Scientia Pharmaceutica — Open Access Journal

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. Full article

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. Full article

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. Full article

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. Full article

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. Full article

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. Full article

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. Full article

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. Full article

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. Full article

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. Full article

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. Full article

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. Full article

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. Full article

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. Full article

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 C_max, AUC_0–t, AUC_0–∞, T_max, and T_half 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. Full article

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 AUC_0–4h and AUC_0–12h 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. Full article

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. Full article

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. Full article