Iranian Journal of Pharmacology and Therapeutics
Volume:16 Issue: 1, 2018

The purpose of the present work was to introduce 141Ce-EDTMP as a novel potential future pain palliative agent to patients suffering from disseminated skeletal metastases and diagnostic imaging radioisotope as well. Cerium-141 [T1/2 = 32.501 days, Eβ (max) = 0.580 (29.8%) and 0.435(70.2%) MeV, Eγ = 145.44 (48.2%) keV] possesses radionuclidic properties suitable for use in palliative therapy of bone metastases. 141Ce also has gamma energy of 145.44 keV, which resembles that of 99mTc. Therefore, the energy window is adjustable on the Tc-99m energy because of imaging studies. 141Ce can be produced through a relatively easy route that involves thermal neutron bombardment on natural CeO2 in medium flux research reactors (4–5×1013 neutrons/cm2·s). The requirement for an enriched target does not arise. Ethylenediamine (tetramethylene phosphonic acid) (EDTMP) was synthesized and radiolabeled with 141Ce. The experimental parameters were optimized to achieve maximum yields (>99%). The radiochemical purity of 141Ce-EDTMP was evaluated by radio-thin layer chromatography. The stability of the prepared formulation was monitored for one week at room temperature, and results showed that the preparation was stable during this period (>99%). Biodistribution studies of the complexes carried out in wild-type rats exhibited significant bone uptake with rapid clearance from blood. The images showed high uptake of complex in bone after 72h and 2 weeks clearly. The percentage injected dose per gram of tissue (%ID/g) for each organ or tissue was calculated. The results show significant bone uptake with rapid clearance from blood. The properties of produced 141Ce-EDTMP suggest applying a new efficient bone pain palliative therapeutic agent to overcome metastatic bone pains.

In recent years, nanotechnology has gained serious attention for diagnosis, prevention and treatment roles. In this study we synthesized nanoceria or CeO2NPs (cerium oxide nanoparticles) and compared toxicity of cerium oxide powder in nano and bulk forms in two cancerous and one normal cell lines. The cell lines were cultured in a standard humidified incubator, at 37 °C in a 5% CO2 atmosphere, in RPMI 1640 medium. The cells were incubated with different concentrations of cerium oxide (from 2 μg/mL to 64 μg/mL) in bulk and nano forms. To determine the effect of cerium oxide on cell viability after 24 h, 48 h, and 72 h incubation, a MTT assay was performed using SKBR3 (human breast cancer cell line), A431 (Human epidermoid carcinoma cell line) and C2Cl2 (ATCC mouse skeletal muscle cell line) cells. Analysis of variance followed by Sidak post-hoc test, shows the toxicity of nanoceria is significantly deferent from bulk form on three cell lines in this study and is more on cancerous cells in compared to normal cells especially in higher level of concentrations after 24, 48 and 72 hours (All P<0.05). Additionally, the effect of cell lines, cerium oxide forms and concentrations cerium oxide leads in significantly the lowest amount of viability after 72 hours compared with 24 hours and 48 hours.

The aim of this study was to describe and evaluate the prevention of drug administration errors by clinical pharmacologist interventions in patients with cancer. This observational study was performed in the hematology-oncology ward of an academic hospital. The clinical pharmacologist in coordination with the professors of the ward reviewed patients’ medical records and monitored patients’ drug treatment regimen. All administration errors detected by clinical pharmacologist in 296 patients between Mars to September 2017 were reported in the format of medical consultation and his comments and recommendations was told to the residents and nurses to reform them. SPSS version 18.0 was used for data analysis. Descriptive statistic was used to determine frequency of each type of delivery errors..A total of 296 patients included in this study with a median age of 46.55 years of which 47.97% were female. 71.28% of the admitted patients experienced at least one medication error that is equal to a median of 1.33 errors per patient. Most administration errors were related to improper distance between the two drugs (52.40%), improper dilution (31.14%) and inappropriate infusion rate (13.17%)respectively. In 2.28% of errors, the clinical pharmacologist find that laboratory results werenot reported. Adverse drug reactions were 1.01% of the errors, which was diagnosed by the clinicalpharmacologist. Nurses accepted 371 out of these 395 (93.92%)clinical pharmacologist’s recommendations. The trust of physicians and nurses in the views of the clinical pharmacologist led to a large part of these errors being accepted and resolved.

