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The antipyretic effect of some newer alpha-1 adrenergic antagonists
2279 determined rectal (Tre) and ear skin temperature (Te), metabolic rate (M) - calculated from oxygen consumption and carbon dioxide production, evaporative heat loss (Eres) - measured by higrometric method. Fever was produced by intravenous injection of lipopolysaccharide E. coli (LPS, I mcg/kg). Immediately after py=ogen administration, body temperature started increasing so that it reached the maximum level (1.7 o C) at the 3rd hour of the experiment. The febrile response was accompanied by stimulation of metabolic heat production (maximum by 0.31 W/kg), falls in Te (maximum 7.2 ° C) and Eres (maximum 0.05 W/kg). 30 minutes after pyrogen administration, the rabbits were treated intravenously, in form of bolus injection (1 ml/kg), with 0.75 mg/kg of doxazosin (DOX), prazosin (PRA), dihydrobenzperidol (DHBP) or indoramin (INR); the rest of the febrile rabbits received BE (0.25 mg/kg), corynanthine (CRN, 1.5 mg/kg), urapidil (URP, 10.0 mg/kg). The tested drugs redueeA fever by 39, 62, 104, 87, 31, 48, 23 and 50~, respectively. The antipyretic effect of DOX, BMY, PRA and DHBP was associated with inhibition of metabolism and vasodilation of the ear. The rest of the compounds produced antipyresis mainly by depression of metabolism. Apart from PRA, which inhibited Eres three times, the other compounds did not affect heat exchange from the respiratory tract. It appears that the antipyretic effect is a general feature of alpha-1 adrenergic blocking drugs and it is accompanied by inhibition of heat production and/or stimulation of heat loss processes. The antipyretic propei~ies of these blockers might be significant from the clinical point of view. Reference Mamszek M~, Szreder Zo. 1984, The influence of prazosin on E. coil fipopoly-saccharide-induced fever and noradrenaline hyperthermia. Pol. J. Pharmacol Pharm., 36.
I P.fr.191 I
The anfipyretic effect of some newer alpha-I adrenergic antagonists Matuszek, M., Szreder, Z. and Korolkiewicz, Z. Dep~:rtmentof Pharmacology, Medical Academy, 38 Hibner Street, 80-227 Gdafisk, Poland
Prazosin (PRA) and doxazosin (DOX) are selective and potent blockers of postjunctional alpha adrenoceptors. Clinical observations have revealed that the hypotensive action of prazosin was accompanied by evident hypothermia (Leeuw and Birkenhager, 1980). Moreover, our previous experiments have shown that prazosin inhibits LPS-induced fever as well as noradrenaline hyperthermia (Matuszek and Szreder, 1984). The antipyretic effect of prazosin tended us to investigate the influence of doxazosin and BE 2254 on pyrogen fever and to examine whether the antipyretic effect of these drugs is related to their hypotensive action. Two sets of experiraents were carried out in rabbits at an ambient temperature of 20°C. In the first one the antipyretic activity of prazosin, doxazosin and BE 2254 was examined. Pyrogen (E. coil lipopolysaccharide) was injected intravenously at a dose of I mcg/kg to produce fever. The alpha-1 adrenergic antagonists were administered as a bolus injection (BE 2254 at the doses of 0.25 and 0.50 mg/kg) or as 3 h intravenous infusion (prazosin 0.1 and 0.25 m g / k g / h and doxazosin 0.1; 0.25 and 0.50 m g / k g / h ) 15 min before pyrogen injection. The following them~.oregulatory parameters were determined: rectal (Tre) and ear skin (Te) temperatures, metabolic rate (M) and evaporative heat loss (Eres). Prazosin, at a dose of 0.1 m g / k g / h , decreased rectal temperature by about 50~ while the higher dose of the drug completely abolished pyrogen fever. Moreover, ear skin temperature was significantly higher in comparison to the animals treated with pyrogen. Antipyretic effects of both doxazosin and BE 2254 were not dose-dependent. Both drugs enhanced vasoconstricting effect of LPS. The aim of the second set of experiments was to find out whether antipyretic effects of prazosin and doxazosin depends on their hypotensive actions. The drugs were given intravenously (3 h infusion) at the dose of 0.1 and 0.25 mg kg/h. Blood pressure (BP) and heart rate (HR) were recorded in normotensive rabbits. Antipyretic doses of prazosin and doxazosin caused significant falls in blood pressure and slight decreases in heart rate. The antipyretic e,ction of the tested drugs is mediated at least in part by alpha-1 adrenoceptors. Moreover, the
antipyretic and hypotensive activities seem not to be related reciprocally as the potency of both effects was not correlated with each other.
