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1.  Acknowledgement of manuscript reviewers 2014 
Contributing reviewers
The editors of DARU Journal of Pharmaceutical Sciences would like to thank all our reviewers who have contributed to the journal in Volume 22 (2014).
doi:10.1186/s40199-015-0095-8
PMCID: PMC4323264
2.  The evolution of Taiwan’s National Health Insurance drug reimbursement scheme 
Background
The rapid growth of health care expenditures, especially pharmaceutical spending, is a challenge for many countries. To control increasing pharmaceutical expenditures and to enhance rational use of drugs, Taiwan’s National Health Insurance drug reimbursement system has evolved over time since its introduction in 1995. This study reviewed Taiwan’s drug reimbursement scheme: its development and evolution in the last two decades, and implications and impacts of recent policies for drug pricing. We also provide recommendations for possible improvement.
Methods
We conducted a review of Taiwan’s National Health Insurance drug reimbursement scheme. We focused on three major components of the scheme: (i) the scope of drug coverage; (ii) pricing system for pharmaceuticals under the scheme; and (iii) adjustment of drug reimbursement prices. We reviewed the literature and public policy documents.
Results
The National Health Insurance delisted 176 and another 240 behind-the-counter products (e.g., antacids, vitamins) between 2005 and 2006 to reduce pharmaceutical expenditures. For the pricing of pharmaceuticals, policy evolution can be divided into four phases since 1995; the present system emphasizes stakeholder engagement, health technology assessment, domestic R&D, and improving quality of products. To close the gap between drug reimbursement prices and procurement prices, eight rounds of drug price surveys and adjustments have been implemented since 2000.
Conclusions
Taiwan’s National Health Insurance drug reimbursement scheme has evolved substantially over time to provide more equitable and affordable access to prescription medicines. However, more work is still needed as irrational difference in reimbursement and procurement prices persists and the total expenditure of the drug reimbursement scheme continues to increase at unsustainable rates.
doi:10.1186/s40199-014-0080-7
PMCID: PMC4333892
Universal health coverage; Drug policy; Reimbursement; Medicines coverage; National Health Insurance; Taiwan
4.  Cost analysis of pharmaceutical care provided to HIV-infected patients: an ambispective controlled study 
Background
Studies have shown that pharmaceutical care can result in favorable clinical outcomes in human immunodeficiency virus (HIV)-infected patients, however, few studies have assessed the economic impact. The objective of this study was to evaluate the clinical and economic impact of pharmaceutical care of HIV-infected patients.
Methods
A controlled ambispective study was conducted in Brazil from January 2009 to June 2012. Patients were allocated to either intervention or control group. The control group was followed according to standard care while the intervention group was also followed by a pharmacist at each physician appointment for one year. Effectiveness outcomes included CD4+ count, viral load, absence of co-infections and optimal immune response, and economic outcomes included expenses of physician and pharmaceutical appointments, laboratory tests, procedures, and hospitalizations, at six months and one year.
Results
Intervention and control groups included 51 patients each. We observed significant decreases in total pharmacotherapy problems during the study. At six months, the intervention group contained higher percentages of patients without co-infections and of patients with CD4+ >500 cells/mm3. None of the differences between intervention and control group considering clinical outcomes and costs were statistically significant. However, at one year, the intervention group showed higher percentage of better clinical outcomes and generated lower spending (not to procedures). An additional health care system daily investment of US$1.45, 1.09, 2.13, 4.35, 1.09, and 0.87 would be required for each additional outcome of viral load <50 copies/ml, absence of co-infection, CD4+ >200, 350, and 500 cells/mm3, and optimal immune response, respectively.
Conclusion
This work demonstrated that pharmaceutical care of HIV-infected patients, for a one-year period, was able to decrease the number of pharmacotherapy problems. However, the clinical outcomes and the costs did not have statistical difference but showed higher percentage of better clinical outcomes and lower costs for some items.
doi:10.1186/s40199-014-0074-5
PMCID: PMC4334844
Pharmacoeconomics; Pharmaceutical care; HIV-infected patients
5.  Effect of peptide length on the conjugation to the gold nanoparticle surface: a molecular dynamic study 
Background
Gold nanoparticles now command a great deal of attention for medical applications. Despite the importance of nano-bio interfaces, interaction between peptides and proteins with gold surfaces is not still fully understood, especially in a molecular level.
Methods
In the present study computational simulation of adsorption of 20 amino acids, in three forms of mono-amino acid, homo di-peptide and homo tri-peptide, on the gold nanoparticles was performed by Gromacs using OPLSAA force field. The flexibility, stability, and size effect of the peptides on the gold nanoparticles were studied as well as the molecular structure of them.
Results
According to our results, adsorbed homo tri-peptides on the gold surface had more flexibility, more gyration, and the farthest distance from the GNP in comparison with homo di-peptides and mono-amino acids.
Conclusion
Our findings provide new insights into the precise control of interactions between amino acids anchored on the GNPs.
