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1.  Raloxifene adjunctive therapy for postmenopausal women suffering from chronic schizophrenia: a randomized double-blind and placebo controlled trial 
Cumulative evidence from epidemiological, preclinical and clinical studies suggests estrogens may have psychoprotective effects in schizophrenic patients. Selective Estrogen Receptor Modulators could have therapeutic benefits in schizophrenia for both sexes without being hazardous to gynecological tissues or having feminizing effects. Few studies have been conducted regarding the effects of raloxifene on postmenopausal women suffering from schizophrenia. We conducted this placebo-controlled trial to compare the add-on effect of raloxifene to risperidone versus risperidone with placebo.
This was an 8-week, parallel-group, placebo-controlled trial undertaken at two universities affiliated psychiatric Hospitals in Iran. Forty-six postmenopausal women with the definite diagnosis of schizophrenia were enrolled in the study. Patients received risperidone (6 mg/day in 3 divided doses) combined with either placebo (N = 23) or 120 mg/day of raloxifene (N = 23) for 8 weeks. Patients were assessed by a psychiatrist at baseline and at 2 and 8 weeks after the start of medical therapy. Efficacy was defined as the change from baseline to endpoint in score on Positive and Negative Syndrome Scale (PANSS).
For PANSS scores, the main effect comparing two types of intervention was not significant [F (1, 48) = 1.77, p = 0.18]. For positive subscale scores, there was marginal significant interaction between intervention type and time [F (2, 47) = 2.93, p = 0.06] and there was substantial main effect for time [F (2, 47) = 24.39, p = 0.001] within both groups showing reduction in positive subscale scores across the three time periods. In addition, the main effect comparing two types of intervention was significant [F (1, 48) = 3.78, p = 0.02]. On the other hand, for negative subscale scores, the main effect comparing two types of intervention was not significant [F (1, 48) = 1.43, p = 0.23]. For general subscale scores, the main effect comparing two types of intervention was not significant [F (1, 48) = 0.03, p = 0.86].
According to our findings, raloxifene as an adjunctive treatment to risperidone was only superior in improvement of positive symptoms and it was not effective in treating negative and general psychopathology symptoms.
Trial registration
The trial was registered at the Iranian registry of clinical trials: IRCT201205131556N42
PMCID: PMC4100751  PMID: 25012765
Schizophrenia; Menopause; Raloxifene; Selective estrogen receptor modulators
3.  Drug-drug interactions in inpatient and outpatient settings in Iran: a systematic review of the literature 
Drug-drug interactions (DDIs) are an important type of adverse drug events. Yet overall incidence and pattern of DDIs in Iran has not been well documented and little information is available about the strategies that have been used for their prevention. The purpose of this study was to systematically review the literature on the incidence and pattern of DDIs in Iran as well as the used strategies for their prevention. PubMed, Scopus, electronic Persian databases, and Google Scholar were searched to identify published studies on DDIs in Iran. Additionally, the reference lists of all retrieved articles were reviewed to identify additional relevant articles. Eligible studies were those that analyzed original data on the incidence of DDIs in inpatient or outpatient settings in Iran. Articles about one specific DDI and drug interactions with herbs, diseases, and nutrients were excluded. The quality of included studies was assessed using quality assessment criteria. Database searches yielded 1053 potentially eligible citations. After removing duplicates, screening titles and abstracts, and reading full texts, 34 articles were found to be relevant. The quality assessment of the included studies showed a relatively poor quality. In terms of study setting, 18 and 16 studies have been conducted in inpatient and outpatient settings, respectively. All studies focused on potential DDIs while no study assessed actual DDIs. The median incidence of potential DDIs in outpatient settings was 8.5% per prescription while it was 19.2% in inpatient settings. The most indicated factor influencing DDIs incidence was patient age. The most involved drug classes in DDIs were beta blockers, angiotensin-converting-enzyme inhibitors (ACEIs), diuretic agents, and non-steroidal anti-inflammatory drugs (NSAIDs). Thirty-one studies were observational and three were experimental in which the strategies to reduce DDIs were applied. Although almost all studies concluded that the incidence of potential DDIs in Iran in both inpatient and outpatient settings was relatively high, there is still no evidence of the incidence of actual DDIs. More extensive research is needed to identify and minimize factors associated with incidence of DDIs, and to evaluate the effects of preventive interventions especially those that utilize information technology.
