Use of pharmacokinetic-pharmacodynamic relationships in the development of new anthracyclines.
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Antibiotics, Antineoplastic↗
Biomedical subjects
J Robert
Publications and source records attributed to J Robert.
Pharmacological and molecular characterization of intrinsic and acquired doxorubicin resistance in murine tumor cell lines.
We have studied the pharmacological parameters of doxorubicin resistance in three lines of murine cells selected by long-term culture in the presence of this drug or vincristine. A line originating from rat hepatoma spontaneously presented an intrinsic doxorubicin resistance as compared to the other lines, originating from a rat glioblastoma and from simian-virus-40-transformed mouse hepatocytes. This intrinsic resistance, as well as the doxorubicin resistance exhibited by the vincristine-selected glioblastoma variant, could be entirely attribute to decreased drug accumulation due to drug efflux. In contrast, the doxorubicin-selected variants of the three lines exhibited an intracellular tolerance to this drug. Despite a reduction in drug accumulation when exposed to the same amount of doxorubicin, they accumulated 6-12 times more doxorubicin than wild lines when submitted to equitoxic exposures. Verapamil could restore in these lines the doxorubicin accumulation observed in sensitive lines but could not restore doxorubicin cytotoxicity. Quantitative evaluation of P-glycoprotein expression by Western blotting with the C219 antibody indicated that the wild hepatoma line overexpressed P-glycoprotein by a factor of 5 in comparison with the other wild lines, and that the vincristine-selected glioblastoma variant overexpressed this protein almost as much as the doxorubicin-selected variants. These observations favor the existence of P-glycoprotein-independent mechanisms of doxorubicin resistance, which are added to the classical multidrug-resistant phenotype in doxorubicin-selected highly resistant variant cell lines.
ATP Binding Cassette Transporter, Subfamily B, Mem↗
Expression of P-glycoprotein and anionic glutathione S-transferase genes in non-Hodgkin's lymphoma.
Non-Hodgkin's lymphomas (NHL) are usually sensitive to chemotherapy. A certain percentage of patients are primarily or subsequently resistant to chemotherapeutic agents. Several biological mechanisms are implicated in this phenomenon, including multidrug resistance (mdr1) and glutathione S-transferase (GST pi). We investigated these two systems, using dot blot analysis, in 41 patients who presented NHL with advanced disease. There were 15 patients with low grade, 22 with intermediate grade, and 4 patients with high grade using the Working Formulation for Clinical Usage. Twenty-five patients had not been previously treated and 16 had been treated, including 13 with refractory disease. Eleven out of 25 (44%) patients overexpressed mdr1 mRNA at diagnosis as compared to 6/16 (38%) in relapse, corresponding to 6/13 (46%) refractory patients. Nine out of 25 (36%) patients overexpressed GST pi mRNA at the time of diagnosis, and 6/16 (50%) in relapse. These data indicate that overexpression of these two messengers is not acquired after treatment in NHL. Furthermore, there is no relationship between the stage or histological grade and the overexpression of these two markers. This study shows that mdr1 and GST pi gene expressions are independent of one another. With regard to the clinical response, our results also demonstrated a higher level of treatment failure in the group co-expressing the two transcripts, 6/8 (75%) patients died in progressive disease as compared to 9/15 (60%) patients without overexpression, and 2/8 (25%) vs 6/15 (40%) responded to treatment. On the other hand, overexpression of only one of the two mRNAs did not allow us to observe a difference in the clinical response. Since it seems that coexpression of the mechanisms of resistance present a better clinical impact, it would be of interest to analyse simultaneously different mechanisms involved in the resistance phenomenon in NHL.
ATP Binding Cassette Transporter, Subfamily B, Mem↗
Reversal of multidrug resistance by a new lipophilic cationic molecule, S9788. Comparison with 11 other MDR-modulating agents in a model of doxorubicin-resistant rat glioblastoma cells.
