reduction of HSV-1 replication. The ability of curcumin to interact with the key amino acids in the enzyme binding sites of 1KI7, 1KI4, and 1E2P, as indicated by its docking pattern, rationalized its observed activity. Therefore, curcumin proniosomes could be considered as a successful topical delivery system for the treatment of HSV-1.

Description: Herbal medicine has been in use for centuries for a wide variety of ailments; however, the efficacy of its therapeutic agents in modern medicine is currently being studied. Curcuminoids are an example of natural agents, widely used due to their potential contribution in the prevention and treatment of cancer. In this study, the three main compounds of curcuminoids—curcumin, desmethoxycurcumin, and bisdesmethoxycurcumin—were determined by reversed-phase high performance liquid chromatography (HPLC) to quantify total content in a mixture. Subsequently, the effect of the three curcuminoids, employed as one sample, was evaluated, to study the proliferation, apoptosis, cell cycle, and migration of the human ovarian cancer cell line SKOV-3. The results reveal that curcuminoids inhibit the proliferation of SKOV-3 cells with concentration- and time-dependent mechanisms. The morphological analysis of the treated SKOV-3 cells showed a typical apoptotic phenotype—cell shrinkage and membrane blebbing in a dose-dependent manner. In addition, flow cytometry demonstrated an increase in apoptosis with an IC50 of 30 µM curcuminoids. The migration of SKOV-3 cells was also inhibited, reflected by a decrease in wound area. Furthermore, the curcuminoids were found to have no stimulation effect on the expression of cytokines TNF-α and IL-10. These results suggest that a curcuminoid mixture can effectively suppress epithelial cancer cell growth in vitro by inducing cellular changes and apoptosis.

Description: Recently, the occurrence of cancer has significantly increased; it represents the second-most frequent cause of death after cardiovascular diseases. Many dietary antioxidants have shown large impact as effective agents for cancer prevention by reducing oxidative stress, which has been a part in the development of many diseases, including cancer. One of the obstacles in the delivery of antioxidant therapies into the required domain lies in the inadequate delivery of these agents to their intended site of action. Using nanotechnology in delivery of antioxidants leads to increased therapeutic index and higher drug concentration in tumor tissues, thus enhancing anticancer treatment. In this review, we discuss the role of different antioxidants in cancer therapy and their improved therapeutic effect through their formulation using nanotechnology.

Description: In vitro release testing (IVRT) provides an efficient method for the evaluation of drug release from semi-solid formulations. The aim of this research was to develop and validate a discriminatory IVRT system using vertical diffusion cells (VDCs) to assess generic topical products containing miconazole nitrate (MCZ). A comprehensive approach addressing all essential suitability criteria supporting the reliability of IVRT results was applied. These include mechanical validation of the VDCs, a performance verification test (PVT), validation of the analytical method (HPLC) used to quantify the drug release and validation of the IVRT method to confirm its precision, reproducibility, discriminatory ability, and robustness. Two marketed generic products were tested and assessed in accordance with the acceptance criteria for “sameness” in the FDA’s SUPAC-SS guidance which requires that the 90% confidence interval (CI) should fall within the limits of 75%–133.33%. One product was found to be in vitro equivalent to the reference product whereas the other was not. The results confirmed the suitability of the IVRT method to accurately measure the release of MCZ from topical cream products and, importantly, demonstrated the necessary discriminatory ability to assess “sameness”/differences of dermatological creams containing MCZ. Furthermore, the developed IVRT method was able to detect differences between formulations, which may be attributed to qualitative (Q1) and quantitative (Q2) properties and the microstructure and arrangement of matter (Q3).

Description: Betahistine dihydrochloride is widely used to reduce the severity and frequency of vertigo attacks associated with Ménière’s disease. Betahistine is an analogue of histamine, and is a weak histamine H1 receptor agonist and potent histamine H3 receptor antagonist. The recommended therapeutic dose for adults ranges from 24 to 48 mg given in doses divided throughout the day. Betahistine undergoes extensive first-pass metabolism to the major inactive metabolite 2-pyridyl acetic acid (2PAA), which can be considered a surrogate index for quantitation of the parent drug due to extremely low plasma levels of betahistine. The aim of the present investigation was to assess the pharmacokinetics and dose proportionality of betahistine in Arabic healthy adult male subjects under fasting conditions. A single dose of betahistine in the form of a 8, 16, or 24 mg tablet was administered to 36 subjects in randomized, cross-over, three-period, three-sequence design separated by a one week washout period between dosing. The pharmacokinetic parameters Cmax, AUC0–t, AUC0–∞, Tmax, and Thalf were calculated for each subject from concentrations of 2-PAA in plasma, applying non-compartmental analysis. The current study demonstrated that betahistine showed linear pharmacokinetics (dose proportionality) in an Arabic population over the investigated therapeutic dose range of 8–24 mg.

Description: Recently, we identified the promising anticancer potential of the synthetic 4-thiazolidinone-based anticancer lead compound Les-3833 which demonstrated tumor-suppressing action in vitro and in vivo. Based on the results of previous studies, the aim of this research was to investigate the cytotoxicity in vitro and the biodistribution in laboratory mice to support the biotherapeutic drug development of Les-3833. Les-3833 (2.5 mg/kg) was intravenously injected into male Balb/c mice. Measurements were performed at 5 min, 15 min, 1 h, 4 h, and 24 h time points in blood plasma, brain, liver, and kidney using high-performance liquid chromatography/tandem mass spectrometry. After the administration of Les-3833, the maximum level of this compound was observed in plasma at 2.08 min. In the brain, the mean maximum concentration of Les-3833 was 7.17 ng/mL at 5 min, while after 15 min, it was not found. In the liver, at 5 min, the maximum concentration was 1190 ng/g. At 15 min, concentration of Les-3833 in the liver decreased by 14.3%; at 6 h by 22.8%; and after 24 h by 64.7%. Its maximum concentration in kidney was 404 ng/g within 5–15 min, at 1 h it decreased by 36.1%, and after 24 h by 49.3%. Thus, Les-3833 was rapidly taken up by different organs from the bloodstream, partially metabolized in the liver, and excreted mainly through the kidneys, while in the brain, a very low concentration could be observed for only a short period of time.

Description: Developed methods for routine analysis of medicines should be considered in terms of analytical efficiency, economic cost, as well as their environmental impact. Different chromatographic methods for the routine quantitative analysis of hederacoside C in ivy leaf extract and its original dosage forms (capsules and syrup) are developed. The performance of HPLC and UPLC methods should be done using ACE C18 (150 mm × 4.6 mm, 5.0 μm) and ACQUITY UPLC BEH C18 (50 mm × 2.1 mm, 1.7 μm) columns, respectively, and both of them require a mixture of water and acetonitrile in the ratio 71/29 as a mobile phase. The HPTLC procedure is carried out using the stationary phase pre-coated silica gel 60 F254 glass sheets and a mixture of anhydrous formic acid/acetone/methanol/ethyl acetate (4:20:20:30 v/v). The most suitable conditions of preparation for each sample are established, for instance, the solid-phase extraction (SPE) for the analysis of syrup is applied. Analytical methods are compered by analytical accuracy, calculation of expenses, and assessment of their influence on ecology. All methods are recognized as accurate, precise, and reliable. However, the assessment of the environmental impact shows that HPTLC is the less green method. On the another hand, it is found to be the cheapest, the costs of performing HPTLC are 2.3 and 1.6 times lower than for HPLC and UPLC, respectively.

