Clinical pharmacology in drug development, May 7, 2021
GLPG1205 is a modulator of GPR84, a G-protein-coupled receptor reported to be associated with sev... more GLPG1205 is a modulator of GPR84, a G-protein-coupled receptor reported to be associated with several diseases. Safety, tolerability, pharmacokinetics, and pharmacodynamics of GLPG1205 in healthy subjects were evaluated in 2 randomized, double-blind, placebo-controlled, single-site, phase 1 studies. In study 1, 16 (aged 21-48 years) and 24 (24-50 years) healthy men received single doses of GLPG1205 10 to 800 mg, and GLPG1205 50, 100, or 200 mg once daily for 14 days, respectively, or placebo. Study 2 evaluated the effect of aging on GLPG1205 pharmacokinetics: 24 healthy men (aged 37-83 years), weight-matched into 3 age cohorts (65-74, ≥75, and 18-50 years), received GLPG1205 50 mg or placebo once daily for 14 days; an open-label part of this study evaluated a GLPG1205 250-mg loading dose followed by 50 mg once daily for 13 days in 8 healthy men (aged 68-74 years). Single (up to 800 mg) and multiple (maximum tolerated dose 100 mg once daily) GLPG1205 doses had favorable safety and tolerability profiles. After single administration of GLPG1205, median time to occurrence of maximum observed plasma concentration and arithmetic mean apparent terminal half-life ranged from 2.0 to 4.0 and from 30.1 to 140 hours, respectively. Age did not affect GLPG1205 exposure. GPR84 receptor occupancy with GLPG1205 vs placebo confirmed target engagement. These results support further clinical development of GLPG1205.
Interleukin 17C (IL-17C) modulates epithelial inflammation and has a possible role in atopic derm... more Interleukin 17C (IL-17C) modulates epithelial inflammation and has a possible role in atopic dermatitis (AD) pathology. Four randomized clinical studies (Phase 1 and 2) investigated the safety, tolerability, efficacy, and pharmacokinetic profile of the anti-IL-17C monoclonal antibody MOR106 for up to 12 weeks (NCT03568071: n = 207 adults with moderate–severe AD; NCT03689829 Part 1: n = 32 healthy males; NCT03689829 Part 2: n = 44 adults with moderate–severe AD; and NCT03864627: n = 76 adults with moderate–severe AD). In these studies, MOR106 was either administered intravenously (i.v.) every 2 or 4 weeks at doses between 1–10 mg/kg, or subcutaneously (s.c.), either as a single dose or doses every 2 weeks at 320 mg. Overall, MOR106 was well-tolerated, and the safety profile was consistent with monoclonal antibodies approved for AD. Bioavailability following s.c. dosing was 55%, and steady-state drug levels were reached at 2–4 weeks. Ongoing studies were terminated following a futilit...
R 68 070 or (E)-5-[[[(3-pyridinyl)[3-(trifluoromethyl)phenyl]- methylen]amino]oxy] pentanoic acid... more R 68 070 or (E)-5-[[[(3-pyridinyl)[3-(trifluoromethyl)phenyl]- methylen]amino]oxy] pentanoic acid (Janssen Research Foundation, Belgium), a newly developed compound, combining specific thromboxane A2 (TXA2) synthetase inhibition with TXA2/prostaglandin endoperoxide receptor blockade in one molecule, is active in vivo in man and in experimental animals. In man (n = 5), a single oral 400-mg dose of R 68 070 produces deep and protracted inhibition of platelet TXA2 synthetase activity (greater than or equal to 90% for 48 h), increases serum levels of immunoreactive 6-keto-PGF1 alpha, reduces platelet aggregation in P.R.P. induced by U 46619, collagen (greater than 70% for 8 h), arachidonic acid (greater than 90% for 18 h) and prolongs template bleeding times significantly, without affecting plasma coagulation or fibrinolysis. In rats, R 68 070 (1.25 mg/kg orally, -2 h) singly prolongs tail bleeding times as much as a combination of TXA2 synthetase inhibition (dazoxiben 10 mg/kg) and TXA2/prostaglandin endoperoxide receptor blockade (BM 13177 40 mg/kg). In dogs, the compound reduces coronary thrombosis induced by electrical damage (1.25 mg/kg i.v.) and prevents the evolution of occlusion/reperfusion-induced arrhythmias into ventricular fibrillation (2.5 mg/kg i.v.). R 68 070 thus may be an appropriate pharmacological tool to analyze the roles and interactions of agonistic (TXA2, prostaglandin endoperoxides) and antagonistic (PGD2, PGE2, PGI2) metabolites of arachidonic acid in experimental and human pathologies.
