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Biomedical subjects

H Millart

Publications and source records attributed to H Millart.

At least 37 records · Page 2Linked to original sources
PubMed1997

ATP depletion induces a loss of respiratory epithelium functional integrity and down-regulates CFTR (cystic fibrosis transmembrane conductance regulator) expression.

To mimic the effect of ischemia on the integrity of airway epithelium and expression of cystic fibrosis transmembrane conductance regulator (CFTR), we induced an ATP depletion of the respiratory epithelium from upper airway cells (nasal tissue) and human bronchial epithelial 16HBE14o- cell line. Histological analysis showed that 2 h of ATP depletion led to a loss of the epithelium integrity at the interface between basal cells and columnar cells. The expression of connexin 43 (Cx43, subunit of the gap junctions) and desmoplakins 1 and 2 (DPs 1 and 2, major components of the desmosomes) proteins was inhibited. After 90 min of ATP depletion, a significant decrease of the transepithelial resistance (25%) was observed but was reversible. Similar results were obtained with the 16HBE14o- human bronchial epithelial cell line. ATP depletion led to actin filaments depolymerization. The expression of the mature CFTR (170 kDa) and fodrin proteins at the apical domain of the ciliated cells was down-regulated. The steady-state levels of CFTR, Cx43, DPs 1 and 2 mRNAs, semiquantified by RT-polymerase chain reaction kinetics, remained constant throughout ATP depletion in nasal tissue as in the homogeneous cell population of 16HBE14o- human bronchial epithelial cell line. This suggests that the down-regulation of these proteins might be posttranscriptional. The intercellular diffusion through gap junctions of Lucifer dye was completely inhibited after 90 min of ATP depletion but was reversible. The volume-dependent and the cAMP-dependent chloride secretion were inhibited in a nonreversible way. Taken together, these results suggest that an ATP depletion in human airway epithelium, mimicking ischemia, may induce a marked alteration in the junctional complexes and cytoskeleton structure concomitantly with a loss of apical CFTR expression and chloride secretion function.

Adenosine Triphosphate↗
PubMed1997

Cardiotoxic effects of salmeterol in comparison with salbutamol on the isolated perfused Langendorff-heart of the rat.

beta 2-Adrenoceptor agonists used in the relief of bronchospasm have long been known to produce circulatory side-effects. Salmeterol (CAS 89365-50-4) is a novel long acting highly selective beta 2-agonist. We used the Langendorff-heart rat model (constant perfusion pressure) to compare the direct effects of salbutamol (CAS 18559-94-9, SAL) and salmeterol (SMT) on the cardiac performances and their toxic cardiac effects (induced by 3 mmol/l perfusate calcium). At the first step the concentration-effect curve was established for the maximal concentration (Cmax) of salbutamol leading to the maximal chronotropic effect on the heart for 20 min after a 20 min stabilization period (basal values). All hearts were consequently submitted to a 20 min Krebs-Henseleit perfusion in order to study the reversibility of the myocardial performances. The types of the myocardial and coronary beta-adrenoceptors involved in SAL (Cmax) effects were identified using a selective beta 1 (atenolol) and a beta 2 (butoxamine) antagonist. SAL induced an increase in the heart rate via a selective stimulation of the beta 1-adrenoceptors (beta 1-AR). SMT appeared to be more potent than SAL on the heart rate. Direct toxic drug effects on the heart appeared gradually with SAL whereas they appeared sharply at the highest concentration of SMT. The enzyme leakage observed during the recovery period was more pronounced with SMT than SAL. Perhaps, this phenomenon might be due to the lipophilicity of SMT. However, these direct cardiac effects of SMT have to be considered in association with its airway smooth muscle relaxant effect (therapeutic effect) which has been proven much more potent than those of SAL. Therefore SMT was less cardiotoxic than SAL at similar therapeutic concentrations.

Adrenergic beta-Agonists↗
PubMed1997

[The anti-leukotrienes: their use in asthma].

