Amalia Ubeda

Synthesis and anti-inflammatory activity of chalcone derivatives

Chalcones and their derivatives were synthesized and evaluated for their anti-inflammatory activity. In vitro, chalcones 2, 4, 8, 10 and 13 inhibited degranulation and 5-lipoxygenase in human neutrophils, whereas 11 behaved as scavenger of superoxide. Only four compounds (4-7) inhibited cyclo-oxygenase-2 activity. The majority of these samples showed anti-inflammatory effects in the mouse air pouch model.

Novel anti-inflammatory chalcone derivatives inhibit the induction of nitric oxide synthase and cyclooxygenase-2 in mouse peritoneal macrophages

In a previous work, we tested a series of chalcone derivatives as possible anti‐inflammatory compounds. We now investigate the effects of three of those compounds, CH1, CH8 and CH12, on nitric oxide and prostanoid generation in mouse peritoneal macrophages stimulated with lipopolysaccharide and in the mouse air pouch injected with zymosan, where they showed a dose‐dependent inhibition with inhibitory concentration 50% values in the μM range. This effect was not the consequence of a direct inhibitory action on enzyme activities. Our results demonstrated that chalcone derivatives inhibited de novo inducible nitric oxide synthase and cyclooxygenase‐2 synthesis, being a novel therapeutic approach for inflammatory diseases.

Iron-reducing and free-radical-scavenging properties of apomorphine and some related benzylisoquinolines.

The scavenging and iron-reducing properties of a series of benzylisoquinolines of natural and synthetic origin have been studied. Bulbocapnine, boldine, glaucine, and stepholidine acted as scavengers of hydroxyl radical in the deoxyribose degradation by Fe(3+)-EDTA + H2O2. On the contrary, laudanosoline, apomorphine, protopapaverine, anonaine, and tetrahydroberberine increased deoxyribose degradation by a mechanism related to generation of superoxide anion. Only apomorphine had a stimulating effect in the system using citrate instead of ethylenediaminetetraacetic acid (EDTA) as well as in the absence of chelator. Apomorphine also stimulated DNA damage by Cu2+. The iron-ion reducing ability of apomorphine and laudanosoline was confirmed using cytochrome c. Both compounds scavenged peroxyl radicals in an aqueous medium, while in Fe(3+)-induced microsomal lipid peroxidation apomorphine acted as an inhibitor and laudanosoline stimulated the process. It is suggested that in microsomes the chain-breaking antioxidant properties of apomorphine overcome its possible influence on redox cycling of iron, or prooxidant properties.

Effect of bakuchiol on leukocyte functions and some inflammatory responses in mice

The effects of bakuchiol, a meroterpenoid isolated from the leaves of Psoralea glandulosa L., on phospholipase A2 (PLA2) activity from different sources, human neutrophil responses, zymosan air pouch and topical inflammation in mice, were investigated.

INHIBITION OF INFLAMMATORY RESPONSES BY EPITAONDIOL AND OTHER MARINE NATURAL PRODUCTS

The marine metabolites pacifenol, stypotriol triacetate and epitaondiol were tested for their effects on a number of inflammatory responses. Epitaondiol exhibited a potent topical anti-inflammatory activity related to inhibition of leukocyte accumulation. The other compounds showed a lower potency, similar to that of indomethacin. None of the compounds affected superoxide generation by human neutrophils but pacifenol effectively inhibited the degranulation response. This compound and epitaondiol decreased the release of eicosanoids with a higher potency on the cyclo-oxygenase pathway. Only epitaondiol inhibited human recombinant synovial phospholipase A2 activity in a concentration-dependent manner.

ANTIOXIDANT PROFILE OF MONO- AND DIHYDROXYLATED FLAVONE DERIVATIVES IN FREE RADICAL GENERATING SYSTEMS

Abstract A number of free radical generating systems were used to investigate the antioxidant properties and structure-activity relationships of a series of monohydroxylated and dihydroxylated flavones. Ortho-dihydroxylated flavones showed the highest inhibitory activity on en zymic and non-enzymic microsomal lipid peroxidation as well as on peroxyl radical scavenging. Most flavones were weak scavengers of hydroxyl radical, while ortho-dihydroxylated flavones interacted with superoxide anion generated by an enzymic system or by human neutrophils. This series of compounds did not exert cytotoxic effects on these cells. Scavenging of superoxide and peroxyl radicals may determ ine the antioxidant properties of these active flavones.

Prostaglandin D2 regulates joint inflammation and destruction in murine collagen-induced arthritis.