Electronic supplementary material
The online version of this article (doi:10.1186/s40199-014-0085-2) contains supplementary material, which is available to authorized users.
doi:10.1186/s40199-014-0085-2
PMCID: PMC4312466  PMID: 25630230
Gold nanoparticles; Interface; Amino acid; Interaction; Molecular dynamic
6.  Angiogenic effect of the aqueous extract of Cynodon dactylon on human umbilical vein endothelial cells and granulation tissue in rat 
Background
Cynodon dactylon, a valuable medicinal plant, is widely used in Iranian folk medicine for the treatment of various cardiovascular diseases such as heart failure and atherosclerosis. Moreover, its anti-diabetic, anti-cancer and anti-microbial properties have been also reported. Concerning the critical role of angiogenesis in the incidence and progression of tumors and also its protective role in cardiovascular diseases, we investigated the effects of the aqueous extract prepared from the rhizomes of C. dactylon on vascular endothelial growth factor (VEGF) expressions in Human Umbilical Vein Endothelial Cells (HUVECs) and also on angiogenesis in carrageenan induced air-pouch model in rats.
Methods
In the air-pouch model, carrageenan was injected into an air-pouch on the back of the rats and following an IV injection of carmine red dye on day 6, granulation tissue was processed for the assessment of the dye content. Furthermore, in an in vitro study, angiogenic property of the extract was assessed through its effect on VEGF expression in HUVECs.
Results
Oral administration of 400 mg/kg/day of the extract significantly increased angiogenesis (p < 0.05) and markedly decreased neutrophil (p < 0.05) and total leukocyte infiltration (p < 0.001) into the granulation tissues. Moreover, the extract increased the expression of total VEGF in HUVECs at a concentration of (100 μl/ml).
Conclusion
The present study showed that the aqueous extract of C. dactylon promotes angiogenesis probably through stimulating VEGF expression.
doi:10.1186/s40199-015-0093-x
PMCID: PMC4316609  PMID: 25630338
Cynodon dactylon; Angiogenesis; Air pouch; HUVECs; VEGF
7.  Fatal aluminum phosphide poisonings in Tirana (Albania), 2009 – 2013 
Background
Acute poisonings particularly through pesticides have become a major public health concern in Albania during the last decade.
Findings
The number of fatalities due to aluminum phosphide intoxications was more than doubled during a five year-period from 2009 to 2013, and a cluster of suicides perpetrated with Phostoxin was registered. Several factors are accountable for such a phenomenon, including the fact that aluminum phosphide agents are freely available in the Albanian market, their price is extremely low and they are sold without any legal restriction. The mass media unfortunately warranted an emulating effect to dramatic intoxications, which gained by such means the notoriety of a secure lethal weapon.
Conclusions
Our experience with more than three hundred intoxications with aluminum phosphide agents in the last five years, showed that a considerable delay from the moment of exposure (mainly through ingestion) to specialized medical help seeking, created a considerable obstacle for a successful treatment of cases, and eventually for the survival of patients. The lack of a specific antidote adds further challenges to all these exposures. The need for public health policies aiming at prevention, awareness, and possibly the substitution of Phostoxin or other aluminum phosphide pesticides with less dangerous agents is formulated.
doi:10.1186/s40199-015-0090-0
PMCID: PMC4308883  PMID: 25618461
Poisoning; Aluminum phosphide (AIP); Pesticides; Mortality; Phostoxin
8.  Factors affecting viability of Bifidobacterium bifidum during spray drying 
Background
There is substantial clinical data supporting the role of Bifidobacterium bifidum in human health particularly in benefiting the immune system and suppressing intestinal infections. Compared to the traditional lyophilization, spray-drying is an economical process for preparing large quantities of viable microorganisms. The technique offers high production rates and low operating costs but is not usually used for drying of substances prone to high temperature. The aim of this study was to establish the optimized environmental factors in spray drying of cultured bifidobacteria to obtain a viable and stable powder.
Methods
The experiments were designed to test variables such as inlet air temperature, air pressure and also maltodextrin content. The combined effect of these variables on survival rateand moisture content of bacterial powder was studied using a central composite design (CCD). Sub-lethal heat-adaptation of a B. bifidum strain which was previously adapted to acid-bile-NaCl led to much more resistance to high outlet temperature during spray drying. The resistant B. bifidum was supplemented with cost friendly permeate, sucrose, yeast extract and different amount of maltodextrin before it was fed into a Buchi B-191 mini spray-dryer.
Results
Second-order polynomials were established to identify the relationship between the responses andthe three variables. Results of verification experiments and predicted values from fitted correlations were in close agreement at 95% confidence interval. The optimal values of the variables for maximum survival and minimum moisture content of B. bifidum powder were as follows: inlet air temperature of 111.15°C, air pressure of 4.5 bar and maltodextrin concentration of 6%. Under optimum conditions, the maximum survival of 28.38% was achieved while moisture was maintained at 4.05%.