Description: Medicinal plants hold a significant place as alternative treatments available for inflammatory diseases, with many phytoconstituents being frequently tested in vitro for their biological activities. In the current study, we investigated the in vivo anti-inflammatory properties of a novel active gel formulation, combining Achillea millefolium and Taxodium distichum essential oils with extracts of Aesculus hippocastanum seeds and Plantago lanceolata leaves. The toxicity of the obtained extracts and volatile oils was determined using the invertebrate model based on Daphnia magna. Anti-inflammatory potential was evaluated by the plethysmometric method on Wistar rats, expressed as the inhibition of the inflammatory oedema (%IIO), while the antinociceptive response was determined on NMRI mice, according to the tail-flick latency method. The tested gel’s efficacy was similar to the 5% diclofenac standard (maximal %IIO of 42.01% vs. 48.70%, respectively), with the anti-inflammatory effect being observed sooner than for diclofenac. Our active gel also produced a significant prolongation of tail-flick latencies at both 60 and 120 min, comparable to diclofenac. Consequently, we can imply that the active constituents present in vivo anti-inflammatory properties, and the prepared gel may be suited for use as an alternative treatment of topical inflammatory conditions.

Description: The pharmacotherapy of critically ill patients is challenging due to the variety of drugs that have to be applied. As the majority of pharmaceuticals must be administered intravenously because of the critical condition of the patients, the compatibility of co-applied intravenous drugs is crucial for a safe and successful infusion therapy. Antihypertensive therapy was reported by health care professionals to be ineffective in association with concomitant application of dihydralazine and metamizole (dipyrone). As both drugs are administered in German intensive care units, we analyzed their compatibility, examined the mechanisms of underlying dihydralazine degradation, and identified reaction products of dihydralazine and metamizole. Binary combinations were prepared at the high and the low end of the nominal administration concentration. Validated high performance liquid chromatography/ultraviolet absorption (HPLC-UV) analysis was conducted to quantify drug amount and high performance liquid chromatography/mass spectrometry (HPLC-MS) was used to analyze degradation products. The combinations of dihydralazine and metamizole proved to be incompatible as dihydralazine concentration decreased immediately and considerably. Metamizole also slightly decreased over time. Specific degradation products of dihydralazine were identified and a degradation pathway was postulated. Our findings demonstrate that the intravenous co-administration of dihydralazine and metamizole should be strictly avoided due to the incompatibility of these two drugs.

Description: Objective: This study evaluated the effect of melatonin on the response of patients suffering from metabolic syndrome (MEBS) treated with metformin. Design: This study used two-armed groups in a double-blind, randomized controlled clinical trial. Materials and Methods: A randomized double-blind placebo-controlled study was carried out on female patients diagnosed as having MEBS, according to the International Diabetes Federation (IDF) diagnosing criteria of MEBS (2005), from the outpatient clinic in Al-Zahraa Teaching Hospital/Kut, Iraq. They were diagnosed utilizing laboratory and clinical investigations, then randomized into two groups. The first group (group A) was treated with metformin (500 mg) twice daily, in addition to a placebo formula once daily at bedtime for three months. The second group (group B) was treated with metformin (500 mg) twice daily after meals, in addition to melatonin (10 mg) once daily at bedtime for three months. Results: The treatment of patients with MEBS using metformin–melatonin showed an improvement in most MEBS components such as fasting serum glucose (FSG), lipid profile, and body mass index (BMI), in addition to a reduction in insulin resistance and hyperinsulinemia. Simultaneously, there were increments in serum uric acid (UA), leptin, prolactin (PRL), and estradiol levels, while serum progesterone level decreased. Furthermore, patients treated with metformin–placebo showed less improvement in the studied parameters compared to that produced due to the inclusion of melatonin in the treatment protocol. Conclusion: Melatonin improves the effect of metformin on several components of MEBS such as FSG, lipid profile, and BMI, in addition to insulin resistance and hyperinsulinemia, compared to metformin alone.

Description: Five N-amide substituted melatonin (MLT) derivatives were synthesized and evaluated for antioxidative activities, and compounds 9–12 showed higher electron spin resonance (ESR) response than MLT. 4-Bromobenzoyl and naphthoyl derivatives (10 and 11) presented stronger hydroxyl radical inhibitory effect than MLT in Fenton reaction. The substitution at the N1-position on the MLT core structure with acetyl (8), benzoyl (9), 4-bromobenzoyl (10), and naphthoyl (11) and N2-substitution with 4-bromobenzoyl (12) decreased the reducing power of the derivatives in ferric reducing antioxidant power (FRAP) assay. Compounds 8–11 also presented lower antioxidant capacity than their parent compound in 2,2′-azinobis(3-ethylbenzothiazoline-6-sulfonic acid) disodium salt (ABTS) assay; whereas, compound 12 presented radical scavenging activity similarly to MLT. All aryl derivatives (9–12) showed higher ability to quench peroxyl radicals than MLT about three times, especially the benzoylated derivatives (9 and 10) that presented the highest ability in oxygen radical absorbance capacity (ORAC) assay.

Description: Cariprazine (Car) is a recently approved second generation antipsychotic (SGA) with unique pharmacodynamic profile, being a partial agonist at both dopamine D2/3 receptor subtypes, with almost 10 times greater affinity towards D3. SGAs are known to increase body weight, alter serum lipids, and stimulate adipogenesis but so far, limited information about the adverse effects is available with this drug. In order to study this new SGA with such a unique mechanism of action, we compared Car to substances that are considered references and are well characterized: olanzapine (Ola) and aripiprazole (Ari). We studied the effects on body weight and also assessed the adipogenesis in rats. The drugs were self-administered in two different doses to female, adult, Wistar rats for six weeks. Weekly body weight change, vacuole size of adipocytes, Sterol Regulatory Element Binding Protein-1 (SREBP-1) and Uncoupling Protein-1 (UCP-1) expression were measured from the visceral adipose tissue (AT). The adipocyte’s vacuole size, and UCP-1 expression were increased while body weight gain was diminished by Car. by increasing UCP-1 might stimulate the thermogenesis, that could potentially explain the weight gain lowering effect through enhanced lipolysis.

