Iranian Journal of Pharmaceutical Research
Volume:13 Issue: 1, Winter 2014

Mitochondria are semi-autonomous organelles that play essential roles in cellular metabolism and programmed cell death pathways. Functional, structural and genomic alterations in mitochondria have been associated with carcinogenesis in different cells. Some of those alterations may provide a selective advantage to cells, allowing them to survive and grow under different stresses. Due to the specific alterations that occur in cancer cell mitochondria, these organelles may provide promising targets for cancer therapy. The development of drugs that specifically target metabolic and mitochondrial alterations in tumor cells has become a matter of interest in recent years, with several molecules undergoing clinical trials. This Editorial focuses on the most relevant mitochondrial alterations found in tumor cells, for cancer therapy.

Chemotherapy research highly prioritizes overcoming the multidrug resistance (MDR) in human tumors. Liposomal formulation of fluoxetine, as a fourth generation chemosensitizer, was constructed and characterized for percent entrapment, release profile, morphology, particle size, zeta potential and stability. Liposomes were prepared using different active loading techniques. The influence of different formulation variables such as loading methodology, type of main lipid, addition of PEGylated lipid and cholesterol percentage was evaluated to achieve required entrapment efficiency, in vitro release behavior and stability. The studied parameters had significant effect on physicochemical characteristics of the nanocarriers. High fluoxetine encapsulation efficiency (83% ± 3%) and appropriate particle size (101 ± 12 nm) and zeta potential (-9 ± 2 mv) were achieved for PEGylation liposomes composed of DSPE-PEG, DSPC and cholesterol at respective molar ratio of 5:70:25. An in vitro fluoxetine release of about 20% in 48 h was observed from optimum formulation. Atomic force microscopy (AFM) studies confirmed homogeneous distribution of particles and spherical shape with smooth surface. The optimum formulation was stable for 9 days when incubated at 37°C. The results of this study are very encouraging for application of the developed fluoxetine liposomal formulation in drug-resistant tumor models.

The purpose of this study was to optimize a method for the encapsulation of P5 peptide, a new designed peptide containing MHC class I epitopes from rat HER2/neu protein, into liposomes as an approach for breast cancer vaccine formulation. The efficiency of liposomal encapsulation of peptides is generally low and development of an optimized method to increase encapsulation efficiency is a big challenge. In this study, P5 peptide was encapsulated into liposomes using the following three different methods based on film-hydration procedure. In Method A, the lipid film containing P5 was hydrated using buffer and then extruded to 100 nm using polycarbonate filter. In Method B all the steps were the same as method A except that the lipid film was hydrated in buffer containing 10% (v/v) of DMSO and P5 peptide. In Method C, P5 peptide was added to preformed liposomes (40 mM) in the presence of ethanol (30% v/v) and incubated at 25 ºC for 1h. The highest peptide encapsulation efficiency was achieved using Method C (44%). The presence of P5 peptide in purified liposomes was also confirmed using SDS- PAGE analysis. Investigation on the effects of procedure parameters of method C on encapsulation efficiency demonstrated this method is an optimized procedure for encapsulating P5 peptide. Maximal recovery from liposomes for the accurate quantification of peptide was discovered using acidified isopropanol at 1:2 of sample to solvent ratio (v/v). The optimal methods of encapsulation and peptide content determination in liposomes can accelerate the development of liposomal vaccine formulations.

A major problem in the formulation of therapeutic proteins is the irreversible protein aggregation. Recombinant human interferon alpha2b (rhIFN2b) has poor stability and undergoes physical degradation. The aim of this study was to investigate the effect of solution conditions on the heat-induced aggregation of rhIFNα2b. The protein was incubated for 1 h at 40°C–70°C and for up to 240 h at 50C and its aggregation tendency was then studied using optical density (at 350 nm), SE-HPLC, dynamic light scattering and SDS-PAGE methods. The effect of various pH (5, 6 and 7) and buffer concentrations of (10, 55 and 100 mM) on the aggregation of protein following incubation at 50C for 72 h was also evaluated. The results obtained for samples incubated at 50C for up to 240 h showed that OD350 and the amount of higher molecular weight aggregates (HMW) increased and the monomer content decreased significantly (p<0.05) as the incubation time increased. Following incubation at various temperatures, a significant increase in OD350, drop in monomer content and increase in the amount of HMW aggregates were observed (p<0.05). Data obtained from incubation of samples at 50C for 72 h confirmed that regardless of the buffer concentration, the percent of monomer at pH 6 was significantly higher than that at pH 7 and pH 5 (p<0.05). At constant pH, although not significant, the same trend was observed when the buffer concentration increased to 100 mM. In conclusion, the change in solution conditions can influence the aggregation rate of rhIFN2b.

