Sci. Pharm., Volume 86, Issue 1 (March 2018) – 9 articles

In order to determine the regularities of the structure–analgesic activity relationship, the peculiarities of obtaining, the spatial structure, and biological properties of 4-methyl-2,2-dioxo-1H-2λ⁶,1-benzothiazine-3-carboxylic acid and some of its derivatives have been studied. Using nuclear magnetic resonance (NMR) spectroscopy and X-ray diffraction analysis, it has been proven that varying the reaction conditions using alkaline hydrolysis of methyl 4-methyl-2,2-dioxo-1H-2λ⁶,1-benzothiazine-3-carboxylate makes it possible to successfully synthesize a monohydrate of the target acid, its sodium salt, or 4-methyl-2,2-dioxo-1H-2λ⁶,1-benzothiazine. The derivatographic study of the thermal stability of 4-methyl-2,2-dioxo-1H-2λ⁶,1-benzothiazine-3-carboxylic acid monohydrate has been carried out; based on this study, the optimal conditions completely eliminating the possibility of unwanted decomposition have been proposed for obtaining its anhydrous form. It has been shown that 4-methyl-2,2-dioxo-1H-2λ⁶,1-benzothiazine is easily formed during the decarboxylation of not only 4-methyl-2,2-dioxo-1H-2λ⁶,1-benzothiazine-3-carboxylic acid, but also its sodium salt, which is capable of losing СО₂ both in rather soft conditions of boiling in an aqueous solution, and in more rigid conditions of dry heating. The NMR spectra of the compounds synthesized are given; their spatial structure is discussed. To study the biological properties of 4-methyl-2,2-dioxo-1H-2λ⁶,1-benzothiazine-3-carboxylic acid and its sodium salt, the experimental model of inflammation caused by subplantar introduction of the carrageenan solution in one of the hind limbs of white rats was used. The anti-inflammatory activity and analgesic effect were assessed by the degree of edema reduction and the ability to affect the pain response compared to the animals of control groups. According to the results of the tests performed, it has been found that after intraperitoneal injection, the substances synthesized demonstrate a moderate anti-inflammatory action and simultaneously increase the pain threshold of the experimental animals very effectively, exceeding Lornoxicam and Diclofenac in a similar dose by their analgesic activity. Full article

The herbal ball has been used as a Thai traditional medicine for relieving many diseases including acne. However, the application process of the herbal ball in practice is complicated and time consuming. The objective of this work was to utilize an herbal ball extract to formulate a gel to reach a more favorable use of the herbal ball for acne treatment. An herbal ball consisting of Andrographis paniculata, Centella asiatica, the Benchalokawichian remedy and the stem bark powder of Hesperethusa crenulata was prepared. The obtained herbal ball was steamed and squeezed to obtain the extract. Gel formulations containing the herbal ball extract at concentrations of 0.1, 1 and 5% w/w were prepared based on a carbomer gel. The herbal ball extract had antioxidant (EC₅₀ = 219.27 ± 36.98 μg/mL) and anti Propionibacterium acnes activities (minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) = 31.25 μg/mL). The 5% w/w gel formulation had antimicrobial activity against P. acnes, showing an inhibition zone value of 10.00 ± 1.00 mm. This indicates that the developed gel formulation has potential for acne treatment. In comparison to the traditional method of herbal ball usage, the application of herbal ball extract in the form of gel should be more convenient to use. Full article