Description: Curcumin nanoemulsion was prepared using coconut oil, Tween 80 (surfactant) and polyethylene glycol (co-solvent) with the addition of honey and glycerol as additives. The nanoemulsion was optimized and systematically characterized for transdermal delivery. Small particle size (15.92 nm), low polydispersity index (0.17) and slight acidic (pH 4.18) curcumin nanoemulsion was obtained without any chemical degradation based on the Fourier transform infrared (FTIR) spectrum. The incorporation of curcumin inside nanoglobul improved curcumin stability and skin permeability. Its high permeability can be seen from Nile dyed curcumin in different layers of skin through fluorescent imaging. The release kinetic of curcumin followed the Higuchi model, which explains why the skin permeation was a Fickian diffusion-controlled process because the Korsmeyer constant was proven to be 0.3 (

Description: The dry, powdered cladodes of Opuntia ficus-indica are often-used in over-the-counter (OTC) pharmaceutical formulations. Gentle drying techniques, such as lyophilization and vacuum drying are compared with convection drying for the cladodes and also compared with another species of economic importance, Opuntia joconostle. The heteropolysaccharide purified from the mucilage extracted from the dried powders were investigated in their monosaccharide composition (HPAEC-PAD, TLC), mineral and protein content, molecular dimensions (SEC) and fermentability by probiotic bacteria (Bioscreen technique) for evaluation of the prebiotic potential of the mucilage. The heteropolysaccharide is composed of galactose, arabinose, xylose, galacturonic acid and rhamnose. O. ficus-indica includes an additional 13% of glucose coming from an α-glucan. The content of Ca (0.3%) and Mg (0.4%) is relatively low in both species; the content of protein adds up to 1.5% in O. ficus-indica but is significantly lower in O. joconostle with 0.8%. The average molecular mass Mw of the extracted mucilage ranges from 3.7 to 4.7 × 105 g∙mol−1 for both species; only the mucilage from long-time convection drying (C2) delivers a lower average Mw of 2.6 × 105 g∙mol−1, due to partial breakdown of the mucilage matrix. All tested probiotic strains utilized the mucilage to some extent; C2 being the most active, and thus confirms the prebiotic potential of cladode’s powder and its derived products. In general, the molecular dimensions and prebiotic potential are not extremely sensitive to the drying treatment, yet temperature and drying time can modify the cladode’s powder to a profile with better prebiotic characteristics.

Description: Helichrysum petiolare (Asteraceae family) is part of the Helichrysum genus which comprises of an estimated 600 species. Several parts of the plant have been used traditionally for the treatment of various ailments, such as cough, infection, asthma, chest problems, diabetes and wounds. Given its various chemical constituents with anticancer properties, there has been no scientific evidence of its usage for the treatment of cancer. This study aims to investigate the anti-proliferative and genotoxic activities of H. petiolare methanol extract. The cytotoxic effect and cell cycle analysis of mouse melanoma cells (B16F10) and human melanoma cells (MeWo) were assessed using the ImageXpress Micro XLS Widefield High-Content Analysis System. The genotoxic potential of the extract towards Vero cells was also assessed using the micronucleus assay. The extract displayed cytotoxicity towards B16F10 and MeWo skin melanoma cells, thereby showing a dose-dependent decrease in cell density. This was preceded by cell cycle arrest in B16F10 cells at the S phase and MeWo cell arrest at the early M phase with a significant increase in apoptosis in both cells. Furthermore, the extract displayed genotoxic potential at the tested concentrations (12.5–200 μg/mL). Overall, the results revealed that H. petiolare extract may have the potential to eradicate skin cancer.

Description: The prevalence of obesity is increasing worldwide and is commonly associated with comorbidities. The use of several drugs is often necessary, which leads to Potential Drug Interactions (PDI) that may increase the morbidity and mortality. This study aimed to analyze the prevalence of drug interaction and its association with socio-demographics, health status, and drug use in severely obese individuals. Baseline data from a randomized clinical trial registered at Clinicaltrial.gov (NCT02463435) were used. A total of 150 individuals aged 18–65 years with a body mass index of 35 kg/m2 were included. The outcome variable was the presence of PDI, and the explanatory variables were divided into the following four levels: socio-demographic, lifestyle, health, and medication use. The prevalence of PDI was 50% (n = 75) (95% CI 41–58). The variables associated with drug–drug interactions in the multiple analyses were arterial hypertension (PR 1.83, 95%, CI 1.10–3.04), polypharmacy (PR 3.12, 95%, CI 2.17–4.50), and diabetes mellitus (PR 0.60, 95%, CI 0.45–0.81). The risk factors for the occurrence of drug interaction were the presence of diabetes mellitus, hypertension, and polypharmacy.

Description: (1) Background: this research aims at studying the nephroprotective properties of BNO 2103 in a model of chromate-induced renal failure in rats and at proving the possibility of using BNO 2103 in clinical practice for the complex treatment of chronic kidney disease (CKD). (2) Methods: fifty rats divided into five groups were studied. The drugs BNO 2103, Prednisolone and Lespephril were administered within 20 days. The excretory function and the functional state of kidneys, blood biochemical parameters and indicators of nitrogen metabolism were determined. (3) Results: under the influence of BNO 2103, there was a significant improvement in renal excretory function, in nitrogen metabolism and blood biochemical parameters compared with the control pathology group. BNO 2103 also outperformed the comparators in most indicators. (4) Conclusions: BNO 2103 has demonstrated nephroprotective, hypoazotemic and diuretic effects; and can be used to implement to the combined therapy of CKD.

Description: Electron transfer plays a vital role in drug metabolism and underlying toxicity mechanisms. Currently, pharmaceutical research relies on pharmacokinetics (PK) and absorption, distribution, metabolism, elimination and toxicity (ADMET) measurements to understand and predict drug reactions in the body. Metabolic stability (and toxicity) prediction in the early phases of the drug discovery and development process is key in identifying a suitable lead compound for optimisation. Voltammetric methods have the potential to overcome the significant barrier of new drug failure rates, by giving insight into phase I metabolism events which can have a direct bearing on the stability and toxicity of the parent drug being dosed. Herein, we report for the first time a data-mining investigation into the voltammetric behaviour of reported drug molecules and their correlation with metabolic stability (indirectly measured via t½), as a potential predictor of drug stability/toxicity in vivo. We observed an inverse relationship between oxidation potential and drug stability. Furthermore, we selected and prepared short- (2 h) drug molecules to prospectively survey the relationship between oxidation potential and stability.

