Use of plasma cytotoxic activity to model cytotoxic pharmacodynamics of anticancer drugs

Summary We have developed a pharmacokinetic/pharmacodynamic approach that integrates the disposition, cytotoxic activity and interaction of anticancer drugs. Fundamental to this approach is the measurement of the cytotoxicity, against a target cell line, of patient plasma collected at different times after administration of the anticancer agent(s). To illustrate this approach, we have studied the plasma cytotoxic activity (PCA), against HL-60 cells, of plasma from 11 acute myeloblastic leukemic patients treated with daunorubicin (DNR). Plasma, obtained before and serially for 24 h after DNR treatment, was assayed by HPLC for DNR and daunorubicinol (DNRol), its active metabolite. The corresponding observed PCA values (PCA_obs) against HL-60 cells were also measured with a flow-cytometric cell-survival assay that we had developed previously. The pharmacodynamics, i.e. PCA, were co-modeled (dual Hill equation with an interaction term to allow synergism or antagonism) with the pharmacokinetics. The intergration of the PCA profile provided the area under the observed PCA versus time curve (AUC_obs). For each patient, we also generated an interaction panel, by adding known amounts of DNR and DNRol to his or her pretreatment plasma. The corresponding cytotoxicities were measured, and then applied to the pharmacodynamic model. This provided a standard surface from which the PCA of each sample obtained after therapy was predicted (PCA_prd), on the basis of assayed concentrations of DNR and DNRol in that sample. For plasma samples obtained after treatment, the model simultaneously fit all three outputs, i.e. PCA and DNR/DNRol concentration, very well. We observed substantial interpatient variability in HL-60 growth rate in medium containing patient pretreatment plasma, in DNR activity in pretreatment plasma, and in the in vitro activity (PCA) of plasma obtained after DNR treatment. We also compared the AUC_prd to the AUC_obs for each patient, and we identified a subset of 4/11 acute myeloblastic leukemic patients who had developed much more PCA after DNR administration than could be explained by the measured concentrations of DNR and DNRol. This may be due to unidentified active metabolites or to factors produced in the plasma in response to the treatment. This pharmacokinetic/pharmacodynamic model is promising to describe pharmacodynamics and interactions of anticancer drugs in cancer patients.This work was presented, in part, at the 31st annual meeting of the American Society of Hematology, Atlanta, Ga., December 1989, and at the 91st Annual Meeting of the American Society for Clinical Pharmacology and Therapeutics, San Francisco, Calif., March 1990. Supported in part by grant RO-1-CA40 188 from the National Institutes of Health, National Cancer Institute, a grant from the Scientific Committee of NATO, Brussels, Belgium, and a grant from the Oeuvre Belge du Cancer, Brussels, Belgium     

Intrathecal administration of etoposide in the treatment of malignant meningitis: feasibility and pharmacokinetic data

Summary Two patients presenting with malignant meningitis resulting from small-cell carcinoma of the lung and with lymphoblastic leukemia, respectively, were treated by intrathecal administration of etoposide. In both cases, this treatment was well tolerated and produced relief of the central nervous system symptoms. Pharmacokinetic data showed that cerebrospinal fluid drug levels of up to 5.2 g/ml were achieved, which were considerably higher than those obtained after i.v. administration of high-dose etoposide.     

Poor predictive value of hematocrit and hemodynamic parameters for erythrocyte deficits after extensive elective vascular operations.

Fluid resuscitation and transfusion therapy are particularly critical in patients undergoing extensive vascular operations because of diffuse atherosclerosis and the risk of perioperative myocardial infarction. Sophisticated perioperative monitoring has reduced the mortality rate substantially, but indications for transfusion remain controversial. We determined erythrocyte volume, (EV), total blood volume (TBV) and plasma volume (PV) preoperatively and 18 to 24 hours postoperatively in 41 elderly patients (68.8 +/- 1.3 years) undergoing elective vascular operations (30 abdominal aortic aneurysmorrhaphy, ten aortofemoral bypass and one carotid endarterectomy). EV was measured using 51chromium-labeled autologous erythrocytes; TBV and PV were calculated from EV and total body hematocrit (peripheral venous hematocrit [HCT] x 0.89). Ideal blood volumes were calculated from nomograms based on body surface area and gender. Relationships between body volumes (percentage of ideal), simultaneously measured peripheral venous HCT and hemodynamic parameters heart rate, mean arterial pressure, central venous pressure, pulmonary capillary wedge pressure, cardiac index and systemic vascular resistance index were studied by stepwise regression. In 24 patients, blood volumes and hemodynamic parameters were also measured in the recovery room. HCT significantly correlated with EV at all three time periods (p less than 0.001), but the ability of HCT to predict EV in an individual patient was relatively poor (r = 0.50 preoperatively; r = 0.54 in recovery room and r = 0.66 24 hour postoperatively). By 24 hours postoperatively, EV had decreased to 78.3 +/- 2.4 percent of ideal EV (range of 47 to 112 percent). However, only two patients had HCT less than 30 despite the fact that 13 of 41 patients had an EV deficit of greater than 30 percent. No patient had a HCT of less than 25 percent. Hemodynamic parameters did not contribute to the prediction of EV, PV or TBV at any time. Two patients had myocardial infarctions postoperatively associated with 24 hour EV deficits of 18.5 and 29.6 percent. One patient died of a pulmonary embolus. Because of these findings, the concept of a "transfusion trigger" must be viewed with caution, since many patients undergoing vascular operations will have considerable EV deficits despite an "acceptable" HCT.     

