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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).
PMCID: PMC4323264
3.  Growing burden of diabetes in Pakistan and the possible role of arsenic and pesticides 
This review is undertaken to address the possible role of arsenic and pesticides in the prevalence of diabetes in Pakistan and to highlight a resourceful targeted research in this area.
A bibliographic search of scientific databases was conducted with key words of “epidemics of diabetes in Pakistan”, “diabetes in Asia”, “diabetes mellitus and environmental pollutants”, “diabetes mellitus and heavy metals”, “diabetes mellitus and pesticides”, “prevalence of pesticides in Pakistan”, and “heavy metals contamination of drinking water, “vegetables and fruits in Pakistan”. More than 200 articles were examined. Studies reporting the prevalence of diabetes mellitus (DM), pesticides and heavy metal contamination of drinking water, fruits and vegetables were included in the study. According to WHO 2011 report, about 12.9 million people are suffering from DM and the number is constantly increasing. Water pollution is a major public health threat in Pakistan. Most of the people in Pakistan are exposed to arsenic and pesticides either in drinking water or through vegetables, fruits, and other edible items with various concentrations above the WHO/FAO permissible limits. Being an agricultural country, a 1169% increase has been recorded with the use of different types of pesticides since last two decades, and almost similar rise in the burden of diabetes.
There is a growing global concern of arsenic and pesticides exposure with the incidence of DM. Besides other factors, the environmental attributors in the incidence of DM in Pakistan have not been conclusively elucidated yet which in turn deserve a resourceful targeted research.
PMCID: PMC4271443  PMID: 25530951
Arsenic; Diabetes mellitus; Environmental pollutants; Heavy metals; Pakistan; Pesticides; Review
4.  The Influence of Pregnancy and Lactation on Maternal Bone Health: A Systematic Review 
Osteoporosis is considered as an important public health problem especially in postmenopausal women. There are some hypotheses support the contributory effect of pregnancy and lactation on osteoporosis later in life. High calcium demand during pregnancy and lactation and low estrogenic state support those hypotheses. Numerous studies have investigated on the issue but there is no consensus about the contributory effect of pregnancy and lactation on osteoporosis. To explore the current state of fact, in the present study, all bibliographic databases were searched and all relevant studies on the topic of osteoporosis, lactation, and pregnancy were reviewed.
The review shows that despite of controversial results, pregnancy may have protective effect on bone especially if followed by lactation.
PMCID: PMC4266784  PMID: 25530765
bone loss; pregnancy; lactation; parity
5.  Haptoglobin Duplicon, Hemoglobin, and Vitamin C: Analyses in the British Women's Heart and Health Study and Caerphilly Prospective Study 
Disease Markers  2014;2014:529456.
Background. Haptoglobin acts as an antioxidant by limiting peroxidative tissue damage by free hemoglobin. The haptoglobin gene allele Hp2 comprises a 1.7 kb partial duplication. Relative to allele Hp1, Hp2 carriers form protein multimers, suboptimal for hemoglobin scavenging. Objective. To examine the association of haptoglobin genotype with a range of phenotypes, with emphasis on vitamin C and hemoglobin levels. Methods. We applied a quantitative PCR assay for the duplication junction to two population cohorts including 2747 British women and 1198 British men. We examined the association of haptoglobin duplicon copy number with hemoglobin and vitamin C and used the copy number to complete a phenome scan. Results. Hemoglobin concentrations were greater in those with Hp2,2 genotype, in women only (Hp1,1 13.45 g/dL, Hp1,2 13.49 g/dL, Hp2,2 13.61 g/dL; P = 0.002), though statistically there was no evidence of a difference between the sexes (z value = 1.2, P = 0.24). Haptoglobin genotype was not associated with vitamin C or any other phenotype in either cohort. Conclusions. Our results do not support association of haptoglobin genotype with vitamin C or with other phenotypes measured in two population cohorts. The apparent association between haptoglobin genotype and hemoglobin in the women's cohort merits further investigation.