OBJECTIVE Prostaglandin D2 (PGD2) may exert proinflammatory or antiinflammatory effects in different biologic systems. Although this prostanoid and the enzymes responsible for its synthesis are up-regulated by interleukin-1β (IL-1β) in human chondrocytes in vitro, the role of PGD2 in arthritis remains unclear. This study was undertaken to investigate the role of PGD2 in the inflammatory response and in joint destruction during the development of collagen-induced arthritis (CIA) in mice. METHODS PGD2 and cytokine levels in mice with CIA were determined by enzyme-linked immunosorbent assay. Expression of hematopoietic PGD synthase (h-PGDS), lipocalin-type PGD synthase (l-PGDS), and DP1 and DP2 receptors was analyzed by immunohistochemical methods. PGE2 levels were determined by radioimmunoassay. RESULTS The arthritic process up-regulated the expression of h-PGDS, l-PGDS, DP1, and DP2 in articular tissue. PGD2 was produced in the joint during the early phase of arthritis, and serum PGD2 levels increased progressively throughout the arthritic process, reaching a maximum during the late stages of CIA. Treatment of arthritic mice with the DP1 antagonist MK0524 soon after the onset of disease increased the incidence and severity of CIA as well as the local levels of IL-1β, CXCL-1, and PGE2, whereas IL-10 levels were reduced. The administration of the DP2 antagonist CAY10595 did not modify the severity of arthritis. The injection of PGD2 into the paw, as well as the administration of the DP1 agonist BW245C, significantly lowered the incidence of CIA, the inflammatory response, and joint damage. CONCLUSION Our findings indicate that PGD2 is produced in articular tissue during the development of CIA and plays an antiinflammatory role, acting through the DP1 receptor.

Antidepressant utilization in primary care in a Spanish region: impact of generic and reference-based pricing policy (2000-2004).

ObjectiveTo describe the evolution of antidepressant use in primary care in the Valencian region (Spain) from 2000 to 2004 and to analyze the effects of reference-based price and generic drugs introduction on drug utilization and cost saving.MethodsRetrospective observational study in primary care using sales data collected from antidepressant group (N06A), corresponding to the period 2000–2004. Defined daily dose (DDD)/1000 inhabitants per day were obtained as consumption data. Cost and cost/DDD rate evolution was related to reference price system implantation.ResultsAntidepressant utilization progressively increased by 44.0% from 30.3 DDDs/1000 per day in 2000 to 43.5% in 2004. Selective serotonin reuptake inhibitors (SSRIs) comprised 77% of the total consumption where paroxetine, sertraline and fluoxetine were the most used drugs in 2004. The proportion of relative use and cost of fluoxetine declined after a reference price and the introduction of generic competitors were put into effect in 1999; cost/DDD was reduced by 1.8. Third-generation antidepressants showed a fast rising rate i.e. venlafaxine utilization multiplied by 2.2; this drug with the higher cost/DDD was not subjected to the reference price system. Reduction in citalopram utilization was related to a replacement by its recently marketed enantiomer escitalopram.ConclusionsIn 2004, reference price policy and the implementation of generic drugs reduced the antidepressant cost by DDD. However, antidepressant expenditure increased since 2000 due to a continued growth in consumption (SSRIs and novel agents) and a displacement of prescriptions to drugs that were not included in the reference price policy.

Blood pressure reduction in hypertensive patients after withdrawal of effervescent medication

Raised blood pressure associated with the sodium excipient content of soluble or effervescent analgesic has been previously reported. However, the influence of other anions associated with sodium on blood pressure is still controversial.

Effect of imidazo[1,2-α]pyrimidine derivatives on leukocyte function

Abstract:Objective and Design: A series of six imidazo[1,2-α]pyrimidine (IP) derivatives were evaluated for their effects on leukocyte functions in vitro as well as on the inflammatory response induced by zymosan in the mouse air pouch.¶Materials and Subjects: Human neutrophils and murine peritoneal macrophages were used for in vitro assays. Mouse air pouch was performed in Swiss mice.¶Treatment: Test compounds were incubated with either human neutrophils or mouse peritoneal macrophages at concentrations not showing cytotoxic effects. For in vivo experiments, IPs were injected into the air pouch.¶Methods: Elastase and myeloperoxidase release, superoxide generation and LTB4 production were assayed in human neutrophils treated with different stimuli. Mouse peritoneal macrophages were stimulated with lipopolysaccharide (LPS), followed by determination of nitrite and PGE2 levels in supernatants. Zymosan was injected into six days-old mouse air pouches. Dunnetts t-test was employed for statistical analysis.¶Results: All IPs inhibited human neutrophil degranulation with IC50 values in the μM range. IP-1, IP-2 and IP-5 also decreased superoxide generation. In LPS-stimulated macrophages, IP-4 and IP-6 inhibited nitrite production with a moderate reduction in PGE2 generation. In addition, these two compounds at 100 nmol/pouch inhibited leukocyte migration and LTB4 levels in the exudate of the mouse air pouch.¶Conclusions: Imidazo[1,2-α]pyrimidines are a class of compounds with antiinflammatory potential.