Research in Pharmaceutical Sciences
Volume:10 Issue: 2, Apr 2015

The solubility, bioavailability and dissolution rate of drugs are important parameters for achieving in vivo efficiency. The bioavailability of orally administered drugs depends on their ability to be absorbed via gastrointestinal tract. For drugs belonging to Class II of pharmaceutical classification, the absorption process is limited by drug dissolution rate in gastrointestinal media. Therefore, enhancement of the dissolution rate of these drugs will present improved bioavailability. So far several techniques such as physical and chemical modifications, changing in crystal habits, solid dispersion, complexation, solubilization and liquisolid method have been used to enhance the dissolution rate of poorly water soluble drugs. It seems that improvement of the solubility properties ofpoorly water soluble drugscan translate to an increase in their bioavailability. Nowadays nanotechnology offers various approaches in the area of dissolution enhancement of low aqueous soluble drugs. Nanosizing of drugs in the form of nanoparticles, nanocrystals or nanosuspensions not requiring expensive facilities and equipment or complicated processes may be applied as simple methods to increase the dissolution rate of poorly water soluble drugs. In this article, we attempted to review the effects of nanosizing on improving the dissolution rate of poorly aqueous soluble drugs. According to the reviewed literature, by reduction of drug particle size into nanometer size the total effective surface area is increased and thereby dissolution rate would be enhanced. Additionally, reduction of particle size leads to reduction of the diffusion layer thickness surrounding the drug particles resulting in the increment of the concentration gradient. Each of these process leads to improved bioavailability.

Dracocephalum kotschyi is an essential oil containing plant found in Iran. In Iranian traditional medicine, D. kotschyi has been used as antispasmodic and analgesic but so far there is no pharmacological report about its antispasmodic activity. Therefore, the objective of this research was to study antispasmodic activity of the essential oil of D. kotschyi and two of its constituents namely limonene and a-terpineol. The essential oil was obtained from aerial parts of D. kotschyi using hydrodistillation method. The main components found in the essential oil were a-pinene (10%), neral (11%), geraniol (10%), a-citral (12%), limonene (9%) and a-terpineol (1.1%). For antispasmodic studies, a portion of rat ileum was suspended under 1 g tension in Tyrode’s solution at 37 °C and gassed with O2. Effect of the D. kotschyi essential oil, limonene and a-terpineol were studied on ileum contractions induced by KCl (80 mM), acetylcholine (ACh, 500 nM) and electrical field stimulation (EFS). The essential oil, in a concentration dependent manner inhibited the response to KCl (IC50=51 ± 8.7 nl/ml), ACh (IC50=19 ± 2.7 nl/ml) and EFS (IC50=15 ± 0.5 nl/ml). Limonene and a-terpineol showed same pattern of inhibitory effect on ileum contraction. Their inhibitory effects were also concentration dependent. However, limonene was more potent than the essential oil while the a-terpineol was less potent than either limonene or the essential oil. From this experiment it was concluded that D. kotschyi essential oil has inhibitory effect on ileum contractions. Limonene contribute a major role in inhibitory effect of the essential oil while a-terpineol has weak antispasmodic activity.

In the present study possible effects of black pomegranate peel extract (PPE) on the B16F10 melanoma cells proliferation and Human Umbilical Vein Endothelial Cells (HUVECs) angiogenesis were investigated. PPE was added into the cell lines (B16F10 and HUVECs) media with different concentrations (10–450 μg/ml). After 48 h, the cell survival was measured by 3-(Dimethylthiazol-2-yl)-2, 5-diphenyl-tetrazolium bromide (MTT) assay. Angiogenesis was investigated by matrigel assay (PPE (200, 300, 400 μg/ml)); HUVECs, vascular endothelial growth factor (VEGF) mRNA expression was detected by quantitative reverse transcriptase–polymerase chain reaction (QRT-PCR) assay. VEGF concentration in culture medium of HUVECs was determined by enzyme-linked immunosorbent assay (ELISA). PPE had positive anti proliferative effect on melanoma cells in a dose-dependent manner, but not on HUVECs. The matrigel assay results indicated that PPE significantly inhibited length, size and junction of the tube like structures (P<0.05). VEGF mRNA expression and concentration levels in culture medium of PPE treated HUVECs reduced significantly in a concentration-dependent manner (P<0.05). Simultaneous inhibition of melanoma cell proliferation and angiogenesis proposed that, PPE can be a good candidate against melanoma development. Based on the results, PPE could effectively suppress angiogenesis potentially through a VEGF dependent mechanism. Further studies are needed to confirm these results.

