Biomedical subjects

O Petitjean

Publications and source records attributed to O Petitjean.

69 records · Page 4Linked to original sources

PubMed1989

[Pharmacokinetic interaction of cefixime and 2 antacids. Preliminary results].

A crossover study was undertaken in 8 healthy volunteers to evaluate the pharmacokinetics of cefixime administered orally alone or combined with an antacid. Each subject received successively: cefixime alone, Maalox followed 30 min later by cefixime, then Maalox followed 4 hours later by cefixime and finally Alka-Seltzer followed 30 min later by cefixime. Sixteen blood samples were drawn from 0 to 24 hours after oral administration, and plasma cefixime parameters were determined, using a HPLC assay. Four parameters were used to detect a possible interaction: Cmax, Tmax, AUCO-N and AUCO-alpha. No significant difference was observed between the four parameters. Thus, poor absorption of cefixime when combined with an antacid can be ruled out.

Adult↗

PubMed1989

The systemic availability of meptazinol in man after oral and rectal doses.

We have studied the pharmacokinetics of the centrally-acting analgesic meptazinol after oral and rectal administration to 15 healthy men. Each subject took a standard 200 mg tablet orally and Witepsol H12 suppositories containing 75, 100, and 150 mg of the drug in a cross-over design. Meptazinol plasma concentrations were measured by HPLC using fluorescence detection and the pharmacokinetics determined. The tmax values for the 100 mg and 150 mg suppositories (median = 0.5 h) were statistically significantly shorter than for the tablet (median = 1.13 h), suggesting that meptazinol was more rapidly absorbed via the rectal route. Despite substantial intersubject variation in Cmax the plasma concentrations after rectal dosage were higher than after oral administration. There was a statistically significant (p less than 0.001) improvement in systemic availability for each of the suppository doses (mean approximately 15.5% compared with the oral tablet (mean approximately 4.5%).

Administration, Oral↗

PubMed1988

Effective high-performance liquid chromatographic determination of glafenine in plasma: pharmacokinetic application.

A high-performance liquid chromatographic method for an effective determination of glafenine and its main metabolite, glafenic acid, is described. The assay involves separate extraction procedures for glafenine and for its metabolite, but the same internal standard (floctafenine) and the same chromatographic conditions (including a 5-micron C8 column, a quaternary solvent mixture of water-acetonitrile-diethylamine-acetic acid and an ultraviolet detector set at 360 nm). For 1 ml of plasma, the detection limit is 0.05 mg/l for glafenine and 0.25 mg/l for glafenic acid. Compared with previously described techniques, this assay uses a very low glafenine linearity range, which allows the true pharmacokinetics of this drug to be described for the first time.

Chromatography, High Pressure Liquid↗

PubMed1988

Pharmacokinetics of paracetamol, diclofenac and vidarabine during plasma exchange.

In order to establish guidelines for prescribing drugs in patients treated with plasma exchange (PE), we studied the pharmacokinetics of paracetamol (5 patients), diclofenac (4 patients) and vidarabine (3 patients) during one or several PE. Results were compared with those obtained without PE. Diclofenac and paracetamol were chosen because they presented different volume distribution and protein binding characteristics. Vidarabine was studied because we use it for the treatment of patients with polyarteritis nodosa related to hepatitis B virus. Diclofenac (100 mg) and paracetamol (1000 mg) were given 1 hour before PE. Samples were obtained 60 and 30 min before PE, every 15 min during PE and hourly for 2 hours after the end of PE. Vidarabine was given in continuous infusion, 15 mg/kg/d during the first week of treatment and 7.5 mg/kg/d during subsequent weeks. Samples were obtained before PE, 3 times during PE and every 30 min for 4 hours after the end of PE. Paracetamol, diclofenac, vidarabine and hypoxanthine arabinoside were assayed by high performance liquid chromatography. During each PE 60 ml/kg were removed and replaced by albumin. We found that 17% of diclofenac, 4.3% of paracetamol and 4.9% of vidarabine were removed during each session. Plasmapheresis clearance was 51% of plasma clearance for diclofenac, 15% for paracetamol and 10% for vidarabine. Drugs which are mainly removed during PE are those which are bound to proteins with a small distribution volume. Those drugs, such as diclofenac, must be administered after the end of each PE session. Drugs which present a large distribution volume and low protein binding can be given before the session. Vidarabine can be administered during PE without loss of effectiveness due to drug removal.

