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P Lapalus

Publications and source records attributed to P Lapalus.

At least 55 records · Page 3Linked to original sources
PubMed1990

Determination of optimal dosage regimen for amikacin in healthy volunteers by study of pharmacokinetics and bactericidal activity.

The pharmacokinetics and serum killing curves of amikacin, which was administered by a 30-minute intravenous infusion of single doses of 7.5 mg/kg and then 15 mg/kg, were investigated in six healthy volunteers who received the two doses in a crossover study with a washout period of 20 days. The serum killing curves were determined for four bacterial species: Escherichia coli, Serratia marcescens, Enterobacter cloacae, and Pseudomonas aeruginosa. All strains were serum resistant, and the bactericidal activity was analyzed by separating the early phase (first 5 h) and the late phase (24 h) of the killing curve. For the early phase, the bactericidal activity was evaluated by correlating an index of surviving bacteria with amikacin concentrations. This methodology allowed determination of two parameters: the maximal effective concentration and the lowest effective concentration. For the late phase, the threshold values separating bacteriostatic and bactericidal activities were lower than 10 mg/liter for each strain. The concentration dependence of amikacin bactericidal activity was confirmed for Escherichia coli and Enterobacter cloacae and, to a lesser extent, for Serratia marcescens and Pseudomonas aeruginosa. Correlation of these data with amikacin pharmacokinetic data in volunteers indicated that a daily dose of 15 mg/kg may be effective in the treatment of Escherichia coli and Enterobacter cloacae infections. For Pseudomonas aeruginosa and Serratia marcescens, the partially time-dependent activity probably necessitates two daily administrations and combination with another antibiotic.

Adult↗
PubMed1990

Acidic fibroblast growth factor distribution in normal human eye and possible implications in ocular pathogenesis.

Using a rabbit anti-acidic fibroblast growth factor (anti-aFGF) antiserum, we tried to establish a precise mapping of aFGF localization in normal human ocular structures, from samples obtained by autopsies. Cell cultures of retinal pigment epithelium and ciliary pigment epithelium were also established and immunofluorescence studies were performed after 1 month. Corneal and conjunctival epithelia were strongly positive for anti-aFGF antibodies as well as the subcapsular epithelium of the lens. The cortical fibers were weakly reactive and the lens nucleus negative. A strong intracytoplasmic reactivity was observed in the pigmented and nonpigmented epithelial cells of ciliary processes and pars plana, both ex vivo and in vitro. Retina was brightly positive, mostly in the photoreceptor and plexiform layers. The possible involvement of aFGF in normal eye growth and in various ocular diseases was then discussed.

Adult↗
PubMed1990

Effect of N-acetyl-aspartyl-glutamate (Naaga) on in-vitro leukotriene synthesis by macrophage cell line P388D1.

The magnesium salt of N acetyl-aspartyl glutamic acid (Naaga), used in ophthalmic allergies, is a synthetic dipeptide analogue of a natural peptide found in mammalian brains. It has been shown in vitro that Naaga inhibits complement activation, mast-cell degranulation and leukotriene anaphylactic release. In order to verify Naaga's action on leukotriene production, we used the macrophage cell line P388D1 activated by calcium ionophore A23187. Leukotriene determination was performed by high-performance liquid chromatography. It was found that Naaga inhibits 15 to 80% macrophage eicosanoid secretion (10(-9) M to 10(-2) M), acting mainly on LTC4-D4-E4 synthesis. Naaga was as potent as the leukotriene inhibitor nordihydroguaiaretic acid and as dexamethasone in this model. This inhibition of leukotriene secretion could partially explain the in-vivo antiallergic effects of Naaga.

Animals↗
PubMed1990

Cytotoxicity studies in ophthalmology.

