In this review paper, the authors summarize the studies which support the theory that a defect in production of energy by the myocardial cells is a determinant factor in the genesis and/or aggravation of dilated cardiomyopathy. Points that are common to this metabolic theory and to the other pathogenetic mechanisms usually described (notably viral or toxic mechanisms) are presented.

Prodrugs are pharmacologically inert and nontoxic chemical compounds which are transformed in vivo into pharmacologically and therapeutically active compounds, i.e. drugs. Prodrugs are used to solve problems which cannot be solved by the drugs themselves. There are three types of problems: problems arising before the drug enters the body (solubilization, stabilization and improved acceptability); problems associated with the penetration and fate of the drug in the body (absorption, barrier crossing, duration of action); problems relating to the therapeutic target (selective local delivery). The principal prodrugs that solve these problems and the mechanisms of the solutions they provide are described and discussed.

The pharmacokinetic studies of anticancer drugs still go on after they are out on the market. The therapeutic protocol is then more precise and depends on the dosage results of these drugs. Some examples of dosage adjustment according to their plasmatic level are reported here for high-dose methotrexate infusion and for CDDP infusion over five days. The test dose and the bayesian method (pharmacokinetic population) are used to predict the adapted individualized dosage for each patient.

Animal extrapolation of antitumor drug pharmacokinetics deals with either the determination of equations describing drug disposition or the determination of physiological parameters governing this distribution. Papers on this subjects show the need for numerous animal species to predict quantitative evolution curves and the lack of precision in the obtained results. Practical interest of such studies is limited since the pharmacokinetic parameters are systematically evaluated in man during phase I trials. On the contrary, analysis of the mechanism of drug distribution cannot be performed without interspecies scaling to evaluate physiological parameters which are not measurable in humans.

Vinca alkaloids (VA) represent a family of closely related molecules, which includes vincristine (VCR), vinblastine (VLB), vindesine (VDS) and navelbine (NVB), a new synthetic VA presently in phase II clinical trial. Development of sensitive and specific analytical tools (polyclonal and monoclonal antibodies) enabled us to investigate the kinetic behavior of VDS and NVB after IV bolus or long term administration. Following IV bolus injection, the mean pharmacokinetic parameters are: total plasma clearance: 0.53 l/h-1kg-1, 0.72 l/h-1kg-1 and apparent elimination half-life: 23.2 h, 39.5 h for VDS and NVB, respectively. Chronic treatment reveals time- and dose-dependence relationships and detailed observations of individual kinetics demonstrate an important interindividual variability for both drugs. Renal excretion of VDS and NVB is low (from 5 to 12% of the total dose), suggesting the important role of the liver in their rapid elimination.

During long-term venous catheter implantation, septic and thrombotic complications are quite frequent. In the case reported, the failure of systemic and local antibiotic therapy during repeated septicaemia due to Bacillus cereus at the time of intensive chemotherapy led to a scanning electron microscopy study of the used silicone catheter. There were marked changes of the inner surface with a lot of cellular remains, in contrast with the usual non thrombogenic property of the silicone. An in vitro study was carried out with antitumour agents. Duration of exposure and drug concentration were identical to those used in in vivo perfusions. There were marked changes of the inner surface, which could lead to important modifications of the properties of the silicone. The damage depended on the drug. Silicone was slightly sensitive to vicristin and carmustin, but highly sensitive to cisplatin and doxorubicin. The compatibility of catheter material with the drugs used, especially for oncologic chemotherapy, must be tested systematically.

Two short-lived vitamin K-dependent factors, factor VII and protein C, were measured by both functional and antigenic techniques in 3 hematological conditions known for their risk of hepatotoxicity: Following use of asparaginase and bisantrene, and patients at high risk of hepatic veno-occlusive disease after allogenic bone marrow transplantation for relapse of acute leukemia of accelerated phase of evoluted chronic myelogenic leukemia. In these 3 conditions functionally measured levels of protein C and factor VII, and antigenically measured levels of both these factors proved to be early markers of incipient hepatic involvement. These tests were easy to use routinely were reproducible, and proved to be predictive of veno-occlusive disease in grafted patients at the preconditioning stage. In the follow-up of bone marrow grafted patients plasma markers of endothelial function (von Willebrand's factor, tissue type plasminogen activator, and plasma activity of angiotensin converting enzyme) were significantly altered at the time of overdose with cyclosporin A, probably due to a drug-induced in vivo lesion of the endothelium. In the search for cytoprotective drugs for the prevention of veno-occlusive disease in bone marrow grafted patients prostaglandin E1 (PGE1) was given prior to and for at least 4 weeks after transplantation and proved to be effective by biological criteria (the level of protein C mainly). This deserves further study in a prospective clinical trial of the potential usefulness of PGE1 in preventing liver veno-occlusive disease in bone marrow grafted patients.

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...).

The authors report a case of successful pregnancy 8 years after surgery and chemotherapy for biliary cancer with secondaries in the liver. The authors, in considering this case, have analysed the sequelae of chemotherapy for cancer on fertility. They discuss the need to preserve the ability to produce oocytes in young women who need treatment for cancer.

A paradoxical effect of radiotherapy and chemotherapy for cancer is that some of these treatments can themselves cause new cancers. Most epidemiologic methods can be applied successfully to the investigation of this problem and this paper reviews various approaches that have already been used by various researchers. The authors first review the more traditional methods, i.e., cohort and case-control studies and they then describe designs that have been proposed more recently, such as case-cohort studies. A distinction is established between internal comparisons, carried out within the study population, and external comparisons, in which a general population external to the population under study is used as the reference category. This presentation is mainly aimed at investigators using tumor registry data. However, the general principles formulated here are easily generalized to contexts other than that of registries.

The authors studied distraction osteogenesis in an animal subjected to prolonged anti-mitotic chemotherapy (Methotrexate and Doxorubicin). This chemotherapy decreased osteogenesis (essentially at the expense of external regeneration) though without inhibiting it totally. Distraction bone consolidation is thus possible in the animal, permitting reconstruction of limb segments by mobilization of an axial fragment in accordance with the Ilizarov technique.