Estrogenic activity of Sage (Salvia officinalis L.) aerial parts and its isolated ferulic acid in immature ovariectomized female rats.

ETNOPHARMACOLOGICAL RELEVANCE: Common sage (Salvia officinalis L., Lamiaceae), a medicinal plant of Mediterranean origin, has been traditionally applied in cases of excessive sweating, and in menopausal complaints, including hot flushes. AIM OF THE STUDY: This study aims to study the possible estrogenic effect of the aerial parts of S. officinalis ethanolic extract in immature ovariectomized female rats. MATERIALS AND METHODS: The ethanolic extract was subjected to qualitative and quantitative HPLC analysis and phytochemical isolation. The estrogenic activity of S. officinalis ethanolic extract at oral doses of 50, 100 and 200 mg/kg b.wt. and its isolated ferulic acid at a dose of 50 mg/kg b.wt. for a week, was assessed on ovariectomized immature Wistar rats. The experiment was confirmed by luteinizing hormone (LH) and follicle stimulating hormone (FSH) serum levels determination, a histopathological examination and a histomorphometrical study. RESULTS: HPLC/PDA analysis revealed fourteen phenolic compounds the major constituents were methyl rosmarinate (24.86 mg/100 g) and ferulic acid (6.06 mg/100 g) together with five flavonoids where the major constituents were rutin, naringenin and quercetin. Two compounds were isolated from the polar fraction and identified as methyl rosmarinate (1) and ferulic acid (2). Oral administration of sage ethanolic extract and ferulic acid revealed a significant increase in the uterine weight compared to ovariectomized control rats. Moreover, S. officinalis and ferulic acid showed different phases of estrus cycle denoting estrogenic activity, and significantly decreased the serum levels of FSH and LH. CONCLUSION: From these results it could be concluded that S. officinalis ethanolic extract and its content of ferulic acid could be useful as a safe natural source for estrogenic activity, supporting its traditional use to improve postmenopausal symptoms.

EVESOR, a model-based, multiparameter, Phase I trial to optimize the benefit/toxicity ratio of everolimus and sorafenib.

AIM: This novel multiparameter Phase I study aimed to optimize doses/dosing schedules of everolimus and sorafenib drug combination, based on modeling/simulation (NCT01932177). PATIENTS & METHODS: About 26 patients with solid tumors were treated in four different dosing schedules. Everolimus once daily + sorafenib twice daily were given continuously in arms A and B, and intermittently in arms C (alternating every other week) and D (everolimus continuous and sorafenib 3 days on/4 days off). RESULTS: Continuous schedules exhibited higher toxicity risks than intermittent schedules (64.1 vs 35.9%; p < 0.0001), and trends for lower disease control rates (80 vs 100%). No significant pharmacokinetic interaction was identified. CONCLUSION: Feasibility of EVESOR trial is demonstrated. Intermittent schedules might provide better tolerance and efficacy than continuous schedules.

Effect of a topical copper indomethacin gel on inflammatory parameters in a rat model of osteoarthritis.

OBJECTIVE: We aimed to investigate the effect of topical application of a Copper indomethacin (Cu-Indo) gel preparation on monosodium iodoacetate (MIA) induced arthritis of the knee joint of rats and to test our hypothesis that copper complex of indomethacin could be a more potent anti-inflammatory agent than its parent compound. METHODS: After induction of osteoarthritis by the intracapsular injection of 50 µL with 40 mg/mL MIA, we compared the anti-inflammatory efficacy and safety of a topical application of 1% indomethacin gel in a dose of 1 g/kg of the gel (equivalent to 10 mg/kg of the active substance) daily for 3 weeks versus three decremental dose levels of Cu-Indo gel: an equivalent dose, half the dose, and 25% of the dose of indomethacin. Anti-inflammatory efficacy was assessed in all treated groups by measurement of serum inflammatory cytokines: interleukin 6, interleukin 8, and tumor necrosis factor alpha; and by the weekly assessment of knee joint swelling. Joint mobility and motor coordination were also assessed once weekly by the accelerating rotarod apparatus; histopathological examination of affected joints was also performed. Safety of topical application of Cu-Indo (0.25, 0.5, and 1 g/kg) for up to 3 months to rats' skin was determined by the estimation of a complete blood count, liver and kidney functions, and histopathologic examination for target tissues. RESULTS: Cu-Indo gel at lower doses was superior to or at least as effective as its parent substance, indomethacin, in most of the studied parameters of inflammation. The lowest tested dose of Cu-Indo, corresponding to 25% of the parent substance indomethacin, exhibited the highest efficacy in reducing the elevated serum-tested interleukins and in increasing the time of duration on the rotarod test, whereas its effect on reduction of edema and tumor necrosis factor alpha was comparable to that of the others. After 3 months of daily application, there were no notable changes in studied safety parameters with the lowest Cu-Indo dose, but the group treated with the higher dose showed a small but statistically significant increase in serum-unconjugated bilirubin and a slight decrease in hemoglobin levels, red blood cells, and platelet count, with normal indices denoting a slight hemolytic effect at the highest dose. CONCLUSION: Cu-Indo gel has potent anti-inflammatory activity against joint inflammation in the MIA-treated rat model of osteoarthritis at doses of 0.25, 0.5, and 1 g/kg. The lowest studied dose was better on both safety and efficacy parameters.

