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   Table of Contents - Current issue
July-December 2019
Volume 8 | Issue 2
Page Nos. 115-302

Online since Wednesday, October 30, 2019

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Quantitative structure–activity relationship analysis of thiophene derivatives to explore the structural requirements for c-Jun NH2-terminal kinase 1 inhibitory activity p. 115
Ashima Nagpal, Monika Chauhan
Background: With an aim to design a validated two-dimensional quantitative structure–activity relationship (2D QSAR) model, a probe was executed on a series of reported c-Jun NH2-terminal kinase-1 (JNK1) inhibitors, exhibiting selectivity toward JNKs (and not other members of MAPK family). Objective: The present work focused on obtaining valuable insights from the structural architecture of the selected compounds and their effects on JNK1 inhibitory activity. The present work deciphers the importance of descriptive variables, namely Verloop L (Subst. 1), Bond Dipole Moment (Subst. 2), LogP (Subst. 1), Balaban Topological index (Subst. 1), and  VAMP Total Dipole (whole molecule), in molecules possessing JNK1 inhibitory profile. Results: These explanatory variables, obtained after iteratively reducing the data, did not only provide us with the substantial evidence pertaining to the dependence of bioactivity on the structural features of molecules, but also suggested the measures to optimize the selected compounds so as to obtain potent JNK1 inhibitors with good selectivity profile. Based on these distinct descriptors, exhibiting no apparent intercorrelation and manifesting good correlation with biological activity, a 2D QSAR model was generated. Conclusion: Robustness of the developed model was evaluated by performing multiple linear regression, partial least square, and artificial neural network studies. The reliability and predictive ability of the developed model was ascertained through the values of standard statistical parameters, such as s = 0.38, F = 97.22, r = 0.95, r2 = 0.90, and r2cv = 0.88, for the training set compounds. The generated model was validated through the test set compounds, as well as by leave one out method.
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Analysis of phenolics in Calligonum polygonoides in vitro cultured roots p. 124
Asmaa I Owis, Nada S Abdelwahab, Adel A Abul-Soad
Background: Calligonum polygonoides L. subsp. Comosum (L’Hér.) Sosk. is an endangered plant species belonging to family Polygonaceae. Although the plant is rich in phytoconstituents and has multipurpose medicinal applications, but in vitro root culture studies and phytochemical investigations of these cultures are rare. Objectives: To establish in vitro root, callus and cell suspension cultures from in vitro germinated fruits of C. polygonoides to investigate the production of phenolics through root, callus and cell suspension cultures and attempt to enhance cell capacity to accumulate phenolics. Materials and Methods: Modified Murashige and Skoog medium supplemented with 1 mg l-1 indole-3-butyric acid was used to establish the root culture. Elicitation of cell suspension culture was performed using salicylic acid and yeast extract. The phenolic compounds in root, callus and cell suspension cultures were evaluated using reversed phase high performance liquid chromatography technique. Results: The unorganized cell suspension culture contained fewer amounts of phenolic compounds than the differentiated roots tissue. Elicitation produced quantitative reprogramming of phenolic content. Conclusion: The present study provides a chance to improve secondary metabolite yield from this valuable natural plant.
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Comparing the protective effect of L-carnitine, chromium, and vitamin D with metformin on kidney parameters, lipid profiles, and antioxidant indices in streptozotocin-diabetic rats p. 128
Elham Tabatabaie, Kahin Shahanipour, Ali Noori, Parisa S Samani, Mohammad Adibnejad
Introduction: Type 1 diabetes mellitus is believed to be caused by decline of insulin secretion because of destruction of the pancreatic β cell, which is characterized with symptoms such as hyperglycemia, polyuria, polydipsia, weight loss, and other symptoms. Due to the lack of sufficient data about protective effect of L-carnitine, chromium, and vitamin D as compared with metformin on biochemical indices in streptozotocin-diabetic rats, it seems necessary to determine the effects of these medications on diabetes. Materials and Methods: Sixty Wistar rats were divided into 12 diabetic and healthy groups, and 10 groups of witness, metformin )150 mg/kg(, L-carnitine )200 mg/kg(, and chromium )2 mg/kg(, vitamin D (0.06 µg) and a group treated with simultaneous combined therapy of L-carnitine, chromium, and vitamin D. Diabetes mellitus was induced by streptozotocin. Rats with glucose levels of more than 300 mg/dL were considered as diabetic. After 30 days of treatment, the serum concentrations of renal parameters, lipid profile, malondialdehyde, and activity of superoxide dismutase were measured in the studied groups. Results: Malondialdehyde had a significant decrease in all diabetic groups but an increase in nondiabetic metformin and L-carnitine groups (P < 0.05). In all groups, a significant reduction of triglyceride was observed (P < 0.05). Urea increased in the diabetic metformin and chromium treatment groups, whereas in the other groups it decreased (P < 0.05). Among diabetic metformin groups, a significant increase in serum creatinine was found (P < 0.05). High-density lipoprotein also decreased in the combined group of L-carnitine, chromium, and vitamin D (P < 0.05). Cholesterol in diabetic L-carnitine, chromium treatment, and combined group showed a significant decrease (P < 0.05). Conclusion: These data showed that all three drugs of L-carnitine, chromium, and vitamin D such as metformin seemed appropriate, which had the hypoglycemic, antilipidemic, and antioxidant effects.