PMCID: PMC4079175  PMID: 24965959
Adverse drug events; Developing countries; Drug-drug interaction; Medication errors; Incidence; Intervention; Iran
4.  Selenium supplementation in patients undergoing hematopoietic stem cell transplantation: effects on pro-inflammatory cytokines levels 
Pro-inflammatory cytokines including tumor necrosis factor alpha (TNF-α), interleukin-1β (IL-1β) and interleukin-6 (IL-6) play an important role in the development of hematopoietic stem cell transplantation (HSCT) complications. We explored the effect of Selenium as an antioxidant and anti-inflammatory agent on pro-inflammatory cytokines levels in HSCT candidates.
Plasma concentrations of TNF-α, IL-1β and IL-6 were measured in 74 patients from a double-blind, randomized, placebo-controlled study. In both groups, there were 37 patients with median age of 32 years. Patients received oral Se tablets (200 mcg) or placebo twice daily beginning from the first day of high dose chemotherapy (HDC) through 14 days after HSCT. Cytokine levels were determined before starting HDC (prior to first dose of Se), 7 and 14 days after HSCT. Plasma levels of TNF-α were not significantly different between Se and control group (P = 0.13). IL-1 levels were similar between two groups (P = 0.88). No significant differences were detected in IL-6 levels between Se and control group (P = 0.96).
Selenium had no effect on pro-inflammatory cytokines levels in patients undergoing HSCT. It is likely that earlier initiation and/or larger doses of Se are required to affect inflammatory cytokines significantly.
PMCID: PMC4077582  PMID: 24942646
Selenium; TNF-α; IL-6; Hematopoietic stem cell transplantation; Oral mucositis
5.  A stability indicating HPLC method for the determination of clobazam and its basic degradation product characterization 
Clobazam is used for the treatment of different types of seizure and epilepsy. The present research is undertaken to study the systematic forced degradation of clobazam and to identify its main degradation product under basic conditions.
The degradation of clobazam was studied under different conditions. Clobazam and its degradation products were separated using a Nova-Pak C18 column and a mixture of KH2PO4 50 mM (pH 8.5) and acetonitrile (50:50, v/v) as the mobile phase with UV detection at 230 nm.
The within-day and between-day precision values in the calibration range of 0.1-20 μg/ml were within 0.5-1.5%. Clobazam was relatively stable in solid from under exposure to visible and UV light and also heat. The clobazam aqueous solution of clobazam was more labile under exposure to visible and UV light. The bulk drug was significantly degraded under exposure to 2 M HCl, 0.1 M NaOH or 3% H2O2. Using the tablet powder, higher degradation rates were observed under different stress conditions. The main degradation product of clobazam under basic condition was subsequently characterized.
The developed method could be used for the determination of clobazam in the presence of its degradation products with acceptable precision and accuracy. The applicability of the proposed method was evaluated in commercial dosage forms analysis.
PMCID: PMC4063431  PMID: 24919821
Clobazam; HPLC; Stability indicating; Stress degradation
6.  Formulation of inhalable lipid-based salbutamol sulfate microparticles by spray drying technique 
The aim of this work was to develop dry powder inhaler (DPI) formulations of salbutamol sulfate (SS) by the aid of solid lipid microparticles (SLmPs), composed of biocompatible phospholipids or cholesterol.
The SLmPs were prepared by using two different solvent systems (ethanol and water-ethanol) and lipid carriers (dipalmitoylphosphatidylcholine (DPPC) and cholesterol) with/without L-leucine in the spray drying process. The spray-dried microparticles were physically-mixed with coarse lactose monohydrate in order to make our final DPI formulations and were investigated in terms of physical characteristics as well as in vitro drug release profile and aerosolization behavior.
We observed significant differences in the sizes, morphologies, and in vitro pulmonary depositions between the formulations. In particular, the SS-containing SLmPs prepared with water-ethanol (30:70 v/v) solution of DPPC and L-leucine which had then been blended with coarse lactose (1:9 w/w) exhibited the highest emitted dose (87.9%) and fine particle fraction (42.7%) among the formulations. In vitro drug release study indicated that despite of having a significant initial burst release for both cholesterol and DPPC-based microparticles, the remained drug released more slowly than the pure drug.
This study demonstrated the potential of using lipid carriers as well as L-leucine in DPI formulations of SS to improve its aerosolization behavior and retard the release profile of the drug.
PMCID: PMC4077687  PMID: 24919924
Dry powder inhalation; Spray drying; Salbutamol sulfate; Solid lipid microparticles; Particle engineering; L-leucine
7.  The antimicrobial effects of selenium nanoparticle-enriched probiotics and their fermented broth against Candida albicans 
Lactic acid bacteria are considered important probiotics for prevention of some infections. The aim of this work was to investigate the effect of selenium dioxide on the antifungal activity of Lactobacillus plantarum and L. johnsonii against Candida albicans.