Description: The decreased hepatic drug metabolism (predominately first phase) is one of the essential reasons for numerous side effects and for increased drug toxicity during influenza virus infection (IVI). The present study aims to investigate some mechanisms of the preventive effect of a standardized polyphenol complex from the medicinal plant Geranium sanguineum L. (PPhC) (10 mg/kg nasally). A verified experimental model of IVI A/Aichi/2/68 (H3N2) (4.5 lg LD50) in male ICR (Institute of Cancer Research, USA) mice was used. Changes in hepatic monooxygenase activities as well as nicotinamide adenine dinucleotide phosphate (NADPH)-cytochrome C reductase activity and cytochtome P450 content were studied on days 2, 6, 9, 21 of the infection together with thiobarbituric acid reactive substances in the liver supernatant. Our data clearly demonstrates that IVI affects all components of the electronic chain of cytochrome P-450. N-demethylases and hydroxylases as well as the activity of cytochrome C reductase and cytochtome P-450 content were decreased in the course of the virus infection. This implies that free radicals play an important role not only in the pathogenesis of IVI, but also in the modulation of the hepatic monooxygenase activity. This is also consistent with the established polyphenol complex PPhC from the medicinal plant Geranium sanguineum L. preventive effect against increased thiobarbituric acid reactive substances (TBARS)-levels. PPhC restored most of the monooxygenase activities that were inhibited in IVI animals, even over the control levels, probably via multiple mechanisms that may entail antioxidant activity and selective antiviral and protein-binding effects. In contrast to infected animals, in healthy mice, PPhC showed moderate reversible inhibitory effect on hepatic monooxygenase activities.

Description: Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is a coronavirus that causes the pandemic Coronavirus Disease 2019 (COVID-19). There is no current specific treatment for this new coronavirus. In this study, we employed a virtual screening repurposing strategy to search for potential SARS-CoV-2 Mpro inhibitors. The databases PDB, ChEMBL, BindingDB and DrugBank were queried with several filtering steps based on ligand-based and structure-based approaches. As a result, we obtained 58 molecules (37 from ChEMBL and 21 from DrugBank) that potentially inhibit SARS-CoV-2 Mpro. These molecules have on their chemical structure functional groups that favor stronger docking scores than the inhibitor N3. Several of these molecules are reported experimentally as SARS-CoV Mpro inhibitors. Hence, a combined virtual screening strategy allowed finding chemical compounds with a high potential for the inhibition of SARS-CoV-2 Mpro.

Description: The World Health Organization (WHO) officially announced coronavirus disease 2019 (COVID-19) as a pandemic in March 2020. Unfortunately, there are still no approved drugs for either the treatment or the prevention of COVID-19. Many studies have focused on repurposing established antimalarial therapies, especially those that showed prior efficacy against Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) and Middle East Respiratory Syndrome Coronavirus (MERS-CoV), such as chloroquine and hydroxychloroquine, against COVID-19 combined with azithromycin. These classes of drugs potentially induce prolongation of the QT interval, which might lead to lethal arrhythmia. Beta-blockers, as a β-adrenergic receptor (β-AR) antagonist, can prevent an increase in the sympathetic tone, which is the most important arrhythmia trigger. In this literature review, we aimed to find the effect of administering azithromycin, chloroquine, and hydroxychloroquine on cardiac rhythm disorders and our findings show that bisoprolol, as a cardio-selective beta-blocker, is effective for the management of the QT (i.e., the start of the Q wave to the end of the T wave) interval prolongation in COVID-19 patients.

Description: Intestinal and hepatic function have been investigated in phase II metabolic reactions and elimination of p-nitrophenol (PNP) in the rat. A jejunal loop was cannulated and recirculated with isotonic solutions containing PNP in different concentrations (0, 20, 100, 500, 1000 µM). Samples were obtained from the perfusate at given intervals. To investigate the metabolic and excretory functions of the liver, the bile duct was cannulated, and the bile was collected. Metabolites of PNP were determined by validated HPLC (high pressure liquid chromatography) methods. The results demonstrated the relative importance of the small intestine and the liver in phase II metabolic transformations and elimination of PNP. There were significant differences between the luminal and biliary appearances of p-nitrophenol-glucuronide (PNP-G) and p-nitrophenol–sulfate (PNP-S). The PNP-G appeared in the intestinal lumen at the lower PNP concentrations (20 µM and 100 µM) at higher rate than in the bile. No significant difference was found between the intestinal and the biliary excretion of PNP-G when PNP was administered at a concentration of 500 µM. However, a reverse ratio of these parameters was observed at the administration of 1000 µM PNP. The results indicated that both the small intestine and the liver might play an important role in phase II metabolic reactions and elimination of PNP. However, the relative importance of the small intestine and the liver can be dependent on the dose of drugs.

Description: Glochidion wallichianum (GW) is a good source of antioxidants, including gallic acid, promoting its development as a microemulsion. We constructed five pseudo-ternary phase diagrams comprising isopropyl myristate (IPM), water, and surfactant mixture (Smix)—i.e., Labrasol®:HCO-40® (1:1) with Transcutol® (1:1, 2:1, 3:1), and Tween80:Span80 (3:2) with Transcutol® or propylene glycol:ethanol (1:1). Additionally, blank and GW extract-loaded microemulsions were prepared at an IPM:Water:Smix ratio of 10:30:60 (high water content) and 30:10:60 (high oil content) from each Smix. The physical characteristics, skin permeation, and disposition were evaluated. The formulations with high water content and conductivities provided higher gallic acid permeation and disposition than those with high oil content. The Smix of Labrasol®:HCO-40® (1:1) and Transcutol® (1:1) promoted the highest gallic acid permeation (enhancement ratio 1.78 ± 0.12) and was suitable for transdermal delivery. However, the 1% hydroxypropyl methylcellulose control gel, the microemulsion with Smix of Labrasol®:HCO-40® (1:1) with Transcutol® (2:1), and Smix of Tween80:Span80 (3:2) with propylene glycol:ethanol (1:1) could provide higher skin accumulation of gallic acid than that with other formulations. The microstructures, ratio of surfactant:cosurfactant, and compositions of microemulsions were found to affect the skin permeation and disposition of gallic acid and require optimization to act as transdermal or topical delivery carriers.

Description: Vaccination is one of the main methods for the specific prevention of infectious diseases. The disadvantage of vaccination is the use of pathogens (live or attenuated viruses and bacteria) that can lead to the development of a disease. Recombinant technologies are capable of producing specific DNA or protein molecules that possess antigenic properties and do not cause disease. However, individual antigen molecules are low-immunogenic, and therefore, require conjugation with a compound possessing stronger immunogenic properties. In this study, we examined the immunogenic properties of the new anionic copolymer consisting of glycidyl methacrylate, butyl acrylate, triethylene glycol dimethacrylate, and acrylic acid, in mice. The experimental polymer induced a stronger immunogenic response than aluminum hydroxide. The histological studies have established that immunization both with aluminum hydroxide and the polymer studied does not cause damage to the liver, kidneys, or the spleen. No negative side effects were observed. It has been concluded that the new synthetic anionic polyelectrolyte hydrogel (PHG) has a potential as an adjuvant for vaccine development.

