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Olivier Tribut

Publications and source records attributed to Olivier Tribut.

17 recordsLinked to original sources
PubMed2007

The use of drug resistance algorithms and genotypic inhibitory quotient in prediction of lopinavir-ritonavir treatment response in human immunodeficiency virus type 1 protease inhibitor-experienced patients.

BACKGROUND: Different approaches using genotypic, pharmacokinetic parameters or combination of both have been recently developed to monitor antiretroviral treatment in HIV-1-infected individuals. Their uses in clinical practice may improve the benefit of protease inhibitor-based salvage therapy while reducing treatment toxicity and emergence of viral resistance. OBJECTIVES: To assess the prediction of genotypic inhibitory quotient (GIQ) using different genotypic drug resistance interpretation's algorithms and lopinavir plasma concentration in PI-experienced patients treated by lopinavir/ritonavir (LPV/r). Genotypic susceptibility score (GSS) was also evaluated. STUDY DESIGN: Forty-seven HIV-1 PI-experienced, but LPV naïve patients were included in a retrospective cohort study. Plasma HIV-1 viral load (VL), CD4 cell count and LPV plasma concentrations were assessed at weeks (W) 12 and 24. Interpretation of baseline resistance genotype was achieved according to four different algorithms and GSS calculated using two expert systems. GIQ was defined as the ratio of LPV concentration to the number of LPV resistance mutations at day 0 (D0) and patients classified by units of GIQ. The end point of the study was the virological response expressed in HIV VL median decrease from D0 to W24. RESULTS: The overall median VL decrease from D0 to W24 was -2.42 log(10)copies/mL and 60% of patients had VL below 400 copies/mL. The LPV mutation score was predictive of response for all algorithms whereas plasma concentrations of LPV were not. Mean VL decrease was greater for higher GIQ classes and difference reached statistical significance at W24. When considering virological response at W24, GSS calculated with ANRS and Stanford system were good predictor scores as areas under the receiver operating characteristics (ROC) curves were 0.76 for both. CONCLUSION: GIQ was found to be a useful drug-monitoring tool which could be helpful in targeting LPV concentrations in order to achieve long-term undetectable viral load, particularly in genotypic resistant patients.

Adult↗
PubMed2006

Influence of tenofovir, nevirapine and efavirenz on ritonavir-boosted atazanavir pharmacokinetics in HIV-infected patients.

OBJECTIVE: The influence of nevirapine, efavirenz and tenofovir co-administration on ritonavir-boosted atazanavir pharmacokinetics was investigated in HIV (human immunodeficiency virus)-infected patients. METHODS: A population pharmacokinetic analysis was performed in the context of therapeutic drug monitoring (87 patients, 121 samples). RESULTS: A significant increase of atazanavir clearance (Cl/F) was found when either tenofovir (group B), efavirenz (group C), or nevirapine (group D) were co administered with atazanavir/ritonavir in comparison with patients treated with atazanavir/ritonavir and nucleoside reverse transcriptase inhibitors (group A): 6.24+/-0.36 l h(-1) (group A) versus 7.42+/-0.25 l h(-1) (group B) versus 9.60+/-0.27 l h(-1) (group C) versus 17.53+/-0.57 l h(-1) (group D) (P<0.001). However, the decrease of the mean trough plasma concentration of atazanavir was significant only in group D: 1.02+/-0.86 mg/l (group A) versus 0.21+/-013 mg/l (group D) (P<0.001). CONCLUSION: The increase in atazanavir clearance when it is used in combination with nevirapine, efavirenz and/or tenofovir suggests that therapeutic drug monitoring of atazanavir should be performed in such circumstances.

Adenine↗
PubMed2005

Gentamicin-loaded calcium carbonate materials: comparison of two drug-loading modes.