Conclusion
Viable and cost effective spray drying of Bifidobacterium bifidum could be achieved by cultivating heat and acid adapted strain into the culture media containing nutritional protective agents.
doi:10.1186/s40199-014-0088-z
PMCID: PMC4334592
Spray drying; Bifidobacterium bifidum; Viability; Moisture; Response surface methodology
9.  Synthesis, HIV-1 RT inhibitory, antibacterial, antifungal and binding mode studies of some novel N-substituted 5-benzylidine-2,4-thiazolidinediones 
Background
Structural modifications of thiazolidinediones at 3rd and 5th position have exhibited significant biological activities. In view of the facts, and based on in silico studies carried out on thiazolidine-2,4-diones as HIV-1- RT inhibitors, a novel series of 2,4-thiazolidinedione analogs have been designed and synthesized.
Methods
Title compounds were prepared by the reported method. Conformations of the structures were assigned on the basis of results of different spectral data. The assay of HIV-1 RT was done as reported by Silprasit et al. Antimicrobial activity was determined by two fold serial dilution method. Docking study was performed for the highest active compounds by using Glide 5.0.
Results
The newly synthesized compounds were evaluated for their HIV-1 RT inhibitory activity. Among the synthesized compounds, compound 24 showed significant HIV-1 RT inhibitory activity with 73% of inhibition with an IC50 value of 1.31 μM. Compound 10 showed highest activity against all the bacterial strains.
A molecular modeling study was carried out in order to investigate the possible interactions of the highest active compounds 24, 10 and 4 with the non nucleoside inhibitory binding pocket(NNIBP) of RT, active site of GlcN-6-P synthase and cytochrome P450 14-α-sterol demethylase from Candida albicans (Candida P450DM) as the target receptors respectively using the Extra Precision (XP) mode of Glide software.
Conclusion
A series of novel substituted 2-(5-benzylidene-2,4-dioxothiazolidin-3-yl)-N-(phenyl)propanamides (4–31) have been synthesized and evaluated for their HIV-1 RT inhibitory activity, antibacterial and antifungal activities. Some of the compounds have shown significant activity. Molecular docking studies showed very good interaction.
doi:10.1186/s40199-014-0086-1
PMCID: PMC4308940  PMID: 25617150
Antibacterial; Antifungal; Docking; HIV-1 RT inhibitory activity; Thiazolidinediones; Synthesis
10.  Carum induced hypothyroidism: an interesting observation and an experiment 
Carum carvi is a widely available herb that has been used as a food additive and as a medication in traditional medicine for many years. Its potential biological effects include analgesic, anti-inflammatory, anti-anxiety and antispasmodic activities. We report a patient with papillary thyroid carcinoma who were under treatment with levothyroxine and experienced an elevated TSH level by ingestion of Carum carvi. TSH level was increased to 60.3 mIU/L with no change in levothyroxine dosage and decreased to normal range after discontinuation of the Carum carvi. Observing this dramatic change in TSH level by carum ingestion, carum carvi capsules was produced and one of the researcher tried the medication on herself with a dose of 40 mg/kg/day. She had a history of hypothyroidism and was taking 100 ugr/day of levothyroxine. TSH was markedly increased 2 weeks after ingestion of Carum carvi and returned to normal range 5 months after discontinuation of it. This case report shows the effect of consumption of Carum carvi in increasing TSH level in hypothyroid patients treating with levothyroxine. The exact mechanism of action of carum carvi remains unknown.
doi:10.1186/s40199-015-0094-9
PMCID: PMC4310175  PMID: 25616491
Thyroid; Carum carvi; TSH; Hypothyroidism
11.  Clinical results with two different pharmaceutical preparations of riboflavin in corneal cross-linking: an 18-month follow up 
Background
Comparison of long-term clinical results of two different pharmaceutical formulations used in corneal cross-linking (CXL) in keratoconus patients.
Methods
Sixty eyes of 60 keratoconus patients underwent CXL in two groups. We used riboflavin preparations from Sina Darou, Iran in group A, and Streuli Pharma, Switzerland in group B. Here we made inter-group comparison of changes in vision, refraction, Pentacam indices, corneal biomechanical indices, and endothelial cell count (ECC) 18 months after CXL.
Results
Since four patients were lost to follow-up, 56 eyes (28 eyes in each group) were compared. Mean improvement in uncorrected visual acuity (UCVA) was 0.31 ± 0.65 LogMAR (P = 0.014) in group A and 0.24 ± 0.62 LogMAR (P = 0.082) in group B. Best corrected visual acuity (BCVA) remained quite unchanged in both groups (P = 0.774). Mean spherical refractive error reduced by 0.45 ± 1.15 diopter (D) (P = 0.041) in group A and 0.27 ± 1.73 D (P = 0.458) in group B (P = 0.655). Cylinder error and spherical equivalent had a similar trend without any change. Max-K (P = 0.006) and mean-K (P = 0.044) decreased significantly more in group A compared to group B. The reduction in CCT was significantly more in group A than group B (P = 0.004). Q-value was quite unchanged in both groups (P = 0.704). The inter-group difference in CH reduction was borderline significant statistically (P = 0.057). Changes in corneal resistance factor and endothelial cell count were not significantly different between two groups (P = 0.117 and P = 0.229).
Conclusion
Clinical results of CXL with the domestic preparation of riboflavin are similar to that achieved with the Swiss made product in some aspects, and it is the preferred brand in some other aspects. This study will continue to report longer follow-up results.