References Leeuw P.W., Birkenhager W.H., 1980, Hypothermia: a possible side effect of prazosin. Brit. J. Med., 281. Matuszek M., Szreder 7,., 1984, The influence of prazosin on E. coil fipopolysaccharide-induced fever and noradrenaline hyperthermia, P¢~I.J. PharmacoL Pharm., 3 .
1
[ Glutathione modulation by piroxicam in brain and muscle of rat Cerretani, D., Micheli, L., Fiaschi, A.I. and Giorgi, G. Istituto di Farmacologia, Facoltd di Medicina e Chirurgia, Universitd degii Studi di Siena, 53100 Siena, Italy
Piroxi~m; N-(2•pyridy•)-4-hydr•xy-2-methy••2H•••2-benz•thiazine-3-carb•xamide-••••di•xide• is a powerful antiinflammatory agent, which inhibits the secondary phase of platelet aggregation induced by adenosine diphosphate or collagen. In vitro and in vivo, piroxicam is an inhibitor of prostaglandin synthesis, being a selective reversible inhibitor of cyclo-oxygenase step of a~chidonic acid cascade. Available data, suggest that piroxicam is extensively metabolized by several routes, 5"pyridine ring hydroxylation, glucuronide formation, cyclo dehydration and amide hydrolysis leading to decarboxilation, ring contraction and N-dealkylation. The main metabofite is that produced by hydroxylafion of the pyridyl-ring and exists eithe,_-free and conjugated with glucuronic acid (Brogden, 1981). Despite of a lot of literature on piroxicam metabolism, very little is known about its distribution and potential toxicity. Being glutathione (GSH) an ubiquitous low-molecular weight thiol involved in many detoxification and redox processes, we studied in brain and muscle of rat the effect of the administration of piroxicam (6 m g / K g os) on the levels of this tripeptide. Animals (male albino Wistar rats) fasted 24 hours before the experiments, were killed by decapitation 0.5-1-2-4-8-16-24 hours after pi_roxicam administration, all at the same hour of the day (16:00). The brain and the right leg adductor were quickly drew and homogenized and hhe piro.xJcam levels evaluated by HPLC with a method developed by us. GSH was determined by the Tietze's method with an automatic procedure developed in our laboratory (Glory, 1987). The obtained results put into evidence in brain (table) a possible relationship between piroxicam Cmax (4.1/tg/g tissue) and the maximum GSH decrease. Control Piroxicam (/tg/g tissue) mean s.d. n 5 GSH (nniol/mg protein) mean 15.0 s.d. 3.40 n 5
0.5 h
1h
2h
4h
8h
2.0 0.25 5
3.5 0.89 5
4.1 2.25 5
2.3 0.43 5
2.6 0.13 5
7.1 2.04 5
6.8 1.18 5
6.8 2.01 5
11.4 2.08 5
16.9 3.73 5
16 h
24 h
-
-
5
5
13.7 2.36 5
13.1 1.58 5
On the contrary in muscle, piroxicam ( G m ~ - 2.8/~g/g tissue) does not seem to influence GSH levels. Such a difference could be explained aSSumingthat metabolites in muscle are different from those in brain or hypothesizing a different behavior with respect to the redox systems involving GSH. This work was supported by a grant from Ministry of Education (60~)
References Brogden, R.N., Heel, R.C., Speight, T.M., 1981, Drugs 22, 165. Giorgi, G., Micheli, U, 1987, Int. Lab. 17, 52.
I P.fr.191 I
The anfipyretic effect of some newer alpha-I adrenergic antagonists Matuszek, M., Szreder, Z. and Korolkiewicz, Z. Dep~:rtmentof Pharmacology, Medical Academy, 38 Hibner Street, 80-227 Gdafisk, Poland
Prazosin (PRA) and doxazosin (DOX) are selective and potent blockers of postjunctional alpha adrenoceptors. Clinical observations have revealed that the hypotensive action of prazosin was accompanied by evident hypothermia (Leeuw and Birkenhager, 1980). Moreover, our previous experiments have shown that prazosin inhibits LPS-induced fever as well as noradrenaline hyperthermia (Matuszek and Szreder, 1984). The antipyretic effect of prazosin tended us to investigate the influence of doxazosin and BE 2254 on pyrogen fever and to examine whether the antipyretic effect of these drugs is related to their hypotensive action. Two sets of experiraents were carried out in rabbits at an ambient temperature of 20°C. In the first one the antipyretic activity of prazosin, doxazosin and BE 2254 was examined. Pyrogen (E. coil lipopolysaccharide) was injected intravenously at a dose of I mcg/kg to produce fever. The alpha-1 adrenergic antagonists were administered as a bolus injection (BE 2254 at the doses of 0.25 and 0.50 mg/kg) or as 3 h intravenous infusion (prazosin 0.1 and 0.25 m g / k g / h and doxazosin 0.1; 0.25 and 0.50 m g / k g / h ) 15 min before pyrogen injection. The following them~.oregulatory parameters were determined: rectal (Tre) and ear skin (Te) temperatures, metabolic rate (M) and evaporative heat loss (Eres). Prazosin, at a dose of 0.1 m g / k g / h , decreased rectal temperature by about 50~ while the higher dose of the drug completely abolished pyrogen fever. Moreover, ear skin temperature was significantly higher in comparison to the animals treated with pyrogen. Antipyretic effects of both doxazosin and BE 2254 were not dose-dependent. Both drugs enhanced vasoconstricting effect of LPS. The aim of the second set of experiments was to find out whether antipyretic effects of prazosin and doxazosin depends on their hypotensive actions. The drugs were given intravenously (3 h infusion) at the dose of 0.1 and 0.25 mg kg/h. Blood pressure (BP) and heart rate (HR) were recorded in normotensive rabbits. Antipyretic doses of prazosin and doxazosin caused significant falls in blood pressure and slight decreases in heart rate. The antipyretic e,ction of the tested drugs is mediated at least in part by alpha-1 adrenoceptors. Moreover, the
antipyretic and hypotensive activities seem not to be related reciprocally as the potency of both effects was not correlated with each other.