Synthetic aragonite-based porous materials were drug loaded with gentamicin sulphate, an antibiotic active on Staphylococcus aureus responsible for osteomyelitis. Drug loading was accomplished by two different ways: by integration of gentamicin in material during processing or by soaking material into gentamicin solutions. We first investigated the influence of drug loading on compressive strength of materials. Results indicate that soaked materials presented the same compressive strength than unloaded materials with the same porosity. By contrast, the integration of gentamicin during processing increased significantly the compressive strength of materials. The materials drug content before elution was a least 10 times higher when gentamicin was integrated during processing comparatively to soaked materials. The study of in vitro gentamicin release showed that for materials with gentamicin integrated during material processing, high concentrations of gentamicin were released up to 8 or 12 days, against 4 days for soaked materials. The transport coefficients calculation, for the first step of release, indicated that the rate of release was higher for materials with integrated gentamicin because of the higher gentamicin content. The porosity rate influenced the rate of release for materials positively with gentamicin integrated during processing contrary to soaked materials for which a higher porosity rate allowed a deeper penetration of gentamicin during drug loading and then a slightly slower release. Results indicate that aragonite-based material with gentamicin integrated during material processing may be used either as resorbable device for release of high concentrations of gentamicin or as biomaterial for combined therapy: bone substitution and prevention or treatment of osteomyelitis.

Anti-Bacterial Agents↗
PubMed2005

RBC 6-TGN and hematological parameters in patients with Crohn's disease treated by azathioprine.

OBJECTIVE: The immunosuppressive properties of azathioprine (AZA) are mediated by intracellular metabolism of 6-MP into its active metabolites 6-thiguanine nucleotide (6-TGN) and 6-methylmercaptopurine (6-MMP). The aims of this study were to correlate red blood cell (RBC) 6-TGN and hematological parameters and their change in adult patients with Crohn's disease (CD) treated by AZA and to determine independent factors enabling determination of RBC 6-TGN. METHODS: RBC 6-TGN concentration was determined with high performance liquid chromography (HLPC) performed on 74 hepa-rinized blood samples from 32 patients. Changes of hematological parameters were measured for each RBC 6-TGN concentration. RBC 6-TGN concentration above 235 pmol/8x108 RBC was proposed as the therapeutic level in patients treated by AZA. Correlations between the various parameters were assessed as appropriate. Logistic regression analysis was used to determinate independent variables. P<0.05 was considered significant. RESULTS: There was a positive correlation between RBC 6-TGN and decreased red cell count (DeltaRBC) (r=0.314; P=0.006), platelet count (DeltaPlatelets) (r=0.314; P=0.007), White cell count (DeltaWC) (r=0.241; P=0.04) and neutrophil count (DeltaPMN) (r=0.292; P=0.02). RBC 6-TGN in the therapeutic zone was positively correlated with mean corpuscular volume (MCV) (r=0.527; P=0.01), mean corpuscular hemoglobin concentration (MCHC) (r=0.437; P=0.04), increase in MCV (DeltaMCV) (r=0.512; P=0.012), decrease in White cell count (DeltaWC) (r=0451; P=003) and in neutrophil count (DeltaPMN) (r=0.463; P=0.03). Multivariate analysis showed that low activity of CD (P<0.02), young age at onset of treatment by AZA (P<0.03) and a low red cell distribution width (RDW) (P=0.003) were independent factors for RBC 6-TGN situated in therapeutic zone. RBC 6-TGN could be determined by logistic regression from AZA dose (mg/kg/d) and MCV increase. CONCLUSION: This study confirms that hematological parameters or their change can be used to determine whether RBC 6-TGN concentration has reached the therapeutic level. Logistic regression analysis showed that decreased RDW and increased MCV were independent factors for RBC 6-TGN level.

Adult↗
PubMed2005

Simultaneous quantitative assay of atazanavir and 6 other HIV protease inhibitors by isocratic reversed-phase liquid chromatography in human plasma.

Several liquid chromatography methods for assay of antiretroviral drugs in human plasma have been described, but none included atazanavir. The authors describe a user-friendly, validated, and rapid technique, derived from a procedure the authors have already published, allowing simultaneous quantification of amprenavir, indinavir, lopinavir, nelfinavir (and its M8 metabolite), ritonavir, saquinavir, efavirenz, and nevirapine. Assays were performed after diethyl ether liquid-liquid extraction from 250 microL plasma samples. Chromatographic separation was achieved on an X-TERRA column using a 58% water (with 3 mM pyrrolidine) and 42% acetonitrile mobile phase; 240 nm ultraviolet wavelength was used for atazanavir detection. This method has been in routine use in our laboratory for antiretroviral drug monitoring and now allows quantitative assay of a novel HIV protease inhibitor, atazanavir, with satisfactory intra- and interassay precision (CV<12%).