PMCID: PMC4265517  PMID: 25525287
7.  Effect of folic acid on bone metabolism: a randomized double blind clinical trial in postmenopausal osteoporotic women 
In spite of several studies, the impact of homocysteine level and folic acid supplementation on bone metabolism is yet to be recognized. In this registered clinical trial (IRCT2014042217385N1), we aimed to find out the power of 6-month folic acid supplementation on homocysteine level and bone metabolism.
Forty postmenopausal osteoporotic women (50 to 87 years) were enrolled in the study. All participants were randomized to receive folic acid 1 mg (n = 17) or placebo (n = 14). At baseline, 3 months, and finally 6 months post intervention, the level of homocysteine, vitamin B12, and bone biomarkers were measured.
Both groups were similar at baseline. The homocysteine decreased in both groups but statistically non-significant (P > 0.05). The changes of the serum level of vitamin B12, osteocalcin, and β cross laps were significant between groups after 6 months (P ≤ 0.05).
The trend of changes of bone biomarkers after 6 months folic acid supplementation shows that homocysteine concentration and/or folic acid supplementation have impact on the rate of bone metabolism. However, further investigations by larger sample size and differentiating age and gender are still needed to clarify the exact role of folate, homocysteine and vitamin B12.
PMCID: PMC4172791  PMID: 25223378
Homocysteine; Folic acid; BMD; Bone biomarkers; Osteoporosis; Clinical trial
8.  The effect of preoperative intravenous paracetamol administration on postoperative fever in pediatrics cardiac surgery 
Post-operative fever is a common complication of cardiac operations, which is known to be correlated with a greater degree of cognitive dysfunction 6 weeks after cardiac surgery. The aim of the present study was to examine efficacy and safety of single dose intravenous Paracetamol in treatment of post-operative fever in children undergoing cardiac surgery.
Materials and Methods:
In this randomised, double-blind, placebo-controlled clinical trial, 80 children, aged 1-12 years, presenting for open heart surgery were entered in the trial and randomly allocated into two groups: Placebo and Paracetamol. After induction of anaesthesia, 15 mg/kg intravenous Paracetamol solution was infused during 1 h in the Paracetamol group. Patients in placebo group received 15 mg/kg normal saline infusion during the same time. Since the end of operation until next 24 h in intensive care unit, axillary temperature of the two group patients was recorded in 4-h intervals. Any fever that occurred during this period had been treated with Paracetamol suppository (125 mg) and the amount of antipyretic drug consumption for each patient had been recorded. In order to examine the safety of Paracetamol, patients were evaluated for drug complication at the same time.
Mean axillary temperature during first 24 h after operation was significantly lower in Paracetamol group compared with placebo group (P = 0.001). Overall fever incidence during 24 h after operation was higher in placebo group compared with Paracetamol group (P = 0.012). Of Paracetamol group patients, 42.5% compared with 15% of placebo group participants had no consumption of antipyretic agent (Paracetamol suppository) during 24 h after operation (P = 0.001).
This study suggests that single dose administration of intravenous Paracetamol before paediatric cardiac surgeries using cardiopulmonary bypass; reduce mean body temperature in the first 24 h after operation.
PMCID: PMC4178333  PMID: 25298601
Cardiac surgery; paracetamol; paediatric; post-operative fever
9.  Hypertonic saline solution reduces the oxidative stress responses in traumatic brain injury patients 
Oxidative stress processes play an important role in the pathogenesis of secondary brain injury after traumatic brain injury (TBI). Hypertonic saline (HTS) has advantages as being preferred osmotic agent, but few studies investigated oxidant and antioxidant effects of HTS in TBI. This study was designed to compare two different regimens of HTS 5% with mannitol on TBI-induced oxidative stress.