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Antidepressant-like effect of vitamin B6 in mice forced swimming test and the possible involvement of the noradrenergic system p. 133
Azadeh Mesripour, Sepide Sajadian, Valiollah Hajhashemi
Background: Vitamin B6 is a cofactor for various enzymes that are involved in neurotransmitter production. It has been shown that vitamin B6 administration reduces immobility time in mice forced swimming test (FST), which suggests potential antidepressant activity in humans. The aim of this study was to observe the possible involvement of the noradrenergic system in the antidepressant effects of vitamin B6 during FST in mice. Material and methods: Each of the following drugs was administered with vitamin B6: a tricyclic antidepressant (imipramine), α1 adrenoceptor antagonist (prazosin), α2 adrenoceptor antagonist (yohimbine), and β adrenoceptor antagonist (propranolol) and α-methyl-p-tyrosine (AMPT), a selective inhibitor of the enzyme tyrosine hydroxylase. Results: The antidepressant effect of vitamin B6 (100 mg/kg) was increased by adding imipramine (5 mg/kg), prazosin (1 mg/kg) to the treatment and slightly by propranolol (2 mg/kg). Yohimbine (1 mg/kg), to some extent, reversed vitamin B6 effects although not completely compared with the control group, whereas AMPT (100 mg/kg) administration absolutely reduced vitamin B6 antidepressant effect during the FST. Conclusion: This study provides evidence indicating that the antidepressant-like effect of vitamin B6 in the FST is dependent on its interaction with α and β adrenoceptors and the noradrenergic system plays a critical role in its antidepressant benefits.
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Appraising the neuroprotective competence of nitrogen-enriched Arthrospira platensis in comparison to commercial resource in depressed mice models p. 139
Arockiya Anita Margret, Muppliyan Kalaiyarasan, Arockiya Avila Jerley, Theboral Jeevaraj
Back ground: Arthrospira platensis encompasses vital nutrients and is commercialized globally. It comprises of imperative resource that has the potential to combat neurological deformities caused due to stress and anxiety. Objective: This work evaluates the neuroprotective effect of spirulina cultivated on nitrogen enriched medium and compares it with the commercial samples. Materials and Methods: The study is authenticated with an antioxidant assay and the vital compounds are relatively profiled by GC-MS study. Furthermore, a molecular docking analysis is implemented to investigate the therapeutic potentials of the phytocompounds against Monoamine Oxidase –A and establish them as inhibitors. The ethanolic extract of spirullina as are fed on depressed mice models to assay its neuroprotective effect and rehabilitation of brain cells by a histopathological study. Results: The antioxidant content of the augmented sample was consistent on par with the commercial sample. The in silico assay was performed with 10 extricated compounds of both the samples where, Butanoic acid, 3-hydroxy- furnished a minimum binding affinity energy value of -56.24 kcal/mol and dodecanamide was efficient to bind with the active site of the amino acid residue TYR 69 with a minimum energy of -87.8 kcal/mol. The histopathological examination upholds the refurbished parameter of vital phytocompounds with placid cellular edema and perivascular infiltration. Conclusion: There is a wide range of need to develop research against stress and anxiety and the study fortifies the restorative efficacy of the phytocompounds as a neuroprotective drug.
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In vitro anti-leishmanial activity of Satureja khuzestanica jamzad and Oliveria decumbens vent. Extracts on Leishmania major and Leishmania infantum promastigotes p. 149
Shahram Khademvatan, Alborz Eskandari, Batool Sadeghi Nejad, Shahla Najafi
Background and Objectives: Leishmaniasis is the main health problem and affects millions of people, especially in developing countries. On the other hand, there is no immunoprophylaxis (vaccination) accessible for the treatment of Leishmania infections and commercial drugs are unsatisfactory. Therefore, there is an effort to find alternative herbal remedies. The objective of the present study was to state the antileishmanial activity of two herbal medicines such as Satureja khuzestanica Jamzad and Oliveria decumbens Vent. leaf extracts on the promastigotes of Leishmania major and Leishmania infantum. Materials and Methods: The hydroethanolic extracts of each plant were extracted and their antileishmanial effects evaluated in different concentrations (0–156 μg/ml) and at various hours (24, 48, and 72h) using colorimetric (3[4, 5dimethylthiazol2yl]2, 5 diphenyltetrazolium bromide) assay. The concentrationresponse curves of tested extracts and glucantime solutions as a reference were designed, and 50% of inhibitory concentration (IC50) values were recorded. Results: Antileishminal activity of S. khuzestanica, O. decumbens, and glucantime drug on L. major and L. infantum promastigotes were revealed with IC50 values of 4.3 and 5.5 μg/ml for S. khuzestanica, 0.85 and 0.23 μg/ml for O. decumbens, and 40.2 and 18.5 μg/ml for glucantime after 72h incubation. Conclusion: These results revealed that compounds from S. khuzestanica and O. decumbens have antileishmania properties that necessary to survey the effects of these extracts on leishmania genus in animal models in the future.
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Comparative antibacterial activity of synthetic N,S-Heterocyclic derivatives, MgO nanoparticles, and glycine on zoonotic Vibrio fluvialis p. 155
Maliheh Abdollahi, Hamid Beyzaei, Seyed Hadi Hashemi, Behzad Ghasemi
Background: Vibrio fluvialis is an emerging zoonotic pathogen that its antibiotic-resistant strains are rapidly expanding. Discovering new antibacterial agents is one way to control it.Aims and Objectives: In this research, inhibitory potentials of glycine, magnesium oxide nanoparticles (NPs), and some synthesized thiazole, imidazolidine-2-thione, and tetrahydropyrimidine-2-thione derivatives were studied against V. fluvialis in an in vitro manner.Materials and Methods: Thiazoles were prepared through Hantzsch reaction. Cyclic thioureas were synthesized from the reaction of diaminoalkanes and carbon disulfde. MgO NPs were created in 23.7–25.7nm by sol–gel processing. Antibacterial properties of all compounds as inhibition zone diameter, the minimum inhibitory concentration, and the minimum bactericidal concentration values were assessed through both disk diffusion and broth microdilution methods.Results: No inhibitory activity on V. fluvialis was observed with MgO NPs and glycine. Among thiazole derivatives, only compound 7e could effciently block the growth of this pathogen. All thioureas except derivative 6c showed antibacterial properties. The best results belonged to imidazolidine-2-thione 7a.Conclusion: Significant inhibitory potentials were observed with some synthetic thiazoles and cyclic thioureas. If antibacterial activates of these heterocycles are proved on resistant strains and their toxic effects are desirable, an important step will be taken in the introduction of these new antibacterial agents.