Inflammation in asthma plays a predominant role in the genesis of bronchial obstruction and hyperreactivity. Treatment of bronchial inflammation since the early stages of asthma has become an essential element of therapeutic strategy and rests chiefly on inhaled glucocorticoids. However, inhaled glucocorticoids pose some problems in terms of inhalation technique, compliance, local tolerance and, to a lesser extent and at high doses, of systemic tolerance. Antileukotrienes represent a new class of potential anti-asthma drugs. They act either by inhibition of 5-lipoxygenase, a key enzyme in the leukotriene (LT) synthesis pathway, or by blocking LT receptors. The LT antagonists developed in asthma are mainly specific for a receptor subtype, the CysLT1 receptor, involved in the bronchoconstrictor and inflammatory effects of sulfidopeptide leukotrienes (LTC4, D4 and E4). Two antagonists of CysLT1 receptors have been recently launched on the market: ONO-1078, pranlukast, Onon and ICI-204,219, zafirlukast, Accolate. The CysLT1 antagonists cause bronchodilatation with a beta 2-agonist additive effect, confer effective protection in bronchial provocation studies and particularly, they improve clinical scores, pulmonary function and beta 2-agonist rescue inhaler use. Additional studies, especially comparative with respect to reference treatments, mainly inhaled glucocorticoids, will be required to define their place in the global strategy for asthma management.

Anti-Asthmatic Agents↗
PubMed1997

[Relationships between selenium deficiency and 3,5,3'-triiodothyronine (T3) synthesis].

Several enzymes, the main being type I 5' deiodinase, ensure thyroxin (T4) into 3,5,3'-triiodothyronine (T3) deiodination, both in the thyroid and in peripheral tissues. One of the feature of this enzymatic reaction is its regulation. It depends in part on individual selenium and iodine status. It has been shown by an analysis of thyroid hormones concentrations variations, when one of these trace elements is missing. During thyroid hormone synthesis, selenium and iodine are also implied in oxidative process control. Then, how selenium and iodine status balance modifications contribute to thyroidal diseases outbreak, becomes easier to understand. Besides, providing, adapted to individual requirements, selenium and iodine supplies could be useful for hypothyroidism and hyperthyroidism treatment.

Animals↗
PubMed1995

Compared effects of ruthenium red and cis [Ru(NH3)4Cl2]Cl on the isolated ischaemic-reperfused rat heart.

The sequence ischaemia-reperfusion is characterized by reperfusion damage. The calcium overload occurring at the beginning of reperfusion is one of the main mechanisms responsible for reperfusion damage. Ruthenium red, a blocker of the mitochondrial calcium uniport system, could prevent this damage by preserving the ATP synthesis in the mitochondria. We tested ruthenium red and another ruthenium compound, cis-tetrammine dichlororuthenium (III) chloride in our experimental model of ischaemic-reperfused rat hearts. After a 15 minute-stabilization period, the hearts were submitted to a 30 minute global ischaemia period and then reperfused for 45 minutes with the standard perfusion solution or with ruthenium red or cis-tetrammine dichlororuthenium (III) chloride at 1, 3 or 9 microM. Ruthenium red at 3 microM exerted a protective effect in our experimental conditions by showing a significant improvement of the contractility recovery at the end of reperfusion and a significant decrease of the malondialdehyde production, which reflects free radical production. The cis-tetrammine dichlororuthenium (III) chloride (containing 1 Ru ion per molecule) at 9 microM was slightly less efficient than ruthenium red at 3 microM (containing 3 Ru ions per molecule). The heart ruthenium binding was better for the ruthenium red than for the cis-tetrammine dichlororuthenium (III) chloride, suggesting a role of the ruthenium ion complexation in the crossing of the membrane, whereas the cardiac effect seemed to be linked to the ruthenium ion heart concentration, which was similar for the ruthenium red at 3 microM and for the cis-tetrammine dichlororuthenium (III) chloride at 9 microM. One can hope that ruthenium compounds would limit reperfusion damage and infarct size after ischaemia in in vivo models.

Animals↗
PubMed1995

Red blood cell magnesium concentrations: analytical problems and significance.

