Publications by authors named "Mohammad-Reza Rouini"

75 Publications

Efficacy assessments of tretinoin-loaded nano lipid carriers in acne vulgaris: a double blind, split-face randomized clinical study.

Arch Dermatol Res 2021 Jun 19. Epub 2021 Jun 19.

Center for Research and Training in Skin Diseases and Leprosy, Tehran University of Medical Sciences, No. 415 Taleqani Ave, Tehran, Iran.

Here, we assessed the efficacy and safety of Nano lipid carrier (NLC) drug delivery system containing tretinoin (NLC-TRE) in comparison with the conventional 0.05% tretinoin cream (TRE cream) in mild to moderate acne vulgaris. A stable and appropriate NLC-TRE formulation was prepared using a high-pressure homogenizer and particle characterization and physicochemical properties were evaluated under accelerated conditions. Efficacy assessment was performed via a split-face clinical study, by comparing the number of acne lesions, porphyrin production and skin biophysical parameters in both sides of the face randomly treated with NLC-TRE and TRE cream. Plasma concentration of tretinoin after topical application of NLC-TRE was measured for primary safety evaluation. We acquired a stable, spherical nanoparticles with particle size of 118.5 nm, PI equal to 0.485 and ZP of - 44.7 mV. The rate of decrease of acne lesions was significantly higher in NLC- TRE side (p value < 0.001). The size and intensity of porphyrin production in pilosebaceous follicles were significantly reduced only on NLC-TRE side (p value < 0.01). The plasma concentration of the tretinoin, after 8 weeks' application remained lower than the toxic levels. The NLC-TRE formula provides better efficiency and good loading capacity of TRE in the drug delivery system.
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http://dx.doi.org/10.1007/s00403-021-02256-5DOI Listing
June 2021

Area under the Curve-Based Dosing of Vancomycin in Critically Ill Patients Using 6-Hour Urine Creatinine Clearance Measurement.

Crit Care Res Pract 2020 24;2020:8831138. Epub 2020 Dec 24.

Department of Clinical Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.

Background: The area under the curve- (AUC-) guided vancomycin dosing is the best strategy for individualized therapy in critical illnesses. Since AUC can be calculated directly using drug clearance (CL), any parameter estimating CL will be able to achieve the goal of 24-hour AUC (AUC). The present study was aimed to determine CL based on 6-hour urine creatinine clearance measurement in critically ill patients with normal renal function.

Method: 23 adult critically ill patients with an estimated glomerular filtration rate (eGFR) ≥60 mL/min who received vancomycin infusion were enrolled in this pilot study. Vancomycin pharmacokinetic parameters were determined for each patient using serum concentration data and a one-compartment model provided by MONOLIX software using stochastic approximation expectation-maximization (SAEM) algorithm. Correlation of CL with the measured creatinine clearance in 6-hour urine collection (CL) and estimated creatinine clearance by the Cockcroft-Gault formula (CL) was investigated.

Results: Data analysis revealed that CL had a stronger correlation with CL rather than CL ( = 0.823 vs. 0.594; < 0.001 vs. 0.003). The relationship between CL and CL was utilized to develop the following equation for estimating CL: CL (mL/min) = ─137.4 + CL (mL/min) + 2.5 IBW (kg) (  = 0.826, < 0.001). Regarding the described model, the following equation can be used to calculate the empirical dose of vancomycin for achieving the therapeutic goals in critically ill patients without renal impairment: total daily dose of vancomycin (mg) = (─137.4CL (mL/min) + 2.5 IBW (kg)) × 0.06 AUC (mg.hr/L).

Conclusion: For AUC estimation, CL can be obtained by collecting urine in a 6-hour period with good approximation in critically ill patients with normal renal function.
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http://dx.doi.org/10.1155/2020/8831138DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7775160PMC
December 2020

Evaluation of changes in cytochrome P450 2C19 activity in type 2 diabetic rats before and after treatment, by using isolated perfused liver model.

Iran J Basic Med Sci 2020 May;23(5):629-635

Biopharmaceutics and Pharmacokinetic Division, Department of Pharmaceutics, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.

Objectives: Alteration in drug metabolism is very likely in diabetes mellitus. This study assessed changes in CYP2C19 enzymatic activity in the liver using omeprazole as a probe in the animal model of type II diabetes (T2DM) before and after treatment with metformin and cinnamon.

Materials And Methods: Twenty-eight male Wistar rats were randomly divided into seven groups. Fourteen days after induction of type 2 diabetic mellitus (T2DM), rats in the test group received metformin, cinnamon, and metformin plus cinnamon daily for 14 days. On day 28, rats were subjected to liver perfusion by Krebs-Henseleit buffer containing omeprazole as a CYP2C19 probe. Perfusate samples were analyzed by HPLC-UV to evaluate the activity of CYP2C19.

Results: Mean metabolic ratio of omeprazole was changed from 0.091±0.005 in the control group to 0.054±0.005 in the untreated-diabetic rats. This average was increased inordinately to 0.218±0.036 in the treated rats with metformin. Interestingly, the administration of cinnamon in combination with metformin in diabetic rats caused the enzyme activity to return to (0.085±0.002) approximately the observed levels in the control group (0.091±0.005).

Conclusion: Results showed that despite the suppression of the CYP2C19 enzyme activity in T2DM rats, metformin treatment could increase the enzyme activity. Simultaneous application of cinnamon and metformin can modulate the function of CYP2C19 to the observed level in the control group and make it more predictable to treat diabetes mellitus and fate of drugs that are metabolized by this enzyme.
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http://dx.doi.org/10.22038/ijbms.2020.40836.9642DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7374996PMC
May 2020

Assessment of tramadol pharmacokinetics in correlation with CYP2D6 and clinical symptoms.

Drug Metab Pers Ther 2020 06 29;35(2). Epub 2020 Jun 29.

Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.

Objectives Due to lack of adequate data on tramadol kinetic in relevance of CYP2D6 toxicity, this study was designed to investigate the effect of CYP2D6 phenotype in tramadol poisoning. The saliva, urine and blood samples were taken at the admission time. Consequently, concentration of tramadol and its major metabolites were measured. Methods A pharmacokinetic and metabolic study was developed in cases of tramadol poisoned (n=96). Cases of tramadol poisoned evidenced seizure, hypertension, dizziness, nausea and vomiting symptoms participated. Results Female cases showed higher N-desmethyltramadol (M2) tramadol concentrations than male cases: in urine (40.12 ± 124.53 vs. 7.3 ± 7.13), saliva (16.91 ± 26.03 vs. 5.89 ± 7.02), and blood (1.11 ± 1.56 vs. 0.3 ± 0.38) samples. Significant correlation between blood, saliva, and urine concentrations were found (r = 0.5). Based on the metabolic ratio of O-desmethyltramadol (M1) of male (0.53 ± 0.22) and female (0.43 ± 0.26), poisoning and severe symptoms like seizure in female occurs statistically fewer (13.04%) than in male (50.6%). Assessment of CYP2D6 phenotype showed all of the participants were extensive metabolizers (EM) and their phenotype was associated with clinical symptoms. Conclusions According to our results, M1 as a high potent metabolite has an important role in toxicity and the likelihood of poisoning in people with EM phenotype. Finally, tramadol metabolic ratio may justify the cause of various symptoms in human tramadol poisoning.
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http://dx.doi.org/10.1515/dmpt-2019-0021DOI Listing
June 2020

Assessment of tramadol pharmacokinetics in correlation with CYP2D6 and clinical symptoms.

