alpha1-Acid glycoprotein production in rat dorsal air pouch in response to inflammatory stimuli, dexamethasone and honey bee venom.

This study shows the rapid and differential production of the 40-43 kDa and the 70-90 kDa alpha1-acid glycoprotein (AGP) fucosylated glycoforms after treatment of the dorsal air pouch with bacterial lipopolysaccharide (LPS), HgCl(2) or Freund's complete adjuvant (FCA). The 40-43 kDa and the 70-90 kDa AGP production is peaked 1-3 h post-LPS treatment. We observed that the responses to LPS and FCA are similar in that both AGP isoforms are induced whereas they differ in that the FCA exhibits a 6 h lag period. The response to HgCl(2,) however, exhibits the specific biphasic induction only of the 40-43 kDa AGP. The serum 40-43 kDa AGP glycoform gradually increases in response to all of the above stimulants and peaks by 24 h post- treatment. The increase of the 70-90 kDa AGP levels in the air pouch occurs in association with the accumulation of polymorphonuclear (PMN) cells while dexamethasone (DEX) increases only the 40-43 kDa AGP production in the absence of PMN accumulation. Macrophage-monocyte lineage cells forming the air pouch lining tissue may potentially be the cells that secrete the 40-43 kDa AGP while polymorphonuclear cells that infiltrate the air pouch secrete the 70-90 kDa AGP. The 40-43 kDa and 70-90 kDa AGP production induced by LPS in the air pouch precedes that of interleukin-1 (IL-1) or interleukin-6 (IL-6) while the 40-43 kDa AGP glycoform potentially increases IL-6 production by air pouch PMN exudate cells. These significant differences suggest a local pro-inflammatory role of AGP. Honeybee venom suppressed arthritis development and exhibited differential local or systemic regulation of AGP in serum vs. air pouch exudate or synovial fluid. This study with the air pouch model of facsimile synovium tissue suggests that local alpha1-acid glycoprotein (AGP) production may contribute to pro-inflammatory and anti-inflammatory activities during the local acute phase response or during chronic inflammatory stress as in arthritis.

Treatment of squamous cell carcinoma of the anterior faucial pillar-retromolar trigone.

Cancer of the anterior faucial pillar-retromolar trigone is an uncommon head and neck tumor, which has historically been shown to be associated with poor prognosis. In this retrospective study, we reviewed our experience with primary surgery followed by postoperative radiation therapy in order to determine the impact of our treatment protocols on patients' outcome. Between January 1994 and December 1998, 31 patients with histologically proven squamous cell carcinoma (SCC) of the anterior faucial pillar-retromolar trigone were treated in our department. Surgical excision of the primary lesion and ipsilateral neck dissection were performed in all patients. Reconstruction was accomplished using masseter muscle flap or tongue flap. Postoperatively, most patients (90%) received radiation therapy (51-58 Gy) to the primary side and neck. Adjuvant chemotherapy was offered if histologic signs of aggressive behavior were identified. Four out of 31 patients were initially seen at stage I or II and 27 patients at stage III or IV of the disease. Metastatic disease was demonstrated in 78% of ipsilateral neck nodes. Occult metastases were found in 64% of clinically N0 necks. The 3-year loco-regional recurrence rates were 44.8%. SCC of retromolar trigone is considered as an aggressive and insidious tumor. The reconstruction of the deficit of the anterior faucial pillar-retromolar area with masseter muscle flap is a reliable, safe and absolutely functional method.

Anti-inflammatory properties of diclofenac transition metalloelement complexes.

