In vitro and in vivo modulatory effects of fluoxetine on gene expression and antioxidant enzymes in CFA-induced chronic inflammatory model: drug repurposing for arthritis.

Fluoxetine, being a selective serotonin uptake inhibitor, has been broadly used to modulate the neurotransmission of serotonin in the central nervous system. Fluoxetine performs a number of crucial central nervous system-related tasks, including neuroprotective effects against microglial neurotoxicity and protecting oxidative cell damage produced by stress in a variety of stress-related unfavourable health disorders. Studies have shown that the drug (fluoxetine) also has analgesic and anti-inflammatory characteristics in addition to its other basic benefits. Furthermore, existing treatment approaches (NSAIDs, DMARDs, corticosteroids and other immunosuppressants) for RA have limited effects on chronic immunological models. These facts served as the basis for carrying out a study on fluoxetine to explore its therapeutics in a chronic inflammatory rat model called Freund's complete adjuvant (FCA)-induced arthritis. The therapeutic effect of the fluoxetine in FCA-induced arthritic rats was assessed by paw volume, paw diameter, arthritic index and body weight at specific days through the experiment of 28 days. These findings were further co-investigated by haematological, biochemical parameters and radiographic imaging at the end of experiment. Furthermore, the modulatory effects on gene expression (NF-κB, PGE2, COX2, INF-γ, IL-4 and IL-10) and antioxidant properties were gritty using qRT-PCR and ELISA kits, respectively, in experimental arthritic rats. Fluoxetine at 10, 20 and 40 mg/kg doses reduced (p < 0.001) the serum concentration of C-reactive protein and rheumatoid factor as well as suppressed the expression of PGE2, NF-kB, COX2 and INF-γ when compared to arthritic control. Moreover, fluoxetine (at higher doses) caused significant rise of IL-4 and IL-10. These findings supported the anti-inflammatory and antioxidant potential of fluoxetine in chronic inflammatory model and endorsed it for clinical trials.

Enhanced Intestinal Permeability of Cefixime by Self-Emulsifying Drug Delivery System: In-Vitro and Ex-Vivo Characterization.

BACKGROUND: Cefixime (CFX) belongs to a group of third-generation cephalosporin antibiotics with low water solubility and low intestinal permeability, which ultimately leads to significantly low bioavailability. AIM: This study aimed to increase solubility, improve drug release, and intestinal permeability of CFX by loading into SEDDS. METHODS: Suitable excipients were selected based on drug solubility, percent transmittance, and emulsification efficiency. Pseudo-ternary phase diagram was fabricated for the identification of effective self-emulsification region. The best probably optimized formulations were further assessed for encumbered drug contents, emulsification time, cloud point measurement, robustness to dilution, mean droplet size, zeta potential, polydispersity index (PDI), and thermodynamic and chemical stability. Moreover, in vitro drug release studies and ex vivo permeation studies were carried out and apparent drug permeability Papp of different formulations was compared with the marketed brands of CFX. RESULTS: Amongst the four tested SEDDS formulations, F-2 formulation exhibited the highest drug loading of 96.32%, emulsification time of 40.37 ± 3 s, mean droplet size of 19.01 ± 1.12 nm, and demonstrated improved long-term thermodynamic and chemical stability when stored at 4 °C. Release studies revealed a drug release of 97.32 ± 4.82% within 60 min in simulated gastric fluid. Similarly, 97.12 ± 5.02% release of CFX was observed in simulated intestinal fluid within 120 min; however, 85.13 ± 3.23% release of CFX was observed from the marketed product. Ex vivo permeation studies displayed a 2.7-fold increase apparent permeability compared to the marketed product in 5 h. CONCLUSION: Owing to the significantly improved drug solubility, in vitro release and better antibacterial activity, it can be assumed that CFX-loaded SEDDS might lead to an increased bioavailability and antibacterial activity, possibly leading to improved therapeutic effectiveness.

Mucoadhesive, Fluconazole-Loaded Nanogels Complexed with Sulfhydryl-ß-cyclodextrin for Oral Thrush Treatment.