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Acetyl glycyrrhetinic acid methyl ester as a promising glycyrrhizin derivative against the breast cancer cells (MCF-7) p. 161
Mohamed G Ibrahim, Fardous F El-Senduny, Magdy M Youssef, Diaaeldin M Elimam, Fatma M Abdel Bar, Farid A Badria
Background: Breast cancer remains the most potent threat to women’s life worldwide. So far, no ideal drug for treatment of breast cancer, all available drugs exhibit severe side effects, poor therapeutic index, and high cost. Objective: Therefore, this study aimed to investigate the potential use of the natural pentacyclic triterpenoids such as Boswellic, Betulinic (BA), Urosolic, Oleanolic acids, Glycyrrhizin and their derivatives for treatment of breast cancer. Materials and methods: The cell viability was firstly determined after treatment with 50 µM of each compound. The effect of the treatment on cell cycle, apoptosis, cell migration and colony formation was evaluated. The ability of the new glycyrrhizin derivative to activate p53 was investigated by flow cytometry. Results: The cytotoxicity assay revealed that glycyrrhizin derivative AM-GA (3-acetyl-18β-glycyrrhetinic-30-methyl ester) and BA were the most cytotoxic against breast cancer cell line MCF-7 with IC50 values 4.5±0.1 and 4±0.1 µM, respectively. Both AM-GA and BA were selective towards breast cancer cells rather than the normal lung fibroblast cell line WI-38. Both AM-GA and BA were able to inhibit the cancer cell migration in the wound healing assay and inhibited colony formation. Studying the mechanism of action revealed that AM-GA inhibited the growth of the breast cancer cells via cell cycle arrest at sub-G1 phase, induction of apoptosis and activation of the tumor suppressor protein p53. Conclusion: This work highlights the unique role of AM-GA against breast cancer via different mechanisms and will be the gate for new potent analogues and fights different cancer types.
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Characterization and application of Borassus aethiopum (Arecaceae) shoot pregelatinized starch as binding agent in paracetamol tablets p. 172
Chukwuemeka Paul Azubuike, Uloma Ubani-Ukoma, Shadrack Joel Madu, Oluwateniola Yomi-Faseun, Suliat Yusuf
Aims: The study sought to characterize the physicochemical properties and assess the binding properties of pregelatinized starch (PGSb) derived from Borassus aethiopum shoot at various concentrations in paracetamol (PCM) tablet formulation. Methods and Materials: PGSb was obtained by suspending 100g of the native starch (NS) in 100ml of deionized water at 55°C for 10min. PGSb was characterized using different techniques and compared with a commercial brand of pregelatinized starch (PGSs). The compatibility of PGSb with PCM powder was evaluated using Fouriertransform infrared (FTIR) spectroscopy and differential scanning calorimetry (DSC) techniques. Three batches of PCM granules containing different concentrations of the PGSb as test binder were formulated and compared with two batches containing 1.78% polyvinylpyrrolidone and 1.78% NS as binder, respectively. Results: The evaluated parameters of PGSb were comparable to PGSs. PGSb had improved solubility, lower gelatinization temperature, and better hydration capacity properties compared to the NS. FTIR and DSC studies confirmed the modification of the NS and its compatibility with PCM powder. The tablets formulated were within acceptable limits for the parameters evaluated (tablet thickness, uniformity of weight, hardness, friability, disintegration, and dissolution profile) except the batch that contained NS as binder that failed uniformity of weight and friability tests. All the batches released more than 70% of the active drug at 30min. The dissolution study indicated that there were variations in the drug release profiles among tablets formulated with different binding agents. Conclusions: The findings of this study indicate that PGSb has desirable physicochemical and binding properties.
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Hepatoprotective activity of royal jelly on mercuric chloride–induced damage model in rats p. 181
Cyrus Jalili, Shiva Roshankhah, Amir Jalali, Mohammad Reza Salahshoor
Background: Mercuric chloride (MC) is the chemical composition of mercury and chlorine with many side effects such as oxidative stress referring to mercury toxicity. Royal jelly (RJ) as a honey bee secretion has antioxidant activities. This study was designed to evaluate the effects of RJ against the parameters of hepatic damage in male rats induced by MC toxicity. Materials and Methods: In this study, 48 male rats were randomly assigned into six groups: sham (saline) and MC control (50 mg/kg) groups; RJ groups (200 mg/kg RJ for 1 day and 200 mg/kg RJ for 7 days, orally) and MC + RJ groups (200 mg/kg RJ orally + 50 mg/kg MC intraperitoneally for 1 day, and 200 mg/kg RJ orally and 50 mg/kg MC intraperitoneally for 7 days). Griess technique was used for the determination of serum nitric oxide (NO) level. Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) concentrations were determined for liver functional disturbances value. In addition, thiobarbituric acid reactive species, antioxidant capacity, the diameter of hepatocytes, and the central hepatic vein (CHV) were investigated. Results: MC administration significantly increased the liver malondialdehyde (MDA) and NO levels, the mean diameter of CHV and hepatocyte, hepatic enzymes, and decreased tissue Ferric reducing antioxidant power (FRAP) level compared to the sham group (P < 0.01). The RJ and RJ + MC in all treatments significantly reduced the mean diameter of hepatocyte and CHV, hepatic enzymes, renal MDA and NO levels, and increased tissue FRAP level compared to the MC control group (P < 0.01). It seems that RJ administration recovers the hepatic injury induced by MC in rats.