Trial registration
IRCT201212034333N2
doi:10.1186/s40199-015-0091-z
PMCID: PMC4314761  PMID: 25616392
Keratoconus; Cross linking; Riboflavin; Sina Darou; Streuli Pharma; Clinical trial
12.  Formulation and optimization of itraconazole polymeric lipid hybrid nanoparticles (Lipomer) using box behnken design 
Background
The objective of the study was to formulate and to investigate the combined influence of 3 independent variables in the optimization of Polymeric lipid hybrid nanoparticles (PLHNs) (Lipomer) containing hydrophobic antifungal drug Itraconazole and to improve intestinal permeability.
Method
The Polymeric lipid hybrid nanoparticle formulation was prepared by the emulsification solvent evaporation method and 3 factor 3 level Box Behnken statistical design was used to optimize and derive a second order polynomial equation and construct contour plots to predict responses. Biodegradable Polycaprolactone, soya lecithin and Poly vinyl alcohol were used to prepare PLHNs. The independent variables selected were lipid to polymer ratio (X1) Concentration of surfactant (X2) Concentration of the drug (X3).
Result
The Box-Behnken design demonstrated the role of the derived equation and contour plots in predicting the values of dependent variables for the preparation and optimization of Itraconazole PLHNs. Itraconazole PLHNs revealed nano size (210 ± 1.8 nm) with an entrapment efficiency of 83 ± 0.6% and negative zeta potential of −11.7 mV and also enhance the permeability of itraconazole as the permeability coefficient (Papp) and the absorption enhancement ratio was higher.
Conclusion
The tunable particle size, surface charge, and favourable encapsulation efficiency with a sustained drug release profile of PLHNs suggesting that it could be promising system envisioned to increase the bioavailability by improving intestinal permeability through lymphatic uptake, M cell of payer’s patch or paracellular pathway which was proven by confocal microscopy.
doi:10.1186/s40199-014-0087-0
PMCID: PMC4312448  PMID: 25604353
Polymeric lipid hybrid nanoparticles; Box-behnken design; Entrapment efficiency; Drug loading; Optimization
13.  Sustained-release methylphenidate in methamphetamine dependence treatment: a double-blind and placebo-controlled trial 
Background
The objective of this randomized, double-blind, placebo-controlled study was to evaluate the efficacy of sustained-release methylphenidate (MPH-SR) in treatment of methamphetamine dependence.
Methods
Fifty-six individuals who met DSM-IV-TR criteria for methamphetamine dependence participated in this 10-week trial. The participants were randomly allocated into two groups and received 18 to 54 mg/day sustained-released methylphenidate or placebo for 10 weeks. Craving was evaluated by a visual analogue craving scale every week. Urinary screening test for methamphetamine was carried out each week. The Beck Depression Inventory-II (BDI-II) was used to monitor participant depressive symptoms at baseline and bi-weekly during the treatment period.
Results
At the end of the trial, the MPH-SR group was less methamphetamine positive compared to the placebo group and the difference was significant (p = 0.03). By the end of the study, MPH-SR group showed significantly less craving scores compared to the placebo group [MD (95% CI) = -10.28(0.88-19.18), t(54) = 2.19, p = 0.03]. There was greater improvement in the depressive symptoms scores in the intervention group compared to the placebo group [MD (95% CI) =2.03(0.31-3.75), t (54) =2.37, p = 0.02].
Conclusion
Sustained-released methylphenidate was safe and well tolerated among active methamphetamine users and significantly reduced methamphetamine use, craving and depressive symptoms.
Trial registration
IRCT201202281556N38
doi:10.1186/s40199-015-0092-y
PMCID: PMC4298048  PMID: 25588930
Clinical trial; Dependence; Methamphetamine; Methylphenidate
14.  Physico-chemical characterization and pharmacological evaluation of sulfated polysaccharides from three species of Mediterranean brown algae of the genus Cystoseira 
Background
Seaweed polysaccharides are highly active natural substances having valuable applications. The present study was conducted to characterize the physico-chemical properties of sulphated polysaccharides from three Mediterranean brown seaweeds (Cystoseira sedoides, Cystoseira compressa and Cystoseira crinita) and to evaluate their anti-radical, anti-inflammatory and gastroprotective activities.
Methods
The different rates of neutral sugars, uronic acids, L-fucose and sulphate content were determined by colorimetric techniques. The different macromolecular characteristics of isolated fucoidans were identified by size exclusion chromatography equipped with a triple detection: multiangle light scattering, viscometer and differential refractive index detectors, (SEC/MALS/VD/DRI). Anti-inflammatory activity was evaluated, using the carrageenan-induced rat paw edema test in comparison to the references drugs Acetylsalicylate of Lysine and Diclofenac. The gastroprotective activity was determined using HCl/EtOH induced gastric ulcers in rats and to examine the antioxidant effect of fucoidans in the three species, the free radical scavenging activity was determined using 1,1-diphenyl-2-picrylhydrazyl.
