Iranian Journal of Pharmaceutical Sciences

The present study was designed to investigate the anti-melanogenic and cytotoxic activities of methanol extract of Phlomis kurdica. The antioxidant and anti-tyrosinase activity of MeOH extract from P. kurdica (MPk) were examined by DPPH radical scavenging and mushroom tyrosinase activity assays (in vitro), respectively. Furthermore, the effect of MPk on the melanin content, cellular tyrosinase activity and cytotoxicity was studied on human melanoma SKMEL-3 cells (in vivo). The results showed that the MPk inhibited DPPH radicals and mushroom tyrosinase activity in a dose dependent-manner, but these effects were weaker than positive controls. The extract revealed cytotoxic effect in SKMEL-3 cells at high concentrations (> 0.2 mg/mL). Moreover, at concentration of 0.25 mg/mL, it reduced melanin content and cellular tyrosinase activity about 7% and 28% of control, respectively. These findings suggest that the MPk can be considered as a cytotoxic extract in melanoma skin cancers and exhibited inhibitory effect on melanogenesis process.

Ovarian cancer is the most lethal gynecological cancer in which cisplatin-based treatment plays a fundamental role as the first line chemotherapy option. However, development of platinum-resistance is a critical and poorly understood problem in ovarian cancer treatment. Although in vitro generation of platinum-resistant ovarian cancer cell lines is a long established approach to uncover the molecular mechanisms underlying resistance development, the methodology of this resistance induction is poorly explained in publications. The aim of this study was to propose a method for induction of resistance in ovarian cancer cell lines. To reach this aim, A2780 human ovarian cancer cell line was continuously exposed to stepwise increasing concentrations of cisplatin (0.5–2.6μM) over a period of 6 months and three resistant sublines were collected. Cisplatin resistance was examined by clonogenic survival assay and growth curve analysis was carried out in order to evaluate the proliferation characteristics of the established sublines. The A2780 resistant sublines exhibited 5.1 to 11.7 fold resistance to cisplatin, compared to their parental cells, and although growth rate and plateau saturation density significantly decreased by cisplatin resistance enhancement, all three resistant sublines presented a typical growth curve even though they were cultured in the cisplatin containing medium. These results suggest that reliable drug resistant human ovarian cancer cell lines can be successfully established by this method.

A rapid and sensitive liquid chromatography–tandem mass spectrometry (LC-MS) method was developed for the estimation of enalapril and enalaprilat in human plasma. Detection of analytes was achieved by tandem mass spectrometry with electrospray ionization (ESI) interface in positive ion mode was operated under the multiple-reaction monitoring mode. Sample pretreatment involved in a one-step protein precipitation (PPT) with percholoric acid (HClO4) of 0.15ml plasma. The reconstituted samples were chromatographed on C18 column by pumping methanol: water: acid formic74:24:2 (v/v) at a flow rate of 0.2 mL/min. Each plasma sample was chromatographed within 1.25 min. The standard curves were found to be linear in the range of 0.1–20 ng/mL for enalapril and enalaprilat with mean correlation coefficient of ≥0.999 for each analyte. The intra-day and inter-day precision and accuracy results were well within the acceptable limits. The limit of quantification (LOQ) was 0.1 ng/ml for enalapril and enalaprilat. The mean (SD) Cmax, Tmax, AUC0–tand AUC0–∞ values of enalapril versus enalaprilat after administration of the 10 mg enalapril are 141.33(3.51) versus73.33 (5.03) ng/mL, 1.15(1.45) versus 4.12 (1.74) hours, 142.57 (34.34) versus 425.94(13.09) ng/mL/h, and 150.74 (16.69) versus 455.80 (65.11) ng/mL/h respectively. The mean (SD) t1/2 was 2.72 (2.01) hours for the enalapril and 6.34 (2.13) hours for the enalaprilat. The developed assay method was successfully applied to a pharmacokinetic study in human male volunteers.

