Iranian Journal of Pharmaceutical Research
Volume:14 Issue: 1, Winter 2015

The aim of this investigation was to design and develop nanoemulsions as novel delivery systems for rapamycin. Phase behavior of quaternary systems composed of Traicetin (as oil), various surfactants and co-surfactants and water at different surfactant/co-surfactant weight ratios were investigated by the construction of phase diagrams. Formulations were taken from the o/w NE region of the phase diagrams, depending upon the extent of NE domain. The spontaneous emulsification method was used to prepare various formulations containing 1 mg/mL of the drug. The NEs were characterized and subjected to stability tests at various temperatures over 9-12 months. Cumulative drug release from the selected formulations were determined for a period of 48 hr, using a dialysis sac. Assay of rapamycin was carried out using an HPLC technique. The effect of NEs on the viability of SKBR-3 cells was evaluated by MTT assay. The integrity of Caco-2 cell monolayers was measured by Transepithelial Electrical Resistance (TEER) and the transport of rapamycin-loaded NEs across Caco-2 cell monolayers was then assessed. The uptake of NEs by SKBR-3 cells was also investigated using florescence microscopy. Maximum drug release was observed in case of 4 formulations prepared with Tween 80 and Tween 20. MTT test results revealed different toxicity of NEs for SKBR-3 cell line and TEER demonstrated that formulations containing Tween 20 caused more considerable decrease in cell integrity in comparison with those prepared with Tween 80. The results obtained from cellular uptake experiments were in consistent with those obtained from TEER and cytotoxicity experiments.

Diclofenac sodium as ophthalmic dosage form is used in patients treatment of eye pain, swelling and redness recovering from cataract surgery but it faces the bioavailability limitation of eye drops due to effective protective mechanisms and corneal barrier functions in the eyes. Therefore, this investigation was aimed to develop ocular film formulations to achieve controlled drug release. Drug films were prepared using polymers, namely hydroxypropyl methylcellulose (HPMC) and polyvinyl pyrrolidone (PVP), Eudragit RL PO, and Eudragit RS PO by solvent casting method considering parameters such as drug: polymer ratio, different polymer combinations as well as plasticizer effect. Ocular films were evaluated for various physicochemical parameters such as physical characters, film thickness, uniformity of weight, drug content, swelling index, mucoadhesion time and in vitro release study. Ocular films complied with all the physicochemical parameters underwent for in vitro release study. Finally the film formulation with HPMC: Eudragit RS PO 1:1 ratio, Drug: Polymer ratio 1:45 and glycerin as plasticizer showed controlled and prolonged release following zero order and non-Fickian transport.

A validated HPLC method was developed to determine doxorubicin concentration in a small volume of rat plasma (60 µl) with convenient fluorescence detection. Sample preparation includes a simple one-step liquid-liquid extraction using minimum amount of organic solvent, with extraction recoveries more than 95%. The analysis was accomplished using PerfectSil C18 column maintained at 35 °C and a mobile phase consisted of acetonitrile and water (32:68, v/v; pH=2.6). The flow-rate was kept at 1 mL/min and column effluent was monitored with a fluorescence detector at an excitation and emission wavelength of 470 and 555 nm, respectively. The detection limit was 5 ng/mL. No analytical interference was observed from endogenous components in rat plasma. This method was feasibly applied to the pharmacokinetic study of 5 mg/kg of doxorubicin after intravenous administration to rats.

this study a novel High Performance Liquid Chromatography for the assay of nystatin in oral and vaginal tablets were optimized and validated using Box–Behnken experimental design. The method was performed in the isocratic mode on a RP-18 column (30 °C) using a mobile phase consisting of 0.05 M ammonium acetate buffer/ Methanol mixture (30:70) and a flow-rate of 1.0 ml/min. The method was validated by specificity, linearity, precision, accuracy, LOD and LOQ. The method was linear over the range of 5–500 µg/ml with a good correlation coefficient (r2 = 0.9996). The limit of detection (LOD) and quantification (LOQ) were 0.01 and 0.025 µg/ml respectively. The obtained results clearly indicate that the proposed validated method can be used as an alternative method for assay of nystatin.