Ocular tissues and cells are more and more in direct contact not only with drugs but also with biomaterials, such as contact lenses, intraocular implants, corneal shields, and the cell reactivity study is an indispensable step before any clinical and human utilization. The cell toxicity may be direct, by cell membrane damaging, metabolic disturbance, or indirect by mitosis or cell differentiation blocking. In order to evaluate the unwanted effects, cell cultures are performed according to the drug or to the biomaterial to be tested: conjunctival and corneal epithelial cells, lens epithelium, ciliary processes epithelium... In this report, the cytotoxicity of three substances were evaluated on corneal cultured cells: Benzalkonium chloride (BAK), an ophthalmic preservative; Novesine (Oxybuprocaine + BAK), local anaesthetic; Neosynephrine (Phenylephrine chlorydrate), a commonly used mydriatic in ocular surgery. Results of cell counting (cell viability) are given according to curves and histograms (percentage of dead cells depending on time and doses). These data are discussed according to the different mechanisms of action of the three drugs BAK and Oxybuprocaine were found to exert a more direct cell toxicity whereas phenylephrine chloride acted indirectly by causing the sloughing of the cell monolayer.

Anesthetics, Local↗
PubMed1990

[Evaluation of the placebo effect on blood pressure profile during exercise in patients with mild uncomplicated hypertension].

UNLABELLED: The administration of placebo (pharmacologically inactive substance) is justified in clinical trials of antihypertensive drugs, in order to avoid the inclusion of placebo-responders. The evaluation of antihypertensive treatments during exercise is an interesting end point, since aerobic exercising is part of antihypertensive treatment. The aims of this study are to determine the placebo impact on blood pressure, heart rate and catecholamine secretion profiles during exercise testing. METHOD: 10 untreated essential mild to moderate hypertensives participated to a single blind study comprising two successive submaximal exercise testings (85% of maximal theoretical heart rate), separated by a single oral administration of placebo. Blood pressure and heart rate were measured after 10 minutes of resting position and at the end of each effort step (2 mm, 20 Watts), both before and after placebo. Blood samples (5 ml) were collected at rest and during maximal exercise before and after placebo, in order to determine the effect of placebo on circulating catecholamines. RESULTS: there was no significant variations between the "control" and exercise testings after placebo, neither on blood pressure or heart rate profiles, nor in values of circulating catecholamines [Noradrenaline at rest: 1.88 +/- 0.96, exercise: 6.43 +/- 1.93 nm/l before placebo, 1.65 +/- 0.83 nm/l and 5.71 +/- 2.12 nm/l after placebo respectively (NS)]. CONCLUSION: the placebo, which effect is generally determined on blood pressure at rest by sphygmomanometry, seems devoid of any activity on blood pressure, heart rate or catecholamine profile during exercise, in essential moderate hypertensives. Thus, antihypertensive treatments at exercise can be evaluated by comparison to baseline cardiovascular parameters without placebo groups.

Adult↗
PubMed1990

A new approach to optimal antibiotic dosage regimen by coupling pharmacokinetics and killing curve parameters.

Antibiotic therapy is directed against bacteria responsible for infectious pathology which are able to resist treatment mainly when the dosage is misadapted. The choice of the initial dosage regimen actually takes into account toxicological, bacteriological and pharmacokinetic parameters. The determination of the classical bacteriological data is performed in vitro using fixed drug concentrations that are far from human therapy conditions, and moreover the efficiency is not well defined. The estimation of the pharmacokinetic parameters is realized in animals, healthy subjects or ill patients but takes into account only the drug disposition without correspondence with the kinetics of the antibiotic effect on the bacteria. Thus, each type of evaluation is made independently from the others without any correlation between the observed phenomena. It appears, therefore, interesting to propose a new approach including pharmacokinetic and bacteriological data to enable approximation of drug efficacy. The coupled evaluation of individual pharmacokinetic estimation and the killing curve determinations of an antibiotic will allow this type of development. On the basis of these data, a preliminary profile of the optimal dosage would be possible. This methodology has been applied to three antibiotics: teicoplanin, amikacin and ofloxacin and demonstrates a time- or dose-dependent activity, with interesting possibilities for optimization of dosage.

