Publications by authors named "Faisal Imam"

36 Publications

Protective Effect of Essential Oil on Cadmium-Induced Nephrotoxicity in Rats, through Suppression of Oxidative Stress and Downregulation of NF-κB, iNOS, and Smad2 mRNA Expression.

Molecules 2021 Feb 26;26(5). Epub 2021 Feb 26.

Department of Basic Sciences, Preparatory Year Deanship, Prince Sattam Bin Abdulaziz University, Al-Kharj 11942, Saudi Arabia.

The purpose of the research was to examine the protective effect of essential oil from Hochst. ex Benth. (TSA oil) against cadmium (Cd)-induced renal toxicity. The experimental protocol was designed using 30 healthy adult Wistar albino rats allocated into five groups containing six animals in each group. Group 1 was treated as normal control and groups 2, 3, 4, and 5 were treated with cadmium chloride (CdCl, 3 mg/kg, IP) for 7 days. Group 3 was also treated with silymarin (100 mg/kg, PO) as a standard group, while groups 4 and 5 were administered with TSA oil at doses of 100 and 200 mg/kg PO, respectively. The nephrotoxicity was measured with various parameters such as kidney function markers, oxidative stress markers (glutathione (GSH) and malondialdehyde (MDA)), and messenger ribonucleic acid (mRNA) expression levels of inflammatory factors. The histological studies were also evaluated in the experimental protocol. The CdCl-treated groups showed a significant increase in the levels of serum kidney function markers along with MDA levels in kidney homogenate. However, renal GSH level was found to be reduced significantly. It was found that CdCl significantly upregulated the nuclear factor levels of kappaB (NF-κB p65), inducible nitric oxide synthase (iNOS), and small mothers against decapentaplegic (Smad2) as compared to the normal control group. On the other hand, TSA oil significantly improved the increased levels of serum kidney function markers, non-enzymatic antioxidants, and lipid peroxidation. In addition, TSA oil significantly downregulated the increased expression of NF-κB p65, iNOS, and Smad2 in Cd-intoxicated rats. Moreover, the histological changes in the tissue samples of the kidney of Cd-treated groups were significantly ameliorated in the silymarin- and TSA-oil-treated groups. The present study reveals that TSA oil ameliorates Cd-induced renal injury, and it is also proposed that the observed nephroprotective effect could be due to the antioxidant potential of TSA oil and healing due to its anti-inflammatory action.
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http://dx.doi.org/10.3390/molecules26051252DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7956168PMC
February 2021

Role of carnitine in regulation of blood pressure (MAP/SBP) and gene expression of cardiac hypertrophy markers (α/β-MHC) during insulin-induced hypoglycaemia: Role of oxidative stress.

Clin Exp Pharmacol Physiol 2021 Apr 27;48(4):478-489. Epub 2020 Dec 27.

Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.

Cardiovascular disease is a leading cause of death in diabetic patients. Hyperglycaemia and iatrogenic hypoglycaemia exacerbate several pathogenic mechanisms underlying hypertension and heart diseases. Carnitine is a potent endogenous antioxidant and cellular fatty acid transporter for antioxidative stress and energy production in the cardiovascular system. The current study aimed to find the role of carnitine in the regulation of hypoglycaemia-induced hypertension and cardiac hypertrophy. Male rats received insulin glargine (InG) to induce hypoglycaemia followed by D-carnitine or acetyl-L-carnitine for carnitine depletion or carnitine supplementation, respectively. The obtained results showed that carnitine deficiency provoked hypoglycaemia-induced hypertension. Mean arterial pressure was elevated from 78.16 ± 11.4 to 100 ± 5.11 mm Hg in InG treated group, and from 78.2 ± 8.5 to 123.4 ± 28.2 mm Hg in InG + D-carnitine treated group. Acetyl-L-carnitine resisted the elevation in blood pressure in all hypoglycaemic animals and kept it within the normal values (68.33 ± 6.7 mm Hg). Acetyl-L-carnitine increased myocardial carnitine content leading to the attenuation of hypoglycaemia-induced oxidative stress, which was evaluated through measurement of the oxidative stress biomarkers such as inducible nitric oxide synthase, NAD(P)H quinone dehydrogenase-1, heme oxygenase-I, and glutathione S-transferase. Moreover, acetyl-L-carnitine prevented induction of gene expression of cardiac hypertrophy markers during hypoglycaemic conditions, which was assessed via the evaluation of mRNA expression of α-myosin heavy chain and β-myosin heavy chain. These findings demonstrate that carnitine might play an essential role in prevention of hypoglycaemia-induced hypertension and cardiac hypertrophy through providing energy and antioxidants to the cardiovascular system.
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http://dx.doi.org/10.1111/1440-1681.13455DOI Listing
April 2021

Effect of Roflumilast in airways disorders via dual inhibition of phosphodiesterase and Ca-channel.

Saudi Pharm J 2020 Jun 25;28(6):698-702. Epub 2020 Apr 25.

Department of Pharmacology, College of Pharmacy, Jouf University, Sakakah 72341, Saudi Arabia.

The bronchodilator effects of Roflumilast "a selective phosphodiesterase type-4 (PDE4)" inhibitor studied in this experimental protocol. The spiral strips of isolated guinea-pig tracheal chains mounted in organ bath and maintained in Krebs solution ventilated with carbogen at 32 °C and in Ca restricted krebs solution. PDE inhibitory activity was evaluated by recording dose response curves using inhibitory effect of isoprenaline on CCh induced contractions. For confirmation of PDE inhibition the intracellular cAMP levels were also estimated. Roflumilast resulted a sharp inhibition in contractile responses of carbachol (CCh, 1 µM) and K (80 mM) and the results were almost similar to verapamil. In Ca restricted Krebs solution, a rightward shift in the Ca response curves observed in the tracheal chain strips which were pretreated with Roflumilast (0.001-0.003 mg/mL) and the maximum response was suppressed, similarly as with verapamil. PDE inhibitory effect of Roflumilast evaluated by recording dose-dependent (0.03-0.1 mg/mL) responses, the isoprenaline-induced inhibitory dose response curves shifted leftward similar to papaverine (PDE inhibitor). Pretreatment with Roflumilast exhibited elevated intracellular cAMP levels in tracheal strips. Findings of the experiment conclude bronchodilatory influence of Roflumilast via PDE and Ca channel inhibition. Results of current experiment offers comprehensive mechanistic background of Roflumilast in future as therapeutic bronchodilator for hyperactive bronchial airway diseases.
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http://dx.doi.org/10.1016/j.jsps.2020.04.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7292871PMC
June 2020

Determination of isoniazid acetylation patterns in tuberculosis patients receiving DOT therapy under the Revised National tuberculosis Control Program (RNTCP) in India.

Saudi Pharm J 2020 Jun 19;28(6):641-647. Epub 2020 Apr 19.

Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Central Laboratory Research Center, P.O. Box 2457, Riyadh 11451, Saudi Arabia.

Isoniazid is the most commonly used drug for treatment of tuberculosis, and is administered individually or in combination with other drugs as standard first line therapy. Offsetting its efficacy, severe adverse effects, especially peripheral neuropathy and hepatotoxicity, are associated with isoniazid therapy, limiting its use in tuberculosis. Isoniazid is acetylated producing hydrazine and acetyl hydrazine, which are responsible for hepatotoxicity. Marked pharmacogenetic differences in acetylation have been reported among different population across the globe. This study evaluates isoniazid acetylation patterns in tuberculosis patients receiving DOT therapy under the Revised National Tuberculosis Control Program (RNTCP) in a specialized tuberculosis hospital in north India. Of 351 patients from whom samples were taken for biochemical analysis of adverse events, 36 were assessed for acetylation patterns. Blood samples were taken 1 h after administration of a 600 mg dose of isoniazid, and plasma concentrations of isoniazid were determined using a validated HPLC method. Of these 36 patients, 20 (55.56%) were slow acetylators and 16 (44.44%) were fast acetylators. Our results are consistent with those of an earlier study conducted in a different region of India. Most biochemical changes produced during long-term isoniazid therapy resolve after therapy is terminated.
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http://dx.doi.org/10.1016/j.jsps.2020.04.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7292862PMC
June 2020

Role of rivaroxaban in sunitinib-induced renal injuries via inhibition of oxidative stress-induced apoptosis and inflammation through the tissue nacrosis factor-α induced nuclear factor-κappa B signaling pathway in rats.

J Thromb Thrombolysis 2020 Aug;50(2):361-370

Department of Pharmacology, College of Pharmacy, Jouf University, Sakakah, 72341, Saudi Arabia.

Rivaroxaban (RIVA) inhibits factor Xa and exhibits antithrombotic and anti-inflammatory activities by inhibiting several cellular signaling molecules. Sunitinib (SUN) is FDA approved first-line drug for metastatic renal cancers and advanced cancerous states of gastrointestinal tract. Present hypothesis was aimed to examine the nephroprotective potential of RIVA in SUN-induced nephrotoxicity, mediated through the inhibition of oxidative stress-induced apoptosis and inflammation, via the TNF-α/NFk-B signaling pathways. Wistar rats 200-250 g were selected and divided randomely in 5 groups (n = 6): Group 1 kept as normal control; Group 2 as disease control and exposed to SUN 50 mg/kg thrice-weekly upto 21 days; Groups 3 and 4, were treatment groups and administered SUN 50 mg/kg thrice-weekly as of group 2 and treated with RIVA 5 and 10 mg/kg/daily for 21 days, respectively; and Group 5 fed with RIVA alone (10 mg/kg/daily for 21 days). Serum was separated from blood to estimate serum biochemical parameters and kidney tissues were collected to estimate antioxidant enzyme, mRNA and protein expression. SUN exposure significantly elevated levels of creatinine, urea, uric acid, blood urea nitrogen, albumin, and bilirubin, and decreased serum magnesium and iron levels. Malondialdehyde and catalase levels were significantly increased and glutathione and glutathione reductase levels were significantly decreased. Intracellular levels of caspase-3 and TNF-α were significantly increased; RIVA treatment restored the altered levels. In SUN-exposed animals, western blotting revealed significantly elevated NFk-B, IL-17, and MCP-1 expression, and IKBα levels were significantly downregulated; RIVA restored these levels to normal values.RIVA treatment significantly restored the apoptotic and inflammatory parameters in SUN-damaged renal tissues.
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http://dx.doi.org/10.1007/s11239-020-02123-6DOI Listing
August 2020

Adverse drug reaction prevalence and mechanisms of action of first-line anti-tubercular drugs.

Saudi Pharm J 2020 Mar 31;28(3):316-324. Epub 2020 Jan 31.

Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, P.O. Box: 2457, Riyadh 11451, Saudi Arabia.

Purpose: Understanding the appearance of anti-tubercular drug-related adverse drug reactions (ADRs) in patients receiving tuberculosis (TB) treatment is important, and may be related to morbidity and mortality if not recognized early. Here, we aimed to characterize the mechanisms underlying adverse drug reactions due to combination anti-tuberculosis therapy of the Revised National Tuberculosis Control Program (RNTCP).

Methods: This was a prospective observational study conducted in 9 DOTS centers of New Delhi, India. All enrolled TB patients receiving first-line tuberculosis treatment as per RNTCP guidelines were monitored for ADRs. All ADRs that appeared during the treatment were recorded and analyzed.

Results: The study included 1011 TB patients on anti-TB treatment under DOTS. According to Naranjo's probability scale, of a total 351 (34.72%) reported adverse events, 102 (10.09%) were definite, 59 (5.83%) probable, 123 (12.17%) possible, and 67 (6.63%) doubtful. On the Hartwig severity scale, of the 351 adverse drug events, 225 (22.26%) were mild, 105 (10.38%) were moderate, and 21 (2.08%) were severe. Out of 102 reported adverse drug reactions, 81 (79.41%) were moderate and 21 (20.59%), while 65.28% did not experience any ADRs.

Conclusions: Directly Observed Treatment (DOT) is effective and safe compared to daily treatment regimens. Patients receiving DOTS therapy needed close monitoring for adverse events. Therefore, a pharmacovigilance program should be added at the National level to accesses the adverse event incidence.
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http://dx.doi.org/10.1016/j.jsps.2020.01.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7078525PMC
March 2020

Evaluation of bronchodialatory and antimicrobial activities of A multi-mechanistic approach.

Saudi Pharm J 2020 Mar 31;28(3):281-289. Epub 2020 Jan 31.

Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.

, a plant belonging to the family Lamiaceae, is endemic to Ethiopia. In Ethiopian traditional medicine, has been used for the treatment of several respiratory-related disorders. The present study was designed to evaluate the bronchodilatory and antimicrobial activities of leaves crude extract (Of.Cr). Ex-vivo experiments were conducted on guinea-pig trachea provided with physiological oxygenated buffer solution using emkaBath setup. The crude extract was analyzed by gas chromatography-mass spectrometry. Of.Cr, showed the presence of terpenes, fragrance components, saponins, and higher fatty acids. Of.Cr when tested on contracted tracheal chains with carbamylcholine (CCh, 1 µM) and high K (80 mM) produced relaxation by showing higher potency against CCh with incomplete inhibition of high K. Dicyclomine, used as a positive control, also showed selectively higher potency to inhibit CCh when compared with its effect against K. In the anticholinergic curves, Of.Cr at 1 mg/mL deflected CCh-induced concentration-response curves (CRCs) competitively to the right like dicyclomine (0.03 µM) and atropine whereas a higher dose of Of.Cr (3 mg/mL) produced a non-parallel shift in the CCh curves like a higher dose of dicyclomine (0.1 µM). In the calcium channel inhibitory assay, Of.Cr at 3 & 5 mg/mL, deflected CRCs of Ca to the right like verapamil, used as positive control. Of.Cr, at concentrations (1-3 mg/mL) increases cAMP levels in isolated tracheal homogenates, similar to positive control phosphodiesterase inhibitor (papaverine). When tested for antibacterial activity against standard and clinical strains, Of.Cr was found more active (MIC 475 µg/ml) against S. aureus (NCTC 6571), while the maximum inhibition (MIC 625 µg/ml) was observed by the extract when tested against MRSA. These results determine the mechanistic pathways of the observed bronchodilatory effect of with a combination of anticholinergic and dual inhibition of phosphodiesterase and voltage-gated Ca channels.
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http://dx.doi.org/10.1016/j.jsps.2020.01.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7078568PMC
March 2020

Development of Lipomer Nanoparticles for the Enhancement of Release, Anti-microbial Activity and Bioavailability of Delafloxacin.