Tissue distribution and efficacy of gold nanorods coupled with laser induced photoplasmonic therapy in ehrlich carcinoma solid tumor model.

Gold nanorods (GNR) within tumor microregions are characterized by their ability to absorb near IR light and emit heat in what is called photoplasmonic effect. Yet, the efficacy of nanoparticles is limited due to intratumoral tissue distribution reasons. In addition, distribution of GNRs to normal tissue might result in non specific toxicity. In the current study, we are assessing the intratumoral and tissue distribution of PEGylated GNRs on the top of its antitumor characteristics when given intravenously or intratumoral to solid tumor bearing mice and coupled with laser photoplasmonic sessions. PEGylated GNRs with a longitudinal size of less than 100 nm were prepared with aspect ratio of 4.6 showing strong surface plasmon absorption at wavelength 800 nm. Pharmacokinetics of GNR after single I.V. administration (0.1 mg/kg) showed very short systemic circulating time (less than 3 h). On the other hand, tissue distribution of I.V. GNR (0.1 mg/kg) to normal animals showed preferential deposition in spleen tissue. Repeated administration of I.V. GNR resulted in preferential accumulation in both liver and spleen tissues. In addition, I.V. administration of GNR to Ehrlich carcinoma tumor bearing mice resulted in similar tissue distribution; tumor accumulation and anti-tumor effect compared to intratumoral administration. In conclusion, the concentration of GNR achieved within tumors microregions after I.V. administration was comparable to I.T. administration and sufficient to elicit tumoral growth arrest when coupled with laser-aided photoplasmonic treatment.

Antihypercholesterolaemic effect of ginger rhizome (Zingiber officinale) in rats.

INTRODUCTION: Many herbal medicinal products have potential hypocholesterolaemic activity and encouraging safety profiles. However, only a limited amount of clinical research exists to support their efficacy. AIM OF THE WORK: The present study was designed to evaluate the antihypercholesterolaemic effects of aqueous ginger (Zingiber officinale) infusion in hypercholesterolaemic rat models. METHODS: 48 rats were used throughout the experiment, which were divided into six groups, eight animals each as follows: normal control group (normal rats which fed with standard diet). After induction of hypercholesterolaemia by feeding rats with high cholesterol diet, the remaining rats were divided into five groups: group 1, hypercholesterolaemic control group (hypercholesterolaemic rats group); groups 2, 3 and 4, rats were given aqueous infusion of ginger (100, 200 and 400 mg/kg, respectively) orally; and group 5, rats were given atorvastatin (0.18 mg/kg) orally as a reference antihypercholesterolaemic drug. The blood was obtained from all groups of rats after being lightly anaesthetized with ether and the following lipid profile [serum total cholesterol (TC), HDL-cholesterol (HDL-C), LDL-C and triglyceride levels] was measured at zero time and 2 and 4 weeks after ginger and atorvastatin treatment, and the risk ratio (TC/HDL-cholesterol) was assessed. RESULTS: The results revealed that the hypercholesterolaemic rats treated with aqueous ginger infusion in the three doses used after 2 and 4 weeks of treatment induce significant decrease in all lipid profile parameters which were measured and improved the risk ratio.

Polyphenolic profile and bioactivity study of Oenothera speciosa Nutt. aerial parts.

Two new flavonol glycosides, myricetin 4'-O-alpha-L-rhamnopyranoside (1) and quercetin 3'-O-alpha-L-rhamnopyranoside (2), together with a novel biflavonol compound, speciin (3), as well as eleven phenolic metabolites, namely myricitrin (4), europetin 3-O-alpha-L-(1)C(4)-rhamnopyranoside (5), quercitrin (6), hyperin (7), rhamnetin 3-O-beta-galacto-pyranoside (8), caffeic acid (9), caffeic acid methyl ester (10), chlorogenic acid (11), chlorogenic acid methyl ester (12), gallic acid (13) and gallic acid methyl ester (14), were identified from the 80 % methanol extract of the aerial parts (leaves and stems) of Oenothera speciosa Nutt. (Onagraceae). In addition myricetin (15), quercetin (16) and ellagic acid (17) were identified from the chloroform extract. The structures were established depending on their chemical and physical analyses (UV, HR-ESIMS, 1D and 2D NMR). It was found that 80 % aqueous methanol extract of O. speciosa is non-toxic to mice up to 5 g kg(-1)b wt. The investigated extract exhibited significant antihyperglycaemic and anti-inflammatory activities in a dose dependant manner. Also, the 80 % methanol extract, myricitrin(4) and hyperin(7) showed potent antioxidant activity in vitro using 1,1-diphenyl 2-picryl hydrazyl (DPPH) radical assay.

Comparative evaluation of the protective effect of selenium and garlic against liver and kidney damage induced by mercury chloride in the rats.

