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Biomedical subjects

E Albengres

Publications and source records attributed to E Albengres.

At least 37 records · Page 2Linked to original sources
PubMed1992

Cyclosporin and ketoconazole, drug interaction or therapeutic association?

Coadministration of cyclosporin and ketoconazole results in marked elevation in blood levels of cyclosporin, which is believed to be the result of competition for hepatic P-450 mixed function oxidase enzymes. This requires a significant reduction in cyclosporin dosage regimen which may result in savings of nearly $5,000/year per transplant recipient. As a consequence, the idea of intentionally adding ketoconazole to cyclosporin for the purpose of decreasing toxicity and cost has been advanced. This article reviews the reported cases and studies of which the ketoconazole/cyclosporin interaction is the major concern. From a pharmaceutical standpoint, it is stressed that further investigations are needed to clarify the actual consequences of the inhibitory effect of ketoconazole on cyclosporin metabolism as well in short-term as in long-term treatments, before taking advantage of metabolic interaction to supply the two drugs as a unique preparation for clinical use. It is concluded that at the time of this review, individual monitoring of adjunctive ketoconazole therapy still remains the best therapeutic choice.

Animals↗
PubMed1991

The significance of circulating antiethinyl-estradiol antibodies (AEEA) in the occurrence of thrombosis in women while taking the pill.

The aim of the study was to investigate the hypothesis that oral contraceptives (OC) lead to antiethinyl-estradiol antibody (AEEA) synthesis which might in turn be responsible for the thrombo-embolic complications observed in women users. The trial included 428 women divided into a) 204 healthy female volunteers as the control group (CONT), b) 139 women who had suffered thrombo-embolic accidents (THR), c) 85 women suffering from recurrent fetal loss (RFL). In each of these three categories, 50% were pill users (OC+) and 50% were not (OC-). Specific immune markers of systemic autoimmunity and anticardiolipin antibodies were looked for, as they are thought to be present in increased amounts in thrombosis or recurrent fetal loss. The AEEA prevalence differed significantly (p less than 0.05) between the CONT OC+ (32%) and the CONT OC- (13%) women. It also differed (p less than 10(-5)) between the RFL OC+ (60%) and the RFL OC- (12%) women. It did not differ between THR OC+ (36%) and THR OC- (39%) women. Within the OC+ women, the difference between the THR and the CONT groups was not found to be significant, whereas it was found to differ significantly between the RFL and the CONT groups (odds-ratio RFL/CONT estimated at 3.20, confidence interval 1.53, 6.69). Within the OC-women, the AEEA prevalence was found to differ significantly between the THR (39%) and the CONT (13%) groups (odds-ratio THR/CONT estimated at 4.40, confidence interval 2.07, 9.38%) but not between the RFL and the CONT groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1990

Onset and development of cyclosporin A effects on lymphocytes of cardiac patients before heart transplantation.

The effects of cyclosporin A (CSA) in low dosage (4 mg/kg/24 h i.v.) were studied in 17 patients awaiting heart transplantation. The lymphocyte subsets were typed, enumerated, and their proliferation measured before CSA perfusion, after infusion (over 24 h), and then again after two further 24 h intervals (T0 h, T24 h, T48 h, and T72 h). No significant change was found in T or B enumerations although lymphocyte function was markedly modified. For all 17 patients, there was a significant decrease in lymphocyte proliferation that was, however, re-established after 72 h for 14 of the patients, but not for the remaining 3. Inhibition of the proliferative response was found to occur rapidly, to be potent although rapidly reversible in most cases, while yet subject to wide interindividual variability. These four features suggest that (a) CSA in fixed doses may later the balance between helper and suppressor cells in varying degrees according to the patient, and that (b) CSA given immediately or shortly after heart transplantation could be beneficial.

Adult↗
PubMed1990

How chronically administered valproate increases chlordiazepoxide transfer through the blood-brain barrier.

Sodium valproate (VPA) is a drug widely used in the treatment of epileptics often in association with benzodiazepines. Recent animal studies have shown that the addition of valproate increases diazepam levels in the cortex and the cerebellum (Hariton et al, 1985). The aim of our study was to determine the effect of VPA on the transfer of benzodiazepines through the blood-brain barrier. They were investigated using the intracarotid injection technique in rats as described by Oldendorf (1971). Our results show that the 14C-chlordiazepoxide brain extraction is significantly higher in rats on prolonged valproate treatment than in controls. With regard to plasma protein binding effects on chlordiazepoxide transport, our data indicate that a fraction of the protein-bound chlordiazepoxide could transfer from the intracapillary space to the brain tissue space because of enhanced drug dissociation from albumin in the brain microcirculation (Kd in vitro = 74.1 microM; Kd in vivo = 793.7 microM). Two distinct mechanisms can be deduced from this study: 1) chlordiazepoxide is displaced from HSA by valproate, 2) in addition, this fatty acid could increase drug permeation through the blood brain barrier (PS/F (chlordiazepoxide) = 0.60 in controls, PS/F (chlordiazepoxide) = 0.97 in treated rats). On the contrary, the washout of the benzodiazepine from the rat brain does not seem to be modified by the addition of valproate.

