فهرست مطالب

Research in Pharmaceutical Sciences
Volume:15 Issue: 6, Dec 2020

  • تاریخ انتشار: 1399/09/09
  • تعداد عناوین: 10
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  • Dion R. Brocks*, Dalia A. Hamdy Pages 503-514

    Bayesian estimation of pharmacokinetic parameters (PKP), as discussed in this review, provides a powerful approach towards the individualization of dosing regimens. The method was first described by Lewis Sheiner and colleagues and it is well suited in clinical environs where few blood fluid measures of drugs are available in the clinic. This makes it a valuable tool in the effective implementation of therapeutic drug monitoring. The principle behind the method is Bayes theorem, which incorporates elements of variability in a priori</em>-known population estimates and variability in the pharmacokinetic parameters, and known errors intrinsic to the assay method used to estimate the blood fluid drug concentrations. This manuscript reviews the Bayesian method. The literature was scanned using Pubmed to provide background into the Bayesian method. An Add-in for Excel program was used to show the ability of the method to estimate PKP using sparse blood fluid concentration vs</em> time data. Using a computer program, the method was able to find reasonable estimates of individual pharmacokinetic parameters, assessed by comparing the estimated data to the true PKP. Education of students in clinical pharmacokinetics is incomplete without some mention and instruction of the Bayesian forecasting method. For a complete understanding, a computer program is needed to demonstrate its utility.

    Keywords: Clinical pharmacology, Dosage regimen design, Pharmacy education, Therapeutic drugmonitoring
  • Afshin Fassihi*, Farshid Hasanzadeh, Ahmad Movahedian Attar, Lotfalah Saghaie, Mehrdad Mohammadpour Pages 515-528
    Background and purpose

     Reactive oxygen species (ROSs) are continuously produced as byproducts of cell metabolism. Free radicals are an unstable form of ROSs with the tendency to react readily with biomolecules such as amino acids, lipids and DNA. These reactions lead to oxidative damages to the cell. Oxidative stress occurs when the concentration of the ROSs exceeds the capacity of antioxidative protection systems of the body. 5-Hydroxypyridin-4-one derivatives can chelate Fe2+</sup> and Fe3+</sup> due to their α-hydroxyketone moiety. Also, tautomerism in hydroxypyridinone ring leads to enough level of aromaticity resulting in a catechol-like behavior that provides them with good chelating and radical scavenging properties.

    Experimental approach

     Different compounds were synthesized with 5-hydroxypyridine-4-one moiety as the core. The antioxidant properties of molecules were evaluated experimentally by DPPH scavenging method and theoretically using DFT/B3LYP with a 6-31++G (d,p) basis set. Electronic properties were investigated using frontier molecular orbital theory calculations. Furthermore, global descriptive parameters were obtained to find the chemical reactivity of molecules. The natural bond orbital analysis was performed to investigate charge distribution and hydrogen bonding.

    Findings/ Results

    Structures of the synthesized compounds were confirmed using IR, 1</sup>H-NMR, and 13</sup>C-NMR spectral analyses. Among all the synthesized compounds, Va and Vb showed the best antioxidant effect experimentally and computationally.

    Conclusion and implications

     Results of this study were valuable in terms of synthesis, in silico,</em> and in vitro</em> antioxidant evaluations and can be useful for future investigations about the design of novel 5-hydroxypyridin-4-one derivatives possessing iron-chelating and radical scavenging abilities. 

    Keywords: Antioxidant, DFT, Hydroxypyridinone, Radical scavenging
  • Parisa Ghasemiyeh, Afsaneh Vazin, Farid Zand, Amir Azadi, Iman Karimzadeh, Soliman Mohammadi Samani, * Pages 529-540
    Background and purpose

    Vancomycin is a glycopeptide antibiotic which is the drug of choice against methicillin-resistant Staphylococcus aureus</em>. It has a narrow therapeutic index, and thus therapeutic drug monitoring (TDM), and clinical pharmacokinetic assessment are necessary in order to prevent adverse drug reactions such as nephrotoxicity. In this study, we aimed to develop a simple and validated HPLC method for vancomycin assay in order to establish a TDM center for patients admitted to the ICU of Nemazee Hospital in southern Iran.

    Experimental approach

    In this study, a brief review of different parameters and variables which could affect the sensitivity, selectivity of the validated HPLC method for vancomycin determination were considered. According to the previous studies a simple, fast, and the relatively low-cost method was established for vancomycin determination in plasma samples.

    Findings/ Results

     The developed HPLC assay indicated a calibration curve with R-square of > 0.999, acceptable selectivity, the accuracy of 90-105%, CV% of less than 15%, the limit of quantification of 1 µg/mL, and limit of detection of 300 ng/mL. Vancomycin trough level, the area under the curve, renal clearance, the volume of distribution,, and elimination constant were measured in patients using this validated method.