A number of N-arylmethyl substituted indole derivatives have been synthesized and their effectiveness against ADP and arachidonic acid induced platelet aggregation in human plasma was determined. The desired compounds were synthesized by reacting the appropriate aniline derivative with isatin (or substituted isatin) to form the corresponding imine structures. The so formed compound was then activated using sodium hydride and reacted with the proper substituted benzyl halides. Among the tested compounds, derivatives 4a, 4c, 4d, 4f-i and 4k were the most potent compounds with satisfactory IC50 values (under 38.5 µM) for inhibition of platelet aggregation induced by arachidonic acid.All indole derivatives without substitution on position 1 of the indole ring, exhibited either weaker activities or were not active at all.

A gradient reversed-phase high performance liquid chromatography (HPLC) method was developed for the assay of cetrorelix acetate, a synthetic decapeptide with gonadotropin-releasing hormone (GnRH) antagonistic activity used in infertility treatment. The HPLC method, which is used to determine cetrorelix in bulk and pharmaceutical dosage forms, was validated per ICH guidelines. The chromatographic separation was achieved on a C18 reversed-phase column using acetonitrile, water and trifluoroacetic acid (TFA) as mobile phase and wavelength was set at 275 nm. The calibration curve was linear (r2 = 0.999) over cetrorelix concentrations ranging from 62.50 to 12.50 µg/ml (n = 6). The limits of detection (LOD) and quantification (LOQ) were calculated from the peak-to-noise ratio as 15.6 and 62.5 µg/ml, respectively. The method had an accuracy of > 95% and intra- and inter-day RSD of < 0.3% and < 0.5%, respectively and was validated with excellent specificity, sensitivity, and stability. The validated method was successfully applied for determination of cetrorelix in bulk and pharmaceutical dosage forms.

Inhibitors of soluble epoxide hydrolase (sEH) represent one of the novel pharmaceutical approaches for treating hypertension, vascular inflammation, pain and other cardiovascular related diseases. Most of the potent sEH inhibitors reported in literature often suffer from poor solubility and bioavailability. Toward improving pharmacokinetic profile beside favorable potency, two series of 4-benzamidobenzoic acid hydrazide derivatives with hydrazide group as a novel secondary pharmacophore against sEH enzyme were developed. The designed compounds were synthesized in acceptable yield and their in vitro assay was determined. Most of the synthesized compounds have appropriate physical properties and exhibited considerable in vitro sEH in comparison with 12-(3-Adamantan-1-yl-ureido)-dodecanoicacid(AUDA), a potent urea-based sEH inhibitor. 4-(2-(4-(4-chlorobenzamido)benzoyl)hydrazinyl)-4-oxobutanoic acid 6c was found to be the most potent inhibitor with inhibitory activity of 72% targeting sEH enzyme.

