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E Albengres

Publications and source records attributed to E Albengres.

At least 19 recordsLinked to original sources
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↗
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↗
PubMed2000

[Interactions and incompatibilities in prescription drugs. Incidents in dental surgery].

Drug interactions can be classified according to their pharmacodynamic and pharmacokinetic mechanisms. Pharmacodynamic interactions are observed when two drugs share a common effect or have the same effect on different receptors of a common function. They can be predicted if the elementary effects of each drug are known. Such are pharmacodynamic interactions are particularly interesting as they are selective for the common effect(s). Pharmacokinetic interactions are more difficult to predict. They occur when one drug modifies the pharmacokinetic parameters of a second drug. Modification may involve variations in oral absorption, tissue distribution, rate of metabolism and/or rate of renal excretion. This interaction cannot be selective as drug concentrations are modified, affecting all the concentration-dependent effects. Mastering drug interactions involve the knowledge of the underlying mechanisms. Answers to following questions are needed: does the association produce conjugated effects? can one drug modify pharmacokinetic parameters of another? Potentially toxic effects may be suspected when at least one drug involved is known for its toxicity. Risk is increased when it also exhibits a narrow range between active and toxic concentrations. Many databases in printed form or as interactive software provide information on drug interactions. Clinicians can also consult a Pharmacovigilance Center for a safe prescription procedure. Finally, the main danger lies in the simultaneous prescriptions by different practitioners unaware of their colleagues prescription. In this case, the pharmacist plays an important role of evaluation of the drugs prescribed.

Drug Antagonism↗
PubMed2000

[Allergen potential of drugs and ex vivo demonstration of an immune response].

Drugs are able to activate the immune system, which may generate hypersensitivity states in individuals. In a first part, this article deals with the critical processes that are involved in drug sensitizations: what are the specific features of drugs as immunogens; how drugs are recognized as non-self by immunocompetent cells; what is the spontaneous outcome of drug allergic states, does a genetic predisposition regulate the immune response. The second part is mostly devoted to the biological investigation of drug sensitizations: what are we looking for and why, are all the available methods equally suitable for routine diagnosis, what are the major methological problems that we have to face at and how to escape them.

Antibody Formation↗
PubMed1998

[Exploration of 112 children suspected of amoxicillin allergy. Indications and efficacy of oral provocation test].

BACKGROUND: One to 10% of treatments using betalactams, particularly synthetic penicillin, are complicated by allergic reactions, usually cutaneous, and not easily imputable to immunologic sensitization in children. PATIENTS AND METHODS: The aim of this study was to identify, using cutaneous and biological tests, those from a group of 112 children suspected of amoxicillin allergy (evidenced by rash) who were actually sensitized, and to confirm the absence of allergy in others by an oral provocation test (OPT) associated to a long-term survey. The cutaneous tests were made by prick test and intra-dermo reaction (IDR) with Allergopen and with amoxicillin or amoxicillin + clavulanic acid. The biological tests included examination for penicillin and amoxicillin antibodies by using various techniques including enzyme-linked immunosorbent assay (ELISA) immunoglobulin G (IgG) and IgE, FARR, radioallergo sorbent test (RAST) and a histaminoliberation. When these tests were negative, an OPT with the suspected antibiotic was subsequently performed. RESULTS: Thirty-nine children (36.4%) confidently presented at least one positive cutaneous test (38 Allergopen, ten amoxicillin); 25 biological tests were positive (16 ELISA IgE, one ELISA IgG and eight histaminolibarations), seven times with negative cutaneous test. Forty-five children were judged to be sensitized to amoxicillin, with only one who subsequently took amoxicillin again. Among the 67 others, 52 received an OPT, six of them with moderate cutaneous reactions. Fifty-one (45.5%) children were allergic and 46 (41%) were allowed to take amoxicillin again; 17 did, one of them with a benign cutaneous reaction. CONCLUSION: Efficacy and safety of this type of investigation seems clear; it will have to be confirmed by other studies.