Perindopril arginine and Indapamide hemihydrate in combination were proven to have a synergistic antihypertensive impact when compared with the use of each component alone. Therefore, a new Ultra-High Performance Liquid Chromatography coupled with Ultraviolet detector (UHPLC-UV) method has been developed and subsequently validated for simultaneous determination of the anti-hypertensive combination of Perindopril arginine and Indapamide hemihydrate. The separation of Perindopril arginine and Indapamide hemihydrate was achieved using a BEH C18 (1.7 μm, 2.1 × 50 mm) analytical column (Waters^® Acquity UPLC) and a mobile phase composed of 0.01% v/v formic acid in water adjusted to pH 4 with acetic acid and acetonitrile (40:60 v/v). The method was able to separate Perindopril arginine and Indapamide hemihydrate within less than 4.5 min with high accuracy, precision, resolution, and sensitivity. The content of Perindopril arginine and Indapamide hemihydrate present in the dosage form Coversyl Plus^® (5000 µg of Perindopril arginine/1250 µg of Indapamide hemihydrate) was determined in triplicate to give a concentration of 4991 µg and 1247 µg, respectively, from the manufacturer’s stated amounts with Relative Standard Deviation (%RSD) of ±0.63% for Perindopril arginine and ±0.84% for Indapamide hemihydrate. Moreover, the degradation products of the combination were elucidated by UHPLC-Quadrupole Time of Flight-Mass spectrometry (UHPLC-QToF-MS) under acidic, basic, and thermal conditions. In conclusion, the developed UHPLC-UV method was sensitive, rapid, and precise. Furthermore, forced degradation studies were performed and the degradants were identified by UHPLC-Electro-Spray Ionization-QToF (UHPLC-ESI-QToF). Full article

Apium graveolens (celery) is an edible and traditionally medicinal plant that is used worldwide, among others for the treatment of hypertension. Combining celery with antihypertensive drugs can affect the pharmacodynamics and pharmacokinetics of the latter drugs. The aim of the study is to assess the effects of administrating the celery extract on captopril pharmacokinetics. Sprague-Dawley strain rats were divided into two groups (n = 6). Group I was given captopril (10 mg/kg Body Weight (BW)) orally, while Group II was pretreated with celery extract orally (40 mg/kg BW) an hour before administration of captopril. The blood samples were withdrawn at various intervals after drug administration. The captopril concentration was determined using liquid chromatography–mass spectrometry (LC-MS/MS) and from the blood data, the values of K_e, C_max, T_max, T_1/2, and area under the curve (AUC) were calculated. The results showed that oral administration of the celery extract increased C_max (38.67%), T_1/2 (37.84%), and AUC (58.10%) and decreased K_e (27.45%) of captopril in Group II (celery + captopril) compared with Group I (captopril). In conclusion, celery extract can alter the pharmacokinetic of captopril when given in combination. The combination might be beneficial for the treatment of hypertension, as celery causes an increase in the plasma level of captopril, which can enhance its efficacy. Full article

Pinostrobin (PNS) belongs to the flavanone subclass of flavonoids which shows several biological activities such as anti-inflammatory, anti-cancerogenic, anti-viral and anti-oxidative effects. Similar to other flavonoids, PNS has a quite low water solubility. The purpose of this work is to improve the solubility and the biological activities of PNS by forming inclusion complexes with β-cyclodextrin (βCD) and its derivatives, heptakis-(2,6-di-O-methyl)-β-cyclodextrin (2,6-DMβCD) and (2-hydroxypropyl)-β-cyclodextrin (HPβCD). The A_L-type diagram of the phase solubility studies of PNS exhibited the formed inclusion complexes with the 1:1 molar ratio. Inclusion complexes were prepared by the freeze-drying method and were characterized by differential scanning calorimetry (DSC). Two-dimensional nuclear magnetic resonance (2D-NMR) and steered molecular dynamics (SMD) simulation revealed two different binding modes of PNS, i.e., its phenyl- (P-PNS) and chromone- (C-PNS) rings preferably inserted into the cavity of βCD derivatives whilst only one orientation of PNS, where the C-PNS ring is inside the cavity, was detected in the case of the parental βCD. All PNS/βCDs complexes had a higher dissolution rate than free PNS. Both PNS and its complexes significantly exerted a lowering effect on the IL-6 secretion in LPS-stimulated macrophages and showed a moderate cytotoxic effect against MCF-7 and HeLa cancer cell lines in vitro. Full article

