Hepatic oxygen exchange and energy metabolism in hyperdynamic porcine endotoxemia: effects of the combined thromboxane receptor antagonist and synthase inhibitor DTTX30

Q1 · MEDICINE

Article

Author: Uwe B. Brückner ; Martin Matejovic ; Carl Zülke ; Arnim Vlatten ; Jürgen Altherr ; Michael Georgieff ; Karl W. Jauch ; Peter Radermacher ; Josef Vogt ; Karl Träger ; Ulrich Wachter ; Alexander Brinkmann

OBJECTIVEWe compared the effects of thromboxane receptor antagonist and synthase inhibitor DTTX30 on systemic and liver blood flow, oxygen (O2) exchange and energy metabolism during 24 h of hyperdynamic endotoxemia with untreated endotoxemia.DESIGNProspective, randomized, experimental study with repeated measures.SETTINGInvestigational animal laboratory.SUBJECTSTwenty-seven domestic pigs: 16 during endotoxemia with volume resuscitation alone; 11 with endotoxemia, volume resuscitation and treatment with DTTX30.INTERVENTIONSContinuous infusion of Escherichia coli lipopolysaccharide (LPS) for 24 h together with volume resuscitation. After 12 h of endotoxemia, DTTX30 was administered as a bolus of 0.12 mg kg-1 followed by 12 h continuous infusion of 0.29 mg kg-1 per h.MEASUREMENTS AND RESULTSDTTX30 effectively counteracted the endotoxin-associated increase in TXB2 levels and increased 6-keto-PGF1 alpha with a significant shift of the thromboxane/prostacyclin ratio towards predominance of prostacyclin. DTTX30 prevented the significant progressive endotoxin-induced decrease of mean arterial pressure (MAP) below baseline while maintaining cardiac output (CO), and increased the fractional contribution of liver blood flow to CO without an effect on either hepatic O2 delivery or O2 uptake. The mean capillary hemoglobin O2 saturation (HbO2) on the liver surface and HbO2 frequency distributions remained unchanged as well.CONCLUSIONSDTTX30 significantly attenuated the endotoxin-induced derangements of cellular energy metabolism as reflected by the diminished progressive decrease in hepatic lactate uptake rate and a blunted increase in hepatic venous lactate/pyruvate ratios. While endotoxin significantly increased the endogenous glucose production (EGP) rate, EGP returned towards baseline levels in the DTTX30-treated group. Thus, in our model DTTX30 resulted in hemodynamic stabilization concomitant with improved hepatic metabolic performance.

01 Apr 2000·ShockQ2 · MEDICINE

EFFECTS OF THE COMBINED THROMBOXANE RECEPTOR ANTAGONIST AND SYNTHASE INHIBITOR DTTX-30 ON INTESTINAL O2-EXCHANGE AND ENERGY METABOLISM DURING HYPERDYNAMIC PORCINE ENDOTOXEMIA

Q2 · MEDICINE

Article

Author: Brückner, U B ; Träger, K ; Georgieff, M ; Matejovic, M ; Jauch, K W ; Zülke, C ; Brinkmann, A ; Altherr, J ; Vlatten, A ; Radermacher, P

Sepsis may lead to deranged thromboxane-prostacyclin ratio with consecutive organ dysfunction. Because of the suggested role of the gut in the pathogenesis of septic shock and multiple organ failure, we investigated the effects of the novel dual thromboxane synthase inhibitor and receptor antagonist DTTX-30 (TRASI) on intestinal tissue perfusion, O2 kinetics, and energy metabolism over 24 h of hyperdynamic, normotensive porcine endotoxemia. Before, 12, 18, and 24 h after starting continuous i.v. endotoxin (LPS), we measured portal venous (PV) blood flow, intestinal oxygen extraction (iO2ER), intracapillary hemoglobin O2 saturation (HbO2%) of the ileal wall, intramucosal ileal PCO2, PV lactate-pyruvate (L-P) ratio, and plasma levels of thromboxane and prostacyclin. Treatment with TRASI (0.12 mg/kg i.v. bolus injection followed by an infusion of 0.29 mg/kg/h) initiated after 12 h of LPS infusion markedly reduced the plasma thromboxane levels and attenuated the LPS-induced fall in systemic vascular resistance, resulting in hemodynamic stabilization. TRASI did not influence the LPS-induced increase in PV blood flow nor intracapillary HbO2%, thus reflecting unchanged microcirculatory O2 availability and decreased iO2ER, possibly because of reduced O2 requirements. Nevertheless, TRASI prevented the LPS-induced increase in the PV L-P ratio, attenuated the progression of the ileal mucosal-arterial PCO2 gap, and tended to attenuate the gradual fall of PV pH. Hence, compounds like TRASI may beneficially influence LPS-related derangements of gut energy metabolism.

01 Feb 2000·Thrombosis ResearchQ3 · MEDICINE

Effect of DT-TX 30, a Combined Thromboxane Synthase Inhibitor and Thromboxane Receptor Antagonist, on Retinal Vascularity in Experimental Diabetes Mellitus

Q3 · MEDICINE

Article

Author: Marı́a I. Ruiz-Ruiz ; Antonio Moreno ; José P. De La Cruz ; Felipe Sánchez De La Cuesta

Combined thromboxane synthase inhibitors and thromboxane receptors antagonists have been shown to have a beneficial effect on different models of thrombosis in vivo. We studied the action of one of these compounds (DT-TX 30) compared with dazoxiben (a thromboxane synthase inhibitor) on retinal vascularity in streptozotocin-diabetic rats. Ten nondiabetic animals were treated with isotonic saline, 30 (10 animals per group) were given 0.4, 4, and 8 mg kg(-1) per day of DT-TX 30 (p.o.) and 30 (10 animals per group) were given 10, 50, and 100 mg kg(-1) per day of dazoxiben (p.o.) over a 90-day study period. DT-TX 30 caused a dose-dependent decrease of platelet aggregation and thromboxane B2 synthesis. There was an increase of 9, 65, and 166% in the synthesis of prostacyclin after treatment with 0.4, 4, and 8 mg kg(-1) per day, respectively. Retinal vascularity increased in 51, 72, and 182% of animals in response to the three doses used. Synthesis of prostacyclin and the degree of retinal vascularity showed a linear correlation (r2=0.6528,p<0.00001). Dazoxiben, at doses that inhibited thromboxane synthesis as much as DT-TX 30, increased prostacyclin production and retinal vascularity with less potency than DT-TX 30. In conclusion, the antagonism of thromboxane receptors may be an important additional effect to the inhibition of thromboxane synthase in the prevention of ischemic retinal lesions in experimental diabetes.

100 Deals associated with Samixogrel

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Indication	Highest Phase	Country/Location	Organization	Date
Angina Pectoris	Phase 2	DE	Boehringer Ingelheim International GmbH	-
Angina, Unstable	Phase 2	DE	-	-
Diabetes Complications	Phase 2	ES	-	-
Thromboembolism	Phase 2	DE	Boehringer Ingelheim International GmbH	-
Thrombosis	Phase 2	DE	-	-
Thrombosis	Phase 2	-	C.H. Boehringer Sohn AG & Co. KG	-

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