Experimental and theoretical studies of Ficus religiosa as green corrosion inhibitor for mild steel in 0.5 M H2SO4 solution

Corrosion inhibition analysis and adsorption behaviour of Ficus religiosa fruits extract for mild steel in 0.5 M H₂SO₄ solution has been inquired utilizing scanning electron microscopy (SEM), atomic force microscopy (AFM), gravimetric measurements, electrochemical impendence spectroscopy (EIS), potentiodynamic polarization techniques, Ultraviolet-visible spectroscopy (UV–vis.), Fourier-transform infrared spectroscopy (FT-IR) and quantum chemical calculations. Electrochemical investigation and gravimetric estimations say that the fruits extract of Ficus religiosa shows the most extreme inhibition efficiency of 92.26% at 500 mg/L. The appearance of Myricetin, Serotonin and Campesterol as major phytochemical constituents in the extract of Ficus religiosa, decrease the corrosion rate of mild steel in acidic media. The adsorption of this extract obeys the Langmuir adsorption isotherm. Due to the presence of heteroatoms and aromatic rings in the major components of Ficus religiosa, it can serve as an effective corrosion inhibitor for mild steel corrosion in 0.5 M H₂SO₄.     

Effect of hydroalcoholic extract of leaves of Colocasia esculenta on marble-burying behavior in mice: Implications for obsessive–compulsive disorder

Abstract

Context: Over the past decades, the inhibition of spontaneous burying of glass marbles by mice has been used as an index of anxiolytic drug action in the so-called marble-burying test. Although Colocasia esculenta Linn. (Araceae), commonly known as elephant ear (English), possesses several medicinal properties, little is known for its use in neurological activity.

Objective: The current research evaluated the anti-obsessive–compulsive disorder (anti-compulsive) activity of the hydroalcoholic extract of leaves of Colocasia esculenta (HECE) for the first time using the marble-burying behavior test in mice.

Materials and methods: In the present study, the effect of HECE (25 and 50?mg/kg) intraperitoneally (i.p.) was examined using the marble-burying behavior test, which is an animal model of obsessive compulsive disorder (OCD), using Swiss albino mice.

Results and discussion: The acute toxicity studies showed that the LD₅₀ value of the HECE in mice was 1000?mg/kg by i.p. route. The effect of HECE (25 and 50?mg/kg, i.p.) was characterized by significant reduction in the number of buried marbles as compared with the control group (p?<?0.001). The effect of HECE was comparable with that of fluoxetine (5?mg/kg, i.p.) – a reference standard drug used in the treatment of obsessive–compulsive disorder (p?<?0.001). Fluoxetine and HECE do not produce any overt motor dysfunction.

Conclusions: The results of the study for the first time show that the plant possesses anti-compulsive activity, confirming the traditional claims. Future research should focus on the identification and the anti-compulsive activity of the constituents from this plant.     

Possible mechanisms of action of the aqueous extract of Artocarpus altilis (breadfruit) leaves in producing hypotension in normotensive Sprague–Dawley rats

Context and objectives: Artocarpus altilis (Parkinson) Fosberg (Moraceae) (breadfruit) leaves are used as an antihypertensive remedy. We investigated the possible mechanisms of action of its aqueous extract and its effect on cytochromes P450 (CYP) enzyme activities.

Materials and methods: Intravenous administration of an aqueous leaf extract (20.88–146.18 mg/kg) of A. altilis on mean arterial pressure and heart rate were recorded via cannulation of the carotid artery on anaesthetized normotensive Sprague–Dawley rats. Recordings of the contractile activity of the aortic rings to the extract (0.71–4.26 mg/mL) were studied using standard organ bath techniques. Inhibitions of human CYP3A4 and CYP2D6 enzyme activities were evaluated by means of a fluorometric assay in 96 well plates using heterologously expressed microsomes.

Results: A. altilis caused significant (p < 0.05) hypotensive and bradycardiac responses unaffected by atropine (2 mg/kg) and mepyramine (5 mg/kg), but attenuated by propranolol (1 mg/kg) and N(G)-nitro-l-arginine methyl ester (5 mg/kg). The extract (0.71–4.26 mg/mL) significantly (p < 0.05) relaxed phenylephrine (10^?9–10^?4 M) and 80 mM KCl-induced contractions in endothelium intact and denuded aortic rings; and caused a significant (p < 0.05) rightward shift of the Ca²⁺ dose-response curves in Ca²⁺-free Kreb’s solution. Moderate inhibitions of cytochrome P450s (CYP3A4 and CYP2D6) enzyme activities with IC₅₀ values of 0.695 ± 0.187 and 0.512 ± 0.131 mg/mL, respectively, were produced.