Amikacin↗
PubMed1990

[Treatment of chronic cardiac insufficiency with intravenous bolus enoximone. Study of a pharmacokinetic-hemodynamic relation].

The aim of this study was to evaluate the efficacy and pharmacokinetics of enoximone administered as an intravenous bolus in 12 patients (mean age 62 years) with severe chronic congestive cardiac failure (Stage IV of the NYHA) due to ischemic (N = 6) or idiopathic (N = 6) cardiomyopathy. The haemodynamic parameters and plasma concentrations of enoximone and its metabolite were measured 15, 30, 60, 90, 120 minutes, 4 and 6 hours, after IV bolus of enoximone 1 mg/kg in 10 minutes. Enoximone increased the cardiac index by an average of 37 p. 100 (1.92 +/- 0.3 to 2.63 +/- 0.35 l/mn/m2; p less than 0.001); pulmonary artery diastolic pressures fell by 33 p. 100 (p less than 0.01). Systemic arterial resistances decreased by 23 p. 100 (p less than 0.05). No significant changes in heart rate or blood pressure were observed. The peak effect was recorded between the 15th and 30th minute. The pharmacokinetic study showed the half life of enoximone to be 2.2 +/- 0.78 hours, the area under the curve to be 2,818 +/- 953, the volume of distribution to be 69.6 +/- 24 l and the total clearance to be 22.8 +/- 8.5 l/hour. The half life of the metabolite was 4.45 +/- 1.05 hours. There was a significant correlation between the percentage increase in cardiac index and peak enoximone concentration (r = 0.91; p less than 0.001). In conclusion, an IV bolus of enoximone is an effective treatment for chronic cardiac failure. The haemodynamic response was related to the peak enoximone plasma concentration.

Aged↗
PubMed1990

[Role of myocardial beta-adrenergic receptors in cardiac insufficiency].

The beta-adrenoceptors are now well individualized. They are divided into three distinct units: the receptor site, a regulating protein and a catalytic unit. The receptor density of the cell membrane varies according to the degree of stimulation of the receptor by agonists or the degree of blockade by antagonists. The myocardial or lymphocytic beta-adrenoceptor density is measured by "radioreceptor" assay using a radioactive beta-blocker. The myocardial beta-receptor density falls during heart failure, mainly to the detriment of beta 1 receptors. The density of beta 2 receptors remains unchanged. This fall in beta 1 receptors is related to the increase in the circulating catecholamines (down regulation) and is proportional to the severity of the disease. These physiological and physiopathological consequences can be directly applied to the treatment of heart failure by positive inotopic drugs or by beta-blockers.

Heart↗
PubMed1990

[Preliminary study on the transport of AZT (Retrovir-zidovudine) through the placenta].

The authors selected six patients who were HIV positive and who had requested termination of pregnancy to study the passage of zidovudine through the placenta. After the patients had been warned about the procedure and given consent, 1 gram of zidovudine (Azitothymine) was given in five doses of 200 mg each orally. Ethical Committee consent had been obtained. At a mean age of 17.5 weeks of amenorrhoea, samples were taken from the mothers' blood, from the amniotic fluid and from the fetal blood between one and two hours and forty five minutes after the last dose of AZT had been taken. Pregnancy was terminated immediately after the amniotic fluid had been obtained. The levels of zidovudine and its metabolite glucuronide (G-AZT) were carried out using High Performance Liquid Chromatography (HPLC). The concentrations of the drug in the liquor and in the fetal blood were higher or equalled those found in the maternal blood. This makes it likely that the half life elimination was longer and the metabolism of the product slower when it had been metabolised to glucuronide. This study does not concern the teratogenic effect or the toxicity for the fetus. The drug remains contra-indicated in pregnancy. There is no proposal at present to use it to lessen transmission of the virus from the mother to the fetus.

