The Experts below are selected from a list of 177 Experts worldwide ranked by ideXlab platform
Patrick P Michel - One of the best experts on this subject based on the ideXlab platform.
-
probenecid potentiates mptp mpp toxicity by interference with cellular energy metabolism
Journal of Neurochemistry, 2013Co-Authors: Daniel Alvarezfischer, Carmen Noelker, Anne Grunewald, Franca Vulinovic, Serge Guerreiro, Julia Fuchs, Anne Lombes, Etienne C Hirsch, Wolfgang H Oertel, Patrick P MichelAbstract:The Uricosuric Agent probenecid is co-administered with the dopaminergic neurotoxin MPTP to produce a chronic mouse model of Parkinson's disease. It has been proposed that probenecid serves to elevate concentrations of MPTP in the brain by reducing renal elimination of the toxin. However, this mechanism has never been formally demonstrated to date and is questioned by our previous data showing that intracerebral concentrations of MPP(+), the active metabolite of MPTP, are not modified by co-injection of probenecid. In this study, we investigated the potentiating effects of probenecid in vivo and in vitro arguing against the possibility of altered metabolism or impaired renal elimination of MPTP. We find that probenecid (i) is toxic in itself to several neuronal populations apart from dopaminergic neurons, and (ii) that it also potentiates the effects of other mitochondrial complex I inhibitors such as rotenone. On a mechanistic level, we show that probenecid is able to lower intracellular ATP concentrations and that its toxic action on neuronal cells can be reversed by extracellular ATP. Probenecid can potentiate the effect of mitochondrial toxins due to its impact on ATP metabolism and could therefore be useful to model atypical parkinsonian syndromes.
-
Modelling Parkinson-like neurodegeneration via osmotic minipump delivery of MPTP and probenecid.
Journal of neurochemistry, 2008Co-Authors: Daniel Alvarez-fischer, Serge Guerreiro, Etienne C Hirsch, Stéphane Hunot, Françoise Saurini, Marc Marien, Pierre Sokoloff, Andreas Hartmann, Patrick P MichelAbstract:Mouse models of MPTP intoxication have been used extensively to explore the molecular mechanisms of Parkinson's disease. However, these models present some limitations since; (i) Dopaminergic (DA) cell death occurs rapidly in contrast to the presumably slow evolution of the disease process. (ii) Some of the key histological features of the disease such as Lewy body like inclusions and long-term inflammatory changes are lacking. Fornai et al. [Proc. Natl Acad. Sci. USA 102 (2005), 3413] suggested that continuous delivery of MPTP with Alzet osmotic minipumps may possibly circumvent these problems. Our results show, however, that MPTP infusion via Alzet osmotic minipumps (40 mg/kg/day) produces only a transient depletion in striatal dopamine (DA) without causing dopaminergic cell loss in the substantia nigra. Neuronal cell loss occurred, however, if MPTP was infused concomitantly with probenecid, an Uricosuric Agent which potentiates the effects of the toxin injected via the i.p. route. Even under these conditions, dopaminergic cell loss was moderate (-25%) and other neurodegenerative changes characteristic of Parkinson's disease remained undetectable.
Serge Guerreiro - One of the best experts on this subject based on the ideXlab platform.
