Showing papers in "DARU in 2013"
TL;DR: The data suggest that upregulation of the AKR gene might give a new insight into the mechanism of azole resistance, and the aldo-keto-reductase superfamily (AKR gene) was upregulated in the resistant clinical isolates as assessed by cDNA-AFLP.
Abstract: Candida glabrata causes significant medical problems in immunocompromised patients. Many strains of this yeast are intrinsically resistant to azole antifungal agents, and treatment is problematic, leading to high morbidity and mortality rates in immunosuppressed individuals. The primary goal of this study was to investigate the genes involved in the drug resistance of clinical isolates of C. glabrata. The clinical isolates of C. glabrata were collected in an epidemiological survey of candidal infection in immunocompromised patients and consisted of four fluconazole and itraconazole resistant isolates, two fluconazole and itraconazole sensitive isolates, and C. glabrata CBS 138 as reference strain. Antifungal susceptibility patterns of the organisms were determined beforehand by the Clinical and Laboratory Standards Institute (CLSI). The potential gene(s) implicated in antifungal resistance were investigated using complementary DNA- Amplified Fragment Length Polymorphism (cDNA-AFLP). Semi-quantitative RT-PCR was carried out to evaluate the expression of gene(s) in resistant isolates as compared to sensitive and reference strains. The aldo-keto-reductase superfamily (AKR gene) was upregulated in the resistant clinical isolates as assessed by cDNA-AFLP. Semi-quantitative RT-PCR revealed AKR mRNA expression approximately twice that seen in the sensitive isolates. Overexpression of the AKR gene was associated with increased fluconazole and itraconazole resistance in C. glabrata. The data suggest that upregulation of the AKR gene might give a new insight into the mechanism of azole resistance.
124 citations
TL;DR: Albumin conjugated PLGA nanoparticles may represent a promising drug delivery system in cancer therapy and results in more cytotoxicity against tumor cell lines compared with free docetaxel and unconjugated PL GA nanoparticles.
Abstract: Background: Poly lactic-co-glycolic acid (PLGA) based nanoparticles are considered to be a promising drug carrier in tumor targeting but suffer from the high level of opsonization by reticuloendothelial system due to their hydrophobic structure. As a result surface modification of these nanoparticles has been widely studied as an essential step in their development. Among various surface modifications, human serum albumin (HSA) possesses advantages including small size, hydrophilic surface and accumulation in leaky vasculature of tumors through passive targeting and a probable active transport into tumor tissues. Methods: PLGA nanoparticles of docetaxel were prepared by emulsification evaporation method and were surface conjugated with human serum albumin. Fourier transform infrared spectrum was used to confirm the conjugation reaction where nuclear magnetic resonance was utilized for conjugation ratio determination. In addition, transmission electron microscopy showed two different contrast media in conjugated nanoparticles. Furthermore, cytotoxicity of free docetaxel, unconjugated and conjugated PLGA nanoparticles was studied in HepG2 cells. Results: Size, zeta potential and drug loading of PLGA nanoparticles were about 199 nm, �11.07 mV, and 4%, respectively where size, zeta potential and drug loading of conjugated nanoparticles were found to be 204 nm, �5.6 mV and 3.6% respectively. Conjugated nanoparticles represented a three-phasic release pattern with a 20% burst effect for docetaxel on the first day. Cytotoxicity experiment showed that the IC50 of HSA conjugated PLGA nanoparticles (5.4 μg) was significantly lower than both free docetaxel (20.2 μg) and unconjugated PLGA nanoparticles (6.2 μg). Conclusion: In conclusion surface modification of PLGA nanoparticles through HSA conjugation results in more cytotoxicity against tumor cell lines compared with free docetaxel and unconjugated PLGA nanoparticles. Albumin conjugated PLGA nanoparticles may represent a promising drug delivery system in cancer therapy.
98 citations
TL;DR: The results suggested that the better prognosis could be achieved by oral administration of SeNP-enriched L. brevis in highly metastatic breast cancer mice model.
Abstract: Background and the purpose of the study: Selenium enriched Lactobacillus has been reported as an immunostimulatory agent which can be used to increase the life span of cancer bearing animals. Lactic acid bacteria can reduce selenium ions to elemental selenium nanoparticles (SeNPs) and deposit them in intracellular spaces. In this strategy two known immunostimulators, lactic acid bacteria (LAB) and SeNPs, are concomitantly administered for enhancing of immune responses in cancer bearing mice. Methods: Forty five female inbred BALB/c mice were divided into three groups of tests and control, each containing 15 mice. Test mice were orally administered with SeNP-enriched Lactobacillus brevis or Lactobacillus brevis alone for 3 weeks before tumor induction. After that the administration was followed in three cycles of seven days on/three days off. Control group received phosphate buffer saline (PBS) at same condition. During the study the tumor growth was monitored using caliper method. At the end of study the spleen cell culture was carried out for both NK cytotoxicity assay and cytokines measurement. Delayed type hypersensitivity (DTH) responses were also assayed after 72h of tumor antigen recall. Serum lactate dehydrogenase (LDH) and alkaline phosphatase (ALP) levels were measured, the livers of mice were removed and prepared for histopathological analysis. Results: High level of IFN-γ and IL-17 besides the significant raised in NK cytotoxicity and DTH responses were observed in SeNP-enriched L. brevis administered mice and the extended life span and decrease in the tumor metastasis to liver were also recorded in this group compared to the control mice or L.brevis alone administered mice. Conclusion: Our results suggested that the better prognosis could be achieved by oral administration of SeNP-enriched L. brevis in highly metastatic breast cancer mice model.
97 citations
TL;DR: The compounds with electron donating group and higher hydrophobic interaction with active site of enzyme prevents hydrolysis of substrate and reduced urease inhibitory activity are reported.