A group of regioisomeric 5-oxo-1,4,5,6,7,8 hexahydroquinoline derivatives possessing a COX-2 SO2Me pharmacophore at the para position of the C-2 or C-4 phenyl ring, in conjunction with a C-4 or C-2 phenyl (4-H) or substituted-phenyl ring (4-F,4-Cl,4-Br,4-OMe,4-Me, 4-NO2), were designed for evaluation as selective cyclooxygenase-2 (COX-2) inhibitors. These target 5-oxo-1,4,5,6,7,8 hexahydroquinolines were synthesized via a Hansch condensation reaction. In vitro COX-1/COX-2 isozyme inhibition structure-activity studies identified 7,8-dihydro-7,7-dimethyl-2-(4-methoxyphenyl)-4-(4-(methylsulfonyl)phenyl)quinolin-5(1H,4H,6H)-one (9c) as a potent COX-2 inhibitor (IC50 = 0.17 microM) with a high COX-2 selectivity index (S.I. = 97.6) comparable to the reference drug celecoxib (COX-2 IC50 = 0.05 microM; COX-2 S.I= 405). A molecular modeling study where 9c was docked in active site of COX-2 showed that the p-SO2Me substituent on the C-2 phenyl ring is inserted into the secondary COX-2 binding site. The structure activity data acquired indicate that the position of the COX-2 SO2Me pharmacophore and type of substituent are important for COX-2 inhibitory activity.

Two set of 2-aryl-5,6-dihydropyrrolo[2,1-a] isoquinolines were designed and synthesized to evaluate their biological activities as topoisomerase inhibitors. Cytotoxic activity of the synthesized compounds 4a-e and 7a-d was assessed against several human cancer cell lines, including MCF-7 (breast cancer cell), HepG2 (liver hepatocellular cells), A549 (adenocarcinomic human alveolar basal epithelial cells), T47D (Human ductal breast epithelial tumor cell line) and Hela (Human cervix cancer). According to our results, HepG2 seems to be the most sensitive cell line for these compounds with mean IC50 values ranging from 4.25 to 70.05 µM. Our results indicated that compound 7b exhibited the best potency against the tested cell lines. These results also suggest that pyrroloisoquinoline moiety constitutes a suitable scaffold to design new anti-proliferative agents.

To obtain drugs which are more selective at benzodiazepine (BZD) receptors, design and synthesis of functionally selective ligands for BZD receptors is the current strategy of our pharmaceutical chemistry department. The affinity of newly synthesized ligands is assessed by radioligand receptor binding assays. Based on our previous studies, 2-phenyl-5-oxo-7-methyl-1,3,4-oxadiazolo[a,2,3]-pyrimidine (compound A) was chosen for design and synthesis of new triazole derivatives as GABAA BZD receptor agonist. The cortical membrane of male Sprague-Dawley rats was prepared as the source of the BZD receptors. Different concentrations of membrane protein and [3H]-flumazenil were incubated at room temperature at different time periods to reach the steady-state. To saturate the receptors, increased amounts of radioligand were incubated with membrane protein. The bound and un-bound ligands were separated by centrifugation. The affinity of compound A was measured in competition studies at optimum conditions by displacement of [3H]-Flumazenil from rat cortical membrane. Based on results, the optimum conditions of radioligand receptor binding assay of benzodiazepines were 35 min incubation of ligands with 100 g cortical membrane protein and 6×10-5 nmole 3H-flumazenil in a final volume of 0.5 mL Tris-HCl buffer (50 mM, pH 7.4) at 30°C. The binding parameters of [3H]-flumazenil, Bmax and Kd were determined through saturation studies as 0.638±0.099 pmol/mg and 1.35±0.316 nM respectively. The affinity of compound A was 1.9 nM comparable with diazepam (1.53nM). This finding makes the compound an interesting lead for further optimization. Starting from this compound, new ligands were synthesized and screened in vitro by competitive binding assays.

The occurrence of deoxynivalenol (DON) in retail foods in Tehran (Iran) was determined using high-performance liquid chromatography technique and immunoaffinity column as the clean-up step. A method was validated for analysis of DON in rice, bread, puffed corn snack and wheat flour. The average recoveries and precision (RSD) for DON in different foods ranged 84.2-93.1% and 2.9-12.0%, respectively. A survey of DON was performed on the 72 samples of rice, bread, puffed corn snack, and wheat flour collected from Tehran retail market. The data showed that 10 samples (13.9%) out of 72 samples were contaminated with DON with the maximum level of 368.7 ng/g. The samples had contamination level lower than the maximum tolerated level of DON in foods in Iran. The total intake of DON was under the provisional maximum tolerable daily intake set for DON by the JECFA.

