Publications (123) View all
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Article: Novel Analgesic/Anti-inflammatory Agents: 1,5-Diarylpyrrole Nitro-oxyalkyl Ethers and Related Compounds as Cyclooxygenase-2 Inhibiting Nitric Oxide Donors.
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ABSTRACT: A series of 3-substituted 1,5-diarylpyrroles bearing a nitro-oxyalkyl side chain linked to different spacers were designed. New classes of pyrrole-derived nitro-oxyalkyl-inverse esters, -carbonate and -ethers (7-10), as COX-2 selective inhibitors and NO donors were synthesized and are herein reported. By taking into account the metabolic conversion of nitro-oxyalkyl ethers (9,10) into corresponding alcohols, derivatives 17 and 18 were also studied. Nitro-oxy derivatives showed NO-dependent vasorelaxing properties while most of the compounds proved to be very potent and selective COX-2 inhibitors in in vitro experimental models. Further in vivo studies on compounds 9a,c and 17a, highlighted good anti-inflammatory and anti-nociceptive activities. Compound 9c was able to inhibit glycosaminoglycans (GAG) release induced by interleukin-1β (IL-1β), showing cartilage protective properties. Finally, molecular modeling, (1)H- and (13)C-NMR studies performed on compounds 6c,d, 9c and 10b allowed the right conformation of nitro-oxyalkyl ester and -ether side chain of these molecules within the COX-2 active site to be assessed.Journal of Medicinal Chemistry 03/2013; · 4.80 Impact Factor -
Article: Myrtucommulone from Myrtus communis: Metabolism, Permeability, and Systemic Exposure in Rats.
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ABSTRACT: Nonsteroidal anti-inflammatory drug intake is associated with a high prevalence of gastrointestinal side effects, and severe cardiovascular adverse reactions challenged the initial enthusiasm in cyclooxygenase-2 inhibitors. Recently, it was shown that myrtucommulone, the active ingredient of the Mediterranean shrub Myrtus communis, dually and potently inhibits microsomal prostaglandin E2 synthase-1 and 5-lipoxygenase, suggesting a substantial anti-inflammatory potential. However, one of the most important prerequisites for the anti-inflammatory effects in vivo is sufficient bioavailability of myrtucommulone. Therefore, the present study was aimed to determine the permeability and metabolic stability in vitro as well as the systemic exposure of myrtucommulone in rats. Permeation studies in the Caco-2 model revealed apparent permeability coefficient values of 35.9 · 10-6 cm/s at 37 °C in the apical to basolateral direction, indicating a high absorption of myrtucommulone. In a pilot rat study, average plasma levels of 258.67 ng/mL were reached 1 h after oral administration of 4 mg/kg myrtucommulone. We found that myrtucommulone undergoes extensive phase I metabolism in human and rat liver microsomes, yielding hydroxylated and bihydroxylated as well as demethylated metabolites. Physiologically-based pharmacokinetic modeling of myrtucommulone in the rat revealed rapid and extensive distribution of myrtucommulone in target tissues including plasma, skin, muscle, and brain. As the development of selective microsomal prostaglandin E2 synthase-1 inhibitors represents an interesting alternative strategy to traditional nonsteroidal anti-inflammatory drugs and cyclooxygenase-2 inhibitors for the treatment of chronic inflammation, the present study encourages further detailed pharmacokinetic investigations on myrtucommulone.Planta Medica 11/2012; · 2.15 Impact Factor -
Article: Evaluation of cosmetic product exposures reported to the Milan Poison Control Centre, Italy from 2005 to 2010.
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ABSTRACT: Introduction. To the average consumer, "cosmetics" are not considered to cause damage to human health under normal conditions of use. Thus, cosmetic "safety" does not require any particular attention to the possibility that cosmetics may result in a toxic exposure, especially for children. Poison Control Centres (PCCs) provide specialized and rapid information for consumers and health professionals to ensure management of events related to the exposures to different agents, including Cosmetics. Poison Control Centres also represent a unique source of information to investigate the frequency and type of exposures to cosmetic and the related risks. Objective. An analysis of cases concerning human exposures to cosmetics collected from 2005 to 2010 by the PCC at the Ospedale Niguarda Ca' Granda (Milan, Italy) was performed. Results. During this period, 11 322 human exposure cases related to cosmetics were collected accounting for 4.5% of the total human clinical cases. Almost, all the requests for assistance came from consumers (53%) and hospitals (40%). The most frequently reported site of exposure was the consumer's own residence (94%). The exposures mainly involved children younger than 4 years (77%). No difference in gender distribution was observed (female 49%, male 51%). Almost, all of the exposures were unintentional (94%). Intentional exposures, mainly related to suicide attempts and accounted for 6% of cases involving persons aged more than 12 years. Personal hygiene products (30%), perfumes and hair care products (excluding hair dyes) (both 13%) were the most frequently involved categories. Symptoms were present only in 26% of the exposures and were mostly gastrointestinal (46%). Most of the cases were managed at home (43%) whereas hospital intervention was required in 38%. Conclusion. Since the exposure frequency seems more likely to reflect product availability and accessibility to ingestors, our results call for closer attention to this type of hazard, especially for children younger than 4 years of age.Clinical Toxicology 11/2012; · 2.22 Impact Factor -
Article: Improving the solubility of a new class of antiinflammatory pharmacodynamic hybrids, that release nitric oxide and inhibit cycloxygenase-2 isoenzyme.
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ABSTRACT: The development of a novel class of pharmacodynamic hybrids that inhibits COX-2 isoform is reported. These molecules display enhanced nitric oxide releasing properties due to the presence of an ionisable moiety. The in vivo analgesic/anti-inflammatory activity was maintained in relation to the parent compounds.European journal of medicinal chemistry 10/2012; 58C:287-298. · 3.27 Impact Factor -
Article: The novel Sinupret® dry extract exhibits anti-inflammatory effectiveness in vivo.
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ABSTRACT: Sinupret® is frequently used as a herbal medicinal product to treat sinusitis, and it was assumed that anti-inflammatory effects might contribute to its overall beneficial properties. Here, we investigated the effects of a Sinupret® drug mixture (SIN) as well as of the novel Sinupret® dry extract (SIN DE) with the latter containing higher concentrations of active ingredients, in an in vivo model of acute inflammation, the carrageenan-induced pleurisy in rats. Both SIN and SIN DE were administered to rats orally at doses of 100mg/kg (low dose) and 500mg/kg (high dose) 1h prior to intrapleural injection of carrageenan. Although both SIN and SIN DE significantly reduced the exudate volume and leukocyte numbers in the pleural exudate at the high and the low dose 4h after carrageenan injection, the novel SIN DE was more efficient than SIN at the low dose, implying higher efficiency. In parallel, the novel dry extract SIN DE, but not SIN, at 500mg/kg significantly lowered the levels of prostaglandin (PG)E(2) in the exudates and reduced the amounts of cyclooxygenase (COX)-2 protein in the lungs. Together, SIN and SIN DE exert significant oral anti-inflammatory effects, which rationalize their therapeutic use in the management of sinusitis and other viral/microbial nasal infections that are associated with inflammation. Moreover, our results suggest that based on the higher efficiency and the accompanied reduction of COX-2 expression and PGE(2) formation, the novel dry extract SIN DE might be superior over the former SIN drug mixture.Fitoterapia 03/2012; 83(4):715-20. · 1.85 Impact Factor