Description: Alzheimer’s disease (AD) is a common chronic neurodegenerative disorders. Melatonin (MLT) has been reported to be neuroprotective agent, and its modified structures exhibit potent antioxidant and anti-inflammation activities. Therefore, the activity of MLT and its derivatives against AD was investigated. Herein, the targeted enzymes, such as β-secretase (BACE1) and acetylcholinesterase (AChE), as well as the neuroprotective and neuritogenic effects on P19-derived neurons were evaluated. All the derivatives (1–5), including MLT, displayed potent inhibitory activity for BACE1, with inhibition values of more than 75% at 5 µM. A molecular docking study predicted that MLT, 5-MT, and 5 bound with BACE1 at catalytic amino acids Asp32 and the flap region, whereas 1–4 interacted with allosteric residue Thr232 and the flap region. The additional π-π interactions between 2, 3, and 5 with Tyr71 promoted ligand-enzyme binding. In addition, MLT, 1, 3, and 5 significantly protected neuron cells from oxidative stress by increasing the cell viability to 97.95, 74.29, 70.80, and 69.50% at 1 nM, respectively. Moreover, these derivatives significantly induced neurite outgrowth by increasing the neurite length and number. The derivatives 1, 3, and 5 should be thoroughly studied as potential AD treatment and neuroprotective agents.

Description: While contraceptive drugs have enabled many people to decide when they want to have a baby, more than 100 million unintended pregnancies each year in the world may indicate the contraceptive requirement of many people has not been well addressed yet. The vagina is a well-established and practical route for the delivery of various pharmacological molecules, including contraceptives. This review aims to present an overview of different contraceptive methods focusing on the vaginal route of delivery for contraceptives, including current developments, discussing the potentials and limitations of the modern methods, designs, and how well each method performs for delivering the contraceptives and preventing pregnancy.

Description: Glimepiride is an antidiabetic drug which is one of the third generation sulfonylureas. It belongs to class II, according to the BCS (Biopharmaceutical Classification System), which is characterized by low solubility and high permeability. The aim of this work was to formulate glimepiride as solid dispersion using water-soluble carriers to enhance its aqueous solubility and thus enhance its bioavailability. Nine formulations of glimepiride solid dispersion were prepared by a solvent evaporation technique using three different carriers (mannitol, polyethylene glycol 6000, and β-cyclodextrin) with three different drug carrier ratio (1:1, 1:3, and 1:6). Formulation variables were optimized using 32 full factorial design. The prepared formulations were evaluated for production yield, drug content, micromeritic properties, thermal analysis, in-vitro release, and in-vivo hypoglycemic effect. All prepared formulations showed high production yield ranged from 98.4 ± 2.8 to 99.8 ± 2.2% and high drug content in the range of 97.2 ± 3.2 to 99.6 ± 2.1%. The micromeritic properties revealed that all prepared glimepiride formulations showed good flowability. The differential scanning calorimetry study revealed the presence of the drug in the more soluble amorphous form. In accordance with the results of in vitro release study, it was found that the solubility of glimepiride was increased by increasing the drug carrier ratio, compared with the pure form of the drug. It was found that F9 showed a high and rapid reduction in blood glucose levels in diabetic rats, which indicated the success of a solid dispersion technique in improving the solubility and hence the bioavailability of glimepiride.

Description: A new series of amino acid derivatives of quinolines was synthesized through the hydrolysis of amino acid methyl esters of quinoline carboxamides with alkali hydroxide. The compounds were purified on silica gel by column chromatography and further characterized by TLC, NMR and ESI-TOF mass spectrometry. All compounds were screened for in vitro antimicrobial activity against different bacterial strains using the microdilution method. Most of the synthesized amino acid-quinolines show more potent or equipotent inhibitory action against the tested bacteria than their correspond esters. In addition, many of them exhibit fluorescent properties and could possibly be utilized as fluorophores. Molecular docking and simulation studies of the compounds at putative bacterial target enzymes suggest that the antimicrobial potency of these synthesized analogues could be due to enzyme inhibition via their favorable binding at the fluoroquinolone binding site at the GyrA subunit of DNA gyrase and/or the ParC subunit of topoisomerase-IV.

Description: A series of triterpenic acid amides were synthesized incorporating a 2-ethoxy-3-phenylpropanoic acid pharmacophore fragment. The synthesized compounds were tested for their ability to improve glycemic control and to counter lipid abnormalities in C57BL/6 mice placed on a high-fat/high-cholesterol diet. Of all tested compounds, the dihydrobetulonic derivative (16b) had the most pronounced effect in decreasing blood glucose levels, total cholesterol (TC), and high-density lipoproteins (HDL). All the synthesized compounds displayed a relatively safe profile in the animal studies carried out in this work.

Description: Antibiotic-resistant infection is a major health problem, and a limited number of drugs are currently approved as antibiotics. Soil bacteria are promising sources in the search for novel antibiotics. The aim of the present study is to isolate and assess soil bacteria with anti-MRSA activity and improve their capabilities by UV mutagenesis. Soil samples from the upper south of Thailand were screened for antibacterial activity using the cross-streak method. Agar well diffusion was used to examine the activity of isolates against a spectrum of human pathogens. The most active isolate was identified by 16S rRNA sequencing, and the production kinetics and stability were investigated. The most promising isolate was mutated by UV radiation, and the resulting activity and strain stability were studied. The results show that isolates from the cross-streak method could inhibit Staphylococcus aureus TISTR 517 (94 isolates) and Escherichia coli TISTR 887 (67 isolates). Nine isolates remained active against S. aureus TISTR 517 and MRSA, and eight isolates inhibited the growth of E. coli TISTR 887 as assessed using agar well diffusion. The most active strain was Brevibacillus sp. SPR-20, which had the highest activity at 24 h of incubation. The active substances in culture supernatants exhibited more than 90% activity when subjected to treatments involving various heat, enzymes, surfactants, and pH conditions. The mutant M201 showed significantly higher activity (109.88–120.22%) and strain stability compared to the wild-type strain. In conclusion, we demonstrate that soil Brevibacillus sp. is a potential resource that can be subjected to UV mutagenesis as a useful approach for improving the production of anti-MRSA in the era of antibiotic resistance.

Description: Combating the COVID-19 pandemic warrants the exploitation of all the available tools and implies a major focus on both the biological and the physical properties of the causing virus (SARS-CoV2). We hereby introduce a new prophylaxis hypothesis by decreasing the viral load in the body entrances such as the nose and the mouth using pharmaceutical and cosmeceutical preparations that incorporate viral electrostatic repulsive nanofibers fabricated from an abundant marine-derived or a fermentation product polymer; Ԑ-poly-l-lysine was prepared using the electrospinning technique.