Lactobacillus plantarum and L. johnsonii cells, grown in the presence and absence of selenium dioxide, and their cell-free spent culture media were tested for antifungal activity against C. albicans ATCC 14053 by a hole-plate diffusion method and a time-kill assay.
Both L. plantarum and L. johnsonii reduced selenium dioxide to cell-associated elemental selenium nanoparticles. The cell-free spent culture media, from both Lactobacillus species that had been grown with selenium dioxide for 48 h, showed enhanced antifungal activity against C. albicans. Enhanced antifungal activity of cell biomass against C. albicans was also observed in cultures grown with selenium dioxide.
Selenium dioxide-treated Lactobacillus spp. or their cell-free spent broth inhibited the growth of C. albicans and should be investigated for possible use in anti-Candida probiotic formulations in future.
PMCID: PMC4060857  PMID: 24906455
Candida albicans; Secretory products; Selenium nanoparticles; Antimicrobial effect; Lactobacillus plantarum; Lactobacillus johnsonii
8.  Evaluation of antitumor activity of a TGF-beta receptor I inhibitor (SD-208) on human colon adenocarcinoma 
Transforming growth factor-β (TGF-β) pathway is involved in primary tumor progression and in promoting metastasis in a considerable proportion of human cancers such as colorectal cancer (CRC). Therefore, blockage of TGF-β pathway signaling via an inhibitor could be a valuable tool in CRC treatment.
To evaluate the efficacy of systemic targeting of the TGF-β pathway for therapeutic effects on CRC, we investigated the effects of a TGβRI (TGF-β receptor 1) or TβRI kinase inhibitor, SD-208, on SW-48, colon adenocarcinoma cells. In this work, in vitro cell proliferation was studied by methyl thiazolyl tetrazolium (MTT) and bromo-2′-deoxyuridine (BrdU) assays. Also, the histopathological and immunohistochemical evaluations were conducted by hematoxylin and eosin, and Ki-67 and CD34 markers were stained, respectively.
Our results showed no significant reduction in cell proliferation and vessel formation (170 ± 70 and 165 ± 70, P > 0.05) in treated SW-48 cells with SD-208 compared to controls.
Our data suggested that SD-208 could not significantly reduce tumor growth and angiogenesis in human colorectal cancer model at least using SW-48 cells.
PMCID: PMC4077684  PMID: 24902843
SD-208; Colorectal cancer; SW-48; Immunohistochemistry staining
9.  Current approaches of the management of mercury poisoning: need of the hour 
Mercury poisoning cases have been reported in many parts of the world, resulting in many deaths every year. Mercury compounds are classified in different chemical types such as elemental, inorganic and organic forms. Long term exposure to mercury compounds from different sources e.g. water, food, soil and air lead to toxic effects on cardiovascular, pulmonary, urinary, gastrointestinal, neurological systems and skin. Mercury level can be measured in plasma, urine, feces and hair samples. Urinary concentration is a good indicator of poisoning of elemental and inorganic mercury, but organic mercury (e.g. methyl mercury) can be detected easily in feces. Gold nanoparticles (AuNPs) are a rapid, cheap and sensitive method for detection of thymine bound mercuric ions. Silver nanoparticles are used as a sensitive detector of low concentration Hg2+ ions in homogeneous aqueous solutions. Besides supportive therapy, British anti lewisite, dimercaprol (BAL), 2,3-dimercaptosuccinic acid (DMSA. succimer) and dimercaptopropanesulfoxid acid (DMPS) are currently used as chelating agents in mercury poisoning. Natural biologic scavengers such as algae, azolla and other aquatic plants possess the ability to uptake mercury traces from the environment.
PMCID: PMC4055906  PMID: 24888360
Mercury compounds; Chelating agents; Poisoning; Gold nanoparticles; Natural biologic scavengers
10.  Effect of myrtle fruit syrup on abnormal uterine bleeding: a randomized double-blind, placebo-controlled pilot study 
Myrtle (Myrtus communis L.) has been used in the Iranian Traditional Medicine as a treatment for abnormal uterine bleeding-menometrorrhagia. The main aim of this study is to evaluate the effect of myrtle fruit syrup on abnormal uterine bleeding-menometrorrhagia.
A randomized, double-blind, placebo-controlled pilot study was conducted on 30 women suffering from abnormal uterine bleeding-menometrorrhagia. Treatment comprised of giving 15 ml oral myrtle syrup daily (5 ml three times a day) for 7 days starting from the onset of bleeding. The myrtle syrup along with placebo was repeated for 3 consecutive menstrual periods. Menstrual duration and number of used pads were recorded by the Pictorial Blood loss Assessment Chart at the end of each menstrual period. The quality of life was also evaluated using the menorrhagia questionnaire.