Materials and Methods:
Thirty-three adult patients with TBI were recruited and have randomly received one of the three protocols: 125 cc of HTS 5% every 6 h as bolus, 500 cc of HTS 5%as infusion for 24 h or 1 g/kg mannitol of 20% as a bolus, repeated with a dose of 0.25-0.5 g/kg every 6 h based on patient's response for 3 days. Serum total antioxidant power (TAP), reactive oxygen species (ROS) and nitric oxide (NO) were measured at baseline and daily for 3 days.
Initial serum ROS and NO levels in patients were higher than control(6.86± [3.2] vs. 1.57± [0.5] picoM, P = 0.001, 14.6± [1.6] vs. 7.8± [3.9] mM, P = 0.001, respectively). Levels of ROS have decreased for all patients, but reduction was significantly after HTS infusion and mannitol (3. 08 [±3.1] to 1.07 [±1.6], P = 0.001, 5.6 [±3.4] to 2.5 [±1.8], P = 0.003 respectively). During study, NO levels significantly decreased in HTS infusion but significantly increased in mannitol. TAP Levels had decreased in all patients during study especially in mannitol (P = 0.004).
Hypertonic saline 5% has significant effects on the oxidant responses compared to mannitol following TBI that makes HTS as a perfect therapeutic intervention for reducing unfavorable outcomes in TBI patients.
PMCID: PMC4268196  PMID: 25535502
Hypertonic saline; mannitol; oxidative stress response; traumatic brain injury patients
10.  Beneficial effect of butyrate, Lactobacillus casei and L-carnitine combination in preference to each in experimental colitis 
World Journal of Gastroenterology : WJG  2014;20(31):10876-10885.
AIM: To investigate the beneficial effect of the combination of butyrate, Lactobacillus casei, and L-carnitine in a rat colitis model.
METHODS: Rats were divided into seven groups. Four groups received oral butyrate, L-carnitine, Lactobacillus casei and the combination of three agents for 10 consecutive days. The remaining groups included negative and positive controls and a sham group. Macroscopic, histopathological examinations, and biomarkers such as tumor necrosis factor-alpha (TNF-α) and interlukin-1β (IL-1β), myeloperoxidase (MPO), thiobarbituric acid reactive substances (TBARS), and ferric reduced ability of plasma (FRAP) were determined in the colon.
RESULTS: The combination therapy exhibited a significant beneficial effect in alleviation of colitis compared to controls. Overall changes in reduction of TNF-α (114.66 ± 18.26 vs 171.78 ± 9.48 pg/mg protein, P < 0.05), IL-1β (24.9 ± 1.07 vs 33.06 ± 2.16 pg/mg protein, P < 0.05), TBARS (0.2 ± 0.03 vs 0.49 ± 0.04 μg/mg protein, P < 0.01), MPO (15.32 ± 0.4 vs 27.24 ± 3.84 U/mg protein, P < 0.05), and elevation of FRAP (23.46 ± 1.2 vs 15.02 ± 2.37 μmol/L, P < 0.05) support the preference of the combination therapy in comparison to controls. Although the monotherapies were also effective in improvement of colitis markers, the combination therapy was much better in improvement of colon oxidative stress markers including FRAP, TBARS, and MPO.
CONCLUSION: The present combination is a suitable mixture in control of experimental colitis and should be trialed in the clinical setting.
PMCID: PMC4138466  PMID: 25152589
Butyrate; L-carnitine; Colitis; Inflammatory bowel disease; Oxidative stress; Lactobacillus casei; Probiotic
11.  Toxicity of nanomaterials; an undermined issue 
Nanomaterials are employed in extensive variety of commercial products such as electronic components, cosmetics, food, sports equipment, biomedical applications, and medicine. With the increasing utilization of engineered nanomaterials, the potential exposure of human to nanoparticles is rapidly increasing. Nowadays when new nanomaterials with new applications are introduced, mostly good and positive effects are mentioned whereas possible hazards arising from nanosize of the compounds are undermined. Toxicology studies of nanomaterials demonstrate some adverse effects in some human organs such as central nerve system, immune system, and lung. There is lack of complete information about human toxicity and environmental waste of nanomaterials. We aimed to highlight current toxicological concerns of potentially useful nanomaterials which are now used in pharmaceutical and biomedical sciences.