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Comparative phytochemical screening, in vivo antioxidant and nephroprotective effects of extracts of cassava leaves on paracetamol-intoxicated rats p. 188
Israel O Okoro, Helen E Kadiri, Eferhire Aganbi
The phytochemical screening, antioxidant, and nephroprotective effects of methanol and acetone extracts of cassava (Manihot esculenta Crantz) leaves were comparatively investigated using standard procedures. Fifty-four male Wistar rats (albino) were divided into nine groups of six rats each. Group 1 = negative control (normal untreated rats + normal saline); group 2 = positive control (rats + 2g/kg bw acetaminophen + normal saline), groups 3, 4, and 5 = 200 mg/kg bw, 100 mg/kg bw, and 50 mg/kg bw of methanol extract, respectively, + 2g/kg bw acetaminophen; groups 6, 7, and 8 = 200 mg/kg, 100 mg/kg bw, and 50 mg/kg bw of acetone extract, respectively, + 2g/kg bw acetaminophen; and group 9 = 100 mg/kg silymarin + 2g/kg bw acetaminophen. The phytochemical screening of the methanol and acetone leaves extracts showed the presence of flavonoids, alkaloids, saponins, anthocyanins, tannins, and triterpene, whereas, cardiac glycoside, steroids, and anthraquinone were absent in both extracts. Acetaminophen administration significantly elevated the levels of serum urea, creatinine, sodium, and potassium with a corresponding decrease in the levels of total protein, albumin, and calcium in the group 2 rats compared with that in the group 1 rats. Similarly, the levels of superoxide dismutase, catalase, glutathione peroxidase, glutathione, and glutathione S-transferase were significantly less in the acetaminophen-intoxicated group than that in the negative control group. However, pretreatment with either extracts, dose dependently prevented the acetaminophen-induced derangement of the aforementioned parameters. The extracts showed antioxidant activity similar to the reference drug (silymarin). Comparatively, the methanol extract gave higher in vivo antioxidant and nephroprotective effects than the acetone extract. The results suggest the extracts of cassava leaves have high nephroprotective potential and may be based on their phytoconstituents and antioxidant activity.
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Synthesis, antioxidant, and anti-tyrosinase activity of some aromatic oximes: an experimental and theoretical study p. 195
Rafik Bensegueni, Mounia Guergouri, Chawki Bensouici, Mustapha Bencharif
In this study, five oximes were synthesized, characterized, and their antioxidant activity investigated experimentally and theoretically. Labeled OX1–OX5, our oximes were subjected to three antioxidant activity assays (1,1-diphenyl-2-picrylhydrazyl, cupric reducing antioxidant capacity test [CUPRAC], and ferric reducing antioxidant power test). The related results were very fulfilling presenting certain antioxidant properties for the majority of the studied compounds, especially with CUPRAC test where OX1 and OX2 presented a better result than the used standard antioxidants. Besides, the thermodynamic molecular descriptors (bond dissociation enthalpy, ionization potential, and proton affinity) of our molecules were calculated with the density functional theory to elucidate the experimental results. The resulting values were in a good agreement with the experimental results. The second part of this work consisted of an anti-tyrosinase activity evaluation of the five oximes where three of them displayed an inhibitory effect against this enzyme. To analyze this result, a molecular docking was conducted and the obtained values were in accordance with the experience. Absorption, distribution, metabolism, and excretion properties were also assessed via Molinspiration software and all our molecules satisfied the related conditions. Thus, the conducted theoretical and experimental studies were in excellent harmony, together supporting the antioxidant power of our compounds, which could permit their use in cosmetic, pharmaceutical, or food industry domains, after further clinical tests.
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Anti-inflammatory effect of Myrtus communis hydroalcoholic extract and essential oil on acetic acid–induced colitis in rats p. 204
Parnian Khosropour, Sayed-Ebrahim Sajjadi, Ardeshir Talebi, Mohsen Minaiyan
Background: Colitis is an inflammatory bowel disease, many causes are involved in its pathogenesis and development. Myrtus communis (M. communis) contains anti-inflammatory and antioxidant ingredients that are useful for the treatment of inflammatory disease. Objectives: The purpose of this study was to investigate the effect of M. communis hydroalcoholic extract (MCHE) and essential oil (MCEO) on acetic acid–induced colitis model. Materials and Methods: MCHE (50, 100, 200, and 400 mg/kg) and MCEO (62.5, 125, 250, and 500 µL/kg) were given orally to rats, 2h before induction of colitis and continued for further 4 days. Prednisolone (4 mg/kg) and mesalazine (100 mg/kg) were used as reference drugs. After 5 days, colitis markers and indices were investigated on isolated colons. Biochemical evaluation of inflamed colon was performed using assay of myeloperoxidase (MPO) activity. Results: Acetic acid caused significant inflammatory reactions as indicated by macroscopic and microscopic changes in control groups. Extracts with three doses and volatile oil with two lower doses were effective to reduce weight of distal colon (8cm) as a marker of inflammation and tissue edema. Similarly, MCHE (50, 100, and 200 mg/kg) and MCEO (62.5 and 125 µL/kg) were statistically effective in dip of ulcer index, total colitis index, and MPO activity compared to control groups. Conclusion: The beneficial effect of M. communis was comparable with that of prednisolone and mesalazine; however, by its dose escalation, this activity tends to be diminished. This research showed the anti-inflammatory activity of MCHE and MCEO on experimentally induced acute colitis.
