mohammadreza rouini

Sofosbuvir (SOF) is a revolutionary treatment for patients with hepatitis C virus (HCV). However, its efficacy and safety among patients with end-stage renal disease (ESRD) remains controversial. In this study, we examined the levels of SOF metabolite (GS-331007) (SOF-007) in human plasma of patients infected with HCV having ESRD using an optimized liquid chromatography-mass spectrometry (LC-MS) analytical method.

In this case-control study, 10 clinically confirmed cases and five controls were enrolled. SOF-007 was extracted from plasma using methanol precipitation. The limit of detection (LOD) for the drug and its metabolite were 0.85 and 2.3, respectively. Such a wide range of quantification in a period of separation time shorter than 3.0 minutes (run time) allowed monitoring of the plasma concentration of analytes up to 4 hours (pre-dialysis and post-dialysis) for 12 weeks in non-cirrhotic patients with HCV infection undergoing dialysis.

SOF-007 in the plasma of HCV patients with healthy kidneys showed no cumulative effect. An analysis comparing patients with ESRD and healthy participants showed that their behaviour was similar, followed by dialysis with a relatively small cumulative effect.

The plasma concentrations of SOF-007 decreased significantly after the 4-hour period of dialysis compared with the plasma concentrations hemodialysis of pre-dialysis in HCV patients with ESRD.

 Administering Cinacalcet HCl (CINA) can be challenging because of its low oral bioavailability (20 to 25%) due mainly to its high first-pass metabolism and poor aqueous solubility. However, nanosuspensions are an effective way of enhancing solubility by reducing size. Furthermore, pulmonary delivery of the drug as a promising alternative route can bypass the hepatic first-pass metabolism.

 A CINA nanosuspension was produced by sonoprecipitation and optimized to achieve minimum particle size and polydispersity index (PDI). These nanosuspensions were then spray-dried with different types of sugars to form nano-in-micro composite particles. The particles were then analyzed by scanning electron microscopy (SEM), X-ray diffraction (XRD), Fourier transform infrared (FTIR), and differential scanning calorimetry (DSC), and the dissolution rate, solubility, and in vitro aerosol deposition behavior were determined.

 The particle size of nanosuspensions was in the range of 239.5 to 1281.8 nm and the size was dependent on the process parameters. The spray-dried microparticles had a smooth and spherical surface morphology. The particle size of the composite particles was in the range of 2 to 10 µm and the dissolution rate of processed powders was significantly higher than raw CINA powder. Its crystallinity was partially diminished and no polymorphic conversion were observed. The in vitro deposition study, using a twin-stage impinger (TSI), presented fine particle fractions up to 76.7 percent.

 The utilization of nano-in-micro composite particles as a pulmonary delivery system for CINA has shown great potential in enabling a more efficient drug delivery.

 In this study, we prepared inhalable buserelin microparticles using the spray freeze-drying (SFD) method for pulmonary drug delivery. Raffinose as a cryoprotectant carrier was combined with two levels of five different cyclodextrins (CDs) and then processed by SFD.

 Dry powder diameters were evaluated by laser light scattering and morphology was determined by scanning electron microscopy (SEM). Differential scanning calorimetry (DSC) and X-ray diffraction (XRD) analysis were utilized for the determination of crystalline structures. The aerodynamic properties of the spray freeze-dried powders were evaluated by twin stage impinger (TSI) and the stability of prepared samples was assessed under normal and accelerated conditions.

 The prepared powders were mostly porous spheres and the size of microparticles ranged from 9.08 to 13.53 μm, which are suitable as spray-freeze dried particles. All formulations showed amorphous structure confirmed by DSC and XRD. The aerosolization performance of the formulation containing buserelin, raffinose and 5% beta-cyclodextrin (β-CD), was the highest and its fine particle fraction (FPF) was 69.38%. The more circular and separated structures were observed in higher concentrations of CDs, which were compatible with FPFs. The highest stability was obtained in the formulation containing hydroxypropyl beta-cyclodextrin (HP-β-16. CD) 5%. On the contrary, sulfobutylether beta-cyclodextrin (SBE-β-CD) 5% bearing particles showed the least stability.

 By adjusting the type and ratio of CDs in the presence of raffinose, the prepared formulations could effectively enhance the aerosolization and stability of buserelin. Therefore, they can be proposed as a suitable career for lung drug delivery.

