Comparison of the synergistic potentiation of etoposide, doxorubicin, and vinblastine cytotoxicity by dipyridamole.

Dipyridamole (DPM) enhanced sensitivity to etoposide (VP-16), doxorubicin (DOX), and vinblastine (VBL) in a human ovarian carcinoma cell line that was already relatively sensitive to all three agents. This interaction was shown to be truly synergistic by median effect analysis over a 2 log cell kill. The combination index at 50% cell kill (CI50) was used to quantitate the extent of synergy. The CI50s were 0.42, 0.66, and 0.30 for VP-16, DOX, and VBL, respectively. We compared the effect of DPM on the cellular pharmacology of each chemotherapeutic drug. DPM increased the steady state cellular content of VP-16 by a maximum of 3.2-fold, and that of DOX and VBL by 1.7- and 3.7-fold, respectively. There was a good correlation between the CI50 and the DPM-induced increase in cellular drug content (r = 0.94). DPM had no effect on the initial influx VP-16 or DOX but did increase the initial influx of VBL by 3.5-fold. DPM inhibited the initial efflux of all three compounds. However, there was no relation between the extent of efflux inhibition and the magnitude of the DPM-induced increase in cellular drug content, indicating that DPM must have other effects as well. DPM has chemical characteristics similar to other known modulators of VP-16, DOX, and VBL sensitivity. When compared to verapamil, DPM was as efficacious but twice as potent in its synergistic enhancement of VP-16 sensitivity. These results demonstrate that DPM can markedly increase the cytotoxicity of VP-16, DOX, and VBL and suggest possible clinical applications.

Pharmacokinetics of 5-fluorouracil during hyperthermic pelvic isolation-perfusion.

The pharmacokinetics of 5-fluorouracil (5-FU) injected into a surgically isolated pelvic circuit during hyperthermic perfusion was studied in five patients with local recurrence of anorectal cancer. 5-FU doses ranged from 11 to 23 mg/kg. The geometric mean ratio of peak plasma 5-FU in the isolated to systemic circuits was 10, the ratio at the end of the 45-minute perfusion was 12.5. The mean half-life of 5-FU in the isolated circuit was 18.5 minutes. Total drug exposure for the isolated circuit was 7.8-fold greater than for the systemic compartment. These results demonstrate a large pharmacologic advantage for the use of the isolation-perfusion technique.

Long-term survival of advanced refractory ovarian carcinoma patients with small-volume disease treated with intraperitoneal chemotherapy.

Ninety ovarian carcinoma patients failing primary intravenous (IV) combination chemotherapy were treated with cisplatin-based combination intraperitoneal therapy. Sixty-five patients had residual disease greater than 2 cm at the start of intraperitoneal therapy. Their median survival was 8 months. Twenty-five patients had disease less than 2 cm; their median survival was greater than 49 months, and the survival curve has an apparent plateau at 69%, with no relapses having occurred after 32 months. The median survival for all 90 patients was 15 months. The median duration of follow-up for all patients was 37 months. These results confirm the critical role of tumor bulk in determining the effectiveness of intraperitoneal therapy, and suggest a role for intraperitoneal salvage treatment in patients with small-volume disease.

Comparison of the pharmacokinetics of ultrafilterable cisplatin species detectable by derivatization with diethyldithiocarbamate or atomic absorption spectroscopy.

The pharmacokinetics of the cisplatin (DDP) species detected by measurement of diethyldithiocarbamate (DDTC)-reactive species (DDTC-DDP) were compared to the pharmacokinetics of the species detected by measurement of total ultrafilterable platinum in patients receiving DDP alone or in combination with the nephroprotective agent sodium thiosulfate. The doses of DDP studied were 100 mg/m2 (11 courses given to eight patients) and 202.5 mg/m2 (five courses given to four patients) given as 2 h i.v. infusions, the latter with concurrent thiosulfate. When DDP was given alone (100 mg/m2) the two assays yielded the same area under the curve (AUC) values for DDTC-DDP and total ultrafilterable platinum during the first 4 h after the start of infusion; however, beyond 4 h post-infusion, the AUC for total ultrafilterable platinum was consistently greater than that for DDTC-DDP. When DDP was given with thiosulfate (202.5 mg/m2), the AUC for total ultrafilterable platinum was significantly greater than that of DDTC-DDP during the whole sampling period. The ratio of the AUC for total ultrafilterable platinum to DDTC-DDP, when DDP was given with thiosulfate, was barely significantly greater than that when DDP was given alone. These data indicate that during and immediately following a short infusion of DDP the major platinum-containing species present in plasma ultrafiltrate are still capable of reacting with nucleophilic sites on molecules such as DDTC; however, as the reactive species are eliminated, longer half-lived non-reactive ultrafilterable platinum species begin to predominate. They also indicate that although thiosulfate does neutralize a measurable amount of DDP in the plasma on the schedule employed, this degree of neutralization is not sufficient to explain the protection against DDP-induced nephrotoxicity produced by thiosulfate.