Aortic rings from rats, rabbits and guinea-pigs produce different amounts of 6-oxoprostaglandin F... more Aortic rings from rats, rabbits and guinea-pigs produce different amounts of 6-oxoprostaglandin Fl, (6-oxo-PGF1,,), the stable breakdown product of prostacyclin, i.e. 2760 ± 195, 160 ± 10 and 87 ± 17 pg 6-oxo-PGF1a per mg wet weight in 30 min. 2 Vitamin C enhances the production of 6-oxo-PGFi,m by the aortic tissue of these three species, independent of their basal release. This increase was only significant if vitamin C was present in the preincubation as well as in the incubation fluid. 3 15-Hydroperoxy-arachidonic acid inhibits the production of 6-oxo-PGF1, (IC5o:6 jAM) and this inhibitory effect was completely neutralized by vitamin C. 4 The increased production of 6-oxo-PGF,,, is not due to an increased release of the substrate arachidonic acid. It is suggested that vitamin C enhances the formation of 6-oxo-PGF1,, by protecting the cyclo-oxygenase and PGI-synthase.
Levels of 6~xo-prostaglandin FI~ (6-oxo-PGFla), the non-enzymic degradation product of prostacycl... more Levels of 6~xo-prostaglandin FI~ (6-oxo-PGFla), the non-enzymic degradation product of prostacyclin, were measured in arterial blood from anaesthetized rabbits, before and after intravenous (i.v.) administration of endotoxin (Lipopolysaccharide W E. coli 0111:B4, 5 mg/kg). 6-Oxo-PGFIa was assessed by radioimmunoassay after extraction and separation by thin-layer chromatography. The basal concentration of 6-oxo-PGFla in blood was less than 100 pg/ml in 19 out of 20 rabbits. This indicates that the level of circulating prostacyclin is generally below 100 pg/ml. The administration of endotoxin induced a biphasic hypotension, and increased levels of 6-oxo-PGFla were found in all endotoxin-treated animals during the secondary hypotension after 60 and 120 rain. Pretreatment with indomethacin (2.5 mg/kg) prevented the secondary fall in arterial blood pressure and significantly suppressed the rise in 6-oxo-PGFla. However, indomethacin failed to alter the endotoxin-induced thrombocytopenia and did not modify the endotoxin-induced platelet aggregation in vitro. It is concluded that prostacyclin contributed to the secondary hypotension which accompanied the i.v. administration of endotoxin. Thromboxane A2 seems not to be of primary importance in the endotoxin-platelet interaction. Non-steroid anti-inflammatory drugs Thrombocytopenia Prostacyclin Hypotension Endotoxin Rabbits
The pathways contributing to the platelet adhesion/aggregation reaction elicited by collagen micr... more The pathways contributing to the platelet adhesion/aggregation reaction elicited by collagen microfibrils, administered to cats in vivo, were analysed. 2 The intra-aortic infusion of collagen (I00 yg kg1 in 1 min) caused an extensive activation of platelets, as evidenced by the time-dependent drop of free platelet numbers in whole blood, and the increases of 5-hydroxyindoles (5-HI), 5-hydroxytryptamine (5-HT) and thromboxane B2 (TXB2) levels in plasma, prepared from effluent venous blood sampled from the inferior caval vein. 3 5-HT2 receptor blockade with ketanserin (0.63mgkg-1 i.v., 10min) and cyclo-oxygenase inhibition with aspirin (10mg kg-1 i.v., min) slightly attenuated the peak reduction of free platelets in whole blood in response to collagen without affecting changes in plasma 5-HI. Aspirin, but not ketanserin, reduced the collagen-induced changes in plasma TXB2, prostaglandin E2 (PGE2) and 6K-PGFl. 4 Dual TXA2 synthetase inhibition/TXA2-prostaglandin endoperoxide receptor antagonism with ridogrel (5mgkg-1 i.v., 10min) halved the drop in free platelets, reduced the release of platelet 5-HI, inhibited the increase in plasma TXB2 and elevated that of 6K-PGF1, and PGE2 in response to collagen. 5 Combined treatment with ketanserin and aspirin reduced the collagen-induced drop of free platelets and the release of platelet 5-HI to a similar extent as ridogrel alone; plasma prostanoids were affected as with aspirin alone. 6 Combined administration of ketanserin and ridogrel virtually eliminated the collagen-induced platelet adhesion/aggregation response and release of 5-HI; prostanoids were affected as with ridogrel alone. 7 The results indicate that the interplay between 5-HT and arachidonic acid metabolites is causally involved in the platelet reaction to activation induced by collagen in cats in vivo.