As part of our research into understanding drug-metalloelement interactions, we have prepared complexes of Cu(II), Co(II), Ni(II), Mn(II), Fe(II), Fe(III), and Pd(II) with Diclofenac, in order to investigate their anti-inflammatory activity. Their inhibitory effects on rat or mouse paw edema induced by Carrageenan, Con-A, Nystatin, and Baker's yeast were compared with those of Diclofenac. Furthermore, the action of Diclofenac's metalloelement complexes on phagocytosis of yeast by rat peritoneal cells, as well as the capacity of some of the metalloelement complexes to inhibit lipid peroxidation of liver microsomal membranes was also investigated. These complexes exhibited a strong inhibitory effect on Carrageenan-, ConA-, and Nystatin-induced edemas (35-80% inhibition) comparable to the inhibition caused by Diclofenac (61-76% inhibition). Furthermore, complexes with Co(II), Ni(II), Pd(II), and Mn(II) were found to have an anti-inflammatory profile (35-50% inhibition) superior to diclofenac (17% inhibition) when inhibiting inflammations due to Baker's yeast, the mechanism of which involves mainly the activation of lipoxygenase and/or complement system. Complexes of Ni(II) and Pd(II), which showed significant inhibition of induced-edemas in rats, were also tested in mice at lower and higher doses and showed a significant dose-dependent inhibition of edemas in mice. Some of these complexes also interfere with in vitro phagocytosis. The most active anti-inflammatory complexes Co(II), Pd(II), and Ni(II), also offered significant protection against lipid peroxidation in vitro, acting as antioxidant compounds, properties that are not demonstrated by Diclofenac. Finally, it is noted that almost all metalloelement complexes of Diclofenac showed high anti-inflammatory activity at molecular concentrations much lower than that of Diclofenac. From the present study it is suggested that the anti-inflammatory activity of Diclofenac is enhanced by the formation of coordination complexes with transition metalloelements.

Synthesis of novel derivatives of aroylaminoalcohols and 3-amino-substituted 1-phenylpropanols with potential anti-inflammatory and immunomodulating activities.

The synthesis of aroylaminoalcohols and 3-amino-substituted 1-phenylpropanols is described. These novel basic compounds have potent anti-inflammatory activity, significantly inhibiting rat paw oedema induced by a variety of phlogistic agents as a result of the release of inflammatory mediators such as histamine, 5-hydroxytryptamine, kinins, prostaglandins or leukotrienes. The biological activity of a selected, representative number of these compounds was examined on adjuvant-induced arthritis, a good animal model for rheumatoid arthritis in man. The results show that 3-(1-hydroxymethylpropylamino)-1-phenylpropan-1-one hydrochloride (2) and 3-(3-hydroxypiperidin-1-yl)-1-phenylpropan-1-one hydrochloride (4) effectively suppress the secondary lesions of adjuvant arthritis. 2-(3-Hydroxy-3-phenylpropylamino)-butan-1-ol hydrochloride (6) had no preventive activity in this animal model. In addition, several of the compounds suppressed the mitogenic responses of T-lymphocytes to concanavalin A, suggesting direct or indirect action on lymphocytes and therefore possible immunosuppressive properties. Finally, we investigated the in-vitro effects of compounds 2 and 4 on production of interleukins 1 and 2 (IL-1 and IL-2). We found that compound 4 suppressed the in-vitro production or action of IL-2 and IL-1. In contrast, compound 2 significantly increased the IL-1 activity of arthritic macrophages while reducing the ability of normal and arthritic splenocytes to produce or release IL-2. Our data suggest that compounds 2 and 4 have immunomodulatory properties that influence T lymphocyte functions.

Anti-inflammatory and immunomodulating properties of grape melanin. Inhibitory effects on paw edema and adjuvant induced disease.

Natural or synthetic melanin (CAS 8049-97-6) is a high molecular weight heteropolymer, product of the enzyme tyrosinase, found to possess radical scavenging and antioxidant functions. It was of interest, therefore, to study in detail the possible anti-inflammatory and/or immunosuppressive properties of a melanin isolated from grapes. The inhibitory effect of melanin on carrageenin-induced edema, as well as on edemas produced by other phlogistics, was remarkable suggesting that melanin interferes with the prostaglandin as well as the leukotriene and/or complement system mediated inflammation. Grape melanin showed potent inhibitory effect on adjuvant induced disease (AID) in rat, suppressing significantly the primary inflammation and almost totally the secondary lesions of arthritis. Melanin under the present experimental conditions not only strongly inhibited the in vitro lipid peroxidation of rat liver microsomal membranes, but furthermore protected the in vivo hepatic peroxidation occurring in AID rats, demonstrating its antioxidant and cytoprotective properties. The serum proinflammatory cytokines IL-1, IL-6 and TNF-a and the serum globulin fraction were elevated in AID rats, parameters which were more or less normalised by melanin treatment in contrast to the reduced serum levels of IL-2 which were not affected. Similarly to other lipoxygenase inhibitors and hydroxyl radical scavenger NSAIDs, melanin treatment did not affect IL-1 neither increased the splenic mitogenic responses, unlike the classical cyclooxygenase inhibitory NSAIDs. The subpopulation Th1 (T4+ or T8+) of lymphocytes is mainly responsible for cellular immune responses and thus their possible inhibition by melanin could lead to suppression of the development of AID, a model for cell-mediated immunity. The effect of melanin on T-cells is exhibited by the reduced spleen mitogenic responses to a T-cell mitogen and the reduced serum levels of IL-2 of treated rats. In conclusion, grape melanin is an interesting anti-inflammatory and immunomodulating natural product which appears to have multiple cellular targets within the reticuloendothelial and immune system.

