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J Robert

Publications and source records attributed to J Robert.

At least 361 records · Page 20Linked to original sources

[Pharmacokinetics of new anthracyclines].

Several new anthracyclines have been recently made available for clinical use or for clinical trials. Each molecule is characterized by original metabolic and pharmacokinetic features, which can be compared to those of the reference anthracyclines, doxorubicin and daunorubicin. Idarubicin is transformed into idarubicinol to a high extent, similarly to the transformation of daunorubicin to daunorubicinol, whereas the 13-dihydroderivatives of esorubicin, epirubicin or pirarubicin are present in plasma at lower levels than the parent drugs. Epirubicin is the only anthracycline able to form glucuronides, and pirarubicin can be transformed into doxorubicin itself. The elimination half-life of epirubicin or esorubicin is similar to that of doxorubicin (30 h) and the elimination half-life of unchanged idarubicin or pirarubicin is shorter (15-20 h). The novel anthracyclines have generally a higher plasma clearance than doxorubicin or daunorubicin, and a higher volume of distribution. Less than 10% of the injected dose of any anthracycline is found in urines, the major elimination pathway being the bile. The knowledge of anthracycline pharmacokinetics may allow the prediction of their behavior when special administrations are used (continuous infusion, locoregional therapy...).

Antibiotics, Antineoplastic↗

The remarkable specificity of a new transcription termination factor suggests that the mechanisms of termination and antitermination are similar.

E. coli lysogenic for the temperate, lambda-related phage HK022 do not support lambda growth. The exclusion of lambda is caused by the HK022 nun gene product, which blocks the expression of genes located downstream of and in the same transcription unit as the lambda nutL and nutR sequences. Transcripts terminating prematurely at or near nutR have been detected after inactivation of lambda repressor in lambda, HK022 dilysogens. Nun therefore appears to be a transcription termination factor with a remarkable specificity; it converts the lambda nut sequences, which normally interact with lambda N protein to suppress transcription termination, into terminators. These and other similarities between Nun-promoted termination and N-promoted antitermination argue strongly that the mechanisms of the two reactions have steps in common.

Bacteriophage lambda↗

Free fatty acid uptake is increased in doxorubicin-resistant rat glioblastoma cells.

We have investigated the mechanism by which the rat glioblastoma C6 cell line resistant to doxorubicin presented an increase of free fatty acid utilization from the nutrient source as compared to the wild sensitive strain. We have shown that this was not due to an accelerated turnover of the phospholipid hydrophobic or hydrophilic moieties, but to an important increase of the uptake of the free fatty acids. This was demonstrated by studies performed with linoleic and linolenic acids during very short incubations, at low temperatures, and in the absence of albumin in the medium. This enhancement of free fatty acid uptake may explain the differences which exist in the acyl group composition of membrane lipids between doxorubicin-sensitive and -resistant C6 cells, because of the suppression of the essential fatty acid-deficient status of the cells.

Acetates↗

Effects of tumor necrosis factor on tumor cell plasma membrane permeability.

Ehrlich ascites tumor cells incubated with rabbit tumor necrosis factor (TNF)-serum showed a temperature-dependent functional impairment of the plasma membrane as reflected by permeability changes. Trypan blue inclusion and Ca2+-transport were considerably increased at hyperthermia temperature. This characteristic of the TNF-plasma membrane interaction may explain the cytotoxicity of TNF.

Animals↗

Hepatic extraction, metabolism and biliary excretion of doxorubicin in the isolated perfused rat liver.

The hepatic extraction, metabolism, and biliary excretion of doxorubicin (DX) were studied in the isolated perfused rat liver. Three doses of DX equivalent to 2, 20, and 100 mg/kg in rats were studied over a period of 3 h after bolus injection into the reservoir. DX and metabolites concentration in perfusate, bile, and liver were determined by high-pressure liquid chromatography. The hepatic extraction ratio was low (less than 0.24) and decreased progressively over the 3 h. The hepatic extraction and clearance were significantly lower at the highest dose. Doxorubicinol (DX-OL) was the only metabolite detected in the perfusate, accounting for less than 4% of the total AUC. Thirty-one to thirty-three percent of the dose was excreted into bile over 3 h as unchanged DX. This was reduced to 22% at the highest dose. Only 0.35%-1.33% of the dose was excreted as DX-OL. DX aglycones were found only in the liver, where they represented 20%-30% of the total fluorescence at 3 h. In conclusion, in this model DX has a low extraction ratio, is poorly metabolized and extensively excreted into bile.

Animals↗

Pharmacokinetics of doxorubicin in sarcoma patients.