In past decades, aminoglycosides have been commonly used to treat gram-negative infections as well as multi-drug resistant tuberculosis strains. However, in recent years, intrinsic, adaptive and acquired resistances have been raised against aminoglycosides which limits the uptake of these antibiotics. Acquired resistance to Acinetobacter baumannii responsible for nosocomial infection against aminoglycosides, has been led to a medical dilemma. In the present study, we aimed to investigate the prevalence rate of A. baumannii resistance to aminoglycosides using a meta-analysis and systematic review. International databases of Scopus, PubMed, Web of Science and Google Scholar, as well as national databases, include SID, Magiran, IranDoc, and IranMedex, were searched carefully and 62 articles published during years 1993 and 2016 were selected. After data extraction, random-effects model was used for analysis. Also, data heterogeneity was assessed using the I2 index and the final statistical analysis was done using STATA and R software. The total sample size of 28,055 extracted from the chosen articles and entered the meta-analysis process. The drug resistance value of A. baumannii isolates to various antibiotics was determined as follows: Amikacin 69% (57% to 81%), Tobramycin61% (52% to 71%), Netilmicin 35% (11% to 59%) and Gentamicin 68% (57% to 80%). The highest and lowest sensitivity of A. baumannii was considered against Netilmicin 57% (32% to 82%) and Gentamicin 26% (12% to 39%), respectively. According to our findings, the drug-resistance rate of A. baumannii clinical isolates to aminoglycosides, especially Amikacin, Tobramycin, and Gentamicin are relatively high. So, Gentamicin and Amikacin are not recommended as first-line treatment of A. baumannii isolates.

Sulfur mustard (SM) is a mutagenic compound that causes oxidative stress, antioxidant depletion even several years after exposure. Melatonin is an alternative medication that has antioxidant peroperties. The aim of this study was to investigate the effect of melatonin treatment on serum levels of several mineral elements, total antioxidant (TAC) and total oxidant status (TOS) in sulfur mustard-exposed patients. Victims with lung and sleep disorders was divided randomly to placebo and melatonin groups. They received melatonin or placebo for 56 days. Blood samples were taken before and after drug usage. The concentrations of serum trace elements (manganese, zinc, copper, and iron) and one other essential element (magnesium) were determined by graphite furnace and flame atomic absorption spectroscopy. TAC and TOS in serum were determined colorimetrically. Results showed that melatonin administration increases the magnesium and TAC concentrations. After the drug usage, placebo and melatonin groups had the highest TOS and TAC contents, respectively. Therefore, melatonin can be considered as a compound suitable for suppression of oxidative stress and helps to decrease oxidative damages induced by mustard gas.