Phenobarbital is still one of the drugs of choice in managing patients with brain injury in the intensive care unit (ICU). However, the impact of acute physiological changes on phenobarbital pharmacokinetic parameters is not well studied. This study aimed to evaluate the pharmacokinetic parameters of parenteral phenobarbital in critically ill patients with brain injury. Patients with severe traumatic or non-traumatic brain injury at high risk of seizure were included and followed for seven days. All patients initially received phenobarbital as a loading dose of 15 mg/kg over 30-minutes infusion, followed by 2 mg/kg/day divided into three doses. Blood samples were obtained on the first and fourth day of study at 1, 2, 5, 8, and 10 hours after the end of the infusion. Serum concentrations of phenobarbital were measured by high-pressure liquid chromatography (HPLC) with an ultraviolet (UV) detector. Pharmacokinetic parameters, including the volume of distribution (Vd), half-life (t1/2), and the drug clearance (CL), were provided by MonolixSuite 2019R1 software using stochastic approximation expectation-maximization (SAEM) algorithm and compared with previously reported parameters in healthy volunteers. Data from seventeen patients were analyzed. The mean value±standard deviation of pharmacokinetic parameters was calculated as follows: Vd: 0.81±0.15 L/kg; t1/2: 6.16±2.66 days; CL: 4.23±1.51 ml/kg/h. CL and Vd were significantly lower and higher than the normal population with the value of 5.6 ml/kg/h (P=0.002) and 0.7 L/kg (P=0.01), respectively. Pharmacokinetic behavior of phenobarbital may change significantly in critically ill brain-injured patients. This study affirms the value of early phenobarbital therapeutic drug monitoring (TDM) to achieve therapeutic goals.

Despite the widespread use of clopidogrel as a prodrug in a wide range of patients, the researchers found that the drug couldn't have sufficient antiplatelet effects at a usual dose in three to forty percent of patients. So on, measuring clopidogrel active metabolite concentration is seems necessary to evaluate the effects of this drug in each patient.

Due to the importance of determining clopidogrel active metabolite plasma level, in this article, we reviewed and compared all the analysis methods for that which could affects on correct pharmacokinetic evaluation of clopidogrel and thus play an important role in prescribing the appropriate dose of that in each individual therapy. Despite numerous reports of the clopidogrel analysis method, only thirteen studies have been published to analyzing the concentration of clopidogrel active metabolite in a biological matrices. As a result of the very low concentration and short half-life of the clopidogrel active metabolite in the biological matrice, the method used for determining itʹs concentration profile should be able to measure values in picogram per millilitre scale.

According to the complete summary of the analyzing methods, employing advanced device analysis systems such as UHPLC lead to much more accurate separation and quantification of analytes. Also, employing the MS / MS detector adding the possibility of measuring the clopidogrel plasma level in the same matrices.

MDMA (methylenedioxymethamphetamine) is a synthetic compound, which is a structurally derivative of amphetamine. Also, it acts like an amphetamine, structurally, and functionally. MDMA uses mechanism-based inhibition, to inhibit isoenzyme CYP2D6. It can also inhibit other isoenzymes contributing to its metabolism, including CYP3A4 which is the most important member of the cytochrome P450 superfamily. Since more than 50% of drugs are metabolized by CYP3A4, its inhibition may cause harmful and even lethal drug interactions. Tramadol, as an opioid-like analgesic, is mainly metabolized into O-desmethyl tramadol (M1), by CYP2D6 and undergoes N-demethylation to M2, by CYP2B6 and CYP3A4. Due to the significant potential of abusing tramadol, either alone or in combination with MDMA, the rate of its toxicity and side effects may increase following possible MDMA relevant enzyme inhibition.

Different doses of MDMA (1-10 mg/Kg) were intraperitoneally administered to Wistar male rats of both control and treatment groups. Then, after one hour, their isolated livers were perfused by perfusion buffer containing tramadol (1 µg/mL). Afterward, perfusate samples were collected. They were analyzed by HPLC to determine the concentrations of tramadol and its metabolites.

MDMA administration in treatment groups reduced M1 production. On the other hand, by following the treatment with different MDMA doses, the M2 metabolic ratio increased by 46 to 101%.

it seems that the regular doses of MDMA cannot inhibit the CYP3A4 activity.

The present study assessed the effects of cinnamon on the activity of the liver CYP2D1 enzyme and hepatic clearance in the rat model of type 1 and 2 diabetes mellitus.