Conclusion: A. altilis exhibits negative chronotropic and hypotensive effects through α-adrenoceptor and Ca²⁺ channel antagonism. Drug adversity effects are unlikely if the aqueous leaf extract is consumed with other medications reliant on CYP3A4 and CYP2D6 metabolism. This study thus provides scientific evidence for the use of the breadfruit in the treatment of hypertension.     

Production of nZVI–Cl nanocomposite as a novel eco–friendly adsorbent for efficient As(V) ions removal from aqueous media: Adsorption modeling by response surface methodology

By combination of the nano zero–valent iron (nZVI) nanoparticles and clinoptilolite (Cl) natural zeolite and by chemical reduction method, the nZVI–Cl nanocomposite was produced. The physical and chemical characteristics of the produced nanocomposite were examined using FE–SEM, EDX, VSM and zeta potential analyses and its fine structure was confirmed. The produced nanocomposite was applied for efficient As(V) heavy metal ions removal from aqueous media as a novel eco–friendly adsorbent. The adsorption process was optimized using a minimum number of designed experiments by Design–Expert software using central composite design (CCD) and response surface methodology (RSM) and the adsorption optimum conditions were determined as solution pH of 4, nZVI–Cl dosage of 1 g L^?1 and As(V) concentration of 50 mg L^?1 by the numerical optimization of the software. In these conditions, the removal efficiency was 88.10% and desirability parameter was 0.986. The adsorption kinetic study showed that the chemisorption effectively controls the adsorption process by a better fit of pseudo–second order model with the experimental data. The adsorption isotherms study demonstrated that the Langmuir model had the best fit with the experimental data, proving homogeneous surface of nZVI–Cl adsorbent and monolayer adsorption of As(V) ions on it. The adsorption thermodynamic study illustrated that the adsorption is thermodynamically spontaneous and exothermic in nature. Also, the adsorbent reusability test verified the adsorbent stability after five consecutive adsorption–desorption cycles without a tangible reduction in removal efficiency.     

Impulsivity as a moderator of the intention–behavior relationship for illicit drug use in patients undergoing treatment

Introduction

Evident across clinical practice and clinical trials is a divergence between stated intentions and subsequent drug-related behaviors in substance abuse treatment settings. Impulsivity, itself related to drug abuse, may be one variable which may moderate the degree of disconnect in the intention–behavior relationship. The present study examines the relationship between self-stated desire to quit, impulsivity, and drug use in a group of outpatients receiving methadone maintenance treatment. In particular, we examined the direct and moderating influence of different facets of impulsivity (urgency, lack of premeditation, sensation seeking, and lack of perseverance) on drug use in the context of a stated desire to abstain from drugs.

Method

84 opioid-dependent individuals undergoing counseling and methadone maintenance treatment completed a battery of self-report questionnaires including measures of impulsivity (UPPS Impulsivity Scale), stated desire to quit, and past 30-day drug use. We hypothesized that two facets of impulsivity, urgency and (lack of) premeditation, would moderate the relationship between desire to quit and past 30-day drug use, such that the relationship between intention and behavior would be weaker in those with high levels of these facets of impulsivity.

Results

Consistent with the disconnect between intentions and drug-use behaviors typical of treatment settings, desire to quit was not directly associated with self-reported past month drug use. However, in separate regression analyses, 2 facets of impulsivity, premeditation and sensation seeking, moderated the relationship between desire to quit and past month use. Whereas there was not a significant relationship between desire to quit and drug use in individuals high in sensation-seeking or lack of premeditation, the relationship between intention and drug use behaviors was preserved in those low in these facets of impulsivity.

Conclusion

These findings indicate that the relationship between desire to quit and self-reported past-month drug use is weak for those high in sensation seeking or low in premeditation. These results are discussed in the context of current interventions for substance dependence.     

Exposure–response for biomarkers of anticoagulant effects by the oral direct thrombin inhibitor AZD0837 in patients with atrial fibrillation

AimsAZD0837 is a novel oral anticoagulant investigated in clinical studies for stroke prevention in patients with atrial fibrillation (AF). It is bioconverted to its active form, AR‐H067637, a potent, specific and reversible thrombin inhibitor. The effects on coagulation biomarkers were correlated with the pharmacokinetic (PK) exposure of AR‐H067637 to guide selection of the effective dose regimen for a confirmatory efficacy study in AF patients.MethodsBlood samples were obtained from 601 AF patients randomized to one of four doses of AZD0837 (blinded treatment) or dose‐adjusted vitamin K antagonists (VKA, open treatment) for 3–9 months. A pharmacodynamic model was developed to describe the time course of the AR‐H067637 exposure dependent effects and the effect of VKA on fibrin D‐dimer. The thrombin generation measured ex vivo in venous plasma was also investigated.ResultsThe PK exposure of AR‐H067637 was stable with an interindividual variability of 33% and no or minor influence of patient demographics or comedications. For AZD0837, D‐dimer levels decreased with more rapid onset than for VKA. The decrease in D‐dimer levels correlated with steady‐state plasma concentrations (C _ss) of AR‐H067637, with a maximum decrease of baseline D‐dimer levels estimated to approximately 60% for both AZD0837 and VKA therapy. The effect on thrombin generation correlated closely with the plasma concentration of AR‐H067637.ConclusionsThe effects on thrombin generation and fibrin D‐dimer levels correlated with the plasma concentration of its active form and provided comparable effects to well‐controlled VKA therapy at an exposure at least corresponding to the 300 mg once daily dose of AZD0837.     

