Disease relevance of Cariporide

• In conclusion, selective inhibition of the Na(+)/H(+) exchanger by cariporide may represent an effective therapeutic strategy in the treatment of hepatic fibrosis [1].
• Selective Na+/H+ exchange inhibition by cariporide reduces liver fibrosis in the rat [1].
• After the desired duration of acidosis, NHE was reactivated (by reintroduction of [Na+]o or removal of cariporide), and the rate of recovery of pHi (dpHi/dt) was measured as the index of NHE activity [2].
• In contrast, recent clinical studies with the NHE inhibitors cariporide and eniporide in patients with evolving myocardial infarction (MI) and those at risk of MI have provided mixed and somewhat contradictory data [3].
• METHODS: Twenty-six isolated rat hearts and 23 in situ porcine hearts were submitted to no-flow ischemia followed by reperfusion, with or without pre-treatment with cariporide (7 microM in rats and 3 mg/kg in pigs) [4].

Psychiatry related information on Cariporide

• At day 36, patients treated with cariporide 120 mg demonstrated a 10% risk reduction in death or MI compared with placebo (p = 0.12) [5].

High impact information on Cariporide

• Treatment with cariporide reduced the degree of liver injury, as determined by alanine aminotransferase (ALT) values, also when administered after the induction of hepatic damage [1].
• Inhibition of NHE by amiloride or cariporide resulted in a similar reduction of secretin-stimulated bile flow and bicarbonate secretion [6].
• Preincubation of the cells with zinc was followed by robust activation of Na+/H+ exchange, which was eliminated by cariporide (0.5 microm); indicating that zinc enhances the activity of NHE1 [7].
• Thus, in the GUARDIAN trial, the cardioprotective efficacy of cariporide was limited to the subset of high-risk patients who underwent coronary artery bypass graft surgery, in whom both prerequisites could be readily fulfilled [3].
• (d) Small effects of incubation in cariporide and S3705 at low pHe to increase the net cell kill after treatment with melphalan [8].

Chemical compound and disease context of Cariporide

• We tested if combining treatment with cariporide, an Na(+)/H(+) exchange inhibitor, and diazoxide, a mitochondrial ATP-sensitive K(+) (K(ATP)) channel opener, would reduce myocardial infarct size (IS) to a greater extent than either intervention alone [9].
• After hypoxia, relaxation to acetylcholine was preserved in adult rings treated with cariporide (-22.3% vs. -9.3% of baseline value in control and treated groups respectively, P<0.05) but not in senescents [10].
• CONCLUSIONS: Pretreatment with cariporide in the setting of ischemia-reperfusion injury provides greater protection against the development of diastolic abnormalities than probucol when Celsior solution is used for both arrest and preservation [11].
• We tested whether pharmacologic pre-conditioning with adenosine and the Na(+)/H(+) exchanger inhibitor, cariporide, combined with controlled reperfusion, would prevent injury in porcine hearts that had sustained 30 minutes of hypoxia/ischemia in closed-chest animals [12].
• These animals exhibited focal myocardial fibrosis and increased ejection fraction, in association with a tendency to increased left ventricular wall thickness and heart weight, after six months of follow-up, both bosentan and cariporide prevented these responses [13].

Biological context of Cariporide

• RESULTS: The two doses of cariporide did not differ in their effects after 1 month of treatment, since both induced a slight decrease in systolic blood pressure (SBP) of approximately 6 mmHg and regression of the heart weight to body weight ratio (mg/g) from 3.28+/-0.05 to 3.04+/-0.05 (0.3 mg) and 2.99+/-0.10 (3.0 mg, P<0.05) [14].
• Blockade of impulse propagation (transmembrane action potentials in rat hearts) was also markedly delayed by cariporide (from 14+/-1 to 20+/-1 min, P<0.001) [4].
• Hydrogen peroxide induced impairment of post-ischemic ventricular function is prevented by the sodium-hydrogen exchange inhibitor HOE 642 (cariporide) [15].
• A rapid ischemia-induced apoptosis in isolated rat hearts and its attenuation by the sodium-hydrogen exchange inhibitor HOE 642 (cariporide) [16].
• 1. Specific inhibitors of the sarcolemmal Na(+)/H(+) exchanger (NHE) such as cariporide are being evaluated for cardioprotective therapy during cardiac surgery [17].