Some species of Allium family have been shown to offer cardioprotection in animal studies. This study aimed at examining possible role of oxidative stress in the cardioprotective effects of hydroalcoholic extract of Allium eriophyllum in rats with simultaneous type 2 diabetes and renal hypertension. Six groups of male Spargue-Dawley rats (8-10 rats each) including a sham-control, a diabetic group, a renal hypertensive group, three groups of animals with simultaneous diabetes and hypertension receiving vehicle, or the extract at 30 or 100 mg/kg/day were used. Four weeks after receiving vehicle or extract, blood pressure, fasting blood glucose, and serum superoxide dismutase and glutathione reductase levels were measured, and isolated heart studies were performed. Systolic blood pressure, fasting blood glucose, coronary effluent creatine kinase-MB, infarct size and coronary resistance of diabetic hypertensive group receiving vehicle were significantly higher than those of the sham-control group and treatment with the extract prevented the increase of these variables. Moreover, rate of rise and decrease of left ventricular pressure, left ventricular developed pressure, rate pressure product and serum levels of superoxide dismutase and glutathione reductase of diabetic hypertensive group receiving vehicle were significantly lower than those the sham-control group, and treatment with the extract prevented the decrease of these variables. The findings indicate that hydroalcoholic extract of A. eriophyllum leaves, possibly by an antioxidant mechanism, protected against simultaneous diabetes and hypertension-induced cardiac dysfunction.

Multipotent mesenchymal stem cells (MSCs) are recently found to alter the tumor condition. However their exact role in tumor development is not yet fully unraveled. MSCs were established to perform many of their actions through paracrine effect. Thus investigation of MSC secretome interaction with tumor cells may provide important information for scientists who are attempting to apply stem cells in the treatment of the disease. In this study we investigated the effect of human Wharton’s jelly derived MSC (WJ-MSCs) secretome on proliferation, apoptotic potential of A549 lung cancer cells, and their response to the chemotherapeutic agent doxorubicin. WJ-MSCs were isolated from human umbilical cord and then characterized according to the International Society for Cellular Therapy criteria and WJ-MSC secretome was collected. BrdU cell proliferation assay and Annexin V-PI staining were used for the evaluation of cytotoxic and proapoptotic effects of WJ-MSC secretome on A549 cells. WJ-MSC secretome neither induced proliferation of lung cancer cells nor affected the apoptotic potential of the tumor cells. We also studied the combinatorial effect of WJ-MSC secretome and the anticancer drug doxorubicinwhich showed no induction of drug resistance when A549 cells was treated with combination of WJ-MSC secretome and doxorubicin. Although MSCs did not show antitumor properties, our in vitro results showed that MSC secretome was not tumorigenic and also did not make lung cancer cells resistant to doxorubicin. Thus MSC secretome could be considered safe for other medical purposes such as cardiovascular, neurodegenerative, and autoimmune diseases which may exist or occur in cancer patients.

Statins are widely used as anti hyperlipidemic agents. Hepatotoxicity is one of their adverse effects appearing in some patients. No protective agents have yet been developed to treat statins-induced hepatotoxicity. Different investigations have suggested L-carnitine as a hepatoprotective agent against drugs-induced toxicity. This study was designed to evaluate the effect of L‑carnitine on the cytotoxic effects of statins on the freshly-isolated rat hepatocytes. Hepatocytes were isolated from male Sprague-Dawley rats by collagenase enzyme perfusion via portal vein. Cells were treated with the different concentrations of statins (simvastatin, lovastatin and atorvastatin), alone or in combination with L‑carnitine. Cell death, reactive oxygen species (ROS) formation, lipid peroxidation, and mitochondrial depolarization were assessed as toxicity markers. Furthermore, the effects of statins on cellular reduced and oxidized glutathione reservoirs were evaluated. In accordance with previous studies, an elevation in ROS formation, cellular oxidized glutathione and lipid peroxidation were observed after statins administration. Moreover, a decrease in cellular reduced glutathione level and cellular mitochondrial membrane potential collapse occurred. L‑carnitine co‑administration decreased the intensity of aforementioned toxicity markers produced by statins treatment. This study suggests the protective role of L-carnitine against statins-induced cellular damage probably through its anti oxidative and reactive radical scavenging properties as well as its effects on sub cellular components such as mitochondria. The mechanism of L-carnitine protection may be related to its capacity to facilitate fatty acid entry into mitochondria; possibly adenosine tri-phosphate or the reducing equivalents are increased, and the toxic effects of statins toward mitochondria are encountered.

The purpose of the present study was to compare the stabilizing effect of four disaccharides alone or in combination on the lactoperoxidase (LP) derived from bovine milk during lyophilization. Sucrose, lactose, maltose, and trehalose at different concentrations (5-500 mM) were used to compare their protective effects on LP activity. The activity of lyophilized and native LP enzyme was evaluated using the procedure of Schindler with slight modifications. The antibacterial activity of the lyophilized enzyme against Pseudomonas aeroginosa, Escherichia coli, and Staphylococcus aureus was also investigated using the antimicrobial effectiveness test. Trehalose at concentration of 500 mM was the most effective cryoprotectant in protecting the enzyme activity. It preserved LP activity for 40 days, while the native enzyme lost its activity after 6 days. Combinations of disaccharides resulted in an increment in the stability of the enzyme, compared to the native enzyme. Combination of 200 mM trehalose and 200 mM sucrose were found most effective cryoprotectant in freeze-drying of LP. The lyophilized LP decreased the growth rate of Ps.aeroginosa, E.coli, and S.aureus between up to 30.8% in 106 cfu/ml and 53.3% in 105 cfu/ml. Antimicrobial efficacy of LP was more pronounced when 105 cfu/ml was used as compared to 106 cfu/ml.