PMCID: PMC4189150  PMID: 25123555
Adverse health effects; Drug delivery; Nanomaterials; Nanomedicine; Toxicity
12.  The immunological benefit of higher dose N-acetyl cysteine following mechanical ventilation in critically ill patients 
Sepsis complication is a major cause of death in multiple trauma critically ill patients. Defensin (cysteine rich anti-microbial peptides), as an important component of immune system, might play an important role in this process. There is also rising data on immunological effects of N-acetyl-cysteine (NAC), a commonly used anti-oxidant in oxidative stress conditions and glutathione (GSH) deficiencies. The aim of the present study was to evaluate the potential beneficial effects of NAC administration on multiple trauma patients with sepsis.
In a prospective, randomized controlled study, 44 multiple trauma critically ill patients who were mechanically ventilated and met the criteria of sepsis and admitted to the intensive care unit (ICU) were randomized into two groups . Control group received all standard ICU therapies and NAC group received intravenous NAC 3 gr every 6 hours for 72 hours in addition to standard therapies. Acute Physiology and Chronic Health Evaluation II (APACHE II) and Sequential Organ Failure Assessment (SOFA) scores, length of ICU stay, ICU mortality were recorded. Levels of serum Immunoglobulin M (IgM), Human β-Defensin 2 (HβD2) and GSH were assessed at baseline and 24, 72, 120 hours after intervention.
During a period of 13-month screening, 44 patients underwent randomization but 5 patients had to be excluded. 21 patients in NAC group and 18 patients in control group completed the study. For both groups the length of ICU stay, SOFA score and systemic oxygenation were similar. Mortality rate (40% vs. 22% respectively, p = 0.209) and ventilator days (Mean ± SD 19.82 ± 19.55 days vs. 13.82 ± 11.89 days respectively, p = 0.266) were slightly higher for NAC group. IgM and GSH levels were similar between two groups (p = 0.325, 0.125 respectively), HβD2 levels were higher for NAC group (at day 3).
High dose of NAC administration not only did not improve patients’ outcome, but also raised the risk of inflammation and was associated with increased serum creatinine.
PMCID: PMC4223415  PMID: 25027749
N-Acetyl; Cysteine (NAC); Glutathione (GSH); Human β Defensin 2 (HβD2); Immunoglobulin M (IgM); Multiple trauma; Sepsis
13.  Improvement in The Function of Isolated Rat Pancreatic Islets through Reduction of Oxidative Stress Using Traditional Iranian Medicine 
Cell Journal (Yakhteh)  2014;16(2):147-163.
Pancreatic islets have fewer antioxidant enzymes than other tissues and thus are vulnerable to oxidative stress. In the present study, the effects of nine specifically selected Iranian medical plants on the mitochondria function and survival of isolated rat islets were examined.
Materials and Methods
In this experimental study, following laparotomy, pancreases of rats were removed and the islets isolated and incubated in vitro for 24 hours. Logarithmic doses of plant materials were added to the islets and incubated for an additional 24 hours after which the viability of the cells and production of reactive oxygen species (ROS) were measured. Levels of insulin production in relation to static and stimulated glucose concen- trations were also determined.
The tested compounds markedly increased survival of the islet cells, their mi- tochondrial activity, and insulin levels at the same time as reducing production of ROS. Greatest effects were observed in the following order: Peganum harmala, Glycyrrhiza glabra, Satureja hortensis, Rosmarinus officinalis, Teucrium scordium, Aloe vera, Zingiber officinale, Silybum marianum, and Hypericum perforatum at doses of 10, 103, 104, 10, 102, 102, 10-1, 10 and 103μgmL-1, respectively.
