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J P Tillement

Publications and source records attributed to J P Tillement.

At least 19 recordsLinked to original sources
PubMed2005

[Pharmacology, an innovative factor in therapeutic research].

As members of the pharmacology training group set up by the committee of pharmacological science of the French Academy of Pharmacy, we examine the situation of pharmacology in drug discovery. Today, it is obvious that by integrating genome sequencing, cellular and molecular biology, and bioinformatics, pharmacology has become a cross-disciplinary science. Pharmacologists must become knowledgeable in a wide range of domains, using the major points in each to direct them towards the discovery and development of new therapeutic agents. It is also clear that pharmacology remains a major factor in the different steps of drug discovery, from the molecular and cellular stages, to clinical and pharmaceutical developments.

Drug Therapy↗
PubMed2003

Evidence for resveratrol-induced preservation of brain mitochondria functions after hypoxia-reoxygenation.

We have previously shown, as have other authors, that trans-resveratrol (E-resveratrol, 3,4,5-trihydroxy-E-stilbene) reduces reactive oxygen species (ROS) generation of mitochondria freshly isolated from healthy rat brains and that it also counteracts the effect of uncouplers (CCCP) on mitochondrial respiration and oxidative phosphorylation. Two main mechanisms have been shown: firstly, a scavenger effect toward O2- and secondly inhibition of complex III ROS generation. We now report on the effects of resveratrol in a pathological model that mimics the ischemia followed by the reperfusion process which may occur in the human brain. Isolated brain mitochondria were submitted first to hypoxia then to reoxygenation. The aim of this study was to determine the extent of mitochondrial damage induced by this experimental model, to demonstrate which mitochondrial functions were altered and to quantify the extent to which they were prevented by resveratrol. Resveratrol was either added to mitochondria freshly isolated from healthy rat brains or was injected by subcutaneous chronically implanted pumps (0.5, 2 and 10 mg/kg/day for 7 days). The rats were then sacrificed and mitochondria were extracted from brains. To evaluate the respective effects of hypoxia and reoxygenation on mitochondrial functions and the relevant effects of resveratrol, this drug was added (first protocol) either before the complete process (i.e., hypoxia and reoxygenation), or after anoxia before reoxygenation. We found that resveratrol prevented alterations of mitochondrial functions. This substance partly counteracted the decrease in respiratory control and the increase in ROS generation. It fully inhibited the alteration of membrane fluidity and the mitochondrial step of the apoptotic process (evidenced by cytochrome c release and membrane potential collapse). The effects of resveratrol were concentration-dependent (in vitro) or dose-dependent (ex vivo, second protocol). They were not significantly different when the drug was added before or after hypoxia, which suggests that in this model, reoxygenation was the most deleterious process and the stage at which resveratrol was most effective.

Animals↗
PubMed2002

Dehydroepiandrosterone and alpha-estradiol limit the functional alterations of rat brain mitochondria submitted to different experimental stresses.

The effects of dehydroepiandrosterone (DHEA), dehydroepiandrosterone-sulfate (DHEA-S), alpha-estradiol and beta-estradiol on the main functions of purified rat brain mitochondria were investigated in basal conditions and after being submitted to various stresses including anoxia-reoxygenation, uncoupling and apoptosis. In basal conditions, DHEA (1 microM) and alpha-estradiol (1 microM) inhibited the respiratory control ratio (RCR) from 3.1 to 2.3 (25%). After anoxia-reoxygenation, DHEA (1 microM) and alpha-estradiol (1 microM) reversed significantly (P<0.01) the RCR decrease from 1.4 to 2.0 (21.5%) by restoring the state 4. This effect was observed when DHEA was added either before anoxia or before reoxygenation and when alpha-estradiol was added before anoxia. The mitochondrial membranes damaged after the anoxia-reoxygenation were 70 and 50%, respectively, protected by DHEA and alpha-estradiol at 1 microM. They also limited by about 50%, the cytochrome c release induced by the anoxia-reoxygenation. The oxygen consumption of mitochondria in presence of NADH (130 microM) and cytochrome c (5 microM) was significantly inhibited by DHEA and alpha-estradiol with high EC(50) of 30 and 22 pM, respectively. At 1 microM, they also inhibited the 10 microM carbonyl cyanide m-chlorophenylhydrazone-induced uncoupling to about 35% whereas beta-estradiol only decreased it to 9%. Our results indicated that DHEA and alpha-estradiol partly preserved the mitochondrial functions altered by an anoxia-reoxygenation with a concentration-dependent effect. The mechanism involved was independent of the classical genomic effect of steroids, the antioxidant properties but implicated a direct action on the mitochondrial membranes.