We have compared the properties of the novel multidrug resistance modulator, S9788, to a panel of 11 well-known modulators in a model of rat glioblastoma cells resistant to doxorubicin and displaying a P-glycoprotein-mediated multidrug-resistance phenotype complemented by a mechanism of intracellular drug tolerance not yet identified (Br J Cancer 1992, 65, 538-544). S9788, like most modulators, was able to completely restore drug accumulation in the resistant line to the level obtained in the sensitive cells. This was obtained with 10 mumol/l of modulator, which is slightly higher than required for cyclosporine A (3 mumol/l) verapamil and nicardipine (6 mumol/l), but lower than for amiodarone, trifluoperazine and dipyridamole (20 mumol/l), tamoxifen and diltiazem (40 mumol/l), quinine, quinidine and nifedipine (> 100 mumol/l). Complete restoration of drug cytotoxicity was, however, obtained only with amiodarone, and a residual resistance factor of 4 could not be overcome by cyclosporine A or S9788, while other modulators gave residual resistance factors of 5-20 (trifluoperazine, tamoxifen, verapamil, quinine, nicardipine, dipyridamole) or even higher (diltiazem, quinidine, nifedipine). When studying doxorubicin accumulation obtained for an exposure to the IC50 of this drug, it appeared that some modulators were able to decrease this "intracellular IC50" independently of their efficiency in resistance reversal (cyclosporine A, S9788, amiodarone, trifluoperazine, quinine, tamoxifen), thus reversing intracellular drug tolerance, whereas other modulators could not reduce this parameter (verapamil, nicardipine, dipyridamole, diltiazem, quinidine). It is suggested that drugs of the first group could be able to segregate doxorubicin in subcellular compartments from which it could not reach its nuclear targets.
Animals↗
Expression of MDR1/P glycoprotein in human sarcomas.
Conflicting reports of MDR1 gene expression in human tumours are observed according to whether studies are performed at the mRNA or P-glycoprotein level. We have investigated this expression in 22 clinically drug-resistant sarcomas at the mRNA level by Northern blot (NB), Dot blot (DB), in situ hybridisation (ISH), and at the protein level by immunohistochemistry (IHC) using three monoclonal antibodies (MoAbs): C219, JSB1, MRK16. Increased MDR1 mRNA expression was detected by NB, DB, and ISH in 1/22 sarcoma (an Ewing's sarcoma). ISH was perfectly correlated with DB hybridisation and confirmed the expression of tumoral cells alone. Specific staining of 100% of tumoral cells was obtained with the three MoAbs in the same sarcoma. Expression in tumoral cells of 12 other sarcomas was detected with MRK16, and positive staining of stromal cells with both C219 (1/22) and MRK16 (8/22) was observed. This study confirms that MDR1 overexpression occurs in human sarcomas but is not the principal mechanism of drug-resistance. Furthermore, positivity with one antibody does not necessarily imply the presence of P glycoprotein (P-gp) and a disparity may exist between the levels of P-gp and its mRNA in the same sample. So care must be taken in interpreting results and more sensitive techniques such as the polymerase chain reaction (PCR) could prove useful.
ATP Binding Cassette Transporter, Subfamily B, Mem↗
Pharmacodynamics of antibiotics in fibrin clots.
Fibrin is an integral component of intravascular thrombus, surgical wounds, haematomas, vegetations and foreign bodies which predispose to infection. The tropism that many pathogens have for fibrin may favour bacterial growth and lead to infection. To improve our understanding of the pharmacodynamic interaction between antibiotics and pathogens infecting fibrin clots, this review will: define the role of fibrin as a protective environment for microorganisms; give an historical perspective of in-vitro and in-vivo fibrin clots; describe the pharmacodynamic model of infected fibrin clots; review pharmacodynamic determinants of outcome; and discuss intramicrobial pharmacokinetics. Fibrin clots are hard to penetrate following antibiotic administration and there is a major gradient of concentration from the surface to the core of the clots which has great influence on bacterial growth and lysis. Resistance can develop and morphological and structural changes in bacteria may vary within the different regions of the clot.
Animals↗
Clinical pharmacokinetics of idarubicin.