Anatomical context of Cariporide

• RESULTS: Human ventricular myocytes exhibited readily detectable sarcolemmal NHE activity after the induction of intracellular acidosis, and this activity was suppressed by the NHE1-selective inhibitor HOE-642 (cariporide) at 1 micromol/L [18].
• RESULTS: Pre-treatment with cariporide delayed ATP depletion (luminescence assay in rat myocardium) and onset of rigor contracture (tension recordings or ultrasonic crystals) during ischemia both in rat and pig hearts (P<0.05) [4].
• Using intracellular acidifications in the presence of 3 mM external sodium on the CR5 fibroblasts, we isolated two revertants which exhibited a complete recovery for sodium affinity but were still resistant to cariporide [19].
• Cariporide counteracts atherosclerosis-related functions in monocytes from obese and normal individuals [20].
• Fifteen Sprague-Dawley rats were randomized to receive bolus injections of cariporide or placebo in a dose of 3 mg/kg into the right atrium either 5 mins before or at 8 mins after onset of ventricular fibrillation [21].

Associations of Cariporide with other chemical compounds

• Four groups of rabbits were studied (n = 10 each): cariporide (0.3 mg/kg), diazoxide (10 mg/kg), both drugs, and saline control, given 15 min before a 30-min coronary artery occlusion and 3 h reperfusion [9].
• OBJECTIVE: This study aimed to show the effect of high glucose concentrations in combination with a pharmaceutical analog of the Na+/H+ antiport inhibitor, cariporide, on scavenger receptor CD36 expression, cell adhesion, and cell migration of human monocytes derived from obese and normal individuals [20].
• In HEPES-buffered solutions, cariporide depressed cell length shortening of normal myocytes (1-3 Hz) by 16+/-5.4% (n=9, P=0.005) [22].
• A <1% dimensional change occurred in myocytes from cariporide-fed animals, and the hyporesponse to isoproterenol was reversed [23].
• Infarct sizes were unaffected by cariporide, and the drug had no influence on either blood pressure or the depressed inotropic response of infarcted hearts to dobutamine [24].

Gene context of Cariporide

• Using this assay system, we demonstrated that the acylguanidine derivatives, cariporide and eniporide, cause selective inhibition of hNHE1 (IC50 value of 30 nM for cariporide, IC50 value of 4.5 nM for eniporide) [25].
• Cariporide is an orally active inhibitor of NHE-1 (6000 ppm in rat chow) [26].
• Furthermore, a diabetes-induced upregulation of ET-1 and ET-3 mRNA expression after six weeks was corrected with cariporide treatment [26].
• Chronic treatment of GC-A(-/-) mice with the NHE-1 inhibitor cariporide normalized cardiomyocyte pH and Ca2+ levels and regressed cardiac hypertrophy and fibrosis, despite persistent arterial hypertension [27].
• The results demonstrate that all 4 pathways were activated in GC-A(-/-) mice, but only CaMKII and Akt activity regressed during reversal of the hypertrophic phenotype by cariporide treatment [27].

Analytical, diagnostic and therapeutic context of Cariporide

• The lack of an effect of additional IB4 treatment may indicate that GSH/cariporide retroinfusion itself affects leukocyte-dependent reperfusion injury [28].
• BACKGROUND: The aim of this study was to determine the efficacy of cariporide (a sodium-hydrogen exchanger inhibitor), BMS180448 (a pharmacologic ischemic preconditioning agent), and the combination thereof, as adjuvant therapies for extended cardiac allograft preservation [29].
• The aorta was endoclamped, and in situ perfusion of the aortic root was maintained with University of Wisconsin solution and cariporide [30].
• METHODS: Treatment with cariporide was commenced either 1 week pre or 30 min, 3 h, 24 h or 7 days after ligation of the left ventricular artery and was continued until haemodynamic parameters were obtained 6 weeks after MI in conscious rats [31].
• CONCLUSION: In this porcine model of extended cardiac allograft preservation, cariporide was more effective than BMS180448 as an adjuvant to our usual preservation solution [29].

References