Mechanisms underlying the anti-inflammatory activity and gastric safety of acemetacin.

BACKGROUND AND PURPOSE: Acemetacin is regarded as a pro-drug of indomethacin and induces significantly less gastric damage but the reasons for this greater gastric safety of acemetacin are unclear. The anti-inflammatory effects of acemetacin have been attributed, at least in part, to its hepatic biotransformation to indomethacin. The aim of this study was to determine the effects of acemetacin and indomethacin in an in vivo model of acute inflammation and to examine the importance of biotransformation of acemetacin (to indomethacin) to its anti-inflammatory actions. EXPERIMENTAL APPROACH: The zymosan airpouch model was used in rats. Indomethacin or acemetacin (2.7-83.8 micromol kg(-1)) were administered orally or directly into the pouch. Leukocyte infiltration, prostaglandin (PG) E(2) and leukotriene (LT) B(4) levels in exudates, and whole blood thromboxane (TX) B(2) synthesis were measured. KEY RESULTS: Acemetacin was rapidly converted to indomethacin after its administration. Both acemetacin and indomethacin elicited comparable, dose-dependent reductions of leukocyte infiltration and of PGE(2) and TXB(2) synthesis. However, indomethacin induced more gastric damage than acemetacin and elevated LTB(4) production in the airpouch. CONCLUSIONS AND IMPLICATIONS: The similar effects of acemetacin and indomethacin on leukocyte infiltration and PG synthesis are consistent with rapid biotransformation of acemetacin to indomethacin. Some of this biotransformation may occur extra-hepatically, for instance in inflammatory exudates. Acemetacin probably exerts actions independent of conversion to indomethacin, given the different effects of these two drugs on LTB(4) production. Such differences may contribute to the relative gastric safety of acemetacin compared to indomethacin.

Role of interferon-alpha in arachidonic acid metabolism by the rat uteri from spayed animals: effect of 17 beta-estradiol.

Interferon-like trophoblastic proteins modulate prostaglandin (PG) synthesis from endometrium in early ovine and bovine pregnancy. We attempted to explore the effect of interferon (IFN)-alpha in the isolated rat uterus from ovariectomized animals on the metabolism of labelled arachidonic acid (AA). The experiments were performed with uterine preparations isolated from spayed rats treated or untreated with 17 beta-estradiol prior to sacrifice. The pre-incubation of uterine tissue isolated from ovariectomized rats with three different doses (4, 150 and 300 IU/ml) of IFN-alpha decreased the radioconversion of [14C]AA into 6-keto PGF1 alpha, PGF2 alpha and PGE2, whereas the formation of thromboxane B2 (TXB2) decreased after treatment with 4 IU/ml of INF-alpha but was augmented with 150 and 300 IU/ml. The three doses used diminished the synthesis of 5-hydroxyeicosatetraenoic acid (5-HETE) and increased the production of 12-HETE. We also studied the synthesis of uterine products of cyclooxygenase and lipoxygenase in uterine tissue from ovariectomized rats injected with 17 beta-estradiol and preincubated with IFN-alpha. We found that the three doses of IFN-alpha diminished the production of 6-keto-PGF1 alpha, PGE2, PGF2 alpha and TXB2 as well as 5-HETE and 12-HETE. These findings show that IFN-alpha modifies the basal synthesis of PGs from uterine tissue. Ovine and bovine trophoblastic protein prevents luteolysis by inhibiting the synthesis of PGF2 alpha. On the other hand, IFN-alpha shows 70% homology with ovine trophoblastic protein and binds to the same receptor. The results of the present study suggest that IFN-alpha may also act in the rat as a luteotrophic agent.

Antiphospholipid antibodies enhance thrombin-induced platelet activation and thromboxane formation.

In a group of 6 patients with lupus anticoagulant (LA) and antiphospholipid (aPL) antibodies detected by ELISA overnight urine and blood were simultaneously collected. A significantly increased urinary excretion of the platelet-derived thromboxane (TX) metabolite 11-dehydro-TXB2 was found in this group, as compared to 12 healthy individuals. In contrast, a small but significant reduction of the vascular prostacyclin (PGI2) metabolite 2,3-dinor-6-keto-prostaglandin F1 alpha was observed. To further elucidate the effect of these antibodies on platelet activation we isolated the F(ab')2 fragments from IgG of the 6 patients and 5 controls, and we evaluated the effect of these fragments on the responses of isolated normal platelets to thrombin. Patients' F(ab')2 increased platelet aggregation and serotonin release of platelets stimulated by low dose thrombin (0.01 U/ml). At threshold thrombin concentration (0.05 U/ml) an enhanced TXB2 production was also observed. In summary, our results show, in addition to the altered TXA2/PGI2 balance observed in vivo, a direct stimulatory effect of aPL antibodies on platelet activation in vitro. This effect is related to recognition of phospholipid epitopes on platelets as shown by its neutralization upon preincubation with phospholipids. This phenomenon may be relevant for the thrombotic tendency of these patients.