Description: Background: Ganoderma fungus is rich in terpenoids. These compounds are known for their anti-hyperglycemic activities. However, the study of terpenoids as the secondary metabolite from Ganoderma as a dipeptidyl peptidase-4 (DPP-4) inhibitor remains unexplored. In addition, we examined the α-glucosidase inhibition activity. Objective: This study aimed to isolate the major terpenoid from non-laccate Ganoderma and examined its inhibitor activity on DPP-4 and α-glucosidase enzymes, and its interaction. Methods: The compound was isolated using column chromatography from Ganoderma australe. The structure of the isolated compound was confirmed by 1H and 13C nuclear magnetic resonance spectroscopy, while the inhibitory activity was evaluated using an enzymatic assay. The interaction of the isolated compound with DPP-4 and α-glucosidase enzymes was investigated using an in silico study. Results: The isolated compound was identified as stellasterol; IC50 values for DPP-4 and α-glucosidase inhibitor were 427.39 µM and 314.54 µM, respectively. This study revealed that the inhibitory effect of stellasterol on DPP-4 enzyme is through hydrophobic interaction, while the α-glucosidase enzyme is due to the interaction with six amino acids of the enzyme. Conclusion: Stellasterol is the major component of the steroid from G. australe. Enzyme inhibitory assay and in silico study suggest that stellasterol may contribute antidiabetic activity with a mechanism closer to acarbose rather than to sitagliptin.

Description: Berberis goudotii is an endemic Colombian plant found in the paramo ecosystem. It has been used in food preparation and as a medicinal plant for diverse treatments. Additionally, it is used as a mouthwash to strengthen the gums and combat throat irritations and periodontitis. The present research evaluated Berberis goudotii aerial parts extract and fractions antimicrobial activities. Ultrasonic-assisted extraction was used to attain total ethanol-water extract. Solid-liquid fractionation was used to obtain hexane fraction. The residue was dispersed in water and liquid-liquid fractionation was carried-out to acquire dichloromethane, butanol and water fractions. Preliminary phytochemical analysis was performed on total extract and phenol, polyphenol, flavonoid, and proanthocyanidin, while tannin content was quantified. Antimicrobial activity assessment was performed by agar diffusion method using disks and wells employing Ceftazidime as a positive control against Streptococcus mutans, Streptococcus sobrinus, Lactobacillus acidophilus, Lactobacillus casei, Porphyromonas gingivalis, Prevotella intermedia and Fusobacterium nucleatum. Antimicrobial activity was determined as relative percentage inhibition (RPI), minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC). Phenols (92.5 ± 7.7 mg GA/10 g), polyphenols (87.7 ± 8.1 mg PG/10 g) and tannins (44.1 ± 4.3 mg PG/10 g) were among the highest secondary metabolites observed. Total extract presented an MBC of 1.0 µg/µL against cariogenic bacteria (Streptococcus mutans and Streptococcus sobrinus) and 0.12 µg/µL against bacteria associated with periodontal disease (Porphyromonas gingivalis, Prevotella intermedia and Fusobacterium nucleatum). Butanol and hexane fractions showed antiperiodontal activity with MBC of 0.12 and 1.0 µg/µL, respectively. In conclusion, Berberis goudotii total extract demonstrated antimicrobial activity against cariogenic and periodontal microorganisms, on the other hand, hexane and butanol fractions displayed antiperiodontal activity.

Description: Agrimonia pilosa Ledeb. produces an antinociceptive effect in ICR mice in both chemically induced and thermal pain models. In the present study, we examined the antinociceptive effects of single components isolated from Agrimonia pilosa Ledeb. (AP) extract in ICR mice. Three active compounds isolated from AP, including rutin, luteolin-7-O-glucuronide, and apigenin-7-O-glucuronide, were isolated and identified by comparing EI-MS, 1H-, 13C-NMR, and UV. We studied the antinociceptive effects of three single components administered orally at doses of 10 and 20 mg/kg in monosodium urate (MSU)-treated pain model as measured by von Frey test. Among these compounds, apigenin-7-O-glucuronide was more effective in the production of antinociceptive effects. We further characterized the antinociceptive effects and possible mechanisms of apigenin-7-O-glucuronide in writhing and formalin tests. Oral administration of Apigenin-7-O-glucuronide caused a reduction in the number of writhing and effectively reduced the pain behavior observed during the second phase of the formalin test in a dose-dependent manner. In addition, the pretreatment of yohimbine instead of naloxone or methysergide attenuated apigenin-7-O-glucuronide-induced antinociception in the writhing test. Moreover, apigenin-7-O-glucuronide caused reduction in the expression of p-P38, p-CREB, and p-mTOR induced by formalin injection. Our results indicate that apigenin-7-O-glucuronide shows an antinociceptive effect in various pain models. In addition, spinal α2-adrenergic receptors appear to be involved in the production of antinociception induced by apigenin-7-O-glucuronide. Furthermore, the antinociceptive effect of apigenin-7-O-glucuronide appears to be mediated by reduction in the expression of p-P38, p-CREB and p-mTOR levels in the spinal cord.

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Description: The article presents the synthesis of 2-arylimino-4-methyl-2,3-dihydro-1,3-thiazoles via Hantzsch reaction of thioureas and 3-chloropentane-2,4-dione or ethyl 2-chloro-3-oxobutanoate. The structure of synthesized compounds was confirmed by LCMS, 1H, and 13C NMR spectra. Cardioprotective activity of synthesized thiazole derivatives were studied in vitro on the isolated rings of the thoracic aorta of laboratory rats. Based on pharmacological studies, the tested compounds possessed a moderate to high cardioprotective effect. A prospective 1-[2-(4-methoxyphenylimino)-4-methyl-3-(4-methylpiperazine-1-yl)-2,3-dihydro-1,3-thiazole-5-yl] ethan-1-one hydrochloride 4c was identified. The mentioned compound has delayed the development of constrictor responses of isolated rings of the thoracic rat aorta and exceeds the activity of L-carnitine by 18.2% and meldonium by 12.9%. The compound 4c may be proposed as a potential cardioprotective agent for in-depth pharmacological studies.

Description: Diabetes is a major metabolic disorder whose prevalence is increasing daily. Medicinal plants have played an important role in the prevention and treatment of type 2 diabetes via prophylactic and therapeutic management. In this study, Mangifera Indica leaf (MIL) extract was investigated for its promising anti-diabetic activity via an in vitro model. It was found that MIL extract possessed significant inhibition on alpha-amylase activity up to (51.4 ± 2.7)% at a concentration of 200 µg/mL. Moreover, glucose adsorption capacity of MIL was identified at (2.7 ± 0.19) mM glucose/g extract. Furthermore, the extract caused a significant increase in glucose uptake up to (143 ± 9.3)% in LO-2 liver cells. Notably, MIL extract was effective in scavenging (63.3 ± 2.1)% 1,1-diphenyl-2-picryl-hydrazyl (DPPH) and (71.6 ± 4.3)% 2,2-azinobis-3-ethyl benzothiazoline-6-sulfonic acid (ABTS)+ radicals and inhibiting (66 ± 4.9)% NO production from RAW264.7 cells without any cytotoxicity effects. Accordingly, M. indica leaves are suggested as a promising material for development of hypoglycemic products.