    Conclusion and implications

     Validated method for assay of vancomycin plasma levels was used to quantify vancomycin levels of four patients who were admitted to the ICU of Nemazee Hospital. According to the results, two of these patients showed lower levels than recommended therapeutic purposes while one of them showed a toxic level. According to the results, the TDM assessment of vancomycin is strongly recommended for patients who are hospitalized in ICU. 

    Keywords: Acute kidney injury, AUC, HPLC, ICU, TDM, Vancomycin
  • Cyrus Jalili, Nasim Akhshi, Iraj Rashidi, Ali Ghanbari* Pages 541-550
    Background and purpose

     Mercuric chloride (Merc) can cause kidney toxicity. Harmine (Harm), an herbal alkaloid has various pharmacological and medicinal effects mainly because of its antioxidant activity. In this study, therefore, Harm’s protective mechanisms on Merc-induced nephrotoxicity in BALB/c male mice were investigated.

    Experimental approach

     Forty-eight male mice were randomly divided into six groups (n = 8). Groups  were received saline, Merc (0.5 mL/day of 0.5 ppm aqueous), Harm (5, 10, 15 mg/kg/day), Merc + Harm   (5, 10, 15 mg/kg/day) for 14 consecutive days. Saline and Harm were administrated intraperitoneally and Merc dissolved in drinking water. Urea and creatinine serum levels, body weight, kidney weight, quantitative and qualitative histological alterations, apoptosis rate, total antioxidant capacity (TAC), superoxide dismutase (SOD), and nitric oxide (NO) levels were evaluated.

    Findings/ Results

    There was a significant reduction in total body and kidney weights, renal histological criteria, TAC, SOD levels in the Merc group compared to the control group (P</em> < 0.05), whereas these parameters in the Merc + Harm groups, were significantly increased compared to the Merc group (P</em> < 0.05). Urea and creatinine serum levels, levels of NO, and apoptosis were significantly higher in the Merc group than the control, while these parameters were decreased in the Merc + Harms groups in comparison with the Merc group (P</em> < 0.05).

    Conclusion and implications

     Harm protected Merc-induced renal damage in mice. This protection was observed in both histological and biochemical respects. The beneficial effect of Harm was related to its antioxidant properties that diminish NO production and apoptosis induction in the kidney.

    Keywords: Antioxidants, Apoptosis, Harmine, Mercuric chloride, Kidney
  • Ghader Babaei, MohammadHassan Khadem Ansari*, Shiva Gholizadeh Ghaleh Aziz, Masoumeh Rajabi Bazl Pages 551-562
    Background and purpose

     Cancer stem cells (CSCs), as the subpopulation of cancer cells, are associated with carcinogenesis, chemoresistance, and metastasis in malignancies. Also, CSCs are considered as the major reason for treatment failure in prostate cancer (PCa). Alantolactone (ALT), exerts anticancer activity in different types of cancers. In the present study, the relationship between ALT and CSCs in PCa metastasis and the molecular mechanisms involved in the progression of PCa were investigated.

    Experimental approach

     In this study, to evaluate cell viability, MTT assay was performed. Then, PC3 cells were treated with nontoxic concentrations of ALT and after this step wound-healing assay, colony-formation assay and chemosensitization assay were applied to determine cell migration, the ability of colony formation, and chemoresistance, respectively. Also, real-time polymerase chain reaction and western blotting were used for the determination of genes and protein expression, respectively.

    Findings/ Results

     Our finding showed that ALT at nontoxic concentrations (0.01 and 0.1 µM) for 72 h suppressed the STAT3 phosphorylation and signaling pathway. Also, ALT was able to modulate the stemness of PCa cells through downregulation of expression of SOX2, Oct-4, Nanog, CD133, CD44, and upregulation of p53 expression. On the other hand, we further found that ALT in nontoxic concentrations sensitized PCa cells to cisplatin.

    Conclusion and implications:

    ALT combated the stemness of cancer cells and metastasis by antagonizing of STAT3 signaling pathway. In addition, ALT exhibited anti-metastatic properties and may have potential as a new chemotherapy agent for the reduction of PCa metastasis.

    Keywords: Alantolactone, Cancer stem cell, Prostate cancer, Sesquiterpene lactone
  • Shahab Bohlooli, Negin Nejatkhah, Saghi Sepehri, Donya Doostkame, Nima Razzaghi Asl* Pages 563-570
    Background and purpose

     Considering the undesirable consequences of prevalent cancer diseases, design and development of potent and selective anticancer chemotherapeutics is a major concern. Several studies have unraveled the potential of dihydropyrimidinone (DHPM) scaffold toward generating anticancer agents. 