Schizophrenia is a chronic and often debilitating illness which affects about 1% of the world population. Some reagents have been used to simulate schizophrenic disorders in laboratory animals, such as amphetamine and ketamine. Previous studies have suggested that reactive oxygen species (ROS) production, reduced levels of ATP, mitochondrial dysfunction and apoptosis are involved in the pathophysiology and etiology of schizophrenia. In this study we divided Wistar rats in to 2 groups; control group received normal saline and test group received ketamine 30mg/kg daily for five consecutive days. Then, locomotor activity including side to side head rocking and arcing of neck, proved schizophrenia in the test group rats. Rats in both control and test groups were then decapitated and brain mitochondria were isolated. Our results showed increased ROS formation, mitochondrial membrane potential collapse, mitochondrial swelling and cytochrome c release in mitochondria of schizophrenic test group. Our findings suggested that mitochondrial ROS formation and apoptosis signaling are likely involved in cellular pathology of Schizophrenia. To our knowledge this the first report that provides a mechanistic justification between mitochondrial events and neuodegeneration in the Schizophrenia.

Metronidazole is used to treat trichomoniasis, bacterial vaginosis, and other diseases. There are controversy aspects about its teratogenicity. A teratogenic agent can alter morphology or subsequent function of the fetus. The aim of this study was to examine an alternative method for the recognition of the mechanism or the bimolecular potential changes in mice fetus caused by Metronidazole using FTIR micro spectroscopy. The mice were injected with metronidazole (60mg/kg) on gestation day 9. Fetuses were dissected on day 15 of gestation and morphological and histological studies on the fetus were carried out. Serial sectioning (10µm) of normal and metronidazole-treated brains and livers were used for FTIR measurement in the wave number region of 600- 3600 cm-1.The results showed that there were some variations between the fetus of normal and treated brain and liver. The band intensities in fetus brain and liver of test animals were reduced and shifted at 707 cm-1, 1155 cm-1, 1054 cm-1,, 1256 cm-1 and 1219 cm-1, 1453 cm-1 and 1525 cm-1, 1622 cm-1, 1645 cm-1 and 2944 cm-1,while the band intensities were increased and shifted at 879 cm-1, 810 cm-1, 1223 cm-1, 1256 cm-1 1360 cm-1, 1723 cm-1. It was concluded that most of variations in brain and liver of Metronidazole treated fetuses are in amid bands, nucleic acid and carbohydrate related bands. Based on these findings FTIR spectroscopy can be a useful tool for bio diagnostic.

Androgenetic alopecia is the most common form of hair loss in men. The present study was designed to evaluate the hair growth-promoting activity of a preparation of the Adiantum capillus veneris Linn. (A. capillus veneris Linn.) on albino mice using a testosterone-induced alopecia model. Five groups of albino mice were studied: (A) Testosterone solution only (n=6); (B) Testosterone + Finasteride solution (2%) (n=6); (C) Testosterone + vehicle (n=6); (D) Testosterone + A. capillus veneris Linn. solution (1%) (n=6); (E) intact control (n=2, without testosterone). Alopecia was induced in all intervention groups by testosterone 1.0 mg subcutaneous. A. capillus veneris Linn. solution was applied topically to the back skin of animals in the respective group. Hair growth was evaluated by visual observation and histological study of several skin sections via various parameters as follicle density (number of follicles/mm) and anagen/telogen ratio. After 21 days, a patch of diffuse hair loss was seen in animals received testosterone while animals treated with A. capillus veneris Linn. showed less hair loss as compared to those treated with testosterone only. The follicular density observed in the A. capillus veneris Linn.-treated group was 1.92±0.47, compared to 1.05±0.21 in testosterone-group and 2.05±0.49 in finasteride-treated animals. Anagen/telogen ratio was significantly affected by A. capillus veneris Linn., which was 0.92±0.06 as compared with 0.23±0.03 and 1.12±0.06 for testosterone and finasteride treated groups, respectively. According to visual observation and quantitative data (follicular density and anagen/telogen ratio), A. capillus veneris Linn. was found to possess good activity against testosterone-induced alopecia.