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Comparison of donepezil and riluzole in improving spatial memory of male Wistar rats p. 211
Sina Andalib, Mojtaba Ziaee, Faezeh Mozafari, Reza Hosseini, Mahdieh Anoush
Purpose: Alzheimer’s disease (AD) is a degenerative brain disorder and the major cause of dementia and cognitive deficits in the elderly. Riluzole modulates glutamate concentration and improves memory performance in aged rats and may be of benefit in AD. Donepezil is a cholinesterase inhibitor that is used for the treatment of mild-to-moderate AD. In this study, we compared their effects on attenuation of learning and memory deficits in a rat model of AD. Materials and Methods: Scopolamine injection for 14 consecutive days induced memory impairment. Effect of riluzole on this impaired memory was evaluated by Morris water maze protocols: accusation phase and probe trial test. Adult male Wistar rats (250–300g) were trained for 4 consecutive days, 24 hours after last scopolamine injection. Spatial memory and learning index (%) were measured depending on the time taken to find the platform and the time utilized in the target quadrant (Q2). The time/distance was measured by the computer. Results were analyzed by one-way analysis of variance and Tukey post hoc. Results: Riluzole was effective in the treatment of memory impairment of scopolamine-injected group. The riluzole-treated group, on test day, showed better spatial memory rather than scopolamine-treated group. Besides, learning index (%) improvement was significantly higher in the riluzole-treated group, rather than scopolamine-injected group. Conclusion: It can be concluded that riluzole administration at the same time with scopolamine injection or after it causes marked improvements in learning index during training days and the spatial memory on the test day. Therefore, this study strengthens the hypothesis that acute riluzole treatment is capable of treatment of diseases related to memory impairment such as AD.
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Effect of sodium benzoate on liver and kidney lipid peroxidation and antioxidant enzymes in mice p. 217
Forouzan Khodaei, Hossein Kholghipour, Masood Hosseinzadeh, Marzieh Rashedinia
Introduction: Sodium benzoate (SB), as a chemical preservative, is used in many kinds of foodstuff. Some studies reported toxicity effects of SB in food products and suggested to limit its usage. The aim of this study was to evaluate the effects of oral administration of SB on antioxidant enzymes and lipid peroxidation in the liver and kidney of mice. Materials and Methods: A total of 24 animals were divided into four groups: Control group and three treated groups that received 150, 300, and 600 mg/kg/day of SB, respectively, in drinking water for 4 weeks. The malondialdehyde level, glutathione (GSH) content, superoxide dismutase (SOD), and catalase (CAT) activities of the liver and kidney were measured and the results of the treated groups were compared with those of the control group (one-way analysis of variance). Results: Results showed that SB caused histological alterations in the liver and kidney tissues. Moreover, SB significantly increased lipid peroxidation and GSH content in the kidney tissues (P < 0.05). Also, CAT activity significantly declined in the kidney (P < 0.05), without changing the SOD activity, but SB did not have any effect on the biochemical parameter of the liver tissue. Conclusion: The results of this study showed that SB caused kidney injury more than liver injury, but as a food preservative, which is consumed for a long period of life, it may cause liver damage additionally. For that reason, the excessive SB intake in the food is disturbing.
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Effect of ethyl acetate and aqueous fractions of Ziziphus jujuba extract on biochemical and hematological parameters in rat p. 224
Reza Mohebbati, Yasamin Kamkar-Del, Mohammad Naser Shafei
Introduction: Despite the numerous therapeutic effects of the Ziziphus jujuba (ZJ), its effect on biochemical and hematological parameters are unknown. Therefore, in this study, the effect of ethyl acetate (EA) and aqueous (AQ) fractions of the ZJ fruit extract on biochemical and hematological parameters were explored. Material and Methods: Thirty-six male Wistar rats randomly were divided into six groups as follows: (1) Control, (2) ZJ extract (200mg/kg), (3, 4) EA fraction of ZJ (EA150 and EA300mg/kg), and (5, 6) AQ fraction of ZJ (AQ150 and AQ300mg/kg). Saline, ZJ extract, and its fractions were gavage once a day for 4 weeks. At the day of the experiment (28th day), one blood sample was collected in citrated tube for the counting of the complete blood cell count calculation. The serum was used for biochemical parameters (cholesterol, triglyceride, and glucose concentrations) evaluation. Results: The results showed that the blood glucose, cholesterol, and triglyceride levels in all treated groups, especially in AQ groups, significantly decreased compared to the control (P < 0.01 to P < 0.001) group. Furthermore, the number of red blood cell and white blood cell in treating rats with ZJ extract and its AQ fraction significantly increased (P < 0.05), whereas the number of platelets significantly decreased (P < 0.05) compared to the control. Conclusion: In conclusion, both AQ and EA fractions of ZJ have beneficial effects on biochemical and hematological parameters. Since the effect of AQ fraction is higher than EA, it is suggested that these effects of ZJ mostly mediated by compounds of ZJ that soluble in the polar solvent.
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Ethanol extract of jati belanda (Guazuma ulmifolia L.) as therapy for chronic kidney disease in in vitro model p. 229
Sijani Prahastuti, Meilinah Hidayat, Stella Tinia Hasiana, Wahyu Widowati, Annisa Amalia, Rismawati Laila Qodariah, Rizal Rizal, Hanna Sari W Kusuma, Zakiyatul Khoiriyah
Background: People with diabetes mellitus in Indonesia are predicted to increase until 2035. High glucose in body (hyperglycemia) leads to increased fibronectin synthesis. Fibronectin that gets accumulated in glomerulus (mesangial cells), at the end, will lead to diabetic glomerulosclerosis. Jati belanda (Guazuma ulmifolia L.) leaf is well known as an Indonesian traditional medicine to have effects as antidiabetic by the presence of its secondary metabolites such as alkaloid, tannin, saponin, flavonoid, and terpenoid, which are very important in health recovery. Objectives: To evaluate the activity of ethanol extract of jati belanda (EEJB) as a protection agent on induced-glucose mesangial cells of SV40 MES 13 cell line (glomerular mesangial kidney, Mus musculus). Materials and Methods: EEJB (3.125 and 6.25 µg/mL) was extracted based on maceration method using ethanol (70%) as the solvent. Proliferation and viability were performed based on (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) (MTS) method. The level of transforming growth factor β1 (TGF-β1) and fibronectin in glucose-induced mesangial cells was assayed and determined using enzyme-linked immunosorbent assay kit. Reactive oxygen species (ROS) level was measured using flow cytometer. Results: EEJB (3.125 and 6.25 µg/mL) increased cell proliferation and viability in glucose-induced mesangial cells and significantly reduced the level of TGF-β1, fibronectin, and ROS compared to that in positive control (glucose-induced cells). Conclusion: Our study suggests that EEJB is able to reduce TGF-β1, fibronectin, and ROS levels in glucose-induced mesangial cells, which correlate to diabetic glomerulosclerosis condition and increase the mesangial cell proliferation and viability.