Animals↗
PubMed1990

Current French system of post-marketing drug surveillance.

The French system of drug surveillance is characterized by several original features: thirty regional centres are selected to cover all of France to collect, analyze and enter the adverse drug events in the national data bank. The system is based on a bank of well documented files submitted to a decision of imputation; the report of severe events by prescribers is mandatory; cases are collected either by spontaneous reporting (routine) or by direct request (intensive validation study); the system is being involved in studies of epidemiological type as carried out by the national system of health or a few societies of medicine as well as by the centres themselves in cooperative works on defined populations.

Drug-Related Side Effects and Adverse Reactions↗
PubMed1989

Evidence for isoxicam binding to site I as a primary site and to site II as a secondary site of human serum albumin.

Isoxicam binding to HSA was studied using equilibrium dialysis and fluorescence methods. It was shown that this drug binds to or near site I (warfarin or azapropazone site) and to site II (the diazepam site) as a secondary site, although it is generally considered that their respective drug structural requirements are often exclusive. The binding parameters were calculated with different mathematical models; a site oriented model with or without fixing the number of binding sites as integer values and a stoichiometric model. The relevant results are in good agreement under the selected experimental conditions. The stoichiometric method indicates that no positive cooperativity occurred during the binding process but other interactions between the two sites cannot be excluded.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1989

Blood distribution of tenoxicam in humans: a particular HSA drug interaction.

Blood binding of tenoxicam was studied in vitro by equilibrium dialysis. Isolated human plasma proteins and blood cells were checked, and the distribution of the bound form was then calculated. The results showed that tenoxicam is mainly bound to HSA and that binding percentages are not different when measured in plasma (98.4%) and in an HSA solution at physiological concentration (704 microM, 98.15%). In these conditions, within the range of 1-150 microM, the tenoxicam binding percentage remained constant, evidence of a nonsaturable process. When a lower HSA concentration (10 microM) was used, the binding parameters of the tenoxicam interaction were calculated by using the same equilibrium dialysis data, by 3 methods of analysis- a stoichiometric method and site-oriented methods, fixing or not the number of HSA binding sites (n) as integer values. The best fit was observed with the first method, suggesting that two main interactions occurred. The site-oriented method gave lesser fits, the better being observed when n was not fixed. Its value, 1.77, suggest the possibility of two binding sites, one of them not preformed. The effects of known markers of site I, warfarin and apazone, of site II, diazepam and ibuprofen and of palmitic acid showed that tenoxicam is bound simultaneously to both sites I and II. The binding capacity of site I for tenoxicam is enhanced by diazepam: as this compound alone is bound to site II, this result suggests that the two HSA binding sites are not independent.

Bilirubin↗
PubMed1988

Effects of the binding of imipramine to erythrocytes and plasma proteins on its transport through the rat blood-brain barrier.

Brain extraction of a tricyclic antidepressant, imipramine, was investigated using the carotid injection technique in the rat. The extent to which drug binding to plasma proteins and erythrocytes could inhibit the brain extraction was measured. Equilibrium dialysis showed that imipramine is highly bound to human serum albumin (HSA), alpha 1-acid glycoprotein (AAG), lipoproteins, and erythrocytes. The free dialyzable drug fraction was inversely related to the protein concentration. Despite this degree of binding, no significant reduction in the brain extraction of the drug was observed in the presence of HSA, lipoprotein, or erythrocytes. Only AAG reduced the brain transport of this drug in a ratio related to the protein concentration. However, the rat brain extraction was higher than expected from the in vitro measurement of the dialyzable fraction. These data indicate that the amount of circulating imipramine available for penetration in brain exceeds widely the dialyzable fraction of the drug as measured in vitro.

Algorithms↗
PubMed1988

Blood binding and tissue uptake of drugs. Recent advances and perspectives.

The free drug hypothesis, which states that only the unbound moiety of drug in blood is available for tissue diffusion, is discussed according to recent investigations. In some experimental conditions, it must be assumed that part of the protein-bound drug in plasma is extracted during a single passage through the organ studied. The mechanisms underlying these observations are not unequivocal and remain hypothetical. In the liver, high-affinity binding sites for serum albumin have been demonstrated, and they would explain the high extraction by liver of endogenous and exogenous compounds. However, these experiments measure the unidirectional transfer of a drug from the vascular to the extravascular space in non-steady-state conditions. Hence, in steady-state conditions, the free drug hypothesis cannot be ruled out because it is supported by numerous pharmacokinetic studies.

Animals↗
PubMed1988

Pharmacological criteria for risk-benefit evaluation of NSAIDs.

