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Antipyretic activity of nimesuude in rats
Pharmacological
260
Research, Vol. 26, Supplement 1, 1992
EFFECT OF L-CARNITINE AND L-ACETYL-CARNITINE ON AN ANIMAL SYNDROME M.Visentin, M.T.Tacconi and M. Salmona Istituto di Ricerche Farmacologiche Mario Negri, via Eritrea 62, Milano.
MODEL
OF REYE
Reye syndrome (RS) is an acute disorder initially caused by a failure of mitochondrial metabolic processes, followed by a toxic accumulation of short and medium chain acyl-CoA compounds into the cytoplasm. During acute RS disease, camitine is mobilized from muscle to liver to buffer the level of acyl-CoA compounds, but most is lost in the urine and endogenous levels are not sufficent to mantain the buffering effect. We have evaluated the pharmacofogical effect of a supplementation of carnitine, as L-carnitine (LC) and Lacetyl-carnitine (LAC), on a RS model in rats described by Kilpatrick (Metabolism, 38, 73, 1989). Starving rats treated with LPS (0.2 mg/Kg i.p.,12 hours before kitling, b.k.) plus ASA (50 mglKg i.p.,ll hours b.k.) showed similar biochemical alterations in plasma and liver as in human RS: i.e. a decrease of liver ketone bodies (KB), of ATP/ADP ratio and of acetyI-CoA. We have found that IX or LAC given twice (500 mgikg p.o.,12 and 2 hours b.k.) were able to prevent the above described alterations. Since impairment of mitochondrial function in RS is associated to mitochondrial swelling, we have studied whether mitochondrial membrane fluidity was involved. We have evaluated microviscosity of lipidic fraction of LPS+ASA-treated mitochondria with and without LC or LAC; content of cholesterol (CHOL) and phospholipids (PL) and CHOL/PL ratio were also measured as important determinants of membrane microviscosity. Fluidity of mitochondria from LPS+ASA-treated rats was increased and CHOWPL ratio decreased; LC and LAC significantly prevented these changes, suggesting that they may play a role in protecting mitochondria from damage. Studies arc ongoing to determine whether the protective effect of LC and LAC on mitochondrial membrane is associated to an improvement in functionality.
ANTIPYRETIC ACTtVlTY OF Nih4ESULlDE IN RATS Annamaria Passoni, Patrizia Mainardi, Roberto Ceserani Boehringer Mannheim ltalia S.p.A., Research Center, Monza (Italy) Nimesulide (N) is a non-steroidat antiinfiammatory drug endowed with noticeable antiinflammatory and analgesic properties (1,2). The antipyretfc activity of nimesulide was evaluated in rats with brewer’s yeast- induced fever, after oral (p-o.) or rectal administration, in comparison with paracetamol (P). The antipyretic activity of N and P, avaluated durfng the plateau phase of the increased body temperature and expressed as EDm and confidence limits (95%) fs the following (n = 12Idose). 6h 7h 6h 9h N P
0.39 (0.30-0.49) 102 (92-l 13)
ED, msh (P.o.) 0.33 (0.09-0.64) n.e. ED, mg/rat (rectal) 0.22 (0.140.24) 0.25 (0.20-0.31) 17 (14-22) n.e.
0.44 (0.30-0.63) 116 (105-135)
0.57 (0.23-0.95) ne.
N 0.23 (0.20-0.26) 0.27 (0.2sO.36) P 10 (6.2-13) n.e n.e. = not evakrable N showed a very potent antipyretic activity when compared with P; it was about 260 and 60 times respectively more potent than P, when administered orally or rectally; N was about 3 times more potent after o&than rectal route; N effects were more prolonged than those of P. as the ED, of paracetamol was not evafuabis 7and 8 hours after yeast The antfpyreticeffectof N appears at doses lower than those actfve in carrageenin- induced edema in rats [ ED, = 4 (35.7) mg/kg p.o. ] Comparing the antipyretfc and antinflammatory ED,, N fs about 10 times more potent as antipyretii. In condusion, N is a potent antipyretic drug in this model and this property is confirmed by clinical trials (1). REFERENCES 1. Swingfe K.F.. Moore G.G.I. (1964); Drugs Exptf Clin Res 10597-597. 2. Ward A., Brogden R.N. (1963); Drugs 36: 732-753.