Anti-inflammatory properties of new adamantane derivatives. Design, synthesis, and biological evaluation.

A series of adamantane-containing molecules consisting of two lipophilic centers which are linked by different bridges (oxime esters, oxime ethers, amides, and symmetric alcohols), were designed and synthesized as anti-inflammatory agents. Their anti-inflammatory activity was evaluated as their ability to inhibit phlogistic-induced mouse paw edema. Some of the tested compounds exhibited activity comparable to that of diclofenac, others had a weaker activity, while some oxime esters proved to enhance the inflammatory response. In all cases, activity was dose-dependent. The deacylated compound 10 was found to be the most active of the series, inhibiting inflammation due to Baker's yeast, the mechanism of which involves mainly the activation of lipoxygenase and/or complement systems, a property which is absent from most selective cyclooxygenase only inhibiting non-steroidal anti-inflammatory drugs (NSAIDs).

Regulation of cytokine gene expression by adjuvants in vivo.

Antibody isotype affects biological activity of the antibodies and therefore should be considered in prevention of disease by vaccination. In previous reports, we demonstrated that adjuvants affect the antibody isotype switching process and favour the production of certain isotypes. The present study extends these findings and shows fundamental differences in the cytokine induction pattern according to the adjuvant used. Cytokine mRNA levels were determined by in situ RNA-RNA hybridization performed on splenocytes isolated from mice injected with different adjuvants. The results revealed that Freund's complete adjuvant (FCA), Freund's incomplete adjuvant (FIA), Al(OH)3 and QuilA administration results in a type-2 (humoral) response, increasing IL-4, IL-5 and IL-13 gene expression, while poly I:C exhibits a type-1 (cell-mediated) response, increasing the production of interferon-gamma (IFN-gamma), IL-2 and IL-6 mRNA. Finally, BeSO4 and poly A:U augment IL-5 and IL-6 mRNA production, while lipopolysaccharide (LPS) and LiCl augment IL-6 and tumour necrosis factor-alpha (TNF-alpha) mRNA production. Also, the adjuvants appear capable of overcoming the inherent IL-2/IFN-gamma and IL-4 dichotomy of C57B1/6 and BALB/c mice, respectively, in response to cellular antigens such as Leishmania and herpes simplex virus (HSV). The overall data suggest that adjuvants direct the isotype switching process via induction of certain cytokines, a finding that can be useful in selection of the most efficient isotype of protective antibodies for disease prevention by vaccination.

Experimental hyperlipidemia and the effect of NSAIDs.

The effects of ip administration of NSAIDs in experimentally induced hyperlipidemia in rats was studied. An isotonic solution of Triton WR1339 (tyloxapol) was administered ip to rats one hour after ip administration of the examined anti-inflammatory drug. After 24 h, blood was collected for the determination of plasma total cholesterol (TC), LDL and trigluceride (TG) concentrations. The NSAIDs used in our experimental model are selective or non selective COX-1 inhibitors as well as one non selective COX-2 inhibitor. Most of the drugs significantly reduced the TC, TG and LDL concentrations in the plasma of hyperlipidemic rats. While studies link atheromatosis to inflammation, our results potentially also link anti-inflammatory activity with hypolipidemia. Thus, NSAIDs not only may address the inflammatory aspect of atherosclerosis but also may contribute directly by inducing hypolipidemia.