The mean number of bleeding days significantly declined from 10.6 ± 2.7 days to 8.2 ± 1.9 days after 3 months treatment with the syrup (p = 0.01) and consequently the participants in the intervention group used fewer pads after 3 months (16.4 ± 10.7) compared with the number of pads used at the beginning of the treatment (22.7 ± 12.0, p = 0.01). Bleeding days and number of pads used by the participants in the placebo group did not change significantly. Also significant changes of quality of life scores were observed in the intervention group after 3 months compared to the baseline.
Myrtle syrup is introduced as a potential remedy for abnormal uterine bleeding-menometrorrhagia.
PMCID: PMC4079189  PMID: 24888316
Abnormal uterine bleeding-menometrorrhagia; Effrat-e-tams; Iranian traditional medicine; Myrtus communis L; Myrtle; Myrtaceae
11.  Preparation, characterization and in vitro efficacy of magnetic nanoliposomes containing the artemisinin and transferrin 
Artemisinin is the major sesquiterpene lactones in sweet wormwood (Artemisia annua L.), and its combination with transferrin exhibits versatile anti-cancer activities. Their non-selective targeting for cancer cells, however, limits their application. The aim of this study was to prepare the artemisinin and transferrin-loaded magnetic nanoliposomes in thermosensitive and non-thermosensitive forms and evaluate their antiproliferative activity against MCF-7 and MDA-MB-231 cells for better tumor-targeted therapy.
Artemisinin and transferrin-loaded magnetic nanoliposomes was prepared by extrusion method using various concentrations of lipids. These formulations were characterized for particle size, zeta potential, polydispersity index and shape morphology. The artemisinin and transferrin-loading efficiencies were determined using HPLC. The content of magnetic iron oxide in the nanoliposomes was analysed by spectrophotometry. The in vitro release of artemisinin, transferrin and magnetic iron oxide from vesicles was assessed by keeping of the nanoliposomes at 37°C for 12 h. The in vitro cytotoxicity of prepared nanoliposomes was investigated against MCF-7 and MDA-MB-231 cells using MTT assay.
The entrapment efficiencies of artemisinin, transferrin and magnetic iron oxide in the non-thermosensitive nanoliposomes were 89.11% ± 0.23, 85.09% ± 0.31 and 78.10% ± 0.24, respectively. Moreover, the thermosensitive formulation showed a suitable condition for thermal drug release at 42°C and exhibited high antiproliferative activity against MCF-7 and MDA-MB-231 cells in the presence of a magnetic field.
Our results showed that the thermosensitive artemisinin and transferrin-loaded magnetic nanoliposomes would be an effective choice for tumor-targeted therapy, due to its suitable stability and high effectiveness.
PMCID: PMC4053270  PMID: 24887240
Artemisinin; Transferrin; Liposome; MCF-7 cells; In vitro
12.  Effect of Linum usitatissimum L. (linseed) oil on mild and moderate carpal tunnel syndrome: a randomized, double-blind, placebo-controlled clinical trial 
Carpal tunnel syndrome is known as the most common entrapment neuropathy. Conservative treatments cannot reduce the symptomatic severity satisfactorily; therefore, effectiveness of Linum usitatissimum L. (linseed) oil on carpal tunnel syndrome, as a complementary treatment, was evaluated in the current study. Linseed oil is a well-known preparation in Iranian traditional medicine and its analgesic, anti-inflammatory and anti-oxidative effects have been shown in previous studies.
A randomized, double-blind, placebo-controlled clinical trial was conducted. One hundred patients (155 hands) with idiopathic mild to moderate carpal tunnel syndrome aged between 18 and 65 years old were randomized in two parallel groups. These two groups were treated during 4 weeks with topical placebo and linseed oil. In addition, a night wrist splint was prescribed for both groups. Symptomatic severity and functional status were measured using Boston Carpal Tunnel Questionnaire. In addition, median sensory nerve conduction velocity, motor distal latency, sensory distal latency and compound latency as electrodiagnostic parameters were measured at baseline and after the intervention period.
After the intervention, significant improvement was observed regarding Boston Carpal Tunnel Questionnaire symptomatic severity and functional status mean differences (p <0.001) in the linseed oil group compared with those in the placebo group. Also, regarding the mean differences of both groups, significant improvement of nerve conduction velocity of the median nerve was seen in the linseed oil group by a value of 2.38 m/sec (p < 0.05). However, motor distal latency and sensory distal latency of the median nerve showed no between-group significant changes (p = 0.14 for both items). Finally, compound latency was improved slightly in the case group, comparing mean differences between the groups (p <0.05). No significant adverse events were reported from using linseed oil.
