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1-(Theophyllin-7yl)-ethyl-2-[2-(p-chlorophenoxy)-2-methylpropionate] (etofylline clofibrate, ML 1024, Duolip) was shown to be a potent inhibitor of experimental thrombus formation in the microvasculature of the hamster cheek pouch and of platelet aggregation and adhesiveness in the cynomolgus monkey. Inhibitory effect on thrombus formation was superior to that obtained with either of the molecule components (clofibric acid and etofylline) or their 1 : 1 mixture and a synergistic effect was apparent. Etofylline clofibrate was more active than a commercial antithrombotic drug combination of acetylsalicylic acid (ASA) and dipyridamole as an inhibitor of thrombus formation in this test system (p less than 0.05) at the proposed therapeutic dose level for each drug. In the cynomolgus monkey, etofylline clofibrate was shown again to be a potent inhibitor of platelet aggregation induced by ADP and collagen and of platelet adesiveness after administration of 12 mg/kg/day for 21 days. A mixture of clofibrate and etofylline (21.25 mg/kg/day and 3.75 mg/kg/day, respectively) had relatively less effect on platelet aggregation and no consistent effect on platelet adhesiveness. The activity found in both test systems indicates a promising antithrombotic potential for etofylline clofibrate and warrants further investigation in humans.

Prostaglandin E1 incorporated in lipid microspheres (lipo-PGE1) was evaluated following intravenous administration as an inhibitor of ADP-induced thrombus growth rate and as a thrombus disaggregating agent following vascular damage in the microcirculation of the hamster cheek pouch. The drug was shown to be significantly more active and longer acting than PGE1 in the first experiment. Following vascular damage lipo-PGE1 was very efficacious as a thrombus disaggregating agent and was significantly more effective when infused after, rather than before, vascular damage. These data suggested that the drug might be targeted to the site of damage. When incorporated in lipid microspheres, PGE1 appeared to be more stable, longer acting and more efficacious than PGE1 alone.

Sodium dl-4-[1R,2R,3aS,8bS)-1,2,3a,8b-tetrahydro- 2-hydroxy-1-[(3S,4RS)-3-hydroxy-4-methyl-oct-6- yne-(E)-1-enyl]-5-cyclopenta[b]benzofuranyl]butyrate (TRK-100) is a stable analogue of prostacyclin (epoprostenol, PGI2). The drug was shown to be a potent inhibitor of platelet aggregation in vitro, induced by adenosine diphosphate (ADP), using platelet-rich plasma (PRP) from human and several animal species. The inhibitory activity of TRK-100 using human platelets was half that of PGI2 and eight times that of PGE1. There was a marked tendency for platelet clumps to disaggregate following secondary aggregation in the presence of TRK-100 at final concentrations higher than 1 ng/ml. This activity was similar to PGI2 and more than 30 times that of PGE1. TRK-100 was shown to induce the disaggregation of a pre-existing thrombus in the microcirculation of the hamster cheek pouch. A dose-dependent response was obtained following oral administration of the drug at levels of 50-200 micrograms/kg. Optimal activity was observed 30-60 min after dosing and activity was sustained throughout the experimental period. TRK-100 was more active than PGE1 in the test system and appeared to be of a similar potency to PGI2. Since this drug is stable, orally active and without the hypotensive activity of PGI2, it is considered to be a potentially useful agent for antithrombotic therapy.

This study was designed to evaluate the hypolipidaemic and anti-atherosclerotic potential of cicletanine in a genetic hypercholesterolaemic rabbit model. In a pilot study the effect of 8 weeks oral administration of 2 treatment levels of cicletanine (10, 30 mg.kg-1.day-1) was compared with vehicle alone. In the main study, 8 weeks oral administration of 2 treatment levels of cicletanine (5, 30 mg.kg-1.day-1) was compared with parallel treatment with probucol (15 mg.kg-1.day-1) and with nifedipine (10 mg.kg-1.day-1). At the start of each study and at scheduled points throughout, blood samples were collected for routine biochemical and lipid/lipoprotein analyses. At the end of each test period all animals were examined at post mortem. Aortae were dissected and examined for the presence ans degree of atheroma. Hearts were examined for the presence of lesions. Sections of aortae were stained for lipid, examined histologically and scored for extent of atheroma using an atherosclerotic index. In the pilot study cicletanine had no effect on blood lipid levels. Gross pathology indicated a reduction in the extent of aortic atheroma in cicletanine-treated animals. Histopathological examination of thoracic and abdominal regions of the aortae confirmed these gross findings. The atherosclerotic index was significantly reduced (p less than 0.06) in all drug treated animals. In the main study similar data were achieved. None of the test drug affected plasma lipid/lipoprotein levels. Gross pathology indicated a reduction in the extent of aortic atheroma in all cicletanine-treated animals and also in the nifedipine-treated group. This was confirmed by histopathological examination of thoracic and abdominal regions of the aortae.(ABSTRACT TRUNCATED AT 250 WORDS)

Thirty baboons were injected intravenously and intra-articularly with material from the joints of 19 patients with active rheumatoid arthritis or with control material. Fifteen of the 30 animals received synovial fluid cells or synovial membrane cells from 3 patients with seronegative arthritis. Ten animals received pooled cells from a total of 16 cases of seropositive arthritis. Five animals were given nonrheumatoid cells. No signs of arthritis were recognised in the 27 surviving animals during 3 years of observation. No significant biochemical, haematological, or serological changes occurred during this period, and no gross or microscopic evidence of synovial or systemic disease was found post mortem.

1-(7-Theophyllinyl)-2-ethyl-[2-(p-chlorophenoxy)-isobutyrate] (etofylline clofibrate, theofibrate, Duolip) was shown to possess substantial thrombus disaggregating activity in the microcirculation of the hamster cheek pouch following minor vascular damage by electrical stimulation. At 12 mg/kg p.o. the moderate effect of a single dose (12% reduction in disaggregation time) increased to a maximum reduction of 31 and 43% following 5 and 7 consecutive daily applications, respectively. Etofylline clofibrate was more active than other drugs already tested in this test system, but less than the prostaglandins PGE1 and PGI2. The antithrombotic efficacy found in both in vivo tests, thrombus formation and disaggregation, suggests as mode of action of etofylline clofibrate an agonistic interaction with intimal PGI2. This could be by enhancement of its production or by a synergistic interaction with this prostanoid, rather than inhibition of thromboxane A2 synthetase.

Ditazole (4,5-diphenyl-2-bis-(2-hydroxyethyl)-aminoxazol) is a weak anti-inflammatory drug and has been shown to inhibit thrombus formation following electrically stimulated vascular damage in the microcirculation of the hamster cheek pouch. The drug was found to inhibit thromboxane A2 (TXA2) production ex vivo as determined by radioimmunoassay (RIA) and to reversibly antagonise the effect of TXA2 on smooth vascular tissue. However, in contrast to acetylsalicylic acid (ASA), it does not inhibit vessel cyclooxygenase. The apparent vascular protective effect of ditazole could not be ascribed to an enhanced production of vascular prostacyclin (PGI2) since the latter, when estimated ex vivo by RIA, was not enhanced following oral treatment with the drug. It is suggested that the mode-of-action of ditazole may be different from the cyclo-oxygenase/PG synthetase blocking action of most other non-steroidal anti-inflammatory drugs.