The objective of this study was to generate fluconazole-loaded mucoadhesive nanogels to address the problem of hydrophobicity of fluconazole (FL). An inclusion complex was formulated with sulfhydryl-ß-CD (SH-ß-CD) followed by nanogels formation by a Schiff base reaction of carbopol 940 (CA-940) and gelatin (GE). For characterization, PXRD, FT-IR analysis, drug content, and phase solubility studies were performed. Similarly, nanogels were assessed for particle size, zeta potential, organoleptic, and spreadability studies. Moreover, drug contents, rheological, in vitro drug permeation, release kinetics, toxicity, and stability studies of nanogels were performed. Furthermore, mucoadhesive characteristics over the buccal mucosal membrane of the goat were evaluated. The nanogels formulated with a higher amount of CA-940 and subsequently loaded with the inclusion complexes of FL showed promising results. PXRD and FT-IR analysis confirmed the physical complexes by displaying a reduction in the intensity of peaks of FL. The average particle size of nanogels was in the range of 257 to 361 nm. The highest drug content of 88% was encapsulated within the FL-SH-ß-CD complex. All formulations at 0.5-1% concentration displayed no toxicity to the Caco-2 cell lines. Nanogels loaded with FL-SH-ß-CD complexes showed 18-fold improved mucoadhesion on the buccal mucous membrane of the goat when compared to simple nanogels. The in vitro permeation study exhibited significantly enhanced permeation and first-order concentration-dependent drug release was observed. On the bases of these findings, we can conclude that a mucoadhesive nanogel-based drug delivery system can be an ideal therapy for candidiasis.

Anti-rheumatic activity of pseudoephedrine (a substituted phenethylamine) in complete Freund's adjuvant-induced arthritic rats by down regulating IL-1ß, IL-6 and TNF-α as well as upregulating IL-4 and IL-10.

Pseudoephedrine (substituted phenethylamine) is well known as psychotic and bronchodilator. Numerous studies on phenethylamine derivatives indicated that these agents have the potential to abolish inflammatory responses in the non-biological and biological systems. These facts provided the basis to conduct a study on pseudoephedrine to explore its therapeutics in Complete Freund's Adjuvant (CFA)-induced arthritis. Furthermore, existing treatment approaches for RA associated with limited effect on chronic immunological models. Real-time polymerase chain reaction (q-PCR) was performed to execute the expression of pro and anti-inflammatory cytokines in treated and non-treated arthritic rats. These findings were further co investigate by histological observations. The paw volume, paw diameter, weight variations and arthritic score were determined at specific days throughout the experiment of 28 days. Pseudoephedrine at all doses significantly (p < 0.001) suppressed the expression of PGE2, TNF-α, IL-1ß and IL-6. Moreover, pseudoephedrine (20 and 40 mg/kg) caused significant augmentation of IL-4 and IL-10. Similarly, the drug expressed a significant anti-arthritic effect by reducing the paw volume, paw diameter and arthritic score. Similarly, it also reverts the reduction in body weight of arthritic rats at all above-mentioned doses. These findings supported the anti-arthritic potential of pseudoephedrine and recommended it for clinical trials.

Venlafaxine demonstrated anti-arthritic activity possibly through down regulation of TNF-α, IL-6, IL-1ß, and COX-2.

Venlafaxine is a serotonin-norepinephrine reuptake inhibitor used to treat depression. Previous studies demonstrated its anti-nociceptive and anti-inflammatory activities through the suppression of pro-inflammatory cytokines. Present research aimed to explore its anti-arthritic potential. Different in-vitro assays including egg albumin, bovine serum albumin denaturation and human red blood cell (RBC) membrane stabilization assays along with in-vivo models of formaldehyde and complete Freund's adjuvant-induced arthritis were used to study its anti-arthritic effect. Venlafaxine inhibited egg albumin and bovine serum albumin denaturation and preserve the integrity of red blood cells membrane in concentration-dependent manner. In formaldehyde-induced arthritis venlafaxine significantly (p < 0.001) reduced the paw edema on treatment for 10 days. Chronic administration of venlafaxine for 28 days in Freund's adjuvant-induced arthritis model decreased the paw volume (p < 0.001), arthritic index (p < 0.01), flexion pain score (p < 0.05), mobility score (p < 0.05), and improved the stance score (p < 0.05). Venlafaxine also significantly declined the rheumatoid factor (p < 0.01) and C-reactive protein (p < 0.05) levels and increased the RBC count (p < 0.01) and Hb value (p < 0.001). Upon PCR analysis venlafaxine remarkably turndown the mRNA expression of TNF-α, IL-6, IL-1ß, and COX-2. Taken together it is inferred from current findings that venlafaxine possesses the significant anti-arthritic activity and could be a potential therapeutic option for the treatment of rheumatoid arthritis.

