Pharmaceutical Studies on Piperazine-Based Compounds Targeting Serotonin Receptors and Serotonin Reuptake Transporters.

Depression is a debilitating mental illness that has a significant impact on an individual's psychological, social, and physical life. Multiple factors, such as genetic factors and abnormalities in neurotransmitter levels, contribute to the development of depression. Monoamine oxidase inhibitors, tricyclic antidepressants, serotonin reuptake inhibitors (SSRIs), serotonin-noradrenaline reuptake inhibitors, and atypical and new-generation antidepressants are well-known drug classes. SSRIs are the commonly prescribed antidepressant medications in the clinic. Genetic variations impacting serotonergic activity in people can influence susceptibility to diseases and response to antidepressant therapy. Gene polymorphisms related to 5-hydroxytryptamine (5-HT) signaling and subtypes of 5-HT receptors may play a role in the development of depression and the response to antidepressants. SSRIs binding to 5-HT reuptake transporters help relieve depression symptoms. Research has been conducted to identify a biomarker for detecting depressive disorders to identify new treatment targets and maybe offer novel therapy approaches. The pharmacological potentials of the piperazine-based compounds led researchers to design new piperazine derivatives and to examine their pharmacological activities. Structure-activity relationships indicated that the first aspect is the flexibility in the molecules, where a linker of typically a 2-4 carbon chain joins two aromatic sides, one of which is attached to a piperazine/phenylpiperazine/benzyl piperazine moiety. Newly investigated compounds having a piperazine core show a superior antidepressant effect compared to SSRIs in vitro/in vivo.

Untargeted metabolomics to discriminate liver and lung hydatid cysts: Importance of metabolites involved in the immune response.

The Echinococcus granulosus sensu lato species complex is responsible for the neglected zoonotic disease known as cystic echinococcosis (CE). Humans and livestock are infected via fecal-oral transmission. CE remains prevalent in Western China, Central Asia, South America, Eastern Africa, and the Mediterranean. Approximately one million individuals worldwide are affected, influencing veterinary and public health, as well as social and economic matters. The infection causes slow-growing cysts, predominantly in the liver and lungs, but can also develop in other organs. The exact progression of these cysts is uncertain. This study aimed to understand the survival mechanisms of liver and lung CE cysts from cattle by determining their metabolite profiles through metabolomics and multivariate statistical analyses. Non-targeted metabolomic approaches were conducted using quadrupole-time-of-flight liquid chromatography/mass spectrometry (LC-QTOF-MS) to distinguish between liver and lung CE cysts. Data processing to extract the peaks on complex chromatograms was performed using XCMS. PCA and OPLS-DA plots obtained through multiple statistical analyses showed interactions of metabolites within and between groups. Metabolites such as glutathione, prostaglandin, folic acid, and cortisol that cause different immunological reactions have been identified both in liver and lung hydatid cysts, but in different ratios. Considering the differences in the metabolomic profiles of the liver and lung cysts determined in the present study will contribute research to enlighten the nature of the cyst and develop specific therapeutic strategies.

Quinazolinone-based benzenesulfonamides with low toxicity and high affinity as monoamine oxidase-A inhibitors: Synthesis, biological evaluation and induced-fit docking studies.

The research in selective monoamine oxidases (MAO-A and MAO-B) inhibitors has been increased due to their therapeutic value for neurodegenerative diseases. In this study, 4-((2-(aryl)-4-oxoquinazolin-3(4H)-yl)amino)benzenesulfonamides were synthesized and their MAOs inhibition potentials were investigated applying in vitro fluorometric technique. The most potent compounds 7 and 8 against MAO-A had IC50 values of 0.058 ± 0.002 and 0.094 ± 0.003 µM, respectively, while the reference moclobemide had an IC50 value of 6.061 µM. Compounds 7 (>1724 times) and 8 (>1063 times) more selective and reversible inhibitors of MAO-A rather than MAO-B. Toxicity studies of 7 (IC50 = 210.23 µM) and 8 (IC50 = 259.27 µM) showed that compounds can be considered as non-toxic towards SH-SY5Y cell line at their effective concentrations against MAO-A. In silico docking simulations successfully explained the observed activities and also highlighted structural water molecules to play a key role in the ligand-enzyme interactions. Calculated molecular descriptors are also obeying Lipinski's rule of five and brain/blood partition coefficients, a critical parameter in neurodegenerative diseases. These reversible inhibitors can have considerable advantages compared to irreversible inhibitors which may possess serious pharmacological side effects.

ltrafiltration-based sample preparation and HPLC-UV determination of diclofenac in human plasma samples.