The effect of temperature on copper tolerance ofParamecium

Summary The copper tolerance ofParamecium tetraurelia decreases with increased temperatures over the range of 12 C to 34 C. The relationship is linear and the correlation=–0.98. The regression equation has an intercept of 16 M Cu⁺⁺ at 0 C, and tolerance is reduced by 0.33 M for each degree increase in temperature.     

Influence of time and mode of exposure on biotransformation of naphthalene by Juvenile starry flounder (Platichthys stellatus) and rock sole (Lepidopsetta bilineata)

Juvenile starry flounder (Platichthys stellatus) and rock sole (Lepidopsetta bilineata) were force-fed 56 Ci each of 1-³H-naphthalene dissolved in salmon oil. Values for radioactivity associated with naphthalene and the metabolite fraction were determined for various tissues and body fluids. Results show that these pleuronectids extensively metabolize dietary naphthalene. The rates of decline in naphthalene concentrations (expressed as disintegrations per minute per milligram of dry tissue) were greater than the rates of decline in metabolite concentrations (dpm/mg) in liver, blood, and skin; therefore, relative proportion of metabolites to naphthalene increased with time and at 168 hr after the initiation of the naphthalene-exposure, more than half of the total radioactivity in both species of fish was associated with the metabolites.Profiles of metabolites in liver, skin, and bile were obtained using thin-layer chromatography. 1,2-Dihydro-1,2-dihydroxynaphthalene constituted 38.7 and 39.7%, respectively, of the total extracted metabolites in livers of the naphthalene-exposed rock sole and starry flounder at 24 hr, whereas the bile from both species contained primarily (>90%) conjugates. From 24 to 168 hr, a significant (P < 0.05) decrease in the proportion of the dihydrodiol derivative and a concomitant increase in the proportion of conjugates—specifically, sulfate/glucoside fraction-were observed with livers of both rock sole and starry flounder. No significant change occurred in the spectrum of biliary metabolites with time. The pattern of metabolites in skin of both species was qualitatively similar to that in liver; however, the proportion of the dihydrodiol was greater in skin than in liver at 24 hr.When naphthalene (56Ci) dissolved in salmon oil was administered to starry flounder via intraperitoneal injection, the extent of biotransformation was less than after dietary exposure. Moreover, metabolites in the livers of the fish in the injection study were predominantly (76.7% of total extracted metabolites) non-conjugates at 24 hr. Once again, from 24 to 168 hr, an increase in the proportion of the sulfate/glucoside fraction and a concomitant decrease in the proportion of the dihydrodiol was observed with liver.These studies demonstrate that the extent of biotransformation of naphthalene and the types of metabolites remaining in tissues (e.g., liver) of flatfish are greatly influenced by both the mode of exposure and the time elapsed after the exposure is initiated. It appears therefore, that different exposures (e.g., in water, food, or sediment) of pleuronectids to polycyclic aromatic hydrocarbons may result in different degrees of alteration in genetic material because of variability in accumulation of non-conjugated metabolites, some of which are implicated in covalent binding with DNA in terrestrial mammals.     

A multivariate laboratory data analysis system: Introduction

In an era severely affected by the advanced stages of technocracy, it should not astound anyone that highly sophisticated technologies have metastasized throughout our hospital system. While simplifying many complex problems, the advantages of modern technology also create many interesting conflicts. One such dilemma surfaces as a consequence of clinical laboratories being able to produce a large number of test results in a relatively short time with a high degree of accuracy. Optimization of laboratory information must precede successful utilization of this extensive and expensive wealth of data.     

Are the modified "simple questions" a valid and reliable measure of health related quality of life after stroke?

OBJECTIVES: Two "simple questions" were developed as a minimalist measurement tool to assess outcome in large trials and epidemiological studies after stroke. A previous study of their validity had disclosed ambiguities in their wording. In this study, the clarity, validity, and reliability of a modified version of these simple questions were examined. The relation between patients' responses to these questions and two widely used generic measures of health related quality of life were also studied. METHODS: A hospital based stroke register cohort of 152 patients, who were all visited at home by a study nurse, was used to study validity. A cohort of 1753 patients derived from the International Stroke Trial was used to study the relation with measures of quality of life. The sensitivity, specificity, and accuracy with which responses to each question predicted the patients' outcome measured using standard instruments was assessed. The distribution of scores for the EuroQol and SF-36 was examined for patients classified as dependent, independent, and fully recovered by the combined use of the modified simple questions. RESULTS: The modified "dependency" question had excellent sensitivity (>85%), specificity (>79%), and accuracy (>82%) for identifying dependency after stroke. The "problems" question had good sensitivity (65-88%) and moderate specificity (36-72%) for the detection of problems in a broad range of domains. The combined use of the modified dependency and problems questions provided a valid, simple, and reliable overall indicator of health related quality of life after stroke. CONCLUSIONS: The modified simple questions have excellent face validity and good measurement properties for the assessment of outcome after stroke. They are particularly well suited for large epidemiological studies and randomised trials.