Results
The pharmacological evaluation of the isolated fucoidans for their anti-inflammatory, and their gastroprotective effect established that these products from C. sedoides, C. compressa and C. crinita exhibited a significant anti-inflammatory activity at a dose of 50 mg/kg, i.p; the percentages of inhibition of the oedema were 51%, 57% and 58% respectively. And, at the same dose, these fucoidans from C. sedoides and C. compressa showed a significant decrease of the intensity of gastric mucosal damages compared to a control group by 68%, whereas, the fucoidan from C. crinita produced a less gastroprotective effect. Furthermore, the isolated fucoidans exhibited a radical scavenging activity.
Conclusion
The comparative study of fucoidans isolated from three species of the genus Cystoseira showed that they have similar chemicals properties and relatives anti-radical, anti-inflammatory and gastroprotective activities which are found to be promising.
doi:10.1186/s40199-015-0089-6
PMCID: PMC4298055  PMID: 25582169
Fucoidans; Cystoseiraceae; Cystoseira; SEC/MALS/VS/DRI; Anti-inflammatory activity; Gastroprotective activity
15.  Novel heteroaryl phosphonicdiamides PTPs inhibitors as anti-hyperglycemic agents 
Background
Chronic and oral administration of benzylamine improves glucose tolerance. Picolylamine is a selective functional antagonist of the human adenosine A2B receptor. Phosphonic diamide derivatives enhance the cellular permeability and in turn their biological activities.
Methods
A series of heteroaryl phosphonicdiamide derivatives were designed as therapeutics to control and manage type2 diabetes. Initially defined Lipinski parameters encouraged them as safer drugs. Molecular docking of these compounds against Protein tyrosine phosphatase (PTP), the potential therapeutic target of type 2 diabetes, revealed their potential binding ability explaining their anti-diabetic activity in terms of PTP inhibition. Human intestinal absorption, Caco-2 cell permeability, MDCK cell permeability, BBB penetration, skin permeability and plasma protein binding abilities of the title compounds were calculated by PreADMET server. A convenient method has been developed for the synthesis of title compounds through the formation of 1-ethoxy-N,N’-bis(4-fluorobenzyl/pyridin-3-ylmethyl)phosphinediamine by the reaction of 4-fluorobenzylamine/ 3-picolylamine with ethyldichlorophosphite, subsequently reacted with heteroaryl halides using lanthanum(III) chloride as a catalyst.
Results
All the compounds exhibited significant in vitro anti-oxidant activity and in vivo evaluation in streptozotocin induced diabetic rat models revealed that the normal glycemic levels were observed on 12th day by 9a and 20th day by 5b, 5c, 9e and 9f. The remaining compounds also exhibited normal glycemic levels by 25th day.
Conclusion
The results from molecular modeling, in vitro and in vivo studies are suggesting them as safer and effective therapeutic agents against type2 diabetes.
Graphical AbstractDevelopment of PTPs inhibitors.
Electronic supplementary material
The online version of this article (doi:10.1186/s40199-014-0076-3) contains supplementary material, which is available to authorized users.
doi:10.1186/s40199-014-0076-3
PMCID: PMC4305230  PMID: 25542373
16.  Design, synthesis, docking study and cytotoxic activity evaluation of some novel letrozole analogs 
Background
Breast cancer is the most common type of female cancer. One class of hormonal therapy for breast cancer drugs -non steroidal aromatase inhibitors- are triazole analogues. In this work, some derivatives of these drugs was designed and synthesized. All synthesized compounds were evaluated for their cytotoxic activities on breast cancer cell lines (MDA-MB-231, T47D and MCF-7).
Methods
Our synthetic route for designed compounds started from 4-bromotolunitrile which was reacted with 1H-1,2,4-triazole to afford 4-(4-cyanobenzyl)-1,2,4-triazole. The reaction of later compound with aromatic aldehydes led to formation of the designed compounds. Eleven novel derivatives 1a-k were tested for their cytotoxic activities on three human breast cancer cell lines.
Results
Among the synthesized compound, 4-[2-(3-chlorophenyl)-1-(1H-1,2,4-triazol-1-yl)ethenyl]benzonitrile (1c) showed the highest activity against MCF-7 and MDA-MB-231 cell lines and 4-[2-(4-methoxyphenyl)-1-(1H-1,2,4-triazol-1-yl)ethenyl]benzonitrile (1 h) exhibited highest activity against T47D cell line. According to cytotoxic activities results, compound 4-[2-(4-dimethylamino)-1-(1H-1,2,4-triazol-1-yl)ethenyl]benzonitrile (1 k) showed comparative activity against T47D and MDA-MB-231 cell lines with compound (1 h) and our reference drug Etoposide.
Conclusion
In the process of anti-cancer drug discovery, to find new potential anti-breast cancer agents, we designed and synthesized a novel series of letrozole analogs. Cytotoxicity evaluation revealed that compounds (1c) and (1 k) were the most potent compounds with comparative activity with Etoposide. The results revealed that π-π interactions are responsible for the enzyme inhibitions of compounds (1 c) and (1 k).
doi:10.1186/s40199-014-0083-4
PMCID: PMC4284924  PMID: 25539909
Breast cancer; Non-steroidal aromatase inhibitor; Cytotoxic activity
18.  Hydroxylation index of omeprazole in relation to CYP2C19 polymorphism and sex in a healthy Iranian population 
Background
Polymorphism of CYP2C19 gene is one of the important factors in pharmacokinetics of CYP2C19 substrates. Omeprazole is a proton pump inhibitor which is mainly metabolized by cytochrome P450 2C19 (CYP2C19). The aim of present study was to assess omeprazole hydroxylation index as a measure of CYP2C19 activity considering new variant allele (CYP2C19*17) in Iranian population and also to see if this activity is sex dependent.