Abortion, Therapeutic↗
PubMed1990

[Influence of some antibiotics on eicosanoid production by human macrophages in vitro].

Non antibacterial effects of antibiotics are presently investigated by several authors. They estimate the effects of different molecules on polynuclear chemotaxis, cytokine production or macrophage activity. In this experiment we have studied the effects of two betalactams, two macrolides, a fluoroquinolone and a tetracycline on eicosanoïd production by stimulated human macrophages in vitro. All evaluated antibiotics are able to modify the prostaglandin and/or leukotriene production. Taking into account the immunomodulative and inflammatory properties of the eicosanoids, the variation of their production could be relevant in clinical practice.

Anti-Bacterial Agents↗
PubMed1989

Immunohistologic study of proliferative vitreoretinopathy.

An immunohistologic study was performed on pars plana specimens obtained by biopsy in ten patients with rhegmatogenous retinal detachment, with or without proliferative vitreoretinopathy. Using immunofluorescence or immunoperoxidase procedures, linear deposits of IgG, IgA, and complement components were found in the eight cases of retinal detachment with proliferative vitreoretinopathy at the basal pole of the pigment epithelial cells and within the stroma. In contrast, these deposits were absent from the normal pars plana and from the retinal detachment without proliferative vitreoretinopathy. Moreover, pigment and nonpigment epithelial cells were found to express HLA-DR and HLA-DQ determinants in six of the eight patients with proliferative vitreoretinopathy. Our results are similar to those obtained in a previous study on proliferative diabetic retinopathy, which suggests the involvement of autoimmune phenomena in proliferative diseases and eventual interactions between the immune system and peptide growth factors. However, whether or not this immune reaction functions in the initiation or extension of intraocular proliferative syndromes remains to be determined.

Complement System Proteins↗
PubMed1989

Application of Bayesian estimation for the prediction of an appropriate dosage regimen of amikacin.

A Bayesian approach was developed to determine an amikacin dosage regimen to achieve the desired plasma concentrations for each patient. Statistical characteristics of pharmacokinetic parameters were first evaluated in a group of patients (reference population), which when combined with three individual plasma concentrations of drug led to a Bayesian estimation of individual pharmacokinetic parameters. By using these parameters, an individual dosage regimen was then established to avoid residual and peak amikacin concentrations of up to 3 and 25 micrograms/mL, respectively. In a test group of 33 patients, adapted amikacin dosage regimens ranged from 4 to 43 mg/kg/d, with schedules requiring up to four infusions per day. Infusion time varied from 40 min to 4 h. These differences in drug administration protocol result from the wide interindividual variability of amikacin pharmacokinetic parameters. Performance of the developed methodology was evaluated by computing bias and precision of the estimated total body clearance and of the trough and peak amikacin concentrations that were reached after dosage regimen determinations.

Adolescent↗
PubMed1989

Human lymphocyte and myocardial beta-adrenoceptors: up and down regulation.

Radioreceptor assays have extended the knowledge of beta-adrenoceptor regulation. To evaluate the usefulness of this method in cardiovascular pharmacology, this study was designed to determine: (1) the correlation between beta-adrenoceptor density in human lymphocytes and myocardial cell membranes. This was achieved by using simultaneously harvested left auricles and whole blood samples in 10 patients scheduled to undergo cardiothoracic surgery. The correlation was found to be linear (r = 0.65; P less than 0.05; N = 10); (2) the changes in lymphocyte receptor density and affinity in heart failure. Lymphocytes were harvested from 6 healthy volunteers, 8 patients with moderate heart failure (NYHA class I or II) and 8 patients with severe heart failure (NYHA class III or IV). Mean densities observed were 75.6 +/- 11, 46.3 +/- 18 and 26.4 +/- 5.9 fmol/mg protein, respectively, and dissociation constants were 62.8 +/- 16; 67.8 +/- 14, and 46 +/- 26 pM. The number of receptors fell significantly from one heart failure class to that immediately above it (P less than 0.01; N = 22); (3) the beta-adrenoceptor regulatory properties of a class I antiarrhythmic drug, propafenone, the chemical structure of which is similar to that of the beta-blocking drug propranolol. Five patients needing antiarrhythmic treatment were given 10 d of oral propafenone treatment (450-900 mg/day). Mean adrenoceptor densities (Bmax) were 22.7 +/- 9 and 43.7 +/- 9 fmol/mg protein, and dissociation constants (KD) values were 24.7 +/- 20 and 27 +/- 18 pM respectively, before and after 10 d of chronic treatment. The number of receptors increased significantly after 10 d of treatment (P less than 0.01; N = 5).(ABSTRACT TRUNCATED AT 250 WORDS)