The influence of antioxidants on the conversion of arachidonic acid and prostagiandin endoperoxid... more The influence of antioxidants on the conversion of arachidonic acid and prostagiandin endoperoxide Hz by ram seminal vesicle microsomes was investigated. The antioxidants ascorbic acid and propylgallate enhanced significantly the formation of 6-0x0-PGF,,. They shifted the pathway of the endoperoxide Hz from the non-enzymic decomposition to the enzymic formation of prostacyclin. It is suggested that those antioxidants partially act through neutralisation of an oxidative species which is formed during the conversion of arachidonic acid. The other mechanisms through which they act remains to be elucidated.
Naunyn-schmiedebergs Archives of Pharmacology, Jul 1, 1989
Oxatomide potently (EDso 0.9 mg/kg orally,-2 h) attenuates the reduction of pulmonary tidal volum... more Oxatomide potently (EDso 0.9 mg/kg orally,-2 h) attenuates the reduction of pulmonary tidal volume elicited by PAF (250 ng/kg i.v.) in anaesthetized, ventilated and propranolol-treated guinea-pigs. The increase of the pulmonary inflation pressure elicited by PAF (40 ng/kg i. v.) in such animals, ventilated at a fixed tidal volume, is also significantly reduced by the compound, but substantially higher doses (5 mg/kg i.v.,-15 min) are required. The potency of oxatomide in the latter respect (50.4% reduction) is equivalent to that of ketotifen at 5 mg/kg i.v. (55% reduction). In spontaneously breathing, anaesthetized guinea-pigs, oxatomide (5 mg/kg i.p.,-1 h) significantly reduces the increase in pulmonary resistance, but not the reduction in dynamic compliance, elicited by PAF (30, 60, 90 ng/kg i. v.), suggesting a pharmacological interference mainly with PAF-induced processes in the larger airways. Changes in arterial blood pressure, haemoconcentration, thrombocytopenia and leukopenia induced by PAF in vivo, contraction of guinea-pig lung parenchymal strips, production of superoxide anion by alveolar macrophages, aggregation and release of ATP by platelets challenged with PAF in vitro are not affected by the compound. These observations suggest that oxatomide attenuates the PAF-induced pulmonary reactions by inhibiting the release and/or the effect of allergic mediators elicited by the phospholipid rather than by a direct antagonism at the PAF receptors.
Ketoconazole inhibits in vitro (~:2.6 X 10e5 M) the formation of 5-HETB and LTB., by isolated, ca... more Ketoconazole inhibits in vitro (~:2.6 X 10e5 M) the formation of 5-HETB and LTB., by isolated, carrageenin-elicited rat peritoneal PMN leukocytes, challenged with the Ca2+-ionophore A23187 in the presence of ['4C]-arachidonic acid ([14C]-AA). The relative potency of various compounds tested in this respect is NDGA > nafazatrom > phenidone > ketoconazole 9 BW 75513. In contrast to the other compounds studies, ketoconazole in uitro, up to 1 X 10m4 M, has no effect on the fatty acid cycle-oxygenase or the 12-lipoxygenase-mediated metabolism of [t4C]-AA by isolated human platelets; however, it stimulates the 15-lipoxygenase activity in phenylhydrazin-induced rabbit reticulocytes. After oral administration (l@tO mg/kg,-2 hr), ketoconazole inhibits in a dose-dependent way, the leukotriene-mediated anaphylactic bronchoconstriction in guinea pigs. This study demonstrates that ketoconazole is a comparatively specific and orally active inhibitor of the .5-lipoxygenase activity bearing on the production of leukotrienes derived from arachidonic acid.