Evaluation of new non-steroidal anti-inflammatory drugs (NSAIDs) must compare efficacy and toxicity with existing compounds. Real progress involves maintaining effectiveness while decreasing toxicity. It is relatively easy to assess the effects of NSAIDs in animal models, and to determine gastrointestinal toxicity. However, although the ratio of active and toxic doses in animals can be extrapolated to man, the approach is limited and the NSAID needs to be assessed in a clinical setting as early as possible. In France, a national survey system has reported a wide range of adverse effects related to NSAIDs and shown important differences between compounds. Overdosage may be one of the factors responsible for toxicity, therefore pharmacokinetic evaluation is useful. In some disease states e.g. rheumatoid arthritis, there is a higher possibility of saturation pharmacokinetics with some drugs. Other pharmacokinetic parameters of interest are half-life, functions limiting activity, and hepatotoxicity. Furthermore, different pharmacokinetic parameters are required for different forms of disease. In acute states, the NSAID should have a short half-life and low protein binding and vice versa in chronic states. An important goal is to develop more selective NSAIDs regarding mechanisms of action or distribution into diseased tissues.

Animals↗
PubMed1988

Features of the French postmarketing drug surveillance system. Application to cutaneous effects of nonsteroidal antiinflammatory drugs.

The French drug surveillance system is characterized by several original features: 29 regional centers in France collect, analyze and enter the adverse drug reactions (ADR) in a national data bank; reporting of severe ADR by prescribers is mandatory; data are collected either as spontaneous reports (warming-step) from prescribers or by direct request when an intensive validation study is set up from the data of the spontaneous reports; each validation study evaluates only well documented cases which thus can lead to a decision of imputability to assess the drug effect relationship; the reaction time of the system is fast: severe ADR (agranulocytosis, Lyell's syndrome) can be identified as soon as they occur, and it takes less than one year between the first warning case report and the final restrictive decisions for any drug concerned. Such a system answers the question whether an individual patient in a drug treated group developed the adverse reaction because of the drug. This type of analysis can lead to emphasis on some special features, pathological causes, genetic or environmental factors, pharmacological causes, which may serve to initiate epidemiological studies as a next step. These studies can indicate, in statistical terms, a greater occurrence of an ADR group and thus are an aid to define the population at risk. The results of a national inquiry on cutaneous adverse effects of nonsteroidal antiinflammatory drugs observed in France in 1985 have led to an original classification of drugs regarding that risk.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1988

Plasma and tissue binding as determinants of drug body distribution. Possible applications to toxicological studies.

1. Drugs are distributed through all body tissues via blood circulation. Consequently, most drugs rarely elicit one specific pharmacological effect but more generally have several, in different tissues. 2. In other words, drug effects are not unique or isolated, because drug distribution is not selective. Thus, considering a drug with a given liposolubility, its quantitative distribution in the body may be predicted in taking into account the physico-chemical properties of the compound and the blood flows and the lipid contents of the different tissues and organs it will reach. 3. This paper attempts to show that plasma binding can influence the tissue distribution of drugs and may be applied to the minimization of toxic effects by decreasing the amounts of drug reaching the relevant tissues. 4. The value of an early determination of drug binding in human blood will be emphasized. This is justified by the fact that tissue distribution of drugs does not vary greatly between species whereas plasma binding may show important inter-species differences. Thus different plasma binding in humans may lead to large variations in tissue distribution as compared with experimental animals.

Animals↗
PubMed1987

Binding of two anthranilic acid derivatives to human albumin, erythrocytes, and lipoproteins: evidence for glafenic acid high affinity binding.

The binding of two anthranilic acid derivatives, glafenic and floctafenic acids, to human erythrocytes and plasma proteins has been investigated in vitro by equilibrium dialysis. Despite their close chemical structures it was shown that the binding of the two compounds to serum albumin, lipoproteins, and erythrocytes was dramatically different both in quality and quantity. Using various techniques including fluorometry and circular dichroism, it was shown that glafenic acid binds to the human serum albumin (HSA) warfarin/azapropazone site and that floctafenic acid binds to both warfarin/azapropazone and benzodiazepine sites. Glafenic acid is strongly bound to HSA with n = 1, k = 2.4 X 10(6) liters/mol and to erythrocytes with N = 12.4 mumol/liter, K = 1.7 X 10(6) liters/mol. Floctafenic acid is bound with a weaker affinity to HSA, n = 2, k = 0.3 X 10(6) liters/mol and to erythrocytes, N = 2900 mumol/liter and K = 0.007 X 10(6) liters/mol.

Analgesics↗
PubMed1987

Comparative study of bepridil and nicardipine action on respiration and calcium transport in mitochondria.

Effects of the calcium antagonists bepridil and nicardipine on mitochondrial functions were studied and their effects on respiratory control and calcium fluxes were compared. Results show that bepridil and nicardipine similarly increase Ca2+ intracellular movements, but that intramitochondrial Ca2+ storage is increased by bepridil whereas it is decreased by nicardipine. The in vivo significance of these findings remain to be determined. The effect of bepridil might be related to an enhancement of mitochondrial ATPase activity whereas nicardipine would act on mitochondria by a different mechanism.

Adenosine Triphosphatases↗