References Leeuw P.W., Birkenhager W.H., 1980, Hypothermia: a possible side effect of prazosin. Brit. J. Med., 281. Matuszek M., Szreder 7,., 1984, The influence of prazosin on E. coil fipopolysaccharide-induced fever and noradrenaline hyperthermia, P¢~I.J. PharmacoL Pharm., 3 .
1
[ Glutathione modulation by piroxicam in brain and muscle of rat Cerretani, D., Micheli, L., Fiaschi, A.I. and Giorgi, G. Istituto di Farmacologia, Facoltd di Medicina e Chirurgia, Universitd degii Studi di Siena, 53100 Siena, Italy
Piroxi~m; N-(2•pyridy•)-4-hydr•xy-2-methy••2H•••2-benz•thiazine-3-carb•xamide-••••di•xide• is a powerful antiinflammatory agent, which inhibits the secondary phase of platelet aggregation induced by adenosine diphosphate or collagen. In vitro and in vivo, piroxicam is an inhibitor of prostaglandin synthesis, being a selective reversible inhibitor of cyclo-oxygenase step of a~chidonic acid cascade. Available data, suggest that piroxicam is extensively metabolized by several routes, 5"pyridine ring hydroxylation, glucuronide formation, cyclo dehydration and amide hydrolysis leading to decarboxilation, ring contraction and N-dealkylation. The main metabofite is that produced by hydroxylafion of the pyridyl-ring and exists eithe,_-free and conjugated with glucuronic acid (Brogden, 1981). Despite of a lot of literature on piroxicam metabolism, very little is known about its distribution and potential toxicity. Being glutathione (GSH) an ubiquitous low-molecular weight thiol involved in many detoxification and redox processes, we studied in brain and muscle of rat the effect of the administration of piroxicam (6 m g / K g os) on the levels of this tripeptide. Animals (male albino Wistar rats) fasted 24 hours before the experiments, were killed by decapitation 0.5-1-2-4-8-16-24 hours after pi_roxicam administration, all at the same hour of the day (16:00). The brain and the right leg adductor were quickly drew and homogenized and hhe piro.xJcam levels evaluated by HPLC with a method developed by us. GSH was determined by the Tietze's method with an automatic procedure developed in our laboratory (Glory, 1987). The obtained results put into evidence in brain (table) a possible relationship between piroxicam Cmax (4.1/tg/g tissue) and the maximum GSH decrease. Control Piroxicam (/tg/g tissue) mean s.d. n 5 GSH (nniol/mg protein) mean 15.0 s.d. 3.40 n 5
0.5 h
1h
2h
4h
8h
2.0 0.25 5
3.5 0.89 5
4.1 2.25 5
2.3 0.43 5
2.6 0.13 5
7.1 2.04 5
6.8 1.18 5
6.8 2.01 5
11.4 2.08 5
16.9 3.73 5
16 h
24 h
-
-
5
5
13.7 2.36 5
13.1 1.58 5
On the contrary in muscle, piroxicam ( G m ~ - 2.8/~g/g tissue) does not seem to influence GSH levels. Such a difference could be explained aSSumingthat metabolites in muscle are different from those in brain or hypothesizing a different behavior with respect to the redox systems involving GSH. This work was supported by a grant from Ministry of Education (60~)
References Brogden, R.N., Heel, R.C., Speight, T.M., 1981, Drugs 22, 165. Giorgi, G., Micheli, U, 1987, Int. Lab. 17, 52.