    Experimental approach

     In the present work, a series of new dihydropyrimidinethiones (DHPMTs) along with a few acyclic enamino amides were synthesized and evaluated for their cytotoxic activity against human gastric (AGS), liver (Hep-G2), and breast (MCF-7) cancer cell lines.

    Findings/ Results

     Among the assessed compounds, one of the DHPMT derivatives (compound 5</strong>: </strong>4-(3-fluorophenyl)-6-methyl-N</em>-phenyl-2-thioxo-1,2,3,4-ttrahydropyrimidine-5-carboxamide) exhibited superior cytotoxicity in all of the target cell lines (AGS, IC50 </sub>9.9 µM; MCF-7, IC50 </sub>15.2 µM; and Hep-G2, IC50 </sub>40.5 µM). Cytotoxicity assessments showed that non-cyclic enamino amides exhibited weaker activities when compared to cyclic analogues (DHPMs).

    Conclusion and implications

     DHPMTs were better cytotoxic agents than non-cyclic enamino amides. Structure activity relationship studies guided us toward the design of DHPMT derivatives with OH and NH groups particularly on meta </em>position of 4-phenyl ring and hydrophobic bulky substituents on carboxamide side chain within the structure. Possible interaction with the hydrophobic site(s) of the cellular target was supposed. The results of this study emphasized the potential role of DHPMTs and their optimized derivatives as privileged medicinal scaffolds to inhibit the growth of gastric, breast, and liver cancer cells. 

    Keywords: Cancer, Cytotoxicity, Dihydropyrimidinethione, Enamino amide, MTT
  • Shima Shirzad, Ali Neamati*, Farzaneh Vafaee, Hamed Ghazavi Pages 571-582
    Background and purpose

    Venenum Bufonis is a Chinese traditional medicine produced from the glandular secretions of toads that contain biogenic amines, which have anti-inflammatory properties. The present study aimed to examine the effect of Bufo viridis</em> secretions (BVS) on anxiety and depression-like behavior and hippocampal senile plaques volume in an animal model of Alzheimer’s disease (AD).

    Experimental approach

    Thirty-eight male Wistar rats were used. AD was induced by amyloid-beta (Aβ1-42</sub>)(10 µg/2 µL, intracerebroventricular injection, </strong>icv) and then BVS at 20, 40, and 80 mg/kg were injected intraperitoneally (ip) in six equal intervals over 21 days. Anxiety and depression-like behavior were assessed using behavioral tests including open field test (OFT), elevated plus maze (EPM), and forced swimming test (FST) 21 days after the surgery.  The volume of senile plaques was assessed based on the Cavalieri principle.

    Findings/ Results

    Results of the OFT showed that the central crossing number and the time in the AD group were significantly decreased compared to the sham group (P</em> </em>˂ 0.01 and P</em> ˂ 0.001, respectively). Also, the values of these two parameters significantly increased in the AD + BVS80 group than the AD group (P </em>˂ 0.05 and P</em> ˂ 0.001, respectively). The time spent in the closed arm in the EPM dramatically increased in the AD group compared to the sham group (P </em>˂ 0.05) and significantly decreased in the AD + BVS80 group compared to the AD group (P </em>˂ 0.05). Results of the FST indicated that immobility time had a reduction in the AD + BVS20 (P </em>˂ 0.01), AD + BVS40, and AD + BVS80 groups compared to the AD group (P </em>< 0.001). The volume of senile plaques in the hippocampus showed a reduction in the treatment groups in comparison with the AD group (P</em> < 0.001 for all).

    Conclusion and implications

    Results revealed that BVS injection could improve symptoms of anxiety and depression and decrease senile plaques in the hippocampus in an animal model of AD. </strong>

    Keywords: Amyloid-β1-42, Bufo viridis secretion, Depression, Elevated plus-maze, Forced swimming test, Open field test
  • Iman Karimzadeh, Asma Sepehr Sobhani, MohammadJavad Khoshnoud, *, MohammadMahdi Sagheb, Reza Vejdani, Atefeh Jalali, Motahareh Mahi Birjand Pages 583-591
    Background and purpose

    The most important adverse reaction of amphotericin B (AmB) is nephrotoxicity. The aim of this study was to assess the potential effectiveness of intravenous saline + sodium bicarbonate versus intravenous sodium chloride hydration in preventing or attenuating AmB nephrotoxicity. 

    Experimental approach:

    A randomized, non-placebo-controlled, single-blinded clinical trial was conducted in two adult hematology-oncology wards of Namazi hospital. Eligible patients were randomly assigned into either the normal saline or normal saline + sodium bicarbonate groups by the ratio of 1:2. In the normal saline group, 1000 mL of sodium chloride 0.9% (154 meq sodium) was given intravenously as two equal 500 mL volumes before and during the infusion of AmB. Patients in the saline + sodium bicarbonate group received 500 mL sodium chloride 0.9% (72 meq sodium) before and 500 mL isotonic sodium bicarbonate (72 meq sodium) intravenously during AmB infusion. 

