Spinal actions of lipoxin A4 and 17(R)-resolvin D1 attenuate inflammation-induced mechanical hypersensitivity and spinal TNF release.

Lipoxins and resolvins have anti-inflammatory and pro-resolving actions and accumulating evidence indicates that these lipid mediators also attenuate pain-like behavior in a number of experimental models of inflammation and tissue injury-induced pain. The present study was undertaken to assess if spinal administration of lipoxin A4 (LXA4) or 17 (R)-resolvin D1 (17(R)-RvD1) attenuates mechanical hypersensitivity in the carrageenan model of peripheral inflammation in the rat. Given the emerging role of spinal cytokines in the generation and maintenance of inflammatory pain we measured cytokine levels in the cerebrospinal fluid (CSF) after LXA4 or 17(R)-RvD1 administration, and the ability of these lipid metabolites to prevent stimuli-induced release of cytokines from cultured primary spinal astrocytes. We found that intrathecal bolus injection of LXA4 and17(R)-RvD1 attenuated inflammation-induced mechanical hypersensitivity without reducing the local inflammation. Furthermore, both LXA4 and 17(R)-RvD1 reduced carrageenan-induced tumor necrosis factor (TNF) release in the CSF, while only 17(R)-RvD1attenuated LPS and IFN-γ-induced TNF release in astrocyte cell culture. In conclusion, this study demonstrates that lipoxins and resolvins potently suppress inflammation-induced mechanical hypersensitivity, possibly by attenuating cytokine release from spinal astrocytes. The inhibitory effect of lipoxins and resolvins on spinal nociceptive processing puts them in an intriguing position in the search for novel pain therapeutics.

Pentoxifylline and melatonin in combination with pioglitazone ameliorate experimental non-alcoholic fatty liver disease.

Insulin resistance, oxidative stress and cytokine imbalance are key pathophysiological mechanisms in non-alcoholic fatty liver disease (NAFLD). This study aimed at evaluating the effect of treatment with the insulin sensitizer, pioglitazone, the tumor necrosis factor-α inhibitor, pentoxifylline, and the antioxidant, melatonin and their combinations in rats with NAFLD. Rats were fed a high-fat diet (HFD) for eight weeks to induce NAFLD. For an additional eight weeks, rats were fed the HFD along with pioglitazone, pentoxifylline, melatonin alone or in combination. Liver index and insulin resistance index were calculated. Serum liver enzyme activities, total cholesterol, triglycerides and tumor necrosis factor-α (TNF-α) were determined. Tissue triglycerides, malondialdehyde and reduced glutathione were measured and liver injury was evaluated by histopathological examination. HFD induced severe hepatic steatosis, inflammation and fibrosis. In addition, liver index, insulin resistance index, activities of liver enzymes and serum level of total cholesterol, triglycerides and TNF-α were elevated. This was coupled with an increase in tissue triglycerides, malondialdehyde and depletion of reduced glutathione. Pioglitazone, pentoxifylline and melatonin, alone or in combination; reduced the insulin resistance index, activities of liver enzymes, hepatic malondialdehyde and increased hepatic reduced glutathione level. Pentoxifylline led to a decrease in serum TNF-α level, however, pioglitazone and melatonin reduced serum total cholesterol and triglycerides. In conclusion, data in this study indicate that pentoxifylline and melatonin can be used as promising adjuvant therapies to pioglitazone in the clinical management of NAFLD.

Cisplatin-induced cardiotoxicity: Mechanisms and cardioprotective strategies.