Down-Regulation↗
PubMed1989

Alpha2-adrenergic receptors in rat and rabbit eye: a tritium-sensitive film autoradiography.

Using a tritium-sensitive film and [3H]-clonidine, alpha 2-adrenergic receptors were localized in entire eye sections of rabbits and rats. This radioactive agonist specifically labelled three structures in albino animals: ocular muscles, ciliary processes and retina. In pigmented animals, uvea with melanin was intensively but nonspecifically labelled. Microscopic analysis of autoradiograms obtained with iris-ciliary bodies, revealed that the major localization of binding sites was in the ciliary process epithelium. In displacement studies, [3H]-clonidine binding was inhibited by alpha 2-adrenergic compounds while alpha 1- or beta-selective drugs had no inhibitory effects.

Adrenergic alpha-Agonists↗
PubMed1989

Pharmacokinetic and autoradiographic studies of basic fibroblast growth factor on de-epithelialized and intact rabbit eye.

In a previous work, we showed and compared the wound healing properties of aFGF and bFGF topically administered on totally de-epithelialized rabbit corneas. Pharmacokinetic and autoradiographic studies were then performed to investigate the sites of accumulation of bFGF in ocular structures, both on de-epithelialized and intact rabbit eyes. After one single instillation of 125I-bFGF, all the ocular structures were dissected and the measurement of the radioactivity allowed to establish kinetic curves. The results showed a very important and early fixation of bFGF on denuded cornea (10 minutes) and a posterior distribution of the drug between 10 and 30 minutes. A second accumulation of bFGF in the anterior segment appeared 8 hours after application and then decreased till the 48th hour. These findings were confirmed by the macroautoradiographies and the microautoradiographies pointed out the fixation of bFGF not only at the location of the Bowman membrane, but also on the corneal endothelium. These experiments also demonstrated the systemic diffusion of bFGF into the untreated controlateral eye. The integrity of bFGF in the cornea and other structures was then confirmed by SDS PAGE followed by autoradiography. In the intact eye, bFGF was shown to penetrate in extremely low amounts, illustrating the major role of the corneal barrier. For a therapeutic use bFGF may be recommended as an efficient wound healing agent for epithelial but also endothelial defects. Its eventual unwanted side effects must be kept in mind to perfect an efficient low dose and short term clinical treatment.

Animals↗
PubMed1989

Dopamine receptors in rabbit and rat eye: characterization and localization of DA1 and DA2 binding sites.

In vitro autoradiography is used to characterize and localize DA1 and DA2 receptors in rabbit and rat eyes. The bindings of 125I-SCH 23982 (DA1 antagonist) and of 125I-Iodosulpride (DA2 antagonist) to slide mounted tissue sections take place with characteristics expected of substances that recognize DA1 and DA2 receptors respectively. They are saturable, have high affinity and exhibit an appropriate pharmacology. The regional distribution of these receptors indicates that they are mainly present in retina. Precise cellular localizations are visualized in retinal structures by means of histoautoradiography: DA1 receptors are found in inner plexiform layer, outer plexiform layer and inner nuclear layer and DA2 binding sites are present in the two plexiform layers.

Animals↗