Description: Rhodiola rosea has been used in folk medicine as ethanolic macerates for a long time. This study aims to provide a quantitative and qualitative analysis and comparison of different ethanolic Rhodiola rosea rhizome macerates (35%, 70%, and 96% v/v) and accelerated solvent extraction (ASE) extracts prepared with 85% methanol, in order to shed light on the effectivity of different extraction methods. Extract samples were analyzed by UHPLC-DAD-ESI-MSn on a ZORBAX SB-C18 column (100 × 2.1 mm, 1.8 μm) with a mobile phase consisting of water + 0.1% formic acid and acetonitrile. Qualitative analysis lead to the tentative identification of 18 compounds: Two cyanogenic glycosides (rhodiocyanoside A, lotaustralin), three phenylethanoids (salidroside, viridoside, 2-phenylethyl-vicianoside), two procyanidin and catechin derivatives (epigallocatechin-epigallocatechin gallate, epigallocatechin-3-O-gallate), five phenylpropanoids (cinnamyl alcohol, rosarin, rosavin, rosin, cinnamyl-(6’-O-β-d-xylopyranosyl)-O-β-glucopyranoside), two monoterpene alcohols (rhodioloside E, rosiridin) and four flavonols (rhodionidin, rhodiosin, rhodionin, kaempferol). Quantity was determined for salidroside, cinnamyl alcohol and its three major glycosides (rosarin, rosavin, rosin), as well as three flavonols (rhodionidin, rhodiosin, rhodionin). Methanolic ASE proved to be the superior extraction method for different substance groups. For macerates, high ethanol content increased yield and lowered hydrolysis of glycosides during extraction, but ethanolic macerates still showed low reproducibility and high fluctuations in quantity of marker compounds salidroside and rosavins, as well as flavonols. Rhodiola rosea rhizomes of wild origins seemed to underly great variability in chemical composition dependent on grow site.

Description: In order to study polymorphic modifications of N-(4-trifluoromethylphenyl)-4-hydroxy-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxamide, which is of interest as a promising analgesic, its three colorless crystal forms with different habitus have been obtained: sticks of ethyl acetate, plates of meta-xylene and blocks of ortho-xylene. However, the X-ray diffraction analysis has shown that all the forms studied have the identical molecular and crystal structure in spite of such significant differences in appearance. Moreover, pharmacological tests have revealed significant differences in the analgesic activity in these samples (a total of five experimental models were used: “acetic-acid-induced writhing”, “hot plate”, “thermal irritation of the tail tip” (tail-flick), “tail electric stimulation” and “neuropathic pain”), acute toxicity and the ability to cause gastric damage. As a result, only the plate crystal form of N-(4-trifluoromethylphenyl)-4-hydroxy-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxamide is recommended for further studies. Thus, it has been proven that the habitus of crystals is an important characteristic of the drug substance and is able to have a noticeable effect on its biological properties. Changes in habitus should be considered as a guide to the mandatory verification of at least the basic pharmacological parameters of the new form regardless of whether the molecular and crystal structure changes.

Description: We investigated the effect of 21 flavonoids in a three-dimensional in vitro system for their ability to inhibit gap formation by MCF-7 breast cancer spheroids in monolayers of lymphendothelial cells. Different representatives of the classes of flavones, flavonols, and flavanones were tested in the circular chemorepellent-induced defects (CCID)-assay. Bay11-7082, a known inhibitor of CCID formation served as the positive control. This study provides the first comparison of the potential of flavonoids to suppress features influencing the intravasation of MCF-7 breast cancer cells aggregates through the lymph endothelial barrier. The most significant effects were seen after incubation with the flavones luteolin, chrysin, and apigenin. Additional hydroxylation or methoxylation in positions 6 or 8, as expected, resulted in decreased activity. The tested flavanones remained without or low efficacy.

Description: Microparticles, microspheres, and microcapsules are widely used constituents of multiparticulate drug delivery systems, offering both therapeutic and technological advantages. Microparticles are generally in the 1–1000 µm size range, serve as multiunit drug delivery systems with well-defined physiological and pharmacokinetic benefits in order to improve the effectiveness, tolerability, and patient compliance. This paper reviews their evolution, significance, and formulation factors (excipients and procedures), as well as their most important practical applications (inhaled insulin, liposomal preparations). The article presents the most important structures of microparticles (microspheres, microcapsules, coated pellets, etc.), interpreted with microscopic images too. The most significant production processes (spray drying, extrusion, coacervation, freeze-drying, microfluidics), the drug release mechanisms, and the commonly used excipients, the characterization, and the novel drug delivery systems (microbubbles, microsponges), as well as the preparations used in therapy are discussed in detail.

Description: Dengue infection is caused by a mosquito-borne virus, particularly in children, which may even cause death. No effective prevention or therapeutic agents to cure this disease are available up to now. The dengue viral envelope (E) protein was discovered to be a promising target for inhibition in several steps of viral infection. Structure-based virtual screening has become an important technique to identify first hits in a drug screening process, as it is possible to reduce the number of compounds to be assayed, allowing to save resources. In the present study, pharmacophore models were generated using the common hits approach (CHA), starting from trajectories obtained from molecular dynamics (MD) simulations of the E protein complexed with the active inhibitor, flavanone (FN5Y). Subsequently, compounds presented in various drug databases were screened using the LigandScout 4.2 program. The obtained hits were analyzed in more detail by molecular docking, followed by extensive MD simulations of the complexes. The highest-ranked compound from this procedure was then synthesized and tested on its inhibitory efficiency by experimental assays.

Description: In the last decade, high-performance liquid chromatography/tandem mass spectrometry (LC/MS/MS) combined with electrospray ionization (ESI) has been widely used for determining low concentrations of steroids, and derivatization has often been employed to enhance detection. In the present study, endogenous steroids were extracted using a Strata-XL polymeric reverse phase cartridge. The isolated steroids were reacted with 2-hydrazino-1- methylpyridine (HMP) at 50 °C for 30 min. A liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used in a positive mode with multiple reaction monitoring (MRM) for the quantification of testosterone (T) and its precursor, dehydroepiandrosterone (DHEA), in saliva samples collected from twenty young Saudi professional soccer players. The analytes were separated on an ACE Ultracore 2.5 Superphenylhexyl column (150 × 3.0 mm id). The extraction recovery during the pre-treatment was 〉89% and gave

Description: Treatment of certain central nervous system disorders, including different types of cerebral malignancies, is limited by traditional oral or systemic administrations of therapeutic drugs due to possible serious side effects and/or lack of the brain penetration and, therefore, the efficacy of the drugs is diminished. During the last decade, several new technologies were developed to overcome barrier properties of cerebral capillaries. This review gives a short overview of the structural elements and anatomical features of the blood–brain barrier. The various in vitro (static and dynamic), in vivo (microdialysis), and in situ (brain perfusion) blood–brain barrier models are also presented. The drug formulations and administration options to deliver molecules effectively to the central nervous system (CNS) are presented. Nanocarriers, nanoparticles (lipid, polymeric, magnetic, gold, and carbon based nanoparticles, dendrimers, etc.), viral and peptid vectors and shuttles, sonoporation and microbubbles are briefly shown. The modulation of receptors and efflux transporters in the cell membrane can also be an effective approach to enhance brain exposure to therapeutic compounds. Intranasal administration is a noninvasive delivery route to bypass the blood–brain barrier, while direct brain administration is an invasive mode to target the brain region with therapeutic drug concentrations locally. Nowadays, both technological and mechanistic tools are available to assist in overcoming the blood–brain barrier. With these techniques more effective and even safer drugs can be developed for the treatment of devastating brain disorders.