-
probenecid potentiates mptp mpp toxicity by interference with cellular energy metabolism
Journal of Neurochemistry, 2013Co-Authors: Daniel Alvarezfischer, Carmen Noelker, Anne Grunewald, Franca Vulinovic, Serge Guerreiro, Julia Fuchs, Anne Lombes, Etienne C Hirsch, Wolfgang H Oertel, Patrick P MichelAbstract:The Uricosuric Agent probenecid is co-administered with the dopaminergic neurotoxin MPTP to produce a chronic mouse model of Parkinson's disease. It has been proposed that probenecid serves to elevate concentrations of MPTP in the brain by reducing renal elimination of the toxin. However, this mechanism has never been formally demonstrated to date and is questioned by our previous data showing that intracerebral concentrations of MPP(+), the active metabolite of MPTP, are not modified by co-injection of probenecid. In this study, we investigated the potentiating effects of probenecid in vivo and in vitro arguing against the possibility of altered metabolism or impaired renal elimination of MPTP. We find that probenecid (i) is toxic in itself to several neuronal populations apart from dopaminergic neurons, and (ii) that it also potentiates the effects of other mitochondrial complex I inhibitors such as rotenone. On a mechanistic level, we show that probenecid is able to lower intracellular ATP concentrations and that its toxic action on neuronal cells can be reversed by extracellular ATP. Probenecid can potentiate the effect of mitochondrial toxins due to its impact on ATP metabolism and could therefore be useful to model atypical parkinsonian syndromes.
-
Modelling Parkinson-like neurodegeneration via osmotic minipump delivery of MPTP and probenecid.
Journal of neurochemistry, 2008Co-Authors: Daniel Alvarez-fischer, Serge Guerreiro, Etienne C Hirsch, Stéphane Hunot, Françoise Saurini, Marc Marien, Pierre Sokoloff, Andreas Hartmann, Patrick P MichelAbstract:Mouse models of MPTP intoxication have been used extensively to explore the molecular mechanisms of Parkinson's disease. However, these models present some limitations since; (i) Dopaminergic (DA) cell death occurs rapidly in contrast to the presumably slow evolution of the disease process. (ii) Some of the key histological features of the disease such as Lewy body like inclusions and long-term inflammatory changes are lacking. Fornai et al. [Proc. Natl Acad. Sci. USA 102 (2005), 3413] suggested that continuous delivery of MPTP with Alzet osmotic minipumps may possibly circumvent these problems. Our results show, however, that MPTP infusion via Alzet osmotic minipumps (40 mg/kg/day) produces only a transient depletion in striatal dopamine (DA) without causing dopaminergic cell loss in the substantia nigra. Neuronal cell loss occurred, however, if MPTP was infused concomitantly with probenecid, an Uricosuric Agent which potentiates the effects of the toxin injected via the i.p. route. Even under these conditions, dopaminergic cell loss was moderate (-25%) and other neurodegenerative changes characteristic of Parkinson's disease remained undetectable.
Etienne C Hirsch - One of the best experts on this subject based on the ideXlab platform.
-
probenecid potentiates mptp mpp toxicity by interference with cellular energy metabolism
Journal of Neurochemistry, 2013Co-Authors: Daniel Alvarezfischer, Carmen Noelker, Anne Grunewald, Franca Vulinovic, Serge Guerreiro, Julia Fuchs, Anne Lombes, Etienne C Hirsch, Wolfgang H Oertel, Patrick P MichelAbstract:The Uricosuric Agent probenecid is co-administered with the dopaminergic neurotoxin MPTP to produce a chronic mouse model of Parkinson's disease. It has been proposed that probenecid serves to elevate concentrations of MPTP in the brain by reducing renal elimination of the toxin. However, this mechanism has never been formally demonstrated to date and is questioned by our previous data showing that intracerebral concentrations of MPP(+), the active metabolite of MPTP, are not modified by co-injection of probenecid. In this study, we investigated the potentiating effects of probenecid in vivo and in vitro arguing against the possibility of altered metabolism or impaired renal elimination of MPTP. We find that probenecid (i) is toxic in itself to several neuronal populations apart from dopaminergic neurons, and (ii) that it also potentiates the effects of other mitochondrial complex I inhibitors such as rotenone. On a mechanistic level, we show that probenecid is able to lower intracellular ATP concentrations and that its toxic action on neuronal cells can be reversed by extracellular ATP. Probenecid can potentiate the effect of mitochondrial toxins due to its impact on ATP metabolism and could therefore be useful to model atypical parkinsonian syndromes.
-
Modelling Parkinson-like neurodegeneration via osmotic minipump delivery of MPTP and probenecid.