Abstract: A straightforward and efficient method for the synthesis of pyrano[2,3-d]pyrimidine diones derivatives from the reaction of barbituric acid, malononitrile and various aromatic aldehydes using SBA-Pr-SO3H as a nanocatalyst is reported. Reactions proceed with high efficiency under solvent free conditions. Urease inhibitory activity of pyrano[2,3-d]pyrimidine diones derivatives were tested against Jack bean urease using phenol red method. Three compounds of 4a, 4d and 4l were not active in urease inhibition test, but compound 4a displayed slight urease activation properties. Compounds 4b, 4k, 4f, 4e, 4j, 4g and 4c with hydrophobic substitutes on phenyl ring, showed good inhibitory activity (19.45-279.14 μM). The compounds with electron donating group and higher hydrophobic interaction with active site of enzyme prevents hydrolysis of substrate. Electron withdrawing groups such as nitro at different position and meta-methoxy reduced urease inhibitory activity. Substitution of both hydrogen of barbituric acid with methyl group will convert inhibitor to activator.
86 citations
TL;DR: Calendula extract gel could be effective on decreasing the intensity of radiotherapy- induced OM during the treatment and antioxidant capacity may be partly responsible for the effect.
Abstract: This study was designed to determine the effect of Calendula officinalis flowers extract mouthwash as oral gel on radiation-induced oropharyngeal mucositis (OM) in patients with head-and-neck cancer. Forty patients with neck and head cancers under radiotherapy or concurrent chemoradiotherapy protocols were randomly assigned to receive either 2% calendula extract mouthwash or placebo (20 patients in each group). Patients were treated with telecobalt radiotherapy at conventional fractionation (200 cGy/fraction, five fractions weekly, 30–35 fractions within 4–7 weeks). The oropharyngeal mucositis was evaluated by two clinical investigators (a radiation oncologist and a dentist), using the oral mucositis assessment scale (OMAS). Trying to find out the possible mechanism of action of the treatment, total antioxidant, polyphenol and flavonoid contents, and quercetin concentration of the mouth wash were measured. Calendula mouthwash significantly decreased the intensity of OM compared to placebo at week 2 (score: 5.5 vs. 6.8, p = 0.019), week 3 (score: 8.25 vs. 10.95, p < 0.0001) and week 6 (score: 11.4 vs. 13.35, p = 0.031). Total antioxidant, polyphenol and flavonoid contents and quercetin concentration of the 2% extract were 2353.4 ± 56.5 μM, 313.40 ± 6.52 mg/g, 76.66 ± 23.24 mg/g, and 19.41 ± 4.34 mg/l, respectively. Calendula extract gel could be effective on decreasing the intensity of radiotherapy- induced OM during the treatment and antioxidant capacity may be partly responsible for the effect.
81 citations
TL;DR: The majority of risks in pharmaceutical supply chain were internal risks due to processes, people and functions mismanagement which could be managed by suitable mitigation strategies.
Abstract: Supply of medicine as a strategic product in any health system is a top priority. Pharmaceutical companies, a major player of the drug supply chain, are subject to many risks. These risks disrupt the supply of medicine in many ways such as their quantity and quality and their delivery to the right place and customers and at the right time. Therefore risk identification in the supply process of pharmaceutical companies and mitigate them is highly recommended. In this study it is attempted to investigate pharmaceutical supply chain risks with perspective of manufacturing companies. Scopus, PubMed, Web of Science bibliographic databases and Google scholar scientific search engines were searched for pharmaceutical supply chain risk management studies with 6 different groups of keywords. All results found by keywords were reviewed and none-relevant articles were excluded by outcome of interests and researcher boundaries of study within 4 steps and through a systematic method. Nine articles were included in the systematic review and totally 50 main risks based on study outcome of interest extracted which classified in 7 categories. Most of reported risks were related to supply and supplier issues. Organization and strategy issues, financial, logistic, political, market and regulatory issues were in next level of importance. It was shown that the majority of risks in pharmaceutical supply chain were internal risks due to processes, people and functions mismanagement which could be managed by suitable mitigation strategies.
77 citations
TL;DR: A stable copolymeric network of PVA was developed with MAA and the prepared hydrogels were highly pH responsive and could be a potential delivery system for colon targeting of 5-FU in colorectal cancers.
Abstract: Background of the Study: The propose of the present work was to develop chemically cross-linked polyvinyl alcohol-co-poly(methacrylic acid) hydrogel (PVA-MAA hydrogel) for pH responsive delivery of 5-Fluorouracil (5-FU). Methods: PVA based hydrogels were prepared by free radical copolymerization. PVA has been cross-linked chemically with monomer (methacrylic acid) in aqueous medium, cross-linking agent was ethylene glycol di-methacrylate (EGDMA) and benzoyl peroxide was added as reaction initiator. 5-FU was loaded as model drug. FTIR, XRD, TGA and DSC were performed for characterization of copolymer. Surface morphology was studied by SEM. pH sensitive properties were evaluated by swelling dynamics and equilibrium swelling ratio at low and higher pH. Results: FTIR, XRD, TGA and DSC studies confirmed the formation of new copolymer. Formulations with higher MAA contents showed maximum swelling at 7.4 pH. High drug loading and higher drug release has been observed at pH 7.4. Conclusions: The current study concludes that a stable copolymeric network of PVA was developed with MAA. The prepared hydrogels were highly pH responsive. This polymeric network could be a potential delivery system for colon targeting of 5-FU in colorectal cancers.
77 citations
TL;DR: This work emphasizes that this part of the nanoscience must not be undermined and toxicologists must be sensitive to set up suitable in vivo or in vitro toxicity models for NPs’ structure-size-efficacy-toxicity (SSET).