[Omega-6 and omega-3 polyunsaturated fatty acids in healthy and sick children under 5. I. Normal metabolism]. / Acidos grasos poliinsaturados omega 6 y omega 3 en niños sanos y enfermos menores de 5 años. Parte I. Metabolismo normal.

The polyunsaturated fatty acids, omega 6 and omega 3, are organic compounds that have to do with the daily caloric intake; the tissue deposits of energy reserve, as well as the general intermediary metabolism of the human organisms and the composition of all the cellular membranes. This article is about its general characteristics: chemical structure, essenciality, biosynthesis, and physiological and metabolical functions; its compounds and metabolites derived; its organic distribution, and the quantity found in food in general. Of all these, special emphasis are made on the essenciality of linoleic and alpha-linolenic acids, due to its metabolic importance.

An aqueous extract of guaraná (Paullinia cupana) decreases platelet thromboxane synthesis.

The effects of an aqueous extract of guaraná (Paullinia cupana) on rabbit platelet aggregation and thromboxane synthesis were examined. The guaraná extract (100 mg/ml) and fractions separated by TLC (origin and xanthines) decreased platelet aggregation (37, 27 and 31% of control values, respectively) and platelet thromboxane formation from [14C]-arachidonic acid (78, 70 and 50% of control values, respectively). The decreased thromboxane synthesis could be responsible, at least in part, for the antiaggregatory action of guaraná.

An aqueous extract of guaraná (Paullinia cupana) decreases platelet thromboxane synthesis

The effects of an aqueous extract of guaraná (Paullinia cupana) on rabbit platelet aggregation and thromboxane synthesis were examined. The guaraná extract (100 mg/ml) and fractions separated by TLC (origin and xanthines) decreased platelet aggregation (37.27 and 31% of control values, respectively) and platelet thromboxane formation from [14C]-arachidonic acid (78, 70 and 50% of control values respectively). The decreased thromboxane synthesis could be responsible, at least in part, for the antiaggregatory action of guaraná

Production of thromboxanes by transformed lymphocytes--effect on heart contractility.

We studied the effect of transformed lymphocytes from patients with chronic lymphocytic leukaemia (CLL) and the Raji cell (Raji) on the response of rat isolated atria to sodium arachidonate (AA). In contrast to normal lymphocytes, CLL cells and Raji cells decrease the contractile tension of rat isolated atria. Addition of exogenous AA (1.98 X 10(-6) M) to Raji, further reduced the isometric developed tension. Time of culture of Raji was important, as the negative inotropic effect was greater at 72 h than at 24 h of culture. Living cells were required and cell-free supernatants were inactive. Preincubation of CLL cells or Raji with cyclooxygenase inhibitors (acetyl salycilic acid, indomethacin) or inhibitors of thromboxane (TX) synthesis (imidazole, L-8027) abolished the negative inotropic response suggesting the contribution of TXs. L-8027 also reduced the growth rate of Raji cells, indicating that TXs may play a role in the regulation of cell division. The production of TXs by CLL and Raji cells from both endogenous and exogenous sources provided additional support to this hypothesis and suggested that activation of this metabolic pathway may be related to cell transformation.

Impaired cytoplasmic ionized calcium mobilization in inherited platelet secretion defects.

Defects in platelet cytoplasmic Ca++ mobilization have been postulated but not well demonstrated in patients with inherited platelet secretion defects. We describe studies in a 42-year-old white woman, referred for evaluation of easy bruising, and her 23-year-old son. In both subjects, aggregation and 14C-serotonin secretion responses in platelet-rich plasma (PRP) to adenosine diphosphate (ADP), epinephrine, platelet activating factor (PAF), arachidonic acid (AA), U46619, and ionophore A23187 were markedly impaired. Platelet ADP and adenosine triphosphate (ATP), contents and thromboxane synthesis induced by thrombin and AA were normal. In quin2-loaded platelets, the basal intracellular Ca++ concentration, [Ca++]i, was normal; however, peak [Ca++]i measured in the presence of 1 mmol/L external Ca++ was consistently diminished following activation with ADP (25 mumol/L), PAF (20 mumol/L), collagen (5 micrograms/mL), U46619 (1 mumol/L), and thrombin (0.05 to 0.5 U/mL). In aequorin-loaded platelets, the peak [Ca++]i studied following thrombin (0.05 and 0.5 U/mL) stimulation was diminished. Myosin light chain phosphorylation following thrombin (0.05 to 0.5 U/mL) stimulation was comparable with that in the normal controls, while with ADP (25 mumol/L) it was more strikingly impaired in the propositus. We provide direct evidence that at least in some patients with inherited platelet secretion defects, agonist-induced Ca++ mobilization is impaired. This may be related to defects in phospholipase C activation. These patients provide a unique opportunity to obtain new insights into Ca++ mobilization in platelets.