Fruits of Olea europaea L. have been used for centuries in folk medicine to treat many inflammatory diseases. In order to evaluate the anti-nociceptive activities of the methanolic and aqueous extracts of defatted fruits of O. europaea, formalin test was used and for evaluation of anti-inflammatory effects of the extract, the volume of paw edema was measured. The results revealed that both extracts did not exhibit significant analgesic activity in the first phase of formalin test, whereas methanolic extract at the 600 mg/kg dose and aqueous extract at the 450 and 600 mg/kg doses could inhibit induced pain in the second phase of formalin test. Furthermore, the results of paw edema volume measurement indicated that the aqueous extract has anti-inflammatory effects at dose of 600 mg/kg. Induced anti-nociception by aqueous olive extract was not reversed by naloxone, which indicates that the opioid receptors are not involved in the analgesic effects of the extracts. The present data pointed out that the extracts of olive defatted fruit have anti-nociceptive and anti-inflammatory effects in rats but further studies are needed to elucidate the mechanism(s) of action and active components which are involved in analgesic and anti-inflammatory effects.

The dentate gyrus of hippocampus has long been considered as a focal point for studies on mechanisms responsible for the development of temporal lobe epilepsy (TLE). Change in intrinsic properties of dentate gyrus granule cells (GCs) has been considered as an important factor responsible in temporal lobe seizures. In this study, we evaluated the intrinsic properties of GCs, during acute phase of seizure (24h after i.p. injection of pilocarpine) compared to sham group using whole cell patch-clamp recordings. Our results showed a significant increase in the number of action potentials (APs) after applying depolarizing currents of 200pA (p<0.01) and 250pA (p<0.05) compared to sham group. The evaluation of AP properties revealed a decrease in half-width of AP in GCs of seizure group compared to sham group. Moreover, addition of BAPTA to pipette solution prevented changes in AP half-width in seizure group compared to sham group. In contrast, an increase in the amplitude of fast afterhyperpolarization was observed in GCs of seizure group compared to sham group. Also, GCs of seizure group showed a significant increase in both firing rate and instantaneous firing frequency at depolarizing currents of 200 pA (P<0.01) and 250 pA (P<0.05) compared to sham group. The changes in electrophysiological properties of GCs were attenuated after bath application of paxilline suggesting possible involvement of large conductance Ca2+- activated K+ channel (BK channel). Our results suggested the possible involvement of certain potassium channels in early changes of intrinsic properties of GCs which eventually facilitate TLE development.

Aptamers, or single stranded oligonucleotides, are produced by systematic evolution of ligands by exponential enrichment, abbreviated as SELEX. In the amplification and regeneration step of SELEX technique, dsDNA is conversed to ssDNA. Asymmetric PCR is one of the methods used for the generation of ssDNA. The purpose of this study was to design a random DNA library for selection of aptamers with high affinity for protein targets and develop an efficient asymmetric PCR amplification. Thus, the influence of factors including annealing temperature, number of amplification cycles, primer ratio, Mg2+ concentration and the presence of a PCR enhancer on the amplification of the desired product were evaluated. Results obtained by agarose gel electrophoresis showed that the annealing temperature of 64C, Mg2+ concentration of 0.25mM, reverse to forward primer ratio of 15:1, amplification cycle of 25 and the presence L-ectoin as a PCR enhancer with the concentration of 0.4M were the optimal conditions. Our results supported that the yield of this type of ssDNA production is sufficient for combinatorial screening of aptamers.

The aim of this investigation was to improve the storage stability and survival rate of intravesical BCG product, manufactured with an attenuated strain of Mycobacterium bovis (Pasteur strain 1173P2 of BCG) in the presence of sodium glutamate. Formulations with various concentrations of trehalose (a known protectant) were developed as liquid and lyophilized forms. Formulations were evaluated by different methods, including optical density measurement, safety assessment, skin reaction test, moisture content determination, viability assay, bacterial and fungal contaminations and the results were compared with those obtained for sodium glutamate-containing formulations. The stability tests were also carried out in various storage durations and different temperatures. To develop the lyophilization protocol, glass transition temperatures in the presence of both stabilizers were determined using differential scanning calorimetry. In general, results showed that trehalose could considerably increase the stability of the product against freezing and drying processes, increase the survival rate even in the liquid formulations, as well as the production of an acceptable cake. However, further studies are required to optimize the product characteristics.