    Findings/ Results:

    The rate of AmB nephrotoxicity was comparable between normal saline and sodium bicarbonate groups (54.2% and 41.6%, respectively; P = 0.3). This difference did not reach the level of statistical significance after considering AmB dose and duration of the treatment. The frequency of hypokalemia and hypomagnesemia did not differ significantly between the two groups even after adjusting the results according to AmB dose and treatment duration.

    Conclusion and implications

    The results of the current preliminary clinical trial suggested that the combination of sodium bicarbonate and normal saline compared to normal saline alone appears to have no superiority in preventing or attenuating different studied aspects of AmB nephrotoxicity in patients with hematological malignancies.

    Keywords: Amphotericin B, Sodium bicarbonate, Sodium chloride, Nephrotoxicity, Prevention
  • Esmaeil Khajeh, Yousef Rasmi*, Fatemeh Kheradmand, Hassan Malekinejad, Pornanong Aramwit, Ehsan Saboory, Behrokh Daeihassani, Mahdieh Nasirzadeh Pages 592-601
    Background and purpose

     Crocetin is a natural antioxidant that is found in the crocus flower and Gardenia jasminoides  (fruit). Previous studies have reported its anticancer activity both in vivo</em> and in vitro</em>. In addition, crocetin suppresses the growth and migration of human colorectal cancer cells, however, its mechanism of action remains to be elucidated. Therefore, the present study investigated the molecular mechanism of crocetin effect on colorectal cancer cells (HCT-116) in vitro.

    Experimental approach

     HCT-116 cells were treated with different concentrations (0, 200, 400, 600, and  800 μM) of crocetin for 24 h. The cell survival rate was measured by MTT assay. Cell migration capacity was evaluated using the wound healing assay. The expression levels of vascular endothelial growth factor (VEGF) and matrix metalloproteinase (MMP-9) was monitored by RT-PCR. Phosphorylation of focal adhesion kinase (FAK) and p38 mitogen-activated protein kinase (MAPK) was determined using western blot.

    Findings/ Results

     The proliferation of HCT-116 was inhibited by crocetin at 800 μM (P</em> < 0.001). Crocetin prevented migration of HCT-116 cells (P</em> < 0.05) and suppressed VEGF and MMP-9 mRNA expression   (P</em> < 0.001) and increased phosphorylation of p38 (MAPK; P</em> < 0.001). However, no significant change in the phosphorylation of FAK was observed.

    Conclusion and implication

     These data suggested that crocetin-induced growth- and migration-suppressing effects on HCT-116 cells may partially depend on the regulation of the p38 (MAPK) signaling pathway. 

    Keywords: Crocetin, HCT-116 cells, Matrix metalloproteinase 9, p38-mitogen activated protein kinase, Vascular endothelial growth factor
  • Nilesh Kumar Mitra*, Kong Yu Xuan, Charmaine Caryn Teo, Ng Xian Zhuang, Anudeep Singh, Jestin Chellian Pages 602-611
    Background and Purpose

    Multiple sclerosis (MS) is an autoimmune disorder characterized by demyelination and axonal loss. Quantitative estimation of behavioral, locomotor, and histological changes following the use of alpha-tocopherol (AT) in the animal model of MS have not been reported. The present study was planned to evaluate whether AT can improve sensorimotor dysfunction and reduce demyelination in the cuprizone (CPZ)-induced rat model of MS.

    Experimental approach

    Female Sprague-Dawley rats (8 weeks) were fed with cuprizone diet for 5 weeks followed by intraperitoneal injections of alpha-tocopherol (100 mg/Kg) or PBS for 2 weeks (groups E1 and E2, n = 8). Group C (n = 8) was fed with normal pellets followed by intraperitoneal doses of PBS. Open-field test and beam walking were carried out on every 10th day. The mean area of demyelination in the corpus callosum was quantified in Luxol® fast blue (LFB) stained histological sections of the forebrain. Qualitative grading for relative changes in the stains of myelinated fibers was also done.

    Findings/ Results

    During withdrawal of CPZ, AT treatment increased the average speed by 22% in group E1, compared to group E2 (P < 0.05). The mean time to walk the beam was reduced in group E1 by 2.6% compared to group E2 (P < 0.05). The rearing frequency was increased in group E1 during week 6-7 compared to that in the period of CPZ treatment. The mean area of demyelination in the corpus callosum showed a 12% reduction in group E1 compared to group E2 (P < 0.05). 

    Conclusion and implications:

    Short-term AT therapy showed improvement in motor dysfunction and reduction of demyelination in the animal model of MS.

    Keywords: Alpha-tocopherol, Cuprizone, Demyelination, Multiple sclerosis, Neuroprotection