Disease relevance of R 75231

• Tissue adenosine at the end of ischemia was elevated by draflazine compared with saline-treated hearts: after low-flow ischemia to 0.10+/-0.05 versus 0.00+/-0.00 micromol x g(-1) dry wt (P<.05) and after zero-flow ischemia to 1.73+/-0.82 versus 0.15+/-0.03 micromol x g(-1) dry wt (P<.05) [1].
• Similar to the allosteric enhancer, the nucleoside uptake blocker draflazine (0.1 mumol/L) also increased by twofold the S-H interval prolongation caused by hypoxia [2].
• Neither the pre- nor postischemic effects of R 75231 were abolished by 8-cyclopentyl-1,3-dipropylxanthine or glybenclamide, except for the preischemic bradycardia [3].
• In 14 fetal lambs (3 to 5 d after surgery, gestational age 124.1 +/- 1.1 d), seven fetuses were pretreated with R-75231 (0.1 mg/kg estimated fetal weight as a bolus injection in the inferior vena cava), whereas the other seven served as controls [4].
• After 1 h of severe asphyxia, induced by restriction of uterine blood flow, those fetuses treated with R-75231 showed a faster normalization of aortal pH and, in contrast to the control group, did not develop tachycardia [4].

High impact information on R 75231

• After the intravenous draflazine infusion, these values were 1.6 +/- 0.2 ml/100 ml forearm per min for placebo and 2.1 +/- 0.3, 3.3 +/- 0.6, 5.8 +/- 1.1, 6.9 +/- 1.4, 14.4 +/- 2.9, and 23.5 +/- 4.0 ml/100 ml forearm per min, respectively (Friedman ANOVA: P < 0.05 before vs after draflazine infusion) [5].
• Draflazine significantly improved percent recovery of left ventricular systolic pressure both in the low-flow protocol (92+/-3% versus 75+/-2% [saline] and 73+/-3% [8SPT], P<.001 for both) and in the zero-flow protocol (76+/-3% versus 59+/-4% [saline] and 46+/-9% [8SPT], P<.05 for both) [1].
• In a dose-finding study on draflazine infusions into the brachial artery (n=10), we identified an optimal dose of 250 ng/min per deciliter of forearm tissue that induced considerable local nucleoside transport inhibition (approximately 40%) without systemic effects [6].
• In the main study, we investigated the effects of this draflazine dose on sympathetic-mediated norepinephrine spillover during lower body negative pressure (-25 mm Hg) by the use of the [3H]norepinephrine isotope dilution technique (n=25) [6].
• The ENT1 transporters exhibit distinctive species differences in their sensitivities to inhibition by dipyridamole, dilazep and draflazine (human>mouse>rat) [7].

Chemical compound and disease context of R 75231

• We explored the effects of the nucleoside transport inhibitor draflazine on regional blood flow, O2 extraction capabilities, and tumor necrosis factor (TNF) release in acute endotoxic shock [8].

Biological context of R 75231

• However, increased endogenous levels by draflazine enhance downregulation of function and reduce signs of anaerobic metabolism [9].
• However, draflazine enhanced the reduction in heart rate, contractile force and MVO(2), with less release of H+ and CO2 [9].
• 3. The pharmacokinetics of draflazine in blood were determined in each subject and characterized by a two-compartment pharmacokinetic model [10].
• We conclude that nucleoside transport inhibition with draflazine does not alter global and hepatosplanchnic hemodynamics but may decrease gut mucosal perfusion and renal blood flow [8].
• Dose-response curves indicated that the IC50 values of draflazine and R88016 were approximately 0.5 microM and 10 microM, respectively [11].

Anatomical context of R 75231

• 5. The data provide evidence that draflazine specifically binds to the nucleoside transporter of the human heart and erythrocytes with high affinity.(ABSTRACT TRUNCATED AT 250 WORDS)[12]
• Studies of the nucleoside transporter inhibitor, draflazine, in the human myocardium [12].
• In the control group, only three fetuses recovered and survived, whereas in the R-75231 group, all seven animals recovered after severe asphyxia [4].
• Draflazine concentration-dependently inhibited binding of [3H]-NBTI to myocardial and erythrocyte membranes with a K(i)-value of 4.5 nmol l-1 [12].
• On the basis of these findings it is suggested that a 15 min infusion of 1 mg draflazine followed by an infusion of 1 mg h-1 could be appropriate in patients undergoing a coronary artery bypass grafting [13].

Associations of R 75231 with other chemical compounds

• Physiological red blood cell kinetic model to explain the apparent discrepancy between adenosine breakdown inhibition and nucleoside transporter occupancy of draflazine [14].
• The cardioprotective effects of R 75231 and lidoflazine are not caused by adenosine A1 receptor activation [3].
• When cardiac index was reduced by tamponade to study the O2 extraction capabilities, renal blood flow and ileum mucosal perfusion remained lower in the draflazine group [8].
• These draflazine analogues also varied in their differential affinities for mouse vs. human es/ENT1 transporters, and the degree of species discrimination was strongly dependent on the position of the aminocarbonyl group on the piperazine ring [15].
• Starting on day 4, serum creatinine was lower in the R 75231 group than in the control group (p < 0.005) [16].

Gene context of R 75231

• Draflazine and a series of 15 chemically related compounds were compared for their abilities to: (a) inhibit the binding of [3H]NBMPR to the es/ENT1 transporter in mouse Ehrlich cell and human erythrocyte membranes, and (b) inhibit the es/ENT1 and ei/ENT2 transporter-mediated uptake of [3H]uridine in Ehrlich cells [15].
• Thus, the cardioprotective effects of R 75231 are not mediated by adenosine A1 receptor activation and, thus, probably are not caused by its activity as a nucleoside transport inhibitor [3].
• At end of LFI mRNA-level of PLB was higher in draflazine-treated hearts compared to both other groups (P<0.01 vs both) [9].
• In the R 75231 group, renin, angiotension I, and angiotensin II levels were significantly lower [16].

Analytical, diagnostic and therapeutic context of R 75231

• Intravenous injection of 0.5 mg draflazine did not affect any of the measured hemodynamic parameters but still induced a significant ex vivo nucleoside-transport inhibition of 31.5 +/- 4.1% (P < 0.05 vs placebo) [5].
• Draflazine did not affect forearm blood flow (venous occlusion plethysmography) [5].
• The percentage increase in myocardial blood flow during asphyxia, measured with radioactive microspheres, was significantly higher in the R-75231-treated group compared with the control group (437 and 284%, respectively) [4].
• R 75231 caused only modest improvements in reperfusion contractile function, whereas it profoundly reduced LDH release [3].
• Nucleoside transport inhibitors, like draflazine, are of potential importance for cardiopreservation of donor hearts for heart transplantation [12].

References