P-glycoprotein (P-gp) and cytochrome P450 3A4 (CYP3A4) play a significant role in the disposition and elimination of drugs. The objective of this study was to investigate the mechanism underlying the interaction between sitagliptin (substrate of P-gp and CYP3A4) and verapamil (known modulator of P-gp and CYP3A4) using in vivo, ex vivo and in situ models. Rats were treated with sitagliptin (10 mg/kg, oral and/or 5 mg/kg, intravenous) alone and in combination with verapamil (40 mg/kg, oral) for 15 consecutive days. Blood samples were collected from the tail vein on 1st day in single dose pharmacokinetic study (SDS) and on 15th day in multiple dose pharmacokinetic study (MDS). The plasma concentrations of sitagliptin were significantly higher in the verapamil pretreated group when compared to sitagliptin control group. Verapamil pretreatment significantly increased the mean area under the plasma concentration-time curve from 0 to 24h (AUC0-24h), peak plasma concentration (Cmax), percent absolute bioavailability (AB%), elimination half-life (t1/2) and decreased the volume of distribution (Vz/F), clearance (CL/F) and apparent volume of distribution at steady state (Vss/F) of sitagliptin in both SDS and MDS (oral and intravenous). Ex vivo study results showed that the apparent permeability coefficient (Papp), net efflux and efflux ratio values were significantly increased by the known P-gp and CYP3A4 inhibitors (itraconazole and ketoconazole) and verapamil. In single pass intestinal perfusion (In situ) study, the effective permeability coefficient (Peff) and intestinal absorption rate constant (Ka) were increased in the presence of verapamil (p<0.05). The present study results revealed that verapamil enhanced the bioavailability of sitagliptin probably by inhibiting its absorption via P-gp and/or the CYP3A4-mediated biotransformation in rats. Verapamil can be co‐administered with sitagliptin without dose adjustment due to high safety margin of sitagliptin.

The objective of the study aims to evaluate the combined protective effects of coenzyme Q10 and magnesium sulphate on isoproterenol induced myocardial damage in rats. CoenzymeQ10 (50 mg/kg) and magnesium sulphate (10 mg/kg) were administered orally to wistar rats in individual or in combination for 30 days. At the end of this period, rats were administered isoproterenol (85 mg/kg i.p.) intraperitonially for two consecutive days to induce myocardial injury. After induction, rats were anaesthetized and plasma was collected to analyze various biochemical parameters. Further, immunohistochemistry and histopathology of the heart tissue was performed. Induction of rats with isoproterenol resulted in a marked (p<0.001) elevation of infarct size , level of serum marker enzymes (AST, ALT, LDH and CK- MB), lipid peroxidation , protein expression of alpha- smooth muscle actin (α SMA) along with alterations in histopathology. Pretreatment with combination of coenzyme Q10 (CoQ10) and magnesium sulphate (MgSO4) exhibited a significant (p<0.001) decrease in serum marker enzyme, infarct size , lipid peroxidation , protein expression of α- smooth muscle actin (α-SMA) and showed preservation of cardiomyocytes histo-architecture when compared with individual treated groups. This study demonstrated the synergistic cardio protective effect of coenzymeQ10 (CoQ10) and magnesium Sulphate (MgSO4) in isoproterenol induced myocardial damage in rats demonstrated that the oral pre-treatment with CoQ10 and Magnesium sulphate were associated with moderate protection against ISO-induced cardio toxicity and cardiac hypertrophy. The mechanism might be associated with the enhancement of antioxidant defense system. The present results can form the basis that combination of CoQ10 and magnesium sulphate proved to be a potential therapeutic agent for pharmacological management of ischemic heart disease. It could provide experimental evidence to support the rationality of combinatorial use in the prevention of the onset and progression of myocardial injury.

Trachyspermum copticum is one of the most important Iranian Apiaceae species which is widely distributed in the northern region of Iran. In this study, chemical compounds, anti-tumor and antibacterial activities of T. copticum essential oil were evaluated. The essential oil obtained by Clevenger apparatus and then the chemical composition was analyzed by GC-MS. Antibacterial activity of essential oil was evaluated by well diffusion method. The minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) were determined by the macrodilution method. An MTT cytotoxicity assay was employed to test effects of the essential oil on each human breast cancer cell lines. The GC-MS spectrums showed 9 major compounds, in which the highest chemical composition was related to thymol (42.16%), g-Terpinene (31.49%) and p-cymen (23.29%) compounds. T. copticum essential oil showed good antitumor activity on SKOV3 and MDA-MB-231cell lines (IC50 of 208.13.6µg/ml and IC50 236.16µg/ml, respectively). It also showed good activity against to tested bacteria. The MIC and MBC values of the bacterial strains sensitive to the essential oil were in the ranges of 0.4 to 3.1 mg/ml and 0.4 to 6.25 mg/ml, respectively. Because of the high concentration of phenolic compounds, the essential oil from T. copticum exhibited antimicrobial and antitumor activities, which deserve further research into the chemoprevention and treatment of human ovary and breast cancers as well as infectious diseases.