Blood pressure reactivity to exercise: stability, determinants, family aggregation, and prediction.

Previous studies have shown blood pressure reactivity to exercise predicts future resting blood pressure. Subjects in this study were 206 healthy Mexican-American and Anglo-American families with fifth or sixth grade children. A total of 539 children (mean age = 12 years) and parents (mean age = 37 years) had complete data at baseline, and 79% were remeasured 48 months later. Blood pressure was measured during a submaximal cycle ergometer fitness test. Reactivity measures included systolic blood pressure at 70% of maximal heart rate (SBP70) and slope of the blood pressure-heart rate association during exercise (SLOPE). Stability of reactivity measures over 24 months varied from .22 to .63 (all p less than 0.001). Correlates of blood pressure reactivity in parents included resting heart rate, gender, age, and sodium intake. Correlates of reactivity in children included resting heart rate, body mass index, and age. Modest but significant levels of family aggregation of blood pressure reactivity were observed. In stepwise multiple regression analyses, SBP70 at baseline predicted resting blood pressure 48 months later in parents but not in children. The present results confirm previous studies indicating systolic blood pressure reactivity to exercise is a significant predictor of later resting blood pressure.

The Hound of the Baskervilles effect: natural experiment on the influence of psychological stress on timing of death.

OBJECTIVE: To determine whether cardiac mortality is abnormally high on days considered unlucky: Chinese and Japanese people consider the number 4 unlucky, white Americans do not. DESIGN: Examination of cardiac and non-cardiac mortality on and around the fourth of each month in Chinese and Japanese subjects and white controls. SETTING: United States. SUBJECTS: All Chinese and Japanese (n=209 908) and white (n=47 328 762) Americans whose computerised death certificates were recorded between the beginning of January 1973 and the end of December 1998. MAIN OUTCOME MEASURES: Ratio of observed to expected numbers of deaths on the fourth day of the month (expected number was estimated from mortality on other days of the month). RESULTS: Cardiac mortality in Chinese and Japanese people peaked on the fourth of the month. The peak was particularly large for deaths from chronic heart disease (ratio of observed to expected deaths = 1.13, 95% confidence interval 1.06 to 1.21) and still larger for deaths from chronic heart disease in California (1.27, 1.15 to 1.39). Within this group, inpatients showed a particularly large peak on the fourth day(1.45, 1.19 to 1.81). The peak was not followed by a compensatory drop in number of deaths. White controls, matched on age, sex, marital status, hospital status, location, and cause of death, showed no similar peak in cardiac mortality. CONCLUSIONS: Our findings of excess cardiac mortality on "unlucky" days are consistent with the hypothesis that cardiac mortality increases on psychologically stressful occasions. The results are inconsistent with nine other possible explanations for the findings-for example, the fourth day peak does not seem to occur because of changes in the patient's diet, alcohol intake, exercise, or drug regimens.

Measuring cognitive change in a cohort of patients with Alzheimer's disease.

Annualized rates of cognitive change in Alzheimer's disease (AD), an important index of disease progression, show marked variability. To determine factors leading to such variability, we computed rates of change in a cohort of patients with AD tested annually with the Mini Mental State Examination (MMSE) and the more detailed Dementia Rating Scale (DRS). Estimates of rates of change (slopes) and intercepts were calculated using least squares and best linear unbiased predictors (BLUPs). Potential predictors of rates of change were examined using multivariate linear regression analysis. We found that the MMSE had more noise than the DRS. For the MMSE, slopes showed a moderate floor effect and a slight ceiling, depending on initial MMSE scores. These effects were less prominent for the DRS, for which slopes increased as intercepts decreased. In analyses of predictors of change, the MMSE was less useful than the DRS. In multiple linear regression models using DRS data, predictors showed statistically stronger effects and explained a greater extent of variation of slopes than did similar models using MMSE data. For example, among patients who died and underwent brain examination at autopsy, neuropathology of Lewy bodies plus AD (Lewy Body variant; LBV) was associated with significantly faster rates of cognitive decline compared to pure AD in analyses that used the DRS, but only trends were identified with the MMSE. The metric properties and longitudinal characteristics of cognitive tests and the statistical methods used to calculate change are key factors in obtaining reliable estimates of change in studying cohorts of patients with AD.