Abstract: In spite of the extreme rise to the knowledge of nanotechnology in pharmaceutical sciences, there are currently limited experimental works studying the interactions between nanoparticles (NPs) and the biological system. Adjustment of size and surface area plays the main role in the reaction between NPs and cells leading to their increased entrance into cells through skin, gastrointestinal and respiratory system. Moreover, change in physicochemical reactivity of NPs causes them to interact with circulatory and cellular proteins differentially leading to the altered parameters of their biokinetics, including adsorption, distribution, translocation, transformation, and elimination. A direct relationship between the surface area, reactive oxygen species generating capability, and proinflammatory effects of NPs have been found in respiratory tract toxicity. Additionally, complement-mediated hypersensitivity reactions to liposomes and other lipid-based nanodrugs have been well defined. Inhalation studies of some NPs have confirmed the translocation of inhaled materials to extra pulmonary organs such as central nervous system (CNS) via olfactory neurons and induction of inflammatory response. Injectable uncoated NPs have a tendency to remain on the injection site while the poly ethanol glycol (PEG)-coated NPs can be notably drained from the injection site to get as far as the lymph nodes where they accumulate. This confirms the existence of channels within the extracellular matrix for NPs to move along. Furthermore, induction of DNA strand breaks and formation of micronuclei have been recorded for exposure to some NPs such as single-walled carbon nanotubes. In the recent years, most of the studies have simply outlined better efficacy of nanodrugs, but few discussed their possible toxic reactions specially if used chronically. Therefore, we emphasize that this part of the nanoscience must not be undermined and toxicologists must be sensitive to set up suitable in vivo or in vitro toxicity models. A system for collecting data about the relationships between NPs’ structure-size-efficacy-toxicity (SSET) should be specified with special regard to portal of entry and target organ.
63 citations
TL;DR: Six extracts revealed > 50% ACE inhibition activity at 330 μg/ml concentration, and Quercus infectoria possessed the highest total phenolic content with 7410 ± 101 mg gallic acid/100 g dry plant.
Abstract: Background and purpose of the study: Angiotensin converting enzyme (ACE) inhibitors plays a critical role in treating hypertension The purpose of the present investigation was to evaluate ACE inhibition activity of 50 Iranian medicinal plants using an in vitro assay Methods: The ACE activity was evaluated by determining the hydrolysis rate of substrate, hippuryl-L-histidyl-L-leucine (HHL), using reverse phase high performance liquid chromatography (RP-HPLC) Total phenolic content and antioxidant activity were determined by Folin-Ciocalteu colorimetric method and DPPH radical scavenging assay respectively Results: Six extracts revealed >50% ACE inhibition activity at 330 μg/ml concentration They were Berberis integerrima Bunge (Berberidaceae) (882± 17%), Crataegus microphylla C Koch (Rosaceae) (809±13%), Nymphaea alba L (Nymphaeaceae) (663 ± 12%), Onopordon acanthium L (Asteraceae) (802 ± 20%), Quercus infectoria G Olivier (Fagaceae) (939 ± 25%) and Rubus sp (Rosaceae) (513 ± 10%) Q infectoria possessed the highest total phenolic content with 7410 ± 101 mg gallic acid/100 g dry plant Antioxidant activity of Q infectoria (IC50 value 17 ± 003 μg/ml) was more than that of BHT (IC50 value of 103 ± 015 μg/ml) and Trolox (IC50 value of 32 ± 006 μg/ml) as the positive controls Conclusions: In this study, we introduced six medicinal plants with ACE inhibition activity Despite the high ACE inhibition and antioxidant activity of Q infectoria, due to its tannin content (tannins interfere in ACE activity), another plant, O acanthium, which also had high ACE inhibition and antioxidant activity, but contained no tannin, could be utilized in further studies for isolation of active compounds
59 citations
TL;DR: In this paper, the cytotoxic activity of 11 phytochemicals (conferone, farnesiferol A, acantrifoside E, mogoltadone, diversin, galbanic acid, herniarin, 7-isopentenyloxycoumarin, umbelliprenin, stylosin and tschimgine) together with a newly synthesized prenylated derivative of curcumin (gercumin II) was investigated.
Abstract: Background
Ferula species are reputed in folk medicine for the treatment of a variety of disorders. There have been sporadic reports on the chemopreventive and chemosensitizing activities of some terpenoid coumarin derivatives from the genus Ferula. The present study investigated the cytotoxic activity of 11 phytochemicals (conferone, farnesiferol A, acantrifoside E, mogoltadone, diversin, galbanic acid, herniarin, 7-isopentenyloxycoumarin, umbelliprenin, stylosin and tschimgine) from Ferula species together with a newly synthesized prenylated derivative of curcumin (gercumin II).
59 citations
TL;DR: The most reported types of and the highest percentages for any type of ME in Iran were administration errors, and studying sources, underreporting of, and preventive measures for MEs are suggested.
Abstract: Medication error (ME) is the most common single preventable cause of adverse drug events which negatively affects patient safety. ME prevalence is a valuable safety indicator in healthcare system. Inadequate studies on ME, shortage of high-quality studies and wide variations in estimations from developing countries including Iran, decreases the reliability of ME evaluations. In order to clarify the status of MEs, we aimed to review current available literature on this subject from Iran. We searched Scopus, Web of Science, PubMed, CINAHL, EBSCOHOST and also Persian databases (IranMedex, and SID) up to October 2012 to find studies on adults and children about prescription, transcription, dispensing, and administration errors. Two authors independently selected and one of them reviewed and extracted data for types, definitions and severity of MEs. The results were classified based on different stages of drug delivery process. Eighteen articles (11 Persian and 7 English) were included in our review. All study designs were cross-sectional and conducted in hospital settings. Nursing staff and students were the most frequent populations under observation (12 studies; 66.7%). Most of studies did not report the overall frequency of MEs aside from ME types. Most of studies (15; 83.3%) reported prevalence of administration errors between 14.3%-70.0%. Prescribing error prevalence ranged from 29.8%-47.8%. The prevalence of dispensing and transcribing errors were from 11.3%-33.6% and 10.0%-51.8% respectively. We did not find any follow up or repeated studies. Only three studies reported findings on severity of MEs. The most reported types of and the highest percentages for any type of ME in Iran were administration errors. Studying ME in Iran is a new area considering the duration and number of publications. Wide ranges of estimations for MEs in different stages may be because of the poor quality of studies with diversity in definitions, methods, and populations. For gaining better insights into ME in Iran, we suggest studying sources, underreporting of, and preventive measures for MEs.