Alzheimer’s disease (AD) is the most popular type of dementia in elderly and is described by a progressive loss of cognitive capacity and severe neurodegeneration which typically begins with memory deficits. The major biomarkers of AD include total tau, phosphorylated-tau and 42 amino acid isoform of amyloid beta that reflect neurodegeneration and indicate the pathophysiological processes in AD. Biomarkers have been analyzed in different kinds of body fluid. Cereberospinal fluid (CSF) biomarkers are particularly valuable to discriminate early AD from other diseases associated with memory impairment. However, access to CSF is invasive and researchers try to find valuable biomarkers in other body fluids. In this article, we reviewed different kinds of biomarkers and their validity to diagnose and effectiveness in AD therapy.

Hepatotoxicity is the most common disorder with severe effects on quality of life. Tragopogon graminifolius DC. has been used in Iran as an astringent and bleeding inhibitor, wound healer and gastro-protector agent. To our knowledge, there are little evidence at hand on hepatoprotective activity of T. graminifolius. The present study was carried out to assess hepatoprotective property of T. graminifolius ethanolic extract on carbon tetrachloride (CCl4) induced hepatotoxicity in mice for 45 consecutive days. Fifty male mice were divided into five groups (n=10). Group 1 (control) received 1 ml/kg olive oil intraperitoneally (i.p.) and distilled water orally; Group 2 (untreated) received CCl4 (50% in olive oil, 1 ml/kg; i.p.); Groups 3, 4 and 5 received CCl4 and 30, 90 and 270 mg/kg of T. graminifolius (T30, T90 and T270), respectively. At 45th day, the mice were killed, dissected, then blood and liver samples were collected for biochemical and stereological parameters analysis. Biochemically, T. graminifolius at all doses (especially T270) could significantly (p≤0.05) reduce the raised levels of cholesterol, low density lipoprotein (LDL), triglyceride, alkaline phosphatase (ALP), aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyl transferase (GGT), total and conjugated bilirubin, and increase the decreased levels of high density lipoprotein (HDL), total protein, albumin, superoxide dismutase (SOD) and catalase (CAT). Stereologically, different doses of T. graminifolius (especially T270) decreased the weight and volume of the hepatic structures as compared to the untreated group significantly (p≤0.05). The obtained results indicate that T. graminifolius ethanolic extract, potential applications as a therapeutical supplement or medicine, after confirming clinical trial studies.

Precise identification of microorganisms involved in candidiasis together with antifungal susceptibility evaluation could help clinicians to prescribe appropriate medicine, especially in patients with critical conditions. The present study has been conducted to evaluate discriminatory power of Integral System Yeast Plus (ISYP) for rapid identification and determination of antifungal susceptibility of clinically important Candida species (sp.). Validation of ISYP results was performed using molecular and Broth Micro Dilution (BMD) assays. Referring to the present results, it can be said that ISYP was to some extent successful for identification of C. albicans isolates. Major misidentification was observed in cases of non C. albicans sp. (NAC) in comparison with sequencing results. The relatively unsatisfied outcome of ISYP performance was correlated to antifungals susceptibility assay as well. It is noteworthy to emphasize the potential advantages of ISYP for simultaneous identification of Candida sp. together with antifungal susceptibility evaluation that brings hope to the defeat of severe complications. But an essential defect was observed in both identification and antifungal susceptibility tests.