In order to assess total magnesium concentrations in human red blood cells (erythrocytes--ErMg), atomic absorption spectrometry (AAS) provides high accuracy and precise method rapid and amenable to automation. Taking care of eliminating the chronic marginal magnesium deficits, normal values of ErMg evaluated through a direct method and expressed as mmol/litre of packed cells are 2.3 +/- 0.24. Inductively coupled plasma-mass spectromettry (ICP-MS) is a multielemental analytical technique. Particle induced x-ray emission (PIXE) also provides multielemental capability, but is time-consuming and costly. Microelectrodes are the gold standard for intracellular Mg2+ measurements. But microelectrodes and fluorescence probes measure the activity of magnesium ions, not the concentrations. Ionized magnesium content of human intact erythrocyte is mainly assessed with the NMR method and with the zero point titration. The concentration of ionized magnesium as estimated by NMR (31P NMR method) was found to be 0.20 +/- 0.02 mmol/litre cell water and with the zero point titration 0.55 +/- 0.12. The uncertainty concerning the two current used techniques for free magnesium determination is worsened by the fact that magnesium inside red cells continually oscillates in vivo. Free magnesium constitutes a small part of total magnesium. Further studies are necessary to assess the importance of its variations in clinical medicine. Efflux of ErMg is controlled through membranous sodium-dependent and sodium-independent pathways and through genetic and neurohormonal regulations. Variations in the total or ionized ErMg do not necessarily mean that similar changes should exist in the magnesium pool. But it remains the basic static cellular magnesium item. Its value will be subsequently enhanced when it takes place among the clinical and paraclinical data of dynamic magnesium investigations.

Blood Chemical Analysis↗
PubMed1994

Comparative pharmacokinetics of two diastereoisomers dexamethasone and betamethasone in plasma and cerebrospinal fluid in rabbits.

The two diastereoisomers dexamethasone (DXM) and betamethasone (BTM) were infused at two different doses (2, 10 mg.kg-1) in anesthetized rabbits. Samples of plasma and cerebrospinal fluid were collected over a 180-min period. Steroid concentrations were measured by high performance liquid chromatography. The terminal half life (85.7 +/- 20.8 min and 102.2 +/- 29.6 min for DXM; 117.6 +/- 19.8 min and 118.5 +/- 15.8 min for BTM) and the mean residence time (121.4 +/- 27.7 min and 146.1 +/- 41.3 min for DXM; 168.6 +/- 28.1 min and 172.2 +/- 20.6 min for BTM) were unchanged between the doses. Dose-dependent changes in the area under the curve normalized by the dose, then volume distribution and clearance were observed. The average percentage of DXM and BTM bound to plasma proteins were 78.1 +/- 11.5% and 88.3 +/- 5.1% respectively at the lower dose, and decreased significantly with 10 mg.kg-1. DXM appeared more rapidly in the CSF, the highest concentrations of DXM were obtained within 15 min after the end of the injection. The CSF levels were lower than that of plasma unbound and the passage through the blood-brain barrier was saturable. These results will complicate pharmacokinetic and pharmacodynamic analysis.

Animals↗
PubMed1994

Gallium chloride effects on neonatal rat heart cells in culture, in standard and oxidative conditions.

The effects of gallium chloride (GaCl3) at 7.17, 28.68 and 114.7 microns (0.5, 2 and 8 mg/l of Ga3+) were checked in cardiac cells derived from 2-4 day-old newborn rats, cultured for 72 h in Eagle's minimum essential medium (MEM), enriched with 10% foetal calf serum (v/v) and 2 mM of glutamine at 37 degrees C, with 95% air plus 5% CO2. After 3 hours of standard culture conditions (MEM with glucose 5 mM), Ga treatment induced an increase of glycogen stores without any influence on ATP, ADP, and AMP concentrations. A slight and transient decrease in the beat rate was noted after 15 min of exposure to GaCl3 at all concentrations, whereas there was no difference in the beat rate nor in the cell contraction amplitude after 3 hours of exposure. After 1.5 h in conditions of oxidation (Tyrode solution without glucose, FeCl2 20 microM, ascorbic acid 0.2 mM), GaCl3 at 8 mg/l decreased the malondialdehyde (MDA) production as assessed by the decrease of intracellular concentrations and the decrease of its release in the supernatant. The decreased MDA production following oxidative stress, the increase in glycogen stores in normal oxygen concentrations, as well as the maintenance of ATP concentrations and the lack of any chronotropic effect induced by GaCl3 suggests a protective rather than a deleterious cardiac effect.

Animals↗
PubMed1993

Sensitive high-performance liquid chromatographic method for the determination of coumarin in plasma.

