Heart rate variability (HRV) spectral analysis has been used as a tool for short-term assessment of parasympathetic (PNS) and sympathetic nervous system (SNS) control of heart rate. However, it has been suggested that the PNS and SNS indicators are superimposed on a broad-band noise spectrum in which the power spectral densities are inversely proportional to their frequency (1/f beta). In this study, we have used coarse-graining spectral analysis to extract the harmonic components for calculation of PNS and SNS indicators and to obtain the slope (beta) of the 1/f beta component to estimate fractal dimension (DF) of a trail of HRV. DF was regarded as an indicator of cardiovascular system complexity. Ten healthy young subjects (6 women and 4 men) were studied in supine rest and with sequential applications of four levels of lower body negative pressure (LBNP; -10, -20, -30, and -50 mmHg) and head-up tilt (HUT; 10, 20, 30, and 70 degrees). In the 20 tests, there were six occurrences of presyncopal symptoms that required the test to be terminated before the planned end point. At low levels of LBNP or HUT, arterial pulse pressure (PP) was not changed from rest, and calculated DF was very high (beta approximately 1.00). At the higher levels of LBNP and HUT, PP decreased. Coincident with this reduction in PP, PNS activity decreased, SNS activity increased, and DF was reduced, each with a significant linear relationship to the change in PP (PNS: r = 0.56; SNS: r = 0.57; DF: r = 0.70, P < 0.01). Each occurrence of presyncope was associated a low PNS indicator as well as DF < 2.50 (beta > or = 1.80). These data indicate that the cardiovascular system is operating at a reduced level of complexity and further suggest that reduced complexity might not be compatible with cardiovascular homeostasis.

Antineoplastic therapy with combinations of topoisomerase I and II agents is feasible and may produce therapeutic synergy. The appropriate sequence may depend on the particular agents used. The rationale for such therapy, that topoisomerases I and II may have reciprocal and compensatory interactions, is supported by the biochemical data.

The cardiovascular responses to a 10-min 1.22 rad (70 degrees) head-up tilt orthostatic tolerance test (OST) was observed in eight healthy men following each of a 5-min supine baseline (control), 4 h of 0.1 rad (6 degrees) head-down tilt (HDT), or 4 h 0.52 rad (30 degrees) head-up tilt (HUT). An important clinical observation was presyncopal symptoms in six of eight subjects following 4 h HDT, but in no subjects following 4 h HUT. Immediately prior to the OST, there were no differences in heart rate, stroke volume, cardiac output, mean arterial pressure and total peripheral resistance for HDT and HUT. However, stroke volume and cardiac output were greater for the control group. Mean arterial pressure for the control group was less than HDT but not HUT. Over the full 10-min period of OST, the mean arterial pressure was not different between groups. Heart rate increased to the same level for all three treatments. Stroke volume decreased across the full time period for control and HDT, but only at 3 and 9 min for HUT. There was a higher total peripheral resistance in the HDT group than control or HUT. The pre-ejection period to left ventricular ejection time ratio was less in HDT than for control or HUT groups. These data indicate a rapid adaptation of the cardiovascular system to 4 h HDT that appears to be inappropriate on reapplication of a head to foot gravity vector. We speculate that the cause of the impaired orthostatic tolerance is decreased tone in venous capacitance vessels so that venous return is inadequate.

Cyclocreatine, an analog of creatine, is an efficient substrate for creatine kinase, but its phosphorylated form is a poor phosphate donor in comparison with creatine phosphate. Cyclocreatine was not very cytotoxic upon 24 h of exposure of human SW2 small-cell lung cancer cells to concentrations of up to 5 mM. However, combinations of cyclocreatine (0.5 mM, 24 h) with each of four antitumor alkylating agents, cis-diamminedichloroplatinum(II), melphalan, 4-hydroperoxycyclophosphamide, and carmustine, resulted in additive to greater-than-additive cytotoxicity toward exponentially growing SW2 cells. The greatest levels of synergy were seen at higher concentrations of 4-hydroperoxycyclophosphamide and carmustine as determined by isobologram analysis. In vivo cyclocreatine (0.5 or 1 g/kg) was more effective if given i.v. rather than i.p. The longest tumor-growth delays, up to 10 days, were produced by extended regimens of cyclocreatine. Cyclocreatine was an effective addition to therapy with standard anticancer agents including cis-diamminedichloroplatinum(II), cyclophosphamide, Adriamycin, or 5-fluorouracil. No additional toxicity was observed when 10 days of cyclocreatine treatment was given with full standard-dose regimens of each drug. The resultant increases in tumor-growth delay were 1.7- to 2.4-fold as compared with those obtained for each of the drugs alone. These results indicate that cyclocreatine may be an effective single agent and an effective addition to combination chemotherapy regimens.