TL;DR: The Iranian pharmaceutical market has undergone great growth in comparison with developing countries and the pharmerging group, and the market is expanding quickly while a major share goes to biotechnology drugs, which implies the need to commercialization activities in novel fields like pharmaceutical biotechnology.
Abstract: So far, no detailed study of the Iranian pharmaceutical market has been conducted, and only a few studies have analyzed medicine consumption and expenditure in Iran. Pharmaceutical market trend analysis remains one of the most useful instruments to evaluate the pharmaceutical systems efficiency. An increase in imports of medicines, and a simultaneous decrease in domestic production prompted us to investigate the pharmaceutical expenditure structure. On the other hand, analyzing statistics provides a suitable method to assess the outcomes of national pharmaceutical policies and regulations. This is a descriptive and cross-sectional study which investigates the Iranian pharmaceutical market over a 13-year period (1997–2010). This study used the Iranian pharmaceutical statistical datasheet published by the Iranian Ministry of Health. Systematic searches of the relevant Persian and English research literature were made. In addition, official government documents were analyzed as sources of both data and detailed statements of policy. Analysis of the Iranian pharmaceutical market in the 13-year period shows that medicine consumption sales value growth has been 28.38% annually. Determination of domestic production and import reveals that 9.3% and 42.3% annual growth, respectively, have been experienced. The Iranian pharmaceutical market has undergone great growth in comparison with developing countries and the pharmerging group, and the market is expanding quickly while a major share goes to biotechnology drugs, which implies the need to commercialization activities in novel fields like pharmaceutical biotechnology. This market expansion has been in favor of imported medicine in sales terms, caused by the reinforcement of suspicious policies of policy makers that necessitates fundamental rearrangements.
TL;DR: Self nanoemulsification promoting ionic complexation between basic drug and oleic acid hold great promise in enhancing solubility of hydrophobic drugs.
Abstract: Background: Lumefantrine, an antimalarial molecule has very low and variable bioavailability owing to its extremely poor solubility in water. It is recommended to be taken with milk to enhance its solubility and bioavailability. The aim of present study was to develop a Self Nanoemulsifying Delivery system (SNEDs) of lumefantrine (LF) to achieve rapid and complete dissolution independent of food-fat and surfactant in dissolution media. Methods: Solubility of LF in oil, co-solvent/co-surfactant and surfactant solution and emulsification efficiency of surfactant were analyzed to optimize the LF loaded self nanoemulsifying preconcentrate. Effect of LF-oleic acid complexation on emulsification, droplet size, zeta potential and dissolution were investigated. Effect of milk concentration and fat content on saturation solubility and dissolution of LF was investigated. Dissolution of marketed formulation and LF-SNEDs was carried out in pH 1.2 and pH 6.8 phosphate buffer. Results: LF exhibited very high solubility in oleic acid owing to complexation between tertiary amine of LF and carboxyl group of oleic acid (OA). Cremophore EL and medium chain monoglyceride were selected surfactant and co-surfactant, respectively. Significantly smaller droplet size (37 nm), shift in zeta potential from negative to positive value, very high drug loading in lipid based system (> 10%), no precipitation after dissolution are the major distinguish characteristics contributed by LF-OA complex in the SNED system. Saturation solubility and dissolution study in milk containing media pointed the significant increment in solubility of LF in the presence of milk-food fat. LF-SNEDs showed > 90% LF release within 30 min in pH 1.2 while marketed tablet showed almost 0% drug release. Conclusion: Self nanoemulsification promoting ionic complexation between basic drug and oleic acid hold great promise in enhancing solubility of hydrophobic drugs.
TL;DR: The results suggested that the extracted MCP may modulate nitric oxide production in macrophages and promote splenocytes proliferation, and it may act as a potent immunomodulatory agent.
Abstract: Background and the purpose of this study: Mushroom polysaccharides have traditionally been used for the prevention and treatment of a multitude of disorders like infectious illnesses, cancers and various autoimmune diseases. In vitro and in vivo studies suggest that certain polysaccharides affect immune system function. Morchella conica (M. conica) is a species of rare edible mushroom whose multiple medicinal functions have been proven. Thus, the objective of this study is to isolate and characterize of exopolysaccharide from submerged mycelial culture of M. conica, and to evaluate its immunomodulatory activity. Methods: A water-soluble Morchella conica Polysaccharides (MCP) were extracted and isolated from the fermentation broth of M. conica through a combination of DEAE-cellulose and Sephacryl S-300 HR chromatograph. NMR and IR spectroscopy has played a developing role in identification of polysaccharide with different structure and composition from fungal and plant sources, as well as complex glycosaminoglycans of animal origin. Thus, NMR and IR spectroscopy were used to analyze the chemical structure and composition of the isolated polysaccharide. Moreover, the polysaccharide was tested for its immunomodulatory activity at different concentrations using in vitro model. Results: The results showed that MCP may significantly modulate nitric oxide production in macrophages, and promote splenocytes proliferation. Analysis from HPLC, infrared spectra and nuclear magnetic resonance spectroscopy showed that MCP was a homogeneous mannan with an average molecular weight of approximately 81.2 kDa. The glycosidic bond links is →6)-α-D-Man p-(1→. Conclusion: The results suggested that the extracted MCP may modulate nitric oxide production in macrophages and promote splenocytes proliferation, and it may act as a potent immunomodulatory agent.
TL;DR: Sildenafil citrate NPs with small particle size, lipophilic feature, high entrapment efficiency and good loading capacity is produced by this method.