Male Wistar rats were randomly categorized into 8 groups. Fourteen days after induction of diabetes type 1 and 2, type 1 groups received cinnamon and insulin plus cinnamon and type 2 groups received cinnamon and metformin plus cinnamon daily for 14 days. On day 28, rats were subjected to liver perfusion by buffer containing dextromethorphan as the CYP2D1 enzyme activity probe. Perfused samples were analyzed by high-performance liquid chromatography (HPLC) with fluorescence (FL) detection to evaluate the CYP2D1 activity and hepatic clearance.

In the control group, enzyme activity and hepatic clearance changed from 0.0081 ± 0.00009 and 6.09 ± 0.2 mL/min to 0.0059 ± 0.0001 and 3.71 ± 0.07 mL/min in the untreated type 1 diabetic rats and to 0.0006 ± 0.0001 and 5.19 ± 0.02 mL/min in untreated type 2 ones. These pharmacokinetic (PK) parameters changed to 0.0069 ± 0.0005 and 6.27 ± 0.06 mL/min in treated type 1 and 0.0115 ± 0.0003 and 5.79 ± 0.11 mL/min in the treated type 2 rats with only cinnamon administration. Treatment with cinnamon plus insulin or metformin modulated these PK parameters to 0.0039 ± 0.00006 and 4.88 ± 0.13 mL/min in type 1 and 0.0092 ± 0.0005 and 6.13 ± 0.01 mL/min in type 2 diabetic rats.

Cinnamon can act as an effective complementary medicine in order to normalize the metabolism and clearance processes in diabetes mellitus.

Methadone is used for the pain management worldwide. Its special characteristics make it a potential alternative for pain management in critically ill and geriatric patients. Due to lack of studies in this population, we aimed to compare the pharmacokinetic behavior of Methadone following intramuscular and intravenous administration in geriatric Intensive Care Unit (ICU) patients and with previously reports in healthy volunteers.

According to the limitations in ICU setting, we could include 11 patients over 65 years old, who required opioid for pain relief in this study. Patients were randomized to receive 5 mg of Methadone IM or IV injection every 8 hours for 6 days. The Methadone plasma level detected with LC-mass tandem mass spectrometry, and pharmacokinetics parameters were evaluated for each subject in both 1st and 6th days of treatment.

Based on our results, bioavailability of intramuscular Methadone in geriatric ICU patients was low and less than 40% of the dose was absorbed within first 12 hours. The volume of distribution of Methadone in the first day was significantly lower than the previously reported values in healthy subjects and significantly increased during these 6 days. The Methadone half-life in this population also significantly increased through this period.

Pharmacokinetic behavior of Methadone in geriatric ICU patients is unpredictable. Reduced volume of distribution and half-life may be observed initially, following with an increase to the normal range. It seems that IM administration of Methadone in geriatric critically ill patients may not provide target analgesic Methadone serum levels.

This study aimed at investigating the effects of 3,4-Methyl​enedioxy​methamphetamine (MDMA) on liver cytochrome 2C19 enzyme activity, which is a major liver enzyme in the metabolism of a wide range of drugs, using omeprazole as a probe of the CYP2C19 activity in isolated perfused rat liver.

This experimental study was done in 20 male Sprague–Dawley (SD) rats (weighing 250–300 g). After isolating the animal liver, omeprazole was administered at 400 μm and the concentration of omeprazole and its metabolite were determined. The liver was then washed with perfusion buffer, and MDMA was transferred at 300 ng/ml unilaterally from the same liver for 30 minutes. After re-washing the liver with perfusion buffer, omeprazole was passed through the liver for second time and the metabolic ratio was determined after exposure to MDMA. This process was also done in a group of animals at 600 ng/ml of MDMA.

Analysis of data from three end-time intervals after exposure to liver at 300 and 600 ng/ml of MDMA, showed 26.6% and 20.6% reduction in the activity of CYP2C19. Findings showed that MDMA administration could significantly reduce the activity of CYP2C19.

According to this study, liver exposure to MDMA can significantly reduce cytochrome 2C19 activity, but, further studies are needed to examine this issue more closely.

Intracranial hemorrhage (ICH) is a devastating condition with a high mortality and morbidity rate. Neuroprotective agents protect surrounding brain tissue from the toxic effects of hematoma and can result in better outcomes. There is evidence demonstrating the neuroprotective benefits of melatonin in experimental animal models of ICH. Reduced melatonin levels have been reported in the intensive care unit (ICU) patients. The aim of this study was to evaluate baseline melatonin levels and pharmacokinetic profile of melatonin in ICH patients.

