scholarly journals Study of Melatonin as Preventive Agent of Gastrointestinal Damage Induced by Sodium Diclofenac

Cells ◽  
2020 ◽  
Vol 9 (1) ◽  
pp. 180 ◽  
Author(s):  
Aroha B. Sánchez ◽  
Beatriz Clares ◽  
María J. Rodríguez-Lagunas ◽  
María J. Fábrega ◽  
Ana C. Calpena
Keyword(s):  
Side Effects ◽  
Redox State ◽  
Ex Vivo ◽  
Inhibitory Effect ◽  
Experimental Models ◽  
In Vivo Studies ◽  
Histological Evaluation ◽  
Sodium Diclofenac ◽  
Cox 2

Safety profile of nonsteroidal anti-inflammatory drugs (NSAIDs) has been widely studied and both therapeutic and side effects at the gastric and cardiovascular level have been generally associated with the inhibitory effect of isoform 1 (COX-1) and 2 (COX-2) cyclooxygenase enzymes. Now there are evidences of the involvement of multiple cellular pathways in the NSAIDs-mediated-gastrointestinal (GI) damage related to enterocyte redox state. In a previous review we summarized the key role of melatonin (MLT), as an antioxidant, in the inhibition of inflammation pathways mediated by oxidative stress in several diseases, which makes us wonder if MLT could minimize GI NSAIDs side effects. So, the aim of this work is to study the effect of MLT as preventive agent of GI injury caused by NSAIDs. With this objective sodium diclofenac (SD) was administered alone and together with MLT in two experimental models, ex vivo studies in pig intestine, using Franz cells, and in vivo studies in mice where stomach and intestine were studied. The histological evaluation of pig intestine samples showed that SD induced the villi alteration, which was prevented by MLT. In vivo experiments showed that SD altered the mice stomach mucosa and induced tissue damage that was prevented by MLT. The evaluation by quantitative reverse transcription PCR (RT-qPCR) of two biochemical markers, COX-2 and iNOS, showed an increase of both molecules in less injured tissues, suggesting that MLT promotes tissue healing by improving redox state and by increasing iNOS/NO that under non-oxidative condition is responsible for the maintenance of GI-epithelium integrity, increasing blood flow and promoting angiogenesis and that in presence of MLT, COX-2 may be responsible for wound healing in enterocyte. Therefore, we found that MLT may be a preventive agent of GI damages induced by NSAIDs.

Phenolic Acids Exert Anticholinesterase and Cognition-Improving Effects

2018 ◽  
Vol 15 (6) ◽  
pp. 531-543 ◽  
Author(s):  
Dominik Szwajgier ◽  
Ewa Baranowska-Wojcik ◽  
Kamila Borowiec
Keyword(s):  
Phenolic Acids ◽  
Ex Vivo ◽  
Amyloid Β ◽  
Inhibitory Effect ◽  
In Vivo Studies ◽  
Amyloid Β Peptide ◽  
Beneficial Effects ◽  
Aβ Fibrils

Numerous authors have provided evidence regarding the beneficial effects of phenolic acids and their derivatives against Alzheimer's disease (AD). In this review, the role of phenolic acids as inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) is discussed, including the structure-activity relationship. In addition, the inhibitory effect of phenolic acids on the formation of amyloid β-peptide (Aβ) fibrils is presented. We also cover the in vitro, ex vivo, and in vivo studies concerning the prevention and treatment of the cognitive enhancement.

scholarly journals Inhibition of Carrageenan-Induced Acute Inflammation in Mice by Oral Administration of Anthocyanin Mixture from Wild Mulberry and Cyanidin-3-Glucoside

2013 ◽  
Vol 2013 ◽  
pp. 1-10 ◽  
Author(s):  
Neuza Mariko Aymoto Hassimotto ◽  
Vanessa Moreira ◽  
Neide Galvão do Nascimento ◽  
Pollyana Cristina Maggio de Castro Souto ◽  
Catarina Teixeira ◽  
...  
Keyword(s):  
Polymorphonuclear Leukocytes ◽  
Acute Inflammation ◽  
Biological Activities ◽  
Inhibitory Effect ◽  
Experimental Models ◽  
Protein Levels ◽  
Paw Oedema ◽  
Cox 2