Adolescent↗
PubMed1998

Systemic antifungal agents. Drug interactions of clinical significance.

There are 3 main classes of systemic antifungals: the polyene macrolides (e.g. amphotericin B), the azoles (e.g. the imidazoles ketoconazole and miconazole and the triazoles itraconazole and fluconazole) and the allylamines (e.g. terbinafine). Other systemic antifungals include griseofulvin and flucytosine. Most drug-drug interactions involving systemic antifungals have negative consequences. The interactions of amphotericin B, flucytosine, griseofulvin, terbinafine and azole antifungals can be divided into the following categories: (i) additive dangerous interactions; (ii) modifications of antifungal kinetics by other drugs; and (iii) modifications of the kinetics of other drugs by antifungals. Amphotericin B and flucytosine mainly interact with other agents pharmacodynamically. Clinically important drug interactions with amphotericin B cause nephrotoxicity, hypokalaemia and blood dyscrasias. The most important drug interaction of flucytosine occurs with myelotoxic agents. Hypokalaemia can precipitate the long QT syndrome, as well as potentially lethal ventricular arrhythmias like torsade de pointes. Synergism is likely to occur when either QT interval-modifying drugs (e.g. terfenadine and astemizole) and drugs that induce hypokalaemia (e.g. amphotericin B) are coadministered. Induction and inhibition of cytochrome P450 enzymes at hepatic and extrahepatic sites are the mechanisms that underlie the most serious pharmacokinetic drug interactions of the azole antifungals. These agents have been shown to notably decrease the catabolism of numerous drugs: histamine H1 receptor antagonists, warfarin, cyclosporin, tacrolimus, digoxin, felodipine, lovastatin, midazolam, triazolam, methylprednisolone, glibenclamide (glyburide), phenytoin, rifabutin, ritonavir, saquinavir, nevirapine and nortriptyline. Non-antifungal drugs like carbamazepine, phenobarbital (phenobarbitone), phenytoin and rifampicin (rifampin) can induce the metabolism of azole antifungals. The bioavailability of ketoconazole and itraconazole is also reduced by drugs that increase gastric pH, such as H2 receptor antagonists, proton pump inhibitors, sucralfate and didanosine. Griseofulvin is an enzymatic inducer of coumarin-like drugs and estrogens, whereas terbinafine seems to have a low potential for drug interactions. Despite important advances in our understanding of the mechanisms underlying pharmacokinetic drug interactions during the 1990s, at this time they still remain difficult to predict in terms of magnitude in individual patients. This is because of the large interindividual and intraindividual variations in the catalytic activity of those metabolising enzymes that can either be induced or inhibited by various drugs. Notwithstanding these variations, increasing clinical experience is allowing pharmacokinetic interactions to be used to advantage in order to improve the tolerability of some drugs, as recently exemplified by the use of a fixed combination of ketoconazole and cyclosporin.

Antifungal Agents↗
PubMed1997

Differential effects of zidovudine and zidovudine triphosphate on mitochondrial permeability transition and oxidative phosphorylation.

1. The effects of zidovudine (ZDV) and zidovudine triphosphate (ZDV-3P) on Ca2+-induced mitochondrial permeability transition (MPT), respiratory control ratio (RCR) and ATP synthesis have been investigated on isolated rat liver mitochondria. 2. ZDV slightly but significantly decreased RCR and ATP synthesis but was ineffective in inhibiting MPT. In contrast, ZDV-3P did not alter RCR and ATP synthesis but strongly inhibited MPT (IC50 = 3.0 +/- 0.9 microM). 3. The effect of ZDV-3P on mitochondrial swelling required a preincubation time. When incubated 10 min with mitochondria, ZDV-3P (8 microM) 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 effect of ZDV-3P on mitochondrial swelling. Indeed, the IC50 value of ZDV-3P increased from 3.0 to 17.4, 93.6 and 66.5 microM, in the presence of 20 microM, ADP, ATP or atractyloside, respectively. 5. ZDV-3P did not displace [3H]-ATP from its mitochondrial binding site(s) whereas ADP and atractyloside did, suggesting that ZDV-3P and [3H]-ATP do not share the same binding sites. 6. ZDV-3P did not affect either mitochondrial respiration or ATP synthesis but inhibited Ca2+-dependent mitochondrial swelling. It was concluded that mitochondrial toxic effects observed during the chronic administration of ZDV cannot be related to its active metabolite (ZDV-3P).