The sample preparation step is the initial step in pharmaceutical analysis. While ultrafiltration is a well-known technique used in the food and pharmaceutical industries, it has rarely been used to measure the plasma concentration of active pharmaceutical ingredients. This study aimed to analyze diclofenac sodium (DS) in human plasma samples using ultrafiltration-based sample preparation before high-performance liquid chromatography (HPLC) analysis. The advantages and limitations of ultrafiltration-based sample preparation in bioanalysis were evaluated by comparing the results with conventional methods. The precipitating agent was used before ultrafiltration. The analysis was carried on an HPLC-UV system with a C18 column (250 ×4.6 mm, 5 µm) and acetonitrile : phosphate buffer (pH 3.0, 10 mM) (70 : 30 v/v) was used as the mobile phase. The bioanalytical method was validated according to FDA guidelines and applied to spiked samples of DS in commercial human plasma samples. The LOD and LOQ values were 0.006 µg mL-1 and 0.020 µg mL-1, respectively. The method was linear in the range of 0.025-0.50 µgmL-1 with excellent determination coefficients (R2 > 0.9991). The findings of this analysis with low LOD and LOQ values and high recovery values with high trueness and precision proved the matrix minimizing the effect of the presented sample preparation technique.

Evaluation of regular insulin adsorption to polypropylene bag and polyvinyl chloride infusion set.

AIM: Clinical application of insulin infusion therapy is usually accomplished with regular human insulin. It is known that the regular insulin adsorbed to the hydrophobic surfaces and different approaches were implemented into the clinical practices. It was aimed to evaluate the rate of adsorption of insulin to polypropylene (PP) bags and polyvinyl chloride (PVC) infusion sets and stability of insulin during the infusion. METHODS: A 100 IU insulin was added to PP bags containing 100 mL of 0.9% NaCl solution (n = 6). The infusion was started at a rate of 2 mL/h using infusion sets in the PVC structure. Insulin quantification was performed in the samples taken both from the bag and from the end tip of the infusion set during infusion. The stability of insulin solutions stored at room (+25°C) and refrigerator (+4°C) temperatures were compared. Samples were analysed using reverse-phase high-performance liquid chromatography. RESULTS: No statistically significant difference was found between the concentrations of the samples taken from the bags stored at room and refrigerator temperatures at the 4th, 12th, and 24th hours (P > .05). It was seen that the adsorption rate of insulin to PVC set was 57% and PP bags is at most 5% at the 24th hour. CONCLUSION: When PP bags are used for insulin infusion, it is predicted that 24-hour change can be made instead of frequent change. In addition, losses caused by the high rate of insulin adsorption to PVC infusion sets should be considered and PP infusion sets would be the better option to use if available.

Determination of the Physicochemical Properties of Piroxicam.

OBJECTIVES: The aim of this study was to determine the acid dissociation constant (pKa) of piroxicam using high performance liquid chromatography (HPLC) and ultraviolet-visible (UV-Vis) spectrophotometry, and to determine the partition coefficient (Log P), distribution coefficient (Log D), and "Log kw" values of piroxicam using HPLC. MATERIALS AND METHODS: The HPLC studies were performed on a reversed-phase ACE C18 (150x4.6 mm ID, 5 µm) column at a flow rate of 1.0 mL min-1. The detector was set to 360 nm. Log D at different pH values (3.0-6.5) was examined with a phosphate buffer (20 mM) and acetonitrile (30:70 v/v) mixture as the mobile phase. For pKa determination, HPLC studies were performed with a mixture of phosphate buffer (20 mM) and methanol within the pH range of 3.50-6.00. Log kw measurements were performed with phosphate buffer (20 mM) and MeOH (from 20:80 v/v to 10:90 v/v) mixtures within the pH range of 3.50-6.00. UV-Vis spectrophotometric pKa measurements were performed at 285 nm wavelength. RESULTS: The pKa value of piroxicam was found to be 5.3 by HPLC and 5.7 by UV-Vis spectrophotometry. Log P of piroxicam was determined as 1.58 in our experimental conditions. Log D values were 1.57, 1.57, 1.44, 1.13, and 0.46 for pH values of 3.17, 3.79, 4.44, 5.42, and 6.56, respectively. CONCLUSION: In the literature, different Log P (3.1, 2.2, and 0.6) and pKa (6.3 and 4.8) values were reported for piroxicam. The Log P (1.58) and pKa (5.3 and 5.7) values obtained for piroxicam in our study were within the range of the literature values. All these results indicate that different experimental approaches used for the determination of physicochemical properties could provide different values. Although UV spectrophotometry is easy to apply, HPLC is a unique technique for simultaneous determination of pKa, Log D, and Log P values of compounds.

Global omics strategies to investigate the effect of cyclodextrin nanoparticles on MCF-7 breast cancer cells.