Drug Metab Pers Ther 2020 Jun 29. Epub 2020 Jun 29.

Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.

Objectives Due to lack of adequate data on tramadol kinetic in relevance of CYP2D6 toxicity, this study was designed to investigate the effect of CYP2D6 phenotype in tramadol poisoning. The saliva, urine and blood samples were taken at the admission time. Consequently, concentration of tramadol and its major metabolites were measured. Methods A pharmacokinetic and metabolic study was developed in cases of tramadol poisoned (n=96). Cases of tramadol poisoned evidenced seizure, hypertension, dizziness, nausea and vomiting symptoms participated. Results Female cases showed higher N-desmethyltramadol (M2) tramadol concentrations than male cases: in urine (40.12 ± 124.53 vs. 7.3 ± 7.13), saliva (16.91 ± 26.03 vs. 5.89 ± 7.02), and blood (1.11 ± 1.56 vs. 0.3 ± 0.38) samples. Significant correlation between blood, saliva, and urine concentrations were found (r = 0.5). Based on the metabolic ratio of O-desmethyltramadol (M1) of male (0.53 ± 0.22) and female (0.43 ± 0.26), poisoning and severe symptoms like seizure in female occurs statistically fewer (13.04%) than in male (50.6%). Assessment of CYP2D6 phenotype showed all of the participants were extensive metabolizers (EM) and their phenotype was associated with clinical symptoms. Conclusions According to our results, M1 as a high potent metabolite has an important role in toxicity and the likelihood of poisoning in people with EM phenotype. Finally, tramadol metabolic ratio may justify the cause of various symptoms in human tramadol poisoning.
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http://dx.doi.org/10.1515/dmdi-2019-0021DOI Listing
June 2020

Bucladesine Attenuates Spatial Learning and Hippocampal Mitochondrial Impairments Induced by 3, 4-Methylenedioxymethamphetamine (MDMA).

Neurotox Res 2020 Jun 27;38(1):38-49. Epub 2020 Feb 27.

Department of Neurosciences, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran.

Neurotoxic effects of systemic administration of 3, 4- methylenedioxymethamphetamine (MDMA) has been attributed to MDMA and its metabolites. However, the role of the parent compound in MDMA-induced mitochondrial and memory impairment has not yet been investigated. Moreover, it is not yet studied that analogs of 3', 5'-cyclic adenosine monophosphate (cAMP) could decrease these neurotoxic effects of MDMA. We wished to investigate the effects of the central administration of MDMA on spatial memory and mitochondrial function as well as the effects of bucladesine, a membrane-permeable analog of cAMP, on these effects of MDMA. We assessed the effects of pre-training bilateral intrahippocampal infusion of MDMA (0.01, 0.1, 0.5, and 1 μg/side), bucladesine (10 and 100 μM) or combination of them on spatial memory, and different parameters of hippocampal mitochondrial function including the level of reactive oxygen species (ROS) production, mitochondrial membrane potential (MMP), mitochondrial swelling, mitochondrial outer membrane damage, the amount of cytochrome c release as well as hippocampal ADP/ATP ratio. The results showed that MDMA caused spatial memory impairments as well as mitochondrial dysfunction as evidenced by the marked increase in hippocampal ADP/ATP ratio, ROS level, the collapse of MMP, mitochondrial swelling, and mitochondrial outer membrane damage leading to cytochrome c release from the mitochondria. The current study also found that bucladesine markedly reduced the destructive effects of MDMA. These results provide evidence of the role of the parent compound (MDMA) in MDMA-induced memory impairments through mitochondrial dysfunction. This study highlights the role of cAMP/PKA signaling in MDMA-induced memory and mitochondrial defects.
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http://dx.doi.org/10.1007/s12640-020-00183-3DOI Listing
June 2020

Evaluation of Amikacin Pharmacokinetics in Critically Ill Patients with Intra-abdominal Sepsis.

Adv Pharm Bull 2020 Jan 11;10(1):114-118. Epub 2019 Dec 11.

Department of Clinical Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.

Although the current widespread use of amikacin is in intra-abdominal sepsis treatment, its pharmacokinetic changes in the present setting are not yet well known. This study was aimed to evaluate the amikacin pharmacokinetic profile in critically ill patients with intraabdominal sepsis compared to pneumosepsis. Adult septic patients received amikacin therapy were studied. Patients with intraabdominal sepsis were enrolled in group 1 (n=16), and patients with pneumosepsis were enrolled in group 2 (n=13). The amikacin serum concentrations were evaluated in the first, second, fourth and sixth hours after initiating 30-minute infusion. The pharmacokinetic parameters were calculated for each patient. There was no significant difference in the volume of distribution between the two groups (0.33±0.08 vs. 0.28±0.10 L/kg, =0.193). The amikacin clearance was significantly lower in group 1 compared to group 2 (58.5±21.7 vs. 83.9±37.0 mL/min, =0.029). There was no significant correlation between amikacin clearance and creatinine clearance estimated by Cockcroft-Gault formula in all patients (=0.206). The half-life was significantly longer in group 1 compared to group 2 (5.3±2.8 vs. 3.4±3.2 hours, =0.015). Pathophysiologic changes following intra-abdominal sepsis can affect amikacin pharmacokinetics behavior. The clearance and half-life may change, but the alteration of the volume of distribution is not significantly different in comparison with pneumosepsis. Further studies are required to evaluate the pharmacokinetic variables of amikacin in critically ill patients with intra-abdominal sepsis.
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http://dx.doi.org/10.15171/apb.2020.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6983982PMC
January 2020

Improving the biological activity of fingolimod loaded PHBV nanoparticles by using hydrophobically modified alginate.

Drug Dev Ind Pharm 2020 Feb 6;46(2):318-328. Epub 2020 Feb 6.

Department of Pharmaceutics, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.