Adenosine Triphosphatases↗
PubMed2002

[Conclusion].

Explore the source record for details and available documents.

Computational Biology↗
PubMed2001

In vitro effects of nicotine on mitochondrial respiration and superoxide anion generation.

In this study, we investigated the effects of nicotine on rat brain mitochondria. The polarographic studies determined the effects on the respiratory chain, whereas enzymatic assays and [3H]-nicotine binding allowed us to precisely identify its target and site of action. The measurements of oxygen consumption showed a significantly concentration-dependent inhibition by nicotine (EC50 was 4.95x10(-11) M), and a maximal decrease of 23.90% at 10(-7) M. Nicotine bound to complex I of the respiratory chain and inhibited the NADH-Ubiquinone reductase activity. We also showed that nicotine and NADH were competitive on complex I. Effects of cotinine, the main nicotine metabolite, and nornicotine, were also investigated: nornicotine inhibited the mitochondrial respiration whereas cotinine did not. Because the complex I generates superoxide anion, we investigated the effects of nicotine, following NBT oxidation, and showed that nicotine was able to inhibit this reactive oxygen species (ROS) generation by 15.74% with an EC50 of 2.02x10(-11) M. In conclusion, the present study shows that nicotine interacts with the complex I of brain mitochondrial respiratory chain and decreases ROS generation. This may explain a part of the beneficial and protective effects of nicotine in few neurodegenerative diseases, as suggested by many epidemiological studies.

Adenosine Triphosphatases↗
PubMed2001

Curcumin induces the mitochondrial permeability transition pore mediated by membrane protein thiol oxidation.

Curcumin is a natural compound showing antiproliferative properties. Recent studies suggest that these properties might be due to its ability to induce apoptosis in tumor cells. As mitochondria play a pivotal role in the induction of the apoptotic process, we analyzed the effect of curcumin on mitochondrial function. Curcumin induced an increase in rat liver mitochondrial membrane permeability, resulting in swelling, loss of membrane potential and inhibition of ATP synthesis. These effects were mediated by the opening of the permeability transition pore. Curcumin pore induction involved the oxidation of membrane thiol functions and required the presence of low Ca(2+) concentrations. These data suggest that mitochondria might be a target by which curcumin induces apoptosis of tumor cells.

Animals↗
PubMed2001

Inhibition of mitochondrial carnitine palmitoyltransferase-1 by a trimetazidine derivative, S-15176.

The purpose of this study was to investigate the possible effect of the trimetazidine derivative S-15176 on carnitine palmitoyltransferase1 (CPT-1) activity in rat heart and liver mitochondria. S-15176 was compared with the other antianginal agents amiodarone, perhexiline and trimetazidine, which do not show any hemodynamic effects and which are believed to exert their effects by switching the cellular metabolism towards glucose utilization at the expense of lipid metabolism, increasing the yield of oxygen utilization. S-15176 inhibited CPT-1 in vitro and was more effective in heart (IC(50)= 16.8 micro M) than in liver ( 50.8 +/- 3.0 micro M). In the heart, its was less effective than the physiological inhibitor malonyl-CoA (IC(50)= 2.1 micro M), but it was more potent than amiodarone (IC(50)= 140 micro M). Kinetic experiments demonstrated a non-competitive inhibition of CPT-1 by S-15176 indicating that the two compounds did not share the same site of action. CPT-1 inhibition was also obvious ex vivo, in heart and liver tissues, after a 2 week treatment with S-15176. This inhibitory effect may shift heart and liver metabolism from fatty acid to glucose oxidation and contribute to the anti-ischemic effects of the drug.