Lipophilic Arginine Esters: The Gateway to Preservatives without Side Effects.

This study hypothesized that long carbon chain cationic arginine (Arg) esters can be considered as toxicologically harmless preservatives. Arg-esters with C18 and C24 carbon chains, namely, arginine-oleate (Arg-OL) and arginine-decyltetradecanoate (Arg-DT), were synthesized. Structures were confirmed by FT-IR, 1H NMR, and mass spectroscopy. Both Arg-esters were tested regarding hydrophobicity in terms of log Poctanol/water, critical micelle concentration (CMC), biodegradability, cytotoxicity, hemolysis, and antimicrobial activity against Escherichiacoli (E. coli), Staphylococcusaureus (S. aureus), Bacillussubtilis (B. subtilis), and Enterococcusfaecalis (E. faecalis). Log Poctanol/water of arginine was raised from -1.9 to 0.3 and 0.6 due to the attachment of C18 and C24 carbon chains, respectively. The critical micelle concentration of Arg-OL and Arg-DT was 0.52 and 0.013 mM, respectively. Both Arg-esters were biodegradable by porcine pancreatic lipase. In comparison to the well-established antimicrobials, benzalkonium chloride (BAC) and cetrimide, Arg-esters showed significantly less cytotoxic and hemolytic activity. Both esters exhibited pronounced antimicrobial properties against Gram-positive and Gram-negative bacteria comparable to that of BAC and cetrimide. The minimum inhibitory concentration (MIC) of Arg-esters was <50 µg mL-1 against all tested microbes. Overall, results showed a high potential of Arg-esters with long carbon chains as toxicologically harmless novel preservatives.

Thiolated PVP-Amphotericin B Complexes: An Innovative Approach toward Highly Mucoadhesive Gels for Mucosal Leishmaniasis Treatment.

The aim of this study was to synthesize polymeric excipients that can form mucoadhesive hydrogels containing amphotericin B (AmB) for the treatment of mucosal leishmaniasis. 2-(2-Acryloylaminoethyldisulfanyl)-nicotinic acid (ACENA) was copolymerized with N-vinyl pyrrolidone to obtain thiolated polyvinylpyrrolidone (PVP) that was then complexed with AmB to improve its solubility. The resulting structure of thiolated PVP was evaluated by 1H nuclear magnetic resonance to confirm S-protected thiol groups, and the average molecular mass was determined by size exclusion chromatography. Moreover, variants of thiolated PVP-AmB were studied for the thiol content, amount of complexed AmB, cytotoxicity, mucoadhesive properties, and antileishmaniasis activity. The highest achieved degree of thiolation was 772 ± 24.64 µmol/g, and the amount of complexed AmB was 27.05 ± 0.31 µmol per g of polymer. Thiolated PVP and thiolated PVP-AmB variants (0.5% m/v) showed no cytotoxicity, whereas the equivalent concentration of free AmB reduced Caco-2 cell viability to 70% within 24 h. Thiol-functionalized PVP and PVP-AmB complexes displayed 7.66- and 7.20-fold higher adhesion to the mucosal surface in comparison to unmodified PVP and PVP-AmB, respectively. In addition, variants of thiolated PVP-AmB complexes displayed 100% antileishmaniasis activity in comparison to the 80% killing efficiency of Fungizone, which has been applied in the equivalent AmB concentration of 0.2 µg/mL. Thiol-functionalized PVP proved to be a promising novel excipient for the delivery of AmB providing enhanced solubility and improved mucoadhesive properties which are beneficial for the treatment of mucosal leishmaniasis.

Compatibility analysis of bergapten with different pharmaceutical excipients used in nanostructured lipid carriers.