Based on these results, we suggest that pretreatment with these select- ed Iranian medical plants can improve the outcomes of pancreas transplants and grafts through the control of oxidative stress damage.
PMCID: PMC4071980  PMID: 24567945
Islets of Langerhans; Oxidative Stress; Medicine; Iranian Traditional; In Vitro
15.  Oxidative Stress in Aging 
PMCID: PMC3997972  PMID: 24803986
16.  Apolipoprotein E genotype, cardiovascular biomarkers and risk of stroke: Systematic review and meta-analysis of 14 015 stroke cases and pooled analysis of primary biomarker data from up to 60 883 individuals 
Background At the APOE gene, encoding apolipoprotein E, genotypes of the ε2/ε3/ε4 alleles associated with higher LDL-cholesterol (LDL-C) levels are also associated with higher coronary risk. However, the association of APOE genotype with other cardiovascular biomarkers and risk of ischaemic stroke is less clear. We evaluated the association of APOE genotype with risk of ischaemic stroke and assessed whether the observed effect was consistent with the effects of APOE genotype on LDL-C or other lipids and biomarkers of cardiovascular risk.
Methods We conducted a systematic review of published and unpublished studies reporting on APOE genotype and ischaemic stroke. We pooled 41 studies (with a total of 9027 cases and 61 730 controls) using a Bayesian meta-analysis to calculate the odds ratios (ORs) for ischaemic stroke with APOE genotype. To better evaluate potential mechanisms for any observed effect, we also conducted a pooled analysis of primary data using 16 studies (up to 60 883 individuals) of European ancestry. We evaluated the association of APOE genotype with lipids, other circulating biomarkers of cardiovascular risk and carotid intima-media thickness (C-IMT).
Results The ORs for association of APOE genotypes with ischaemic stroke were: 1.09 (95% credible intervals (CrI): 0.84–1.43) for ε2/ε2; 0.85 (95% CrI: 0.78–0.92) for ε2/ε3; 1.05 (95% CrI: 0.89–1.24) for ε2/ε4; 1.05 (95% CrI: 0.99–1.12) for ε3/ε4; and 1.12 (95% CrI: 0.94–1.33) for ε4/ε4 using the ε3/ε3 genotype as the reference group. A regression analysis that investigated the effect of LDL-C (using APOE as the instrument) on ischaemic stroke showed a positive dose-response association with an OR of 1.33 (95% CrI: 1.17, 1.52) per 1 mmol/l increase in LDL-C. In the separate pooled analysis, APOE genotype was linearly and positively associated with levels of LDL-C (P-trend: 2 × 10−152), apolipoprotein B (P-trend: 8.7 × 10−06) and C-IMT (P-trend: 0.001), and negatively and linearly associated with apolipoprotein E (P-trend: 6 × 10−26) and HDL-C (P-trend: 1.6 × 10−12). Associations with lipoprotein(a), C-reactive protein and triglycerides were non-linear.
Conclusions In people of European ancestry, APOE genotype showed a positive dose-response association with LDL-C, C-IMT and ischaemic stroke. However, the association of APOE ε2/ε2 genotype with ischaemic stroke requires further investigation. This cross-domain concordance supports a causal role of LDL-C on ischaemic stroke.
PMCID: PMC3619955  PMID: 23569189
Stroke; lipids; apolipoprotein E; cardiovascular disease; systematic review; meta-analysis; biomarkers
17.  Evaluations of topical application of tranexamic acid on post-operative blood loss in off-pump coronary artery bypass surgery 
Saudi Journal of Anaesthesia  2014;8(2):224-228.
One of the major complications of cardiac surgery is the presence of post-operative bleeding. The aim of the present study was to investigate the topical application of tranexamic acid in the pericardial cavity on post-operative bleeding in off-pump coronary artery bypass graft (CABG) surgery.
