G. P. Velo

Anti‐inflammatory and pharmacokinetic properties of superoxide dismutase derivatized with polyethylene glycol via active esters

Enzymes used as pharmacological agents for systemic therapy offer promise in the treatment of several diseases, but have considerable limitations because of problems of protein immunogenicity, instability and, often, rapid elimination. One method overcoming these difficulties appears to be the masking of the polypeptide structure by linking polymers to the protein surface (Holcenberg 1982). This technique is still in its early stages concerning choice of polymer, method of coupling and long-term toxicity. As a contribution to these studies we report here some results obtained on the enzyme superoxide dismutase, which has anti-inflammatory properties (Merberger et al 1973; Lund-Olesen & Menander 1974; Edsmyr et a1 1976; Rister et al 1978) but has also a very short half-life in animals (Huber & Saifer 1977). The enzyme was derivatized with monomethoxypolyethyleneglycol (PEG) using a new method that employs active esters as the reactive group, a procedure that appears to have significant advantages over the method employing trichloro-s-triazine as the coupling reagent (Abuchowski et a1 1977) the disadvantages of which we have discussed (Boccu et al 1982). Moreover, that method cannot be applied to essential -SH containing enzymes since it give stable thioether derivatives (Boccu et a1 1983). The procedure we used (for details see Boccu et a1 1983) involves the oxidation of the carbinol function of PEG to carboxylate followed by its activation with N-hydroxysuccinimide and dicyclohexylcarbodiimide.

Copper and ceruloplasmin (Cp) concentrations during the acute inflammatory process in the rat

We have measured the concentration of copper and ceruloplasmin in serum of rats with carrageenan footoedema and in serum and exudate of rats with carrageenan pleurisy. Both serum copper and ceruloplasmin were found to increase in both models of inflammation. In these experimental conditions we have shown a strong positive correlation between copper and ceruloplasmin, in the serum of both normal and inflamed rats.

Carrageenan oedema in copper-deficient rats.

Carrageenan-induced hind paw oedema has been studied in rats deprived of copper for different lengths of time.A common feature observed in normally fed and copper-deficient rats was the rise of serum copper levels coccurring between 10 and 24 h after the injection of the irritant.After 1 month of copper-deficient diet no differences are seen in the oedema developed by controls and copperdeprived animals, while after 3 months the oedema developed by copper-deficient rats was significantly greater compared with the controls.These results are briefly discussed.

Concerning the role of endogenous copper in the acute inflammatory process.

The development of two models of acute inflammation (carrageenan-induced foot oedema and pleurisy) was studied in rats after 1 month of a 0.2 p.p.m. copper-deficient diet and after 5 months of a 0.6–0.8 p.p.m. copper-deficient diet.A ‘pro-inflammatory’ effect of copper deficiency was observed with the 0.2 p.p.m. diet, whilst no effect was evident following the 0.6–0.8 p.p.m. copper-deficient diet.These results are briefly commented upon.

Effect of calcitonin on carrageenan foot oedema.

The effect of salmon calcitonin (SCT) on acute inflammation was tested in carrageenan induced foot oedema of the rat. A considerable inhibition of the oedema was obtained with 20 MRC U/kg of SCT. The injection of SCT is followed by decrease of calcemia. A hypothesis of possible inhibition of prostaglandin (PG) synthesis and/or release, caused by decrease of calcemia, is advanced.

Adjuvant arthritis in young copper-deficient rats.

Adjuvant arthritis has been studied in young copper-deficient rats and a very strong inhibition of the disease following 60 days of deficient diet (0.4 ppm of copper) was found. No difference in lung prostaglandin synthesis and in rat stomach strip and colon reactivity to exogenous prostaglandins was noticed between controls and copper-deficient animals.These results are briefly discussed.

Nimesulide and renal impairment

AbstractObjectives: To analyse from spontaneous reporting data the renal adverse reactions associated with the use of nimesulide. Methods: Case reports were obtained from a Northern Italian Regional database (Veneto Pharmacovigilance System), containing all the spontaneous reports filed between 1988 and 1997. The Veneto Region is the principal contributor to the Italian spontaneous reporting system, with an annual report rate of approximately 17 per 100 000 inhabitants. The clinical records of hospitalized patients were also analysed. Results: Of the 120 reports associated with oral nimesulide, 11 referred to suspected renal adverse reactions. The drug was taken by ten patients for a short period. All the patients discontinued the therapy and hospitalization was required in six cases. Other risk factors were identified in six cases. Discussion: Together with the new insights into the possible consequences of renal cyclooxygenase-2 (COX-2) inhibition, the reported cases should draw the attention of doctors and patients to the importance of recognizing any possible signs of renal impairment during nimesulide therapy, although only extensive epidemiological data can define the real impact of its renal toxicity.

The Role of Prostaglandins and Cyclic Nucleotides in Inflammation

One of the main problems surrounding the study of the PG’s in the inflammatory response has been the lack of suitable models. The inflammatory process is a highly dynamic state. There is a constant change in the volume of exudate, increased lymphatic drainage, arrival of different cell types, and even these different cell types change during the inflammatory process. Thus not only do we see tissue cell changes but the arrival of polymorphs which discharge lysosomal enzymes; usually this is followed by the arrival of mononuclear cells which transform into macrophages. These cells are actively phagocytic, they then transform further into “activated macrophages” with surface changes, plus increased numbers of lysosomes. Often these cells may proliferate or fuse into giant cells and even in this form may undergo proliferation.

Prostaglandin System and Inflammation

Prostaglandins (PGs) were first described by Goldblatt and von Euler, in the early thirties, as compounds contained in the crude extract of seminal vesicles and capable of lowering blood pressure and contracting smooth muscles, especially those coming from the gastro-intestinal tract (1,2).