To evaluate the protective effect of Zataria multiflora boiss. (Zm) extract against arsenic-induced oxidative damage in rats. Rats were orally treated with various doses of Zm (200, 400, and 600 mg/kg) and sodium arsenite (5.5 mg/ kg), alone or in combination, once daily for 30 consecutive days. Twenty-four hours after the last dose, rats were euthanized, and biochemical studies were conducted on their blood samples. Sub-acute exposure to the sub-lethal dose of arsenic markedly altered the blood levels of several biomarkers associated with oxidative stress. Treatment with Zm significantly inhibited the elevation of lipid peroxidation and protein carbonylation and the depletion in total antioxidant capacity in plasma. In addition, Zm effectively increased the total antioxidant capacity of plasma in a dosedependent manner in control and arsenic-treated groups. The results reveal that Zm as an antioxidative medicinal plant reduces oxidative damages induced by arsenic in the doses much lower than the lethal dose (2-4 gr/kg). Since Zm is a safe herbal drug routinely used as condiment, it can be used as a good supplement for reducing toxicity of low dose of arsenic in long-term exposure. Further studies on human environmentally exposed to arsenic through drinking water and food are proposed to find out effective dose in human.

For a long period, ethno medicinal plants have been a valuable source of natural products for maintaining human health, especially in the last decade, with more intensive studies for natural therapies. The use of ethno medicinal plant for pharmaceutical purposes has gradually increased in Iran. Gundelia tournefortii has been used as an antibacterial, anti-fungal, antipyretic, anti-inflammatory, and antioxidant agent in Iran. In the recent examination, the testicular protective effect of G. tournefortii aerial parts aqueous extract on diabetic mice has been evaluated. Seventy mice were used and diabetes was induced by administration of 150 mg/kg of alloxan monohydrate intraperitoneally in 60 mature male mice and they were randomly divided into six groups. The treatment groups received glibenclamide 10 mg/kg and 5, 10, 20 and 40 mg/kg of G. tournefortii through gavage for 20 days. Also, one group was considered as the non-diabetic control. At 20th day, the mice were killed, dissected, then blood and testis samples were collected for biochemical and stereological parameters analysis. The data were analyzed by SPSS-21 software. G. tournefortii at all doses (especially GT40) and glibenclamide significantly (p≤0.05) ameliorated the concentrations of fasting blood glucose, testosterone, superoxide dismutase, catalase, glutathione reductase, and glutathione peroxidase. Also, multiple doses of G. tournefortii (especially GT40) and glibenclamide increased the weight and volume of the testis, the volumes of the tubule and interstitial tissue, the length and diameter of the tubule, the height of the germinal epithelium, and the number of the Leydig cell compared to the diabetic untreated group. According to the obtained results, G. tournefortii aerial parts aqueous extract can regulate the concentrations of biochemical parameters and inhibit testicular damages in alloxan monohydrate induced diabetic mice. It seems that G. tournefortii can be offered as a testicular protective supplement or drug for prevention, control, and treatment of testicular toxicity in diabetic patients.

To study the anti-diabetic effects of the crude leaves extract and fractions of Thymus schimperi Ronniger in normal and steptozotocin induced diabetic mice. The crude extract and the fractions were screened for antidiabetic activities in streptozotocin induced diabetic mice. A normoglycemic mice model and oral glucose tolerance test were also undertaken to assess the hypoglycemic and antihyperglycemic effect of the crude extract in normoglycemic and glucose loaded mice, respectively. The methanolic crude extract has significantly reduced blood glucose level in streptozotocin induced diabetic mice at all given doses compared to the negative control and the percentage reduction observed was in a dose dependent manner i.e. [250 mg/kg (14.76±6.1%), 500 mg/kg (25.12±11.5%) and 750 mg/kg (27.15±10.0%)]. The crude methanol extract was devoid of hypoglycemic effect in normoglycemic mice but significantly reduced post prandial hyperglycemia starting from 1 h post glucose administration. Among the fractions, higher percentage reduction was recorded in the n-butanol fraction at a dose level of 500 mg/kg (36±7.3%) compared to 250 mg/kg (22.2±4.3%). The aqueous fraction 250 mg/kg and 500 mg/kg also reduced the blood glucose level by 17.6%±6.0% and 18.4±5.0%, respectively. This study revealed that methanol extract as well as butanol and aqueous fractions of T schimperi possess anti-diabetic activity.