Materials and Methods:
This study was on 71 patients who underwent off-pump CABG. The anesthesia and surgery methods were the same for all patients. Patients were assigned to two equal groups. In the first group, 1 g of tranexamic acid in 100 mL of normal saline solution (NSS) was applied to pericardium and mediastinal cavity at the end of surgery. In the second group, only 100 mL of NSS was applied. Chest drainage of the patients after 24 h and the amounts of blood and blood products transfusion were also recorded during this time.
Patients were the same regarding demographic information and surgery. The average volume of blood loss after 24 h was 366 mL for the first group and 788 mL for the control group. There was a statistically significant difference between the two groups (P < 0.001). The amount of packed red blood cells transfusion in the first group was less than that of the control group, which was not statistically significant. There was no statistically significant difference between the amount of hemoglobin, hematocrit, platelets, prothrombin time and partial thromboplastin time in the post-operative stage in the two groups.
The topical application of tranexamic acid in off-pump CABG patients leads to a decreased post-operative blood loss.
PMCID: PMC4024681  PMID: 24843337
Blood; coronary artery bypass graft; off-pump; topical application; tranexamic acid
18.  A system dynamics model for national drug policy 
Data modeling techniques can create a virtual world to analyze decision systems. National drug authorities can use such techniques to take care of their deficiencies in decision making processes. This study was designed to build a system dynamics model to simulate the effects of market mix variables (5 P’s) on the national drug policy (NDP) indicators including availability, affordability, quality, and rationality. This was aimed to investigate how to increase the rationality of decision making, evaluate different alternatives, reduce the costs and identify the system obstacles.
System dynamics is a computer-based approach for analyzing and designing complex systems over time. In this study the cognitive casualty map was developed to make a concept about the system then the stock-flow model was set up based on the market demand and supply concept.
The model demonstrates the interdependencies between the NDP variables through four cognitive maps. Some issues in availability, willingness to pay, rational use and quality of medicines are pointed in the model. The stock-flow diagram shows how the demand for a medicine is formed and how it is responded through NDP objectives. The effects of changing variables on the other NDP variables can be studied after running the stock-flow model.
The model can initiate a fundamental structure for analyzing NDP. The conceptual model made a cognitive map to show many causes’ and effects’ trees and reveals some relations between NDP variables that are usually forgotten in the medicines affairs. The model also provides an opportunity to be expanded with more details on a specific disease for better policy making about medication.
PMCID: PMC4229987  PMID: 24690531
National drug policy; System dynamics; Modeling
19.  The cost of diabetes chronic complications among Iranian people with type 2 diabetes mellitus 
To evaluate the cost of diabetes related micro- and macrovascular complications in Iranian people with type 2 diabetes mellitus.
In routine clinical practice, people with type 2 diabetes mellitus were assessed for 10 years at a diabetes care center. The type of medications and clinical data were extracted from patients’ documents. Mortality rate and the incidence of micro- and macrovascular complications recorded in patients’ documents were analyzed. Cost analysis was comprised of 1) para clinic costs as well as laboratory, medications, clinical visits and nonmedical costs 2) inpatient costs as well as hospital admission costs, disability, and mortality costs.
From 1562 people with type 2 diabetes mellitus, a total of 1000 patients with mean duration disease of 11.2 years, who had completed information in their documents, were studied. All people were free from complications at baseline. Mean cumulative incidence of diabetes-related complications over 10 years were 10.9 ± 3.5%, 8.0 ± 3.1%, 4.6 ± 1.7%, 9.1 ± 3.6% and 2.3 ± 0.9% for peripheral neuropathy and diabetic foot ulcer, nephropathy, ophthalmic complications, cardiovascular disease and death, respectively. People with better glycemic control had less complication and also related expenditures. Average para clinic cost per patient was 393.6 ± 47.8 and average inpatient cost per patient was 1520.7 ± 104.5 USD.