Uncontrolled distribution of nanoparticles (NPs) within the body can significantly decrease the efficiency of drug therapy and is considered among the main restrictions of NPs application. The aim of this study was to develop a depot combination delivery system (CDS) containing fingolimod loaded poly (3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV) NPs dispersed into a matrix of oleic acid-grafted-aminated alginate (OA-g-AAlg) to minimize the nonspecific biodistribution (BD) of PHBV NPs. OA-g-AAlg was synthesized in two step; First, Alg was aminated by using adipic dihydrazide (ADH). The degree of hyrazide group substitution of Alg was determined by trinitro-benzene-sulfonic acid (TNBS) assay. Second, OA was attached to AAlg through formation of an amide bond. Chemical structure of OA-g-AAlg was confirmed with FTIR and HNMR spectroscopy. Furthermore, rheological properties of OA-g-AAlg with different grafting ratios were evaluated. release studies indicated that 47% of fingolimod was released from the CDS within 28 days. Blood and tissue samples were analyzed using liquid chromatography/tandem mass spectrometry following subcutaneous (SC) injection of fingolimod-CDS into Wistar rats. The elimination phase half-life of CDS-fingolimod was significantly higher than that of fingolimod (∼32 d vs. ∼20 h). To investigate the therapeutic efficacy, lymphocyte count was assessed over a 40 day period in Wistar rats. Peripheral blood lymphocyte count decreased from baseline by 27 ± 8% in 2 days after injection. Overall, the designed CDS represented promising results in improving the pharmacokinetic properties of fingolimod. Therefore, we believe that this sustained release formulation has a great potential to be applied to delivery of various therapeutics.
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http://dx.doi.org/10.1080/03639045.2020.1721524DOI Listing
February 2020

The effect of surface treatment on the brain delivery of curcumin nanosuspension: in vitro and in vivo studies.

Int J Nanomedicine 2019 19;14:5477-5490. Epub 2019 Jul 19.

Nanotechnology Research Centre, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.

Curcumin, a bioactive component with multiple characteristics, has been shown to have many therapeutic effects. However, there are several limitations regarding the use of curcumin such as instability, low solubility, poor bioavailability, and rapid elimination. Different approaches have been used to solve these problems. In this study, surface-modified nanosuspension (NS) is investigated as a novel brain delivery system. Two different methods were used for the preparation of nanosuspensions with two different stabilizers. The surface of the nanosuspensions was coated with D-α-tocopheryl polyethylene glycol 1,000 succinate (TPGS) and Tween 80 using physical adsorption. Curcumin NSs were prepared using two different top-down techniques by high-pressure homogenizer and probe sonicator. A validated sensitive and selective high-performance liquid chromatography method using fluorescence detection was used for the determination and quantification of curcumin. Pharmacokinetics and biodistribution of curcumin NSs and solutions after intravenous administration in rats were studied. Higher levels of curcumin in the brain were detected when Tween 80-coated NS was used compared with the curcumin solution and TPGS coated NS (TPGS-NS) (-value<0.05). Absorption of ApoE and/or B by Tween 80-coated nanoparticles (NPs) from the blood were caused transferring of these NPs into the brain using receptor-mediated endocytosis. Distribution of TPGS-NS in the brain compared with the curcumin solution was higher (-value<0.05). Higher levels of curcumin concentration in the liver, spleen, and lung were also observed with TPGS-NS. The results of this study indicate that the surface-coating of NSs by Tween 80 may be used to improve the biodistribution of curcumin in the brain.
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http://dx.doi.org/10.2147/IJN.S199624DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6649305PMC
October 2019

Pharmacokinetics and Bioequivalence Studies of Teriflunomide in Healthy Iranian Volunteers.

Clin Pharmacol Drug Dev 2020 04 5;9(3):341-345. Epub 2019 Aug 5.

Department of Pharmaceutics, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.

Multiple sclerosis, which is characterized by inflammation and neurodegeneration, is considered a chronic disease of the central nervous system. Given the lack of pharmacokinetic evaluation of teriflunomide in the Iranian context, the present 2-way crossover study aimed to assess the pharmacokinetic properties and bioequivalence of 2 teriflunomide formulations. To this end, 2 single-dose generic and branded teriflunomide formulations were orally administered to 14 healthy Iranian male volunteers. A washout period of 21 days was allowed between the treatments. The plasma samples containing teriflunomide were analyzed by a simple and sensitive high-performance liquid chromatography method using standard ultraviolet detection. In addition, the pharmacokinetic parameters were calculated for bioequivalence evaluation. The peak area ratio between the teriflunomide and the internal standard was the source of calibration curves, which were linear over the range of 20-40,000 ng/mL (R = 0.9994). The results indicated that the 2 formulations had similar pharmacokinetics. Further, the 90%CI of the mean ratios of the test versus the reference formulations of log-transformed area under the concentration-time curve over 72 hours (93% to 107%) and peak concentration (92% to 108%) were within the acceptable range of 80% to 125%. Based on the obtained results, the test formulation of teriflunomide could be similar to that of the reference formulation.
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http://dx.doi.org/10.1002/cpdd.725DOI Listing
April 2020

A randomized controlled trial on the efficacy, safety, and pharmacokinetics of metformin in severe traumatic brain injury.

J Neurol 2019 Aug 16;266(8):1988-1997. Epub 2019 May 16.

Department of Clinical Pharmacy, Faculty of Pharmacy, Tehran University of Medical Sciences, 14155-6451, Tehran, Iran.

Objective: Traumatic brain injury (TBI) is a leading cause of morbidity and mortality worldwide. Metformin is reported to have pleiotropic neuroprotective effects through anti-inflammatory, antioxidative, and anti-ischemic activity, and improvements in vascular hemodynamics and endothelial function. The aim of this study is to examine the efficacy and safety of metformin therapy in severe TBI patients.

Methods: This single-blind, parallel-group, randomized controlled trial enrolled adult TBI patients. Of 158 trauma patients assessed, 30 met the eligibility criteria and were randomly allocated in a one-to-one ratio to receive 1 g metformin every 12 h for five consecutive days (intervention group) or to usual management only (control group). For efficacy analysis, temporal profiles of serum levels of S100b, neutrophil to lymphocyte ratio (NLR), and glial fibrillary acidic protein (GFAP) were assessed. For pharmacokinetic analysis, serum concentrations of metformin were evaluated in the intervention group.

Results: The two study groups were similar in terms of demographics, baseline clinical characteristics, and on-admission biomarkers' serum levels. Longitudinal analysis of S100b and NLR levels showed statistically significant declines in values toward normal levels in the intervention group (p values of < 0.001 and 0.030, respectively), different from the profiles of the control group (p values of 0.074 and 0.645, respectively). Pharmacokinetic analysis demonstrated that metformin absorption is delayed in TBI patients. No events of hypoglycemia and lactic acidosis occurred.