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Formulation and optimization of effervescent tablet containing bismuth sub-citrate p. 236
Somayeh Taymouri, Abolfazl Mostafavi, Mohamad Javanmardi
Objective: The objective of this study was to design, evaluate and optimize effervescent tablets containing bismuth sub-citrate with sufficient hardness and friability in treatment of peptic ulcer. Materials and Methods: Effervescent tablets were prepared by direct compression method and were optimized using irregular factorial design. Amount of citric acid, sodium bicarbonate to citric acid molar ratio, polyvinyl pyrrolidone K 30 (PVP k30), polyethylene glycol 6000 (PEG 6000) were selected as independent variables, whereas disintegration time, amount of carbon dioxide (CO2), friability, pH, and hardness were selected as dependent variables. All the batches were assessed for various pre and post compression characteristics such as flowability, hardness, friability, effervescent time, pH, and content uniformity. For the enhancement of tablets’ palatability, the components of optimized formulation were mixed with same amounts of different flavoring agents. Results: The best results obtained from effervescent tablets prepared by 500 mg citric acid, 5% PEG 6000 and 3% PVP k30 while the molar ratio of the sodium bicarbonate to citric acid was 3. The disintegration time, amount of CO2, friability, pH, and hardness of optimized formulation were confirmed to be 95.33 ± 1.15sec, 398.73 ± 1.46 mg, 0.73%, 6.0 ± 0.06 and 72.3 ± 5.5 N, respectively. The most pleasant taste according to volunteers’ acceptability was the taste of cherry. Conclusion: These results suggest that developed effervescent tablets may be promising for delivery of bismuth sub-citrate in peptic ulcers therapy.
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Formulation and evaluation of Neem (Azadirachta indica A. Juss) seed oil suppositories p. 245
Olusola I Aremu, Kokonne E Ekere, Yetunde C Isimi, Victoria C Nwaogu, Olawale G Agbaje, Olubunmi J Olayemi, Musiliu O Adedokun, Martins O Emeje
Background: Neem seed is very vital because of its rich lipid content and bitter constituents. Aims: This study was designed to provide a scientific rationale for the preparation and use of Neem seed oil as suppositories using dika fat (DF), and macrogol (MG), as bases. Materials and Methods: The suppositories which were prepared by fusion method using a pre-calibrated mould, were characterized using parameters like appearance, crushing strength, weight variation, melting point, pH, liquefaction time and in-vitro release according to standard procedures. Results: Results show that, the suppository strengths were in the order; bland, MG (25.00 ± 1.50N) > DF (12.90 ± 0.72 N), while those containing medicaments were NSM1 (20.00 ± 1.92) > NSD1 (12.90 ± 0.94) > NSM2 (12.70 ± 1.24 N) > NSD2 (10.00 ± 1.35 N). The pH of medicated formulations were NSM1 (6.50 ± 0.01), NSM2 (6.54 ± 0.03) > NSD1 (5.73 ± 0.04) and NSD2 (5.07 ± 0.03). Melting point values show that, macrogol base had mean values of 36.80 °C ± 0.62 and 36.40 °C ± 0.46 for NSM1 and NSM2 respectively, whereas, those with DF gave an average melting point values of 32.10 °C ± 0.87 and 30.90 °C ± 0.79 for NSD1 and NSD2 respectively. Conclusion: Results obtained showed that suppositories prepared with Macrogol (MG) base exhibited better physicochemical properties than Dika fat (DF) base suppositories, therefore water soluble bases may be bases of choice in the delivery of neem seed oil.
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Development of docetaxel-loaded folate-modified Poly(lactic-co-glycolic acid) particles p. 253
Yuri I Poltavets, Vasilisa V Zavarzina, Sergey L Kuznetsov, Anna A Krasheninnikova, Danil O Dronov, Nadezhda V Gukasova, Valentina G Shuvatova, Vadim Yu Balabanyan
Background: Poly(lactic-co-glycolic acid) (PLGA) particles with small vector molecules are used for targeted delivery of anticancer agents. To be effective, they must be small, noncytotoxic, sterile, and stable. Aim: The aim of this study was to prepare docetaxel-loaded folate-modified PLGA-based nanoparticles (FD-Dtx-NPs) and to assess their as parenteral folate-receptor targeted delivery systems during γ-sterilization and long-term storage. Materials and Methods: NPs were prepared by oil/water single emulsion-solvent evaporation method and simultaneous loading of polymer particles with docetaxel and folic acid derivative. NPs’ physicochemical characteristics and antitumor activity were assessed. Findings: FD-Dtx-NPs presented uniform characteristics over repeated measurements: ~250 nm size, <0.100 polydispersity index, and >2.5% docetaxel content in the finished lyophilizate. The observed slow docetaxel release from FD-Dtx-NPs was acceptable for proposed usage. γ-irradiated NPs were sterile under all tested protocols and maintained their physicochemical properties at a 10-kGy cumulative dose, 0.500 Gy/s dose rate, and 5.57-h exposure. No significant differences were observed in physicochemical characteristics of FD-Dtx-NPs over 12 months. Finally, FD-Dtx-NPs showed a high anticancer activity in vitro. Conclusion: The proposed method generates FD-Dtx-NPs with reproducible characteristics, high activity, and elevated stability during the long-term storage. Results of γ-sterilization and stability studies may be valuable for the development of polymer-based drugs.