Feeding a cholesterol-rich diet (0.3 X) to rabbits resulted in an intimal thickening and lipid in... more Feeding a cholesterol-rich diet (0.3 X) to rabbits resulted in an intimal thickening and lipid infiltration of the aorta. The prostacyclin production by the vascular endothelium was significantly decreased, after a transient increase after 2 weeks of diet. The arachidonic acid metabolism in platelets was hardly changed. Addition of a low dose vitamin C (150 mglday) to the cholesterol rich diet resulted in decreased lipid infiltration and intimal thickening and the transient increase of the prostacyclin production was postponed to the 4th week. Although this dose of vitamin C could not restore the decreased prostacyclin production observed after 6 weeks diet, a higher dose of vitamin C (600 mg/day), besides its beneficial effect on the lipid infiltration and the intimal thickening in the thoracic aorta, kept the intimal prostacyclin production at normal levels for at least 8 weeks.
XIth International Congress on Thrombosis and Haemostasis, 1987
F 68070, an oxime-alkane carboxylic acid derivative (Janssen Pharmaceutica), is a potent inhibito... more F 68070, an oxime-alkane carboxylic acid derivative (Janssen Pharmaceutica), is a potent inhibitor of thromboxane A2 (TXA2) synthetase activity (IC50 in vitro against thrombin-stimulated human platelets in plasma : R 68070 : 2.9 x 10-8 M; CGS 13080 : 6 x 10-8 M; OKY-1581 : 8.2 x 10-8 M; dazmegrel : 2.6 x 10-8 M; dazoxiben : 2.3 x 10-8 M).The compound specifically inhibits platelet TXA2 synthetase activity (14C-arachidonic acid metabolism by washed human platelets) without effect on the cyclo-oxygenase, lipoxygenase (platelets, RBL cells) or prostacyclin synthetase activities (rat aortic rings).The inhibitory effect of R 68070 against human platelet TXA2 synthetase activity increases upon prolongation of the contact time (ICsg at 0.5 min of contact : 5.2 x 10-7 M; at 5 min : 8.3 x 10-8 M; at 30 min : 2.5 x 10-8 M) and is reversed by washing of the platelets.In vivo, the compound has a comparatively strong inhibitory effect on platelet TXA2 synthetase activity after oral administratio...
Clinical pharmacology in drug development, May 7, 2021
GLPG1205 is a modulator of GPR84, a G-protein-coupled receptor reported to be associated with sev... more GLPG1205 is a modulator of GPR84, a G-protein-coupled receptor reported to be associated with several diseases. Safety, tolerability, pharmacokinetics, and pharmacodynamics of GLPG1205 in healthy subjects were evaluated in 2 randomized, double-blind, placebo-controlled, single-site, phase 1 studies. In study 1, 16 (aged 21-48 years) and 24 (24-50 years) healthy men received single doses of GLPG1205 10 to 800 mg, and GLPG1205 50, 100, or 200 mg once daily for 14 days, respectively, or placebo. Study 2 evaluated the effect of aging on GLPG1205 pharmacokinetics: 24 healthy men (aged 37-83 years), weight-matched into 3 age cohorts (65-74, ≥75, and 18-50 years), received GLPG1205 50 mg or placebo once daily for 14 days; an open-label part of this study evaluated a GLPG1205 250-mg loading dose followed by 50 mg once daily for 13 days in 8 healthy men (aged 68-74 years). Single (up to 800 mg) and multiple (maximum tolerated dose 100 mg once daily) GLPG1205 doses had favorable safety and tolerability profiles. After single administration of GLPG1205, median time to occurrence of maximum observed plasma concentration and arithmetic mean apparent terminal half-life ranged from 2.0 to 4.0 and from 30.1 to 140 hours, respectively. Age did not affect GLPG1205 exposure. GPR84 receptor occupancy with GLPG1205 vs placebo confirmed target engagement. These results support further clinical development of GLPG1205.