Atazanavir Sulfate↗
PubMed2005

Amprenavir or fosamprenavir plus ritonavir in HIV infection: pharmacology, efficacy and tolerability profile.

Amprenavir is an HIV-1 protease inhibitor, the first in vitro activity studies of which were published in 1995. During in vivo development, it became clear that the pharmacokinetics of the drug would result in patients taking a large number of pills daily. The first comparative studies of amprenavir versus other protease inhibitors showed it had comparatively weak activity. Thus, studies using low doses of ritonavir to enhance the pharmacokinetic profile of amprenavir were first communicated in 2000. Only a small number of clinical trials in HIV-1-infected patients have been published. The pharmacokinetics of amprenavir have been documented in both healthy individuals and in HIV-1-infected patients. Amprenavir trough plasma concentrations increase 3- to 10-fold and the area under the concentration-time curve (AUC) increases 2- to 3-fold when using amprenavir 450 or 600 mg combined with ritonavir 100mg twice daily. Peak concentrations of amprenavir are less influenced by ritonavir coadministration, with a 1- to 2-fold increase. As there is no pharmacokinetic advantage to increasing ritonavir doses, the combination has only been used with low doses of ritonavir (100mg twice daily or 200 mg once or twice daily). Concomitant use of currently available non-nucleoside reverse transcriptase inhibitors (NNRTIs)--efavirenz or nevirapine--is possible when amprenavir is coadministered with ritonavir, despite the pharmacokinetic interactions described when they are used with amprenavir alone. Fosamprenavir (GW 433908) is a prodrug of amprenavir primarily metabolised to amprenavir in the epithelial cells of the intestine. At steady state, plasma trough concentrations and AUC are slightly greater with fosamprenavir (two pills of 700 mg twice daily) than amprenavir (eight soft gel capsules of 150 mg twice daily). The clinical adverse effects of amprenavir are similar whether administered unboosted or in combination with ritonavir. Skin rashes do not appear to be more frequent. With regard to lipid profiles, the addition of ritonavir to amprenavir induces an increase in cholesterol and triglyceride levels; however, prospective comparative studies are lacking. In short-term prospective trials in antiretroviral-naive individuals, virological suppression with highly active antiretroviral therapy containing amprenavir plus ritonavir is similar to or higher than with unboosted amprenavir, with a smaller pill intake. Few comparative data are available in treatment-experienced patients. In several small studies, different salvage regimens which included amprenavir plus ritonavir achieved undetectable viral levels in half of the patients. Although the I50V amino acid substitution is the key mutation conferring resistance to amprenavir, the accumulation of several mutations is needed to increase the IC50 (concentration that produces 50% inhibition) of amprenavir. When used with ritonavir, the accumulation of six or more mutations among L10F/I/V, K20M/R, E35D, R41K, I54V, L63P, V82A/F/T/S and I84V leads to clear decrease in viral response to treatment. In salvage regimens, coadministration of amprenavir with lopinavir/ritonavir induces variations in lopinavir and amprenavir concentrations (decrease or increase in both drug concentrations) compared with the combination with ritonavir alone. Currently, close pharmacokinetic follow-up is mandatory when such combinations are used. There are sufficient data available today to support coadministration of reduced doses of amprenavir with low doses of ritonavir. Compared with amprenavir alone, this results in the administration of fewer pills with equivalent or higher efficacy, but without new clinical adverse effects. The concentrations of amprenavir achieved are high enough for use in treatment-experienced patients who have an accumulation of amino acid substitutions in the HIV-1 protease gene. It also allows combinations with NNRTIs. The pharmacokinetic properties of fosamprenavir and the first clinical trials in treatment-naive and treatment-experienced patients should allow it to be considered as a better alternative to amprenavir in countries where fosamprenavir is already available.