Human Interferon β (INF-β) is a member of cytokines family which different studies have shown its immunomodulatory and antiviral activities. In this study an expression vector was designed and constructed for expression of human INF-β-1b either in shake flasks and bench top bioreactor. The designed vector was constructed based upon pET-25b(+) with T7 promoter. Recombinant human beta interferon (rhINF-β) was codon optimized and overexpressed as a soluble, N-terminal pelB fusion protein and secreted into the periplasmic space of Escherichia coli BL21 (DE3). The sugar, Isopropyl-β-D-thiogalactopyranoside (IPTG) was used as a chemical inducer for rhINF-β production in the shake flasks and bench top bioreactor. Timing of beta interferon expression was controlled by using the T7 promoter. The rhINF-β protein was extracted from periplasmic space by osmotic shock treatment and the expression of the beta interferon encoding gene in random selected transformants, was confirmed by western and dot blot methods. The maximum of product formation achieved at the OD600nm = 3.42 was found to be 35 % of the total protein content of the strain which translates to 0.32 g L-1. The constructed vector could efficiently overexpress the rhINF-β into the periplasmic space of E. coli. The obtained yield of the produced rhINF-β was more than previous reports. The system is easily adapted to include other vectors, tags or fusions and therefore has the potential to be broadly applicable to express other recombinant proteins.

Pulmonary hypertension (PH) is an important cause of heart failure in chronic obstructive pulmonary disease (COPD). The pro brain natriuretic peptide N-terminal (NT-proBNP) has been suggested as a noninvasive marker to evaluate ventricular function. However, there is no evidence to support the use of NT-proBNP in monitoring the benefits of vasodilators in COPD induced PH. Thus, we used NT-proBNP as a biomarker to evaluate the effect of oral vasodilators on cardiac function in COPD-induced PH.Forty clinically-stable PH patients were enrolled with history of COPD, normal left ventricular ejection-fraction (LVEF), right ventricular systolic pressure (RVSP) > 45 mmHg and baseline blood NT-proBNP levels >100 pg/ml. Patients were randomized into two groups, one group received sildenafil and second group were given amlodipine for two weeks. NT-proBNP and systolic pulmonary arterial pressure (systolic PA-pressure) were measured at the beginning and the end of study.NT-proBNP levels in the first group was 1297±912 pg/ml before therapy and 554±5 pg/ml after two weeks drug therapy, respectively. Similarly, in second group NT-proBNP level was 1657±989pg/ml and 646±5 pg/ml before and after treatment. Amlodipine or sildenafil significantly reduced NT-proBNP levels in COPD-induced PH patients (p<0.05).Our study shows that amlodipine and sildenafil have a similar effect on NT-proBNP levels. In both groups NT-proBNP levels were significantly reduced after treatment. Therefore, our findings support the potential benefits of treatment with vasodilators in COPD induced PH.

Adverse effects of antituberculosis agents such as hepatotoxicity may reduce treatment effectiveness, because they significantly contribute to nonadherence and eventually result in treatment failure, relapse or the emergence of drug resistance. Garlic is an ancient herbal substance, which its effectiveness on isoniazid and rifampicin-induced hepatic injury in animal models has been demonstrated (1).In the present study a randomized, double blind, placebo-controlled, parallel group clinical trial was designed to assess the effect(s) of garlic tablets (1000 mg daily) administered for two weeks orally. Fifty eight newly diagnosed, smear positive pulmonary tuberculosis patients, with age ranges between 18-65 years old, were randomly allocated into two groups. Each patient received either garlic or placebo tablets for the first two weeks of tuberculosis treatment.Of total 58 patients, 31 received garlic tablets while 27 received placebo. No significant difference was found between the two groups regarding age, sex, nationality, smoking, underlying diseases and opium usage. During 8 weeks of anti-TB (antituberculosis) treatment, 8 (13.0%) patients developed drug-induced hepatotoxicity (DIH). Of them, 6 (75%) occurred in the first two weeks of treatment. Fifty percent of the patients who developed DIH were in garlic group. Results indicated no significant difference between groups in developing DIH (p=1.000).We could not show a significant role in preventing DIH by 1000 mg daily garlic administration.