It seems that linseed oil could be effective in the management of mild and moderate carpal tunnel syndrome, especially in improving the severity of symptoms and functional status. In addition, its effect on electerodiagnostic parameters, especially on the nerve conduction velocity, can be considered as a valuable point.
PMCID: PMC4045922  PMID: 24887185
Carpal tunnel syndrome; Linum usitatissimum; Linseed oil; Iranian traditional medicine; Randomized controlled trial; Herbal medicine; Complementary therapies
13.  Synthesis and cytotoxic evaluation of some new[1,3]dioxolo[4,5-g]chromen-8-one derivatives 
Homoisoflavonoids are naturally occurring compounds belong to flavonoid classes possessing various biological properties such as cytotoxicity. In this work, an efficient strategy for the synthesis of novel homoisoflavonoids, [1,3]dioxolo[4,5-g]chromen-8-ones, was developed and all compounds were evaluated for their cytotoxic activities on three breast cancer cell lines.
Our synthetic route started from benzo[d][1,3]dioxol-5-ol which was reacted with 3-bromopropanoic acid followed by the reaction of oxalyl chloride to afford 6,7-dihydro-8H-[1,3]dioxolo[4,5-g]chromen-8-one. The aldol condensation of the later compound with aromatic aldehydes led to the formation of the title compounds. Five novel derivatives 4a-e were tested for their cytotoxic activity against three human breast cancer cell lines including MCF-7, T47D, and MDA-MB-231 using the MTT assay.
Among the synthesized compounds, 7-benzylidene-6,7-dihydro-8H-[1,3]dioxolo[4,5-g]chromen-8-one (4a) exhibited the highest activity against three cell lines. Also the analysis of acridine orange/ethidium bromide staining results revealed that 7-benzylidene-6,7-dihydro-8H-[1,3]dioxolo[4,5-g]chromen-8-one (4a) and 7-(2-methoxybenzylidene)-6,7-dihydro-8H-[1,3]dioxolo[4,5-g]chromen-8-one (4b) induced apoptosis in T47D cell line.
Finally, the effect of methoxy group on the cytotoxicity of compounds 4b-4d was investigated in and it was revealed that it did not improve the activity of [1,3]dioxolo[4,5-g]chromen-8-ones against MCF-7, T47D, and MDA-MB-231.
PMCID: PMC4019946  PMID: 24887061
Homoisoflavonoids; [1,3]dioxolo[4,5-g]chromen-8-one; Cancer; Cytotoxic activity
14.  Adenosine deaminase activity modulation by some street drug: molecular docking simulation and experimental investigation 
Adenosine deaminase (ADA) is an enzyme that plays important roles in proliferation, maturation, function and development of the immune system. ADA activity may be altered by variety of substances including synthetic or natural products. Morphine, cocaine and their analogs exert immune suppressive activities by decreasing immune system function. The purpose of this study is to confirm that this possible effect may be modulated by interaction of these substances with ADA activity by experimental and computational method.
The structural changes in ADA have been studied in presence of cocaine, ethylmorphine, homatropine, morphine and thebaine by determination of ADA hydrolytic activity, circular dichroism and fluorescence spectroscopy in different concentrations. Docking study was performed to evaluate interaction method of test compound with ADA active site using AutoDock4 software.
According to in-vitro studies all compounds inhibited ADA with different potencies, however thebaine activated it at concentration below 50 μM, ethylmorphine inhibited ADA at 35 μM. Moreover, fluorescence spectra patterns were differed from compounds based on structural resemblance which were very considerable for cocaine and homatropine.
The results of this study confirms that opioids and some other stimulant drugs such as cocaine can alter immune function in illegal drug abusers. These findings may lead other investigators to develop a new class of ADA activators or inhibitors in the near future.
PMCID: PMC4028107  PMID: 24887139
Adenosine deaminase; Opioid; Cocaine; Immune system; Docking
15.  Tribulus terrestris for treatment of sexual dysfunction in women: randomized double-blind placebo - controlled study 
Tribulus terrestris as a herbal remedy has shown beneficial aphrodisiac effects in a number of animal and human experiments. This study was designed as a randomized double-blind placebo-controlled trial to assess the safety and efficacy of Tribulus terrestris in women with hypoactive sexual desire disorder during their fertile years. Sixty seven women with hypoactive sexual desire disorder were randomly assigned to Tribulus terrestris extract (7.5 mg/day) or placebo for 4 weeks. Desire, arousal, lubrication, orgasm, satisfaction, and pain were measured at baseline and after 4 weeks after the end of the treatment by using the Female Sexual Function Index (FSFI). Two groups were compared by repeated measurement ANOVA test.