Methods
One hundred and eighty healthy unrelated Iranian individuals attended in this study. Blood samples for genotyping and phenotyping were collected 3 hours after administration of 20 mg omeprazole orally. Genotyping of 2C19 variant alleles *2, *3 and *17 was performed by using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and semi-nested PCR methods. Plasma concentrations of omeprazole and hydroxyomeprazole were determined by high performance liquid chromatography (HPLC) technique and hydxroxylation index (HI) (omeprazole/ hydroxyomeprazole) was calculated.
Results
The CYP2C19*17 was the most common variant allele in the studied population (21.6%). Genotype frequencies of CYP2C19*17*17, *1*17, and *2*17 were 5.5%, 28.8% and 3.3% respectively. The lowest and the highest median omeprazole HI was observed in *17*17 and *2*2 genotypes respectively (0.36 vs. 13.09). The median HI of omeprazole in subjects homozygous for CYP2C19*1 was 2.16-fold higher than individuals homozygous for CYP2C19*17 (P < 0.001) and the median HI of CYP2C19*1*17 genotype was 1.98-fold higher than CYP2C19 *17*17 subjects (P < 0.001). However, subjects with CYP2C19*2*17 (median HI: 1.74) and CYP2C19*1*2 (median HI: 1.98) genotypes and also CYP2C19*1*17 (median HI: 0.71) and CYP2C19*1*1 (mean HI: 0.78) did not show any significantly different enzyme activity. In addition, no statistically significant difference was found between women and men in distribution of CYP2C19 genotypes. Furthermore, the hydroxylation index of Omeprazole was not different between women and men in the studied population.
Conclusion
Our data point out the importance of CYP2C19*2 and CYP2C19*17 variant alleles in metabolism of omeprazole and therefore CYP2C19 activity. Regarding the high frequency of CYP2C19*17 in Iranian population, the importance of this new variant allele in metabolism of CYP2C19 substrates shall be considered.
doi:10.1186/s40199-014-0081-6
PMCID: PMC4266903  PMID: 25498969
CYP2C19; Enzyme activity; Genotype; Omeprazole; Phenotype
19.  Computational investigation of inhibitory mechanism of flavonoids as bovine serum albumin anti-glycation agents 
Background
Glycation of serum albumin and its consequence products were considered as an important factor in drug distribution and diabetic complications, therefore finding the glycation inhibitors and their inhibitory mechanisms became a valuable field of study. In this work, bovine serum albumin (BSA) became a subject as a model protein for analyzing the inhibitory mechanism of flavonoids, known as natural BSA glycation inhibitors in the early stage of glycation.
Methods
Firstly, for theoretical study, the three-dimensional model of BSA structure was generated by homology modeling and refined through molecular dynamic simulation. Secondly, several validation methods (statistical assessment methods and also neural network methods) by simultaneous docking study were employed for insurance about accuracy of our simulation. Then docking studies were performed for visualizing the relation between flavonoids’ binding sites and BSA glycation sites besides, the correlation analyzes between calculated binding energy and reported experimental inhibitory IC50 values of the flavonoids set, was considered to explore their molecular inhibitory mechanism.
Results
The quality assessment methods and simultaneous docking studies on interaction of quercetin (as the most studied flavonoids) with BSA and Human serum albumin (HAS), confirm the accuracy of simulation and the second stage of docking results which were in close agreement with experimental observations, suggest that the potential residues in flavonoids binding sites (which were place neighbor of tryptophan 212 within 5Ǻ) cannot be considered as one of glycation sites.
Conclusions
Based on the results, flavonoids don’t participate in inhibitory interference mechanism, and also, the differentiation between complexes of flavonoids with BSA and HSA could destroy the speculation of using them as an exchangeable model protein in study of serum albumin and flavonoids interactions.
doi:10.1186/s40199-014-0079-0
PMCID: PMC4272557  PMID: 25498599
Homology modeling; Molecular dynamics simulation; Correlation analyzes; Glycation sites; Flavonoids; BSA
20.  Determination of stress-induced degradation products of cetirizine dihydrochloride by a stability-indicating RP-HPLC method 
Background
A new, simple and accurate stability-indicating reverse phase high performance liquid chromatography method was developed and validated during the early stage of drug development of an oral lyophilizate dosage form of cetirizine dihydrochloride.
Methods
For RP-HPLC analysis it was used an Eclipse XDB C8 column 150 mm × 4.6 mm, 5 μm (Agilent columns, Barcelona, Spain) as the stationary phase with a mobile phase consisted of a mixture of 0.2 M K2HPO4 pH 7.00 and acetonitrile (65:35, v/v) at a flow rate of 1 mL min −1. Detection was performed at 230 nm using diode array detector. The method was validated in accordance with ICH guidelines with respect to linearity, accuracy, precision, specificity, limit of detection and quantification.