Idarubicin (4-demethoxy-daunorubicin) is a new commercially available anthracycline antibiotic which is more active than daunorubicin, the accepted reference drug, in the treatment of acute myelogenous leukaemia, which generally involves the combination of an anthracycline and cytarabine [corrected]. It is characterised by metabolic transformation into a 13-dihydro derivative, idarubicinol, which is as active as the parent drug in in vitro models. The pharmacokinetics of idarubicin follow a 2- or 3-compartment plasma disappearance with half-life (t1/2) values of 13 min, 2.4h and 16h, clearance approximately 60 L/h/m2 and volume of distribution at steady-state of 1,500 L/m2. Idarubicinol is characterised by a very long elimination t1/2 of 55h. The ratio of metabolite: parent drug area under the plasma concentration-time curve is often > 2 and is even higher after 2 or 3 daily injections of the drug, the normal drug protocol used in induction or consolidation treatments of acute leukaemias. Idarubicin can also be administered orally and the pharmacokinetics are similar to those after intravenous administration, except that the idarubicinol: idarubicin ratio is increased, probably due to a liver first-pass effect. The bioavailability of idarubicin is 20 to 25%, but if the activity of idarubicinol is taken into account, it is effectively about 40%. After idarubicin administration by either route, there is a progressive accumulation of idarubicinol after multiple once-daily but not after once-weekly doses. About 10% of the injected dose is recovered in urine as idarubicin and idarubicinol, and only slightly higher proportions are recovered in bile. This suggests that other unidentified metabolites must be excreted by either or by both pathways.
Animals↗
Epirubicin. Clinical pharmacology and dose-effect relationship.
The pharmacokinetic properties of epirubicin are characterised by a triphasic plasma clearance, with half-lives for the initial (alpha), intermediate (beta) and terminal (gamma) elimination phases of approximately 3 minutes, 1 hour and 30 hours, respectively. These values are similar to or slightly shorter than the corresponding half-lives of doxorubicin. The total plasma clearance of epirubicin is approximately 50 L/h/m2, which is almost 2-fold higher than that of doxorubicin. This difference is mainly due to the relatively high volume of distribution of epirubicin, and the unique glucuronidation metabolic pathway of epirubicin and epirubicinol, which is not available to doxorubicin or doxorubicinol. Glucuronide metabolites of epirubicin and epirubicinol are not active per se, but could divert epirubicin from free radical formation, which may induce cardiotoxic effects. This may explain, at least in part, the lower cardiotoxicity of this new anthracycline relative to that of the parent compound. There is a linear relationship between the dose administered and area under the plasma concentration-time curve (AUC) values of both unchanged drug and metabolites, so that the total plasma clearance of epirubicin is constant with epirubicin doses ranging from 40 to 140 mg/m2. No variation in total plasma clearance as a function of age in the range of 31 to 74 years has been observed, and this parameter is unaffected by subsequent courses of treatment. Hepatic dysfunction causes an increase in the terminal elimination half-life of epirubicin, which is well correlated with serum bilirubin levels and which necessitates a reduction in epirubicin dosage. Epirubicin is responsible for a dose-dependent neutropenia, which is clearly related to drug exposure as established in pharmacodynamic studies. The maximum tolerated dose (MTD) of epirubicin was first established to be approximately 90 mg/m2 but this was re-examined recently and is now deemed to be approximately 150 mg/m2, which is about 2-fold higher than the MTD of doxorubicin. Cumulative cardiac toxicity occurs for both epirubicin and doxorubicin, but the dose ratio for equal risk is about 1.8 in favour of epirubicin (500 to 550 mg/m2 for doxorubicin vs 900 to 1000 mg/m2 for epirubicin). Consequently, there is not a higher risk of developing cardiotoxicity after administration of high dose epirubicin, since this adverse effect is associated with total cumulative anthracycline dose. In several controlled trials, epirubicin exhibited the same anticancer activity as doxorubicin when administered at equimolar doses to patients with advanced breast cancer.(ABSTRACT TRUNCATED AT 400 WORDS)
Breast Neoplasms↗
Acute segmental arterioportal shunt with reversal of portal blood flow after atypical resection for hepatic injury.
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Accidents, Traffic↗
Pharmacokinetics and metabolism of anthracyclines.