This was a randomized clinical trial in which 24 patients with non-traumatic ICH were divided into melatonin and control groups. Subjects in the melatonin group received 30 mg of melatonin for 5 days. Another group of 12 healthy volunteers also were recruited for the study. Baseline serum melatonin levels were measured for all groups. For the pharmacokinetic study, sampling intervals were 0.25, 0.5, 0.75, 1.5, 3, 6 and 10 hours after melatonin administration. Samples were analyzed using an HPLC system with fluorescence detection.

Serum melatonin concentrations found to be decreased in all patients. Patients showed a significant increase in levels by the third day but still lower than healthy volunteers. By day 5, the melatonin group reache melatonin levels, statistically similar to healthy volunteers, but the control group didn’t reach normal levels even on the seventh day of study.

Our study suggests that monitoring melatonin levels and supplementing with exogenous melatonin can correct the reduced levels. Further studies focused on melatonin administration in ICH patients can be helpful in evaluating clinical outcomes in these patients

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. 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. 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). 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.

 It is suggested that surgery results in changes in kinetic profile of some medication. The aim of this study was to investigate possible alterations in pethidine’s half-life in postoperative pain management following orthopedic surgery of the inferior limb.

Twelve patients who were classified as class I patients according to the American society of anesthesiologists physical status classification were enrolled. Following the surgery of the lower limb, 25 mg of pethidine was injected intravenously. After that, 5, 30, 60 and 180 minutes following the injection, blood samples were taken and concentration of pethidine in blood samples were measured by High Performance Liquid Chromatography method. Moreover, patients’ pain levels were assessed on visual analogue scales.

The average half-life of pethidine was measured to be 29.68 minutes. Thirty minutes after the injection, significant relationship between plasma levels of pethidine and pain scale was reported (p= 0.041, r= 0.595). Moreover, men were found to perceive more pain than women. Pain scale was considerably different between smokers and non-smokers (p= 0.006), although blood concentration of pethidine was not significantly different between these two groups (p=0.09).

Orthopedic surgery most probably results in alterations in pharmacokinetic profile of pethidine. Moreover, gender and smoking status of the patients influence pain perception. Thus, pharmacokinetic alterations due to inferior limb orthopedic surgery, gender-related factors and smoking status of the patients should be considered in pain management in clinical settings.

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, P = 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, P = 0.029). There was no significant correlation between amikacin clearance and creatinine clearance estimated by Cockcroft-Gault formula in all patients (P = 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, P = 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.

Phenytoin is an antiepileptic drug used widely for prophylaxis and treatment of seizure after neurotrauma. Phenytoin has a complex pharmacokinetics and monitoring of its serum concentrations is recommended during treatment. Total phenytoin concentration is routinely measured for monitoring of therapy. In this study, we evaluated the correlation between phenytoin total and free concentrations in neurotrauma critically-ill patients to determine whether the phenytoin total concentration is a reliable predictor of free drug, which is responsible for the therapeutic effects.

A total of 40 adult head trauma patients evaluated for free (unbound) and total serum phenytoin concentrations. Patients were divided into two groups. GroupA consists of 20 unconscious patients with severe head injury under mechanical ventilation and Group B consists of 20 conscious self-ventilated patients. Correlation and agreement between total and free phenytoin plasma concentrations were analyzed.

Pearson correlation analysis and Bland-Altman test showed weak to moderate correlation (r = 0.528) and poor agreement between free and total phenytoin concentrations in patients with severe trauma and higher Acute Physiology And Chronic Health Evaluation II (APACHE II) scores (GroupA) and good correlation (r = 0.817) and moderate agreement in patients with mild to moderate trauma and lower APACHE II scores (Group B).

Our results indicated that total phenytoin serum concentration is not a reliable therapeutic goal for drug monitoring in severely-ill head trauma patients even in the absence of hypoalbuminemia, renal and hepatic failure. It seems justifiable to measure free phenytoin concentration in all severely ill neurotrauma patients.

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 ratioof 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 N-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.

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.
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 (P The macroscopic and microscopic evaluations showed that the percentage of wound healing on different days in the control and experimental groups were significant (P Using honey twice a day on open wounds will accelerate the healing process.