Our findings demonstrate considerable incidence of diabetes chronic complications and also high health care expenditure for related complications among our patients. As the number of people with diabetes continues to rise, early detection of the disease and implementation of timely and appropriate therapeutic strategies could decrease the burden of diabetes chronic complications and also huge related expenditures.
PMCID: PMC3975900  PMID: 24593991
Cost; Type 2 diabetes mellitus; Complication; HbA1c; Productivity; QALY
20.  Comparison of the Effects of Enoxaparin and Heparin on Inflammatory Biomarkers in Patients with ST-segment Elevated Myocardial Infarction: A prospective Open Label Pilot Clinical Trial 
Heparin and enoxaparin possess anti-inflammatory properties. We compared the effects of these drugs on inflammatory biomarkers in patients with ST-segment Elevated Myocardial Infarction (STEMI).
Thirty four patients with STEMI randomly separated in two groups and received standard doses of heparin and enoxaparin. The serum concentration of Serum Amyloid A (SAA), C-Reactive Protein (CRP), Interleukin (IL)-6, ferritin and Myeloperoxidase (MPO) were measured at baseline, 12 ,24 and 48 hours after drug administration.
Serum concentrations of SAA (P: 0.02), CRP (P: 0.02) and ferritin (P: 0.01) significantly reduced in heparin group during measurements compared to baseline, circulating levels of IL-6 (P: 0.002), SAA (P: 0.009), CRP (P: 0.01) were significantly decreased in enoxaparin group. The overall difference in inflammatory biomarkers between heparin and enoxaparin group was not significant.
Both heparin and enoxaparine reduced serum levels of inflammatory biomarkers in patients with STEMI. This effect may provide additional clinical benefit of these drugs in the treatment of STEMI patients.
PMCID: PMC4157034  PMID: 25237354
Heparin; Enoxaparin; Acute coronary syndrome; STEMI; Inflammatory biomarkers
21.  Efficacy and tolerability of renzapride in irritable bowel syndrome: a meta-analysis of randomized, controlled clinical trials including 2528 patients 
By targeting different subtypes of 5-hydroxytryptamine (5HT) receptors in the gastrointestinal (GI) tract, several drugs have been introduced for the management of irritable bowel syndrome (IBS). Renzapride is a full agonist for 5HT4 receptor and an antagonist to 5HT2b and 5HT3 receptors which is thought a promising therapeutic agent for constipation predominant IBS (C-IBS) patients due to its accelerating effect on the GI tract. In this meta-analysis, our aim was to evaluate the efficacy and tolerability of renzapride in the management of IBS.
Material and methods
A search was done from 1992 to February 2013 for placebo-controlled trials that investigated the efficacy of renzapride in IBS.
Relative risk (RR) for clinical efficacy in IBS patients treated for 5 weeks or less comparing renzapride to placebo was 1.07 (95% CI = 0.89–1.29, p = 0.38). This value for IBS patients treated for more than 5 weeks was 1.04 (95% CI = 0.78–1.239, p = 0.77). The RR for clinical efficacy in IBS patients treated with renzapride (4 mg) for 5 weeks or less and more than 5 weeks in comparison to placebo was 1.2 (95% CI = 0.97–1.48, p = 0.1) and 1.16 (95% CI = 0.98–1.37, p = 0.08), respectively, which were statistically non-significant but clinically important. The analysis of tolerability demonstrated that amongst different reported adverse effects, renzapride caused diarrhea more than placebo (RR = 1.61 with a 95% CI = 1.16–2.24, p = 0.004). The RR for withdrawals from renzapride compared to placebo was 1.58 (95% CI = 1.26–2.07, p = 0.0007).
Renzapride is not superior to placebo in relieving IBS symptoms and causes significant incidences of diarrhea and drop-outs due to adverse effects in treated patients vs. placebo. Thus, this medicine might be a cost burden to patients without providing good effectiveness.