Thirty women in placebo group and thirty women in drug group completed the study. At the end of the fourth week, patients in the Tribulus terrestris group had experienced significant improvement in their total FSFI (p < 0.001), desire (p < 0.001), arousal (p = 0.037), lubrication (p < 0.001), satisfaction (p < 0.001) and pain (p = 0.041) domains of FSFI. Frequency of side effects was similar between the two groups.
Tribulus terrestris may safely and effectively improve desire in women with hypoactive sexual desire disorder. Further investigation of Tribulus terrestris in women is warranted.
PMCID: PMC4045980  PMID: 24773615
Tribulus terrestris; Sexual dysfunction; Women; Traditional medicine
16.  Beneficial effects of pioglitazone and metformin in murine model of polycystic ovaries via improvement of chemerin gene up-regulation 
Polycystic ovary syndrome (PCO) is recognized as the most common endocrinopathy in female. Chemerin is a novel adipocytokine that is expressed in ovary and upregulated in adipose tissue of obese, PCO patients. To date there is no report about the regulation of ovarian chemerin gene expression after PCO induction and treatment by insulin sensitizing drugs including pioglitazone and metformin.
Thirty female rats were divided into six experimental groups with five rats in each group including control group, PCO group (i.m injection of 4 mg estradiol benzoate for 40 days), metformin treated (200 mg/kg/day for 21 days), pioglitazone treated (20 mg/kg/day, for 21 days), PCO + metformin and PCO + pioglitazone. PCO was detected by microscopic observation of vaginal smear and treatment by metformin and pioglitazone was initiated one week after that. Ovarian chemerin expression was analyzed by real time PCR and western blotting.
Our results demonstrated that PCO induction resulted in elevation of chemerin mRNA and protein levels in ovary in concomitant with incidence of insulin resistance and increasing androgen and progesterone production. We observed that metformin and pioglitazone attenuated ovarian chemerin expression and improved insulin resistance and abnormal steroid production in PCO rats.
Based on data presented here we concluded that alteration of ovarian chemerin expression may has important role in PCO development and manipulation of chemerin expression or signaling by pioglitazone or metformin can be a novel therapeutic mechanism in the treatment of PCO patients by these drugs.
PMCID: PMC4008382  PMID: 24762064
PCO; Chemerin; Gene expression; Ovary; Pioglitazone; Metformin
17.  Silymarin improved 6-OHDA-induced motor impairment in hemi-parkisonian rats: behavioral and molecular study 
Neuroinflammation and oxidative stress has been shown to be associated with the development of Parkinson disease (PD). In the present study, we investigated the effect of intraperitoneal (i.p.) administration of silymarin, on 6-OHDA-induced motor-impairment, brain lipid per-oxidation and cerebrospinal fluid (CSF) levels of inflammatory cytokine in the rats.
The results showed that silymarin is able to improve motor coordination significantly (p < 0.001) in a dose dependent manner. There was a significant (p < 0.001) increase in MDA levels of 6-OHDA-lesioned rats whereas; in silymarin (100, 200 and 300 mg/kg, i.p. for 5 days) pre-treated hemi-parkinsonian rats MDA levels was decreased markedly (p < 0.001). Furthermore the CSF levels of IL-1β was decreased (p < 0.001) in silymarin (100, 200 and 300 mg/kg) pre-treated rats up to the range of normal non-parkinsonian animals.
We found that pre-treatment with silymarin could improve 6-OHDA-induced motor imbalance by attenuating brain lipid per-oxidation as well as CSF level of IL-1β as a pro-inflammatory cytokine. We suggest a potential prophylactic effect for silymarin in PD. However, further clinical trial studies should be carried out to prove this hypothesis.
PMCID: PMC4001109  PMID: 24726284
Silymarin; Catalepsy; MDA; IL-1β; 6-OHDA; Rotarod; Rat
18.  High dose insulin therapy, an evidence based approach to beta blocker/calcium channel blocker toxicity 
Poison-induced cardiogenic shock (PICS) as a result of beta-blocker (β-blocker) or calcium channel blocker (CCB) overdose is a common and potentially life-threatening condition. Conventional therapies, including fluid resuscitation, atropine, cardiac pacing, calcium, glucagon, and vasopressors often fail to improve hemodynamic status. High-dose insulin (HDI) is an emerging therapeutic modality for PICS. In this article, we discuss the existing literature and highlight the therapeutic success and potential of HDI. Based on the current literature, which is limited primarily to case series and animal models, the authors conclude that HDI can be effective in restoring hemodynamic stability, and recommend considering its use in patients with PICS that is not responsive to traditional therapies. Future studies should be undertaken to determine the optimal dose and duration of therapy for HDI in PICS.