A high-performance liquid chromatographic method was developed for the determination of coumarin in plasma at low concentrations. The method involves a single-step extraction of the alkalinized sample with hexane and subsequent evaporation of the organic phase in the presence of hydrochloric acid to collect and concentrate the coumarin. Analysis of the acidic phase was performed on a C8 column and coumarin was detected by measuring the UV absorbance at 275 nm. The limit of detection was 0.3 microgram l-1. The assay was used to study the evolution of concentrations of coumarin in one volunteer after oral administration of a single 10-mg dose.

Calibration↗
PubMed1993

Gas chromatographic determination of meprobamate in human plasma.

A simplified and rapid gas chromatographic method has been developed for the determination of meprobamate in human plasma. The procedure includes a single-step extraction of alkalinized sample with chloroform, and chromatography on a non-polar fused-silica capillary column with flame ionization detection. The method is accurate (97.7 +/- 5.7% at 20 mg/l) and precise (maximum coefficient of variation of 9.5%). It provides an alternative to existing methods and is particularly suitable for toxicological studies.

Aged↗
PubMed1991

Correlation of clinical pharmacokinetic parameters of cisplatin with efficacy and toxicity.

Twenty-two pharmacokinetic studies were carried out in 11 patients receiving cisplatin (20 mg/m2 per d) associated with etoposide (50 mg/m2 per d), as 5-day continuous infusions, every 4 weeks. Blood was withdrawn at 8:30 am from day 1-5. Within 15 min after taking the blood, an aliquot of plasma was filtered for the ultrafilterable platinum (UP) assay. Total platinum (TP) and UP were assayed by flameless atomic absorption. The plasma concentrations and AUC0-120 h of TP were correlated with those of UP (P less than 0.05 to P less than 0.001). TP concentrations increased significantly during the infusion and with each successive course, whereas the increase of plasma concentration of UP during and between courses was not statistically significant. The responders had significantly higher levels of TP (AUC, concentrations) in the first and second courses than the non-responders. No renal toxicity was observed, nevertheless, the AUC0-120 h of TP and UP were positively correlated with the serum creatinine (P less than 0.05). The digestive intolerance (grade 1-3) was significantly correlated with TP concentrations and AUC0-120 h. There was no statistical difference in UP concentrations either between responders and non-responders in any course, nor between toxic and non-toxic courses. Since etoposide was concomitantly administered, we can formulate the conclusion as follows: no "objective" response was observed in the patients with low TP plasma concentrations and AUC0-120 h.

Cisplatin↗
PubMed1991

Influence of sex and oestrogen replacement on the disposition of dexamethasone in rats.

The disposition of dexamethasone (DXM, 2 mg/kg, iv) was studied in ovariectomized female rats treated with oestrogen (0.1 mg and 1 mg of oestradiol benzoate) and in male rats. Oestradiol replacement had no effect on body or liver weights or on the DXM pharmacokinetic parameters (CL, Vdss, AUC, MRT and t1/2) of the female groups. If the Vdss seemed slightly greater in male than in female rats, this difference disappeared after normalization based on body weight. In contrast, CL was greater in the male rats even after normalization. For all the animals, significant correlations were observed between body weight and Vdss (r = 0.731, P less than 0.001) or CL (r = 0.639, P less than 0.001). Terminal half life and MRT were negatively correlated with CL (r = -0.481, P less than 0.01 and r = -0.575, P less than 0.01, respectively) but not with Vdss. Although oestrogen replacement did not seem to affect the pharmacokinetics of DXM, the increase in the CL in male rats should be the main determinant observed between the sexes. These results are consistent with a slower metabolism found for various drugs metabolized by the cytochrome P-450 in female rats.

Analysis of Variance↗
PubMed1989

Determination of pyridoxal 5'-phosphate in human serum by reversed phase high performance liquid chromatography combined with spectrofluorimetric detection of 4-pyridoxic acid 5'-phosphate as a derivative.