The present study was designed to compare the protective effect of selenium and garlic against liver and kidney damage induced by (ip) injection of 0.5 mg/kg mercury chloride (HgCl(2)) in rats. Thirty-six Sprague-Dawley rats were used in the present experiment and divided into six groups: one group was orally given (1 ml) saline and served as a control group; two groups of rats were given either selenium (0.1 mg/kg) or garlic (63 mg/kg) alone, once daily an oral dose for 30 successive days; other two groups of rats were given either selenium or garlic alone, once daily a dose for 15 successive days prior to HgCl(2) injection and on the next 15 successive days simultaneously with HgCl(2) injection; and the last group of rats was injected ip with HgCl(2) for 15 days and at the end of the experiment (which lasted 30 days), blood samples for the biochemical analysis were obtained from all rats after being lightly anesthetized with ether, and specimens of kidney and liver were removed and prepared for histochemical study. Computer image analysis was applied to liver and kidney tissues to evaluate the DNA density and DNA ploidy pattern in different groups. The results revealed that the rats injected with HgCl(2) showed a significant increase in levels of blood urea nitrogen (BUN), serum creatinine, alanine aminotransferase (ALT), aspartate aminotransferase (AST) by 29.3%, 62.5%, 29.46% and 30.61%, respectively, while alkaline phosphatase (ALP) showed a significant decrease by 22.6% as compared with saline control group. Rats that were given selenium in combination with the HgCl(2) injection showed a significant decrease in BUN, Serum creatinine, ALT and AST levels, while ALP was significantly increased as compared with HgCl(2) group. Also rats that were given garlic in combination with HgCl(2) injection showed a significant decrease in BUN, Serum creatinine, ALT and AST levels, although serum ALP level showed an increase as compared to HgCl(2) group. Rats that had been orally administered selenium or garlic alone did not show any significant changes in the serum level of BUN, Serum creatinine, ALT and AST but there was a significant decrease in ALP level as compared with saline control group. The cytometric results revealed that injection of HgCl(2) induced an increase in the DNA density in kidney tissues with an increase in aneuploid cells and decrease in diploid cells. However, DNA density decreased in liver tissues with mild decrease in diploid cells and little percentage of aneuploid cells. We can conclude that oral administration of either selenium or garlic produces a significant protection against liver and kidney damage induced by the HgCl(2) injection, but garlic appears to be more protective.

Antinociceptive and anti-inflammatory steroidal saponins from Dracaena ombet.

Two new steroidal saponins, namely (25R)-5beta-spirostan-3-beta-ol 3-O-beta-D-galactopyranosyl-(1'''-->4'')-O-beta-D-galactopyranosyl-(1''-->3')-O-beta-D-glucopyranoside (2), and (25R)-5beta-spirostan-3-beta-ol 3-O-beta-D-galactopyranosyl-(1'''-->4'')-O-beta-D-glucopyranosyl-(1''-->3')-O-beta-D-glucopyranoside (3), together with six known constituents, have been isolated from the leaves of Dracaena ombet Kotschy & Peyr. (Dracaenaceae). The structures of the two saponins were established by chemical and physicochemical analyses, including FAB- and HR-ESI-MS and 2D NMR. The fraction rich in saponins showed significant analgesic and anti-inflammatory activities (at a high dose of 30 mg/kg b.w.) and non-significant antiulcer activities at the same doses.

Evaluation of the anti-inflammatory and anti-nociceptive effects of different antidepressants in the rat.

The present study was designed to compare the anti-inflammatory and anti-nociceptive effects of different classes of antidepressant drugs on the carrageenan paw oedema and tail-electric stimulation assays in the rat. Drugs were intraperitoneally administered 30 min prior to carrageenan or nociceptive testing. The non-selective noradrenaline (NA) and serotonin (5-HT) reuptake inhibitors imipramine, amitriptyline and clomipramine displayed anti-inflammatory activity in the carrageenan model of paw inflammation. The maximal degree of oedema inhibitions seen with these agents were 28.8, 41.5 and 46.8% for 5, 10 and 20 mg kg(-1) amitriptyline, 26.2, 38.2 and 51.4% for 3.75, 7.5 and 15 mg kg(-1) imipramine and 51.2 and 54.1% for 16 and 32 mg kg(-1) clomipramine, respectively. The heterocyclic agent trazodone significantly inhibited paw oedema by 46 and 41% at 1 and 2h after dosing at the highest dose (40 mg kg(-1)) examined. Fluoxetine, a selective 5-HT reuptake inhibitor (SSRI) caused dose-related reduction of paw oedema, with 20.7% inhibition at the dose of 10 mg kg(-1). In contrast, sertraline, another SSRI caused dose-dependent enhancement of paw oedema. All antidepressant drugs in the study showed anti-nociceptive properties in the tail-electric stimulation assay with amitriptyline and trazodone being the most effective in this respect. Taken together, data in the present study confirm anti-inflammatory and anti-nociceptive effect for some antidepressant drugs and indicate that SSRIs differently affects inflammation.