The anthracycline antibiotics constitute a major series of anti-cancer drugs, the best known and most widely used being doxorubicin. Among hundreds of analogues, only a few have reached routine clinical use. Their main metabolic feature is the reduction of a ketone group to an hydroxyl group, giving an -ol derivative generally less active than the parent compound. Anthracyclines are characterized by a rapid distribution phase and a slow elimination phase. The successive half-lives of doxorubicin in plasma are about 5 minutes, 1 hour and 30 hours. Its total plasma clearance is about 30 l/hr/m2, and its total volume of distribution at steady state is approximately 15 l/kg. Anthracyclines are excreted mostly through bile, and special care must be taken with their use in patients with hepatic dysfunction. The new anthracyclines of clinical interest in solid tumours (epirubicin, pirarubicin) are more lipophilic than doxorubicin and have a higher volume of distribution and an increased total plasma clearance. Idarubicin is active in leukaemia rather than against solid tumours, and an oral form is available. Because of their high tissue fixation, these new anthracyclines are of particular interest for locoregional therapy, especially through the hepatic artery. Myelosuppression is the dose-limiting toxicity of anthracyclines and is related to drug exposure, so that pharmacokinetic-pharmacodynamic relationships have been clearly established for these drugs. A new subfamily, characterized by a morpholino group, presents very original features such as direct covalent linking to DNA after cytochrome P450 activation. These molecules are active at 100-fold lower concentrations than the conventional anthracyclines and are currently in clinical trials.
Antibiotics, Antineoplastic↗
[The swiss experience of ileo-anal anastomosis with reservoir (AIA). Complications and functional results].
Two hundred and thirteen ileal pouch-anal anastomoses were performed in Switzerland from August 1980 to December 1991, 174 (82%) of them in 7 centres. One hundred and sixty four patients (77%) were operated for ulcerative colitis, 47 (22%) for familial polyposis and 2 others (1%) for another reason. A J pouch was created in 176 cases (83%), an S pouch in 35 cases (16%) and a W pouch in 2 cases (1%). Detailed results were available for 157 (74%) of the 213 operated patients: 81 females (52%) and 76 males (48%) with a mean age of 33.5 years (10-65). One hundred and twenty seven patients (81%) were operated for ulcerative colitis, including 42 as an emergency, and 30 (19%) for familial polyposis. One hundred patients (64%) developed complications which required one or several reoperations (laparotomy and/or perineal operation) in 64 cases (41%). Pouchitis was the most frequent complication (19%). Small bowel obstruction and pelvic abscess secondary to an anastomotic leak were the complications most frequently requiring second laparotomy with an incidence of 13% and 11%, respectively. The mean number of stools per 24 hours was 5.5 (2 to 14). 27% of patients passed one or several nocturnal stools every night, 27% occasionally, and 46% never. Occasional faecal incontinence was reported by 8 patients (6%) and 4 patients (3%) reported uncontrollable urgency. Nine patients retained a permanent ileostomy (failure rate: 6%).
Adenomatous Polyposis Coli↗
[Reversion of multidrug resistance in clinical practice].
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Drug Resistance↗
[Pneumoretroperitoneum: diagnostic and therapeutic approach].
This retrospective study deals with etiology, paths of extension, radiological signs and treatment of pneumoretroperitoneum. The 15 cases presented were seen over a 10-year period. Etiology was infectious in 6 patients, traumatic in 5, and iatrogenic in 4. Treatment applied was surgical in 12 patients, the remaining 3 (who all had their pneumoretroperitoneum secondary to endoscopy) could be handled conservatively. Even though pneumoretroperitoneum is seldom encountered, it should be quickly recognized in order to apply prompt adequate therapy.
Adolescent↗
Malignant cells have increased levels of common glycoprotein ligands of the endogenous cerebellar soluble lectin CSL.
The glycoprotein composition of various transformed cells or malignant tumors was analyzed and compared to their respective non-malignant control cells or tissues of several species, including man, using an endogenous carbohydrate-binding protein, the cerebellar soluble lectin CSL (Zanetta et al., J. Neurochem. 49, 1250-1257 (1987). A large variety of transformed cells contain a much higher number and larger quantity of glycoprotein ligands of CSL than the control cells or normal tissues. The glycoprotein profiles were, in most cases, independent of the nature of the cell transformation of the degree of differentiation, of the tissue and species. Thus, it is suggested that many transformed cells have, as a common anomaly, the increased synthesis of the special type of glycan recognized by CSL, expressed on the same polypeptide chains.