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

Imatinib is an orally administered tyrosine kinase inhibitor which inhibits the Bcr-Abl protein-tyrosine kinase with high selectivity. Imatinib is rapidly absorbed from the gut, after oral intake and has an almost absolute bioavailability of 98%. The metabolism of imatinib is mediated by the cytochrome P450 (CYP) isoenzymes in the liver and gut wall. CGP74588 is a major active metabolite of imatinib. The study was performed on Male Sprague-Dawley rats (250-300 g) housing under artificial light on a 12-h light/dark cycle with free access to standard laboratory chow and water. Re-circulating (at imatinib concentration of 1 and 5 µg/ml) and single-pass (imatinib dose of 1mg) perfusion modes in the presence and absence of BSA were tested. Throughout the experiment, perfusate temperature (37±0.5 C°), pH (7.4±0.2) and liver viability (ALT and AST) were monitored. The concentrations of imatinib and its main metabolite in perfusion buffer and liver homogenate were determined by a validated HPLC method. No metabolite was detected in outlet perfusate in all conditions. However negligible amounts of metabolite were found in liver homogenate at 1 and 5 µg/ml imatinib concentrations in re-circulating perfusion mode. The rapid and remarkable disappearance of imatinib from perfusate was related to its accumulation in liver. Statistical moment definition was used to calculate some pharmacokinetic parameters. These calculations also confirmed liver accumulation and slow and sustained dissociation of imatinib from liver.

One of the most important issues in medical sciences is wound healing and repair. Application of natural ingredients and herbs for treating ulcers has been in the history of human life. Nowadays, due to the lack of side effects of medicinal plants and a variety of effective compounds in plants, as well as numerous disadvantages of synthetic drugs there has been tendency to use medicinal plants in clinic. Aloe vera is an herbal drug used for treatment of dermal diseases. In this study we evaluated, effects of aloe vera on the wound healing through the microscopic techniques and cell counting.

In this experimental study, sixty Wistar rats weighing 200-250 g 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. Rats were randomly divided to control and experimental group’s. Each group was divided to three subgroups with 4, 7, and 14 study days. In 1st experimental group aloe vera was used twice on the wound surface and in 2nd experimental group was used once daily and the positive control group were applied phenytoin cream 1% from the zero days of surgery. The control group did not get any treatment on the wound surface. For histological studies, during the fourth, seventh and fourteenth day’s rats were sacrificed and samples were taken from the wound area and adjacent skin. After histological staining with hematoxylin and eosin (H&E) and Masson's trichrome stains, the cells were counted, wound surface and wound healing were investigated.

The macroscopic and microscopic evaluation showed that wound healing increased because the fibroblast numbers in two experimental groups improved compared with control group. The percentage of wound healing on different days in the experimental and control groups were significant. Data were analyzed by using one-way ANOVA test and P< 0.05 was significant.

Present study showed that the twice application of topical aloe vera mucilage can result in rapid wound healing in rats.

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. 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. 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). 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.

There are wide individual differences in pharmacokinetic parameters of mycophenolate mofetil (MMF) among transplanted patients. Some studies have shown that single nucleotide polymorphisms (SNPs) of the Uridine Diphosphate Glucuronosyl Transferase1A9 (UGT1A9) are responsible for these differences in early days after transplantation. Therefore it was decided to evaluate the influence of UGT polymorphism on MMF pharmacokinetics among stable Iranian transplant patients. This was a cross sectional study from March 2008 through December 2008 in Imam Khomeini Hospital affiliated to the Tehran University of Medical Sciences in Iran. Blood samples were taken from 40 de novo stable Iranian renal transplant patients taking 2 g MMF daily with SrCr£1.4 mg/dL with at least 3 months history of transplantation. Appropriate PCR and HPLC methods were used for the determination of SNPs and their impact on MPA pharmacokinetics. T-275A polymorphism occurred in 15% of patients, UGT1A9*3 occurred in 2.5% of patients. Carriers of T-275A polymorphism had significant lower MPA AUC 0-12 in comparison with non-carriers or wild type (73.3±17.8 mg/h/mL vs. 110.8±31.1 mg/h/mL, p = 0.006). There was no significant difference in AUC 6-12 between the two groups although carriers of T-275A SNP had lower MPA AUC 6-12 (22.4±4.5 mg/h/mL vs. 26.8±10.2 mg/h/mL, p=0.24). Cmax was lower in the carriers of (20.2±9.0 mg/mL vs. 37.2±12.5 mg/mL, p=0.004). There was no significant difference in C0 between two groups. (3.0±1.2 mg/mL vs. 3.9±1.6 mg/mL, p=0.1). This study in Iranian stable transplanted patients shows that carriers of T-275A polymorphism had significantly lower MPA exposure compared to non-carriers.