Conclusions: Metformin could potentially be an effective and safe therapeutic intervention in patients with severe TBI. Large-scale, multicentre studies are needed to confirm our encouraging results.
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http://dx.doi.org/10.1007/s00415-019-09366-1DOI Listing
August 2019

Pharmacokinetic changes of tramadol in rats with hepatotoxicity induced by ethanol and acetaminophen in perfused rat liver model.

Alcohol 2019 06 22;77:49-57. Epub 2018 Sep 22.

Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, P.O. Box 13147-789, Tehran, Iran. Electronic address:

Tramadol is an opioid agonist with activation monoaminergic properties. It can be administered orally, rectally, intravenously, or intramuscularly as a centrally acting analgesic. Liver injury can lead to changes in the metabolism of tramadol. In this study, the rate of tramadol metabolism in rats with damaged liver induced by ethanol and acetaminophen was assessed in a recirculation perfusion system. Acetaminophen is a mild analgesic and antipyretic agent, which can cause centrilobular hepatic necrosis in toxic doses, whereas alcohol causes death due to liver diseases. Alcoholic liver disease (ALD), such as alcoholic fatty liver, alcoholic hepatitis, and alcoholic fibrosis, is the most common liver disease. The aim of this study was to investigate the alteration in tramadol metabolism in different hepatotoxicity conditions in animal models. Male rats were randomly assigned to three groups. The control group received normal saline, group 2 received acetaminophen at the dose of 250 mg/kg/day, and group 3 received ethanol at the beginning dose of 3 g/kg/day, which was slowly increased to 6 g/kg/day. Tramadol was added to the perfusion solution at the concentration of 500 ng/mL. Samples were collected during 180 min, and analyte concentrations were determined by the High-Performance Liquid Chromatography (HPLC) method. The concentration of tramadol and its three main metabolites, O-desmethyltramadol (M1), N-desmethyltramadol (M2), and N,O-didesmethyltramadol (M5), were determined in perfusate samples. Ethanol and acetaminophen significantly affected the pattern of weight gain and liver weights before perfusion and caused a significant increase in enzyme activities. Moreover, histopathologic examination revealed that ethanol and acetaminophen caused liver damage. An increase in the elimination half-life and reduced clearance rate of tramadol were seen in the acetaminophen and ethanol groups, in comparison to the control group. Additionally, significant reductions in the Area Under the Curve (AUC) of metabolites of tramadol (M1, M2, and M5) were observed in the acetaminophen and ethanol groups in the perfused rat liver model. Liver damage caused by ethanol and acetaminophen during 45 days in animals leads to a significant reduction in the level of tramadol metabolites. Therefore, in patients with liver damage caused by ethanol and acetaminophen, caution needs to be considered when prescribing tramadol.
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http://dx.doi.org/10.1016/j.alcohol.2018.09.006DOI Listing
June 2019

Prevalence of candidemia and associated candida subtypes following severe sepsis in non-neutropenic critically ill patients.

Acta Biomed 2018 06 7;89(2):193-202. Epub 2018 Jun 7.

Clinical Pharmacy Department, Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, Tehran, Iran.

Background: Invasive candidiasis management through the rapid initiation of appropriate antifungal therapy has been shown to be associated with the better prognosis, improved clinical outcome and reduced mortality in critically ill patients. Therefore, selection of  an appropriate antifungal therapy should be based on the distribution of candida species and the pattern of antifungal resistance. This study aimed to assess the prevalence of candidemia and associated subtypes following severe sepsis in non-neutropenic critically ill patients.

Methods: This study was a cross-sectional study that was conducted on severe sepsis patients stayed at least seven days in intensive care unit. Patients less than 18 years old, pregnant and breastfeeding patients, immunocompromised patients, neutropenic patients, patients with concurrent use of antifungal medicines and cytotoxic agents were excluded.To asses the candidemia, one mililiter of patients' blood sample was collected. Sample analysis was performed by Real-Time PCR and high resolution melting curve analysis method.

Results: Thirty-one critically ill patients were recruited in this study over 12-month period. Candidemia with a detection limit of 100 pg per 0.2 ml blood sample was not recognized in any of the included patients.

Conclusion: The present result indicates low incidence of candidemia in the targeted intensive care units, but other factors such as small sample size, exclusion of patients with compromised immune system and the low fungal load at the time of sampling may also account for our observation.
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http://dx.doi.org/10.23750/abm.v89i2.5385DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6179014PMC
June 2018

Gender Dependency in Streoselective Pharmacokinetics of Tramadol and Its Phase I Metabolites in Relation to CYP2D6 Phenotype in Iranian Population.

Iran J Pharm Res 2018 ;17(2):767-782

Biopharmaceutics and Pharmacokinetics Division, Department of Pharmaceutics, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.

The stereoselective pharmacokinetic of Tramadol (T) and its main metabolites concerning the influence of CYP2D6 phenotype and gender on the phase I metabolism of this compound was studied after administration of 100 mg single oral dose of racemic T to 24 male and female subjects. The pharmacokinetic parameters were estimated from plasma concentrations of the analytes enantiomers. The metabolic ratio of T enantiomers was used for CYP2D6 phenotype determination. The plasma concentrations of both tramadol enantiomers were considerably higher in Poor metabolizers (PM) than in extensive metabolizers (EM), resulting in 43% and 37% increase in AUC values of (+)-T and (-)-T respectively. The plasma concentrations of the (+)- and (-)-M1 enantiomers in EMs were significantly higher than the respective concentrations in PMs. The -demethylation pathway was indirectly affected by CYP2D6 phenotypic differences. The plasma concentration of both enantiomers of M2 in PMs was higher than Ems. Although the concentration profiles and most of the calculated pharmacokinetic parameters of T and its main metabolites appears to be different in EMs and PMs, only the stereoselectivity of M1 enantiomers was significantly different in relation to CYP2D6 subgroups. No significant gender-related difference in the pharmacokinetics of T and its metabolites was observed.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5985193PMC
January 2018

Correlation between plasma concentrations of tramadol and its metabolites and the incidence of seizure in tramadol-intoxicated patients.

Drug Metab Pers Ther 2018 06;33(2):75-83

Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, P.O. Box 1416753955, Tehran, Iran, Tel/Fax: +9821-6640-2569,

Background: Seizure is one of the important symptoms of tramadol poisoning, but its causes are still unknown. The aim of this study is to find a relationship between tramadol and the concentrations of its metabolites versus the incidence of seizures following the consumption of high doses of tramadol.