Abstract: Background and the aim of the study: The objective of the present study was to formulate and optimize nanoparticles (NPs) of sildenafil-loaded poly (lactic-co-glycolic acid) (PLGA) by double emulsion solvent evaporation (DESE) method. The relationship between design factors and experimental data was evaluated using response surface methodology. Method: A Box-Behnken design was made considering the mass ratio of drug to polymer (D/P), the volumetric proportion of the water to oil phase (W/O) and the concentration of polyvinyl alcohol (PVA) as the independent agents. PLGA-NPs were successfully prepared and the size (nm), entrapment efficiency (EE), drug loading (DL) and cumulative release of drug from NPs post 1 and 8 hrs were assessed as the responses. Results: The NPs were prepared in a spherical shape and the sizes range of 240 to 316 nm. The polydispersity index of size was lower than 0.5 and the EE (%) and DL (%) varied between 14-62% and 2-6%, respectively. The optimized formulation with a desirability factor of 0.9 was selected and characterized. This formulation demonstrated the particle size of 270 nm, EE of 55%, DL of 3.9% and cumulative drug release of 79% after 12 hrs. In vitro release studies showed a burst release at the initial stage followed by a sustained release of sildenafil from NPs up to 12 hrs. The release kinetic of the optimized formulation was fitted to Higuchi model. Conclusions: Sildenafil citrate NPs with small particle size, lipophilic feature, high entrapment efficiency and good loading capacity is produced by this method. Characterization of optimum formulation, provided by an evaluation of experimental data, showed no significant difference between calculated and measured data.
TL;DR: Current situation in Iran pharmaceutical market confirms that the sanctions against Iran are affecting ordinary citizens and national health sector which resulted to reduction of availability of lifesaving medicines in the local market and has caused increasing pain and suffering for Iranian patients.
Abstract: Iran in recent decade faced several regional and international sanctions in foreign trade, financial and banking services. Iran national pharmaceutical industry has always played a major role in providing medicines to the Iranian patients. However, following the sanctions it has faced profound difficulties for importing of both finished products and pharmaceutical raw materials. Although medicines are exempted from sanctions, due to restriction on money transaction and proper insurance Iranian pharmaceutical companies have to pay cash in advance for imports of medicines and raw materials or to secure offshore funds at very high risks. Current situation in Iran pharmaceutical market confirms that the sanctions against Iran are affecting ordinary citizens and national health sector which resulted to reduction of availability of lifesaving medicines in the local market and has caused increasing pain and suffering for Iranian patients.
TL;DR: This is the first report about the effectiveness of silymarin in the subjects exposed chronically to H2S and the modulatory effect of TNF-α on the effectiveness, which might be used for individualize therapy.
Abstract: Background and the purpose of the study: Silymarin, a standardized extract of the milk thistle (Silybum marianum), is believed to exert some of its hepatoprotective effects though inhibition of free radicals and inflammation. In this study the effect of some pro- and anti-inflammatory cytokines and also antioxidant genes polymorphisms on the hepatoprotective effects of silymarin in the occupationally exposed individuals to hydrogen sulfide (H2S) in the sour natural gas refinery was investigated. Methods: We genotyped seven polymorphisms in six genes reported by others as modifiers of oxidative stress (NQO1, mEPXH1, GSTT1 and GSTM1) and inflammation (TNF-α and TGF-β1) for an association in effect of decreasing in liver function tests (LFTs). The LFTs of 77 sour gas refinery workers were measured before and after administration of silymarin (140 mg, three times per day for 1 month). Results: A significant reduction of blood AST, ALT and ALP was observed after 30 days of consumption (p < 0.001). The decreasing effect of silymarin on ALT in the subjects with high producer genotype (A allele carriers) was less than low producers. There were no significant associations between TGF-β1 and the studied genes of oxidative stress pathway and the effectiveness of silymarin. Conclusion: This is the first report about the effectiveness of silymarin in the subjects exposed chronically to H2S. Meanwhile, the modulatory effect of TNF-α on the effectiveness of silymarin might be used for individualize therapy.
TL;DR: The present work concluded metformin loaded niosomes to be effective in sustaining the drug release leading to decreased side effects and increased patient compliance.
Abstract: Background: Metformin an oral hypoglycemic has been widely used as a fist line of treatment of Type II Diabetes but in a very high dose 2–3 times a day and moreover suffers from a number of side effects like lactic acidosis, gastric discomfort, chest pain, allergic reactions being some of them. The present work was conducted with the aim of sustaining the release of metformin so as to decrease its side effects and also reduce its dosing frequency using a novel delivery system niosomes (non-ionic surfactant vesicles). Non-ionic surfactant vesicles of different surfactants were prepared using thin film hydration technique and were investigated for morphology, entrapment, in-vitro release, TEM (transmission electron microscopy) and physical stability. Optimized formulation was further studied for the effect of Surfactant concentration, DCP (Dicetyl phosphate), Surfactant: cholesterol ratio and volume of hydration. The release studies data was subjected to release kinetics models. Results: The prepared vesicles were uniform and spherical in size. Optimized formulation MN3 entrapped the drug with 84.50±0.184 efficiency in the vesicles of the size 487.60±2.646 and showed the most sustained release of 73.89±0.126. Also it was resulted that 100 molar concentration of cholesterol and surfactant, Presence of DCP, equimolar ratio of span 60: cholesterol and 15 ml of volume of hydration were found to be optimum for miosome preparation. Conclusions: The present work concluded metformin loaded niosomes to be effective in sustaining the drug release leading to decreased side effects and increased patient compliance.
TL;DR: Design, synthesis and assessment of anticholinesterase activity of 2-(2-(4-Benzylpiperazin-1-yl)ethyl)isoindoline-1,3-dione derivatives showed prepared compounds can function as potential acetylcholinestersterase inhibitor.