Adenosine Triphosphate↗
PubMed1997

Trimetazidine does not modify blood levels and immunosuppressant effects of cyclosporine A in renal allograft recipients.

AIMS: In renal allograft recipients, trimetazidine (Vastarel) was proposed to be associated with the classic immunosuppressant treatments because it displays anti-ischaemic effects which may protect against cyclosporine A nephrotoxicity. The objective of this work was to assess the possibility of coadministering cyclosporin A, Sandimmun, 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, Cmax, tmax, 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.

Adult↗
PubMed1997

Potential interest of anti-ischemic agents for limiting cyclosporin A nephrotoxicity.

Chronic administration of cyclosporin A induces nephrotoxicity in humans. This is related to a cyclosporin A-induced constriction of afferent glomerular arterioles and mesangial cells, which leads to a decrease in filtration pressure and creatinine clearance. Afterwards, cellular lesions are observed involving mainly tubular atrophy and interstitial fibrosis, both of which are nonspecific. The initial mechanism of its toxicity is not clearly explained. The current pharmacological approach is symptomatic in order to counteract or minimize the consequences of a prime cause, which still remains to be defined. However, cyclosporin A has a deletereous effect on mitochondrial functions and mainly on ATP synthesis, which occurs when Ca2+ accumulates in matrix mitochondria. The effects of trimetazidine, an antischemic drug used in the treatment of angina pectoris, have been assessed. This drug is effective in experimental models of hypoxia induced by cyclosporin A: it restores ATP synthesis previously decreased by Ca2+ and cyclosporin A, and releases a part of Ca2+ excess accumulated by mitochondria at concentrations reached in humans at usual dosage regimens. At higher concentrations, it reverses the mitochondrial permeability transition previously generated (opened) by Ca2+ and a pro-oxidant such as terbutylperoxide (t-BH). It was also observed that trimetazidine does not modify the immunosuppressive effects of cyclosporin A in various models. These data suggest that nephrotoxicity of cyclosporin A is not irrevocably linked to its immunosuppressive effect but that it may be possible to counteract at least partly its nephrotoxic effects without altering its effectiveness in preventing graft rejection.

Adenosine Triphosphate↗
PubMed1996

Lack of pharmacodynamic interaction between trimetazidine and cyclosporin A in human lymphoproliferative and mouse delayed hypersensitivity response models.

The hypothesis of an interaction between trimetazidine and the immunosuppressive effect of cyclosporin A was investigated in two models: a) ex vivo, the lymphoproliferative response of normal human lymphocytes to phytohemagglutinin and a murine monoclonal antibody against the CD3 T-lymphocyte membrane complex; b) in vivo, the delayed hypersensitivity response model in mouse. The uptake of methyl-3H-thymidine was measured in both models. For the lymphoproliferative response, statistical analysis showed that there was a significant inhibitory effect of cyclosporin A on cell proliferation (P < 0.001) and confidence intervals obtained by ANOVA showed the equivalence of the results when trimetazidine was combined with cyclosporin A (all CI95% < or = 10). In the delayed hypersensitivity model, cyclosporin A was also found to be very effective in inhibiting the immune response (P < 0.001), while trimetazidine did not interfere with cyclosporin A's effect. It was concluded that trimetazidine exerted neither an immunostimulatory nor an immunosuppressive effect in the two models, suggesting of the absence of interaction between trimetazidine and cyclosporin A's effectiveness when both drugs are given in combination.

