1 The e ects of zidovudine (ZDV) and zidovudine triphosphate (ZDV-3P) on Ca 2+ -induced mitochondrial permeability transition (MPT), respiratory control ratio (RCR) and ATP synthesis have been investigated on isolated rat liver mitochondria. 2 ZDV slightly but signi®cantly decreased RCR and ATP synthesis but was ine ective in inhibiting MPT. In contrast, ZDV-3P did not alter RCR and ATP synthesis but strongly inhibited MPT (IC 50 =3.0+0.9 mM).3 The e ect of ZDV-3P on mitochondrial swelling required a preincubation time. When incubated 10 min with mitochondria, ZDV-3P (8 mM) totally inhibited the rate of swelling. 4 ADP, ATP and atractyloside, which are agents known to interact with the mitochondrial adenine nucleotide carrier (ANC), antagonized the e ect of ZDV-3P on mitochondrial swelling. Indeed, the IC 50 value of ZDV-3P increased from 3.0 to 17.4, 93.6 and 66.5 mM, in the presence of 20 mM, ADP, ATP or atractyloside, respectively. 5 ZDV-3P did not displace [ 3 H]-ATP from its mitochondrial binding site(s) whereas ADP and atractyloside did, suggesting that ZDV-3P and [ 3 H]-ATP do not share the same binding sites. 6 ZDV-3P did not a ect either mitochondrial respiration or ATP synthesis but inhibited Ca 2+ -dependent mitochondrial swelling. It was concluded that mitochondrial toxic e ects observed during the chronic administration of ZDV cannot be related to its active metabolite (ZDV-3P).
Using an original microcalorimetric method, the existence of the Mg2ATP ternary chelate has been studied. The thermodynamic parameters of this complex are delta H = 7.2 +/- 0.5 kJ mole-1 and K = 49 +/- 9 M-1. These values are compared with those previously obtained for binary chelate Mg ATP2-. A possible regulation role of Mg2ATP is discussed.
AimsIn renal allograft recipients, trimetazidine (VastarelA) was proposed to be associated with the classic immunosuppressant treatments because it displays antiischaemic effects which may protect against cyclosporine A nephrotoxicity. The objective of this work was to assess the possibility of coadministering cyclosporin A, SandimmunA, and trimetazidine. Methods Twelve renal transplant patients were selected on the basis of the stability of their cyclosporine A blood concentrations for the previous 3 months. They received trimetazidine, 40 mg twice daily orally for 5 days. Other coadministered drugs were kept unchanged during the study. Before and after trimetazidine administration, cyclosporine A blood concentrations, plasma interleukin-2 and soluble interleukin-2 receptor levels were measured. Results The data showed that neither cyclosporin A blood pharmacokinetic parameters, C max , t max , AUC, nor the concentrations of interleukin-2 and soluble interleukin-2 receptors were significantly modified. Conclusions Therefore, it was suggested that trimetazidine may be coadministered with cyclosporine A without cyclosporine A dosage adjustment.
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