Anthocyanins are flavonoids which demonstrated biological activities inin vivoandin vitromodels. Here in the anti-inflammatory properties of an anthocyanin-enriched fraction (AF) extracted from wild mulberry and the cyanidin-3-glucoside (C3G), the most abundant anthocyanin in diet, were studied in two acute inflammation experimental models, in the peritonitis and in the paw oedema assays, both of which were induced by carrageenan (cg) in mice. In each trial, AF and C3G (4 mg/100 g/animal) were orally administered in two distinct protocols: 30 min before and 1 h after cg stimulus. The administration of both AF and C3G suppresses the paw oedema in both administration times (P<0.05). In the peritonitis, AF and C3G reduced the polymorphonuclear leukocytes (PMN) influx in the peritoneal exudates when administered 1 h after cg injection. AF was more efficient reducing the PMN when administered 30 min before cg. Both AF and C3G were found to suppress mRNA as well as protein levels of COX-2 upregulated by cg in both protocols, but the inhibitory effect on PGE2production in the peritoneal exudates was observed when administered 30 min before cg (P<0.05). Our findings suggest that AF and C3G minimize acute inflammation and they present positive contributions as dietary supplements.

scholarly journals In Silico, Ex Vivo and In Vivo Studies of Roflumilast as a Potential Antidiarrheal and Antispasmodic agent: Inhibition of the PDE-4 Enzyme and Voltage-gated Ca++ ion Channels

Molecules ◽  
2020 ◽  
Vol 25 (4) ◽  
pp. 1008 ◽  
Author(s):  
Najeeb Ur Rehman ◽  
Mohd Nazam Ansari ◽  
Abdul Samad
Keyword(s):  
In Silico ◽  
Ex Vivo ◽  
In Silico Analysis ◽  
Inhibitory Effect ◽  
In Vivo Studies ◽  
Dependent Manner ◽  
Ca Channels ◽  
Response Curves ◽  
Concentration Dependent Manner

The aim of the present study was to evaluate the possible gut inhibitory role of the phosphodiesterase (PDE) inhibitor roflumilast. Increasing doses of roflumilast were tested against castor oil-induced diarrhea in mice, whereas the pharmacodynamics of the same effect was determined in isolated rabbit jejunum tissues. For in silico analysis, the identified PDE protein was docked with roflumilast and papaverine using the Autodock vina program from the PyRx virtual screening tool. Roflumilast protected against diarrhea significantly at 0.5 and 1.5 mg/kg doses, with 40% and 80% protection. Ex vivo findings from jejunum tissues show that roflumilast possesses an antispasmodic effect by inhibiting spontaneous contractions in a concentration-dependent manner. Roflumilast reversed carbachol (CCh, 1 µM)-mediated and potassium (K+, 80 mM)-mediated contractile responses with comparable efficacies but different potencies. The observed potency against K+ was significantly higher in comparison to CCh, similar to verapamil. Experiments were extended to further confirm the inhibitory effect on Ca++ channels. Interestingly, roflumilast deflected Ca++ concentration–response curves (CRCs) to the right with suppression of the maximum peak at both tested doses (0.001-0.003 mg/mL), similar to verapamil. The PDE-inhibitory effect was authenticated when pre-incubation of jejunum tissues with roflumilast (0.03-0.1 mg/mL) produced a leftward deflection of isoprenaline-mediated inhibitory CRCs and increased the tissue level of cAMP, similar to papaverine. This idea was further strengthened by molecular docking studies, where roflumilast exhibited a better binding affinity (-9.4 kcal/mol) with the PDE protein than the standard papaverine (-8.3 kcal/mol). In conclusion, inhibition of Ca++ channels and the PDE-4 enzyme explains the pharmacodynamics of the gut inhibitory effect of roflumilast.