Insight into the pharmacokinetic behavior of tanshinone IIA in the treatment of Crohn’s disease: comparative data for tanshinone IIA and its two glucuronidated metabolites in normal and recurrent colitis models after oral administration

1.?Previous reports implied that tanshinone IIA (TSA) may offer potential benefits for Crohn’s disease (CD). However, the detailed pharmacokinetic behavior of TSA in the treatment of colitis remain unclear. Herein, a recurrent trinitrobenzene sulfonic acid (TNBS)-colitis mouse model was used to investigate whether TSA possesses favorable pharmacokinetic and colonic distribution profiles to serve as a candidate drug.

2.?Although the systemic TSA exposures were low (AUC_0–t approximately 330?ng*h/ml) in both the normal and colitis models after oral administration TSA 20?mg/kg, high levels of TSA were found in the gastrointestinal tract (GI). Such a GI exposure of TSA in colitis mice is adequate to exert anti-inflammatory effects as observed in various in vitro studies.

3.?Interestingly, colonic TSA exposure in the colitis mouse model was much lower than that in the normal mice, which may be explained by a significant upregulation of colonic UDP-glucuronosyltransferase (Ugt)1a9 expression and a higher plasma concentration of TSA glucuronides in the model mice at 0.5, 1 and 2?h after TSA administration.

4.?Together, these results reveal high accumulation at the site of inflammation and minimal systemic concentration of TSA, which are favorable pharmacokinetic behaviors to meet the requirements for CD treatment.     

Ritonavir is the best alternative to ketoconazole as an index inhibitor of cytochrome P450-3A in drug–drug interaction studies

Aims

The regulatory prohibition of ketoconazole as a CYP3A index inhibitor in drug–drug interaction (DDI) studies has compelled consideration of alternative inhibitors.

Methods

The biomedical literature was searched to identify DDI studies in which oral midazolam (MDZ) was the victim, and the inhibitory perpetrator was either ketoconazole, itraconazole, clarithromycin, or ritonavir. The ratios (R_AUC) of total area under the curve (AUC) for MDZ with inhibitor divided by MDZ AUC in the control condition were aggregated across individual studies for each inhibitor.

Results

Mean (± SE) R_AUC values were: ketoconazole (15 studies, 131 subjects), 11.5 (±1.2); itraconazole (five studies, 48 subjects), 7.3 (±1.0); clarithromycin (five studies, 73 subjects), 6.5 (±10.9); and ritonavir (13 studies, 159 subjects), 14.5 (±2.0). Differences among inhibitors were significant (F = 5.31, P < 0.005). R_AUC values were not significantly related to inhibitor dosage or to duration of inhibitor pre-exposure prior to administration of MDZ.

Conclusions

Ritonavir produces CYP3A inhibition equivalent to or greater than ketoconazole, and is the best index CYP3A inhibitor alternative to ketoconazole. Cobicistat closely resembles ritonavir in structure and function, and can also be considered. Itraconazole and clarithromycin are not suitable alternatives since they do not produce inhibition comparable with ketoconazole or ritonavir, and have other significant disadvantages as well.     

Development of a LC–MS/MS method for the determination of antrodin B and antrodin C from Antrodia camphorata extract in rat plasma for pharmacokinetic study

A selective and sensitive liquid chromatography–tandem mass spectrometry (LC–MS/MS) method was developed and validated for the determination of antrodin B and antrodin C in rat plasma. Both target compounds, together with the internal standard (diazepam), were extracted from rat plasma samples by liquid–liquid extraction with ethyl acetate. Chromatographic separation was carried out on an Agilent XDB-C₈ column with an isocratic mobile phase consisting of acetonitrile and water (70:30, V/V) at a flow rate of 0.5 mL/min. The mass spectrometric detection was performed by selected reaction monitoring (SRM) mode via atmospheric pressure chemical ionization (APCI) source operating in positive ionization mode. The assay exhibited a linear dynamic range of 47.6–4760 ng/mL for antrodin B and 56.6–5660 ng/mL for antrodin C. The intra- and inter-day precision was less than 5.3% and the accuracy was less than 2.7% for both analytes. The validated method has been applied to the pharmacokinetic study of antrodin B and antrodin C in rats following oral administration of Antrodia camphorata extract.     