Results
The method results in excellent separation between the drug substance and its stress-induced degradation products. The peak purity factor is >950 for the drug substance after all types of stress, which confirms the complete separation of the drug substance peak from its stress induced degradation products.
Regression analysis showed r2 > 0.999 for cetirizine dihydrochloride in the concentration range of 650 μg mL −1 to 350 μg mL−1 for drug substance assay and a r2 > 0.999 in the concentration range of 0.25 μg mL−1 to 5 μg mL−1 for degradation products. The method presents a limit of detection of 0.056 μg mL −1 and a limit of quantification of 0.25 μg mL−1. The obtained results for precision and accuracy for drug substance and degradation products are within the specifications established for the validation of the method.
Conclusions
The proposed stability-indicating method developed in the early phase of drug development proved to be a simple, sensitive, accurate, precise, reproducible and therefore useful for the following stages of the cetirizine dihydrochloride oral lyophilizate dosage form development.
doi:10.1186/s40199-014-0082-5
PMCID: PMC4276092  PMID: 25487685
21.  Alteration in brain-derived neurotrophic factor (BDNF) after treatment of mice with herbal mixture containing Euphoria longana, Houttuynia cordata and Dioscorea japonica 
Background
Literature data indicate that brain-derived neurotrophic factor (BDNF), cyclic-AMP response element-binding protein (CREB) and phospho-CREB (pCREB) may have a place in depression. BDNF belongs to the neurotrophin family that plays an important role in proliferation, survival and differentiation of different cell populations in the mammalian nervous system. The herbal mixture used in the present study consists of Euphoria longana, Houttuynia cordata and Dioscorea japonica. The purpose of the present study was to determine the neuroprotective effect of herbal mixture. We also tested the hypothesis that administration of herbs reverses memory deficits and promotes the protein expression of BDNF in the mouse brain.
Methods
Mice were randomized into four different treatment groups (n = 10/group). Normal and stress groups received regular lab chow without stress and under stress conditions, respectively, for 3 weeks. The animals in the stress group were immobilized for 4 hours a day for 2 weeks. Different doses of herbal mixture (206 and 618 mg/kg) were administered for 3 weeks to those mice under stress conditions. Mice were analyzed by behavioral tests and immunoblotting examination in the hippocampus and cortex. An additional in vitro investigation was performed to examine whether herbs induce neurotoxicity in a human neuroblastoma cell line, SH-SY5Y cells.
Results
No significant toxicity of herbs on human neuroblastoma cells was observed. These herbs demonstrated an inductive effect on the expression of BDNF, pCREB and pAkt. For spatial working memory test, herbal mixture fed mice exhibited an increased level of spontaneous alternation (p < 0.01) compared to those in stress conditions. Moreover, herbal mixture produced highly significant (p < 0.01) reduction in the immobility time in the tail suspension test. Mice in the herbal mixture groups demonstrated lower serum corticosterone concentration than mice in the stress group (p < 0.05). Effects of the oral administration of herbal mixture on protein levels of BDNF in the hippocampi and cortices were significant.
Conclusions
Our study showed that herbal mixture administration has antidepressant effects in mice. It is proposed that adverse events such as stress and depression can modulate the expression of molecular players of cellular plasticity in the brain.
doi:10.1186/s40199-014-0077-2
PMCID: PMC4268823  PMID: 25431319
Stress; Depression; BDNF; Memory; Euphoria longana; Houttuynia cordata; Dioscorea japonica
22.  Presence of phthalate derivatives in the essential oils of a medicinal plant Achillea tenuifolia 
Background
Phthalate, esters of phthalic acid, are mainly applied as plasticizers and cause several human health and environment hazards. The essential oils of Achillea species have attracted a great concern, since several biological activities have been reported from varieties of these medicinal species. On the other side, due to the problems regarding the waste disposal in developing countries, phthalate derivatives can easily release from waste disposal to the water and soil resulting in probable absorption and accumulation by medicinal and dietary plants. As a matter of fact, although the toxicity of phthalate derivatives in human is well-known, food crops and medicinal plants have been exposing to phthalates that can be detected in their extracts and essential oils. Achillea tenuifolia (Compositea) is one of these herbaceous plants with traditional applications which widely growing in Iran.
Finding
The plant root was subjected to hydro-distillation for 4 h using Clevenger type apparatus to obtain its essential oil before and after acid treatment. Both of the hydro-distilled essential oils were analysed by GC-MS method resulted in recognition of their constituent. Phthalate contamination as (1, 2-benzenedicarboxylic acid, bis (2-methylpropyl) ester (5.4%) and phthalic acid (4.5%), were identified in the first and second extracted oils, respectively.
