Bengt Ingemar Axelsson

Newly discovered anti-inflammatory properties of the benzamides and nicotinamides

Our laboratory has concentrated on the possible regulation the benzamides and nicotinamides may have on the processes of DNA repair and apoptosis. Recent reports [14-16] have suggested that both apoptosis and inflammation are regulated by the transcription factor NF-kB. We have initiated studies regarding the hypothesis that the benzamides and nicotinamides could inhibit the production of tumor necrosis factor alpha (TNFalpha) and the inflammatory response as well as induce apoptosis via inhibition of NF-kB. Our data have shown that nicotinamide and two N-substituted benzamides, metoclopramide (MCA) and 3-chloroprocainamide (3-CPA), gave dose dependent inhibition of lipopolysacharide induced TNFalpha in the mouse within the dose range of 10-500 mg/kg. Moreover, lung edema was prevented in the rat by 3 ï 50 mg/kg doses of 3-CPA or MCA, and 100-200 μM doses of MCA could also inhibit NF-kB in Hela cells. Taken together these data strongly support the notion that benzamides and nicotinamides have potent anti-inflammatory and antitumor properties, because their primary mechanism of action is regulated by inhibition at the gene transcription level of NF-kB, which in turn inhibits TNFalpha and induces apoptosis.

Liposomes as carriers for anti-inflammatory agents

Abstract Anti-inflammatory drugs show a great variety of toxic side effects. One possible way to improve the therapeutic efficacy of these drugs could be liposome encapsulation. This review covers recent work published on liposome encapsulation of four different groups of anti-inflammatory agents, i.e., glucocorticosteroids, nonsteroidal anti-inflammatory drugs, anti-oxidant enzymes and radioisotopes. Representatives of these groups after liposome encapsulation show an improved anti-inflammatory effect upon local or systemic administration. Some reports also claim that liposome-encapsulation leads to decreased toxic side effects, but additional studies need to be performed in order to estimate the degree of reduction of side effects upon liposome-encapsulation. Phagocytic cells (i.e., macrophages and neutrophils) play important roles in induction and maintenance of inflammation. Strategies to optimize, within a localized region of the body, the uptake of anti-inflammatory drugs to these cells using different liposomal formulations are discussed.

6α-Fluoro- and 6α,9α-difluoro-11β,21- dihydroxy-16α,17α-propylmethylenedioxypregn-4-ene-3,20-dione: Synthesis and evaluation of activity and kinetics of their C-22 epimers

Abstract It is generally accepted that the anti-inflammatory effect of glucocorticosteroids cannot be separated from their adverse effects at the receptor level. However, modification of the pharmacokinetics through structural alterations could provide steroids with a better therapeutic index than those currently used. Thus, new 16α,17α-acetals between butyraldehyde and 6α-fluoro- or 6α,9α-difluoro-16α-hydroxycortisol were synthesized and studied. Acetalization of the corresponding 16α,17α-diols or transacetalization of their 16α,17α-acetonides in dioxane produced mixtures of C-22 epimers, which were resolved by preparative chromatography. Alternatively, an efficient method was used to produce the 22R-epimer stereoselectively through performing the acetalization and transacetalization in a hydrocarbon with an inert material present. The C-22 configuration of (22R)-6α,9α-difluoro-11β,21-dihydroxy-16α,17α-propylmethylenedioxypregn-4-ene-3,20-dione was unambiguously established by single crystal X-ray diffraction. The present compounds, especially the 22R-epimer just mentioned, bind to the rat thymus glucocorticoid receptor with high potency. The C-22 epimers of the 6α,9α-difluoro derivatives showed a 10-fold higher biotransformation rate than the budesonide 22R-epimer when incubated with human liver S9 subcellular fraction. The high receptor affinity in combination with the high biotransformation rate indicates that (22R)-6α,9α-difluoro-11β,21-dihydroxy-16α,17α-propylmethylenedioxypregn-4-ene-3,20-dione may be an improved 16α,17α-acetal glucocorticosteroid for therapy of inflammatory diseases, in which the mucous membranes are involved, such as those in the intestinal tract as well in the respiratory tract.

Preparation of poly (A)-binding proteins from endoplasmic reticulum-containing subfractions of RAT liver cells and their use in mRNA purification

SummaryApproximately 2% of the proteins solubilised from rat liver microsomes or rapidly sedimenting endoplasmic reticulum (RS-ER) adsorbed to poly(A)-Sepharose. The adsorption appeared to be selective for a few proteins, and proteins of different apparent molecular weights adsorbed from RS-ER and the microsomes. The proteins from RS-ER with affinity for poly(A) were coupled to Sepharose and used for the purification of mRNA from rabbit mammary glands. A portion of the RNA which did not adsorb to poly(U)-Sepharose adsorbed to protein-Sepharose and was active in a cell-free protein synthesis system.