Pharmaceutics 2020 Mar 11;12(3). Epub 2020 Mar 11.

Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia.

Delafloxacin (DFL) is a novel potent and broad-spectrum fluoroquinolone group of antibiotics effective against both Gram-positive and negative aerobic and anaerobic bacteria In this study, DFL-loaded stearic acid (lipid) chitosan (polymer) hybrid nanoparticles (L-P-NPs) have been developed by single-emulsion-solvent evaporation technique. The mean particle size and polydispersity index (PDI) of optimized DFL-loaded L-P-NPs (F1-F3) were measured in the range of 299-368 nm and 0.215-0.269, respectively. The drug encapsulation efficiency (EE%) and loading capacity (LC%) of DFL-loaded L-P-NPs (F1-F3) were measured in the range of 64.9-80.4% and 1.7-3.8%, respectively. A sustained release of DFL was observed from optimized DFL-loaded L-P-NPs (F3). Minimum inhibitory concentration (MIC) values of the DFL-loaded L-P-NPs (F3) appeared typically to be four-fold lower than those of delafloxacin in the case of Gram-positive strains and was 2-4-fold more potent than those of delafloxacin against Gram-negative strains. The pharmacokinetic study in rats confirmed that the bioavailability (both rate and extent of absorption) of DFL-loaded L-P-NPs was significantly higher (2.3-fold) than the delafloxacin normal suspension. These results concluded that the newly optimized DFL-loaded L-P-NPs were more potent against both Gram-positive and negative strains of bacteria and highly bioavailable in comparison to delafloxacin normal suspension.
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http://dx.doi.org/10.3390/pharmaceutics12030252DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7151119PMC
March 2020

Protective Effect of RIVA Against Sunitinib-Induced Cardiotoxicity by Inhibiting Oxidative Stress-Mediated Inflammation: Probable Role of TGF-β and Smad Signaling.

Cardiovasc Toxicol 2020 06;20(3):281-290

Department of Pharmacology, College of Pharmacy, Jouf University, Sakakah, 72341, Saudi Arabia.

Sunitinib (SUN) is an oral tyrosine kinase inhibitor approved in 2006 as a first-line treatment for metastatic renal cell cancer. However, weak selectivity to kinase receptors and cardiotoxicity have limited the use of sunitinib. Rivaroxaban (RIVA) is a Factor Xa inhibitor with cardioprotective action. It inhibits atherosclerosis and numerous inflammatory cascades. The present study was designed to investigate the cardioprotective effects of RIVA in sunitinib-induced cardiotoxicity. Thirty male Wistar rats were divided into five groups. Group 1 was the normal control (control). Group 2 was administered i.p. SUN 25 mg kg thrice weekly for 3 weeks. Groups 3 and 4 received the same treatment as Group 2 followed by the administration of RIVA 5 mg kg day and 10 mg kg day, respectively, for 3 weeks. Group 5 received only 10 mg kg day RIVA for 3 weeks. Serum levels of Ca, Mg, Fe/Fe, lipid profiles, and cardiac enzymes were measured. Cardiac tissues were isolated for the measurements of oxidant/antioxidant balance gene and protein expressions. Relative to the controls, the administration of SUN significantly altered serum levels of (Ca, Mg, Fe/Fe, lipid profiles, and cardiac enzymes), intracellular antioxidant enzymes, and the expression levels of the genes encoding certain proteins. RIVA treatment significantly restored these parameters to near-normal levels. RIVA treatment significantly mitigated SUN-induced cardiac injuries by restoring antioxidant enzyme levels and attenuating the proinflammatory cascades resulting from SUN-induced cardiac injuries.
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http://dx.doi.org/10.1007/s12012-019-09551-8DOI Listing
June 2020

Protective role of Roflumilast against cadmium-induced cardiotoxicity through inhibition of oxidative stress and NF-κB signaling in rats.

Saudi Pharm J 2019 Jul 2;27(5):673-681. Epub 2019 Apr 2.

Department of Basic Sciences, Preparatory Year Deanship, Prince Sattam Bin Abdulaziz University, Al-Kharj, Saudi Arabia.

Cadmium (Cd), a potent cardiotoxic environmental heavy metal, induces oxidative stress and membrane disturbances in cardiac myocytes. Phosphodiesterase (PDEs) retards the positive inotropic effects of β-adrenoceptor activation by decreasing levels of cAMP via degradation. Hence, PDE inhibitors sensitize the heart to catecholamine and are therefore, used as positive inotropic agents. The present study was designed to probe the potential attenuating effects of the selective PDE4 inhibitor (Roflumilast, ROF), on cardiac biomarkers, lipid profile, lipid peroxidation products, antioxidant status and histology of cardiac tissues against Cd-induced cardiotoxicity in rats. Rats were randomly distributed into four different groups: group 1, served as the normal control group. Group 2, served as the toxic control group and were administered Cd (3 mg/kg, i.p.) for next 7 days. Groups 3 and 4, served as treatment groups that received Cd with concomitant oral administration of ROF doses (0.5 and 1.5 mg/kg), respectively for 7 days. Serum samples of toxic control group rats resulted in significant ( < 0.001) increase in lactate dehydrogenase (LDH), creatine phosphokinase (CPK), total cholesterol (TC), triglycerides (TG) and low density lipoproteins (LDL) levels with concomitant decrease in high density lipoproteins (HDL) levels in serum which were found reversed with both of ROF treatment groups. Cd also causes significant increased ( < 0.001) in myocardial malondialdehyde (MDA) contents while cardiac glutathione (GSH) level, superoxide dismutase (SOD) and catalase (CAT) enzyme activities were found decreased whereas both doses of ROF, significantly reversed these oxidative stress markers and antioxidant enzymes. Cardiotoxicity induced by Cd also resulted in enhanced expression of non-phosphorylated and phosphorylated form of NF-κB p65 and decreased expression of glutathione-S-transferase (GST) and NQO1 which were found reversed with ROF treatments, comparable to normal control group. Histopathological changes were also improved by ROF administration as compared to Cd treated rats alone. In conclusion, Roflumilast exhibited attenuating effect against Cd-induced cardiac toxicity.
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http://dx.doi.org/10.1016/j.jsps.2019.04.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6598217PMC
July 2019

Rutin inhibits carfilzomib-induced oxidative stress and inflammation via the NOS-mediated NF-κB signaling pathway.