A series of cyclic analogues of bioactive thiosemicarbazide derivatives have been synthesized as potential antimycobacterial agents. The 4-amino-1,2,4-triazole-5-thione analogues (Ia-f) were prepared by heating a mixture of thiocarbohydrzide and appropriate carboxylic acids. Reaction of thiocarbohydrazide with γ-ketoesters in the presence of sodium methoxide furnished triazolopyridazine derivatives IIa-b. Finally, condensation of 4-amino-1,2,4-triazole-5-thione with some aldehydes gave Schiff bases IIIa-e. After characterization by different spectroscopic and analytical methods, the derivatives were tested for their inhibitory activity against Mycobacterium bovis BCG. Among the derivatives, compound Ib proved to be the most potent derivatives with MIC value of 31.25 µg/mL. Given the fact that 4-amino-1,2,4-triazole-5-thiones Ia-f were the most active derivatives, it could be suggested that this group of derivatives have the potential to be considered as lead compounds for future optimization efforts.

Predictive quantitative structure–activity relationship was performed on the novel 4-oxo-1,4-dihydroquinoline and 4-oxo-4H-pyrido[1,2-a]pyrimidine derivatives to explore relationship between the structure of synthesized compounds and their anti-HIV-1 activities. In this way, the suitable set of the molecular descriptors was calculated and the important descriptors using the variable selections of the stepwise technique were selected. Multiple linear regression (MLR) and artificial neural network (ANN) as nonlinear system were used for constructing QSAR models. The predictive quality of the quantitative structure–activity relationship models was tested for an external set of five compounds, randomly chosen out of 25 compounds. The findings exhibited that stepwise-ANN model was more efficient at prediction activity of both training and test sets with high statistical qualities. Based on QSAR models results, electronegativity, the atomic masses, the atomic van der Waals volumes, the molecular symmetry and polarizability were found to be important factors controlling the anti-HIV-1 activity.

Dopaminergic signaling is one of the regulatory pathways being investigated for its implication in glucose metabolism. The aim of this study was to determine the effect of cabergoline on biochemical and anthropometric parameters in prediabetes stage (impaired fasting glucose and impaired glucose tolerance). In this double blind, placebo-controlled, pilot study, 27 prediabetic adults were randomized to receive 0.25-mg cabergoline twice weekly for two weeks, followed by 0.5 mg twice weekly for next 14 weeks (n = 13) or placebo (n = 14). All subjects were advised to follow a 500 kcal-deficit energy diet. Fasting plasma glucose (FPG), oral glucose tolerance, glycated hemoglobin (A1c), fasting, and 2-h insulin were measured at baseline and at 16-week follow-up. Homeostasis model assessment (HOMA) 2 was calculated to estimate steady-state beta-cell function, insulin sensitivity, and insulin resistance. Our results showed significant reductions in fasting (P = 0.004) and 2-h plasma glucose (P = 0.01) after treatment, and significant improvements in beta-cell function (P = 0.03) and insulin resistance (P = 0.04) in the cabergoline group. The trend of non-significant A1c changes was decreasing in the cabergoline group versus an increasing trend in the placebo group. All anthropometric parameters were similar between the two groups. Our results revealed that twice-weekly cabergoline could improve glucose metabolism in prediabetes stage. Larger studies of longer duration are warranted to investigate the effect of cabergoline in preventing progression of prediabetes to type 2 diabetes mellitus.