Journal of neurochemistry, 2008Co-Authors: Daniel Alvarez-fischer, Serge Guerreiro, Etienne C Hirsch, Stéphane Hunot, Françoise Saurini, Marc Marien, Pierre Sokoloff, Andreas Hartmann, Patrick P MichelAbstract:Mouse models of MPTP intoxication have been used extensively to explore the molecular mechanisms of Parkinson's disease. However, these models present some limitations since; (i) Dopaminergic (DA) cell death occurs rapidly in contrast to the presumably slow evolution of the disease process. (ii) Some of the key histological features of the disease such as Lewy body like inclusions and long-term inflammatory changes are lacking. Fornai et al. [Proc. Natl Acad. Sci. USA 102 (2005), 3413] suggested that continuous delivery of MPTP with Alzet osmotic minipumps may possibly circumvent these problems. Our results show, however, that MPTP infusion via Alzet osmotic minipumps (40 mg/kg/day) produces only a transient depletion in striatal dopamine (DA) without causing dopaminergic cell loss in the substantia nigra. Neuronal cell loss occurred, however, if MPTP was infused concomitantly with probenecid, an Uricosuric Agent which potentiates the effects of the toxin injected via the i.p. route. Even under these conditions, dopaminergic cell loss was moderate (-25%) and other neurodegenerative changes characteristic of Parkinson's disease remained undetectable.
Hirotoshi Echizen - One of the best experts on this subject based on the ideXlab platform.
-
potentiation of anticoagulant effect of warfarin caused by enantioselective metabolic inhibition by the Uricosuric Agent benzbromarone
Clinical Pharmacology & Therapeutics, 1999Co-Authors: Harumi Takahashi, Teruki Sato, Yoshiaki Shimoyama, Noriko Shioda, Teppei Shimizu, Suzuko Kubo, Noboru Tamura, Hitoshi Tainaka, Toshio Yasumori, Hirotoshi EchizenAbstract:Objective To clarify the mechanism(s) for the interaction between warfarin and benzbromarone, a Uricosuric Agent, and to predict changes in the in vivo pharmacokinetics of (S)-warfarin from in vitro data. Methods Warfarin enantiomers and benzbromarone in serum, 7-hydroxywarfarin in urine, and serum unbound fractions of warfarin enantiomers were measured in patients with heart disease given warfarin with (n = 13) or without (n = 18) oral benzbromarone (50 mg/d). In vitro inhibition constants (Ki) of benzbromarone for (S)-warfarin 7-hydroxylation were determined with use of human CYP2C9 and liver microsomes. The magnitude of changes in the formation clearance for 7-hydroxylation (CLf), the unbound oral clearance (CLoral,u), and the oral clearance (CLoral) for (S)-warfarin were predicted by equations incorporating the in vitro Ki, the theoretical maximum unbound hepatic benzbromarone concentration, and the fractions of warfarin eliminated through metabolism and of CYP2C9-mediated metabolic reaction susceptible to inhibition by benzbromarone. Results The patients given warfarin with benzbromarone required a 36% less (P < .01) warfarin dose than those given warfarin alone (2.5 versus 3.9 mg/d) to attain similar international normalized ratios (2.1 and 2.2, respectively), and the former had 65%, 53%, and 54% lower (P < .05 or P < .01) CLf, CLoral,u, and CLoral for (S)-warfarin than the latter, respectively. In contrast, no significant differences were observed for (R)-warfarin kinetics between the groups. Benzbromarone was found to be a potent competitive inhibitor (Ki < 0.01 μmol/L) for (S)-warfarin 7-hydroxylation mediated by CYP2C9. The average changes in the in vivo CLf, CLoral,u, and CLoral values for (S)-warfarin induced by benzbromarone were largely predictable by the proposed equations. Conclusion Benzbromarone would intensify anticoagulant response of warfarin through an enantioselective inhibition of CYP2C9-mediated metabolism of pharmacologically more potent (S)-warfarin. The magnitude of changes in the in vivo warfarin kinetics may be predicted by in vitro data. Clinical Pharmacology & Therapeutics (1999) 66, 569–581; doi: 10.1053/cp.1999.v66.103378001