The multivalent activity of the tissue factor–thrombin pathway in thrombotic and non-thrombotic disorders as a target for therapeutic intervention

Importance of the field: Tissue factor (TF) is the key initiator of the coagulation cascade. The exposure of subendothelial TF after vessel injury to blood is a critical step in hemostasis and in the pathogenesis of arterial and venous thrombotic disorders. Moreover, an additional role for TF overexpression and subsequent generation of TF:FVIIa complex, FXa and thrombin have been recently emerged, contributing in non-thrombotic manifestations such as inflammation, cancer growth and fibrosis.

Areas covered in this review: The multivalent role of TF and the above mentioned proteases in disease is reviewed, with focus on their implication in non-thrombotic disorders, as suggested by clinical and experimental data. Moreover, potential therapeutic interventions using anticoagulation agents are discussed.

What the reader will gain: A better understanding of the pathogenic role of the TF–thrombin pathway in the pathogenesis of disease and the effect of anticoagulants in the treatment of such disorders.

Take home message: The TF-thrombin pathway, apart from the initiation of hemostasis and thrombosis, exert intracellular signaling activity through protease-activated receptors, participating in inflammation and tumor biology. Both low-molecular-weight heparins and recently developed anticoagulants rise as candidates for the modification of biological functions associated with disorders like sepsis, ischemia–reperfusion or cancer growth and metastasis.     

Mixed-effect circadian rhythm model for human erythrocyte acetylcholinesterase activity—application to the proof of concept of cholinesterase inhibition by acorn extract in healthy subjects with galantamine as positive control

Purpose  

The aim of this study was to develop a non-linear mixed effect circadian rhythm model of acetylcholinesterase (AChE) activity variation and to evaluate the inhibitory effect of acorn extract (2 g) and galantamine (16 mg), used as positive control, on human AChE in red blood cells (RBC).     

The use of partially porous particle columns for the routine,generic analysis of biological samples for pharmacokinetic studies in drug discovery by reversed-phase ultra-high performance liquid chromatography–tandem mass spectrometry

Recent years have seen the introduction of new high performance liquid chromatography (HPLC) instruments and columns that are capable of achieving high resolution, high speed liquid chromatographic separations at back pressures up to 1000 bar, so-called ultra-high performance liquid chromatography (UHPLC). Ultra-high performance liquid chromatography coupled to tandem mass spectrometry (UHPLC–MS/MS) is gaining widespread use for this purpose, and for this approach to be successful a generically applicable, robust column is required. Here, data are presented showing the robustness of a partially porous 2.7 μm diameter particle material in this application and the accuracy and precision of an assay for a typical pharmaceutical in plasma. This stationary phase material is evaluated for performance and compared with other materials frequently used for similar analyses using a test mix currently used routinely in our laboratories to assess the performance of UHPLC–MS/MS systems. The partially porous material demonstrates similar resolving power to sub-2 μm materials under the ballistic gradient chromatography conditions employed and exhibits excellent resilience over the analysis of thousands of protein precipitated plasma extracts. It is suggested that this stationary phase material can be an invaluable tool in generic, high throughput assays for pharmaceutical bioanalysts.     

A validated method for the quantification of IOX-2, a potent prolyl hydroxylase inhibitor in equine urine and plasma using liquid chromatography–high-resolution mass spectrometry

IOX-2 is a potent inhibitor of enzyme prolyl hydroxylases-2 (PHD) that plays a critical role in regulating hypoxia inducible factor (HIF) abundance and oxygen homeostasis. Federation for Equestrian Sports has listed HIF activators as prohibited substances to prevent their usage in doping. Consequently, it became essential to develop adequate knowledge and testing methods to detect it in equine sports drug testing samples. The validated method utilizes ultra-high-performance liquid chromatography coupled to high-resolution mass spectrometry in order to detect extremely low concentration of the analyte present in both matrices. Confirmation for the presence of the analyte was achieved by comparing ion ratios, retention time, and accurate mass. Method linear range for plasma was between 0.25 to 100 ng/ml, and limit of detection (LOD) was 0.075 ng/ml. The linear range for urine was 0.125 to 100 ng/ml, and LOD was 0.025 ng/ml. Intraday precision at 0.5, 10, and 50 ng/ml was between 4.0% and 9.7% for plasma and 4.2% and 10.4% for urine. Accuracy at 0.5, 10, and 50 ng/ml was between 91% and 94% for plasma and 99% and 103% for urine. Elimination profile of IOX-2 in equine plasma and urine was carried out using the developed method in which two horses were intravenously administered IOX-2 and samples were collected. Metabolic profile in plasma and urine was investigated. IOX-2 was detected for a minimum of 54 and 151 h of post administration in plasma and urine, respectively, thereby providing a valuable tool for evaluating its misuse in equine racing.