In pharmaceuticals sciences, Fourier-transform infrared spectroscopy (FTIR) is a very useful technique to measure the compatibility and interaction between ingredients, therefore in the current study, compatibility of bergapten with different excipients was analyzed via FTIR. Nanostructured lipid carriers (NLCs) are the second generation of lipid nanocarriers and very useful for the drug delivery systems. Nanoparticles (NPs) were prepared by a nanotemplate engineering technique and scanning of pure drug, individual ingredients and, physical mixtures of different ingredients was carried out. The characteristic peak of the carboxylic groups of bergapten is shifted from 3088.1 cm-1 to 3399.3 cm-1 due to formulation development and it confirmed that it was properly incorporated into the formulation. Other peaks of the drug were also present in formulation with minor shortening/broadening of peaks. The resulted peaks of IR spectra depicted that the ingredients used in the formulation had no considerable interaction and were found compatible with each other.

Investigating the in-vitro bioactivity, biodegradability and drug release behavior of the newly developed PES/HA/WS biocompatible nanocomposites as bone graft substitute.

The nucleation of carbonate-containing apatite on the biomaterials surface is regarded as a significant stage in bone healing process. In this regard, composites contained hydroxyapatite (Ca10(PO4)6(OH)2, HA), wollastonite (CaSiO3, WS) and polyethersulfone (PES) were synthesized via a simple solvent casting technique. The in-vitro bioactivity of the prepared composite films with different weight ratios of HA and WS was studied by placing the samples in the simulated body fluid (SBF) for 21 days. The results indicated that the the surface of composites containing 2 wt% HA and 4 wt% WS was completely covered by a thick bone-like apatite layer, which was characterized by Grazing incidence X-ray diffraction, attenuated total reflectance-Fourier transform infrared spectrometer, field emission electron microscopy and energy dispersive X-ray analyzer (EDX). The degradation study of the samples showed that the concentration of inorganic particles could not influence the degradability of the polymeric matrix, where all samples expressed similar dexamethasone (DEX) release behavior. Moreover, the in-vitro cytotoxicity results indicated the significant cyto-compatibility of all specimens. Therefore, these findings revealed that the prepared composite films composed of PES, HA, WS and DEX could be regarded as promising bioactive candidates with low degradation rate for bone tissue engineering applications.

Surface Engineering of Magnetic Iron Oxide Nanoparticles for Breast Cancer Diagnostics and Drug Delivery.

Data published in 2020 by the International Agency for Research on Cancer (IARC) of the World Health Organization show that breast cancer (BC) has become the most common cancer globally, affecting more than 2 million women each year. The complex tumor microenvironment, drug resistance, metastasis, and poor prognosis constitute the primary challenges in the current diagnosis and treatment of BC. Magnetic iron oxide nanoparticles (MIONPs) have emerged as a promising nanoplatform for diagnostic tumor imaging as well as therapeutic drug-targeted delivery due to their unique physicochemical properties. The extensive surface engineering has given rise to multifunctionalized MIONPs. In this review, the latest advancements in surface modification strategies of MIONPs over the past five years are summarized and categorized as constrast agents and drug delivery platforms. Additionally, the remaining challenges and future prospects of MIONPs-based targeted delivery are discussed.

Development and Characterization of Thiolated Cyclodextrin-Based Nanoparticles for Topical Delivery of Minoxidil.

PURPOSE: The aim of this research was to prepare adhesive nanoparticles for the topical application of Minoxidil (MXD). METHODS: Thiolated ß-CDs were prepared via conjugation of cysteamine with oxidized CDs. MXD was encapsulated within thiolated and unmodified ß-CDs. Ionic gelation method was used to prepare nanoparticles (Thio-NP and blank NP) of CDs with chitosan. Nanoparticles were analyzed for size and zetapotential. Inclusion complexes were characterized via FTIR. Drug dissolution studies were carried out. An in vitro adhesion study over human hair was performed. An in vivo skin irritation study was performed. Ex vivo drug uptake was evaluated by using a Franz diffusion cell. RESULTS: Thiolated ß-CDs presented 1804.68 ± 25 µmol/g thiol groups and 902.34 ± 25 µmol/g disulfide bonds. Nanoparticles displayed particle sizes within a range of 231 ± 07 nm to 354 ± 13 nm. The zeta potential was in the range of -8.1 ± 02 mV, +16.0 ± 05 mV. FTIR analyses confirmed no interaction between the excipients and drug. Delayed drug release was observed from Thio-NP. Thio-NP retained over hair surfaces for a significantly longer time. Similarly, drug retention was significantly improved. Thio-NP displayed no irritation over rabbit skin. CONCLUSION: Owing to the above results, nanoparticles developed with MXD-loaded thiolated ß-CDs might be a potential drug delivery system for topical scalp diseases.