Interleukin 17C (IL-17C) modulates epithelial inflammation and has a possible role in atopic derm... more Interleukin 17C (IL-17C) modulates epithelial inflammation and has a possible role in atopic dermatitis (AD) pathology. Four randomized clinical studies (Phase 1 and 2) investigated the safety, tolerability, efficacy, and pharmacokinetic profile of the anti-IL-17C monoclonal antibody MOR106 for up to 12 weeks (NCT03568071: n = 207 adults with moderate–severe AD; NCT03689829 Part 1: n = 32 healthy males; NCT03689829 Part 2: n = 44 adults with moderate–severe AD; and NCT03864627: n = 76 adults with moderate–severe AD). In these studies, MOR106 was either administered intravenously (i.v.) every 2 or 4 weeks at doses between 1–10 mg/kg, or subcutaneously (s.c.), either as a single dose or doses every 2 weeks at 320 mg. Overall, MOR106 was well-tolerated, and the safety profile was consistent with monoclonal antibodies approved for AD. Bioavailability following s.c. dosing was 55%, and steady-state drug levels were reached at 2–4 weeks. Ongoing studies were terminated following a futilit...
R 68 070 or (E)-5-[[[(3-pyridinyl)[3-(trifluoromethyl)phenyl]- methylen]amino]oxy] pentanoic acid... more R 68 070 or (E)-5-[[[(3-pyridinyl)[3-(trifluoromethyl)phenyl]- methylen]amino]oxy] pentanoic acid (Janssen Research Foundation, Belgium), a newly developed compound, combining specific thromboxane A2 (TXA2) synthetase inhibition with TXA2/prostaglandin endoperoxide receptor blockade in one molecule, is active in vivo in man and in experimental animals. In man (n = 5), a single oral 400-mg dose of R 68 070 produces deep and protracted inhibition of platelet TXA2 synthetase activity (greater than or equal to 90% for 48 h), increases serum levels of immunoreactive 6-keto-PGF1 alpha, reduces platelet aggregation in P.R.P. induced by U 46619, collagen (greater than 70% for 8 h), arachidonic acid (greater than 90% for 18 h) and prolongs template bleeding times significantly, without affecting plasma coagulation or fibrinolysis. In rats, R 68 070 (1.25 mg/kg orally, -2 h) singly prolongs tail bleeding times as much as a combination of TXA2 synthetase inhibition (dazoxiben 10 mg/kg) and TXA2/prostaglandin endoperoxide receptor blockade (BM 13177 40 mg/kg). In dogs, the compound reduces coronary thrombosis induced by electrical damage (1.25 mg/kg i.v.) and prevents the evolution of occlusion/reperfusion-induced arrhythmias into ventricular fibrillation (2.5 mg/kg i.v.). R 68 070 thus may be an appropriate pharmacological tool to analyze the roles and interactions of agonistic (TXA2, prostaglandin endoperoxides) and antagonistic (PGD2, PGE2, PGI2) metabolites of arachidonic acid in experimental and human pathologies.
Aortic rings from rats, rabbits and guinea-pigs produce different amounts of 6-oxoprostaglandin F... more Aortic rings from rats, rabbits and guinea-pigs produce different amounts of 6-oxoprostaglandin Fl, (6-oxo-PGF1,,), the stable breakdown product of prostacyclin, i.e. 2760 ± 195, 160 ± 10 and 87 ± 17 pg 6-oxo-PGF1a per mg wet weight in 30 min. 2 Vitamin C enhances the production of 6-oxo-PGFi,m by the aortic tissue of these three species, independent of their basal release. This increase was only significant if vitamin C was present in the preincubation as well as in the incubation fluid. 3 15-Hydroperoxy-arachidonic acid inhibits the production of 6-oxo-PGF1, (IC5o:6 jAM) and this inhibitory effect was completely neutralized by vitamin C. 4 The increased production of 6-oxo-PGF,,, is not due to an increased release of the substrate arachidonic acid. It is suggested that vitamin C enhances the formation of 6-oxo-PGF1,, by protecting the cyclo-oxygenase and PGI-synthase.