Inflammopharmacology 2019 Aug 1;27(4):817-827. Epub 2019 Jan 1.

Department of Pathology, College of Medicine, King Khalid University Hospital, Riyadh, Kingdom of Saudi Arabia.

Background: Carfilzomib (CFZ), a proteasome inhibitor approved by the FDA to treat multiple myeloma, may cause nephrotoxicity.

Hypothesis: Rutin is a bioflavonoid with antioxidant properties. We aimed to examine whether rutin protects the kidney from CFZ-induced nephrotoxicity.

Study Design: This study aimed to demonstrate the effect of rutin on CFZ-induced renal injury via the inhibition of oxidative stress and inflammation.

Methods: Wistar albino rats were divided into six groups (n = 6): Group 1 (normal control; NC) was administered normal saline for 3 weeks; Group 2 (CFZ/toxic group) received CFZ [4 mg/kg, intraperitoneal (i.p.) injection] twice weekly for 3 weeks; Group 3 (standard treatment group) was administered CFZ (4 mg/kg, i.p.) and olmesartan (2 mg/kg, p.o.) for 3 weeks; Group 4 was administered CFZ (4 mg/kg, i.p.) and rutin (10 mg/kg, p.o.) for 3 weeks; Group 5 was administered CFZ (4 mg/kg, i.p.) and rutin (20 mg/kg, p.o.) for 3 weeks; and Group 6 was administered CFZ (4 mg/kg, i.p.) and rutin (40 mg/kg, p.o.) for 3 weeks. We carried out haematological and biochemical analyses, determined oxidative stress, caspase-3 activity, and protein levels, and performed a histopathological evaluation to confirm CFZ-induced nephrotoxicity and its prevention by rutin administration.

Results: Exposure to only CFZ significantly (p < 0.05) increased white blood cell (WBC) count, Hb%, and HTC% concentration; however, these features were significantly decreased (p < 0.05) when olmesartan and rutin were administered. CFZ administration significantly decreased (p < 0.0001) the level of antioxidant enzymes; whereas, administration of olmesartan and rutin significantly reversed (p < 0.05) their levels toward the normal range. The levels of caspase-3 enzyme significantly increased (p < 0.001) in the CFZ group and were reduced toward the normal values by olmesartan and rutin administration. Furthermore, the results of NOS-2, NF-κB, IkBa, and IL-17 protein estimation and the histopathological evaluation strengthened our findings that rutin exhibits a protective effect against CFZ-induced nephrotoxicity.

Conclusion: These findings clearly demonstrate that rutin ameliorates CFZ-induced oxidative stress and inflammation in nephrotoxicity via the NOS-mediated NF-κB signaling pathway.
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http://dx.doi.org/10.1007/s10787-018-0550-5DOI Listing
August 2019

Apremilast ameliorates carfilzomib-induced pulmonary inflammation and vascular injuries.

Int Immunopharmacol 2019 Jan 28;66:260-266. Epub 2018 Nov 28.

Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia.

Acute lung injury (ALI) due to chemotherapy occurs frequently. It presents a challenge for clinicians managing therapies for different types of cancers. Carfilzomib (Kyprolis™) is a new proteasome inhibitor that shows promise for the treatment of relapsing multiple myeloma. However, several cases of severe ALI have raised concern about the use of carfilzomib against relapsed multiple myelomas. To improve the efficacy of carfilzomib, a new anti-inflammatory drug for psoriasis treatment, apremilast (Otezla™) was investigated for its protective effects against carfilzomib-induced ALI in rats. RT-PCR analyses revealed that carfilzomib administration in rats markedly increased the levels of tumor necrosis factor-alpha and nuclear factor-kappa B and myeloperoxidase activity with a concomitant increase in lipid peroxidation. The anti-inflammatory cytokine, interleukin-10, was downregulated following carfilzomib administration. Reduction in glutathione levels indicated diminished cellular antioxidant defenses in response to carfilzomib-induced ALI. ALI was confirmed by histopathological observations in lung tissue slices. Apremilast administration reduced lung inflammation in terms of reduction in myeloperoxidase activity and levels of tumor necrosis factor-alpha and alveolar infiltrating cells. Apremilast reversed all observed toxic effects of carfilzomib and prevented ALI in rats.
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http://dx.doi.org/10.1016/j.intimp.2018.11.023DOI Listing
January 2019

Apremilast prevent doxorubicin-induced apoptosis and inflammation in heart through inhibition of oxidative stress mediated activation of NF-κB signaling pathways.

Pharmacol Rep 2018 Sep 29;70(5):993-1000. Epub 2018 Mar 29.

Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.

Background: Doxorubicin is an effective, potent and commonly used anthracycline-related anticancer drug; however, cardiotoxicity compromises its therapeutic potential. Apremilast, a novel phosphodiesterase type 4-inhibitor, reported to have anti-inflammatory effects and modulating many inflammatory mediators.

Methods: The present study investigated the influence of apremilast against doxorubicin-induced cardiotoxicity in male Wistar rats. A total, 24 animals were divided into four groups of six animal each. Group 1, served as control and received normal saline. Group 2 animals, received doxorubicin (20 mg kg, ip). Group 3 and 4, treatment group, received doxorubicin (20 mg kg, ip) with the same schedule as group-2, plus apremilast (10 and 20 mg kg day, po) respectively. Oxidative stress, caspase-3 enzyme activity, gene expression and protein expression were tested.

Results: The results of the present study demonstrated that administration of apremilast reversed doxorubicin-induced cardiotoxicity.

Conclusion: These findings suggested that apremilast can attenuate doxorubicin-induced cardiotoxicity via inhibition of oxidative stress mediated activation of nuclear factor-kappa B signaling pathways.
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http://dx.doi.org/10.1016/j.pharep.2018.03.009DOI Listing
September 2018

Apremilast prevent doxorubicin-induced apoptosis and inflammation in heart through inhibition of oxidative stress mediated activation of NF-κB signaling pathways.

Pharmacol Rep 2018 Oct 29;70(5):993-1000. Epub 2018 Mar 29.

Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.

Background: Doxorubicin is an effective, potent and commonly used anthracycline-related anticancer drug; however, cardiotoxicity compromises its therapeutic potential. Apremilast, a novel phosphodiesterase type 4-inhibitor, reported to have anti-inflammatory effects and modulating many inflammatory mediators.