Safety and Pharmaceutical Evaluation of a Novel Natural Polymer, Ocicum, as Solubility and Dissolution Enhancer in Solid Dispersion.

Plant mucilages are commonly employed as excipients in pharmaceutical manufacturing. Ocimum basilicum (Lamiaceae family), a source of hydrophilic mucilage referred herein as Ocicum, was evaluated for the solubility enhancer of a model drug, aceclofenac, in solid dispersions prepared using different methods. Polymer was extracted from O. basilicum and solid dispersions of aceclofenac were fabricated with Ocicum or Poloxamer 407 using polymer-to-drug ratios of 1:1, 1:2 and 1:3 utilizing solvent evaporation, lyophilization and melt methods. Ocicum was evaluated for its safety via acute toxicity study including different biochemical and hematological parameters including liver and kidney profiles. Moreover, different characterization studies including melting-point, Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), scanning electron microscopy (SEM), differential scanning calorimetry (DSC) and differential thermal analysis (TGA) were used for evaluation of polymer and solid dispersions. Furthermore, solubility and dissolution studies were performed to confirm solubility enhancement. Ocicum was found to be safer, and different characterization studies confirmed the purity of the compounds. In addition, Ocicum exhibited up to 6.27-fold enhanced solubility as compared to pure aceclofenac; similarly, 4.51-fold increased solubility by the synthetic polymer in their respective solid dispersions was shown. Furthermore, Ocicum-based solid dispersions showed substantial improvement in dissolution of aceclofenac. Therefore, it can be concluded from the above-mentioned results that Ocicum might be used as an economical natural oral delivery carrier alternative to the synthetic polymers.

Reduction of Hepatic Steatosis, Oxidative Stress, Inflammation, Ballooning and Insulin Resistance After Therapy with Safranal in NAFLD Animal Model: A New Approach.

INTRODUCTION: Non-alcoholic fatty liver disease (NAFLD) is intimately linked to hepatic steatosis, inflammation, insulin resistance (IR), oxidative stress (OS), and ballooning. A high fat diet (HFD) is considered a major etiological factor that primarily covers the numerous features of NAFLD. METHODS: The present study aimed to evaluate the protective effect of safranal on hepatic steatosis, OS, liver index, IR index, liver function enzymes, plasma lipids, TNF-α, malondialdehyde (MDA), advanced oxidation protein products (AOPPs) and nitrite (NO2 -) levels in a NAFLD rat model fed with a HFD for 12 weeks. The ELISA kits were used to measure TNF-α and insulin in serum and plasma, respectively. RESULTS: HFD significantly induced hepatic steatosis, OS, IR, liver, and oxidative enzyme elevation and inflammation in experimental animals. Rats treated with safranal in ascending order of doses 250 and 500 mg/kg orally for 4-weeks showed a reduction in hepatic lipid's accumulation, liver index, hepatic enzymes, collagen, hepatic oxidonitrative stress markers (like AOPP, MDA and NO2 -), and raised the levels of catalase (CAT) and superoxide dismutase (SOD) enzymes. Glutathione system components, namely glutathione (GSH), glutathione peroxidase (GPx), and glutathione-S-transferase (GST) levels were also restored in the safranal-treated groups. The reduction in serum TNF-α and IR provided further support to the anti-NAFLD effect of safranal. Moreover, the histopathological images indicated reverse of NAFLD activity score (NAS) through mild fatty degeneration, ballooning and inflammation in hepatocytes of treated groups. CONCLUSION: Findings of blood and tissue analysis concluded that safranal can be a good choice in the management and cure of NAFLD.

In-depth drug delivery to tumoral soft tissues via pH responsive hydrogel.