Anti-HIV Agents↗
PubMed2004

Monocyte human leukocyte antigen-DR transcriptional downregulation by cortisol during septic shock.

Monocyte deactivation has been identified as a major factor of immunosuppression in sepsis and is associated with a loss of surface human leukocyte antigen-DR (HLA-DR) expression on circulating monocytes. Using flow cytometry, quantitative reverse transcription-polymerase chain reaction, we investigated this phenomenon in septic patients. We confirmed the early loss of monocyte HLA-DR expression in all infected patients and demonstrated that this persistent lowered expression at Day 6 correlated with severity scores, secondary infection, and death. This phenomenon occurred at a transcriptional level via a decrease in the class II transactivator A (CIITA) transcription. Furthermore, these abnormalities correlated with the high cortisol levels observed in sepsis and not with those of other putative factors such as catecholamines or interleukin-10. Finally, in vitro studies evidenced that glucocorticoids decrease HLA-DR expression at a transcriptional level via a decrease in CIITA mRNA levels, mainly by down modulating its isoforms I and III. We conclude that in human sepsis, the loss of HLA-DR expression on circulating monocytes is associated with a poor outcome. We suggest that the high endogenous cortisol level observed in septic shock may be a possible new factor involved in the loss of HLA-DR expression on monocytes via its effect on HLA-DR and CIITA transcription.

Adult↗
PubMed2004

Drug induced encephalopathy in six epileptic patients: topiramate? valproate? or both?

Six severe epileptic patients developed stuporous encephalopathy with marked cognitive impairment when topiramate (TPM) and sodium valproate (VPA) were coprescribed for five patients, and when monotherapy with TPM was introduced for one patient. In four patients, ammonaemia increased and then returned to normal after TPM or VPA withdrawal. This severe potential side effect must be recognized. Moreover two distinct mechanisms might explain this toxicity: (1). a pharmacokinetic interaction between VPA and TPM, leading to hyperammonaemia, (2). a pharmacodynamic mechanism due to a direct toxicity of TPM in at-risk epileptic patients.

Adolescent↗
PubMed2003

Drug therapy of frontotemporal dementia.

Frontal lobe dementia, or more generally frontotemporal dementia (FTD), includes several clinical entities and, although highly prevalent, lacks any codified therapeutic strategy. The present review is an attempt to depict the main neurochemical correlates of FTD and, as a consequence, to propose the most sound targets for symptomatic drugs. Large scale double-blind controlled clinical trials should be carried out to test any hypothesis: serotonergic agents, glutamate neurotransmission enhancers, monoamine oxidase inhibitors. The recent discovery of tau gene mutations in FTD with Parkinsonism linked to chromosome 17 has reinforced the direct role attributed to abnormal tau proteins (hyperphosphorylation) and thus raised the possibility to target specifically these processes by drugs (aetiopathogenic compounds).

Chromosomes, Human, Pair 17↗
PubMed2003

Alzheimer's disease: the pharmacological pathway.

The current pharmacological treatment of Alzheimer's disease (AD) comes down to four marketed drugs (tacrine, donepezil, rivastigmine and galantamine) all of which are cholinesterase inhibitors, conforming to the cholinergic hypothesis. The future is clearly directed at new biological targets closely linked to the pathophysiology of the disease and more precisely, the pathological hallmark of AD which includes widespread neuronal degeneration, neuritic plaques containing beta-amyloid and tau-rich neurofibrillary tangles. For clinicians, this means that new curative drugs will have to be prescribed early in the course of the disease. This review describes the main entry pathways for drug discovery in AD: (1) supplementation therapy, (2) anti-apoptotic compounds, (3) substances with a mitochondrial impact, (4) anti-amyloid substances, (5) anti-protein aggregation and (6) lipid-lowering drugs. The rapidity at which these compounds will be at our disposal is highly dependent on the policy of the pharmaceutical companies.

Alzheimer Disease↗
PubMed2003

Drugs and vascular dementia.