Dopamine D3 receptor binding by D3 agonist 7-OH-DPAT (7-hydroxy-dipropylaminotetralin) and antipsychotic drugs measured ex vivo by quantitative autoradiography

1999 ◽  
Vol 78 (1) ◽  
pp. 7-11
Author(s):  
Yasusuke Kaichi ◽  
Ryo-ichi Nonaka ◽  
Yoko Hagino ◽  
Masayuki Watanabe
Keyword(s):  
Side Effects ◽  
Receptor Binding ◽  
Antipsychotic Drugs ◽  
Ex Vivo ◽  
Inhibitory Effect ◽  
Potent Inhibitory Effect ◽  
Ex Vivo Autoradiography ◽  
Dopamine D3 ◽  
Rat Nucleus Accumbens

Because the dopamine D3 receptor is primarily expressed in regions of the limbic system of brain, it was proposed that it may represent a target for antipsychotic drugs that is free of extrapyramidal side effects. An ex vivo receptor binding technique employing [3H]7-OH-DPAT was used to evaluate in vivo occupancy of dopamine D3 receptors in the rat nucleus accumbens by selective D3 agonist 7-OH-DPAT (7-hydroxy-dipropylaminotetralin) and various antipsychotic drugs. With an ID50 value of 0.07 mg/kg, the selective D3 agonist (+)-7-OH-DPAT had the most potent inhibitory effect on ex vivo binding of [3H]7-OH-DPAT among all drugs tested. Clinical doses of phenothiazine drugs, such as chlorpromazine and levomepromazine, induce binding to D3 receptors in vivo, while atypical antipsychotic drugs, such as clozapine, pimozide, and sulpiride, are very weak in inhibiting ex vivo binding of [3H]7-OH-DPAT, indicating that the role of D3 receptors as targets of antipsychotic drugs free of extapyramidal side effects may not be important.Key words: dopamine D3 receptor, ex vivo autoradiography, antipsychotic drugs, 7-OH-DPAT (7-hydroxy-dipropylaminotetralin).

A Comparative Ex Vivo Study of Plasminogen Activators and Proteases for Fibrinolytic Activity and Side Effects in Rabbits

1977 ◽  
Vol 37 (01) ◽  
pp. 154-161 ◽  
Author(s):  
B. A Janik ◽  
S. E Papaioannou
Keyword(s):  
Side Effects ◽  
Effective Dose ◽  
Fibrinolytic Activity ◽  
Ex Vivo ◽  
Plasminogen Activators ◽  
Assay System ◽  
Coagulation Parameters ◽  
Ex Vivo Assay

SummaryUrokinase, streptokinase, Brinase, trypsin, and SN 687, a bacterial exoprotease, have been evaluated in an ex vivo assay system. These enzymes were injected into rabbits and the fibrinolytic activity as well as other coagulation parameters were measured by in vitro techniques. Dose-response correlations have been made using the euglobulin lysis time as a measure of fibrinolytic activity and the 50% effective dose has been determined for each enzyme. Loading doses, equal to four times the 50% effective dose, were administered to monitor potential toxicity revealing that Brinase, trypsin, and SN 687 were very toxic at this concentration.Having established the 50% effective dose for each enzyme, further testing was conducted where relevant fibrinolytic and coagulation parameters were measured for up to two days following a 50% effective dose bolus injection of each enzyme. Our results have demonstrated that urokinase and streptokinase are plasminogen activators specifically activating the rabbit fibrinolytic system while Brinase, trypsin and SN 687 increase the general proteolytic activity in vivo.The advantages of this ex vivo assay system for evaluating relative fibrinolytic potencies and side effects for plasminogen activators and fibrinolytic proteases have been discussed.

Ex Vivo Inhibition of Platelet Aggregation in Patients with Severe Limb Arteriopathy Treated with BAY U3405, a Specific IX A2 Receptor Antagonist

1994 ◽  
Vol 72 (05) ◽  
pp. 659-662 ◽  
Author(s):  
S Bellucci ◽  
W Kedra ◽  
H Groussin ◽  
N Jaillet ◽  
P Molho-Sabatier ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
Ex Vivo ◽  
Randomized Study ◽  
In Vivo Studies ◽  
Walking Distance ◽  
Peripheral Blood Flow ◽  
Walking Ability ◽  
Double Blind ◽  
Platelet Factor

SummaryA double-blind, placebo-controlled randomized study with BAY U3405, a specific thromboxane A2 (TX A2) receptor blocker, was performed in patients suffering from severe stade II limb arteriopathy. BAY U3405 or placebo was administered in 16 patients at 20 mg four times a day (from day 1 to day 3). Hemostatic studies were done before therapy, and on day 2 and day 3 under therapy. On day 3, BAY U3405 was shown to induce a highly statistically significant decrease of the velocity and the intensity of the aggregations mediated by arachidonic acid (56 ± 37% for the velocity, 58 ± 26% for the intensity) or by U46619 endoperoxide analogue (36 ± 35% for the velocity, 37 ± 27% for the intensity). Similar results were already observed on day 2. By contrast, such a decrease was not noticed with ADP mediated platelet aggregation. Furthermore, plasma levels of betathrombo-globulin and platelet factor 4 remained unchanged. Peripheral hemodynamic parameters were also studied. The peripheral blood flow was measured using a Doppler ultrasound; the pain free walking distance and the total walking ability distance were determined under standardized conditions on a treadmill. These last two parameters show a trend to improvement which nevertheless was not statistically significant. All together these results encourage further in vivo studies using BAY U3405 or related compounds on a long-term administration.