Description: Cyclodextrins are widely used excipients, composed of glucopyranose units with a cyclic structure. One of their most important properties, is that their inner cavity is hydrophobic, while their surface is hydrophilic. This enables them for the complex formation with lipophilic molecules. They have several applications in the pharmaceutical field like solubility enhancers or the building blocks of larger drug delivery systems. On the other hand, they have numerous effects on cells or biological barriers. In this review the most important properties of cyclodextrins and cyclodextrin-based drug delivery systems are summarized with special focus on their biological activity.

Description: Nanoemulsions (NEs) are colloidal dispersions of two immiscible liquids, oil and water, in which one is dispersed in the other with the aid of a surfactant/co-surfactant mixture, either forming oil-in-water (o/w) or water-in-oil (w/o) nanodroplets systems, with droplets 20–200 nm in size. NEs are easy to prepare and upscale, and they show high variability in their components. They have proven to be very viable, non-invasive, and cost-effective nanocarriers for the enhanced transdermal delivery of a wide range of active compounds that tend to metabolize heavily or suffer from undesirable side effects when taken orally. In addition, the anti-microbial and anti-viral properties of NE components, leading to preservative-free formulations, make NE a very attractive approach for transdermal drug delivery. This review focuses on how NEs mechanistically deliver both lipophilic and hydrophilic drugs through skin layers to reach the blood stream, exerting the desired therapeutic effect. It highlights the mechanisms and strategies executed to effectively deliver drugs, both with o/w and w/o NE types, through the transdermal way. However, the mechanisms reported in the literature are highly diverse, to the extent that a definite mechanism is not conclusive.

Description: Dermal and transdermal drug therapy is increasing in importance nowadays in drug development. To completely utilize the potential of this administration route, it is necessary to optimize the drug release and skin penetration measurements. This review covers the most well-known and up-to-date methods for evaluating the cutaneous penetration of drugs in vitro as a supporting tool for pharmaceutical research scientists in the early stage of drug development. The aim of this article is to present various experimental models used in dermal/transdermal research and summarize the novel knowledge about the main in vitro methods available to study skin penetration. These techniques are: Diffusion cell, skin-PAMPA, tape stripping, two-photon microscopy, confocal laser scanning microscopy, and confocal Raman microscopic method.

Description: Proteins play crucial roles in the transportation and distribution of therapeutic substances, including metal ions in living systems. Some metal ions can strongly associate, while others show low affinity towards proteins. Consequently, in the present work, the binding behaviors of Ca2+, Ba2+, Ag+, Ru3+, Cu2+ and Co2+ with bovine serum albumin (BSA) were screened. BSA and the metal ions were allowed to interact at physiological pH and their binding interactions were screened by using FT-IR spectroscopy. Spectra were collected by using hydrated films over a range of 4000–400 cm−1. The interaction was demonstrated by a significant reduction in the spectral intensities of the amide I (C=O stretching) and amide II bands (C–N stretching coupled to NH bending) of the protein after complexation with metal ions. The binding interaction was further revealed by spectral shifting of the amide I band from 1651 cm−1 (free BSA) to 1653, 1654, 1649, 1655, 1655, and 1654 cm−1 for BSA–Ca2+, BSA–Ba2+, BSA–Ag+, BSA–Ru3+, BSA–Cu2+ and BSA–Co2+ complexes, respectively. The shifting of the amide I band was due to the interactions of metal ions with the O and N atoms of the ligand protein. Estimation of the secondary protein structure showed alteration in the protein conformation, characterized by a marked decrease (12.9–40.3%) in the α-helix accompanied by increased β-sheet and β-turn after interaction with the metal ions. The interaction results of this study were comparable with those reported in our previous investigation of metal ion–BSA interactions using affinity capillary electrophoresis (ACE), which has proven the accuracy of the FT-IR technique in the measurement of interactions between proteins and metal ions.

Description: In order to detect new structural and biological patterns in a series of hetaryl-3-carboxylic acid derivatives, the optically pure (S)- and (R)-enantiomers of N-(1-arylethyl)-4-methyl- 2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxamides, their true racemates, and mechanical racemic mixtures have been synthesized in independent ways. The particular features of the 1Н- and 13С-NMR spectra of all synthesized substances, liquid chromato-mass spectrometric behavior thereof under electrospray ionization conditions, and also the results of polarimetric and X-ray diffraction studies have been discussed. Pharmacological screening on a model of carrageenan inflammation has found a clear relationship between the spatial structure of the studied objects and biological activity thereof. Enantiomers with chiral centers having (S)-configuration showed weak inhibition of pain and inflammatory reactions, while their mirror (R)-isomers exhibited very powerful analgesic and antiphlogistic properties under the same conditions, with the level of specific activity exceeding that of Lornoxicam and Diclofenac. Taking obtained data into account, a noticeable decrease in the activity of mechanical racemic mixtures, consisting of one-half of the “wrong” (S)-enantiomers, is quite natural. The true racemate of N-(1-phenylethyl)-amide proved itself in a similar way, while 4-methoxy-substituted analog thereof stood out against this background with unexpectedly high analgesic and anti-inflammatory activities. A comparative analysis of X-ray diffraction data has found that crystalline and molecular structure of racemic N-[1-(4-methoxyphenyl)ethyl]-4-methyl-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxamide is completely different from that of the original enantiomers and, moreover, very unusual for racemates. Obviously, it is the factor determining the unique character of the biological effects of the said substance.

Description: Ocular drug delivery provides a challenging opportunity to develop optimal formulations with proper therapeutic effects and acceptable patient compliance because there are many restricting factors involved, such as complex anatomical structures, defensive mechanisms, rapid drainage, and applicability issues. Fortunately, recent advances in the field mean that these problems can be overcome through the formulation of innovative ophthalmic products. Through the addition of solubility enhancer cyclodextrin derivatives and mucoadhesive polymers, the permeability of active ingredients is improved, and retention time is increased in the ocular surface. Therefore, preferable efficacy and bioavailability can be achieved. In this short review, the authors describe the theoretical background, technological possibilities, and the current approaches in the field of ophthalmology.