PMCID: PMC3953973  PMID: 24701208
renzapride; 5-hydroxytryptamine; irritable bowel syndrome; clinical trial; meta-analysis; systematic review
22.  Ovarian Aging-Like Phenotype in the Hyperandrogenism-Induced Murine Model of Polycystic Ovary 
There are prominently similar symptoms, effectors, and commonalities in the majority of characteristics between ovarian aging and polycystic ovarian syndrome (PCOS). Despite the approved role of oxidative stress in the pathogenesis of PCOS and aging, to our knowledge, the link between the PCO(S) and aging has not been investigated yet. In this study we investigated the possible exhibition of ovarian aging phenotype in murine model of PCO induced by daily oral administration of letrozole (1 mg/kg body weight) for 21 consecutive days in the female Wistar rats. Hyperandrogenization showed irregular cycles and histopathological characteristics of PCO which was associated with a significant increase in lipid peroxidation (LPO) and reactive oxygen species (ROS) and decrease in total antioxidant capacity (TAC) in serum and ovary. Moreover, serum testosterone, insulin and tumor necrosis factor-alpha (TNF-α) levels, and ovarian matrix metalloproteinase-2 (MMP-2) were increased in PCO rats compared with healthy controls, while estradiol and progesterone diminished. Almost all of these findings are interestingly found to be common with the characteristics identified with (ovarian) aging showing that hyperandrogenism-induced PCO in rat is associated with ovarian aging-like phenotypes. To our knowledge, this is the first report that provides evidence regarding the phenomenon of aging in PCO.
PMCID: PMC3945218  PMID: 24693338
23.  The efficacy and prophylactic characteristics of omega-3 fatty acids in experimental gingivitis in rats 
Objective(s): Gingivitis is an inflammatory disease that affects tooth-supporting tissues and is caused by a microbe-immune response. The aim of this study was to evaluate the effects of omega-3 fatty acids on immune system regulation and the prevention and treatment of gingivitis using an animal model.
Materials and Methods: Gingival inflammation was induced by lipopolysaccharide (LPS) injection. Forty adult male rats were divided into four equal groups: 1. Negative control group (sterile saline was injected into gingival tissue followed by oral gavage with saline); 2. Positive control group (LPS injection was followed by oral gavage with saline); 3. Treatment group (LPS injection was followed by oral gavage with omega-3); 4. Prophylactic group (oral gavage with omega-3 was followed by LPS injection). After 24 days, the rats were sacrificed and histological tissue samples were randomly evaluated for the inflammatory tissue changes. Tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) levels were measured by ELISA.
Results: The levels of IL-1β and TNF-α in the prophylactic group and the level of TNF-α in the treatment group were significantly lower than those in the positive control group (P<0.05). The severity of inflammation was normal, slight, moderate, and severe in the negative control group, prophylactic group, treatment group, and positive control group, respectively. ANOVA was used for the statistical analyses, with P<0.05 regarded as significant.
Conclusion: Prior consumption of omega-3 fatty acids is effective in reducing inflammation in induced rat gingivitis, resulting in a decreased level of biomarkers and fewer destructive effects.
PMCID: PMC3976744  PMID: 24711890
Cytokines; Gingival diseases; Histology; Omega-3; Rat
25.  Safety concerns to application of graphene compounds in pharmacy and medicine 
Graphene, the new allotrope of carbon is a single layer of monocrystalline graphite with sp2 hybridized carbon atoms. This compound has received worldwide attention due to its extraordinary physical and chemical properties. Duo to the widespread application of geraphenes, concerns are raising about its environmental safety or the safety protocols for handling and waste of graphene-based materials. The generation of reactive free radicals, adsorption of important biomolecules, and physical toxicity of graphene also matter. Hereby we criticize the concerns on the toxicity of graphenes to provide some perspective on the potential hazards of future development in graphene-based biomaterials.
PMCID: PMC3922742  PMID: 24450435
Graphene; Graphene oxide; Membrane; Reactive oxygen species; Safety; Toxicity

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