Ovarian cancer is the fifth leading cause of the cancer-related death among women. 9-nitrocamptothecin (9-NC) is a water-insoluble derivative of camptothecin used for the treatment of patients with advanced ovarian cancer. Previous studies showed that the encapsulation of 9-NC in poly (lactic-co-glycolic acid, PLGA) nanoparticles increased the cytotoxic effect of the drug on different cancer cell lines. In the present study, the cytotoxic effects of 9-NC, 9-NC-loaded PLGA and PLGA-polyethylene glycol (PLGA-PEG) nanoparticles with varying degree of PEG (5, 10, and 15%) were evaluated on human ovarian carcinoma cell line. Furthermore, the mode of cell death induced by 9-NC and the optimized 9-NC-loaded PLGA-PEG nanoparticles on A2780 cell line were investigated. 9-NC incorporating nanoparticles were prepared by nanopercipitation method and their physicochemical characteristics were evaluated using standard methods. The results showed that activation of caspase-3 and -9 significantly increased by free 9-NC and PLGA-PEG loaded nanoparticles in A2780 cells. In contrast to the free drug which increased the activation of caspase-8, 9-NC-loaded PLGA-PEG nanoparticles did not alter the activation of caspase-8. Collectively, it appears that apoptosis induced by 9-NC incorporated in PLGA-PEG 5% occurred through the activation of caspase-9 rather than activation of caspase-8 which is the mediator of extrinsic pathway. Moreover, our results confirmed that 9-NC in nanoparticles at the level of gene expression potentiated down-regulation of Bcl-2, up regulation of Bax, and Smac/DIABLO leading to a decrease in mitochondrial membrane potential. Taken together, our results showed that 9-NC incorporated in PLGA-PEG 5% nanoparticles is able to induce apoptosis in A2780 human ovarian carcinoma cells and has the potential for the treatment of ovarian carcinoma.

Descurainia sophia is a plant widely distributed and used as folk medicine throughout the world. Different extracts of aerial parts and seeds of this plant have been shown to inhibit the growth of different cancer cell lines in vitro. In this study, cytotoxic activity of D. sophia seed volatile oil was evaluated. D. sophia seed powder was mixed with distilled water and left at 25 °C for 17 h (E1), 23 h (E2) and 28 h (E3) to autolyse. Then, the volatile fractions of E1, E2, and E3 were collected after steam distillation for 3 h. Cytotoxic effects of the volatile oils alone or in combination with doxorubicin (mixture of E1 or E2 at 50 µg/ml or E1 at 100 µg/ml with doxorubicin at 0.1, 1, 10 µM) against MCF-7 cell line were determined using MTT assay. Cytotoxic effect of E1 volatile oil was also determined on HeLa cell line. The results indicated that 1-buten-4-isothiocyanate was the major isothiocyanate found in the volatile oils. The results of cytotoxic evaluations showed that volatile constituents were more toxic on MCF-7 cells with IC50 < 100 µg/ml than HeLa cells with IC50 > 100 µg/ml. No significant differences were observed between cytotoxic activities of E1, E2 and E3 on MCF-7 cell line. Concomitant use of E1 and E2 (50 µg/ml) with doxurubicin (1 µM) significantly reduced the viability of MCF-7 cells compared to the negative control, doxorubicin alone, or each volatile fraction. The same result was obtained on HeLa cells, when E1 (100 µg/ml) was concurrently used with doxorubicin (1 µM).

Under pathophysiological conditions, infiltration of leukocyte plays a key role in the progression of the neuroinflammatory reaction in the CNS. Prostaglandin E2 (PGE2) is known to accumulate at lesion sites of the post-ischemic brain. Although post-ischemic treatments with cyclooxygenase-2 inhibitors reduce blood-brain barrier (BBB) leukocyte infiltration, the direct effect of PGE2 on BBB has not been fully implemented. Therefore, the direct effect of increasing PGE2 infusion on translocation of labeled albumin into the brain was assessed. Under anesthesia rats were drilled stereo-taxicaly a burr hole in the right forebrain and PGE2 was infused into the forebrain and the hole was occluded. The animals were then injected with fluorescent labeled albumin (FA), via internal right jugular vein and decapitated at different infusion time points. The forebrain was removed and each forebrain hemisphere was homogenized and fluorescence intensities were measured in the supernatant. The fluorescence intensities measured in the right and left forebrain hemispheres of the control group (0.0 µg PGE2) were almost identical. Four hours after infusion of PGE2 at doses higher than 250 µg, fluorescence intensity increased in the right forebrain supernatant, even if it was not statistically significant. The fluorescence intensity was detectable in the brain supernatant 4 h after infusion of PGE2 in doses higher than 250 µg PGE2. The highest fluorescence intensity was 16 h after infusion of 500 µg PGE2, which returned to near control values after 48 h. Increased fluorescence intensity in the brain following PGE2 infusion is concluded to be associated with disruption of the BBB.