Levels of 6~xo-prostaglandin FI~ (6-oxo-PGFla), the non-enzymic degradation product of prostacycl... more Levels of 6~xo-prostaglandin FI~ (6-oxo-PGFla), the non-enzymic degradation product of prostacyclin, were measured in arterial blood from anaesthetized rabbits, before and after intravenous (i.v.) administration of endotoxin (Lipopolysaccharide W E. coli 0111:B4, 5 mg/kg). 6-Oxo-PGFIa was assessed by radioimmunoassay after extraction and separation by thin-layer chromatography. The basal concentration of 6-oxo-PGFla in blood was less than 100 pg/ml in 19 out of 20 rabbits. This indicates that the level of circulating prostacyclin is generally below 100 pg/ml. The administration of endotoxin induced a biphasic hypotension, and increased levels of 6-oxo-PGFla were found in all endotoxin-treated animals during the secondary hypotension after 60 and 120 rain. Pretreatment with indomethacin (2.5 mg/kg) prevented the secondary fall in arterial blood pressure and significantly suppressed the rise in 6-oxo-PGFla. However, indomethacin failed to alter the endotoxin-induced thrombocytopenia and did not modify the endotoxin-induced platelet aggregation in vitro. It is concluded that prostacyclin contributed to the secondary hypotension which accompanied the i.v. administration of endotoxin. Thromboxane A2 seems not to be of primary importance in the endotoxin-platelet interaction. Non-steroid anti-inflammatory drugs Thrombocytopenia Prostacyclin Hypotension Endotoxin Rabbits
The pathways contributing to the platelet adhesion/aggregation reaction elicited by collagen micr... more The pathways contributing to the platelet adhesion/aggregation reaction elicited by collagen microfibrils, administered to cats in vivo, were analysed. 2 The intra-aortic infusion of collagen (I00 yg kg1 in 1 min) caused an extensive activation of platelets, as evidenced by the time-dependent drop of free platelet numbers in whole blood, and the increases of 5-hydroxyindoles (5-HI), 5-hydroxytryptamine (5-HT) and thromboxane B2 (TXB2) levels in plasma, prepared from effluent venous blood sampled from the inferior caval vein. 3 5-HT2 receptor blockade with ketanserin (0.63mgkg-1 i.v., 10min) and cyclo-oxygenase inhibition with aspirin (10mg kg-1 i.v., min) slightly attenuated the peak reduction of free platelets in whole blood in response to collagen without affecting changes in plasma 5-HI. Aspirin, but not ketanserin, reduced the collagen-induced changes in plasma TXB2, prostaglandin E2 (PGE2) and 6K-PGFl. 4 Dual TXA2 synthetase inhibition/TXA2-prostaglandin endoperoxide receptor antagonism with ridogrel (5mgkg-1 i.v., 10min) halved the drop in free platelets, reduced the release of platelet 5-HI, inhibited the increase in plasma TXB2 and elevated that of 6K-PGF1, and PGE2 in response to collagen. 5 Combined treatment with ketanserin and aspirin reduced the collagen-induced drop of free platelets and the release of platelet 5-HI to a similar extent as ridogrel alone; plasma prostanoids were affected as with aspirin alone. 6 Combined administration of ketanserin and ridogrel virtually eliminated the collagen-induced platelet adhesion/aggregation response and release of 5-HI; prostanoids were affected as with ridogrel alone. 7 The results indicate that the interplay between 5-HT and arachidonic acid metabolites is causally involved in the platelet reaction to activation induced by collagen in cats in vivo.
The influence of antioxidants on the conversion of arachidonic acid and prostagiandin endoperoxid... more The influence of antioxidants on the conversion of arachidonic acid and prostagiandin endoperoxide Hz by ram seminal vesicle microsomes was investigated. The antioxidants ascorbic acid and propylgallate enhanced significantly the formation of 6-0x0-PGF,,. They shifted the pathway of the endoperoxide Hz from the non-enzymic decomposition to the enzymic formation of prostacyclin. It is suggested that those antioxidants partially act through neutralisation of an oxidative species which is formed during the conversion of arachidonic acid. The other mechanisms through which they act remains to be elucidated.
Naunyn-schmiedebergs Archives of Pharmacology, Jul 1, 1989
Oxatomide potently (EDso 0.9 mg/kg orally,-2 h) attenuates the reduction of pulmonary tidal volum... more Oxatomide potently (EDso 0.9 mg/kg orally,-2 h) attenuates the reduction of pulmonary tidal volume elicited by PAF (250 ng/kg i.v.) in anaesthetized, ventilated and propranolol-treated guinea-pigs. The increase of the pulmonary inflation pressure elicited by PAF (40 ng/kg i. v.) in such animals, ventilated at a fixed tidal volume, is also significantly reduced by the compound, but substantially higher doses (5 mg/kg i.v.,-15 min) are required. The potency of oxatomide in the latter respect (50.4% reduction) is equivalent to that of ketotifen at 5 mg/kg i.v. (55% reduction). In spontaneously breathing, anaesthetized guinea-pigs, oxatomide (5 mg/kg i.p.,-1 h) significantly reduces the increase in pulmonary resistance, but not the reduction in dynamic compliance, elicited by PAF (30, 60, 90 ng/kg i. v.), suggesting a pharmacological interference mainly with PAF-induced processes in the larger airways. Changes in arterial blood pressure, haemoconcentration, thrombocytopenia and leukopenia induced by PAF in vivo, contraction of guinea-pig lung parenchymal strips, production of superoxide anion by alveolar macrophages, aggregation and release of ATP by platelets challenged with PAF in vitro are not affected by the compound. These observations suggest that oxatomide attenuates the PAF-induced pulmonary reactions by inhibiting the release and/or the effect of allergic mediators elicited by the phospholipid rather than by a direct antagonism at the PAF receptors.