Between 20 and 35% of all dementias are vascular in origin, their etiology is due to cerebrovascular disease and the risk factors are known (e.g. hypertension, diabetes, smoking, or hyperlipidemia). Primary and secondary preventions are the basis of therapeutics. Symptomatic treatment is emerging, notably in the field of cognitive disorders. In that respect, monoamine oxidase inhibitors, and more recently acetylcholinesterase inhibitors, are in the process of being recognized as first-line treatments of established vascular dementia.

Aged↗
PubMed2003

Clinically significant drug interactions with cholinesterase inhibitors: a guide for neurologists.

Cholinesterase inhibitors are the only pharmacological class indicated for the treatment of mild to moderate Alzheimer's disease. These drugs are also being used off label to treat severe cases of Alzheimer's disease or vascular dementia and other disorders. The widespread use of cholinesterase inhibitors raises the possibility of their use in combination regimens, with the subsequent risk of deleterious drug-drug interactions in high-risk populations. The purpose of this review is to present the possible sources of pharmacokinetic or pharmacodynamic drug-drug interactions involving cholinesterase inhibitors. The four cholinesterase inhibitors (tacrine, donepezil, rivastigmine and galantamine) that are currently available have different pharmacological properties that expose patients to the risk of several types of drug interactions of nonequivalent clinical relevance. The principal proven clinically relevant drug interactions involve tacrine and drugs metabolised by the cytochrome P450 (CYP) 1A2 enzyme, as well as tacrine or donepezil and antipsychotics (which results in the appearance of parkinsonian symptoms). The bioavailability of galantamine is increased by coadministration with paroxetine, ketoconazole and erythromycin. It is of interest to note that because rivastigmine is metabolised by esterases rather than CYP enzymes, unlike the other cholinesterase inhibitors, it is unlikely to be involved in pharmacokinetic drug-drug interactions. Care must be taken to reduce the risk of inducing central (excitation, agitation) or peripheral (e.g. bradycardia, loss of consciousness, digestive disorders) hypercholinergic effects via drug interactions with cholinesterase inhibitors. A review of the literature does not reveal any alarming data but does highlight the need for prudent prescription, particularly when cholinesterase inhibitors are given in combination with psychotropics or antiarrhythmics. Possible interactions involving other often coprescribed antidementia agents (e.g. memantine, antioxidants, cognitive enhancers) remain an open area requiring particularly prudent use.

Cholinesterase Inhibitors↗
PubMed2002

Simultaneous quantitative assay of six HIV protease inhibitors, one metabolite, and two non-nucleoside reverse transcriptase inhibitors in human plasma by isocratic reversed-phase liquid chromatography.

A rapid (less than 30 min), sensitive, and specific liquid chromatography method for simultaneous assay of nine antiretroviral drugs in human plasma is described. This technique allows therapeutic drug monitoring of six approved protease inhibitors (amprenavir, indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir) and two approved non-nucleoside reverse transcriptase inhibitors (efavirenz and nevirapine). Assays were performed after diethyl ether liquid-liquid extraction from 250-microL plasma samples. Chromatographic separation was achieved on an X-TERRA (Waters; Saint Quentin, France) column using a 58% water (with 3 mmol/L pyrrolidine) and 42% acetonitrile mobile phase. Three ultraviolet wavelengths were used for detection with a diode array detector. This method allowed quantitative assay of all nine antiretroviral drugs within a concentration range of 25 ng/mL to 9000 ng/mL. The method has been validated extensively and has been in routine use in our laboratory for several months for drug monitoring in plasma samples from patients treated with antiretroviral drugs.

Chromatography, High Pressure Liquid↗
PubMed2002

Early circulating lymphocyte apoptosis in human septic shock is associated with poor outcome.

