Volumen 70 (2020): Edición 4 (December 2020)

Piperazine derivatives are a group of compounds with a psychostimulant effect. They are an alternative to illegal drugs. They are being searched for recreational use due to their psychoactive and hallucinogenic effects. The high popularity of these compounds can be noticed all over the world due to easy purchase, lack of legal regulations and incorrect assessment of the safety of use. The recreational use of piperazine derivatives can often result in chronic and acute health problems and additionally with unpredictable remote effects. It is also common to take mixtures of psychoactive compounds. This hinders the correct diagnosis and treatment of patients with poisoning. The presented work is an illustration of the wide problem of piperazine derivatives abuse. The health effects and the possibility of identifying these compounds in preparations and biological material are described.

This article presents an overview of using process analytical technology in monitoring the roller compaction process. In the past two decades, near-infrared spectroscopy, near-infrared spectroscopy coupled with chemical imaging, microwave resonance technology, thermal effusivity and various particle imaging techniques have been used for developing at-, off-, on- and in-line models for predicting critical quality attributes of ribbons and subsequent granules and tablets. The common goal of all these methods is improved process understanding and process control, and thus improved production of high-quality products. This article reviews the work of several researchers in this field, comparing and critically evaluating their achievements.

Offering a systematic and multivariate analysis of the analytical procedure, development and validation of HPLC methods using Quality by Design approach are in the limelight of current research trends. A new, experimental design-aided HPLC method for fampridine was developed and preliminarily validated according to current in-force international guidelines for linearity, accuracy, robustness and precision.

The method offers a high throughput sample analysis, with an elution time of 2.9 minutes, and signal detection without excipient interference performed at 262 nm. The method proved to be linear between 1–15 µg mL⁻¹ (R²= 0.9996). The mean recovery was found to be 98.7 ± 1.9 % in the tested range of 2.5–7.5 µg mL⁻¹. Low RSD values (< 1 %) were obtained for both model, intra- and inter-day precision. The limit of detection and limit of quantification were 0.24 and 0.78 µg mL⁻¹, resp. The method proved to be applicable for active substance assay in a pharmaceutical dosage form.

The aim of this work is to improve the solubility and bioavailability of chlortetracycline and the function of the immune response. Chlortetracycline bisulfate and chlortetracycline mesylate were successfully synthesized and characterized with several techniques, including spectroscopy, chromatography and mass spectrometry, which demonstrated that the C₄-dimethylamino group of chlortetracycline can accept a proton from sulfuric acid and methanesulfonic acid to form the corresponding salts. In addition, chlortetracycline bisulfate and chlortetracycline mesylate were more soluble in water than chlortetracycline hydrochloride, but the antibacterial activity was not enhanced. The influences of chlortetracycline hydrochloride, chlortetracycline bisulfate and chlortetracycline mesylate on chlortetracycline and immunoglobulin concentrations in mouse serum were also investigated. These results suggested that the chlortetracycline bisulfate and chlortetracycline mesylate have good bioavailability and strong immune response and have potential applications in animal breeding and formulation technologies.

The synthesis of new N-(5-substituted-1,3,4-thiadiazol-2-yl)-2-[(5-(substituted amino)-1,3,4-thiadiazol-2-yl)thio]acetamide derivatives and investigation of their anticancer activities were the aims of this work. All the new compounds’ structures were elucidated by elemental analyses, IR, 1H NMR, ¹³C NMR and MS spectral data. Anticancer activity studies of the compounds were evaluated against MCF-7 and A549 tumor cell lines. In addition, with the purpose of determining the selectivity of cytotoxic activities, the most active compound was screened against a noncancer NIH3T3 cell line (mouse embryonic fibroblast cells). Among the tested compounds, compound 4y (N-(5-ethyl-1,3,4-thiadiazol-2-yl)-2-((5-(p-tolylamino)-1,3,4-thiadiazol-2-yl)thio)acetamide), showed promising cytotoxic activity against MCF7 cancer cell with an IC₅₀value of 0.084 ± 0.020 mmol L⁻¹ and against A549 cancer cell with IC₅₀ value of 0.034 ± 0.008 mmol L⁻¹, compared with cisplatin. The aromatase inhibitory activity was evaluated for compound 4y on MCF-7 cell line showing promising activity with IC₅₀ of 0.062 ± 0.004 mmol L⁻¹.

Cisplatin-induced nephrotoxicity limits its anticancer effectiveness, thus this study’s aim was to assess the potential modulatory effect of perindopril on cisplatin-induced nephrotoxicity and to elucidate the possible underlying mechanisms. Renal dysfunction was induced in mice by a single injection of cisplatin (10 mg kg⁻¹, i.p.) and perindopril was administered orally (2 mg kg⁻¹, once daily) for 5 days. Perindopril remarkably ameliorated cisplatin-induced perturbations in renal histology, renal levels of tumor necrosis factor-alpha, interleukin-6 and interleukin-10, apoptosis-regulating protein expressions (Bax and Bcl2), and partially normalized Bax to Bcl2 ratio and active caspase 3 protein expression. Conversely, perindopril had no significant effect on cisplatin-induced elevations in serum creatinine and urea, microalbuminuria, kidney to body weight ratio, lipid peroxidation marker, superoxide dismutase and catalase activities and reduced glutathione content. In conclusion, perindopril may be safely used with cisplatin in mice since it ameliorated cisplatin-induced histopathological changes, inflammation and apoptosis without affecting renal biomarkers or oxidative stress.