The pharmacokinetics of doxorubicin has been studied in 26 sarcoma patients receiving polychemotherapy. Mean elimination half-life was 34.7 +/- 16.6 h and the total plasma clearance was 29.5 +/- 9.31 X h-1 X m-2. No relationship was found between the pharmacokinetic parameters and the response to treatment, or its toxicity. Special attention was paid to the early-phase kinetics of the drug (3-20 min after injection). A correlation between the early clearance and the ages of the patients was observed. The early clearance was clearly correlated with the total plasma clearance measured over 48 h after injection, indicating the importance of the distribution phase in the overall kinetics of the drug.

Adolescent↗

Pharmacokinetics of idarubicin after daily intravenous administration in leukemic patients.

We have studied the plasma pharmacokinetics of idarubicin (4-demethoxy-daunorubicin) in eight leukemia patients receiving five daily i.v. injections (7-9 mg/m2 per day) of this new anthracycline. For unchanged idarubicin, similar pharmacokinetic parameters were exhibited after the 1st and the 5th injection. Idarubicinol (13-dihydroidarubicin) was identified as the only detectable metabolite of idarubicin in plasma. Due to a protracted half-life (40 h) this compound progressively accumulated in plasma without the occurrence of peaks after the injections. This administration schedule provides therefore an interesting method of dose fractionation of a new anthracycline.

Antibiotics, Antineoplastic↗

Continuous infusion or intravenous bolus: what is the rationale for doxorubicin administration?

In order to achieve a better therapeutic index of anticancer drugs, numerous authors are using continuous infusion therapy rather than classical intravenous bolus injection. In the case of doxorubicin or daunorubicin numerous experimental data have been published, which could provide a rationale to this clinical problem. However, due to the variety of the approaches used, the results are inconsistent and no definitive conclusion can be drawn. Several clinical phase I and II trials have been performed since 1980; they show that the toxicity of doxorubicin may be reduced by the use of continuous infusion, but the preservation of the efficacy of the drug has never been proved. Comparative phase III trials are required before this schedule of administration become routine procedure for this drug.

Animals↗

Results of planned in-vitro fertilization programming through the pre-administration of the oestrogen-progesterone combined pill.

The use of an oestrogen-progesterone combined pill permits the induction of ovulation in the absence of any developing follicle. Two treatments were compared. In the first, patients received no prior treatment before stimulation. In the second, combined oestrogen-progesterone treatment was given during approximately two menstrual cycles prior to stimulation. No differences between the two groups were found in relation to oocyte maturity, fertilization in vitro, cleavage, replacement and pregnancy. Fewer luteinizing hormone surges occurred in patients pre-treated with steroids. The utilization of the oestrogen-progesterone combined pill prior to induction of ovulation facilitates the forward planning of patients for in-vitro fertilization.

Clomiphene↗

[Current role of radionuclide imaging in pediatric cardiology].

Three main nuclear medicine methods are used in paediatric cardiology: sequential first-pass radionuclide imaging of the cardiac cavities, radionuclide equilibrium ventriculography and radionuclide myocardial imaging. Valuable functional information is obtained, and invasive explorations can be avoided in an ever increasing number of cases. Of particular interest is left-to-right shunt measurement which indicates that atrial septal defects must be surgically corrected when the pulmonary/systemic flows ratio (QP/QS) is above 2. This technique is also useful to evaluate the tightness of repairs in ventricular and atrial septal defects. Radionuclide studies of the right and left ventricles may detect dysfunction in one or the other cavity. The left ventricular ejection fraction is reduced in myocardiopathy an in aortic or mitral valve diseases seen at a late stage. The right ventricular function is often abnormal, notably during exercise, after repair of the tetralogy of Fallot and after atrial correction of complete transposition of the great arteries. An altered ejection fraction in patients with single ventricle is also a sign of deterioration. Right ventricular diastolic overload evaluated by radionuclide equilibrium ventriculography correlates with the QP/QS ratio value in atrial septal defects and with the inducibility of ventricular tachycardia by endocavitary pacing in repaired tetralogy of Fallot. Thallium 201 myocardial imaging provides information on myocardial ischaemia, notably that associated with congenital abnormalities of the coronary arteries. Its use had now been extended, albeit with some limitations, to the evaluation of right ventricular systolic overload. Other radionuclide techniques are being developed with new tracers: Kryton 81m for studies of the right ventricle, short-lived radionuclides for first-pass studies, Iodine 123-labelled fatty acids for myocardial imaging. More recently, some substrates, such as deoxyglucose, have been labelled with positron emitters permitting in vivo metabolic studies.

Cardiac Output↗

Effects of concanavalin A on 67Ga binding by tumor cells.

