Sci. Pharm., Volume 88, Issue 3 (September 2020) – 11 articles

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. Full article

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. Full article

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 t_1/2 = 50.2 h. The compound Phe-MEM has also very good hydrolytic stability with t_1/2 = 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 t_1/2 = 17.8 h and t_1/2 = 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. Full article

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. Full article

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. Full article

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. Full article

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. Full article

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. Full article

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. Full article

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. Full article

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. Full article