Acta pharmacologica et toxicologica最新文献

Fenflumizole, (2-(2,4-difluorophenyl)-4,5-bis(4-methoxyphenyl) imidazole), a new non-steroidal anti-inflammatory agent, was investigated for anti-inflammatory, analgesic and anti-pyretic activity in experimental animals. Comparison was made to other non-steroidal anti-phlogistics. Furthermore, general pharmacodynamics and toxicity of fenflumizole was studied. Fenflumizole was comparable to or weaker than indomethacin in models of acute inflammation (carrageenin paw oedema and pleurisy, rats, ultraviolet erythema, guinea-pigs) and stronger than indomethacin as an analgesic (writhing, mice). As an antipyretic agent (arachidonic acid pyresis, rats) fenflumizole was 3 times weaker than indomethacin. The acute gastro-ulcerogenicity and toxicity of fenflumizole was low as compared to reference drugs. No untoward activity of fenflumizole on respiratory and circulatory systems was observed in rabbits and dogs. Fenflumizole is a potential new therapeutic agent with anti-inflammatory, analgesic and anti-pyretic activities comparable to other anti-phlogistics but with reduced side effects.

The activity of some enzymes involved in hepatic function was measured in rats, in vivo, after one week's repeated envenomation with Hornet's (Vespa orientalis) venom sac extract (VSE) and in vitro in monolayers of tissue culture of rat hepatocytes treated with VSE. The maximal serum enzymatic changes observed in vivo were significant: twenty fold rise of alkaline phosphatase (ALP), a 7-8 fold rise of aspartate aminotransferase (AST) and a 4-5 fold rise in alanine aminotransferase (ALP) activity. Also 2-3x increases of both serum lactic dehydrogenase (LDH) and creatine phosphokinase (CPK) were noted. The maximal in vitro changes were observed after six days of daily envenomation. There were five fold rises of the activity of AST in the medium, as well as of two-three fold rises of ALT, ALP and LDH. These changes suggest that Hornet's VSE induces enzymatic changes in the liver after prolonged, repeated exposures. They also exclude a general effect, like shock, that might possibly occur in the intact animal, as the cause of the demonstrated hepatic damage.

Fenflumizole (2-(2,4-difluorophenyl)-4,5-bis(4-methoxyphenyl)imidazole), a new non-steroidal anti-inflammatory agent, was investigated for interference with cyclo-oxygenase activity in vivo, ex vivo and in vitro in comparison with indomethacin (and aspirin). Fenflumizole was comparable to indomethacin ex vivo in inhibition of thromboxane (TX)A2 production in rabbit platelets and inhibition of prostaglandin (PG)I2 (approximately prostacyclin) generation in rabbit mesenteric arteries and in vivo as an inhibitor of PGE2 formation in inflammatory exudates in rats. Fenflumizole was 18 times less active than indomethacin in inhibition of PGE2 synthesis in vitro and 170 times weaker as an inhibitor of PGI2 generation in the rat stomach mucosa ex vivo. Fenflumizole was 20-50 times more potent than indomethacin in vivo in inhibition of arachidonic acid induced bronchoconstriction in guinea-pigs, in inhibition of platelet aggregation on tendons superfused with blood from rabbits and in vitro in inhibition of aggregation of human and rabbit platelets. Neither fenflumizole nor indomethacin inhibited TXA2-synthetase in vitro. Aspirin-when tested-was less potent than fenflumizole and indomethacin. It is concluded that fenflumizole is a potent cyclo-oxygenase inhibitor. The very potent activity of fenflumizole against platelet aggregation and bronchoconstriction suggests a selectivity in the mode of action. The weak inhibition of gastric PGI2 generation may account for the previously observed weak gastro-ulcerogenicity of fenflumizole.

The beta-adrenergic stimulation of cardiac contraction and relaxation is related to an augmented Ca++ oscillation mediated by cAMP. This Ca++ mobilization may secondarily involve calmodulin in a way modulating the mechanical responses. We tested this possibility by studying interferences of trifluoperazine (which is able to block Ca++-calmodulin) with beta-adrenergic responses in rat heart papillary muscles. Trifluoperazine up to 10(-5) mol/l did not change the basal function. 10(-5) mol/l trifluoperazine augmented the contractile response to isoprenaline above 10(-7) mol/l. The inotropic effects of isoprenaline below 10(-7) mol/l and of the partial beta-agonist prenalterol were not influenced by trifluoperazine. 10(-5) mol/l trifluoperazine attenuated the stimulation of initial relaxation by isoprenaline in the entire concentration range. Thus this beta-adrenergic response was more sensitive to trifluoperazine than the contractile response. But trifluoperazine only slightly and non-significantly attenuated the stimulation of initial relaxation by prenalterol. From experiments on broken cell preparations the present results can be explained in terms of calmodulin blockade and thus inhibition of Ca++ efflux across the sarcolemma and of Ca++ uptake by the sarcoplasmic reticulum. Trifluoperazine effects unrelated to calmodulin can hardly account for the results. Thus a full beta-agonist can apparently mobilize enough Ca++ to activate calmodulin systems important for the final effects on the contraction-relaxation cycle.