Effects of Ellagic Acid upon the Rabbit Fibrinolytic System

1972 ◽  
Vol 27 (01) ◽  
pp. 063-071
Author(s):  
S. G Iatridis ◽  
P. G Iatridis
Keyword(s):  
Continuous Infusion ◽  
Ellagic Acid ◽  
Animal Experimentation ◽  
Inhibitory Effect ◽  
In Vivo Studies ◽  
Clot Lysis ◽  
Hageman Factor ◽  
Lysis Activity ◽  
Site Of Action

SummaryThe present investigation deals with in vivo studies of possible relations of active Hageman factor (HFa) to the problems of thrombolysis. The study is based upon animal experimentation in which 40 normal, 5 dicumarolized and 5 heparinized rabbits each received ellagic acid (Elac 10-2 M) by intravenous continuous infusion at a rate of 1 ml/min for a period of 25 min. The data suggest that the Elac infusion induced in vivo activation of HF. Streptokinase (SK) injection 25 min from the start of Elac i. v. infusion failed to induce clot lysis in blood drawn one min after its injection. The phenomenon was more prominent with low (SK 250 U or 500 U) concentrations of SK. With higher concentrations, SK-induced clot lysis activity was not affected by Elac infusion.In dicumarolized and heparinized rabbits Elac infusion still counteracted the fibrinolysis activating effect of low concentration of SK. The possibility that the above described phenomenon was due to either hypercoagulability or to a non-specific inhibitory effect of Elac upon SK was explored and excluded.It is concluded that HFa and SK have the same site of action. Thus it seems that HFa may block the precursor upon which SK acts by forming a complex with it. It is stressed that activation of this precursor by HFa requires a suitable surface.

Chemical Permeation Enhancers for Transdermal Delivery of Thiocolchicoside: Assessment of Ex-vivo Skin Flux and In-vivo Pharmacokinetics

2017 ◽  
Vol 10 (5) ◽  
pp. 3827-3835
Author(s):  
Y Madhusudan Rao ◽  
Gayatri P ◽  
Ajitha M ◽  
P. Pavan Kumar ◽  
Kiran kumar
Keyword(s):  
Passive Control ◽  
Ex Vivo ◽  
Skin Permeation ◽  
In Vivo Studies ◽  
Permeation Enhancers ◽  
Casting Technique ◽  
Chemical Permeation Enhancers ◽  
Chemical Permeation ◽  
In Vivo Pharmacokinetics

Present investigation comprises the study of ex-vivo skin flux and in-vivo pharmacokinetics of Thiocolchicoside (THC) from transdermal films. The films were fabricated by solvent casting technique employing combination of hydrophilic and hydrophobic polymers. A flux of 18.08 µg/cm2h and 13.37µg/cm2h was achieved for optimized formulations containing 1, 8-cineole and oleic acid respectively as permeation enhancers. The observed flux values were higher when compared to passive control (8.66 µg/cm2h). Highest skin permeation was observed when 1,8-cineole was used as chemical permeation enhancer and it considerably (2-2.5 fold) improved the THC transport across the rat skin. In vivo studies were performed in rabbits and samples were analysed by LC-MS-MS. The mean area under the curve (AUC) values of transdermal film showed about 2.35 times statistically significant (p<0.05) improvement in bioavailability when compared with the oral administration of THC solution. The developed transdermal therapeutic systems using chemical permeation enhancers were suitable for drugs like THC in effective management of muscular pain.    