Methods: The present study investigated the influence of apremilast against doxorubicin-induced cardiotoxicity in male Wistar rats. A total, 24 animals were divided into four groups of six animal each. Group 1, served as control and received normal saline. Group 2 animals, received doxorubicin (20mgkg, ip). Group 3 and 4, treatment group, received doxorubicin (20mgkg, ip) with the same schedule as group-2, plus apremilast (10 and 20mgkgday, po) respectively. Oxidative stress, caspase-3 enzyme activity, gene expression and protein expression were tested.

Results: The results of the present study demonstrated that administration of apremilast reversed doxorubicin-induced cardiotoxicity.

Conclusion: These findings suggested that apremilast can attenuate doxorubicin-induced cardiotoxicity via inhibition of oxidative stress mediated activation of nuclear factor-kappa B signaling pathways.
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http://dx.doi.org/10.1016/j.pharep.2018.03.009DOI Listing
October 2018

Anticancer Efficacy of Self-Nanoemulsifying Drug Delivery System of Sunitinib Malate.

AAPS PharmSciTech 2018 Jan 15;19(1):123-133. Epub 2017 Jun 15.

Department of Pharmaceutics, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh, 11451, Saudi Arabia.

Sunitinib malate (SM) is reported as a weakly soluble drug in water due to its poor dissolution rate and oral bioavailability. Hence, in the current study, various "self-nanoemulsifying drug delivery systems (SNEDDS)" of SM were prepared, characterized and evaluated for the enhancement of its in vitro dissolution rate and anticancer efficacy. On the basis of solubilization potential of SM in various excipients, "Lauroglycol-90 (oil), Triton-X100 (surfactant) and Transcutol-P (cosurfactant)" were selected for the preparation of SM SNEDDS. SM-loaded SNEDDS were developed by spontaneous emulsification method, characterized and evaluated for "thermodynamic stability, self-nanoemulsification efficiency, droplet size, polydispersity index (PDI), zeta potential (ZP), surface morphology, refractive index (RI), the percent of transmittance (% T) and drug release profile." In vitro dissolution rate of SM was significantly enhanced from an optimized SNEDDS in comparison with SM suspension. The optimized SNEDDS of SM with droplet size of 42.3 nm, PDI value of 0.174, ZP value of -36.4 mV, RI value of 1.339, % T value of 97.3%, and drug release profile of 95.4% (after 24 h via dialysis membrane) was selected for in vitro anticancer efficacy in human colon cancer cells (HT-29) by MTT assay. MTT assay indicated significant anticancer efficacy of optimized SM SNEDDS against HT-29 cells in comparison with free SM. The results of this study showed the great potential of SNEDDS in the enhancement of in vitro dissolution rate and anticancer efficacy of poorly soluble drug such as SM.
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http://dx.doi.org/10.1208/s12249-017-0826-xDOI Listing
January 2018

Therapeutic potential of carfilzomib, an irreversible proteasome inhibitor, against acetaminophen-induced hepatotoxicity in mice.

J Biochem Mol Toxicol 2017 Apr 30;31(4). Epub 2016 Nov 30.

Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, 11451, Kingdom of Saudi Arabia.

Overdose of acetaminophen (APAP) is often associated with hepatotoxicity. Carfilzomib (CFZ) shows multiple pharmacological activities including anti-inflammatory potential. Therefore, this study was undertaken to evaluate the possible therapeutic effects of CFZ against APAP-induced hepatotoxicity. Hepatotoxicity was induced by administration of APAP (350 mg/kg, intraperitoneal). Mice were given CFZ (0.125, 0.25, or 0.5 mg/kg, intraperitoneal) 1.5 h after APAP administration. Animals were sacrificed on 6 h and blood and liver tissue samples were collected for analysis. In CFZ-post-treated group, there was significant and dose-dependent decrease in serum alanine aminotransferase levels. The level of tumor necrosis factor-α (TNF-α), reactive oxygen species, and NO decreased, whereas glutathione increased significantly by CFZ post-treatment. Upregulated mRNA expression of COX-II and iNOS were significantly downregulated by CFZ post-treatment. CFZ may exert its hepatoprotective action by alleviating inflammatory, oxidative, and nitrosative stress via inhibition of TNF-α, COX-II, and iNOS.
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http://dx.doi.org/10.1002/jbt.21877DOI Listing
April 2017

Apremilast reversed carfilzomib-induced cardiotoxicity through inhibition of oxidative stress, NF-κB and MAPK signaling in rats.

Toxicol Mech Methods 2016 Nov 27;26(9):700-708. Epub 2016 Oct 27.

a Department of Pharmacology and Toxicology, College of Pharmacy , King Saud University , Riyadh , Saudi Arabia.

Carfilzomib (CFZ), is a potent, selective second generation proteasome inhibitor, used for the treatment of multiple myeloma. The aim of the present study was to investigate the possible protective effect of apremilast (AP) on the CFZ -induced cardiotoxicity. Rats were randomly divided into four groups: Group 1, served as the control group, received normal saline. Group 2, served as the toxic group, received CFZ (4 mg/kg, intraperitoneally [i.p.]). Groups 3 and 4, served as treatment groups, and received CFZ with concomitant oral administration of AP in doses of 10 and 20 mg/kg/day, respectively. In the present study, administration of CFZ resulted in a significant increase in serum aspartate transaminase (AST), lactate dehydrogenase (LDH), creatine kinase (CK) and creatine kinase-MB (CK-MB), which were reversed by treatment with AP. CFZ resulted in a significant increase in heart malondialdehyde (MDA) contents and decrease in cardiac glutathione (GSH) level and catalase (CAT) enzyme activity which were significantly reversed by treatment with AP. Induction of cardiotoxicity by CFZ significantly increased caspase-3 enzyme activity which were reversed by treatment with AP. RT-PCR analysis revealed an increased mRNA expression of NF-κB, ERK and JNK which were reversed by treatment with AP in cardiac tissues. Western blot analysis revealed an increased expression of caspase-3 and NF-κB p65 and a decrease expression of inhibitory kappa B-alpha (Iκbα) with CFZ, which were reversed by treatment with AP. In conclusion, apremilast showed protective effect against CFZ-induced cardiotoxicity.
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http://dx.doi.org/10.1080/15376516.2016.1236425DOI Listing
November 2016

Determination of apremilast in rat plasma by UPLC-MS/MS in ESI-negative mode to avoid adduct ions formation.

Bioanalysis 2016 07 28;8(14):1499-1508. Epub 2016 Jun 28.

Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh, 11451, KSA.

Background: Quantification of target analyte by LC-MS/MS is sometimes hampering due to competitive adduct ions formation (sodium and/or ammonium) in positive ionization mode. A UPLC-MS/MS assay was developed for the determination of apremilast in rat plasma using ESI-negative mode to avoid adduct ions formation.

