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Quercetin is a plant-derived flavonoid widely known by its anti-oxidant and anti-inflammatory properties, but its oral bioavailability is very poor and this becomes difficult to assess its therapeutic potential. Here we have compared the anti-inflammatory effect of quercetin-loaded microemulsion (QU-ME) and quercetin suspension (QU-SP) in an experimental model of airways allergic inflammation. Mice received daily oral doses of QU-ME (3 or 10mg/kg; in an oil-in-water microemulsion content 0.02:0.2:1 of lecithin:castor oil:Solutol HS15((R))), QU-SP [10mg/kg, in carboxymethylcellulose (CMC) 0.5% in water] or vehicle from the 18th to the 22nd day after the first immunization with ovalbumin (OVA). Dexamethasone was used as positive control drug. Every parameter was evaluated in the 22nd day (24h after the second OVA-challenge). We have also tried to assess by HPLC-MS a quercetin metabolite in the blood of rats treated with QU-SP or QU-ME. QU-ME was better orally absorbed when compared with QU-SP. Furthermore, oral administration of QU-SP failed to interfere with leukocyte recruitment, while QU-ME inhibited in a dose-dependent way, the eosinophil recruitment to the bronchoalveolar lavage fluid (BALF). QU-ME also significantly reduced both IL-5 and IL-4 levels, but failed to interfere with CCL11, IFN-gamma and LTB(4) levels. In addition, QU-ME oral treatment inhibited the nuclear transcription factor kappa B (NF-kappaB) activation, P-selectin expression and the mucus production in the lung. The present results show that QU-ME exhibits pronounced anti-inflammatory properties in a murine model of airways allergic inflammation and suggest that it might present therapeutic potential for the airways inflammatory diseases management.

The present study examined the antinociceptive effect of the ethanolic extract from Melissa officinalis L. and of the rosmarinic acid in chemical behavioral models of nociception and investigates some of the mechanisms underlying this effect. The extract (3-1000 mg/kg), given orally (p.o.) 1 h prior to testing, produced dose-dependent inhibition of acetic acid-induced visceral pain, with ID50 value of 241.9 mg/kg. In the formalin test, the extract (30-1000 mg/kg, p.o.) also caused significant inhibition of both, the early (neurogenic pain) and the late (inflammatory pain), phases of formalin-induced licking. The extract (10-1000 mg/kg, p.o.) also caused significant and dose-dependent inhibition of glutamate-induced pain, with ID50 value of 198.5 mg/kg. Furthermore, the rosmarinic acid (0.3-3 mg/kg), given p.o. 1 h prior, produced dose-related inhibition of glutamate-induced pain, with ID50 value of 2.64 mg/kg. The antinociception caused by the extract (100 mg/kg, p.o.) in the glutamate test was significantly attenuated by intraperitoneal (i.p.) treatment of mice with atropine (1 mg/kg), mecamylamine (2 mg/kg) or l-arginine (40 mg/kg). In contrast, the extract (100 mg/kg, p.o.) antinociception was not affected by i.p. treatment with naloxone (1 mg/kg) or D-arginine (40 mg/kg). It was also not associated with non-specific effects, such as muscle relaxation or sedation. Collectively, the present results suggest that the extract produced dose-related antinociception in several models of chemical pain through mechanisms that involved cholinergic systems (i.e. through muscarinic and nicotinic acetylcholine receptors) and the L-arginine-nitric oxide pathway. In addition, the rosmarinic acid contained in this plant appears to contribute for the antinociceptive property of the extract. Moreover, the antinociceptive action demonstrated in the present study supports, at least partly, the ethnomedical uses of this plant.

A quantitative study was undertaken to assess the plasma and tissue levels, tissue distribution and skin (ear) absorption of the sesquiterpene alpha-humulene, the main active constituent isolated from the plant Cordia verbenacea (Boraginaceae ), after oral, intravenous and topical administration in mice. The alpha-humulene levels were quantified by GC-MS analysis. The peak alpha-humulene concentration was achieved 15 min following its oral administration (150 mg/kg). Then, the alpha-humulene plasma concentration gradually decreased and it was almost undetectable at 2 hours after intravenous administration and 12 hours after oral administration. When the oil of C. verbenacea was given orally (1 g/kg), the peak alpha-humulene plasma concentration was observed after 30 min, being detectable only up to 2 h. The oral bioavailability of alpha-humulene was found to be 18 %. The half-lives of alpha-humulene were very short, 16.8 min after oral administration and 1.8 min after intravenous administration. However, the elimination half-lives were longer, 118.2 min and 55 min, for oral and intravenous routes, respectively. We also assessed the amount of alpha-humulene in some selected tissues at 0.5 and at 4 h after oral administration. We found a high amount of the compound in the liver, followed by the kidneys, heart, lungs, spleen and brain, 0.5 h after oral administration. Notably, the yield of alpha-humulene decreased significantly in all analyzed tissues, especially in the liver, 4 h after oral administration. Of note, 30 minutes after topical administration of Acheflan formulations (cream and aerosol) containing 0.5 % of C. verbenacea essential oil, a schedule of treatment that produces marked and similar topical anti-inflammatory activity, the amount of alpha-humulene absorbed in the ear was very similar (about 2 microg/ear). It is concluded that alpha-humulene exhibited a rapid onset and relatively good absorption following oral and topical administration. Taken together, these findings further contribute to an explanation of the topical and systemic anti-inflammatory and antinociceptive properties previously reported for the essential oil and for alpha-humulene obtained from Cordia verbenacea, they also provide support for the clinical studies conducted with the phytomedicine Acheflan.

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