The role of lymphocyte apoptosis in septic shock remains a controversial issue. Using Annexin V and flow cytometry analysis on freshly isolated cells, we evaluated circulating lymphocyte apoptosis in 23 septic shock, 25 sepsis without shock, 7 nonseptic critically ill, and 25 control patients. In patients with sepsis, we compared day 1 lymphocyte apoptosis (i.e., within 3 days of the onset of infection) with that observed 5-7 days after (day 6) according to shock state, mortality, and seventy factors. At day 1, patients in septic shock exhibited higher lymphocyte apoptosis than that present in controls (16.5% +/- 3.5% vs. 3% +/- 0.5%, respectively, P = 0.0001). At day 6, patients with sepsis without shock restored undamaged CD4+ T and CD8+ T lymphocyte counts, whereas patients in septic shock increased only CD4+ T cells. Similarly, survivors restored undamaged lymphocyte count at day 6 (+70%, P < 0.001), whereas nonsurvivors did not. Day 6 undamaged lymphocyte count negatively correlated with day 1 SAPS II, day 6 LOD score, mechanical ventilation, and ICU stay duration. We observed no apoptotic effect of septic shock plasma or septic shock circulating mononuclear cells on target lymphoid cell lines. We found no alteration in any death receptors Fas, TRAIL-R1, TRAIL-R2, or in their ligands on circulating blood cells. Catecholamines and interleukin 10 levels significantly increased in patients with septic shock, but did not correlate with apoptosis levels. We conclude that lymphocyte apoptosis is rapidly increased in blood of patients in septic shock and that lymphocyte apoptosis leads to a profound and persistent lymphopenia associated with poor outcome. These results suggest that lymphocyte apoptosis is one of the main components of human septic shock immune dysfunction and could be related more to microcirculatory disturbance than to circulating factors.

Aged↗
PubMed2002

Pharmacogenomics.

Pharmacogenomics, a revolutionary chapter in the history of pharmacology, has received new impetus from the development and accessibility of molecular biotechnologies, notably DNA chips. The longstanding notion of responders/non-responders has given way to a more organic approach, where idiosyncrasy becomes an obsolete concept. This is a major step towards predictive, individualized medicine. In this review, several applications of pharmacogenomics are considered. Genetic polymorphisms of metabolization reactions, mainly with cytochrome P450, explain most of the cases described today. More fundamental and innovative studies have tried to link the structure of receptors or transporters and drug response. A leading topic in neuropsychopharmacology is the relation between the polymorphism of dopaminergic receptors and the efficacy of, or adverse reaction to, neuroleptics. In asthma, the structure of the beta2-adrenergic receptor has been associated with response to treatment. Intrinsic genetic predisposition also plays an important role in cardiovascular diseases, and the role of ion channel mutations will be discussed. Research in oncological molecular epidemiology has explored the connection between the predisposition to certain cancers and specific enzymatic equipment hindering the detoxification of potentially carcinogenic exogenous compounds, or, on the contrary, promoting metabolic activation implicated in the formation of reactive compounds. The search for determinants of addictive behavior is another vast field of pharmacogenomics. Finally, we consider the impact of pharmacogenomics on the methodology of drug development in preclinical and clinical trials. Progress in methods of phenotyping/genotyping should promote diagnosis, guide the choice of drug for an individual (benefit/risk ratio), and determine dosage and regimen.

Cardiovascular Physiological Phenomena↗
PubMedDate not supplied

Salvage therapy with amprenavir and ritonavir: prospective study in 17 heavily pretreated patients.

OBJECTIVE: To evaluate the safety profile and efficacy of salvage regimens containing amprenavir (APV) 600 mg twice daily and ritonavir (RTV) 200 mg twice daily. DESIGN: Prospective, single-center study. METHOD: The patient database of the department of infectious diseases was screened for patients who had failed at least two successive three-drug combinations. These patients were proposed to take APV and RTV in association with two to four other drugs. They were followed monthly for 6 months. RESULTS: Seventeen patients were included. They had been previously treated for 70 +/- 23 months. At baseline, viral load (VL) was 4.86 +/- 0.98 log10 copies/mL and CD4 187 +/- 145 10(6)/L. On week 24, using intent-to-treat analysis, VL decreased to 2.95 +/- 1.59 log10 copies/mL and CD4 increased to 365 +/- 210 10(6)/L. Nine patients (53%) had a VL < 2.3 log10 copies/mL. The most common adverse events were grade 1 or 2 diarrhea and an increase of cholesterol and triglyceride levels. Mean APV trough concentration was 1727 +/- 1749 ng/mL on week 24. CONCLUSION: These data show that the combination of low-dose RTV and reduced doses of APV is safe. This combination can be added to nonnucleoside analogs.

Adult↗