-
pharmacokinetic interaction between warfarin and a Uricosuric Agent bucolome application of in vitro approaches to predicting in vivo reduction of s warfarin clearance
Drug Metabolism and Disposition, 1999Co-Authors: Harumi Takahashi, Hitoshi Tainaka, Toshio Yasumori, Toshitaka Kashima, Sosuke Kimura, Noboru Murata, Toshihiro Takaba, Kazunori Iwade, Tomio Abe, Hirotoshi EchizenAbstract:A Uricosuric Agent, bucolome, has been shown to intensify the anticoagulant effect of warfarin. The aims of the present study were to clarify its mechanism(s) and to apply in vitro approaches for predicting this potentially life-threatening in vivo interaction. An in vivo study revealed that Japanese patients given warfarin with bucolome (300 mg/day, n = 21) showed a 1.5-fold greater international normalized ratio than those given warfarin alone (n = 34) despite that the former received a 58% smaller warfarin dose than the latter. Enantioselective assays revealed that bucolome increased plasma unbound fractions of (S)- and (R)-warfarin by 2-fold (p <.01), reduced unbound oral clearances of (S)- and (R)-warfarin by 84 (p <.01) and 26% (p <.05), respectively, and inhibited the unbound formation clearance for (S)-warfarin 7-hydroxylation by 89% (p <.01). In contrast, bucolome elicited no appreciable changes in the plasma unbound (S)-warfarin concentration versus the international normalized ratio relationship. In vitro studies with recombinant human cytochrome P-450 2C9 and liver microsomes showed that bucolome was a potent mixed-type inhibitor for (S)-warfarin 7-hydroxylation, with K(i) of 8.2 and 20.2 microM, respectively. An in vitro model incorporating maximum unbound bucolome concentration in the liver estimated as a sum of hepatic artery and portal vein concentrations and in vitro K(i) made an acceptable prediction for bucolome-induced reductions in in vivo total (bound + unbound) oral clearance, unbound oral clearance, and unbound formation clearance for (S)-warfarin. In conclusion, the augmented anticoagulant effect of warfarin by bucolome due to the metabolic inhibition for pharmacologically more potent (S)-warfarin may be predictable from in vitro data.
Daniel Alvarezfischer - One of the best experts on this subject based on the ideXlab platform.
-
probenecid potentiates mptp mpp toxicity by interference with cellular energy metabolism
Journal of Neurochemistry, 2013Co-Authors: Daniel Alvarezfischer, Carmen Noelker, Anne Grunewald, Franca Vulinovic, Serge Guerreiro, Julia Fuchs, Anne Lombes, Etienne C Hirsch, Wolfgang H Oertel, Patrick P MichelAbstract:The Uricosuric Agent probenecid is co-administered with the dopaminergic neurotoxin MPTP to produce a chronic mouse model of Parkinson's disease. It has been proposed that probenecid serves to elevate concentrations of MPTP in the brain by reducing renal elimination of the toxin. However, this mechanism has never been formally demonstrated to date and is questioned by our previous data showing that intracerebral concentrations of MPP(+), the active metabolite of MPTP, are not modified by co-injection of probenecid. In this study, we investigated the potentiating effects of probenecid in vivo and in vitro arguing against the possibility of altered metabolism or impaired renal elimination of MPTP. We find that probenecid (i) is toxic in itself to several neuronal populations apart from dopaminergic neurons, and (ii) that it also potentiates the effects of other mitochondrial complex I inhibitors such as rotenone. On a mechanistic level, we show that probenecid is able to lower intracellular ATP concentrations and that its toxic action on neuronal cells can be reversed by extracellular ATP. Probenecid can potentiate the effect of mitochondrial toxins due to its impact on ATP metabolism and could therefore be useful to model atypical parkinsonian syndromes.