Medication errors are commonly encountered in hospital setting. Intravenous medications pose particular risks because of their greater complexity and the multiple steps required in their preparation, administration and monitoring. We aimed to determine the rate of errors during preparation and administration phase of intravenous medications and the correlation of these errors with the demographics of the nurses involved in the process. One hundred patients who were receiving IV medications were monitored by a trained pharmacist. The researcher accompanied the nurses during the preparation and administration process of IV medications. Collected data were compared with the acceptable guidelines. A checklist was filled for each IV medication. Demographic data of the nurses was collected as well. A total of 460 IV medications were recorded. Inappropriate administration rate constituted a large proportion of errors in our study (35.3%). No significant or life threatening drug interaction was recorded during the study. Evaluating the impact of the nurses’ demographic characteristics on the incidence of medication errors showed that there is a direct correlation between nurses’ employment status and the rate of medication errors, while other characteristics did not show a significant impact on the rate of administration errors. Administration errors were significantly higher in temporary 1-year contract group than other groups (P- value < 0.0001). Study results show that there should be more vigilance on administration rate of IV medications to prevent negative consequences especially by clinical pharmacists. Optimizing the working conditions of the nurses may play a crucial role.

Thalamic pain syndrome, a type of central post-stroke pain (CPSP), may develops after a hemorrhagic or ischemic stroke and results in impairment of the thalamus. There is limited experience about gabapentin in treatment of central pains like CPSP.In a prospective observational study, the intensity of pain was recorded using the Numeric Rating Scale (NRS) at the entrance to the study. Patients eligible for treating with gabapentin, received gabapentin 300 mg twice-daily. The pain intensity was measured at entrance to the study and after one month using NRS. Decrease of 3 points from the initial NRS considered to be clinically significant. From a total of 180 primarily screened patients, 84 (44 men and 40 women) were recruited. There was a significant difference between pre-treatment and post-treatment NRS (5.9 ± 2.51 vs. 4.7 ± 3.01; 95% CI: 0.442-1.962, p = 0.002). Fisher's exact test showed no statistically significant effect of clinical and demographic characteristics of patients on their therapeutic response to gabapentin.Given the safety, efficacy, well tolerability and lack of interaction with other drugs we suggest gabapentin to be more considered as a first line therapy or as add-on therapy for reducing the pain severity in patients with thalamic syndrome.

Malaria is the most serious parasitic disease and one of the oldest recorded diseases in the world. Because of the resistance of malaria parasites to current drugs, it is necessary to discover new antiplasmodial drugs. Traditional medicine is one of the important sources of new antiplasmodial drugs.In this study, twenty methanolic extracts from different parts of sixteen medicinal plants used in traditional medicine of Iran for the treatment of “Nobeh fever” and/ or fever were screened for in vivo antiplasmodial activity against Plasmodium berghei and cytotoxic effect on Madin–Darby bovine kidney cells (MDBK).Eleven species (55%) were found to have antiplasmodial activity. Methanolic extract from Rosa damascena Mill. reduced parasitemia by 57.7% compared to untreated control mice at intra-peritoneal (i.p.) injection doses of 10 mg/kg per day. This is the first report that mentioned in vivo antiplasmodial activity of Rosa damascena Mill.

Envenomation by heamotoxic snakes constituted a critical health occurrence in the world. Bleeding is the most sever consequence following snake bite with viperid and crothalid snakes. It is believed that the degradation of vascular membrane caused hemorrhage; in contrast, some suggested that direct cytotoxicity has role in endothelial cell disturbances. This study was to evaluate the direct toxicity effect of V.Lebetina crude venom on Human Umbilical Vein Endothelial Cells (HUVECs). The effect of V. lebetina snake venom on growth inhibition of HUVECs was determined by MTT assay and neutral red uptake test. The integrity of cell membrane through LDH release was measured with the Cytotoxicity Detection Kit. Morphological changes of endothelial cells also were evaluated using a phase contrast microscope. crude venom induced a concentration dependent inhibition on HUVECs with an IC50 value of 11.77 μg/ml after 24 h of incubation at MTT assay and 10.52 μg/ml at neutral red uptake test. In MTT assay, V. Lebetina crude venom showed a cytotoxic effect on endothelial cells which was confirmed by the effect observed with neutral red assay. Also, crude venom caused disturbances in the integrity of cell membrane by LDH release. The morphological alterations enhanced in high concentration and finally total cells number reduced. V. Lebetina venom showed potential direct cytotoxic effects on human endothelial cells in a manner of concentration dependent inhibition.

