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SummaryN (7-carboxyheptyl) imidazole is an inhibitor of platelet thromboxane synthetase that has no effect on the cyclooxygenase activity. An oral dose of the substance to rats (10 mg/kg) prolonged tail bleeding time from 170 ± 13 sec to 284 ± 22 sec. This oral dose also inhibited platelet thromboxane B2 production induced by collagen ex vivo but had little effect on the aggregation dose response curve. There was no effect on thrombin-induced aggregation.Neither the thrombocytopenia induced by the Arthus reaction nor thrombus formation on an implanted cotton thread were inhibited by oral doses of carboxyheptylimidazole up to 30 mg/kg. Similarly neither the prothrombin nor activated partial thromboplastin time were affected.It is postulated that this thromboxane synthetase inhibitor prolongs bleeding time not by inhibiting platelet aggregation or blood coagulation but rather by preventing the vasoconstriction which would normally be caused by thromboxane A2.

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1 CGS 12970 is a potent selective inhibitor of human platelet thromboxane synthestase in vitro (IC50 = 12 nM). It is four orders of magnitude less potent as an inhibitor of sheep seminal vesicle cyclooxygenase, bovine aorta prostacyclin synthetase and human leucocyte 15-lipoxygenase. 2 The compound inhibited collagen-induced thromboxane B2 production by human platelets in vitro without an effect on the accompanying platelet aggregation induced by collagen, ADP, platelet activating factor, thrombin, arachidonic acid or the prostaglandin mimetic, U 46619. 3 Administration of CGS 12970 to rats inhibited collagen-induced thromboxane B2 production but had no effect on platelet aggregation ex vivo. It also had no effect on platelet aggregation induced by thrombin or on plasma clotting times. 4 A single oral dose of 1 or 3 mg kg-' to rabbits inhibited thromboxane B2 production in clotting blood ex vivo for 12 or 24 h respectively. 5 CGS 12970 inhibited thromboxane B2 production in vivo induced by intravenous administration of collagen to rats or calcium ionophore to guinea-pigs. In both cases there was a concomitant elevation of immunoreactive 6-keto-prostaglandin Flr. but no effect on the induced thrombocytopenia.6 As with other thromboxane synthetase inhibitors, CGS 12970 prolonged tail bleeding time in the rat. However, CGS 12970 was not as potent as other thromboxane synthetase inhibitors in this test. 7 In addition to these usual effects of thromboxane synthetase inhibitors, CGS 12970 inhibited the thrombocytopenia induced by the Forssman reaction or ADP administration. In these tests the effect of the compound was of short duration. 8 CGS 12970 had no effect on the thrombocytopenia associated with the Arthus reaction which distinguishes it from cyclo-oxygenase inhibitors. It also had no effect on thrombus formation on a cotton thread in an arteriovenous shunt in the rat.

When sulphinpyrazone (either 200 mg q.d.s. for 7 days or 400 mg b.d.s. for 5 days) was administered to human volunteers, inhibition of platelet function was observed ex vivo. The inhibitory effect was measured by the increase in the concentration of sodium arachidonate required to cause platelet aggregation and a decrease in the biosynthesis by the platelets of malondialdehyde from added sodium arachidonate. ADP-induced primary platelet aggregation was statistically significantly inhibited only on 1 day of the two studies. The inhibitory effect did not correlate with the plasma concentrations of unchanged sulphinpyrazone nor with its sulphone metabolite but correlated with the plasma concentration of the thioether metabolite (r = 0.577, p < 0.001). Platelet count, plasma fibrinogen, β-thromboglobulin, urea and creatinine concentrations were not changed by the drug but there was a clinically insignificant increase in bleeding time in all but one subject.

The use of yohimbine to treat impotence has suggested that decreased male sexual desire may relate to decreased activity of central noradrenergic neurons. Previous trials of yohimbine to treat female sexual problems are not available. Yohimbine is an alpha 2-adrenergic antagonist that stimulates norepinephrine (NE) release. In the present study, plasma concentrations of 3-methoxy-4-hydroxyphenylglycol (MHPG), the major central nervous system metabolite of NE, were measured in 9 women diagnosed with hypoactive sexual desire. Daily logs of mood and sexual activity, and trimonthly MHPG blood drawings, were obtained over an initial baseline menstrual cycle followed by two subsequent treatment cycles (yohimbine or placebo), in randomized order. Blood samples were obtained at 9:00 a.m. during (a) the early follicular phase of each cycle (24 hr after the onset of each cycle), (b) the ovulatory phase (i.e., within 1 day of an oral temperature rise), and (c) the midluteal phase (i.e., 20-25 days into each cycle). Comparisons were made with a group of 7 healthy female controls. Women with hypoactive sexual desire had slightly lower plasma MHPG values than controls at baseline, although there was only a trend toward significance during the early follicular phase (p = .09). Yohimbine (5.4 mg orally, 3 times daily, beginning at menses) caused a sustained rise in plasma MHPG of similar magnitude to that reported in men. However, in terms of improved sexual desire, yohimbine had no obvious therapeutic effect. Thus, plasma MHPG and the alpha 2-adrenergic response to yohimbine appeared within normal ranges in women with hypoactive sexual desire, with no therapeutic response to yohimbine.

West Sussex RHi12 4AB I Rabbit anti-guinea-pig lymphocytic serum was fractionated by gel filtration to obtain partially purified materials possessing anti-inflammatory activity. The pharmacological properties of these materials were then studied. 2 Two fractions were found which reproducibly contained significant activity. One of these activities caused inflammation at the site of injection and was associated with high molecular weight protein (200,000). The other activity was found in a low molecular weight fraction but was shown to be due to small amounts of endotoxin from Gram negative bacteria. These organisms contaminated the fractions in spite of the recommended precautions for gel filtration having been taken. 3 The endotoxin-containing fraction completely abolished leucocyte infiltration into the rat foot which had been injected with kaolin. It had no apparent effect on circulating haemolytic complement. It caused maximal elevation of serum 1 1-hydroxycorticosteroid concentrations and was found to cause the release of pharmacologically active amines. Many of the previously reported naturally occurring anti-inflammatory substances have similar pharmacological properties to those of the endotoxin-containing fraction. 4 It was concluded that doubt will exist about the presence of anti-inflammatory factors in mammalian body fluids unless stringent precautions are taken to exclude measurable bacterial contamination.S These experiments also cast doubt on the validity of accepted procedures for excluding microbial growth from columns used in the fractionation of serum.

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