Method & Results: After extraction from plasma by ethyl acetate, analyte and IS were separated on Aquity BEH C column using acetonitrile-10 mM ammonium acetate (85:15) as mobile phase. The calibration curve was linear between 3.04 and 1000 ng/ml with correlation coefficients (r) of ≥0.995 and lower limit of quantification of 3.04 ng/ml. All validation parameter results were within the acceptable range. The assay was successfully employed in oral PK study with C of 584.29 ng/ml and AUC of 6530 ng.h/ml after apremilast (2 mg/kg) administration.

Conclusion: This result suggests that ESI in negative mode would be an alternative approach for LC-MS/MS quantification of analytes, which produce competitive adducts in positive mode.
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http://dx.doi.org/10.4155/bio-2016-0098DOI Listing
July 2016

Alleviation of Aflatoxin B1-Induced Genomic Damage by Proanthocyanidins via Modulation of DNA Repair.

J Biochem Mol Toxicol 2016 Nov 15;30(11):559-566. Epub 2016 Jun 15.

Department of Pharmacology and Toxicology, Faculty of Pharmacy, King Saud University, PO Box 11451, Riyadh, Saudi Arabia.

In order to study the mechanisms underlying the alleviation of aflatoxin B1-induced genomic damage by proanthocyanidins (PAs), we examined the modulation of oxidative DNA damage induced by aflatoxin B1 in PAs-pretreated animals. The effects of PAs on changes in the expression of DNA damage and repair genes induced by aflatoxin B1 were also evaluated in rat marrow cells. Administration of PAs before aflatoxin B1 significantly mitigated aflatoxin B1-induced oxidative DNA damage in a dose-dependent manner. Aflatoxin B1 treatment induced significant alterations in the expression of specific DNA repair genes, and the pre-treatment of rats with PAs ameliorated the altered expression of these genes. Conclusively, PAs protect against aflatoxin B1-induced oxidative DNA damage in rats. These protective effects are attributed to the antioxidant effects of PA and enhanced DNA repair through modulation of DNA repair gene expression. Therefore, PAs are a promising chemoprotective agent for averting genotoxic risks associated with aflatoxin B1 exposure.
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http://dx.doi.org/10.1002/jbt.21823DOI Listing
November 2016

Dexamethasone Attenuates LPS-induced Acute Lung Injury through Inhibition of NF-κB, COX-2, and Pro-inflammatory Mediators.

Immunol Invest 2016 May 22;45(4):349-69. Epub 2016 Apr 22.

a Department of Pharmacology and Toxicology , College of Pharmacy, King Saud University , Riyadh , Kingdom of Saudi Arabia.

Dexamethasone (DEX) is a synthetic glucocorticoid with potent anti-inflammatory effects that is widely used to treat inflammatory diseases. The aim of the present study was to investigate the possible protective effect of DEX on the lipopolysaccharides (LPS)-induced acute lung injury (ALI) in a mouse model. Animals were pretreated with DEX (5 and 10 mg/kg, i.p.) for seven days and acute lung injury was induced by intranasal (i.n.) administration of LPS on day 7. In the present study, administration of LPS resulted in significant increase in neutrophils and lymphocytes count whereas a substantial reduction in T cell subsets (CD3(+) and CD4(+)) and pro-inflammatory (IL-6 and TNF-α) cytokines occurred, which were reversed by DEX treatment. RT-PCR analysis revealed an increased mRNA expression of IL-6, TNF-α, COX-2, iNOS, and NF-κB p65 and decreased IL-10 in the LPS group, which were reversed by treatment with DEX in lung tissues. Western blot analysis revealed an increased expression of COX-2, iNOS and NF-κB p65 in the LPS-group, which was reduced by treatment with DEX. Compared with the LPS group, the DEX treatment also demonstrated a considerable increase in the protein expression level of IL-10 cytokine. Administration of LPS resulted in marked increase in malondialdehyde (MDA) levels and myeloperoxidase (MPO) activity whereas noticeable decrease in glutathione (GSH) content. These changes were significantly reversed by treatment with DEX. The histological examinations revealed protective effect of DEX while LPS group aggravated lung injury. The present findings demonstrate the potent anti-inflammatory action of the DEX against acute lung injury induced by LPS.
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http://dx.doi.org/10.3109/08820139.2016.1157814DOI Listing
May 2016

Differential Effects of Sunitinib on the Expression Profiles of Xenobiotic-Metabolizing Enzymes and Transporters in Rat Liver and Kidneys.

Basic Clin Pharmacol Toxicol 2016 Aug 16;119(2):173-83. Epub 2016 Feb 16.

Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.

Sunitinib (SUN) is a multi-targeted tyrosine kinase inhibitor that was recently approved for the treatment of gastrointestinal tract and renal cancers. To date, very little is known about the effects of SUN on the expression of hepatic and renal xenobiotic-metabolizing enzymes (XMEs) and transporters. The present study was designed to investigate the capacity of chronic SUN treatment to modulate the mRNA and protein expression levels of phase I cytochrome P450 (CYP), phase II conjugating enzymes, and phase III transporters in rat liver and kidneys. For this purpose, SUN (25, 50 and 100 mg/kg) was injected IP into Wistar albino rats for 4 weeks; thereafter, the mRNA and protein expression levels of several XMEs and transporters were determined by RT-PCR and Western blot analysis, respectively. Real-time PCR analysis showed that SUN significantly induced the hepatic and renal CYP1A1, 1A2, 1B1, 2E1 and 4F4, whereas it inhibited CYP2C11 and 4A2. Furthermore, SUN specifically induced renal, but not hepatic, CYP2J3 and 3A2, while it induced only hepatic CYP4A1. With regard to phase II, SUN induced hepatic GSTA1 and UGT1A and renal NQO1 and UGT1A mRNA levels, whereas it inhibited renal GST1A expression. On the other hand, both renal and hepatic P-gp, MRP2 and BCRP transporters were significantly induced by SUN at the mRNA and protein expression levels. Importantly, these differential effects were associated with changes in oxidative stress genes and lipid peroxidation levels. In conclusion, SUN can serve as XME and transporters modulator, which potentially may counteract the efficacy of the treatment, adverse reactions and drug interactions in SUN treatment.
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http://dx.doi.org/10.1111/bcpt.12555DOI Listing
August 2016

Rutin Attenuates Carfilzomib-Induced Cardiotoxicity Through Inhibition of NF-κB, Hypertrophic Gene Expression and Oxidative Stress.

Cardiovasc Toxicol 2017 01;17(1):58-66

Department of Pharmacology and Toxicology, College of Pharmacy, Taibah University, Madinah, Kingdom of Saudi Arabia.