Acetaminophen↗

PubMed1986

Improved determination of sulpiride in plasma by ion-pair liquid chromatography with fluorescence detection.

A specific and sensitive high-performance liquid chromatographic method for the measurement of sulpiride in plasma is described. The internal standard used was veralipride, a structurally related substituted benzamide. A fluorescence detector with maximum excitation at 300 nm and maximum emission at 365 nm was used for quantitation. After an alkaline extraction procedure, the benzamides were separated on a 5-micron ODS column using a large organic counter ion in the mobile phase. The detector response was linear from 10 to 1000 ng/ml and the detection limit was 10 ng/ml, which is sensitive enough for pharmacokinetic studies. The suitability of the method for the analysis of biological samples was tested by studying the variation with time of plasma concentrations of sulpiride in normal human volunteers after a single therapeutic 200-mg oral dose of three different formulations of sulpiride.

Chromatography, High Pressure Liquid↗

PubMed1985

[Primary hemostatic disorders caused by beta-lactams. Apropos of a postoperative hemorrhagic complication during treatment with cephalexin].

The authors report a case of haemorrhage due to cephalexin therapy. The bleeding started after an orthopedic operation in a patient without renal failure, receiving 3 g/day of cephalexin. Platelet function was very abnormal at the time of the haemorrhage with a bleeding time of over 20 minutes, which returned to normal when treatment was stopped. This case seems to be similar to other reports of haemorrhages during treatment with other beta-lactams.

Aged↗

PubMed1983

[Pulmonary diffusion of gentamicin administered by the direct intravenous route].

Gentamicin diffusion in pulmonary parenchyma was studied in 10 adult patients with normal renal functions before undergoing thoracic surgery. This aminoside was given in a one time dose of 120 mg directly and by way of IV route in 10 min time; blood samples from peripheral and pulmonary sources were drawn at regular intervals between the 10 min period and the 8th hr; parenchymal samples were collected 1 and 2 hrs after drug administration. After separation of residual blood by centrifugation at high speed, the tissues are grinded and homogenized. The assay was performed with an immunological method using a fluorescent polarized detection system. Tissue levels were low in all the patients (0.5 to 2.75 micrograms/g of fresh tissue) and this in spite of the high level of blood collected throughout the administration protocol. As a rule, the relation between tissue/blood is lower than those discussed in literature concerning bronchial secretion. Beside this, the concentrations are similar in peripheral and pulmonary blood collected. Practical conclusions are drawn for therapeutic purpose.

Gentamicins↗

PubMed1983

[Pharmacokinetics of gentamicin in the decompensed alcoholic cirrhotic patient. Therapeutic consequences].

Aminoglycosides and in particular gentamicin are still largely used in the treatment of spontaneous bacterial peritonitis in the decompensed alcoholic cirrhotic patient. For that matter, we decided to study the various passage of gentamicin in the ascites after its administration through IM injection (80 mg in 6 patients and 120 mg in 6 other patients) and through IV injection (120 mg in 6 other patients). What could possibly be the best protocol to replace the daily intraperitoneal injections? We found out that no matter what the style of injection is, the peritoneal levels are only exceptionnaly higher than 3 mg/g at the highest peak period. These results brought us to analyze the passage of gentamicin in the blood when injected intraperitonealy (160 mg in 6 patients), and then to propose a therapeutic protocol combining on the first day, to the peritoneal injection a loading dose of an IP injection of 160 mg, the relay been taken over later with a peritoneal injection of 80 or 120 mg repeated 2 or 3 times daily. For each of the protocol the pharmacokinetic coefficients of gentamicin were calculated.

Bacterial Infections↗

PubMedDate not supplied

Diclofenac, paracetamol, and vidarabine removal during plasma exchange in polyarteritis nodosa patients.