Abstract: Alzheimer’s disease (AD) as neurodegenerative disorder, is the most common form of dementia accounting for about 50-60% of the overall cases of dementia among persons over 65 years of age. Low acetylcholine (ACh) concentration in hippocampus and cortex areas of the brain is one of the main reasons for this disease. In recent years, acetylcholinesterase (AChE) inhibitors like donepezil with prevention of acetylcholine hydrolysis can enhance the duration of action of acetylcholine in synaptic cleft and improve the dementia associated with Alzheimer’s disease. Design, synthesis and assessment of anticholinesterase activity of 2-(2-(4-Benzylpiperazin-1-yl)ethyl)isoindoline-1,3-dione derivatives showed prepared compounds can function as potential acetylcholinesterase inhibitor. Among 12 synthesized derivatives, compound 4a with ortho chlorine moiety as electron withdrawing group exhibited the highest potency in these series (IC50 = 0.91 ± 0.045 μM) compared to donepezil (IC50 = 0.14 ± 0.03 μM). The results of the enzyme inhibition test (Ellman test) showed that electron withdrawing groups like Cl, F and NO2 can render the best effect at position ortho and para of the phenyl ring. But compound 4g with methoxy group at position 3(meta) afforded a favorable potency (IC50 = 5.5 ± 0.7 μM). Furthermore, docking study confirmed a same binding mode like donepezil for compound 4a. Synthesized compounds 4a-4l could be proposed as potential anticholinesterase agents.
TL;DR: The study shows that flavonols are abundant in the leaves of M. azedarach and these compounds seem to be responsible for many of medicinal effects exploited in the traditional uses and seems to be safer in terms of cytotoxicity.
Abstract: Background: Melia azedarach L. is an important medicinal plant that is used for variety of ailments in Iranian traditional medicine. Azadirachta indica A. Juss is its allied species and possesses similar properties and effects. The present study was undertaken to investigate anticancer activity of these M. azedarach in comparison with A. indica on cancer cell lines and also to evaluate their safety in humans by testing them on normal cell line. The study also aimed to determine the active components that are responsible for medicinal effects of M. azedarach in traditional usages. Methods: In this study, the cytotoxic activity of crude extracts from M. azedarach and A. indica leaves, pulps and seeds as well as three main fractions of their leaf extracts were assayed against HT-29, A-549, MCF-7 and HepG-2 and MDBK cell lines. MTT assay was used to evaluate their cytotoxic activities. Methanol leaf fraction of M. azedarach as the safest leaf fraction in terms of cytotoxicity was subjected for phytochemical study. Results: Results of the present study indicated that seed kernel extract of M. azedarach had the highest cytotoxic activity and selectivity to cancer cell lines (IC50 range of 8.18- 60.10 μ gm L -1 ). In contrast to crude seed extract of A. indica, crude pulp and crude leaf extracts of this plant showed remarkably stronger anti-prolifrative activity (IC50 ranges of 83.45 - 212.16 μ gm L -1 and 34.11- 95.51 μ gm L -1 respectively) than those of M. azedarach (all IC50 values of both plants > 650 μ gm L -1 ). The phytochemical analysis led to the isolation of four flavonol 3-O-glycosides including rutin, kaempferol-3-O-robinobioside, kaempferol-3-O-rutinoside and isoquercetin along with a purin nucleoside, β-adenosine. Conclusions: The anti-prolifrative potentials of extracts from different parts of M. azedarach and A. indica were determined. By comparison, methanol leaf fraction of M. azedarach seems to be safer in terms of cytotoxicity. Our study shows that flavonols are abundant in the leaves of M. azedarach and these compounds seem to be responsible for many of medicinal effects exploited in the traditional uses. Keyword: Anti-prolifrative activity, Azadirachta indica, Flavonoid, Melia azedarach, MTT, Neem, Traditional medicine
TL;DR: The inhibition potency of Boswellia carterii compounds is probably due to the formation of appropriate hydrogen bonds and hydrophobic interactions between the investigated compounds and urease enzyme active site and confirms its traditional usage.
Abstract: Background and the purpose of the study
Boswellia carterii have been used in traditional medicine for many years for management different gastrointestinal disorders. In this study, we wish to report urease inhibitory activity of four isolated compound of boswellic acid derivative.
TL;DR: Health providers especially clinicians and emergency medicine specialists should consider colloquial words that Iranian drug users apply and special training courses should be designed and implemented for clinicians in Iran to inform them about methamphetamine and its frequently used colloquIAL words in the community.
Abstract: In recent years, methamphetamine use has dramatically increased in Iran while there is a crucial misunderstanding about the colloquial words related to methamphetamine among health providers, policy makers, clinicians, scholars and people in the community. The word Crystal refers to methamphetamine in some parts of Iran while in some other parts of the country, Crystal refers to a high purity street-level heroin which is called Kerack and its abuse is epidemic. Methamphetamine and heroin Kerack are different drugs in Iran. Methamphetamine is a stimulant drug while heroin Kerack is an opioid. Health providers especially clinicians and emergency medicine specialists should consider colloquial words that Iranian drug users apply. Special training courses should be designed and implemented for clinicians in Iran to inform them about methamphetamine and its frequently used colloquial words in the community. This issue has important clinical and health implications.
TL;DR: This is the first report describing effective anti-inflammatory activity for apo-9’-fucoxanthinone′-fu Coxanthnone isolated from S. muticum, and may be a good candidate for delaying the progression of human inflammatory diseases and warrants further studies.
Abstract: Background: The marine environment is a unique source of bioactive natural products, of which Sargassum muticum (Yendo) Fensholt is an important brown algae distributed in Jeju Island, Korea. S. muticum is a traditional Korean food stuff and has pharmacological functions including anti-inflammatory effects. However, the active ingredients from S. muticum have not been characterized. Methods: Bioguided fractionation of the ethanolic extract of S. muticum, collected from Jeju island, led to the isolation of a norisoprenoid. Its structure was determined by analysis of the spectroscopic data. In vitro anti-inflammatory activity and mechanisms of action of this compound were examined using lipopolysaccharide (LPS)-stimulated RAW 264.7 cells through ELISA assays and Western blot analysis. Results: Apo-9′-fucoxanthinone, belonging to the norisoprenoid family were identified. Apo-9′-fucoxanthinone effectively suppressed LPS-induced nitric oxide (NO) and prostaglandin E2 (PGE2) production. This compound also exerted their anti-inflammatory actions by down-regulating of NF-κB activation via suppression of IκB-α in macrophages. Conclusions: This is the first report describing effective anti-inflammatory activity for apo-9’-fucoxanthinone′-fucoxanthnone isolated from S. muticum.Apo-9′-fucoxanthinone may be a good candidate for delaying the progression of human inflammatory diseases and warrants further studies.