Conclusion
As a warning, due to the potential role of phthalates to cause reproductive toxicity, disturb of endocrine system and causing cancers, medicinal plants have to be considered through quality control for detection of these compounds.
doi:10.1186/s40199-014-0078-1
PMCID: PMC4310173  PMID: 25429772
Achillea tenuifolia; Compositae; Phthalate contamination; Acid treatment
23.  Osteogenic potential of punica granatum through matrix mineralization, cell cycle progression and runx2 gene expression in primary rat osteoblasts 
Background
Osteoporosis is one of the prevalent diseases in ageing populations. Due to side effects of many chemotherapeutic agents, there is always a need to search for herbal products to treat the disorder. Punica granatum (PG) represent a potent fruit-bearing medicinal herb which exerted valuable anti-osteoporotic activities. The present study was carried out to validate the in vitro osteogenic effects of the PG seed extract in primary calvarial osteoblast cultures harvested from neonatal rats.
Methods
The ethanolic extract of PG was subjected to evaluate cell proliferation, regeneration, mineralization and formation of collagen matrix using MTT, alkaline phosphatase, Alizarin Red-S staining and Sirius Red dye, respectively. Cell cycle progression and osteogenic gene Runx2 expression were carried out by flow cytometry and real time PCR, respectively.
Results
Exposure of different concentrations (10–100 μg/ml) of the extract on osteoblastic cells showed characteristic morphological changes and increment in cell number. A significant growth in cell proliferation, ALP activity, collagen contents and matrix mineralization of osteoblasts in a dose dependent manner (p < 0.05), suggested that PG has a stimulatory effect on osteoblastic bone formation or potential activity against osteoporosis. In addition, PG extract also enhanced DNA content in S phase of cell cycle and Runx2 gene expression level in osteoblasts.
Conclusion
The data clearly indicated that PG promoting bone cell proliferation and differentiation in primary osteoblasts might be due to elevating the osteogenic gene Runx2 expression. The present study provides an evidence for PG could be a promising herbal medicinal candidate that able to develop drugs for osteoporosis.
doi:10.1186/s40199-014-0072-7
PMCID: PMC4248434  PMID: 25409708
Cell cycle; Osteoblast; Osteogenesis; Punica granatum; Runx2
24.  Epidural administration of neostigmine-loaded nanofibers provides extended analgesia in rats 
Background
In this study, neostigmine-loaded electrospun nanofibers were prepared and then their efficacy and duration of analgesic action were studied after epidural administration in rats by repeated tail flick and formalin tests.
Methods
The neostigmine poly vinyl alcohol (PVA) nanofibers were fabricated by electrospinning methods. The nanofibers (1 mg) were injected into the lumbar epidural space (L5-L6) of rats (n = 6). Cerebrospinal fluid samples of rats were collected 1, 5 and 24 hours after injection and then were sampled once weekly for 4 weeks. Free-neostigmine concentration was measured in the samples spectrophotometrically. Rat nociceptive responses were evaluated by repeated tail-flick and formalin tests for 5 weeks after the nanofibers (1 mg) injection. Locomotor activity of rats was measured in the open-field at the same period.
Results
The cerebrospinal fluid concentration of free neostigmine reached 5 μg/ml five hours after injection and remained constant until the end of the experiments. The tail-flick latency of treated rats was significantly (p < 0.01) increased and remained constant up to 4 weeks. Pain scores of the rats in both phases of formalin test were significantly (p < 0.01) reduced during the same periods, Epidural injection of the nanofibers had no effect on locomotor activity of rats in an open-field.
Conclusions
Our results indicate that the neostigmine nanofibers can provide sustained release of neostigmine for induction of prolonged analgesia after epidural administration. High tissue distribution and penetration of the nanofibers in dorsal horn can increase thermal and chemical analgesia duration without altering locomotor activity in rats for 4 weeks.
doi:10.1186/s40199-014-0073-6
PMCID: PMC4243326  PMID: 25403313
Neostigmine; Nanofibers; Analgesia; Epidural; Electrospinning
25.  Fungal transformation of androsta-1,4-diene-3,17-dione by Aspergillus brasiliensis 
Background
The biotransformation of steroids by fungal biocatalysts has been recognized for many years. There are numerous fungi of the genus Aspergillus which have been shown to transform different steroid substances. The possibility of using filamentous fungi Aspergillus brasiliensis cells in the biotransformation of androsta-1,4-diene-3,17-dione, was evaluated.
Methods
The fungal strain was inoculated into the transformation medium which supplemented with androstadienedione as a substrate and fermentation continued for 5 days. The metabolites were extracted and isolated by thin layer chromatography. The structures of these metabolites were elucidated using 1H-NMR, broadband decoupled 13C-NMR, EI Mass and IR spectroscopies.
Results
The fermentation yielded one reduced product: 17β-hydroxyandrost-1,4-dien-3-one and two hydroxylated metabolites: 11α-hydroxyandrost-1,4-diene-3,17-dione and 12β-hydroxyandrost-1,4-diene-3,17-dione.
Conclusions
The results obtained in this study show that A. brasiliendsis could be considered as a biocatalyst for producing important derivatives from androstadienedione.
doi:10.1186/s40199-014-0071-8
PMCID: PMC4241229  PMID: 25398302
Aspergillus brasiliensis; Fungi; Androsta-1; 4-diene-3; 17-dione; Steroid; Biotransformation

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