A pH responsive nanoparticle-hydrogel hybrid drug delivery system was investigated for in-depth anticancer drug delivery to solid tumours. It consists of acid susceptible polymer nanoparticles loaded in a chitosan hydrogel. The hybrid formulation was characterized by UV-visible spectroscopy, FTIR, SEM, TEM, particle size analysis, zeta potential measurement and viscosity measurement. Drug encapsulation and nanoparticle loading efficiencies were found to be 48% and 72% respectively which describes the efficient interaction of the chemical entities in this hybrid drug delivery system. The hydrogel exhibited pH responsive behaviour: minimal drug and nanoparticle release at physiological pH but an increase in viscosity under acidic conditions and fast nanoparticle and drug release. The cytotoxicity of the drug loaded hydrogel was investigated against the MCF-7 breast cancer cell line along with the drug and nanoparticles without hydrogel. The drug loaded hydrogel showed a better cytotoxic effect on MCF-7 cancer cells. Thus, drug loaded nanoparticles containing hydrogel could be a better option for maximum drug distribution in tumours.

Nano-Formulation Based Intravesical Drug Delivery Systems: An Overview of Versatile Approaches to Improve Urinary Bladder Diseases.

Intravesical drug delivery is a direct drug delivery approach for the treatment of various bladder diseases. The human urinary bladder has distinctive anatomy, making it an effective barrier against any toxic agent seeking entry into the bloodstream. This screening function of the bladder derives from the structure of the urothelium, which acts as a semi-permeable barrier. However, various diseases related to the urinary bladder, such as hyperactive bladder syndrome, interstitial cystitis, cancer, urinary obstructions, or urinary tract infections, can alter the bladder's natural function. Consequently, the intravesical route of drug delivery can effectively treat such diseases as it offers site-specific drug action with minimum side effects. Intravesical drug delivery is the direct instillation of medicinal drugs into the urinary bladder via a urethral catheter. However, there are some limitations to this method of drug delivery, including the risk of washout of the therapeutic agents with frequent urination. Moreover, due to the limited permeability of the urinary bladder walls, the therapeutic agents are diluted before the process of permeation, and consequently, their efficiency is compromised. Therefore, various types of nanomaterial-based delivery systems are being employed in intravesical drug delivery to enhance the drug penetration and retention at the targeted site. This review article covers the various nanomaterials used for intravesical drug delivery and future aspects of these nanomaterials for intravesical drug delivery.

Protective Effect of Butanolic Fraction of Delphinium brunonianum on Fructose-Mediated Metabolic Alterations in Rats.

The present study was conducted with an intent to evaluate the protective effect of butanolic fraction of Delphinium brunonianum on fructose mediated metabolic abnormalities in rats. Rats in all groups except control group were fed on 10% fructose for 6 weeks; however, rats in the treated group also received butanolic fraction for the last 3 weeks, along with the fructose. Moreover, phytoconstituents present in butanolic fraction were analyzed using LC-MS. All doses of butanolic fraction profoundly reduce the fructose-induced blood pressure, sympathetic over-activity, and weight gain. Furthermore, butanolic fraction prominently reduces the glucose intolerance and hyperinsulinemia in fructose-fed rats. On treatment with butanolic fraction, oxidative enzymes and the functionality of the aorta was also restored. Phytochemical analysis revealed the presence of several active constituents including bergenin, scopolin, rutinoside, kaempferol, coumaric acid, apigenin, and gingerol. In conclusion, butanolic fraction of Delphinium brunonianum has the potential to prevent and recover the fructose-induced metabolic perturbations.

Antihypertensive and Vasorelaxant Effects of Citrus aurantifolia Linn. Fruit: Proposed Mechanisms.

Background: Citrus aurantifolia Linn. fruit, a natural dietary item, has long been used traditionally to treat hypertension in Pakistan. The current research work aims to explore the effect on blood pressure and its mechanisms. Methods: The aqueous methanol extract of plant fruit was used to evaluate hypotensive/antihypertensive, vasorelaxation, and safety profiles. Moreover, the in vitro inhibitory effect of AMECA on phosphodiesterase was also evaluated. Results: In hypotensive studies, extracts of Citrus aurantifolia fruit exhibited a concentration-dependent reduction in SBP, DBP, MAP, and heart rate. A similar effect has been observed on anesthetized rats, but the effects exerted by the extract were not altered significantly in the presence of L-NAME, atropine, captopril, and propranolol. Moreover, in coronary arteries, the extract significantly potentiated relaxations induced by cGMP- and cAMP-dependent relaxing agonists. When exposed to PDEs, the extract concentration dependently subdued cGMP-hydrolyzing activity of different PDEs with IC50 values of 40-130 µg/mL. Conclusion: It is conceivable that extracts obtained from Citrus aurantifolia fruit produced hypotensive and antihypertensive effects in rats. The extract elicited endothelium-independent vasorelaxation, possibly by acting directly on smooth muscles of the coronary artery and by increasing cGMP and cAMP via nonselective inhibition of vascular PDEs.