Methods: For this purpose, the blood samples of 120 tramadol-intoxicated patients were collected. The patients were divided in two groups (seizure and non-seizure). The concentrations of tramadol and its metabolites (M1, M2 and M5) were measured by using a high-performance liquid chromatography method. The relationship between tramadol and the levels of its metabolites and seizure incidences was also investigated.

Results: In 72% of the patients, seizures occurred in the first 3 h after the ingestion of tramadol. The seizure incidences were significantly correlated with the patients' gender, concentrations of tramadol, M1 and M2 and the history of previous seizures (p<0.001). The average concentration of M2 was significantly higher in males (p=0.003). A previous history of the use of sedative-hypnotics and the co-ingestion of benzodiazepines and other opioids were shown to significantly decrease the rate of seizure. The rate of seizure was directly related to the concentrations of tramadol and its metabolites. Higher M2 concentration in males can be considered a reason for increased incidences of seizures in males. The plasma concentration of M1 affected the onset of seizure.

Conclusions: Therefore, it can be concluded that differences in the levels of the metabolites can affect the threshold of seizure in tramadol-intoxicated patients.
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http://dx.doi.org/10.1515/dmpt-2017-0040DOI Listing
June 2018

Evaluation of Epithelial Lining Fluid Concentration of Amikacin in Critically Ill Patients With Ventilator-Associated Pneumonia.

J Intensive Care Med 2020 Apr 22;35(4):400-404. Epub 2018 Feb 22.

Department of Clinical Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.

Introduction: Classically, aminoglycosides are known to have low penetration into the lung tissue. So far, no study has been conducted on human adult patients to evaluate amikacin concentration in epithelial lining fluid (ELF) of the alveoli. Therefore, convincing data are not available from the perspective of pharmacokinetics to support the fact that a dosage of 20 mg/kg of amikacin is sufficient to treat patients with ventilator-associated pneumonia (VAP).

Method: This was a pilot study of amikacin concentration measurement in the alveolar site of action in critically ill adult patients with VAP who required aminoglycoside therapy. A dose of 20 mg/kg of amikacin was administered over a 30-minute infusion. The serum concentrations of amikacin were evaluated in the first, second, fourth, and sixth hours. However, the ELF concentration of amikacin was evaluated in the second hour with the help of bronchoalveolar lavage sampling technique.

Results: A total number of 8 patients was included in the study. The mean (SD) administered dose was 20 (0.9) mg/kg. The mean (SD) peak plasma concentration of amikacin was 59.6 (23) mg/L, with the volume of distribution of 0.36 (0.13)L/kg. The amikacin concentration in ELF was successfully measured in 7 patients (6.3) mg/L. The lung tissue penetration of the drug was described as alveolar percentage, proportional to both the first- and second-hour plasma concentrations, with a mean (SD) of 10.1% (8.4%) and 18% (16.7%), respectively.

Conclusion: To our knowledge, the current study is the first that investigates whether standard doses of amikacin may lead to sufficient alveolar concentration of the drug. The results show that administration of amikacin in doses of 20 mg/kg in critically ill patients with VAP may not provide sufficient concentrations in ELF.
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http://dx.doi.org/10.1177/0885066618754784DOI Listing
April 2020

Changes in CYP2D enzyme activity following induction of type 2 diabetes, and administration of cinnamon and metformin: an experimental animal study.

Xenobiotica 2018 Oct 2;48(10):984-989. Epub 2017 Nov 2.

a Department of Pharmaceutics , Faculty of Pharmacy, Biopharmaceutics and Pharmacokinetics Division, Tehran University of Medical Sciences , Tehran , Iran.

1. Alterations in the activity of hepatic cytochrome P-450 isoenzymes result in changes in the pharmacokinetic behavior of drugs. This study was designed to explore the impact of type II diabetes, metformin and cinnamon on the activity of CYP2D isoenzyme. 2. Streptozotocin-nicotinamide-induced diabetic and normal rats were gavaged by cinnamon and/or metformin for 14 days. Using isolated perfusion of rat livers, the metabolic activity of CYP2D in the study groups was evaluated based on the oxidative biotransformation of tramadol hydrochloride. 3. The metabolic ratios of O-desmethyltramadol, the product of CYP2D-mediated metabolism of tramadol, in normal and diabetic control rats were found to be 0.33 ± 0.12 and 0.29 ± 0.07, respectively. Cinnamon significantly reduced the mentioned ratio in both normal and diabetic rats (0.13 ± 0.05 and 0.15 ± 0.04) and metformin increased the reduced activity in diabetic rats (0.37 ± 0.09 versus 0.29 ± 0.07). 4. In conclusion, it is evident that this study has shown the significant inhibitory effect of cinnamon on CYP2D. This finding suggests that it should be taken into consideration the possible metabolism-related pharmacokinetic drug-cinnamon interactions. 5. Additionally, type 2 diabetes condition reduced the enzyme activity and metformin consumption reversed this reduction; however, the significance of the latest is not clear.
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http://dx.doi.org/10.1080/00498254.2017.1390626DOI Listing
October 2018

Evaluation of the Ecstasy influence on tramadol and its main metabolite plasma concentration in rats.

Drug Metab Pers Ther 2017 09;32(3):137-145

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Background: Tramadol is prone to be abused alone, or in combination with 3,4-methylenedioxymethamphetamine (MDMA, Ecstasy). It was reported that 95% of people with a history of substance abuse in the United States used tramadol in 2004. According to the WHO report in 2016, there was a growing number of tramadol abusers alone or in combination with psychoactive substances such as MDMA in particular in some Middle East countries. Higher concentrations of tramadol in plasma may lead to adverse drug reactions or lethal intoxication. In this study, the effect of MDMA on the pharmacokinetics of tramadol was examined in male rats.

Methods: The effect of MDMA on Tmax, Cmax, area under the curve, elimination rate, and half-life of tramadol and its metabolites was examined. Two control and two treatment groups were designed. The treatment groups received MDMA 18 h before the administration of tramadol. Jugular vein blood samples were analyzed by high-performance liquid chromatography with fluorescent detector to determine the concentrations of tramadol and its metabolites. Independent-sample t-test was used to define the differences between pharmacokinetic parameters of control and treatment groups.

Results: When tramadol administered intraperitoneally, the absorption rate of this drug was reduced, and a lower Cmax (40%) with longer Tmax (eight-fold) was achieved. MDMA exerted greater inhibitory effects on cytochrome P450 3A4 (CYP3A4) than on cytochrome P450 2D6 (CYP2D6). The M2 metabolite ratio was reduced by half, and because of the inhibition of M2 production, the M1 plasma concentration slightly increased.