Animals↗
PubMed2001

Increased oral ganciclovir bioavailability in HIV-infected patients with chronic diarrhoea and wasting syndrome--a population pharmacokinetic study.

AIMS: Despite a lack of data, the antiviral agent ganciclovir is not indicated in AIDS patients with diarrhoea because of its presumed poor oral bioavailability. To assess the effect of diarrhoea on ganciclovir intestinal absorption, we conducted a pharmacokinetic study in 42 HIV-infected patients categorized into three groups: A, HIV stage A and B (n = 15); B, AIDS stage C (n = 13); C, AIDS with chronic diarrhoea and wasting syndrome (n = 14). METHODS: Each patient was evaluated for nutritional (body mass index, albumin, transferrin serum levels), inflammatory (haptoglobin, orosomucoid), immunological (CD4 count, plasma viral load) and intestinal (D-xylose test, faecal fat and nitrogen output, intestinal permeability) status. Ganciclovir (1 g) was administered orally to fasted patients. Six blood samples were collected over 24 h. Serum was analysed for ganciclovir by h.p.l.c. Population pharmacokinetic analysis was performed using a nonlinear mixed effects modelling program, MP2. RESULTS: Mean intestinal permeability (lactulose/mannitol urinary ratio) was increased in group C (0.2) compared with group A (0.05) and B (0.1) patients. Drug concentration-time profiles were best described by a two-compartment model. Apparent oral clearance (CL/F) and central volume of distribution (V1/F) were influenced by clinical status (group). For groups A and B combined, final parameter estimates of CL/F and V1/F were 256 +/- 98 l h(-1) and 1320 +/- 470 l, respectively. Final parameter estimates for group C were 118 +/- 108 l h(-1) and 652 +/- 573 l for CL/F and V1/F, respectively. The 95% confidence intervals on differences between A and B combined and C were statistically significant ([ + 70, + 206] for CL/F, and [+ 314, + 1022] for V1/F). Compared with groups A and B, ganciclovir CL/F was significantly decreased in group C patients. CONCLUSIONS: AIDS patients with diarrhoea and severe disease may benefit from ganciclovir therapy, but a dose adjustment may be required according to their digestive and immunological status.

Acquired Immunodeficiency Syndrome↗
PubMed2001

S15176 and S16950 interaction with Cyclosporin A antiproliferative effect on cultured human lymphocytes.

S15176 and S16950 are trimetazidine derivatives that antagonize more strongly than the parent drug mitochondrial toxicity, which leads to cellular hypoxia and nephrotoxicity in kidneys experimentally exposed to cyclosporin A. We have investigated whether every derivative might interact or not with the inhibitory effect of Cyclosporin A on the proliferation of cultured human lymphocytes. S15176 significantly increased the antilymphoproliferative effect of Cyclosporin A, whereas S15176 by itself neither displayed any antilymphoproliferative effect, nor did it induce any apoptotic process in cultured human lymphocytes. The effect of S16950 was not significant.

Adult↗
PubMed2001

New insights into the second generation antihistamines.