Carfilzomib is a proteasome inhibitor, commonly used in multiple myeloma, but its clinical use may be limited due to cardiotoxicity. This study was aimed to evaluate the influence of rutin in carfilzomib-induced cardiotoxicity in rats. Wistar albino male rats weighing 200-250 g (approximately 10 weeks old) were taken for this study. Animals were divided into four groups of six animals each. Group 1 served as normal control (NC), received normal saline; group 2 animals received carfilzomib (dissolved in 1 % DMSO) alone; group 3 animals received rutin (20 mg/kg) + carfilzomib; and group 4 animals received rutin (40 mg/kg) + carfilzomib. Hematological changes, biochemical changes, oxidative stress, hypertrophic gene expression, apoptotic gene expression, NFκB and IκB-α protein expression and histopathological evaluation were done to confirm the finding of carfilzomib-induced cardiotoxicity. Treatment with rutin decreased the carfilzomib-induced changes in cardiac enzymes such as lactate dehydrogenase, creatine kinase (CK) and CK-MB. For the assessment of cardiotoxicity, we further evaluated cardiac hypertrophic gene and apoptotic gene expression such as α-MHC, β-MHC and BNP and NF-κB and p53 gene expression, respectively, using RT-PCR. Western blot analysis showed that rutin treatment prevented the activation of NF-κB by increasing the expression of IκB-α. Rutin also attenuated the effects of carfilzomib on oxidant-antioxidant including malondialdehyde and reduced glutathione. Histopathological study clearly confirmed that rutin attenuated carfilzomib-induced cardiotoxicity in rats.
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http://dx.doi.org/10.1007/s12012-015-9356-5DOI Listing
January 2017

Design and Synthesis of N-Arylphthalimides as Inhibitors of Glucocorticoid-Induced TNF Receptor-Related Protein, Proinflammatory Mediators, and Cytokines in Carrageenan-Induced Lung Inflammation.

J Med Chem 2015 Nov 5;58(22):8850-67. Epub 2015 Nov 5.

Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University , 2457 Riyadh, Kingdom of Saudi Arabia.

N-Arylphthalimides (1-10P) derived from thalidomide by insertion of hydrophobic groups were evaluated for anti-inflammatory activity, and (4-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-N'-[(4-ethoxyphenyl)methylidene]benzohydrazide 6P was identified as a promising anti-inflammatory agent. Further testing confirmed that compared with the control, 6P treatment resulted in a considerable decrease in CD4(+), NF-κB p65(+), TNF-α(+), IL-6(+), GITR(+), and IL-17(+) cell populations and an increase in the Foxp3(+), CD4(+)Foxp3(+), and IκBα(+) populations in whole blood and pleural fluid of a mouse model of lung inflammation. Moreover, treatment with compound 6P decreased the proteins associated with inflammation including TNF-α, IL-6, IL-17, GITR, NF-κB, COX-2, STAT-3, and iNOS and increased the anti-inflammatory mediators such as IL-10 and IL-4. Further, histopathological examination confirmed the potent anti-inflammatory effects of compound 6P. Thus, the N-arylphthalimide derivative 6P acts as a potent anti-inflammatory agent in the carrageenan-induced lung inflammation model, suggesting that this compound may be useful for the treatment of inflammation in a clinical setting.
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http://dx.doi.org/10.1021/acs.jmedchem.5b00934DOI Listing
November 2015

Diosmin downregulates the expression of T cell receptors, pro-inflammatory cytokines and NF-κB activation against LPS-induced acute lung injury in mice.

Pharmacol Res 2015 Dec 8;102:1-11. Epub 2015 Sep 8.

Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.

Diosmin, a natural flavonoid glycoside present abundantly in the pericarp of various citrus fruits. Because of its anti-inflammatory and antioxidant properties, it can be used in many diseases. In this study, we investigated the possible protective mechanisms of the diosmin on LPS-induced lung injury through inhibition of T cell receptors, pro-inflammatory cytokines and NF-κB activation. Animals were pretreated with diosmin (50 and 100mg/kg, p.o.) for seven days prior to lipopolysaccharides (LPS) treatment. LPS administration increased neutrophils, monocytes, lymphocytes, total leukocyte count (TLC) and platelets which were decreased by diosmin. We observed that mice exposed to LPS showed increased malondialdehyde level and MPO activity whereas marked decrease in glutathione content. These changes were significantly reversed by treatment with diosmin in a dose dependent manner. Diosmin treatment showed a substantial reduction in T cell (CD4(+) and CD8(+)) receptors and pro-inflammatory (IL-2(+) and IL-17(+)) cytokines in whole blood. In addition, RT-PCR analysis revealed increased mRNA expression of IL-6, IL-17, TNF-α, and NF-κB in the LPS group, while reduced by treatment with diosmin. Western blot analysis confirmed the increased protein expression of IL-1β, TNF-α and NF-κB p65 in the LPS group and treatment of animals with diosmin reversed these effects. The levels of cytoplasmic p-IκB-α and p-NF-κB p65 expression also were mitigated by diosmin. The histological examinations revealed protective effect of diosmin while LPS group aggravated lung injury. These results support the potential for diosmin to be investigated as a potential agent for the treatment of lung injury and inflammatory diseases.
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http://dx.doi.org/10.1016/j.phrs.2015.09.001DOI Listing
December 2015

Riboflavin attenuates lipopolysaccharide-induced lung injury in rats.

Toxicol Mech Methods 2015 11;25(5):417-23. Epub 2015 Sep 11.

b Department of Pharmacology and Toxicology , College of Pharmacy, Taibah University , Medina , KSA.

Riboflavin (vitamin B2) is an easily absorbed micronutrient with a key role in maintaining health in humans and animals. It is the central component of the cofactors flavin adenine dinucleotide (FAD) and flavin mononucleotide (FMN) and is therefore required by all flavoproteins. Riboflavin also works as an antioxidant by scavenging free radicals. The present study was designed to evaluate the effects of riboflavin against acute lungs injury induced by the administration of a single intranasal dose (20 μg/rat) of lipopolysaccharides (LPS) in experimental rats. Administration of LPS resulted in marked increase in malondialdehyde (MDA) level (p < 0.01) and MPO activity (p < 0.001), whereas marked decrease in glutathione (GSH) content (p < 0.001), glutathione reductase (GR) (p < 0.001) and glutathione peroxidase (p < 0.01) activity. These changes were significantly (p < 0.001) improved by treatment with riboflavin in a dose-dependent manner (30 and 100 mg/kg, respectively). Riboflavin (100 mg/kg, p.o.) showed similar protective effects as dexamethasone (1 mg/kg, p.o.). Administration of LPS showed marked cellular changes including interstitial edema, hemorrhage, infiltration of PMNs, etc., which were reversed by riboflavin administration. Histopathological examinations showed normal morphological structures of lungs tissue in the control group. These biochemical and histopathological examination were appended with iNOS and CAT gene expression. The iNOS mRNA expression was increased significantly (p < 0.001) and levels of CAT mRNA expression was decreased significantly (p < 0.001) in the animals exposed to LPS, while treatment with riboflavin significantly (p < 0.01) improved expression of both gene. In conclusion, the present study clearly demonstrated that riboflavin caused a protective effect against LPS-induced ALI. These results suggest that riboflavin may be used to protect against toxic effect of LPS in lungs.
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http://dx.doi.org/10.3109/15376516.2015.1045662DOI Listing
July 2016

Protection against tacrolimus-induced cardiotoxicity in rats by olmesartan and aliskiren.