Conclusions: According to the obtained data, MDMA treatment affected the absorption, distribution and metabolism phases of tramadol. This treatment increased the concentration of tramadol if administered intravenously and can latent the absorption of tramadol in oral route. However, MDMA was introduced as CYP2D6 inhibitor; in this study, MDMA inhibited CYP3A4 isoenzymes as well. This finding is important for the compounds that are metabolized through CYP3A4. It can be proposed that in abusers of MDMA who only receive tramadol for medical or nonmedical purposes in short intervals, the dangers of the intravenous administration of tramadol should be considered, and if tramadol is administered orally, the desired effect may not be achieved at the routine dose.
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http://dx.doi.org/10.1515/dmpt-2017-0018DOI Listing
September 2017

Mitochondrial impairments contribute to spatial learning and memory dysfunction induced by chronic tramadol administration in rat: Protective effect of physical exercise.

Prog Neuropsychopharmacol Biol Psychiatry 2017 10 27;79(Pt B):426-433. Epub 2017 Jul 27.

Department of Neuroscience, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran. Electronic address:

Despite the worldwide use of tramadol, few studies have been conducted about its effects on memory and mitochondrial function, and controversial results have been reported. Recently, there has been an increasing interest in physical exercise as a protective approach to neuronal and cognitive impairments. Therefore, the aim of this study was to investigate the effects of physical exercise on spatial learning and memory and brain mitochondrial function in tramadol-treated rats. After completion of 2-week (short-term) and 4-week (long-term) treadmill exercise regimens, male Wistar rats received tramadol (20, 40, 80mg/kg/day) intraperitoneally for 30days. Then spatial learning and memory was assessed by Morris water maze test (MWM). Moreover, brain mitochondrial function was evaluated by determination of mitochondrial reactive oxygen species (ROS) level, mitochondrial membrane potential (MMP), mitochondrial swelling and cytochrome c release from mitochondria. Chronic administration of tramadol impaired spatial learning and memory as well as brain mitochondrial function as indicated by increased ROS level, MMP collapse, increased mitochondrial swelling and cytochrome c release from mitochondria. Conversely, treadmill exercise significantly attenuated the impairments of spatial learning and memory and brain mitochondrial dysfunction induced by tramadol. The results revealed that chronic tramadol treatment caused memory impairments through induction of brain mitochondrial dysfunction. Furthermore, pre-exposure to physical exercise markedly mitigated these impairments through its positive effects on brain mitochondrial function.
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http://dx.doi.org/10.1016/j.pnpbp.2017.07.022DOI Listing
October 2017

Evaluation of the Effects of Local Application of Thyme Honey in Open Cutaneous Wound Healing.

Iran J Public Health 2017 Apr;46(4):545-551

Dept. of Anatomy, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.

Background: Clinicians have been searching for ways to obtain "super normal" wound healing. Honey is a traditional remedy for the treatment of infected wounds. We aimed to evaluate the wound contraction and antibacterial properties of locally produced Thyme honey on managing full-thickness wounds in vivo.

Methods: This experimental study was conducted in 2015, in Department of Pharmacology, School of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran on 54 adult male Wistar rats weighing 200-250 gr, and ages of 3-4 months. A square 1.5*1.5 wound was made on the back of the neck. The rats were divided into control and two experimental groups. Additionally, the control and experimental groups were separated into three subgroups corresponding to 4, 7, and 14 d of study. The control group did not receive any treatment. For histological studies, samples were taken from the wound and adjacent skin. This tissue was examined using histological staining (H&E). Wound surface and wound healing were evaluated. Data were analyzed by using one-way ANOVA with post hoc Tukey test and (0.05) was significant.

Results: The macroscopic and microscopic evaluations showed that the percentage of wound healing on different days in the control and experimental groups were significant (< 0.05).

Conclusion: Using honey twice a day on open wounds will accelerate the healing process.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5439045PMC
April 2017

A disposition kinetic study of Tramadol in bile duct ligated rats in perfused rat liver model.

Biomed Pharmacother 2017 Jul 28;91:251-256. Epub 2017 Apr 28.

Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, P.O. Box 13147-789, Tehran, Iran. Electronic address:

Tramadol hydrochloride is a centrally acting synthetic opioid analgesic drug and is used to treat chronic pain. In this study, the effects of Bile Duct Ligation (BDL) on the pharmacokinetics of tramadol in a liver recirculating perfusion system of male rats were used. Twenty-four Wistar male rats were randomly divided into four groups: control, sham and two weeks BDL and four weeks BDL. Serum levels of liver enzymes were measured before perfusion and the pharmacokinetics of tramadol was evaluated by using liver recirculating perfusion system. Tramadol and metabolites concentrations were determined by HPLC-FL. The sharp increase in liver enzymes level in both BDL groups was observed and significant changes were also observed in liver weight and volume. Tramadol metabolites concentration significantly decreased compared with the control and sham group (P<0.05). The decrease in the hepatic metabolism of tramadol and increase in the half-life of the elimination of tramadol in rats with BDL suggests that personalized treatment and the therapeutic drug monitoring (TDM) data examination are necessary for patients with bile duct diseases and the dose of tramadol should be accordingly adjusted.
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http://dx.doi.org/10.1016/j.biopha.2017.04.082DOI Listing
July 2017

Scale up and pharmacokinetic study of a novel mutated chimeric tissue plasminogen activator (mt-PA) in rats.

Sci Rep 2017 02 22;7:43028. Epub 2017 Feb 22.

Biotechnology Research Center, Pasteur Institute of Iran, Pasteur Avenue, Tehran, Iran.

Because of high mortality caused by cardiovascular diseases, various fibrinolytic agents with diverse pharmacokinetic and pharmacodynamic properties have been developed. A novel mutated chimeric tissue plasminogen activator (mt-PA) was developed by the removal of first three domains of t-PA, insertion of GHRP sequence and mutation towards resistance to plasminogen activator inhibitor-1 (PAI-1). Mt-PA protein was expressed in Expi293F cells. The expression level of mt-PA was found to be 5000 IU/mL. Following purification, the pharmacokinetic properties of mt-PA were evaluated in three doses in rats. Data related to mt-PA were best fitted to two compartment model. With the increase in dose, the Area Under the plasma concentration-time Curve (AUC) increased. The elimination half-life (t) of mt-PA was in the range of 19.1-26.1 min in three doses while that of Alteplase was 8.3 min. The plasma clearance (CLp) of mt-PA ranged from 3.8 to 5.9 mL/min in three doses, which was several times lower than that of Alteplase (142.6 mL/min). The mean residence time (MRT) of mt-PA ranged from 23.3-31.8 min in three doses, which was 4-5 times greater than that of Alteplase (6 min). Mt-PA showed extended half-life and mean residence time and is a good candidate for further clinical studies.
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http://dx.doi.org/10.1038/srep43028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5320447PMC
February 2017

Effect of CYP2D6 polymorphisms on the pharmacokinetics of propafenone and its two main metabolites.