Design, synthesis, and conjugation of mesoporous silica nanoparticles (MSNs) with biomolecules is a matter of growing interest to enhance selective uptake of contrast agents like gadolinium (Gd3+) by cancer cells. Here, by targeting xc-cystine/glutamate antiporter system in breast cancer cells, conjugation of MSN-Gd3+ with cysteine is used to enhance cancer cellular uptake of Gd3+. Reactions designed to make different covalent bonds between MSNs and cysteine to investigate impact of cysteine conjugation of MSNs-Gd3+ on uptake of Gd3+ by breast cancer cells. Cysteine amino acids were attached to the surface of MSNs via its three functional groups using three different conjugation methods. Therefore, the external surface of MSNs were first modified by three different linkers to create amine, epoxy, and isocyanate groups on the surface of MSNs, then pores loaded with Gd3+ complexes and reacted with toile, epoxy, and amine groups of cysteine, respectively (nanoprobe A, B and C). The nanoprobes were characterized using different techniques, including (scanning electron microscope) SEM, Brunauer–Emmett–Teller BET, dynamic light scattering (DLS) and Fourier Transform Infrared (FTIR). The intracellular uptake of nanoprobes by human dermal fibroblasts (HDF) and human breast adenocarcinoma cells (MCF-7) was investigated using inductively coupled plasma atomic emission spectrometer (ICP-AES). Results demonstrated that accumulation of Gd3+ in cancer cells is highly related to method of cysteine conjugation. The amount of Gd3+ was taken by cancer cells increased 7 folds, when thiol group of cysteine was responsible to make covalent bond with MSNs, in other words when the zwitterionic form of cysteine was on the surface (nanoprobe B). The average intracellular uptake of Gd3+ by cancer cells was 0.5±0.09 pg/cell. On the other hand, uptake of Gd3+ delivered by nanoprobe B into cancer cells was up to 4.7 times higher than normal cells. No appreciable cytotoxicity was seen using HDF and MCF-7 cell lines. This study provides MRI nanoprobes using suitable conjugation of Gd3+ based MSNs with cysteine for next studies about MR imaging of cancer.

Quercetin is one of the major flavonoids finding in many fruits and vegetables. Quercetin has many health promoting advantages such as improvement of allergic, arthritis disorder, and reduction of cancer and cardiovascular risk. The aim of this study was to examine hepatoprotective effects of quercetin on doxorubicin induced toxicity in animal model. Thirty male Wistar rats (200-230 g) were randomly divided in to 5 groups including: Quercetin group was orally treated with 20 mg/kg of quercetin for 14 days. Doxorubicin group was treated with 25 mg/kg of doxorubicin i.p. for 3 days. Doxorubicin- Quercetin group (DQ) was orally pre-treated of 20 mg/kg quercetin for 14 days with hepatotoxicity induced by i.p. injection of 25 mg/kg doxorubicin (12th, 13th and 14th days). The control and vehicle group were orally received saline (1 mL/kg), and DMSO (1 mL/kg) respectively. Sample of their livers were used to determine the myeloperoxidase (MPO) activity, superoxide dismutase (SOD), malondialdehyde (MDA), GPX, catalase, and histological analysis. The numerical data were evaluated by ANOVA, followed by the Tukey tests. The results show that doxorubicin could produce hepatotoxicity in rat. Also, increased liver enzymatic (ALT, AST, ALP), MPO, MDA (p<0.001), followed infiltration of inflammatory cell, and necrosis of hepatocytes also Pretreatment with quercetin reduces MPO activity (p=0.0034), MDA (p=0.0335) and the elevated liver ALT (0.009), ALP (p=0.0023) and AST activity (0.0074) in rats in DQ group. This study suggests that quercetin have a protective effect on the liver tissue against toxicity induced by doxorubicin.