Increased oxidative stress and apoptosis have been implicated in the cardiotoxicity that limits the clinical use of cisplatin as an anti-tumoral drug. Our study was conducted to evaluate the protective potential of acetyl-l-carnitine, DL-α-lipoic acid and silymarin against cisplatin-induced myocardial injury. Eighty male albino rats were divided into eight groups. The first four groups were treated with normal saline, acetyl-l-carnitine (500mg/kg, i.p.), DL-α-lipoic acid (100mg/kg, p.o.) and silymarin (100mg/kg, p.o.) respectively, for 10 successive days. The remaining groups were treated with the same doses of normal saline, acetyl-l-carnitine, DL-α-lipoic acid and silymarin, respectively, for 5 successive days before and after a single dose of cisplatin (10mg/kg, i.p.). Serum activities of lactate dehydrogenase (LDH), creatine kinase (CK), creatine kinase isoenzyme MB (CK-MB) and plasma cardiac troponin I (cTnI) concentration were estimated. Malondialdehyde (MDA), reduced glutathione (GSH) contents, superoxide dismutase activity (SOD) and protein content in cardiac tissues were measured. Moreover, integrity of both mitochondrial DNA (mtDNA) and nuclear DNA (nDNA) was also examined. Cisplatin-treated rats experienced a significant elevation of serum activities of LDH, CK, CK-MB and cTnI plasma concentration. These effects were accompanied by a significant increase in MDA level. On the other hand, a significant decrease in GSH content, SOD activity and total protein content was observed. In addition, both mtDNA and nDNA were heavily damaged. However, acetyl-l-carnitine, DL-α-lipoic acid and silymarin significantly attenuated the cisplatin-evoked disturbances in the above-mentioned parameters. In conclusion, the former drugs were proven to be potential candidates to ameliorate cisplatin-induced cardiotoxicity.

Anti-angiogenic effect of resveratrol or curcumin in Ehrlich ascites carcinoma-bearing mice.

The phytochemicals, resveratrol or curcumin, have been shown to possess many pharmacological activities including anti-inflammatory, anti-oxidant, anti-microbial and anti-cancer effects. However, the underlying mechanism for their anti-tumor activity is yet to be evaluated. The present study was carried out to investigate the anti-angiogenic effect of resveratrol or curcumin when used alone or in combination with carboplatin in Ehrlich ascites carcinoma (EAC)-bearing mice. Solid tumors were induced by intradermal injection of EAC cells. These tumors were used for the evaluation of microvessel density, plasma vascular endothelial growth factor (VEGF) and its intra-tumoral receptor type-2 (Flk-1). All parameters were determined as a time course on days 7, 14, and 21 post-inoculation. Individual treatments with resveratrol or curcumin and their combination with carboplatin produced a significant reduction in microvessel density. Plasma levels of VEGF were significantly reduced in groups treated with resveratrol or curcumin and their combination with carboplatin on day 7 post-inoculation. Treatment with resveratrol or curcumin reduced the percentage of Flk-1-rich tumors to reach 42.9% and 28.6%, respectively. Their co-administration with carboplatin has produced a further reduction in the percentage of Flk-1-rich tumors to reach 28.6% and 14.3%, respectively. Correlation studies showed strong association between plasma VEGF and microvessel density. In conclusion, resveratrol or curcumin inhibited angiogenesis as demonstrated by the reduction of microvessel density by these agents. Both proved to exert their anti-angiogenic effect by inhibition of VEGF and its receptor type-2. The results suggest the beneficial role of these phytochemicals as adjuvant to chemotherapy in the treatment of cancer.

Student perspectives on pharmacy curriculum and instruction in Egyptian schools.

OBJECTIVES: To determine student attitudes and opinions towards pharmacy education in Egyptian universities to provide information for designing delivery of a revised pharmacy curriculum. METHODS: Students were recruited from the pharmacy faculties at a government-sponsored university and a privately funded university. Data were gathered using a structured questionnaire and statistically analyzed. Responses from open questions were subjected to thematic analysis. RESULTS: Students spent widely differing amounts of time on non-classroom study, little of which was self-directed. This was reflected in the low frequency of use of library facilities and the preference of students for passively acquired information. Themes that emerged on how students would improve the curriculum were to increase the use of computers and the Internet; make the course more relevant to pharmacy practice and/or clinical pharmacy; improve and expand the practical components of the course; increase their own involvement in learning; and increase their understanding of subjects as well as their knowledge. For many of the questions, there was a significant different between the responses of students at the 2 universities. CONCLUSIONS: Students relied on classroom teaching and devoted little time to self-directed study. However, students were aware of international developments in pharmacy education and practice and are receptive to change.