This study was aimed to evaluate the effects of diets containing some hot and cold temperament herb seeds according to Iranian traditional medicine (ITM) on some metabolic parameters in acute (24 h) and sub-acute (7 day) experiments that were performed on rats. For each experiment, effects of diets containing 10% herb seeds in category of hot (anise, fennel, ajowan) and cold (cucumber, watermelon, pumpkin) temperaments were analyzed on body weight gain, food intake, water consumption, urine output, serum glucose (SG) and insulin levels of rats. In the acute experiment, anise or fennel fed groups showed a significant decrease in food intake and there were not any changes in other parameters. The hot temperament groups in comparison with the cold temperament ones showed a significant decrease in food intake and a significant increase in SG level. In the sub-acute experiment, anise and fennel fed groups had a significant decrease in body weight gain on the 4thday. On the 7th day, the anise fed group experienced a significant decrease in body weight gain and a significant increase in SG levels. The groups that were fed hot temperament diets compared to the ones that consumed cold temperament diets showed a significant decrease in body weight gain and food intake rates and a considerable increase in SG levels. Considering the findings of this study, one can conclude that it is possible that hot temperament herbs such as anise and fennel be useful for humans for certain conditions such as weight control.

Iranian Traditional Medicine (ITM) describes a kind of dementia with similar signs and symptoms of Alzheimer’s disease (AD). It explains the pathology of dementia with cold intemperament of the brain, which means that the brain is colder than its healthy form. ITM strategy for treatment of dementia is to heat the brain up by medical “hot” herbs. Nepeta menthoides (NM) is one of these “hot” herbs. To evaluate the veracity of ITM concept about dementia and its treatment, we first try to examine if coldness of brain can make memory impairment. If so, can NM reverse memory impairment? Rats in cold-water-induced hypothermic (CWH) groups were immersed up to the neck in 3.5°C water, for 5 min during 14 consecutive days. As a control, rats were forced to swim in warm water at the same conditions. To eliminate the impact of forced swimming stress, a group of intact rats was also added. After last swimming in day 14, some groups received drug (100 or 500 mg/kg aqueous extract of NM) or vehicle via i.p. injection. Learning and memory were assessed by Morris water maze, and tau hyperphosphorylation was measured by western blotting. The results showed that CWH impairs learning and memory and induces tau hyperphosphorylation. 100 mg/kg of NM reversed memory impairment as well as tau hyperphosphorylation. ITM theory about the relationship between brain hypothermia and dementia is in accordance with our findings.

Infection with Helicobacter pyloriis the most common cause of stomach and duodenal ulcers. About more than 80 % of people are infected with H. pylori in developing countries. H. pyloriuses urease enzyme product “ammonia” in order to neutralize and protect itself from the stomach acidic condition and urease enzyme activity has been shown to be essential to the colonization of H. pylori. Inhibitory activity of 20 traditional medicinal plants were examined and evaluated against Jack bean urease activity by Berthelot reactionto obtain natural sources of urease inhibitors. Each herb was extracted using 80% aqueous methanol, then tested its IC50 value was determined. Eight of the whole 20 studied plants crude extracts were found the most effective with IC50 values of less than 100µg/ml including Laurus nobilis, Zingiber officinale, Nigella sativa, Angelica archangelica, Acorus calamus, Allium sativum,Curcuma longa, andCitrus aurantiumextracts,from which most potent urease inhibitory was observed for Zingiber officinale, Laurus nobilis, and Nigella sativa with IC50values of 48.54, 48.69 and 59.10µg/ml, respectively.