Toxicol Mech Methods 2014 Dec 23;24(9):697-702. Epub 2014 Sep 23.

Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University , Riyadh , KSA .

Context: Tacrolimus (TAC), a calcineurin inhibitor, is commonly used as an immunosuppressive agent in organ transplantation, but its clinical use may be limited due to cardiotoxicity. Olmesartan (OLM; angiotensin receptor blocker) and aliskiren (ALK; renin inhibitor) may attenuate cardiotoxicity induced by TAC by inhibition of renin-angiotensin aldosterone system.

Objective: The aim of this study was to evaluate the effect of OLM and ALK on TAC-induced cardiotoxicity.

Materials And Methods: Male Wistar albino rats weighing 200-250 g (10-12 weeks old) were used in this study. Animals were divided into four groups. Group 1 received normal saline, group 2 received TAC (2 mg/kg, intraperitoneally for 14 d), group 3 received OLM (2 mg/kg, p.o. for 28 d) + TAC and group 4 received ALK (50 mg/kg, p.o. for 28 d) + TAC. TAC-induced cardiotoxicity was assessed biochemically and histopathologically.

Results: Treatment with OLM or ALK decreased the TAC-induced changes in biochemical markers of cardiotoxicity such as serum aspartate transaminase, creatine kinase and lactate dehydrogenase. OLM or ALK also attenuated the effects of TAC on oxidant-antioxidant parameters such as malondialdehyde, reduced glutathione and catalase. Histopathological and ultrastructural studies showed that OLM or ALK also attenuated TAC-induced cardiotoxicity.

Discussion And Conclusion: These results suggest that OLM as well as ALK has protective effects against TAC-induced cardiotoxicity; implying that angiotensin receptor blocker or renin inhibitor, respectively, may counteract cardiotoxicity associated with immunosuppressant use.
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http://dx.doi.org/10.3109/15376516.2014.963773DOI Listing
December 2014

A validated high-throughput UHPLC-MS/MS assay for accurate determination of rivaroxaban in plasma sample.

J Thromb Thrombolysis 2015 Jan;39(1):79-88

Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, PO BOX 2457, Riyadh, 11451, Saudi Arabia,

Rivaroxaban is a novel, selective and potent oral direct factor Xa inhibitor, therapeutically indicated in the treatment of thromboembolic diseases. Like traditional anticoagulants, routine coagulation monitoring of rivaroxaban is not necessary, but important in some clinical circumstances. In this study, a sensitive UHPLC-MS/MS assay for rapid determination of rivaroxaban in human plasma was developed and validated. Rivaroxaban and its internal standard (IS) were extracted from plasma using acetonitrile as protein precipitating agent. An isocratic mobile phase of acetonitrile: 10 mM ammonium acetate (80:20, v/v) at a flow rate of 0.3 mL/min was used for the separation of rivaroxaban and IS. Both rivaroxaban and IS was eluted within 1 min with a total run time of 1.5 min only. Electrospray ionization source in positive mode was used for the detections of rivaroxaban and IS. Precursor to product ion transition of m/z 436.00 > 144.87 for rivaroxaban and m/z 411.18 > 191.07 for IS were used in multiple reaction monitoring mode. Developed assay was fully validated in terms of selectivity, linearity, accuracy, precision, recovery, matrix effects and stability using official guideline on bioanalytical method.
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http://dx.doi.org/10.1007/s11239-014-1121-2DOI Listing
January 2015

Olmesartan attenuates tacrolimus-induced biochemical and ultrastructural changes in rat kidney tissue.

Biomed Res Int 2014 28;2014:607246. Epub 2014 May 28.

Al-Haya Medical Co., Riyadh 11411, Saudi Arabia.

Tacrolimus, a calcineurin inhibitor, is clinically used as an immunosuppressive agent in organ transplantation, but its use is limited due to its marked nephrotoxicity. The present study investigated the effect of olmesartan (angiotensin receptor blocker) on tacrolimus-induced nephrotoxicity in rats. A total of 24 rats were divided into four groups, which included control, tacrolimus, tacrolimus + olmesartan, and olmesartan groups. Tacrolimus-induced nephrotoxicity was assessed biochemically and histopathologically. Tacrolimus significantly increased BUN and creatinine level. Treatment with olmesartan reversed tacrolimus-induced changes in the biochemical markers (BUN and creatinine) of nephrotoxicity. Tacrolimus significantly decreased GSH level and catalase activity while increasing MDA level. Olmesartan also attenuated the effects of tacrolimus on MDA, GSH, and catalase. In tacrolimus group histological examination showed marked changes in renal tubule, mitochondria, and podocyte processes. Histopathological and ultrastructural studies showed that treatment with olmesartan prevented tacrolimus-induced renal damage. These results suggest that olmesartan has protective effects on tacrolimus-induced nephrotoxicity, implying that RAS might be playing role in tacrolimus-induced nephrotoxicity.
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http://dx.doi.org/10.1155/2014/607246DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4058524PMC
February 2015

Carbon tetrachloride-induced hepatotoxicity in rat is reversed by treatment with riboflavin.

Int Immunopharmacol 2014 Aug 27;21(2):383-8. Epub 2014 May 27.

Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.

Liver is a vital organ for the detoxification of toxic substances present in the body and hepatic injury is associated with excessive exposure to toxicants. The present study was designed to evaluate the possible hepatoprotective effects of riboflavin against carbon tetrachloride (CCl4) induced hepatic injury in rats. Rats were divided into six groups. Hepatotoxicity was induced by the administration of a single intraperitoneal dose of CCl4 in experimental rats. Riboflavin was administered at 30 and 100mg/kg by oral gavage to test its protective effect on hepatic injury biochemically and histopathologically in the blood/liver and liver respectively. The administration of CCl4 resulted in marked alteration in serum hepatic enzymes (like AST, ALT and ALP), oxidant parameters (like GSH and MDA) and pro-inflammatory cytokine TNF-α release from blood leukocytes indicative of hepatic injury. Changes in serum hepatic enzymes, oxidant parameters and TNF-α production induced by CCl4 were reversed by riboflavin treatment in a dose dependent manner. Treatment with standard drug, silymarin also reversed CCl4 induced changes in biomarkers of liver function, oxidant parameters and inflammation. The biochemical observations were paralleled by histopathological findings in rat liver both in the case of CCl4 and treatment groups. In conclusion, riboflavin produced a protective effect against CCl4-induced liver damage. Our study suggests that riboflavin may be used as a hepato-protective agent against toxic effects caused by CCl4 and other chemical agents in the liver.
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http://dx.doi.org/10.1016/j.intimp.2014.05.014DOI Listing
August 2014