By incubation of human citrated plasma with acetone 25% v/v kallikrein inhibitors were destroyed and prekallikrein activated to kallikrein. When the incubation was carried out in the presence of benzamidine 7 mM, the cofactor capacity of high molecular weight kininogen (HMrK) was protected against destruction by a serine protease which was not plasma kallikrein. By analogy with studies in rat plasma this protease might be a plasminogen activator (Berstad & Briseid 1982; Johansen & Briseid 1983). Factor XII in the plasma preparation was activated to unfragmented factor XIIa by adsorption to kaolin, and assayed as prekallikrein activator (PKA). The extent of activation of factor XII was only insignificantly influenced by the 1 + 1 (v/v) dilution of the plasma preparation with a suspension of kaolin. When, however, the preparation was diluted greater than 1 + 5 (v/v) before incubation with the suspension, a stoichiometric HMrK concentration-effect curve could be established, allowing the assay of cofactor-active HMrK. Assays of HMrK in plasma preparations from healthy men and women demonstrated an average lower level of cofactor-active HMrK in the preparations from women. It is suggested that benzamidine is not capable of providing a complete protection of HMrK during the procedure in all plasma samples.

Single intraperitoneal injections of 200 mg/kg octachlorostyrene (OCS) increased the activities of flavin-containing monooxygenase, epoxide hydrolase and glutathione S-transferase in the livers of male Wistar rats. UDP-glucuronyl transferase activities measured with aglycones increased by methylcholanthrene or phenobarbital treatment, were both slightly increased by OCS treatment. A liver 9,000 X g supernatant fraction from OCS pretreated rats increased the bacterial mutagenicity of 2-acetylaminofluorene and 2-aminofluorene compared to controls, while insignificant or only minor effects were seen on N-hydroxy 2-acetylaminofluorene and benzo(a)pyrene mutagenicity. The effect of OCS on mutagen activation was similar to that seen after phenobarbital treatment. The use of monolayers of hepatocytes instead of 9,000 X g subfractions did not reveal any qualitative differences in mutagen activation.

The metabolism of the analgesic drug propoxyphene (alpha-d-propoxyphene) has been investigated in the rat liver 9,000 X g supernatant fraction. The incubations were analyzed by HPLC. The major metabolite was norpropoxyphene carbinol, obtained through demethylation and ester hydrolysis. The demethylated metabolite of propoxyphene, norpropoxyphene, was also detected. Addition of acetaldehyde to the incubation mixture decreased the metabolism of propoxyphene. Reactions between norpropoxyphene carbinol and acetaldehyde resulted in a fast disappearance of the carbinol and the formation of a reaction product, the significance of which is discussed.

Persistent signs of oral dyskinesia (tongue protrusion and facial grimacing) had developed as a result of earlier chronic treatment with neuroleptics in a Cebus apella monkey. When this animal was given single doses of any classical neuroleptic, a transient deterioration of dyskinesia occurred, preceded by a temporary abolishment of dyskinesia sometimes with an attack of acute dystonia. Fluphenazine (5-25 micrograms/kg) causes dose-related deteriorations of dyskinesia. Six different drugs were tested on this monkey for their capacity to elicit aggravation of dyskinetic signs: three antihistamines (brompheniramine, promethazine, diphenhydramine) and three dopamine D2 receptor antagonists (sulpiride, tiapride, metoclopramide). High doses of promethazine and diphenhydramine (5 mg/kg) induced a temporary alleviation of dyskinesia, possibly through sedation. All three D2 receptor antagonists precipitated signs of acute dystonia at some dose levels, but out of the test drugs only metoclopramide caused deterioration of dyskinetic symptoms. According to the present results only metoclopramide stands out as a drug with an inherent propensity to cause tardive dyskinesia.