A very sensitive spectrofluorimetric method for the determination of pyridoxal 5'-phosphate (PLP) in human serum is described. The specificity is based on the selective oxidation of PLP to 4-pyridoxic acid 5'-phosphate with potassium cyanide. Separation of the highly fluorescent 4-pyridoxic acid 5'-phosphate is achieved by reversed-phase high-performance liquid chromatography. Specificity is improved by a careful choice of fluorescence filters, maximised at the excitation (325 nm) and emission (418 nm) wavelengths of 4-pyridoxic acid 5'-phosphate. The detection limit for the reaction is 0.22 ng ml(-1). For quantification, the serum is spiked with PLP before protein precipitation with 3.3% m/V trichloroacetic acid. The method can be used for the determination of PLP in serum, even in vitamin B6 deficient patients. The mean value for human serum PLP from 30 healthy adults was found to be 14.6 +/- 4.8 ng ml(-1) (mean +/- standard deviation).

Chromatography, High Pressure Liquid↗
PubMed1989

Magnesium alterations and pharmacokinetic data in gallium-treated lung cancer patients.

The dose of gallium chloride required to inhibit tumor growth after oral and chronic administration depends on the stage of the cancer disease and of the type of metastases. A dose regimen of 800 mg/24 h of gallium chloride will provide serum gallium concentrations greater than or equal to 600 micrograms/l in lung cancer patients with a small and limited disease. A dose of 1,400 mg/24 h is well tolerated in metastatic patients but may not be high enough to reach the desired serum gallium concentrations especially in patients with bone metastases. Radiotherapy and/or a chemotherapy will permit one to increase the serum gallium concentrations and the tumor gallium uptake by reducing the volume of the tumor. After chronic, oral administration of gallium a decrease in RBC Mg is noted. To avoid the Mg deficiency, the treatment must not be interrupted and may perhaps be decreased with care and slowly without resulting in a decrease of the serum gallium concentrations provided the treatment has been prolonged over a sufficient time to enable one to induce intratumor biological modifications and a decrease in the number of the malignant cells. Acute pharmacokinetic data are related to the histologic type of the tumor and may not be used to predict the serum gallium concentrations after chronic administration. The serum gallium concentrations required to inhibit the tumor growth may be higher in small cell lung carcinomas than in nonsmall cell lung carcinomas. Frequent Mg and Ga blood determinations are necessary to manage effective gallium treatment.

Administration, Oral↗
PubMed1989

[Value of determining dexamethasone in the rapid adrenal suppression test].

During the dexamethasone suppression test (DST), we evaluated the relationship between the 8 a.m. dexamethasone (DXM) level and the pharmacokinetics of this corticoid after the oral administration of a single dose at midnight of DXM (1 mg) in 7 healthy subjects. The half-life time of the terminal phase for DXM was 283 min +/- 132 min (mean +/- s.d.). The 8 a.m. DXM level, which is positively correlated with the DXM half-life time, is useful for the interpretation of the DST. On the other hand, no correlation was observed between the 8 a.m. plasma cortisol and DXM levels in 21 healthy subjects. However, the negative correlation between the dose of DXM/kg and post-DXM cortisol level suggests the possibility of adjusting the dose of DXM in obese patients.

Administration, Oral↗
PubMed1987

Effects of 4-deoxypyridoxine on the isovolumic perfused rat heart: influence of oxygenation and glucose availability.

The study was performed with isolated perfused isovolumic rat hearts. After a 40 min stabilization period, the effect of 4-deoxypyridoxine (DOP) 10(-5) M was studied with 3 Glc concentrations: 0, 3.3 and 11 mM. DOP was perfused during a 20 min normoxic or anoxic period followed by 40 min of normal perfusion. During normoxia with 11 mM Glc, DOP decreased the contracture observed in the control group. With 0 mM Glc, DOP improved developed pressure and dP/dt+ without a decrease in glycogen stores. During anoxia followed by reoxygenation, a partial protection towards CK release was observed with DOP (3.3 mM Glc). Intracellular PLP levels were higher in the 11 mM Glc group than in the other groups with and without DOP, and DOP with 11 mM Glc increased PLP levels (DOP N2 vs. DOP O2). Glycogen stores increased with 11 mM Glc without DOP (O2 vs. N2), whereas they decreased with DOP without Glc (DOP N2 vs. N2). DOP could improve the yield in glycogenolysis in normoxia and might activate mitochondrial anaerobic metabolism during anoxia.

Animals↗