Ketoconazole inhibits in vitro (~:2.6 X 10e5 M) the formation of 5-HETB and LTB., by isolated, ca... more Ketoconazole inhibits in vitro (~:2.6 X 10e5 M) the formation of 5-HETB and LTB., by isolated, carrageenin-elicited rat peritoneal PMN leukocytes, challenged with the Ca2+-ionophore A23187 in the presence of ['4C]-arachidonic acid ([14C]-AA). The relative potency of various compounds tested in this respect is NDGA > nafazatrom > phenidone > ketoconazole 9 BW 75513. In contrast to the other compounds studies, ketoconazole in uitro, up to 1 X 10m4 M, has no effect on the fatty acid cycle-oxygenase or the 12-lipoxygenase-mediated metabolism of [t4C]-AA by isolated human platelets; however, it stimulates the 15-lipoxygenase activity in phenylhydrazin-induced rabbit reticulocytes. After oral administration (l@tO mg/kg,-2 hr), ketoconazole inhibits in a dose-dependent way, the leukotriene-mediated anaphylactic bronchoconstriction in guinea pigs. This study demonstrates that ketoconazole is a comparatively specific and orally active inhibitor of the .5-lipoxygenase activity bearing on the production of leukotrienes derived from arachidonic acid.
Feeding a cholesterol-rich diet (0.3 X) to rabbits resulted in an intimal thickening and lipid in... more Feeding a cholesterol-rich diet (0.3 X) to rabbits resulted in an intimal thickening and lipid infiltration of the aorta. The prostacyclin production by the vascular endothelium was significantly decreased, after a transient increase after 2 weeks of diet. The arachidonic acid metabolism in platelets was hardly changed. Addition of a low dose vitamin C (150 mglday) to the cholesterol rich diet resulted in decreased lipid infiltration and intimal thickening and the transient increase of the prostacyclin production was postponed to the 4th week. Although this dose of vitamin C could not restore the decreased prostacyclin production observed after 6 weeks diet, a higher dose of vitamin C (600 mg/day), besides its beneficial effect on the lipid infiltration and the intimal thickening in the thoracic aorta, kept the intimal prostacyclin production at normal levels for at least 8 weeks.
XIth International Congress on Thrombosis and Haemostasis, 1987
F 68070, an oxime-alkane carboxylic acid derivative (Janssen Pharmaceutica), is a potent inhibito... more F 68070, an oxime-alkane carboxylic acid derivative (Janssen Pharmaceutica), is a potent inhibitor of thromboxane A2 (TXA2) synthetase activity (IC50 in vitro against thrombin-stimulated human platelets in plasma : R 68070 : 2.9 x 10-8 M; CGS 13080 : 6 x 10-8 M; OKY-1581 : 8.2 x 10-8 M; dazmegrel : 2.6 x 10-8 M; dazoxiben : 2.3 x 10-8 M).The compound specifically inhibits platelet TXA2 synthetase activity (14C-arachidonic acid metabolism by washed human platelets) without effect on the cyclo-oxygenase, lipoxygenase (platelets, RBL cells) or prostacyclin synthetase activities (rat aortic rings).The inhibitory effect of R 68070 against human platelet TXA2 synthetase activity increases upon prolongation of the contact time (ICsg at 0.5 min of contact : 5.2 x 10-7 M; at 5 min : 8.3 x 10-8 M; at 30 min : 2.5 x 10-8 M) and is reversed by washing of the platelets.In vivo, the compound has a comparatively strong inhibitory effect on platelet TXA2 synthetase activity after oral administratio...
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