260
Research, Vol. 26, Supplement 1, 1992
EFFECT OF L-CARNITINE AND L-ACETYL-CARNITINE ON AN ANIMAL SYNDROME M.Visentin, M.T.Tacconi and M. Salmona Istituto di Ricerche Farmacologiche Mario Negri, via Eritrea 62, Milano.
MODEL
OF REYE
Reye syndrome (RS) is an acute disorder initially caused by a failure of mitochondrial metabolic processes, followed by a toxic accumulation of short and medium chain acyl-CoA compounds into the cytoplasm. During acute RS disease, camitine is mobilized from muscle to liver to buffer the level of acyl-CoA compounds, but most is lost in the urine and endogenous levels are not sufficent to mantain the buffering effect. We have evaluated the pharmacofogical effect of a supplementation of carnitine, as L-carnitine (LC) and Lacetyl-carnitine (LAC), on a RS model in rats described by Kilpatrick (Metabolism, 38, 73, 1989). Starving rats treated with LPS (0.2 mg/Kg i.p.,12 hours before kitling, b.k.) plus ASA (50 mglKg i.p.,ll hours b.k.) showed similar biochemical alterations in plasma and liver as in human RS: i.e. a decrease of liver ketone bodies (KB), of ATP/ADP ratio and of acetyI-CoA. We have found that IX or LAC given twice (500 mgikg p.o.,12 and 2 hours b.k.) were able to prevent the above described alterations. Since impairment of mitochondrial function in RS is associated to mitochondrial swelling, we have studied whether mitochondrial membrane fluidity was involved. We have evaluated microviscosity of lipidic fraction of LPS+ASA-treated mitochondria with and without LC or LAC; content of cholesterol (CHOL) and phospholipids (PL) and CHOL/PL ratio were also measured as important determinants of membrane microviscosity. Fluidity of mitochondria from LPS+ASA-treated rats was increased and CHOWPL ratio decreased; LC and LAC significantly prevented these changes, suggesting that they may play a role in protecting mitochondria from damage. Studies arc ongoing to determine whether the protective effect of LC and LAC on mitochondrial membrane is associated to an improvement in functionality.
ANTIPYRETIC ACTtVlTY OF Nih4ESULlDE IN RATS Annamaria Passoni, Patrizia Mainardi, Roberto Ceserani Boehringer Mannheim ltalia S.p.A., Research Center, Monza (Italy) Nimesulide (N) is a non-steroidat antiinfiammatory drug endowed with noticeable antiinflammatory and analgesic properties (1,2). The antipyretfc activity of nimesulide was evaluated in rats with brewer’s yeast- induced fever, after oral (p-o.) or rectal administration, in comparison with paracetamol (P). The antipyretic activity of N and P, avaluated durfng the plateau phase of the increased body temperature and expressed as EDm and confidence limits (95%) fs the following (n = 12Idose). 6h 7h 6h 9h N P
0.39 (0.30-0.49) 102 (92-l 13)
ED, msh (P.o.) 0.33 (0.09-0.64) n.e. ED, mg/rat (rectal) 0.22 (0.140.24) 0.25 (0.20-0.31) 17 (14-22) n.e.
0.44 (0.30-0.63) 116 (105-135)
0.57 (0.23-0.95) ne.
N 0.23 (0.20-0.26) 0.27 (0.2sO.36) P 10 (6.2-13) n.e n.e. = not evakrable N showed a very potent antipyretic activity when compared with P; it was about 260 and 60 times respectively more potent than P, when administered orally or rectally; N was about 3 times more potent after o&than rectal route; N effects were more prolonged than those of P. as the ED, of paracetamol was not evafuabis 7and 8 hours after yeast The antfpyreticeffectof N appears at doses lower than those actfve in carrageenin- induced edema in rats [ ED, = 4 (35.7) mg/kg p.o. ] Comparing the antipyretfc and antinflammatory ED,, N fs about 10 times more potent as antipyretii. In condusion, N is a potent antipyretic drug in this model and this property is confirmed by clinical trials (1). REFERENCES 1. Swingfe K.F.. Moore G.G.I. (1964); Drugs Exptf Clin Res 10597-597. 2. Ward A., Brogden R.N. (1963); Drugs 36: 732-753.