Salivary and plasma pharmacokinetics of topotecan in patients with metastatic epithelial ovarian cancer.

The comparative saliva/plasma pharmacokinetics of topotecan were investigated in 13 patients with metastatic epithelial ovarian cancer receiving topotecan (30-min intravenous (i.v.) infusion) on a five consecutive day schedule every 3 weeks. During the first and the second courses of treatment, each patient underwent pharmacokinetic evaluation. Quantitation of the total topotecan (lactone plus carboxylate form) was assessed by a highly specific high-performance liquid chromatographic (HPLC) method. Large patient-to-patient variations in the plasma and saliva concentrations were observed. Plasma and saliva pharmacokinetics could be described using a biexponential pattern. From the saliva data, the half-life of the terminal part of the curve was 2.64 h, it was of the same order of magnitude as the topotecan elimination half-life determined from the plasma data, 3.18 h. Topotecan concentrations were higher in the saliva than in the plasma, the saliva/plasma concentration ratio averaged 2.31 and the ratio area under the parotid saliva (AUC(s)) over plasma (AUC(p)) concentration-time curve (AUC(s)/AUC(p)) averaged 2.11. For each individual, a significant relationship was found between topotecan concentrations in the saliva and in the plasma, the coefficients of correlation ranged from 0.75 to 0.92 according to the patient. Myelosuppression, especially granulocytopenia was the most frequent toxicity encountered during the trial. The percent decrease in the leucocyte count, absolute neutrophil count and platelet count were related to the AUCp/day using sigmoidal E(max) models. The high values of the Hill constant found reflect the very steep AUC-haematoxicity relationship observed. In most cases, abdominal pain occurred in patients presenting high saliva concentrations. One patient with high salivary concentrations (mean S/P ratio=4.60) had grade 1 mucositis. In conclusion, the concentration of topotecan in saliva appeared to be useful as an indirect, non-invasive estimation of the levels of topotecan in the plasma; thus, saliva concentrations could be a good predictor of the behaviour of topotecan in the body.

Population pharmacokinetics of topotecan: intraindividual variability in total drug.

The inter- and intraindividual variabilities in topotecan clearance (CL) were explored using a population pharmacokinetic approach. Total (lactone + hydroxy acid) topotecan plasma concentrations were obtained in 31 women with metastatic epithelial ovarian cancer treated by the 30-min intravenous infusion on 5 subsequent days. The data corresponding to three occasions (days 1 and 5 of cycle 1, and day 1 of cycle 2), were analyzed using the nonlinear mixed effect model program. A large interindividual variability was observed, with CL varying from 9.1 to 42.51 per hour (mean 21.0). Topotecan CL was related to serum creatinine level, and age. A close relationship was also observed between topotecan CL and creatinine clearance. Intraindividual variability both within cycle 1 and between the two first cycles was limited, with a mean variation of -2+/-17%, and + 5+/-20%, respectively. A limited sampling strategy using Bayesian estimation based on two samples (5 min before the end of the 30-min infusion, and 4 h after the end of infusion) was developed. The results of this study combine relationships between topotecan pharmacokinetic parameters and patient covariates that may be useful for a priori dose adjustment, and convenient sampling procedure that can be used for further studies and drug monitoring.

Hepatitis C virus among blood donors: follow-up study.

BACKGROUND: The exact significance of antibodies to hepatitis C virus (HCV) in blood donors remains unknown. Confirmatory tests of anti-HCV-reactive serum and HCV RNA by polymerase chain reaction (PCR) are used to refute a large proportion of false-positive results. STUDY DESIGN AND METHODS: Ninety-two blood donors who were anti-HCV reactive in a first-generation enzyme-linked immunosorbent assay (ELISA) were reevaluated 10 months later with a second-generation ELISA (ELISA-2) as well as with second-generation recombinant immunoblot assay (RIBA-2) and by PCR. RESULTS: Twenty-five (43.9%) of the 57 ELISA-2-positive donors were confirmed as positive by RIBA-2; of these, 84 percent were HCV RNA positive in PCR. Of the 57 who were still anti-HCV positive, 46 were followed up and tested again in the same manner 2 years after the first screening. At that time, the pattern was little changed: 94 percent of RIBA-2- and PCR-positive donors remained positive. Of RIBA-2- and PCR-positive blood donors, 62 percent had abnormal alanine aminotransferase levels in at least one of the three evaluations. Among the anti-HCV-positive donors confirmed by RIBA-2, 60 percent, versus 12.6 percent in the control group, had a significantly (p < 0.001) more frequent risk factor for HCV infection, due to parenteral exposure to blood. CONCLUSION: These data confirm a good correlation between RIBA-2 reactivity and the detection of HCV RNA in a population of anti-HCV-positive blood donors.

Sustained division of protoplast-derived cells from primary leaves of Pinus pinaster, factors affecting growth and change in nuclear DNA content.

Leaf protoplasts were isolated from apical and in vitro-induced axillary buds of Pinus pinaster Ait. seedlings. First divisions were seen after 8-10 days of culture in a 650 mOsm kg H(2)O(-1) medium in which glutamine was the sole nitrogen source. Colony formation was achieved in 6-7 weeks in a modified protoplast culture medium in which a reduction in the concentrations of both calcium and carbon was essential for sustained divisions. To maintain cell suspension growth, it was necessary to subculture every three weeks to a 170 mOsm kg H(2)O(-1) medium. Lowering the C/N ratio did not support better growth. Phenolic compounds were detected in stationary phase cultures. Analysis by HPLC indicated that the cinnamate pathway was involved in their synthesis. After 3 and 7 months of culture, 65 and 74%, respectively, of protoplast-derived cells had a nuclear DNA content comparable to that of leaf protoplasts.

[The psychological universe of the asthmatic]. / L'univers psychologique de l'asthmatique.

The very nature of asthmatic attacks is alarming. Waiting for an attack in itself creates anxiety. The unpredictable nature of the condition is also anxiety producing. However, this type of anxiety is not simple and the patient's attitude to it is often ambiguous. Asthmatic patients do not have a specific type of personality but a neurotic and psychosomatic context is common. By psychosomatic we mean reactional behaviour to the disease rather than "psychogenesis" of attacks, although emotional factors are often observed. Asthmatic patients do not live alone. They live in an environment which affects them and which is affected by them: a special psychodynamic relationship is set up, especially in young patients, and not to recognise it would be to ignore part of the patient and of the disease.

[An ultrastructural study of acid phosphatase activity localized in bud primordia of an organogenic culture of Nicotiana tabacum L. var. P. 19]. / Localisation ultrastructurale de l'activite beta-glycérophosphatasique au niveau des ébauches caulinaires néoformées d'une culture de tissus organogéne de Nicotiana tabacum L. var P. 19.

Acid phosphatase activity in particularly organogenic strain of tobacco has been localized in two kinds of tissue: the internal bud primordia and the adjacent tissues. Generally the reactions are weaker in the undifferentiated cells. In differentiating cells, the localization of precipitates from the reaction shows up the continuity of membrane systems such as the endoplasmic reticulum, the nuclear membrane and the vacuoles. The relative weakness of the reactions observed in the vacuoles is in agreement with the rareness of hydrolysis. Parenchymatous cells between the meristems and the surface of the tissue culture undergo autolysis, which seems to help the growth of buds produced by neoformation. Specific and often intense reactions occur in the cell walls.