Therapie 2017 Jun 19;72(3):373-382. Epub 2016 Dec 19.

Biopharmaceutics and pharmacokinetics division, department of pharmaceutics, faculty of pharmacy, Tehran university of medical sciences, P.O. Box 14155-6451, Tehran, Iran; Department of pharmaceutics, pharmaceutical sciences branch, Islamic Azad university (IAUPS), Tehran 193956466, Iran. Electronic address:

Aim Of The Study: Propafenone (PPF) is an antiarrhythmic drug, metabolized mainly by CYP2D6 to 5-hydroxypropafenone (5OH-PPF) and by CYP3A4 to norpropafenone (NOR-PPF). CYP2D6 shows a high degree of genetic polymorphism which is associated with diminished antiarrhythmic efficacy or cardiac seizures/cardiotoxicity. This study aimed to investigate the effect of the CYP2D6 polymorphism on the pharmacokinetics of PPF and its two main metabolites. The usefulness of PPF/5OH-PPF ratio for CYP2D6 phenotyping in healthy adults was also evaluated.

Methods: Twelve healthy volunteers, 3 poor metabolizers (PM), 2 intermediate metabolizers (IM) and seven extensive metabolizers (EM) received an oral dose of PPF. Concentrations of PPF and its metabolites were analyzed in serum samples over 27h.

Results: The PPF/5OH-PPF ratio distinguished EMs from PMs, but not from IMs. In PMs, the mean transit time (MTT) values were almost the same for PPF and NOR-PPF and much higher than those of EMs and IMs. 5OH-PPF was not detected in EMs. Mean MTT values of 5OH-PPF and NOR-PPF in IMs were 5.27- and 1.52-fold higher than those of EMs.

Conclusion: A single time point serum PPF-MR approach is a useful tool to identify PMs. CYP2D6 polymorphism significantly affects the pharmacokinetics of PPF and its two metabolites.
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http://dx.doi.org/10.1016/j.therap.2016.10.005DOI Listing
June 2017

Protective effects of physical exercise on MDMA-induced cognitive and mitochondrial impairment.

Free Radic Biol Med 2016 10 21;99:11-19. Epub 2016 Jul 21.

Department of Neuroscience, School of Advanced Science and Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran. Electronic address:

Debate continues about the effect of 3, 4-methylenedioxymethamphetamine (MDMA) on cognitive and mitochondrial function through the CNS. It has been shown that physical exercise has an important protective effect on cellular damage and death. Therefore, we investigated the effect of physical exercise on MDMA-induced impairments of spatial learning and memory as well as MDMA effects on brain mitochondrial function in rats. Male wistar rats underwent short-term (2 weeks) or long-term (4 weeks) treadmill exercise. After completion of exercise duration, acquisition and retention of spatial memory were evaluated by Morris water maze (MWM) test. Rats were intraperitoneally (I.P) injected with MDMA (5, 10, and 15mg/kg) 30min before the first training trial in 4 training days of MWM. Different parameters of brain mitochondrial function were measured including the level of ROS production, mitochondrial membrane potential (MMP), mitochondrial swelling, mitochondrial outermembrane damage, the amount of cytochrome c release from the mitochondria, and ADP/ATP ratio. MDMA damaged the spatial learning and memory in a dose-dependent manner. Brain mitochondria isolated from the rats treated with MDMA showed significant increase in ROS formation, collapse of MMP, mitochondrial swelling, and outer membrane damage, cytochrome c release from the mitochondria, and finally increased ADP/ATP ratio. This study also found that physical exercise significantly decreased the MDMA-induced impairments of spatial learning and memory and also mitochondrial dysfunction. The results indicated that MDMA-induced neurotoxicity leads to brain mitochondrial dysfunction and subsequent oxidative stress is followed by cognitive impairments. However, physical exercise could reduce these deleterious effects of MDMA through protective effects on brain mitochondrial function.
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http://dx.doi.org/10.1016/j.freeradbiomed.2016.07.018DOI Listing
October 2016

Transforming growth factor-β (TGF-β) activation in cutaneous wounds after topical application of aloe vera gel.

Can J Physiol Pharmacol 2016 Dec 14;94(12):1285-1290. Epub 2016 Jul 14.

a School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.

Aloe vera is a medicinal plant used to treat various skin diseases. The effects of using aloe vera gel on the healing process were investigated by microscopic methods, cell counting, and TGF-β gene expression in the wound bed. Sixty Wistar rats weighing 200-250 g were placed under anesthesia in sterile conditions. A square 1.5 cm × 1.5 cm wound was made on the back of the neck. The rats were divided into control and 2 experimental groups. Additionally, the control and experimental groups were separated into 3 subgroups corresponding to 4, 7, and 14 days of study. In the first experimental group, aloe vera was used twice on the wound. The second experimental group received aloe vera overtreatment once on the wound. The positive control group received daily application of 1% phenytoein cream following surgical wound creation. The control group did not receive any treatment. This tissue was examined using histological staining (H&E) and Masson's Trichrome. Wound surface and wound healing were evaluated separately. TGF-β gene expression was analyzed by RT-PCR. Results showed that fibroblasts in both experimental groups were significantly increased, thereby acceleration wound healing. Application of aloe vera gel will increase TGF-β gene expression, ultimately accelerating the wound healing process.
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http://dx.doi.org/10.1139/cjpp-2015-0460DOI Listing
December 2016

Synergistic Effect of Honey and Propolis on Cutaneous Wound Healing in Rats.

Acta Med Iran 2016 Apr;54(4):233-9

Medicinal Plants Research Center, School of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.

Accelerating wound healing is now considered as a principle clinical treatment and increasing the quality and speed of healing which has always been emphasized by the scientists. Propolis and honey are natural bee products with wide range of biological and medicinal properties. This study was aimed to determine the synergistic effect of honey and propolis in wound healing of rat skin. A total of 75 Wistar rats weighing 200-250 gr were placed under general anesthesia and sterile conditions. Then a square shape wound with 1.5*1.5 mm dimension was made on the back of the neck. Animals were randomly divided into control, honey, propolis, combined honey propolis and phenytoin 1% groups, respectively. Rats were randomly divided into the following groups: 4th, 7th and, 14th days of treatment in each period of study. Wound area in the experimental group was covered once daily with a fixed amount of thyme honey, propolis, propolis and honey and phenytoin cream (1%), the control group did not receive any treatment. For histological studies, during the fourth, seventh and fourteenth day's rats were sacrificed and samples were taken from the wound and adjacent skin. After histological staining fibroblast, neutrophils, macrophages and vascular sections were counted in the wound bed. The macroscopic and microscopic evaluations showed that the percentage of wound healing on different days in the experimental and control groups were significant (P<0.05). The macroscopic and microscopic evaluation showed that the percentage of wound healing on different days in combined propolis and honey experimental group was significantly different from the control group (Multivariate ANOVA test) (P<0.05). Combined application of propolis and honey on the open wound healing in rats has a synergistic effect.
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April 2016

The effect of excipients on the stability and aerosol performance of salmon calcitonin dry powder inhalers prepared via the spray freeze drying process.