TL;DR: It is emphasized that health policy makers should consider the immediate needs of drug users, their families and the community to be informed about the detrimental health effects associated with methamphetamine-associated psychosis.
Abstract: The rapidly growing popularity of methamphetamine use in Iran has posed a new health challenge to the Iranian health sector. Methamphetamine-associated psychosis (MAP) has been frequently reported in Iran in recent years. Although methamphetamine use and MAP are considerable health problems in Iran but there is still a need to conduct epidemiological studies on the prevalence of MAP and its health-related problems. The present paper emphasizes that health policy makers should consider the immediate needs of drug users, their families and the community to be informed about the detrimental health effects associated with MAP. Although MAP could be managed by prescribing benzodiazepines and psychiatric medications but the most effective regime for stabilizing patients with MAP still needs to be studied in Iran. Constant collaborations among psychiatric services and outpatient psychotherapeutic services should be established to successfully manage MAP in Iran. Iranian clinicians especially emergency medicine specialists should be informed about the differences between the two forms of transient and recurrent MAP in order to implement appropriate pharmacological therapies to manage MAP. It is hoped that special training courses are designed and implemented by health policy makers to inform clinicians, health providers and especially emergency medicine specialists to effectively deal with MAP.
TL;DR: The results demonstrated that the cytotoxic activity of compound 5b against MDA-MB-231 and SK-N-MC cells is more than etoposide, therefore, compound 5 b prototype could be considered as novel cytot toxic agent for further developing new anticancer chemotherapeutics.
Abstract: Background and the purpose of the study: There has been increscent interest in the field of cancer chemotherapy by discovery and development of novel agents with high efficacy, low toxicity, and minimum side effects. In order to find new anticancer agents, we replaced the pyrazolone part of well-known cytotoxic agent SJ-172550 with 7-methoxychroman-4-one. Thus, a novel series of 3-benzylidene-4-chromanones were synthesized and tested in vitro against human cancer cell lines. Methods: The title compounds were prepared by condensation of 7-methoxychroman-4-one with suitable aldehydes in appropriate alcohol in the presence of gaseous HCl. The antiproliferative activity of target compounds were evaluated against MDA-MB-231 (breast cancer), KB (nasopharyngeal epidermoid carcinoma) and SK-N-MC (human neuroblastoma) cell lines using MTT assay. Results: Although the direct analog of SJ-172550 (compound 5d) did not show any cytotoxic activity against tested cell lines, but 2-(2-chloro-6-methoxyphenoxy)acetic acid methyl ester analog 5c showed some activity against MDA-MB-231 and SK-N-MC cells. Further modification of compound 5c resulted in the 3-chloro-4,5dimethoxybenzylidene derivative 5b which demonstrated better cytotoxic profile against all tested cell lines (IC50 values = 7.56–25.04 μg/ml). Conclusion: The results demonstrated that the cytotoxic activity of compound 5b against MDA-MB-231 and SK-N-MC cells is more than etoposide. Therefore, compound 5b prototype could be considered as novel cytotoxic agent for further developing new anticancer chemotherapeutics.
TL;DR: The mechanical strength and controlled release capability of the systems indicate that these co-polymeric hydrogels have a great potential to be used as colon drug delivery device through oral administration.
Abstract: Background and the purpose of the study: Hydrogels, being stimuli responsive are considered to be effective for targeted and sustained drug delivery. The main purpose for this work was to study the release behavior and kinetic evaluation of Tramadol HCl from chemically cross linked ter polymeric hydrogels. Methods: Ter-polymers of methacrylate, vinyl acetate and acrylic acid cross linked with ethylene glycol dimethacrylate (EGDMA) were prepared by free radical polymerization. The drug release rates, dynamic swelling behavior and pH sensitivity of hydrogels ranging in composition from 1-10 mol% EGDMA were studied. Tramadol HCl was used as model drug substance. The release behavior was investigated at pH 8 where all formulations exhibited non-Fickian diffusion mechanism. Results and major conclusion: Absorbency was found to be more than 99% indicating good drug loading capability of these hydrogels towards the selected drug substance. Formulations designed with increasing amounts of EGDMA had a decreased equilibrium media content as well as media penetrating velocity and thus exhibited a slower drug release rate. Fitting of release data to different kinetic models indicate that the kinetic order shifts from the first to zero order as the concentration of drug was increased in the medium, showing gradual independency of drug release towards its concentration. Formulations with low drug content showed best fitness with Higuchi model whereas those with higher concentration of drug followed Hixson-Crowell model with better correlation values indicating that the drug release from these formulations depends more on change in surface area and diameter of tablets than that on concentration of the drug. Release exponent (n) derived from Korse-Meyer Peppas equation implied that the release of Tramadol HCl from these formulations was generally non-Fickian (n > 0.5 > 1) showing swelling controlled mechanism. The mechanical strength and controlled release capability of the systems indicate that these co-polymeric hydrogels have a great potential to be used as colon drug delivery device through oral administration.
TL;DR: Although application of EtBr is going to be restricted and replaced with other tags such as SYBR® products, the safety of the new substituted compounds are still in doubt and except a few data, there is no essential evidence available to confirm that they are safer than EtBr.