Since plasma exchange (PE) represents a major treatment for patients suffering from systemic diseases, its influence on the kinetics of three drugs was investigated: vidarabine, used in patients with polyarteritis nodosa associated with hepatitis B virus (eight subjects), and diclofenac and paracetamol for investigative purposes (five subjects). This study confirmed that vidarabine is so rapidly deaminated to form hypoxanthine arabinoside (Hx-Ara) that no detectable concentrations were measured. Hx-Ara levels were used to evaluate vidarabine kinetics; 19.5 +/- 14.6 mg of Hx-Ara were removed by one PE during the first week of treatment (15 mg kg-1 d-1, continuous infusion) and 7.8 +/- 10.2 mg were eliminated by one PE during the second week of treatment (7.5 mg kg-1 d-1, continuous infusion). Based on the vidarabine intake per hour and the resulting quantity of Hx-Ara removed per hour, PE recovery was quite important (ca. 30 per cent), during both the first and second weeks of continuous infusion. Data were subject to large interindividual variability. However, these results do not favor vidarabine dosage supplementation in this indication because the duration of PE is less than 8 per cent of a daily administration period. For paracetamol (1 g, single oral dose) and diclofenac (100 mg, single oral dose), the fractions of drug removed during PE effected within 2 h of drug intake, were respectively 5.0 +/- 3.1 per cent and 13.6 +/- 9.5 per cent, while plasmapheretic clearance reached, respectively, 13.0 +/- 10.7 per cent of the systemic clearance for paracetamol and 23.0 +/- 1.0 per cent for diclofenac.

Acetaminophen↗

PubMedDate not supplied

Influence of renal function on the pharmacokinetics of diacerein after a single oral dose.

The pharmacokinetics of diacetylrhein following a single oral dose of 50 mg was studied in 12 healthy volunteers and two groups of 8 patients with mild or severe renal insufficiency. Statistical analysis using a Kruskal-Wallis rank sum test showed a significant difference between the three groups for the following parameters. In severely uraemic patients, median AUC0-infinity was multiplied by a factor of about 2: 40.5 mg.h/l versus 21.3 mg.h/l in healthy subjects, P = 0.04; and t1/2 was prolonged by the same factor: 9.6 h versus 4.3 h in the control group, P = 0.003. Apparent drug availability and renal clearance assessed through urinary data decreased with renal failure, respectively: 14.5% and 0.045 l/h versus 35.4% (P = 0.01) and 0.13 l/h (P = 0.008) in healthy subjects. Amounts of glucuro- and sulpho-conjugates in urine were lower in severely uraemic patients. Intermediate values were observed for mildly uraemic patients. Other parameters: lag time, Cmax, tmax, Vss/F, urinary glucuro- to sulpho-conjugate ratios did not change significantly. Apparent total clearance of rhein was poorly correlated with creatinine clearance and this was related to a decrease of non-renal clearance of rhein in renal insufficiency. It was concluded that, from a pharmacokinetic point of view, a reduction (50%) in the initial dosage of diacerein should be considered in severe renal failure.

Adult↗

PubMedDate not supplied

Clinical pharmacokinetics during plasma exchange.

Drug removal during plasma exchange (PE) is a complex phenomenon that is defined by the molecule pharmacokinetic characteristics. Plasma-protein binding and the volume of distribution (Vd) are two kinetic parameters that strongly affect the efficiency of drug removal by PE. The effect of PE on drug kinetics has been specifically studied with antivirals, cardiotonic agents, antibiotics, corticosteroids, antalgics, anti-epileptic agents and non-steroidal anti-inflammatory drugs. This effect can be evaluated using different parameters: extracorporeal clearance, half-life, amount eliminated, and fraction of the drug removed. The estimated fraction eliminated (Fe) from the body by PE is the best parameter to evaluate the effectiveness of the exchange procedure; it can account for 0.5-30 per cent. Results reported in the literature showed that PE most influences drugs with a low Vd, regardless of the extent of protein binding. We established that, during PE, there is a linear relationship between Fe and the fraction of the drug in extracellular fluids. The fraction eliminated during PE is approximately one-seventh of the fraction of the drug in extracellular fluids. We propose to use this extracellular fraction as a predictive index: when < 20, extraction is low; the amount eliminated becomes consequential only when the index > 20. Dosage supplementation may be needed to maintain an adequate drug concentration in the body. Practically, for drugs with a low Vd (< 0.3 l/kg), it seems necessary to adjust the dosage.

Algorithms↗

PubMedDate not supplied

[Extraction of drugs in plasma exchange].