Acta Pharm 2016 Jun;66(2):207-18

Spray freeze drying was developed to produce dry powders suitable for applications such as inhalation delivery. In the current study, the spray freeze drying technique was employed to produce inhalable salmon calcitonin microparticles. Effects of the carrier type, concentration of hydroxyl propyl-β-cyclodextrin and the presence of Tween 80 on the chemical and structural stability, as well as on the aerosol performance of the particles were investigated. The results indicated that hydroxyl propyl-β-cyclodextrin had the most important effect on the chemical stability of the powder and strongly increased its stability by increasing its concentration in the formulation. Chemically stable formulations (over 90 % recovery) were selected for further examinations. Fluorescence spectroscopy and circular dichroism suggested that the formulations were structurally stable. Aerosol performance showed that the Tween-free powders produced higher fine particle fraction values than the formulations containing Tween (53.7 vs. 41.92 % for trehalose content and 52.85 vs. 43.06 % for maltose content).
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http://dx.doi.org/10.1515/acph-2016-0012DOI Listing
June 2016

Achievement of Vancomycin Therapeutic Goals in Critically Ill Patients: Early Individualization May Be Beneficial.

Crit Care Res Pract 2016 17;2016:1245815. Epub 2016 Mar 17.

Clinical Pharmacy Department, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran 14155/6451, Iran; Research Center for Rational Use of Drugs, Tehran University of Medical Sciences, Tehran 14155/6451, Iran.

Objective. The aim of our study was to assess and validate the effectiveness of early dose adjustment of vancomycin based on first dose monitoring in achieving target recommended goal in critically ill patients. Methods. Twenty critically ill patients with sepsis received loading dose of 25 mg/kg of vancomycin and then were randomly assigned to 2 groups. Group 1 received maximum empirical doses of vancomycin of 15 mg/kg every 8 hrs. In group 2, the doses were individualized based on serum concentrations of vancomycin. First dose nonsteady state sampling was used to calculate pharmacokinetic parameters of the patients within 24 hours. Results. Steady state trough serum concentrations were significantly higher in group 2 in comparison with group 1 (19.4 ± 4.4 mg/L versus 14.4 ± 4.3 mg/L) (P = 0.03). Steady state AUCs were significantly higher in group 2 compared with group 1 (665.9 ± 136.5 mg·hr/L versus 490.7 ± 101.1 mg·hr/L) (P = 0.008). Conclusions. With early individualized dosing regimen, significantly more patients achieved peak and trough steady state concentrations. In the context of pharmacokinetic/pharmacodynamic goal of area under the time concentration curve to minimum inhibitory concentration (AUC/MIC) ≥400 and also to obtain trough serum concentration of vancomycin of ≥15 mg/L, it is necessary to individualize doses of vancomycin in critically ill patients.
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http://dx.doi.org/10.1155/2016/1245815DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4814628PMC
April 2016

Genotype and allele frequency of CYP2C19*17 in a healthy Iranian population.

Med J Islam Repub Iran 2015 3;29:269. Epub 2015 Oct 3.

Professor, Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tehran University of Medical sciences, Tehran, Iran.

Background: Cytochrome P450 2C19 (CYP2C19) is important in metabolism of wide range of drugs. CYP2C19*17 is a novel variant allele which increases gene transcription and therefore results in ultra-rapid metabolizer phenotype (URM). Distribution of this variant allele has not been well studied worldwide. The aim of present study was to investigate allele and genotype frequencies of CYP2C19*17 in a healthy Iranian population and compare them with other ethnic groups.

Methods: One hundred eighty healthy unrelated Iranian volunteer took part in this study and were genotyped for CYP2C19 *2, *3, *17 (-3402) by using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and CYP2C19*17 (-806) by a nested-PCR assays. The distribution of CYP2C19*17 polymorphism in Iranian population was then compared with other ethnic groups.

Results: The CYP2C19*17 allele frequency was 21.6% in Iranian population. Among studied subjects 5.5% were homozygous for CYP2C19*17 and phenotyped as ultra-rapid metabolizers; 28.8% were genotyped as CYP2C19*1*17 (extensive metabolizers) and 3.3% as CYP2C19*2*17 (intermediate metabolizers).

Conclusion: The CYP2C19*17 genetic distribution in Iranian population is similar to Middle East or European countries. The high frequency of CYP2C19*17 in Iranian population highlights the importance of this new variant allele in metabolism of CYP2C19 substrates. Thus, future association studies are required to reveal clinical consequence of this genetic polymorphism in carrier individuals.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4715407PMC
January 2016

Systemic delivery of parathyroid hormone (1-34) using spray freeze-dried inhalable particles.

Pharm Dev Technol 2017 Sep 27;22(6):733-739. Epub 2015 Dec 27.

a Department of Pharmaceutics , Faculty of Pharmacy, Tehran University of Medical Sciences , Tehran , Iran.

Pulmonary delivery of peptides remains an important, noninvasive route of administration that is attractive because it offers high bioavailability and patient compliance. Optimization of particle characteristics for deposition in the deep regions of the lung after inhalation and retention of peptide stability are key challenges to their delivery to the lungs. The present study investigated the use of spray freeze-drying to produce porous inhalable parathyroid hormone (1-34)-loaded microparticles suitable for pulmonary delivery. The influence of different excipients in the medium of water or citrate buffer on microparticles characteristics, peptide stability and its systemic delivery in rats were evaluated. Using leucine at 10% (w/w) and hydroxy propyl-β-cyclodextrin (HPβCD) at 0.04% (w/w) in water or citrate medium preserved parathyroid hormone (1-34) stability by spray freeze-drying. Aerosol performance showed that leucine was more effective than HPβCD in producing inhalable microparticles. Nevertheless, there was no statistical difference between bioavailabilities of HPβCD containing formulations and leucine-containing formulations in the presence of citrate buffer; and even in the presence of water, HPβCD resulted in higher bioavailability compared to leucine. The high absolute bioavailability (up to 47.25%) of formulations could facilitate replacement of injected form of parathyroid hormone (1-34) by dry powder inhaler form.
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http://dx.doi.org/10.3109/10837450.2015.1125924DOI Listing
September 2017
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