An investigation into the biopharmaceutics classification and a study of the in vitro bioavailability (permeability and solubility) of the antiviral compound enisamium iodide (4-(benzylcarbamoyl)-1-methylpyridinium iodide) were carried out. The solubility of enisamium iodide was determined in four different buffers. Apparent intestinal permeability (P_app) of enisamium iodide was assessed using human colon carcinoma (Caco-2) cells at three concentrations. The solubility of enisamium iodide in four buffer solutions from pH 1.2 to 7.5 is about 60 mg/mL at 25 °C, and ranges from 130 to 150 mg/mL at 37 °C, depending on the pH. Based on these results, enisamium iodide can be classified as highly soluble. Enisamium iodide demonstrated low permeability in Caco-2 experiments in all tested concentrations of 10–100 μM with permeability coefficients between 0.2 × 10⁻⁶ cm s⁻¹ and 0.3 × 10⁻⁶ cm s⁻¹. These results indicate that enisamium iodide belongs to class III of the Biopharmaceutics Classification System (BCS) due to its high solubility and low permeability. The bioavailability of enisamium iodide needs to be confirmed in animal and human studies. Full article

The objective of this research is to generate leads for developing our ultimate poly-active molecules with utility in central nervous system (CNS) diseases. Indeed, poly-active molecules capable of mitigating brain free radical damage while enhancing acetylcholine signaling (via cholinesterase inhibition) are still being sought for combating Alzheimer’s disease (AD). We differentiate “poly-active” agents from “multi-target” ones by defining them as single molecular entities designed to target only specific contributory synergistic pharmacologies in a disease. For instance, in AD, free radicals either initiate or act in synergy with other pharmacologies, leading to disease worsening. For this preliminary report, a total of 14 (i.e., 4,5-dimethoxy-2-nitrobenzohydrazide plus 1-(1-benzylpiperidin-4-yl)ethan-1-one) derivatives were synthesized and screened, in silico and in vitro, for their ability to scavenge free radicals and inhibit acetylcholinesterase (AChE)/butyrylcholinesterase (BuChE) enzymes. Overall, six derivatives (4a, 4d, 4e, 4f, 4g, 9b) exhibited potent (>30%) antioxidant properties in the oxygen radical absorbance capacity (ORAC) assay. The antioxidant values were either comparable or more potent than the comparator molecules (ascorbic acid, resveratrol, and trolox). Only three compounds (4d, 9a, 9c) yielded modest AChE/BuChE inhibitions (>10%). Please note that a SciFinder substance data base search confirmed that most of the compounds reported herein are new, except 9a and 9c which are also commercially available. Full article

The aim of this study was to develop and validate a fast and simple reversed-phase HPLC method for simultaneous determination of four cardiovascular agents—atorvastatin, simvastatin, telmisartan and irbesartan in bulk drugs and tablet oral dosage forms. The chromatographic separation was accomplished by using Symmetry C18 column (75 mm × 4.6 mm; 3.5 μ) with a mobile phase consisting of ammonium acetate buffer (10 mM; pH 4.0) and acetonitrile in a ratio 40:60 v/v. Flow rate was maintained at 1 mL/min up to 3.5 min, and then suddenly changed to 2 mL/min till the end of the run (7.5 min). The data was acquired using ultraviolet detector monitored at 220 nm. The method was validated for linearity, precision, accuracy and specificity. The developed method has shown excellent linearity (R² > 0.999) over the concentration range of 1–16 µg/mL. The limits of detection (LODs) and limits of quantification (LOQs) were in the range of 0.189–0.190 and 0.603–0.630 µg/mL, respectively. Inter-day and intra-day accuracy and precision data were recorded in the acceptable limits. The new method has successfully been applied for quantification of all four drugs in their tablet dosage forms with percent recovery within 100 ± 2%. Full article