Abstract: Ethidium bromide (EtBr) is a well-known fluorescent tag usually applied in molecular biological techniques like agarose gel electrophoresis. The mechanism of action for such compounds is known, in which these compounds are able to bind to the kinetoplastid DNA and to alter their conformation to Z-DNA molecules that stop replication of kinetoplastid DNA leading to Trypanosoma death. Although the usual amounts used in laboratories are considered as below the level required to cause toxicity (LD50 in oral administration in rat is 1.5 g/Kg), the mentioned concentrations are high enough to involve in replication of mitochondrial DNA in some human cell lines. Regarding the points that EtBr is very stable in the environment and if degraded especially by use of bleaches that result in formation of mutagenic compounds, there is a big concern about its use. Although application of EtBr is going to be restricted and replaced with other tags such as SYBR® products, the safety of the new substituted compounds are still in doubt and except a few data, there is no essential evidence available to confirm that they are safer than EtBr. Further investigations are recommended to compare their relative biosafety hazards.
TL;DR: All brand INF β products are cost effective in Iran except Avonex, and the best strategy among INF β therapies is CBP intramuscular INF β-1a (Cinnovex).
Abstract: Multiple sclerosis (MS) is a highly debilitating immune mediated disorder and the second most common cause of neurological disability in young and middle-aged adults. Iran is amongst high MS prevalence countries (50/100,000). Economic burden of MS is a topic of important deliberation in economic evaluations study. Therefore determining of cost-effectiveness interferon beta (INF β) and their copied biopharmaceuticals (CBPs) and biosimilars products is significant issue for assessment of affordability in Lower-middle-income countries (LMICs). A literature-based Markov model was developed to assess the cost-effectiveness of three INF βs products compared with placebo for managing a hypothetical cohort of patients diagnosed with relapsing remitting MS (RRMS) in Iran from a societal perspective. Health states were based on the Kurtzke Expanded Disability Status Scale (EDSS). Disease progression transition probabilities for symptom management and INF β therapies were obtained from natural history studies and multicenter randomized controlled trials and their long term follow up for RRMS and secondary progressive MS (SPMS). A cross sectional study has been developed to evaluate cost and utility. Transitions among health states occurred in 2-years cycles for fifteen cycles and switching to other therapies was allowed. Calculations of costs and utilities were established by attachment of decision trees to the overall model. The incremental cost effectiveness ratio (ICER) of cost/quality adjusted life year (QALY) for all available INF β products (brands, biosimilars and CBPs) were considered. Both costs and utilities were discounted. Sensitivity analyses were done to assess robustness of model. ICER for Avonex, Rebif and Betaferon was 18712, 11832, 15768 US Dollars ($) respectively when utility attained from literature review has been considered. ICER for available CBPs and biosimilars in Iran was $847, $6964 and $11913. The Markov pharmacoeconomics model determined that according to suggested threshold for developing countries by world health organization, all brand INF β products are cost effective in Iran except Avonex. The best strategy among INF β therapies is CBP intramuscular INF β-1a (Cinnovex). Results showed that a policy of encouraging accessibility to CBPs and biosimilars could make even high technology products cost-effective in LMICs.
TL;DR: Although, increasing the capacity for phthalate free plasticizer productions is the first step to restrict the distribution of these toxic manmade compounds, finding the new ways forphthalate absorption from the soil in agricultural fields may have benefits.
Abstract: Phthalic acid esters (PAEs) have been employed in polymer materials as a plasticizer to form them more flexible, adhesive, and soluble. These compounds are mainly used in paints, varnishes, personal cares, cosmetics, paper coatings, and adhesives even in bottled waters, shampoo, body deodorant, hairspray, and gels. Phthalates are able to possess remarkable toxic variations depending on their structures. So far, Di-(2-EthylHexyl) Phthalate DEHP and Di-n- Butyl Phthalate DBP have been found to cause reproductive and developmental toxicities. The U.S. Environmental Protection Agency (EPA) classified DEHP as probable human carcinogen. To the best of our knowledge, phthalates showed diverse toxicity profiles according to their structures in the liver, kidneys, thyroid, and testes, which are involved in general toxicity. Furthermore, they are introduced as hormonally-active agents, because they can interfere with the endocrine system in human. Incidence of developmental abnormalities (like skeletal malformations and cleft palate, and undescended testes, lowering testes weight and anogenital distance) seems increasing via high exposure to phthalate metabolites. Although, increasing the capacity for phthalate free plasticizer productions is the first step to restrict the distribution of these toxic manmade compounds, finding the new ways for phthalate absorption from the soil in agricultural fields may have benefits. Also, evaluation and examination of diverse sources of medicinal and food plants to determine the level of phthalate accumulation in their organs are extremely recommended to avoid creating toxicity particularly in reproductive systems.
TL;DR: In-vitro and in-vivo release profiles of LA had similar trends after 72 hours, however, the rate of LA release was slower in-Vivo, and the pharmacological analysis showed more inactive ovaries due to release of LA.
Abstract: A poly (lactide-co-glycolide) (PLGA) implant was used to control the release profile of leuprolide acetate (LA) drug. The system is an in-situ polymeric precipitation system. And the formulation consisted of PLGA polymer, LA drug and N-methyl-2-pyrrolidon solvent with no additives. First, the formulation was injected into PBS solution for in-vitro studies and then it was administered to the animal models (female rats) for in-vivo release studies. The release profiles of leuprolide acetate were measured by UV spectrophotometry for a period of 28 days. The initial burst release of LA was 14% in in-vitro whereas it was 7% in in-vivo. In-vitro and in-vivo release profiles of LA had similar trends after 72 hours. However, the rate of LA release was slower in-vivo. This might be attributed to the limited diffusion process of solvent and the drug molecules. This could be due to presence of an additional pressure caused by the surrounding tissue and also the presence of small amount of water between cells in the subcutaneous site. Cross-section and surface of the implants were studied via scanning electron microscopy. Morphology of both in-vitro and in-vivo implants confirmed the release behaviours. No toxicity effects were reported in the histopathological assay. Furthermore, the pharmacological analysis showed more inactive ovaries due to release of LA.