Medicinal plants have been investigated for possible anti-cancer effects. The aim of the present study was to examine the cytotoxic activity of several medicinal plants on different tumor cell lines. 11 selected plant species which have been used in folkloric prescriptions were collected from different sites of Hamedan district of Iran. The methanolic extracts of the plants were prepared and their cytotoxic effects on four human cancer cell lines (A549, human lung adenocarcinoma; MCF7, human breast adenocarcinoma; HepG2, hepatocellular carcinoma and HT-29, human colon carcinoma) and one normal cell line (MDBK, bovine kidney) were examined using the MTT assay. Three of these were exhibited antiproliferative activity against one or more of the cell lines. The extract from Primula auriculata demonstrated the highest cytotoxicity with IC50 of 25.79, 35.79 and 43.34 μg.mL−1 against MCF7, HepG2 and HT-29 cells, respectively. For some of the plants, their traditional use was correlated with the cytotoxic results, whereas for others the results may support the non-cytotoxicity of species used traditionally as natural remedies. The cytotoxic species could be considered as potential of anticancer compounds.

Regarding to rapidly changing and highly competitive business environment it will become increasingly important for organizations to measure their performances appropriately. With respect to special characteristics of pharmaceutical industry and lack of reported performance measurement, this study tries to design an integrated performance measurement model for pharmaceutical companies. For generating this model we first identified key performance indicators and key result indicators of a typical pharmaceutical company and then base on expert opinions the most important of them identified for considering in proposed PM model. Though, this model is more appropriate for measuring performances of pharmaceutical companies, it can be useful for measuring performances of other industries with some modification. We strongly recommended pharmaceutical managers to link these indicators with their payment system and rewards which will dramatically affects performance of employees and consequently their organization`s success.

Drug and health literacy is a key determinant of health outcomes. There are several tools to assess drug and health literacy. The objective of this article is to determine drug literacy level and its relationships with other factors using a single screening tool. A cross- sectional survey was conducted among 1104 people in Qazvin province, Iran. Based on the proportional-to-size method, participants over 15 years old with ability to read were recruited randomly from 6 counties in Qazvin province and were interviewed directly. To determine drug literacy relationship with other variables, Chi-Square and t-test were used. Also, logistic regression model was used to adjust the relationship between drug literacy and other relevant variables. Response rate in clusters was 100%. Findings showed that inadequate drug literacy in Qazvin province is 30.3% and it was in association with (1) age (p=. 000), (2) marital status (p=. 000), (3) educational attainment (p=. 000), (4) home county (p=. 000), (5) residing area (p=. 000), (6) type of basic health insurance (p=. 000), (7) complementary health insurance status (p=. 000), and (8) family socioeconomic status (p=. 000). After adjusting for these variables using logistic regression model, the association between (1), (3), (4), (5) and (8) with drug literacy level was confirmed. The analysis also showed that this method can also be used in other health care settings in Iran for drug and health literacy rapid assessment.

Human Papilloma Virus (HPV) vaccine recently has been added to the Iran Drug List, decision makers need information beyond that available from RCTs to recommend funding for this vaccination program to add it to the National Immunization program in Iran. Modeling and economic studies have addressed some of those information needs in foreign countries. In order to determine the long term benefit of this vaccine and impact of vaccine program on the future rate of cervical cancer in Iran, we described a model, based on the available economic and health effects of human papilloma virus (HPV), to estimate the cost-effectiveness of HPV vaccination of 15-year-old girls in Iran. Our objective is to estimate the cost-effectiveness of HPV vaccination in Iran against cervical cancer based on available data; incremental cost-effectiveness ratio (ICER) calculations were based on a model comparing a cohort of 15-year-old girls with and without vaccination. We developed a static model based on available data in Iran on the epidemiology of HPV related health outcome. The model compared the cohort of all 15-year old girls alive in the year 2013 with and without vaccination. The cost per QALY, which was found based on our assumption for the vaccination of 15-years old girl to current situation was 439,000,000 Iranian Rial rate (IRR). By considering the key parameters in our sensitivity analysis, value varied from 251,000,000 IRR to 842,000,000 IRR. In conclusion, quadrivalent HPV vaccine (Gardasil) is not cost-effective in Iran based on the base-case parameters value.