Adult↗
PubMed1996

Trimetazidine reverses calcium accumulation and impairment of phosphorylation induced by cyclosporine A in isolated rat liver mitochondria.

When applied to rat liver mitochondria in contact with Ca++, cyclosporine A (CsA) induced both an accumulation of this ion and a decrease in oxidative phosphorylation. Trimetazidine (TMZ) reversed both phenomena in a dose-dependent manner. These two effects were demonstrated in separate experiments. A decrease in oxidative phosphorylation was observed with succinate as substrate. V3 and P/O (ratio corresponds to the number of ADP molecules added in the medium per oxygen atom consumed during phosphorylation and represents the yield of ATP synthesis) were simultaneously decreased by CsA (1 microM) and restored by TMZ. Ca++ accumulation in mitochondria was observed when it was added to the mitochondrial suspension; its uptake was followed by a new equilibrium. CsA prolonged its duration, whereas TMZ reduced it in a dose-dependent manner. The same phenomenon was observed when ADP was used instead of CsA. Ca++ efflux from mitochondria could be induced by TMZ without the addition of CsA. It was immediate and always partial and followed by a reuptake process only observed at concentrations of TMZ of >1 microM. Compared with ruthenium red, which blocks Ca++ uniporter, TMZ seemed to act on Ca++ efflux mechanisms. Interestingly, low TMZ doses promote a Ca++ efflux process without activating reentry mechanism, which may explain the correction of deleterious effect of CsA on V3 and P/O. As nephrotoxicity observed in humans after CsA chronic administration is considered to be related, at least in part, to an alteration of Ca++ intracellular homeostasis, TMZ seems to be a candidate for alleviation of CsA nephrotoxic effects in humans.

Animals↗
PubMed1996

[Can one adjust the distribution of a drug in an organism to its target sites? The example of antihistaminics (anti-H1) and cetirizine].

When comparing the fate of a drug in the body with the location of its receptors, it appears that a large amount of the administered dosage will never reach these receptors. Thus this large amount is useless in terms of drug efficacy whereas it may generate side of toxic effects in other tissues. An attempt to optimize drug distribution is to limit or even to suppress its useless localisations. This is possible with H1 antagonists as these drugs develop benefic effects in organs which are distinct from those where toxic effects may occur. Cetirizine is an example of choice of this strategy. It is poorly distributed into tissues, especially in heart and liver which favors preferential binding at its target H1 selected receptors.

Biological Availability↗
PubMed1994

Drug binding in plasma. A summary of recent trends in the study of drug and hormone binding.

The ligands are generally bound in plasma to a significant extent by several transport proteins (both high and low affinity), irrespective of their endogenous or exogenous origin. The protein binding of endogenous compounds (such as hormones) exhibits higher affinity and specificity than those of exogenous compounds (such as drugs). For plasma proteins that bind the same ligand(s), structural similarities or a common genetic origin may be found, although this is not a general rule. Alterations in ligand binding may be due to modifications of either the structure or the level of the binding protein. These modifications may result from genetic make up, physiology or pathology. In some situations, plasma binding may impair the distribution of drugs to tissues, with drug distribution then mainly restricted to the distribution compartment of the drug-binding protein. In other instances, the plasma drug-binding is permissive, and does not limit drug distribution to tissues. A given drug-transport protein system may have either a permissive or a restrictive effect on the drug distribution, depending on the tissue. The physiological significance of the high-affinity transport proteins is not completely understood. These proteins may increase the plasma concentration of poorly hydrosoluble ligands, ensure a more uniform tissue distribution and increase the life of the ligands. The life of the protein may also be increased by ligand binding. High-affinity transport proteins are also involved in some specific carrier mediated transfer mechanisms. It is possible to demonstrate structure-binding relationships or binding selectivity for the plasma transport proteins, but these are quite independent of relationships observed at the receptor level.