Monocytes as Carriers of Magnetic Nanoparticles for Tracking Inflammation in the Epileptic Rat Brain

2019 ◽  
Vol 16 (7) ◽  
pp. 637-644 ◽  
Author(s):  
Hadas Han ◽  
Sara Eyal ◽  
Emma Portnoy ◽  
Aniv Mann ◽  
Miriam Shmuel ◽  
...  
Keyword(s):  
Brain Tissue ◽  
Ex Vivo ◽  
In Vivo Studies ◽  
Nanoparticle Distribution ◽  
Spontaneous Seizures ◽  
Systemic Distribution ◽  
Hippocampal Ca1 ◽  
Pilocarpine Model

Background: Inflammation is a hallmark of epileptogenic brain tissue. Previously, we have shown that inflammation in epilepsy can be delineated using systemically-injected fluorescent and magnetite- laden nanoparticles. Suggested mechanisms included distribution of free nanoparticles across a compromised blood-brain barrier or their transfer by monocytes that infiltrate the epileptic brain. Objective: In the current study, we evaluated monocytes as vehicles that deliver nanoparticles into the epileptic brain. We also assessed the effect of epilepsy on the systemic distribution of nanoparticleloaded monocytes. Methods: The in vitro uptake of 300-nm nanoparticles labeled with magnetite and BODIPY (for optical imaging) was evaluated using rat monocytes and fluorescence detection. For in vivo studies we used the rat lithium-pilocarpine model of temporal lobe epilepsy. In vivo nanoparticle distribution was evaluated using immunohistochemistry. Results: 89% of nanoparticle loading into rat monocytes was accomplished within 8 hours, enabling overnight nanoparticle loading ex vivo. The dose-normalized distribution of nanoparticle-loaded monocytes into the hippocampal CA1 and dentate gyrus of rats with spontaneous seizures was 176-fold and 380-fold higher compared to the free nanoparticles (p<0.05). Seizures were associated with greater nanoparticle accumulation within the liver and the spleen (p<0.05). Conclusion: Nanoparticle-loaded monocytes are attracted to epileptogenic brain tissue and may be used for labeling or targeting it, while significantly reducing the systemic dose of potentially toxic compounds. The effect of seizures on monocyte biodistribution should be further explored to better understand the systemic effects of epilepsy.

Development, Pre-clinical Investigation and Histopathological Evaluation of Metronidazole Loaded Topical Formulation for Treatment of Skin Inflammatory disorders

2020 ◽  
Vol 10 ◽  
Author(s):  
Divya Thakur ◽  
Gurpreet Kaur ◽  
Sheetu Wadhwa ◽  
Ashana Puri
Keyword(s):  
Ex Vivo ◽  
Clinical Investigation ◽  
In Vivo Studies ◽  
Tween 20 ◽  
Inflammatory Disorders ◽  
Rat Paw Edema ◽  
Ex Vivo Permeation ◽  
Permeation Studies ◽  
Anti Inflammatory

Background: Metronidazole (MTZ) is an anti-oxidant and anti-inflammatory agent with beneficial therapeutic properties. The hydrophilic nature of molecule limits its penetration across the skin. Existing commercial formulations have limitations of inadequate drug concentration present at target site, which requires frequent administration and poor patient compliance. Objective: The aim of current study was to develop and evaluate water in oil microemulsion of Metronidazole with higher skin retention for treatment of inflammatory skin disorders. Methods: Pseudo ternary phase diagrams were used in order to select the appropriate ratio of surfactant and co-surfactant and identify the microemulsion area. The selected formulation consisted of Capmul MCM as oil, Tween 20 and Span 20 as surfactant and co-surfactant, respectively, and water. The formulation was characterized and evaluated for stability, Ex vivo permeation studies and in vivo anti-inflammatory effect (carrageenan induced rat paw edema, air pouch model), anti-psoriatic activity (mouse-tail test). Results: The particle size analyses revealed average diameter and polydispersity index of selected formulation to be 16 nm and 0.373, respectively. The results of ex vivo permeation studies showed statistically higher mean cumulative amount of MTZ retained in rat skin from microemulsion i.e. 21.90 ± 1.92 μg/cm2 which was 6.65 times higher as compared to Marketed gel (Metrogyl gel®) with 3.29 ± 0.11 μg/cm2 (p<0.05). The results of in vivo studies suggested the microemulsion based formulation of MTZ to be similar in efficacy to Metrogyl gel®. Conclusion: Research suggests efficacy of the developed MTZ loaded microemulsion in treatment of chronic skin inflammatory disorders.

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