PMCID: PMC3985540  PMID: 24713415
High dose insulin; Beta-blocker; Calcium channel blocker; Overdose
19.  Comparison of clinical results of two pharmaceutical products of riboflavin in corneal collagen cross-linking for keratoconus 
To compare the 6-month results of two formulations of Riboflavin provided by Sina Darou, Iran, and Uznach, Switzerland, in corneal collagen cross-linking (CXL) for keratoconus patients.
Considering the results of the previous study about the similarity of the formulations and the active ingredients of the two types of Riboflavin, they were used in the CXL procedure of 60 keratoconic eyes (30 eyes in each group). After 6 months, the mean improvement of UCVA (0.239), BCVA (0.707), and MRSE (0.513) did not differ significantly between the two groups. The mean decrease in max- K (0.731), mean- K (0.264), central corneal thickness (0.759), and Q-value (0.669) did not show any significant difference between the two groups. The two groups had no significant difference in endothelial cell count decrease (0.229). The Sina Darou formulation decreased corneal hysteresis more than the Swiss formulation (P = 0.057) but there were no significant differences in the mean decrease of corneal resistance factor between the two groups (P = 0.117).
Based on the early results, the results of visual acuity, refraction, and corneal topography using Sina Darou and Uznach formulations of Riboflavin showed that both were effective in CXL. However, considering the relatively significant difference in corneal hysteresis changes between the two groups, this study will continue to report the long-term results.
PMCID: PMC4001359  PMID: 24713424
Riboflavin; Pharmaceutical product; Sina Darou; Cross linking; Keratoconus; Clinical trial
21.  Quantification of verbascoside in medicinal species of Phlomis and their genetic relationships 
The genus Phlomis (Lamiaceae) is introduced by its valuable medicinal species, of which 17 species are growing wildly and ten of them are exclusively endemic of Iran. The main phytochemical characteristic of this genus is presence of iridoid glycosides including ipolamide, auroside, lamiide and also phenylethanoids such as verbascoside (acetoside) found in Lamiales order.
Due to the broad range of biological and pharmacological activities of verbascoside and lack of any report on quantification of this compound within Iranian species of Phlomis, we conducted a research to achieve two main goals, finding a genetic biodiversity by RAPD (Randomly Amplified Polymorphic DNA), as well as detecting and quantifying verbascoside in nine species of Phlomis growing wildly in Iran.
The results showed that various samples of P.olivieri possess different genetic distances from each other. Also, various species of P.olivieri display close relationships to P.anisodonta and P. persica. Phytoanalysis of Phlomis species by means of TLC scanner using verbascoside as a phytochemical marker showed that the highest concentration of verbascoside was found in P. anisodonta, however, P. bruguieri and P. olivieri (from Mazandaran) were in the second and third places. Interestingly, the lowest concentration of verbascoside was detected in P. olivieri (from Azerbayjan), exhibiting the effect of various growing areas and conditions on the measured levels of this compound.
verbascoside can be found in various species of Iranian Phlomis, of which P. anisodonta, P. bruguieri and P. olivieri might be the best choices. In addition, although the concentration of verbascoside in these plants may be affected by the growing areas and conditions, there are a good agreement between genetic relations and verbascoside levels.
PMCID: PMC3998186  PMID: 24650578
Phlomis; RAPD; Verbascoside; Quantification; TLC scanner
22.  A comparative study on the physicochemical and biological stability of IgG1 and monoclonal antibodies during spray drying process 
The main concern in formulation of antibodies is the intrinsic instability of these labile compounds. To evaluate the physicochemical stability of antibody in dry powder formulations, physical stability of IgG1 and a monoclonal antibody (trastuzumab) during the spray drying process was studied in a parallel study and the efficacy of some sugar based excipients in protection of antibodies was studied.
The SDS-PAGE analysis showed no fragmentation of antibodies after spray drying in all formulations. The secondary structure of antibodies contained 40.13 to 70.19% of β structure in dry state. Also, CD spectroscopy showed the similar secondary structure for trastuzumab after reconstitution in water. ELISA analysis and cell culture studies were conducted in order to evaluate bioactivity of monoclonal antibody. Formulations containing combination of excipients provided maximum tendency of trastuzumab to attach to the ELISA antigen (86.46% ± 2.3) and maximum bioactivity when incubated with SKBr3 cell line (the cell viability was decreased to 65.99% ± 4.6). Incubation of formulations with L929 cell line proved the biocompatibility of the excipients and non-toxic composition of formulations.