Cyclodextrins (CD) are natural macrocyclic oligosaccharides linked by α(1,4) glycosidic bonds. Hydrophobic cavity of CDs are able to incorporate small molecules, ions, macromolecules which makes them excellent delegates for forming nanoparticulate carriers upon chemical modification to render amphiphilicity to CDs. In this study, blank 6OCaproßCD nanoparticle was prepared and administered to MCF-7 breast cancer cells. The effects of these nanoparticles on the cells were investigated in depth through biochemical and proteomic tests following 48 h of incubation. Proteomics studies revealed that apoptosis-related protein levels of hnRNP and CBX1 were increased while HDGF was not affected supporting the idea that 6OCaproßCD nanoparticles prevent cell proliferation. Gene expression studies were generally in correlation with protein levels since gene expression was significantly stimulated while protein levels were lower compared to the control group suggesting that a post-transcriptional modification must have occurred. Furthermore, 6OCaproßCD was observed to not trigger multidrug resistance as proved with RT-PCR that effectuates another exquisite characteristic of 6OCaproßCD nanoparticle as carrier of chemotherapeutic drugs. Metabolomic pathways of CD effect on MCF7 cells were elucidated with HMDB as serine biosynthesis, transmembrane transport of small molecules, metabolism of steroid hormones, estrogen biosynthesis and phospholipid biosynthesis. In conclusion, 6OCaproßCD is a promising nanoparticulate carrier for chemotherapeutic drugs with intrinsic apoptotic effect to be employed in treatment of breast cancer and further studies should be conducted in order to comprehend the exact mechanism of action.

Development, characterization, and in vivo assessment of mucoadhesive nanoparticles containing fluconazole for the local treatment of oral candidiasis.

This study aimed to develop a suitable buccal mucoadhesive nanoparticle (NP) formulation containing fluconazole for the local treatment of oral candidiasis. The suitability of the prepared formulations was assessed by means of particle size (PS), polydispersity index, and zeta potential measurements, morphology analysis, mucoadhesion studies, drug entrapment efficiency (EE), in vitro drug release, and stability studies. Based on the optimum NP formulation, ex vivo drug diffusion and in vitro cytotoxicity studies were performed. Besides, evaluation of the antifungal effect of the optimum formulation was evaluated using agar diffusion method, fungicidal activity-related in vitro release study, and time-dependent fungicidal activity. The effect of the optimum NP formulation on the healing of oral candidiasis was investigated in an animal model, which was employed for the first time in this study. The zeta potential, mucoadhesion, and in vitro drug release studies of various NP formulations revealed that chitosan-coated NP formulation containing EUDRAGIT(®) RS 2.5% had superior properties than other formulations. Concerning the stability study of the selected formulation, the formulation was found to be stable for 6 months. During the ex vivo drug diffusion study, no drug was found in receptor phase, and this is an indication of local effect. The in vitro antifungal activity studies showed the in vitro efficacy of the NP against Candida albicans for an extended period. Also, the formulation had no cytotoxic effect at the tested concentration. For the in vivo experiments, infected rabbits were successfully treated with local administration of the optimum NP formulation once a day. This study has shown that the mucoadhesive NP formulation containing fluconazole is a promising candidate with once-a-day application for the local treatment of oral candidiasis.

Synthesis and evaluation of antioxidant activity of new quinoline-2-carbaldehyde hydrazone derivatives: bioisosteric melatonin analogues.

Overproduction of reactive oxygen species results in oxidative stress that can cause fatal damage to vital cell structures. It is known that the use of antioxidants could be beneficial in the prevention or delay of numerous diseases associated with oxidative stress. Melatonin (MLT) is known as a powerful free-radical scavenger and antioxidant. It was found that indole ring of MLT can be employed by bioisosteric replacement by other aromatic rings. Quinoline derivatives constitute an important class of compounds for new drug development. Owing to quinoline and hydrazones appealing physiological properties and are mostly found in numerous biologically active compounds a series of quinoline-2-carbaldehyde hydrazone derivatives were synthesized as bioisosteric analogues of MLT, characterized and in vitro antioxidant activity was investigated by evaluating their reducing effect against oxidation of a redox-sensitive fluorescent probe. Cytotoxicity potential of all compounds was investigated both by lactate dehydrogenase leakage assay and by MTT assay.

Effective topical delivery systems for corticosteroids: dermatological and histological evaluations.

Atopic dermatitis (AD) is a chronic and relapsing skin disease with severe eczematous lesions. Long-term topical corticosteroid treatment can induce skin atrophy, hypopigmentation and transepidermal water loss (TEWL) increase. A new treatment approach was needed to reduce the risk by dermal targeting. For this purpose, Betamethasone valerate (BMV)/Diflucortolone valerate (DFV)-loaded liposomes (220-350 nm) were prepared and incorporated into chitosan gel to obtain adequate viscosity (∼13 000 cps). Drugs were localized in stratum corneum + epidermis of rat skin in ex-vivo permeation studies. The toxicity was assessed on human fibroblast cells. In point of in-vivo studies, pharmacodynamic responses, treatment efficacy and skin irritation were evaluated and compared with previously prepared nanoparticles. Liposome/nanoparticle in gel formulations produced higher paw edema inhibition in rats with respect to the commercial cream. Similar skin blanching effect with commercial creams was obtained via liposome in gels although they contain 10 times less drug. Dermatological scoring results, prognostic histological parameters and suppression of mast cell numbers showed higher treatment efficiency of liposome/nanoparticle in gel formulations in AD-induced rats. TEWL and erythema measurements confirmed these results. Overview of obtained results showed that liposomes might be an effective and safe carrier for corticosteroids in skin disease treatment.