The in vitro uptakes of 67Ga-citrate and 45Ca-chloride in the presence of concanavalin A have shown that at low concentrations (10-50 micrograms/ml) 67Ga presents a significant increase not observed for 45Ca. At higher concentrations there is a sharp augmentation of both 67Ga and 45Ca incorporations. The augmentation of Trypan blue inclusion is a concomitant phenomenon at any concanavalin A concentration that indicates tumor cell plasma membrane changes in direct relationship with 67Ga uptake increase.

Animals↗

[Treatment of soft tissue sarcomas in the adult with a combination of vindesine and cisplatin with doxorubicin or epirubicin: a pilot study].

Twenty-five adult patients, 15 men and 10 women, with a median age of 49, and presenting with metastatic or locally advanced soft tissue sarcomas, have been treated with chemotherapy protocol combining cisplatinum, 100 mg/m2, vindesine, 4 mg/m2, and either adriamycin, 50 mg/m2 (APEL) (16 patients), or epirubicin, 100 mg/m2 (EPEL) (9 patients). The overall toxicity was high, with hematologic, digestive and renal side effects, leading to stop the treatment in 5/25 patients, and to reduce drugs dosage by greater than or equal to 25% in nearly half of the patients. A tumor response (tumor regression of greater than or equal to 50%) was observed in 9/25 patients (36%), including one histologically confirmed complete regression. Among 16 patients presenting with pain, a complete relief was obtained in 7. Thus, APEL/EPEL produced a response rate which compared with that obtained with CYVADIC regimen, but the toxicity of these regimens was higher leading us to stop these protocols. Others associations should be developed. In that regards, epirubicin may be considered as doses as high as 100 mg/m2, was tolerated as 50 mg/m2 of adriamycin, and produced a response in 5 over 9 patients treated.

Adult↗

[Pharmacokinetics and metabolism of anthracyclines in man].

Although they differ only slightly from each other, the various anthracyclines have their own metabolic pathways and pharmacokinetic parameters. Doxorubicin and daunorubicin have a similar reduced metabolite which reaches low plasma levels in the case of doxorubicin, but is predominant in the case of daunorubicin: daunorubicinol. Aglycones are only formed in large quantities from aclarubicin: aklavinone. The plasma decay of doxorubicin levels is triphasic, with successive half-lives of 5 min, 1 h and 30 h. Unchanged daunorubicin is eliminated more rapidly from plasma, but its metabolite is eliminated more slowly. New anthracyclines such as pirarubicin are characterized by a large volume of distribution, suggesting a higher tissue fixation. These pharmacokinetic data must be kept in mind for the design of new protocols which are aimed to dose fractionation or tumor targetting.

Antibiotics, Antineoplastic↗

Effects of hyperthermia and lanthanum on tumor cell leakage.

The effects of hyperthermia temperature and the presence of lanthanum on the release of Ehrlich's ascites cell molecules labelled with radiophosphorus have been studied. The leakage of intracellular molecules is in relationship with the temperature and the time of incubation. The phenomenon presents the characteristics of an increased passive diffusion induced by a thermotropic modification of the protein-lipid environment of the plasma membrane. The possible implication of this phenomenon on hyperthermic energy depletion and enhanced cytotoxicity of chemotherapeutics with poor cell penetration is discussed.

Animals↗

Risk of preangioplasty occlusion and myocardial infarction in one-vessel-disease patients scheduled for percutaneous transluminal coronary angioplasty.

Coronary occlusion or myocardial infarction occurred in 50 of 394 (13%) one-vessel-disease patients awaiting percutaneous transluminal coronary angioplasty (PTCA). To identify risk factors for these events, we first matched the 37 patients who demonstrated occlusion on the immediate preangioplasty repeat angiogram with 37 patients who did not. Matching was based on the time interval between angiograms, the date of the procedure, and the site of the lesion. Preangioplasty occlusion patients did differ from controls by age (47 +/- 11 vs 54 +/- 8 years, P less than .01), smoking status (34/37 vs 24/37, P less than .01), and angina class (2.6 +/- 1.0 vs 2.3 +/- 0.7, P less than .10) at the time of the first angiogram. Second, we pooled the data of the 37 preangioplasty occlusion patients with those of the 13 patients with preangioplasty myocardial infarction. The 50 cases with complication (coronary occlusion or myocardial infarction) were younger (47 +/- 12 vs 54 +/- 8 years, P less than .01), more often smokers (42/50 vs 24/37, P less than .05), and more symptomatic (2.7 +/- 0.8 vs 2.3 +/- 0.7, P less than .05) than the 37 controls. This study suggests that young smokers with severe angina are at high risk of preangioplasty occlusion and/or myocardial infarction; prompt management of these patients, when considered for PTCA, seems advisable.

Angiography↗