Animals↗
Haematological profile of healthy elderly Australians.
OBJECTIVE: To determine normal values for haematological parameters in healthy elderly persons, and document any changes in these over a 12 month period. DESIGN: The study was conducted as part of a randomised controlled trial of low-dose aspirin for primary prevention of cardiovascular disease in the elderly. All participants (380) had a full blood examination performed at entry, which was repeated after 12 months. The baseline results for all patients and the 12 month findings in a cohort of 162 persons allocated placebo were used in the present study. SETTING: Community-based (general practices and residential retirement villages). SUBJECTS: Persons aged 70 years and over (53% females) who were ambulatory, living independently, and volunteered to participate. None had significant vascular disease, peptic ulceration, haemorrhagic symptoms or were currently taking non-steroidal anti-inflammatory drugs. MAIN OUTCOME MEASURES: Full blood examination (excluding white cell differential counts) performed with a Technicon H1 analyser. RESULTS: The mean haemoglobin level +/- standard deviation (SD) was 14.69 +/- 1.10 g/dL (for men) and 13.72 +/- 1.05 g/dL (for women). Significant differences (P less than 0.001) in packed cell volume, red cell and platelet counts were observed between the two sexes. No clinically significant change was observed in any of the parameters over a 12 month period. CONCLUSIONS: Haematological reference values for healthy elderly Australians are consistent with normal values reported in younger populations for both sexes. As a result recommendations are provided for normal reference values among this group in an Australian setting.
Aged↗
Atomic interferences and the topological phase.
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Journal Article↗
Right ventricular overload and induced sustained ventricular tachycardia in operatively "repaired" tetralogy of Fallot.
The aim of the study was to evaluate the main predictors of the inducibility of sustained ventricular tachycardia (VT) in patients with repaired tetralogy of Fallot. Thirty-five patients (age 12 +/- 6 years) underwent right-sided cardiac catheterization, echocardiography, radionuclide angiography and ventricular stimulation; 10 had (group 1) and 25 had no (group 2) sustained VT. Group 1 patients were significantly older at the time of surgery and had longer follow-up periods (7 +/- 3 vs 4 +/- 4 years, p less than 0.02; and 12 +/- 4 vs 5 +/- 2 years, p less than 0.001, respectively). Right ventricular (RV) systolic pressure, end-systolic and end-diastolic normalized RV volumes were higher in group 1 (48 +/- 14 vs 38 +/- 11 mm Hg, p less than 0.05; 1.23 +/- 0.2 vs 0.86 +/- 0.17, p less than 0.001; and 2.35 +/- 0.37 vs 1.70 +/- 0.22, p less than 0.001, respectively). RV end-diastolic pressure, left ventricular and RV ejection fractions were similar in the 2 groups. A stepwise discriminant analysis was made to predict patients with inducible sustained VT (group 1): Time period from surgery to follow-up (p less than 0.001), normalized RV end-systolic volume (p less than 0.002) and RV systolic pressure (p = 0.01) were higher in group 1 and allowed classification of 90% of patients in group 1 and 96% in group 2.(ABSTRACT TRUNCATED AT 250 WORDS)
Adolescent↗
Changes in calcium uptake by liver induced by ferric lactate.
In vitro and in vivo Ca(2+)-uptake by the liver is increased by ferric lactate. In vitro albumin and deferoxamine inhibit ferric lactate effects. Electrophoresis demonstrates the binding of ferric lactate to albumin. In vivo, ferric lactate induces a significant increase of Ca(2+)-uptake by liver, with a maximum of 2.9 nmol/g against 0.66 nmol/g for control livers (P less than 0.005) between 5 and 24 h after administration. This uptake modification is reversible, while the amount of iron (measured as 59Fe taken up) remains constant throughout the experiment. The affinity of ferric lactate for protein and the iron mass-dependence of Ca(2+)-uptake increase support for the hypothesis of a ferric lactate-cell membrane interaction rather than an iron-catalyzed cell injury by lipid peroxidation as the major event leading to an increased Ca(2+)-uptake.
Animals↗