The pharmacological interaction between cannabinoidergic system and vanilloid type 1 (TRPV1) channels has been investigated in various conditions such as pain and anxiety. In some brain structure including hippocampus, CB1 and TRPV1 receptors coexist and their activation produces opposite effect on excitability of neurons. In this study, we tested the hypothesis that TRPV1 channel is involved in the modulation of cannabinoid effects on pentylenetetrazole (PTZ)-induced seizure threshold. In single therapy, male mice (n = 10 per group) received either TRPV1 receptor antagonist capsazepine, CB1 receptor agonist ACEA or anandamide reuptake inhibitor VDM11. In combination therapy, mice were treated with either capsazepine-ACEA or capsazepine-VDM11 combination prior to seizure test. Thirty min later, mice were submitted to infusion of PTZ (1%, 0.25 ml/min) into tail vein and the dose of PTZ to induce clonic convulsion was considered as seizure threshold. Administration of capsazepine and ACEA per se produced protective effects against PTZ-induced seizure, while administration of VDM11 per se did not produce such a protection effect. The anticonvulsant actions of both capsazepine and ACEA were attenuated after co-administration of these compounds. Moreover, the anticonvulsant action of capsazepine was attenuated after co-administration with VDM11. The results suggest an interaction between cannabinoidergic system and TRPV1 receptors in protection against acute PTZ-induced seizure in mice.

Phenobarbital is a phenobarbiturate used as a sedative, anticonvulsant, or hypnotic with the doses prescribed and can cause teratogenic effects. The goal of this study was to examine an alternative method for the recognition of the mechanism or the bimolecular potential changes in mice fetus caused by Phenobarbital using FTIR micro spectroscopy. The mice were injected with Phenobarbital (120mg/kg) on gestation day 9. Fetuses were dissected on day 15 of gestation and morphological and histological studies on the fetus were carried out. Sections (10µm) of normal and Phenobarbital treated fetus brains and livers were used for FTIR measurement in the wave number region of 400- 4000 cm-1. The results were shown by 2ndderivativization of spectra & also subtraction from control spectra. In liver, the intensity at 1054 cm-1, 1155 cm-1, 1353 cm-1, 1453cm-1,1645 cm-1, 1622 cm-1, 2944 cm-1, 2913 cm-1 and 2845 cm-1 were shifted and increased. In the brain, the intensity at 879 cm-1, 911 cm-1, 955 cm-1, 1223 cm-1, 1256 cm-1, 1304 cm-1, 1360 cm-1, 1453 cm-1, 1529 cm-1, 1636 cm-1, 2845 cm-1, 2915 cm-1& 2950 cm-1 were increased and shifted. The most important changes of the fetus brain tissue are on the β structure of proteins due to the amide I bands at 1636 cm-1, while extensive effects on the DNA structure were obvious for the Phenobarbital treated liver tissues. As a conclusion, FTIR spectroscopy might well be assumed as a potentially powerful teratogenic measurement instrument with a unique ability to identify the modified bimolecular structures.

Maternal smoking has been recognized as a common cause of low birth weight, preterm birth and the decrease of gestational age period. Unfortunately, there is an increasing interest within public especially woman in Iran in the tobacco products consumption. On the other hand, the deleterious effect of maternal smoking on human fetus in pregnancy period especially in the first trimester encouraged us to investigate toxicity mechanisms of cigarette smoke on mouse fetus mitochondria. For this purpose different concentrations of standardized cigarette smoke extract (1, 10 and 100%) were administrated on mitochondria isolated from fetus of NMRI mice on the 15 day of gestation. Our results showed a significant increase in ROS formation, lipid peroxidation, mitochondrial membrane potential collapse, mitochondrial swelling and finally a decrease in ATP concentration in the CSE-treated isolated fetus mitochondria. Our results suggest that CSE-induced embryo toxicity is the result of disruptive effect on mitochondrial respiratory chain that leads to ROS formation, lipid peroxidation, mitochondrial MMP decline and decrease of ATP level which starts apoptosis signaling.