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Synthesis of 4-phenyl-4,5-dihydropyranopyrazolone derivatives with activated potassium carbonate: Evaluation of anticancer activity on cancer cell lines and apoptosis mechanism p. 262
Leila Hosseinzadeh, Navid Mahmoudian, Farahnaz Ahmadi, Hadi Adibi
A green and efficient one-pot, four-component synthesis of 4-phenyl-4,5-dihydropyranopyrazolone derivatives 5a–5l is described in ethanol-water with activated potassium carbonate and evaluation of anticancer activity on cancer cell lines and apoptosis mechanism is also investigated. This method provides several advantages such as environmental friendliness, shorter reaction time, excellent yields, and simple workup procedure. The in vitro cytotoxic activity of the synthesized compounds was investigated against cancer cell lines (PC-3, MCF-7, and A-2780) in comparison with doxorubicin, a well-known anticancer drug, using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide colorimetric assay. Also apoptosis studies were investigated by caspase-3 and caspase-9 enzymes and mitochondrial membrane potential. Our compounds showed acceptable and moderate cytotoxicity compared with doxorubicin in the studied cell lines. The compounds 5g in PC3 cell line (half maximal inhibitory concentration (IC50= 104 µM)), 5g and 5i in MCF7 cell line (IC50 = 23 and 87 µM, respectively), and 5g–5i in A2780 cell line (IC50 = 60, 50, and 31 µM, respectively) showed the best results close to the control drug doxorubicin. The compound 5h showed significant result in the activation of caspase-3 and caspase-9 enzymes in comparison with the control. Only the 5g in MCF7 cells and the 5g–5i derivatives in A2780 cells caused increased mitochondrial membrane potential compared to the control group.
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Preparation and evaluation of matrix containing lidocaine and prilocaine for using in transdermal films p. 270
Maryam Kouchak, Saeed Rezaee, Nasrin Moshabeh, Somayeh Handali
Background: Lidocaine and prilocaine are amide-type local anesthetic agents that are expectedly adequate to create a rapid pharmacological effect immediately after using transdermal delivery system. Objective: The aim of this study was to investigate the effect of hydrophilic and hydrophobic materials on drug release from different polymeric films containing lidocaine and prilocaine. Materials and Methods: Several films containing lidocaine and prilocaine were prepared using ethyl cellulose (EC) or hydroxypropyl methylcellulose (HPMC) polymers. The effect of propylene glycol (PG) and polyethylene glycol 4000 (as permeation enhancers) and triacetin or dibutyl phthalate (DBP) as plasticizer on tensile strength, moisture absorption, content uniformity, and drug release properties were investigated. In vitro permeations studies were carried out using Fransz diffusion cells and samples were analyzed by high-performance liquid chromatography for each drug. Results: DBP unlike triacetin had a dramatic effect on drug release rate and moisture absorption in HPMC films. The presence of PG on the formulations containing EC caused an increase in the moisture absorption and drug release and shifted the mechanism of release from Fickian diffusion to Case-II transport. PEG4000 was not a significant effect on these variables in the HPMC films. Conclusion: Hydrophilic additives like PG when used in an water-insoluble membrane act as a channeling agent and increase the rate of drug release because in dissolution medium they dissolve out of the film and leave channels from which drug can be released more rapidly.
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Design and development of transdermal drug delivery of nonsteroidal anti-inflammatory drugs: Lornoxicam p. 277
HN Shivakumar, Ruchira S Kotian
Background: Conventional route, the most common route of administration, has drawbacks such as hepatic first-pass metabolism, poor bioavailability, and ability to alter drug concentrations in the blood. These problems can be overcome by a controlled-release drug delivery system, which can be accomplished with the development of transdermal drug delivery system. Objective: The objective of this study was to design and develop a lornoxicam-loaded matrix-type transdermal films with different permeation enhancers and determine their physicochemical characteristics. Materials and Methods: Lornoxicam-loaded transdermal films were prepared by the solvent evaporation technique. The Fourier transform infrared spectroscopic studies were performed to determine the drug–excipient interactions. Six formulations were prepared with different permeation enhancers such as propylene glycol, dimethylformamide, dimethyl sulfoxide (DMSO), sodium lauryl sulfate, Span 20, and TWEEN 80 by using 500 mg of sodium alginate as the polymer and 60% w/w glycerin as the plasticizer. The prepared formulations were evaluated for thickness, uniformity of weight, moisture loss, moisture uptake, drug content, and tensile strength. The effect of different permeation enhancers on diffusion was determined through a shed snakeskin by using Franz diffusion cells. Results: The preformulation studies conducted were fulfilled to design a matrix-type transdermal film. In vitro diffusion 24 h indicated that the steady state flux were in the order of F3 > F2 > F1 > F6 > F5 > F4. It was observed that the film prepared with DMSO showed higher diffusion than the formulations with other permeation enhancers. Conclusion: It was concluded that permeation enhancer to prepare lornoxicam-loaded matrix-type transdermal film to improve patient compliance.