There is no randomized study carried out in order to compare their pharmacokinetic parameters although midazolam, as a sedative, has been widely administered via continuous infusion as well as intermittent bolus doses in mechanically ventilated critically ill patients. We prospectively investigated the effect of these two principal methods on pharmacokinetic parameters in 23 of mentioned patients (16 males, 7 females) with the mean (± SD) age of 41.22 ± 17.5. All patients received total dose of 72 mg throughout the test days, 9 of whom received 1 mg/h (continuous infusion) and the rest obtained 4 mg / 4 h (intermittent bolus doses). Blood samples were collected at 8 and 4 h prior to the end time of drug administration (zero time), zero time and 4, 8, 12, 20 and 30 h after it. APACHE (Acute Physiology and Chronic Health Evaluation) II required data was recorded daily and the patients’ mean score was 16.26 ± 4.38. The mean (± SD) value of pharmacokinetic parameters of Midazolam in continuous infusion and intermittent bolus doses methods were as follows: (t½ = 17.88 ± 14.65 h, Cl = 21.80 ± 14.95 L/h) vs. (t½ = 19.74 ± 12.45 h, Cl = 29.43 ± 19.45 L/h). Volume of distribution (Vd) was measured in continuous infusion group which was 612.58 ± 582.93 L. The calculated clearance and half-life were found not to be significantly different (p < 0.05). The patients might be exposed to similar undesired effects due to the large volumes of distribution following the administration methods studied.

The purpose of this study was to characterize the pharmacokinetic parameters of mycophenolic acid (MPA) in Iranian kidney transplant patients. Plasma MPA concentration of mycophenolate mofetile (MMF) 1 gram two times a day was measured in 21 Iranian kidney transplant recipients receiving treatment. Patients who entered the study had been transplanted for more than 3 months and their drug level was supposed to be at steady state. MMF concentration was measured with high-performance liquid chromatography (HPLC). The plasma MPA concentration-time curve was characterized by an early sharp peak at about 1 hour postdose. The mean Area Under Curve (AUC), Cmax and Tmax were 47.0±18.3 µg.h/ml, 18.6±8.5 µg/ml and 1.0±0.5 hours respectively. The plasma MPA concentration-time curve pattern of Iranian patients was similar and consistent with previously reported profiles in other populations taking the same dose.

PEGylation is a well-established technique utilized to overcome the problems related to the therapeutic applications of peptides and proteins. Reasons for the PEGylation of these biological macromolecules include reducing immunogenicity, proteolytic degradation and rapid clearance from blood circulation. Octreotide is an octapeptide analogue of naturally-occurred somatostatin. This peptide has elimination half-life of less than 2 h that requires frequent daily subcutaneous or intravenous administration. To address this issue, octreotide modification was investigated using bis-thiol alkylating PEG reagent. The required bis-thiol alkylating reagent (V) was prepared from commercially available 4-acetyl benzoic acid in five steps. Octreotide disulfide bond was mildly reduced to liberate the two cysteine sulfur atoms followed by bis-alkylation to form PEGylated peptide. The PEG modification process was monitored through the reverse phase HPLC and 1H-NMR analysis. According to the HPLC chromatograms of PEGylation reaction, the peak with 30 min retention time was identified to be PEG-octreotide. In addition, 1H-NMR analysis showed a 7.44% degree of PEG substitution.

Metformin is used in treatment of non-insulin-dependent diabetes mellitus (NIDDM). The present study was aimed to study the pharmacokinetic and pharmaco-dynamic of metformin 500 mg tablet in healthy volunteers.
The test and reference metformin hydrochloride 500 mg tablets were administered to 12 healthy volunteers in a cross-over study. Metformin serum concentration and decrease in blood sugar levels (dBSL) were used for study of pharmacokinetic and pharmacodynamic.
There was no correlation between phramacodynamic and pharmacokinetic para-meters. Also there was no increase in dBSL-(AUC0-12) with increase metformin serum concentration-time. The results of our study show that both products could be bioequivalent according to serum concentration and not blood sugar data.
There was no concentration - effect (dBSL) correlation for both products. Metformin didnt decrease the blood glucose in healthy volunteers. In some volunteers there was no increase in blood sugar after meal and dextrose 20% oral solution administration which could be related to decreased absorption of glucose from gastrointestinal tract caused by metformin.