A variety of commonly used hydrogels were utilized in the preparation of calcium alginate beads, which incorporate the chronobiotic hormone melatonin (MLT). The in vitro release of the hormone in aqueous media at pH 1.2 and 6.8 was probed in the conjunction with the swelling of the beads and their thermal degradation properties. It has been found that the release of MLT from the beads was reversibly proportional to the extent of their expansion, which depends on the molecular mass/viscosity of the biopolymers present in the beads; the higher the molecular mass/viscosity of the hydrogels the greater the beads swelling and the less the MLT’s release. Thermogravimetric analysis (TGA) data support the presence of the components in the hybrid hydrogel beads and elucidate their effects on the thermal stability of the systems. Thus, the physicochemical properties of the biopolymers used, along with their stereoelectronic features modulate the release of MLT from the beads, providing formulations able to treat sleep onset related problems or dysfunctions arising from poor sleep maintenance.

This study aims to evaluate the effect of protocatechuic acid (PCA) on human hair follicle melanocytes (HFM). Normal primary HFM were isolated and cultured till logarithmic period of second passage, then treated with different concentrations of PCA (0.1–200 μmol L⁻¹) to study the cell proliferation, melanin contents, tyrosinase activity and protein and mRNA expression of melanogenic genes (tyrosinase-related protein 1 (TRP-1), tyrosinase-related protein 2 (TRP-2), and microphthalmia-associated transcription factor (MITF)) in the cultured HFM. In addition, we have also measured the contents of superoxide dismutase (SOD) and glutathione (GSH) in PCA treated HFM. Vitamin C was used as a positive control. The result showed that PCA can decrease the synthesis of melanin and the tyrosinase activity with IC₅₀ = 8.9 μmol L⁻¹ and IC₅₀ = 6.4 μmol L⁻¹, respectively, at the treatment time of 24 hours, without inducing any cytotoxicity in HFM cells. In addition, the mRNA transcription and protein expression levels of TRP-1, TRP-2 and MITF significantly decreased with a dose-dependent manner after 24-hour PCA treated in HFM cells. Furthermore, PCA has significantly increased the SOD and GSH activity in a dose-dependent manner for 24-hour PCA treatment. This study suggested that PCA has an inhibitory effect on the production of melanin through down-regulation of the expression of melanogenesis-related protein and the effect of anti-oxidation, which could be useful for the therapy of melanin overproduction or skin whitening.

Spilanthes acmella Murr., popularised as toothache plant, is a well-known culinary and medicinal plant for different purposes, but its use as an anthelmintic is apparently exclusive to the Mizo people of India and Myanmar. A chloroform extract of Spilanthes acmella Murr. was analysed in a single quadrupole GC-MS system, from which it was found that the major compound was an alkylamide, N-isobutyl-(2E,4Z,8Z,10E)-dodecatetraenamide. A comparative study was performed on the anthelmintic activity of the plant extract and praziquantel (PZQ) against an intestinal cestode, Raillietina echinobothrida. In terms of efficacy, PZQ was more potent, but the plant extract was also effective at all concentrations tested. PZQ caused severe shrinkage and folds of the tegument, constriction of the suckers, dislocation of spines and erosion of microtriches. The plant extract caused shrinkage and folds on the main body but not on the scolex. Damage on the suckers is more pronounced than in PZQ-treated cestodes. The spines were completely removed. The current findings indicate that S. acmella is a good source of compounds with anthelmintic activity.

Pyrazolone-based derivative metal complexes were reported to have cytotoxicity in some tumor cells. In this study, the antitumor effect of [Cu(PMPP-SAL)(EtOH)] (PMPP-SAL = N-(1-phenyl-3-methyl-4-propenylidene-5-pyrazolone)- salicylidene hydrazide anion) in murine melanoma B16 cells in vitro and in vivo was investigated. The results showed that [Cu(PMPP-SAL)(EtOH)] inhibited the survival of B16 cells in vitro, and the IC₅₀ value was superior to cisplatin (DDP) (p < 0.001). B16 cell apoptosis was significantly higher in comparison to the control group (DMSO) (p < 0.01), and cell cycle arrest occurred at the G0/G1 phase. When challenged C57 BL/6J mice were treated with [Cu(PMPPSAL)(EtOH)], a smaller volume of B16 solid tumors were reported than the control group (p < 0.01), with lower positive expression indices of CD 34, vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) (p < 0.01). Moreover, the tumor growth was suppressed in mice due to the induction of apoptosis, as detected by the TUNEL assay (p < 0.001). In summary, [Cu(PMPP-SAL)(EtOH)] effectively inhibited the growth of B16 cells in vitro and in vivo due to the induction of apoptosis and the inhibition of intra-tumoral angiogenesis, demonstrating its therapeutic potential in melanoma treatment.