Maintenance of peritoneal catheter function by the intraperitoneal administration of 32% dextran 70.

Thirty-two percent dextran 70 was administered to 53 patients receiving intraperitoneal (i.p.) chemotherapy in an attempt to better maintain catheter function. One hundred milliliters of 32% dextran 70 was administered i.p. at the time of catheter placement and at the completion of each course of chemotherapy (every 3 to 4 weeks). Analysis of the functional survival of the dextran treated catheters and 20 historical controls was performed. The cumulative probabilities of catheters maintaining bi-directional function in the dextran treated and control groups were 0.75 and 0.50 respectively. This difference was statistically significant at p = 0.051 by two-tailed Wilcoxon analysis. The difference between survival of dextran treated and control catheters increased if patients who received intraperitoneal doxorubicin were factored out (p = 0.035 by two-tailed Wilcoxon analysis). Plasma and peritoneal dextran levels were measured on 9 courses in 8 patients. Dextran was detectable in the peritoneal cavity up to 7 days after administration. The "apparent half-life" of dextran 70 in the peritoneal cavity was 36 hours. Plasma dextran concentrations increased for 2 days following i.p. administration and then decreased with an apparent half-life of 36 hours. One patient experienced chills and another had an anaphylactoid reaction following administration of the dextran. This study suggests that i.p. administration of 32% dextran 70 may be an effective means of minimizing peritoneal catheter failures.

Longitudinal study of cytomegalovirus retinitis in acquired immune deficiency syndrome.

The authors prospectively evaluated 67 consecutive patients with the acquired immune deficiency syndrome (AIDS) and cytomegalovirus (CMV) retinitis during a 33-month period to assess the clinical patterns of retinal infection, efficacy of treatment, long-term survival, and relationship of retinitis to immune function. Immediately sight-threatening retinitis presented in six patients (9%) with peripapillary disease; primary foveal infection was not observed. Eighty-seven percent of patients were treated with ganciclovir. Thirty-nine patients (58%) presented with unilateral disease and contralateral infection developed in 15% of those while on ganciclovir. Smoldering (incompletely responsive) retinitis was seen in 33% of the 21 patients whose retinitis progressed while receiving ganciclovir. Progression of treated retinitis was associated with a lower lymphocyte count (P = 0.04). Median survival after diagnosis of CMV retinitis was 8 months. This represents the largest reported prospective study of CMV retinitis and indicates that (1) CMV infrequently poses an immediate threat to vision on presentation, (2) response to therapy may be related to immune function, and (3) smoldering retinitis should be recognized as an important clinical entity associated with treatment failure.

A family approach to cardiovascular risk reduction: results from the San Diego Family Health Project.

The effectiveness of a family-based cardiovascular disease risk reduction intervention was evaluated in two ethnic groups. Participants were 206 healthy, volunteer low-to-middle-income Mexican-American and non-Hispanic white (Anglo-American) families (623 individuals), each with a fifth or a sixth-grade child. Families were recruited through elementary schools. Half of the families were randomized to a year-long educational intervention designed to decrease the whole family's intake of high salt, high fat foods, and to increase their regular physical activity. Eighty-nine percent of the enrolled families were measured at the 24-month follow-up. Both Mexican- and Anglo-American families in the experimental groups gained significantly more knowledge of the skills required to change dietary and exercise habits than did those in the control groups. Experimental families in both ethnic groups reported improved eating habits on a food frequency index. Anglo families reported lower total fat and sodium intake. There were no significant group differences in reported physical activity or in tested cardiovascular fitness levels. Significant differences for Anglo-American experimental vs. control adult subjects were found for LDL cholesterol. Significant intervention-control differences ranging from 2.2 to 3.4 mmHg systolic and/or diastolic blood pressure were found in all subgroups. Direct observation of diet and physical activity behaviors in a structured environment suggested generalization of behavior changes. There was evidence that behavior change persisted one year beyond the completion of the intervention program. It is concluded that involvement of families utilizing school based resources is feasible and effective. Future studies should focus on the most cost-effective methods of family involvement, and the potential for additive effects when family strategies are combined with other school health education programs.