The IgG1 and trastuzumab demonstrated similar behavior in spray drying process. The combination of excipients containing trahalose, hydroxypropyl beta cyclodextrin and beta cyclodextrin with proper ratio improved the physical and chemical stability of both IgG1 and monoclonal antibody.
PMCID: PMC3972992  PMID: 24641877
Antibody; Trastuzumab; Spray drying; Trehalose; Hydroxypropyl beta cyclodextrin; Beta cyclodextrin
23.  Doxorubicin-conjugated PLA-PEG-Folate based polymeric micelle for tumor-targeted delivery: Synthesis and in vitro evaluation 
Selective delivery of anticancer agents to target areas in the body is desirable to minimize the side effects while maximizing the therapeutic efficacy. Anthracycline antibiotics such as doxorubicin (DOX) are widely used for treatment of a wide variety of solid tumors.
This study evaluated the potential of a polymeric micellar formulation of doxorubicin as a nanocarrier system for targeted therapy of a folate-receptor positive human ovarian cancer cell in line.
DOX-conjugated targeting and non-targeting micelles prepared by the dialysis method were about 188 and 182 nm in diameter, respectively and their critical micelle concentration was 9.55 μg/ml. The DOX-conjugated micelles exhibited a potent cytotoxicity against SKOV3 human ovarian cancer cells. Moreover, the targeting micelles showed higher cytotoxicity than that of non-targeting ones (IC50 = 4.65 μg/ml vs 13.51 μg/ml).
The prepared micelle is expected to increase the efficacy of DOX against cancer cells and reduce its side effects.
PMCID: PMC3996029  PMID: 24602477
Doxorubicin; Folate; Micelle; PLA-PEG block copolymer
24.  The effects of cichorium intybus extract on the maturation and activity of dendritic cells 
Cichorium intybus is a medicinal plant commonly used in traditional medicine for its benefits in immune-madiated disorders. There are several evidences showing that C. intybus can modulate immune responses. In the present study we have investigated the effects of the ethanolic root extract of this plant on the immune system by targeting dendritic cells (DCs). For this purpose, phenotypic and functional maturity of murine DCs after treatment with the extract was analyzed by flow cytometry and mixed lymphocyte reaction (MLR) assay.
C. intybus did not change the expression of CD40, CD86 and MHC-II molecules as important co-stimulatory markers on DCs compared to the control, indicating that it could not promote DCs phenotypic maturation. Treatment of DCs with lower concentrations of the extract resulted in an increased production of IL-12 by these cells with no change in IL-10 release. The capacity of treated DCs to stimulate allogenic T cells proliferation and cytokines secretion was examined in the co-cuture of these cells with T cells in MLR. C. intybus at higher concentrations inhibited proliferation of allogenic T cells and in lower concentrations changed the level of cytokines such that IL-4 decreased and IFN-γ increased.
These results indicated that C. intybus extract at higher concentrations can inhibit T cell stimulating activity of DCs, whereas at lower concentrations can modulate cytokine secretion toward a Th1 pattern. These data may in part explain the traditional use of this plant in treatment of immune-mediated disorders.
PMCID: PMC3936942  PMID: 24564889
DCs; Cichorium intybus; Dendritic cells; Immunomodulation; T cell responses
25.  Commercialization of biopharmaceutical knowledge in Iran; challenges and solutions 
The objective of this study was to investigate the application of the university research findings or commercialization of the biopharmaceutical knowledge in Iran and determine the challenges and propose some solutions.
A qualitative study including 19 in-depth interviews with experts was performed in 2011 and early 2012. National Innovation System (NIS) model was employed as the study design. Thematic method was applied for the analysis. The results demonstrate that policy making, regulations and management development are considered as fundamental reasons for current commercialization practice pattern. It is suggested to establish foundation for higher level documents that would involve relating bodies and provide them operational guidelines for the implementation of commercialization incentives.
Policy, regulations and management as the most influential issue should be considered for successful commercialization. The present study, for the first time, attempts to disclose the importance of evidence input for measures in order to facilitate the commercialization process by the authorities in Iran. Overall, the NIS model should be considered and utilized as one of the effective solutions for commercialization.
PMCID: PMC3974067  PMID: 24568555
Knowledge translation; Biopharmaceutical research; Facilitators and barriers

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