Plasma exchange has been proposed for treating diseases mediated by circulating immune complexes. Removal of drugs during plasma exchange is a complex function of pharmacokinetic characteristics and specifications of the plasma exchange procedure: the time of plasma exchange, the filtered volume of plasma, the number of procedure. The effect of plasma exchange on the kinetics of drugs can be evaluated by different parameters: amount eliminated, extracorporeal clearance, fractional drug removal, extracorporeal elimination rate constant. Knowledge of the impact of plasma on the elimination of drugs is essential to the design of the dosage regimen in patients treated with plasma exchange. The fraction of the estimated amount in body removed by plasma exchange is the best parameter to evaluate the effectiveness of the exchange procedure, but it is necessary to know the proportion of body pool of drug at the start of the plasma exchange. Drug recovery by each exchange may account for 0.5%-30% of the dose. Controlled studies are needed to quantify the effects of plasma exchange on drug therapy. Dosage adjustment is sometimes required.

Humans↗

PubMedDate not supplied

Cellular localisations of interleukin-1 beta, interleukin-6 and tumor necrosis factor-alpha mRNA in a parasitic granulomatous disease of the liver, alveolar echinococcosis.

Alveolar echinococcosis (AE), an uncommon and very severe parasitic liver disease, can be considered as an "infectious model" of granulomatous disease, where cellular immunity plays a key role in the defence against Echinococcus multilocularis, the larval cestode responsible for the disease. We analysed the localisation of the expression of the pro-inflammatory cytokines IL-1 beta, IL-6 and TNF-alpha mRNA in human AE liver lesions, in the periparasitic granulomas and in the hepatic parenchyma, as well as the phenotypic characteristics of the cells on serial sections. In situ hybridizations, using anti-sense 35S dUTP-labeled IL-1 beta, IL-6 and TNF-alpha riboprobes, were performed on cryostat liver sections; the sense probes were used as negative controls. IL-1 beta, IL-6 and TNF-alpha mRNA were observed in macrophages located at the extreme periphery of the granuloma, between the lymphocytic ring and the liver parenchyma, in patients with active AE. No cytokine mRNA expression was observed in a patient with an abortive case. Only TNF-alpha mRNA was located in the periparasitic area, in cells morphologically identified as macrophages but exhibiting an unusual phenotype (CD 11b-, CD 25+); this particular expression was observed only in those patients with very fertile lesions, associated with centro-granulomatous necrosis. These results show that pro-inflammatory cytokines are consistently produced by macrophages at the periphery of the periparasitic granuloma and can serve as mediators of acute-phase protein secretion and of fibrogenesis in that location.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMedDate not supplied

[Review and use of decision rules for bioequivalence trials].

To declare bioequivalent two different formulations of one active drug, bioavailability studies are conducted, usually based on area under the plasma concentration-time curves and peak concentrations. The decision follows a statistical basis with right statement of the hypotheses of bioequivalence that are described. This procedure allows to control the consumer risk of falsely accepting bioequivalence while minimizing the new formulation risk of erroneously rejecting bioequivalence. Six decision rules meeting these criteria are reviewed and compared with numerical data: classic confidence interval; symmetric confidence interval; Hauck-Anderson method; two one-sided tests procedure; bayesian method; non parametric confidence interval. The six rules all have very similar performance. However, the bayesian procedure which gives a probability of the location of the true relative bioavailability could likely complete the two one-sided tests procedure and/or the classic confidence interval method that are recommended in regulatory guidelines. Some other statistical points that have received different interpretation in the international regulations are finally evoked and discussed.

Biological Availability↗

PubMedDate not supplied

[Value of the theory of the optimal sampling scheme for bioequivalence studies].

Use of optimal sampling theory (OST) in pharmacokinetic studies allows a large reduction of the number of sampling times without loss in parameter estimation precision. OST has been applied to the determination of bioavailability parameters [area under the curve (AUC), maximal concentration (Cmax), time to reach maximal concentration, (Tmax)]. Three different Monte-Carlo simulations in twelve subjects have been performed, corresponding to different pharmacokinetic models: one-compartment with or without a lag time, two-compartment. Bioavailability parameters were estimated using a non-compartmental method (with 12 to 16 sampling times) and OST method (6 to 7 sampling times). Estimates were compared with true values. Bias and RMSE were similar with both methods for AUC and Cmax, while Tmax was better estimated using OST method. However, when a posteriori identifiability of the model was poor, use of a maximum a posteriori Bayesian estimator improved considerably the efficacy of OST method. Potential interest of OST for increasing statistical power of bioequivalence studies at the same cost is discussed, as well as possible limitations.

Biological Availability↗