Animals↗
PubMed1993

An international comparison of case definition of severe adverse cutaneous reactions to medicines.

There is substantial intercountry variation in the proportion of cases of toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS) which are attributed to specific drugs. This study was undertaken to determine whether these differences might reflect biases in diagnosis of these conditions. A total of 138 reactions in 5 countries originally diagnosed as TEN or SJS were coded on to standardised forms. A single observer blind to the original diagnosis assessed each case according to specified criteria. This observer's diagnoses were compared with the original diagnoses. Overall, 111 of the 138 cases had information adequate for assessment. The blinded observer agreed with the diagnosis for 61% of cases where the original diagnosis was TEN and 58% of cases where the original diagnosis was SJS. There was no significant difference in rates of agreement when reactions attributed to sulphonamide antibiotics were compared with reactions attributed to other drugs. There were substantial and significant differences in percentage agreement between the blinded observer's diagnosis and the original diagnoses between countries. The lowest rates of agreement between the blinded observer and the original reports occurred in the US. Our results illustrate the difficulty in comparing reaction rates based on spontaneous reports between countries where the systems for gathering such reports vary. This illustrates the need for a minimum quantity of standard data and precise definitions of reactions if spontaneous reports of adverse reactions are to provide useful information about severe adverse skin reactions associated with drugs.

Adolescent↗
PubMed1993

Nimesulide binding to components within blood.

The binding of nimesulide within human serum to isolated proteins and to erythrocytes was studied by equilibrium dialysis. Within the range of therapeutic concentrations, nimesulide was 99% bound to serum involving a nonsaturated process (NKA = 91). This binding was almost identical to binding of nimesulide to serum albumin (NKA = 95). Physiological concentrations of free fatty acids did not affect binding of nimesulide to serum albumin. The retention of nimesulide by erythrocytes suspended in buffer was moderate (67%), although in whole blood no erythrocyte binding was observed because of the greater affinity of this drug for serum. Over the range of therapeutic concentrations (2.5 to 63 mumol/L), the free fraction of nimesulide in serum remains constant. Serum binding was decreased in samples obtained from patients with renal failure or hepatic cirrhosis associated with hypoalbuminaemia and hyperbilirubinaemia, respectively. At therapeutic concentrations, the binding of nimesulide was unaffected by warfarin, cefoperazone, furosemide (frusemide), glibenclamide, tamoxifen or digitoxin. However, valproic acid and fenofibrate (80 mumol/L) may displace nimesulide. 4-Hydroxy-nimesulide, the principal metabolite, significantly increased the free fraction of nimesulide. Although methotrexate had no effect on the free fraction of nimesulide, the free fraction of methotrexate was significantly increased in the presence of nimesulide. The present study also demonstrated 2 distinct nimesulide binding sites (site I and site II) on serum albumin (10 mumol/L) with different affinities: site II KA = 3.57 x 10(5) L/mol and site I KA = 1.24 x 10(5) L/mol. Interaction studies using markers that bind specifically to site I (warfarin and azapropazone) and site II (diazepam and ibuprofen) indicated that nimesulide binds to site II with higher affinity and to a lesser extent to site I.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1993

Clinical pharmacology of oxicams: new insights into the mechanisms of their dose-dependent toxicity.

Six oxicams, sudoxicam, isoxicam, piroxicam, tenoxicam, meloxicam and lornoxicam, were compared in an attempt to understand why, despite close chemical structures, two of them were associated with an increased risk of toxicity in patients. Different factors have been revealed which may explain these differences. A weak association constant to human serum albumin (HSA), together with a high plasma concentration, favours a rapid increase in unbound concentration (Cu) when total plasma concentration rises (peak of absorption). Pathological states may enhance this increase when both HSA plasma concentration is decreased and free fatty acid concentrations are increased. However, the main cause of toxicity may be the existence in some subjects of HSA natural mutants whose ability to bind oxicams is markedly lower than normal.

Anti-Inflammatory Agents, Non-Steroidal↗