Second generation antihistamines are recognised as being highly effective treatments for allergy-based disease and are among the most frequently prescribed and safest drugs in the world. However, consideration of the therapeutic index or the benefit/risk ratio of the H1 receptor antagonists is of paramount importance when prescribing this class of compounds as they are used to treat non-life threatening conditions. There are many second generation antihistamines available and at first examination these appear to be comparable in terms of safety and efficacy. However, the newer antihistamines in fact represent a heterogeneous group of compounds, having markedly differing chemical structures, adverse effects, half-life, tissue distribution and metabolism, spectrum of antihistaminic properties, and varying degrees of anti-inflammatory effects. With regard to the latter, there is growing awareness that some of these compounds might represent useful adjunct medications in asthma therapy. In terms of safety issues, the current second generation grouping includes compounds with proven cardiotoxic effects and others with the potential for adverse drug interactions. Moreover, some of the second generation H1 antagonists have given cause for concern regarding their potential to cause a degree of somnolence in some individuals. It can be argued, therefore, that the present second generation grouping is too large and indistinct since this was based primarily on the concept of separating the first generation sedating compounds from nonsedating H1 antagonists. Although it is too early to talk about a third generation grouping of antihistamines, future membership of such a classification could be based on a low volume of distribution coupled with a lack of sedating effects, drug interactions and cardiotoxicity.

Anti-Asthmatic Agents↗
PubMed2001

[In vitro protection of cerebral mitochondrial function by E-resveratrol in anoxia followed by re-oxygenation].

Using an experimental model of anoxia-reoxygenation applied to suspensions of mitochondria isolated from rat cortex, we have searched the effects of resveratrol added to the suspension or previously injected to rats from which mitochondria were extracted. With this model, we observe that resveratrol counteracts decoupling effects induced by anoxia-reoxygenation. It also fully inhibits intermembrane cytochrome c release, initial step of mitochondrial apoptosis and blocks ATP generation which achieves it. These effects are concentration-dependent and take place at low concentrations. It is concluded that resveratrol limits or suppresses the mitochondrial deleterious effects promoted by anoxia followed by reoxygenation.

Adenosine Triphosphate↗
PubMed2000

Evidence for different interactions between beta(1)- and beta(2)-adrenoceptor subtypes with adenylyl cyclase in the rat brain: a concentration-response study using forskolin.

The aim of this study was to investigate beta(1)- and beta(2)-adrenoceptor signalling systems in the rat brain studying the synergistic effects between beta-adrenoceptor agonists and forskolin- induced activation of adenylyl cyclase. Experiments were performed in slices from cerebral cortex and cerebellum because they contain mainly beta(1)- and almost exclusively beta(2)- adrenoceptors, respectively. Five beta-adrenergic agonists were used, clenbuterol, flerobuterol, isoproterenol, salbutamol, and tulobuterol. All agonists stimulated cyclic AMP accumulation in the cerebral cortex but flerobuterol was inactive in the cerebellum. Forskolin amplified the generation of cyclic AMP. Forskolin potentiation was observed in glial cells but not in neurons and was not dependent on the number of beta-adrenoceptors. In return the amplitude of the potentiation was highly dependent on the intrinsic activity of the agonist in the cerebral cortex whereas it was constant whatever the agonist tested in the cerebellum. To analyse this difference we developed a modelling approach using a concentration-response study. Isoproterenol and forskolin stimulations of cyclic AMP production were studied either alone or in combination with increasing concentrations of forskolin and isoproterenol, respectively. In the cerebral cortex isoproterenol and forskolin were both able to potentiate the cyclic AMP accumulation induced by the other compound, whereas, in the cerebellum, isoproterenol was unable to increase the stimulation induced by forskolin. The results support the hypothesis that beta(1)- and beta(2)-adrenoceptors display distinct mechanisms of action in the signalling system by which they stimulate the accumulation of cyclic AMP.

Adenylyl Cyclases↗
PubMed2000

Use of tumor markers for differential diagnosis of mesothelioma and secondary pleural malignancies.