Ex vivo, in vitro, and in silico approaches to unveil the mechanisms underlying vasorelaxation effect of Mentha Longifolia (L.) in porcine coronary artery.

OBJECTIVE: Mentha (M.) longifolia (L.) is traditionally used for various ailments. The current study was intended to explore the underlying vasorelaxation mechanisms of M. longifolia. MATERIAL AND METHODS: Aqueous-methanol extract from the aerial parts of M. longifolia was prepared and subjected to activity-guided fractionation. The vasorelaxant activity was performed using porcine coronary arteries with intact and denuded endothelium. In-vitro PDE inhibitory activity of the active fraction was carried out using the radio-enzymatic assay. The active fraction was also subjected to GCMS. Docking and molecular dynamic simulation studies were also performed RESULT: We had observed that aqueous-methanolic extract induced relaxation in the coronary artery in a dose-dependent manner when the endothelium was intact and denuded. n-butanol fraction (MLB) has produced a maximum effect, and it was selected for mechanistic studies. MLB has significantly enhanced the relaxation produced by cAMP and cGMP, elevating atrial natriuretic peptide, sodium nitroprusside, isoproterenol, and forskolin. The pre-treatment with MLB inhibited the contractile response produced by KCl, U46619, and CaCl2 in without endothelium rings. MLB has non-selectively inhibited the PDE isoforms. GCMS analysis of MLB has revealed the presence of menthol, thymol, and carvacrol in the active fraction. Docking and molecular dynamic simulation studies have indicated that thymol can be a competitive inhibitor for PDE1. CONCLUSION: It is postulated that an n-butanol fraction of Mentha longifolia produced endothelium-independent relaxation due to increased levels of cAMP and cGMP caused by the inhibition of various PDEs.

RETRACTED: Potential of ephedrine to suppress the gene expression of TNF-α, IL-1ß, IL-6 and PGE2: A novel approach towards management of rheumatoid arthritis.

This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/our-business/policies/article-withdrawal). This article has been retracted at the request of the Editor-in-Chief. A reader reported that Figure 9 of the above paper contains similar section with Figure 4 of another article authored by the same group in Inflammopharmacology, 29, (2021) 1119-1129, https://doi.org/10.1007/s10787-021-00840-9, and part of the Figure 9 of the above paper is used in Figure 9 of another article authored by the same group in Inflammopharmacology, 29, (2021) 673­682, https://doi.org/10.1007/s10787-021-00804-z. The journal requested the authors to explain the repeated use of the image and provide the raw data. However, the authors were not able to fulfill this request and therefore the Editor-in-Chief has decided to retract the article.

Impact of pharmacist-led interventions in improving adherence to glaucoma medications in the geriatric population.

OBJECTIVES: Geriatric patients can be non-adherent to ophthalmic glaucoma medications because of complex eye drops instillation techniques and forgetfulness, so pharmacists can play their part in improving the clinical outcomes of patients by acting as care providers. The purpose of the current study was to implement various pharmacist-led interventions to improve adherence to glaucoma medications and to evaluate the outcomes of interventions in the geriatric population. METHODS: The Morisky Green Levine (MGL) adherence scale was used for analysis because it measures the extent of non-adherence and analyses the reasons for it. The interview-based sessions were conducted with control and interventional groups followed by educational interventions, including techniques for eye drop instillation, graphical images, precautionary measures, and individual patient counselling for the interventional group. Patients were asked to complete the adherence scale after the conclusion of every follow-up session for a duration of 6 months. RESULTS: After 6 months of pharmacist-led interventions, a significant shift was found in the interventional group from low to high adherence according to MGL scale evaluation. Moreover, the number of patients in the interventional group whose intraocular pressure was in the safe range significantly increased and follow-up sessions significantly improved the patient's knowledge about glaucoma. CONCLUSION: The results of this pharmacist-led educational interventional study showed it was effective in improving adherence to glaucoma medications in the geriatric patients, who showed better adherence scores and improved intraocular pressure.