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Evaluation of potential drug-drug interactions in patients with hematologic malignancies at a referral hematology–oncology hospital: A single-center experience p. 284
Sara Ataei, Kaveh Ardalani, Maryam Mehrpooya, Mojdeh Mohammadi
Background: Drug-drug interaction (DDI) is a complication that results from the combined use of two or more drugs. DDIs can create problems and increase drug toxicity. In some DDIs, a drug can reduce the effectiveness of other drugs. The treatment regimen of hematologic malignancies includes various medicines. Patients may have another disease and receive other medicines in their treatment regimen, resulting in an elevation of DDI rate. This study was aimed to study the rate, pattern, and probable risk factors for moderate and major interactions. Subjects and Methods: In this cross-sectional study, data including type of administrated drugs, type of malignancies, and patients’ demographic data were obtained from medical records of patients referred to Tohid Hospital, Sanandaj, Iran, between 2011 and 2015. Major or moderate interactions were considered eligible for further analysis and minor interactions were excluded. DDIs were identified by Lexicomp software and Drug Interaction Facts book. Data analysis was carried out by descriptive statistics. Results: A total of 441 DDIs (moderate to major) were identified in 76 patients. DDIs in men were higher compared to women. In addition, most of the interactions in terms of intensity were moderate (62% of total interactions) and in terms of mechanism were pharmacodynamic (60% of total interactions). Interaction between acetaminophen and granisetron had the highest frequency. Among cancer drugs, cyclophosphamide (7% of total interactions) and among non-cancer drugs, granisetron (10% of total interactions) had the highest frequencies. Conclusion: Moderate or major DDIs occurred frequently in patients with blood cancer or related diseases. Most of the found DDIs were categorized as moderate with regard to severity. DDIs identification by the treatment team and replacement of treatment regimen will impose fewer complications on patients and increase patients’ survival.
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Quality by design: A Roadmap for quality pharmaceutical products p. 289
Mayur Ashok Chordiya, Hemant Hiraman Gangurde, Vikram Nirmal Sancheti
Quality by design (QbD) refers to a new approach to product development that could increase efficiencies, provide regulatory relief and flexibility, and offer important business benefits throughout the product life cycle. QbD is increasingly becoming an important and widely used technique in the pharmaceutical industry. QbD can be considered to be system-based approach to the design, development, and delivery of any product or service to a consumer. It is an approach to pharmaceutical development that begins with predefined objectives and emphasizes product and process understanding and process control. Process parameters and quality attributes are identified for each unit operation. Benefits, opportunities, and steps involved in QbD of pharmaceutical products are described. The aim of pharmaceutical development is to design a quality product and its manufacturing process to consistently deliver the intended performance of the product. Quality cannot be tested into products, but quality should be built in by design. It includes the quality target product profile, critical quality attributes, and key aspects of QbD. It also gives comparison between product quality by end product testing and product quality by QbD. The foundation of QbD is ICH guidelines. Hence, if we identify the cause and effect relationship between the various inputs and responses by carefully designed experiments, we can control the quality of the product by simply controlling the inputs such as raw material specifications or process parameters.
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Age peculiarity manifestation of antioxidant effect of 6-hexyl-3,6-dimethyl-6,7-dihydro-2H-[1,2,4]triazino[2,3-c]quinazolin-2-one on rats under the intermittent hypobaric hypoxia p. 295
Volodymyr Mykolayovuch Shvets, Alexei Yuriyevich Voskoboynik, Galina Grigorievna Berest, Sergiy Ivanovych Kovalenko, Maxim Vyacheslavovich Agibailov, Oleg Konstantynovuch Kulchitskiy, Nataliya Olegivna Kulchitska, Vadim Vyacheslavovich Davydov
Background: The organism of an old human as well as an experimental animal has decreased adaptive abilities and increased sensitivity to the effect of adverse environmental factors. We point out the high relevance of the search of new pharmacological compounds that have strong antioxidant properties and can be used to treatment and prevention of cardiovascular diseases with ageing. Aims and Objective: The aim of the study was to investigate the antioxidant activity of 6-hexyl-3,6-dimethyl-6,7-dihydro-2H-[1,2,4]triazino[2,3-c]quinazolin-2-one (HTQ). Materials and Methods: Two groups of nonlinear male Wistar rats: 6–8 months (adult) and 24–26 months (old) were used. Determination of the myocardial diene conjugates and products reacting with 2-thiobarbituric acid (TBA-AP) concentration was carried out. Results: Concentrations of diene conjugates in adult and old rats, which were administered HTQ, were 21% and 32%, respectively, lower compared to animals to which the synthesized compound was not administered. After administration of HTQ, the concentration of TBA-AP in old animals decreased by 23% as compared with the animals of the control group. Conclusion: An administration of HTQ has limited the accumulation of intermediate lipid peroxidation products in the hearts of old animals in the condition of hypoxia.
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Antioxidant effects of amygdalin on tunicamycin-induced endoplasmic reticulum stress in the mice liver: Cross talk between endoplasmic reticulum stress and oxidative stress p. 298
Azam Moslehi, Tahereh Komeili-movahed, Mohammad Moslehi
Context: Both endoplasmic reticulum (ER) stress and oxidative stress are involved in pathophysiology of many diseases. Recently, a cross talk between ER stress and oxidative stress has been identified. Amygdalin is an active ingredient in the seeds of apricots, bitter almonds, peaches, and other rosaceous plants. Aim: This study was designed to evaluate the antioxidant effects of amygdalin on the liver-induced ER stress. Materials and Methods: C57/BL6 inbred male mice were placed in five groups comprising saline, vehicle, and amygdalin as control groups. ER stress was induced by tunicamycin (TM) injection (ER stress group). Amygdalin was administered 1h before TM challenge (ER stress + amygdalin group). Liver tissue supernatants were prepared and malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), and glutathione (GSH) were measured. Results: The findings showed that ER stress increased MDA level and decreased SOD and CAT activity and GSH level (P < 0.05). Pretreatment with amygdalin decreased MDA concentration, whereas it increased SOD and CAT levels (P < 0.05). Conclusion: This study showed that amygdalin attenuated TM-induced ER stress and has a considerable antioxidant activity in the liver tissue.
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