Thrombosis triggered by severe arterial lesions is inhibited by oral administration of a glycoprotein IIb/IIIa antagonist

Platelet aggregation and thrombosis play an important role in the onset of acute coronary events. Regardless of the stimulus for activation, platelet thrombus formation is ultimately regulated through the IIb/IIIa receptor complex. The effects of oral administration of xemilofiban, a non-peptide mimetic of the RGDF sequence of the IIb/IIIa receptor complex, on thrombus formation were evaluated in a canine model. Xemilofiban significantly reduced platelet deposition on severely damaged arterial wall. Platelet deposition was reduced at both low (13 ± 1 from 56 ± 18 × 10⁶ platelets cm⁻²; P  < 0.05) and high (23 ± 2 from 111 ± 21 × 10⁶ platelets cm⁻²; P  < 0.01) shear rates. Platelet deposition was reduced to a monolayer as seen by electron microscopy (platelet–vessel wall interaction). Therefore, the availability of an orally active IIb/IIIa antagonist for chronic use may have significant value in preventing thrombus formation in those clinical situations associated with severe arterial injury, such as atherosclerotic plaque disruption.     

Effect of meal volume on gastric emptying

Abstract While the volume of a liquid meal has been identified as the principal accelerator of gastric emptying of liquids, the relationship between meal volume and gastric emptying of solids has been controversial. With solid foods, the need to reduce solid foods into small particles (trituration) before passage might obscure the effect of meal volume on solid propulsion. To distinguish trituration from driving force as the rate-limiting factor for emptying, 75 (1.6 mm) nylon spheres were fed along with different amounts of steak meals (150, 300 and 600 g), or alternatively, 50, 100 or 200 (1.6 mm) nylon spheres were fed to six dogs with 300 g steak meals. To examine the effect of meal volume on gastric emptying, we studied the effect of different meal volumes on the speed of gastric emptying of liquids (150, 300, 600 and 1200 ml of phosphate buffer) and solids (150, 300 and 600 g of cooked beef steak) in five dogs with duodenal fistulas. Intestinal inhibition was eliminated by diverting all chyme through the fistulas. In the absence of intestinal feedback, we found that gastric emptying of steak and spheres were different in that steak emptying was independent of meal volume (g min^-1 was constant across 150–600 g) while sphere emptying was affected by the number of spheres in the stomach and that liquid emptying was dependent on the meal volume (ml min^-1 increased across 150–1200 ml). Thus, meal volume accelerated gastric emptying provided the process is not rate-limited by trituration.     

Liver-infiltrating T helper cells in autoimmune chronic active hepatitis stimulate the production of autoantibodies against the human asialoglycoprotein receptor in vitro.

Autoantibodies against the human asialoglycoprotein receptor (ASGPR) occur in the sera of patients with autoimmune liver disorders. Liver-infiltrating T cell clones that specifically recognize the ASGPR have been described in patients with autoimmune chronic active hepatitis (AI-CAH) and primary biliary cirrhosis (PBC). Recently, we have shown that peripheral blood mononuclear cells (PBMC) from patients with AI-CAH or PBC but not chronic viral hepatitis secreted anti-ASGPR antibodies in vitro. In this study we characterized the influence of liver-infiltrating T cells on the secretion of ASGPR-specific autoantibodies by autologous B cells in cell culture supernatants. T cell clones from liver biopsies of three patients with chronic autoimmune liver disorders (one with AI-CAH, two with PBC) were isolated and investigated for their proliferative response to soluble ASGPR and their helper function provided to autoantibody-secreting B lymphocytes. PBMC from these patients secreted autoantibodies spontaneously in their cell culture supernatants and showed a proliferative response to ASGPR. T cell-depleted PBMC, however, lacked spontaneous antibody secretion. Four CD4+CD8- liver-infiltrating T cell clones showed a proliferative response to ASGPR and also induced spontaneous anti-ASGPR antibody production in cell culture supernatants when added to autologous T cell depleted PBMC. Activated supernatants of these T cell clones failed to induce antibody production. None of seven CD4+CD8- and two CD4-CD8+ T cell clones non-responding to ASGPR provided this help for antibody secretion. Anti-ASGPR secretion in vitro could not be inhibited by the addition of MoAbs raised against monomorphic determinants on HLA class II molecules. The addition of purified ASGPR or polyclonal-activating pokeweed mitogen showed no influence on the production of autoantibodies in these cultures. These data show that B lymphocytes require T cell help for the production of ASGPR-specific antibodies. This help can be provided by ASGPR-responsive T helper cells via cellular interactions.     

The effect of taprostene in patients with acute myocardial infarction treated with thrombolytic therapy: results of the STARTstudy

Taprostene is a prostacyclin analogue that inhibits plateletaggregation and thus might be a useful adjuvant to thrombolyticagents in acute myocardial infarction. In a placebo-controlled dose rising study, taprostene or placebowas intravenously infused in 80 patients treated with the thrombolyticagent saruplase (rscu-PA) for acute myocardial infarction. Threedoses of taprostene were used: 6.25; 12.5; or 25.0 ng.kg^–1.min^–1.Taprostene or placebo was infused for 48 h, followed by a 24h tapering period. All 80 patients had short symptom-to-treatmentdelay and marked ST segment elevation. Patency at 90 min was documented in 58/78 patients (two patientshad no angiography). Success rate varied from 67–82% inthe four treatment arms (P=0.33). Patency after rescue PTCAwas seen in 10 out of 13 patients. Of the 58 patients havinga patent artery at 90 min, none of the 43 taprostene patientsand one of the 15 placebo patients had a reoccluded artery atthe second angiography at 32–48 h (5/58 patients had norecatheterization). Conversely, of nine patients who had successfulrescue PTCA, three of four placebo patients had a re-occludedartery at the second angiography compared to one of five taprostenepatients (one placebo patient had no recatheterization) (P=0.33). Safety evaluation revealed no major difference betweenthe placebo plus saruplase and the taprostene plus saruplasegroups. Taprostene was well tolerated up to 25 ng.kg^–1 .min^–1.Although taprostene did not affect 90 min patency, there wasa trend to better maintenance of patency after rescue PTCA.