STUDY OBJECTIVE: The aim of the study was to assess diagnosis value of tumor markers for differential diagnosis between mesothelioma and other pleural tumors. DESIGN AND METHODS: Prospective study of 85 patients attending our hospital with malignant pleural effusion. The diagnostic approach involved routine pleurocentesis followed by pleural needle. When precise diagnosis was not achieved, thoracoscopy with pleural biopsies was performed. Carcinoembryonic antigen (CEA), hyaluronic acid, tissue polypeptide antigen and cyfra 21 to 1 were measured in serum and pleural fluid. RESULTS: By using receiver operating characteristics curves and area under curves, the best diagnostic characteristics were obtained with pleural and serum CEA concentrations. The area under the curve was larger for pleural ACE than for serum ACE. The sensitivity and specificity of a pleural CEA level exceeding 3 ng/mL for ruling out the diagnosis of mesothelioma were 100% and 77%, respectively. CONCLUSION: A CEA level above 3 ng/mL in pleural fluid eliminated the diagnosis of mesothelioma, whereas the other markers were not sufficiently discriminant. However, despite a negative predictive value of 100% at a cutoff of 3 ng/mL, CEA assay in pleural fluid only avoids a small number of diagnostic thoracoscopies.

Adenocarcinoma↗
PubMed2000

In vitro binding and partitioning of irinotecan (CPT-11) and its metabolite, SN-38, in human blood.

The binding of CPT-11 and SN-38 to human plasma proteins was studied by ultrafiltration at 37 degrees C and pH 7.4. In plasma, CPT-11 was 66-60% bound in the range 100-4000 ng/ml and SN-38 was 94-96% bound in the range 50-200 ng/ml. At these concentrations the plasma binding of CPT-11 was slightly saturable, but the plasma binding of SN-38 was concentration-independent. Albumin was the main carrier of CPT-11 and SN-38 in plasma. In blood, the binding of CPT-11 was moderate (80%), mainly to plasma proteins (47%) and erythrocytes (33%). The binding of SN-38 was high (99%) and most of SN-38 in blood was located in blood cells (approximately 66%) The simulation of a grade 3 hematotoxicity (according to National Cancer Institute's Common Toxicity Criteria grading) on the SN-38 blood distribution yielded an increase in fu (free fraction of drug in plasma) from 1.05 to 2.08 and a decrease in C(Bl)/C(P) from 1.66 to 1.14 (both resulting from a decreased cell binding).

Antineoplastic Agents, Phytogenic↗
PubMed2000

[(3)H]-trimetazidine mitochondrial binding sites: regulation by cations, effect of trimetazidine derivatives and other agents and interaction with an endogenous substance.

Trimetazidine, an antiischaemic drug, has been shown to restore impaired mitochondrial functions. Specific binding sites for [(3)H]-trimetazidine have been previously detected in liver mitochondria. In the present study we confirm this observation and provide additional evidence for the involvement of these sites in the pharmacological effects of the drug. Inhibition experiments using a series of trimetazidine derivatives revealed the presence of three classes of binding sites. An N-benzyl substituted analogue of trimetazidine exhibited a very high affinity (K(i)=7 nM) for one of these classes of sites. Compounds from different pharmacological classes were evaluated for their ability to inhibit [(3)H]-trimetazidine binding. Among the drugs tested pentazocine, ifenprodil, opipramol, perphenazine, haloperidol, and to a lower extent prenylamine, carbetapentane and dextromethorphan competed with high affinity, suggesting a similarity of high affinity [(3)H]-trimetazidine sites with sigma receptors. [(3)H]-Trimetazidine binding was modulated by pH. Neutral trimetazidine had about 10 fold higher affinity than protonated trimetazidine for its mitochondrial binding sites. Various cations also affected [(3)H]-trimetazidine binding. Ca(2+) was the most potent inhibitor and totally suppressed the binding of [(3)H]-trimetazidine to the sites of medium affinity. An endogenous cytosolic ligand was able to displace [(3)H]-trimetazidine from its binding sites. Its activity was not affected by boiling for 15 min, suggesting a non-protein compound. These data suggest that mitochondrial [(3)H]-trimetazidine binding sites could have a physiological relevance and be involved in the antiischaemic effects of the drug.

Algorithms↗