Dates fruit has been used as staple food in the Middle East for thousands of years and various types of dates are found worldwide. Dates and their constituents show various roles in diseases prevention and treatment through anti-oxidant, anti-inflammatory, and anti-bacterial activity. In the present study we investigated the activities of aqueous and n-hexane extracts of Phoenix dactylifera L. fruit at various concentrations on A2780, A172 and HFFF2 cell lines proliferation by means of MTT (3-4, 5-dimethylthiazol-2-yl-2, 5 diphenyl tetrazolium bromide) assay. Aqueous and n-hexane extracts of date showed activatory effects on the cell lines and increased cell proliferation in a dose dependent manner. It has been previously reported that dates fruit possesses anticancer and antimutagenic effects. These disagreements can be explained by differences in cell line properties, type of date fruits, and different solvents in the extracts. However, further investigations are needed to clarify the exact role of date in cell proliferation and cancer. In addition, n-hexane extract acted more powerful than the aqueous extract in increasing the cell lines proliferation. Therefore, it can be concluded that the active components that are responsible for the activatory effects are present in the n-hexane extract.

The utility of carbon paste electrode for the determination of flavoxate HCl modified with flavoxate-tetraphenylborate (FLX-TPB) and flavoxate-phosphotungestic acid (FLX-PTA) ion-pairs in batch mode is demonstrated. The electrodes revealed a Nernstian response over a wide concentration ranges 1.39×10-5-1x10-2 mol L-1 and1×10-5-1x10-2 mol L-1 using FLX-TPB and FLX-PTA, respectively. The detection limits of these sensors are 1.39×10-5 mol L-1, and 1x10-6 mol L-1 using FLX-TPB and FLX-PTA, respectively. The best performance was obtained with carbon paste composition of 5% flavoxate-tetraphenylborate or flavoxate-phosphotungestate, 47.5% graphite and 47.5% o- nitro phenyl octyl ether (o-NPOE). The sensors exhibit a very fast response time (5-7 s) and good selectivity in presence of inorganic cations, sugars and aminoacids. The proposed sensors show great improvement in comparison with other previously reported sensors. The sensors were successfully applied to monitoring of flavoxate in pure solution and pharmaceutical formulation (Genurin tablet) with recovery ranges from 97.2 – 101.0% and 98.1-101.6% using FLX-TPB and FLX-PTA, respectively.

This study aimed to investigate the anti-angiogenic activity of Vitex agnus castus methanol extract in vivo. Eggs were incubated for three days, small whole made on the fine pinpoint. The next day, the egg’s sac was penetrated and a small frame was made in the shell. The window was resealed and the eggs were returned to the incubator until day 10 of chick embryo development, 20 μl of 500mg/ml of the methanol extract was transferred to the Chick Embryo Chorioallantoic Membrane (CAM), and eggs incubated for 72 hours (n = 6); The zone of inhibition was calculated as mean of inhibition area in millimetre (mm) ±standard deviation (SD). Functional groups of the chemicals component inside the extract has been identified by Fourier transform infrared spectroscopy FT-IR and High performance liquid chromatography HPLC was used to identify the most likely causative agent. The results showed that the zones of inhibition area more than 10 mm. FT-IR showed that some of the identified functional group may relate to flavonoids. Casticin has been identified in methanol extract. Because of the above results the mechanism of anti-angiogenic activity for the methanol extract of the Vitex agnus castus may be related to the Casticin which has the ability to block the VEGF-receptor, thereby inhibiting the angiogenesis process.

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.

Ferula gummosa Boiss is a good source of biologically active compounds such as monoterpene and sesquiterpene derivatives. There are also several reports on antioxidant effects of these compounds. The aim of this study was to investigate the effect of daily administration of F. gummosa root hydro-alcoholic extract on serum oxidant-antioxidant status. Twenty four Wistar rats were randomly divided into three groups: (1) control, (2) F. gummosa extract 100 mg/kg, and (3) F. gummosa extract 600 mg/kg. The extract was administered by orogastric gavage once daily for 28 consecutive days. The activity of catalase and superoxide dismutase (SOD) enzymes, and the level of malondialdehyde (MDA, as a marker of lipid peroxidation) and total thiol groups were evaluated in blood samples of fasting animals on day 0 and day 28. F. gummosa extract at both doses significantly increased the activity of catalase (p<0.01). The extract at dose of 600 mg/kg significantly increased the activity of SOD (p<0.05), and reduced the level of MDA. F. gummosa had no effect on content of total thiol groups. In conclusion, long-term consumption of hydro-alcoholic extract of F. gummosa root increases the defense of the body against oxidative stress by increasing the activity of catalase and SOD, and by reducing lipid peroxidation.