Quantitative estimation of renal clearance of N-acetylprocainamide in rats with various experimental acute renal failure.

The dosage regimen of a drug eliminated predominantly through the kidney need to be adjusted for the patients with renal disease. The objective of the present study was to establish a quantitative approach to precisely predicting the renal clearances of basic drugs using N-1-methylnicotinamide (NMN). A variety of experimental acute renal failure (ARF) in rats were prepared and N-acetylprocainamide (NAPA) was used as a model drug. The renal clearances of NAPA were significantly decreased in rats with ARF, resulting in significantly increased plasma concentrations. Remarkable reduction in clearance ratios (CL(ratio)) was observed, indicating that the impairment in tubular and glomerular function did not proceed in a parallel manner. The renal clearance of NAPA (CL(rNAPA)) was better predicted from the renal clearance of NMN (CL(rNMN)) than from GFR. A mathematical equation was also constructed to estimate the CL(rNMN) from the NMN plasma concentration. Therefore, the renal clearance of basic drugs excreted predominantly from the kidney can be easily and more accurately estimated based on the concentrations of endogenous NMN to provide a precise dosage regimen for patients with renal failure.

[Study of anti-tumor effects of hyperthermia combined with hydralazine on experimental tumor].

We analyzed tumor growth delay in experimental tumors after hyperthermia alone, hydralazine (HDZ) injection alone and the combination of these modalities. We also analyzed the energy parameter (ATP/Pi ratio) obtained by 31P-MRS (magnetic resonance spectroscopy). The purpose of this study was to evaluate the usefulness of 31P-MRS as an index of anti-tumor effect. FM3A tumor cells were transplanted subcutaneously in the hind legs of C3H/He mice. We dipped the tumors into a heated circulating water bath. 31P-MRS was performed with a CSI spectrometer. The anti-tumor effect obtained with HDZ alone was insignificant, but combined treatment with hyperthermia and HDZ had a significant synergistic effect. The ATP/Pi ratios for all groups treated separately with HDZ or hyperthermia were not different from the control, but the ATP/Pi ratio decreased after combined use of these agents. There was a significant correlation between the decrease in ATP/Pi ratio and tumor growth delay. We observed a direct relation between the delay in tumor growth and the decline in ATP/Pi ratio after combined treatment with HDZ and hyperthermia. The ATP/Pi ratio 24 hr after treatment may be useful in predicting the efficacy of the combined use of HDZ and hyperthermia.

Evaluation of thermal damage after hyperthermia on murine experimental tumor by 31P-NMR spectroscopy--correlation between ATP and growth delay.

The usefulness of 31P-MRS (phosphate magnetic resonance spectroscopy) for evaluation of the anti tumor effect of hyperthermic treatment was examined. FM3A, an experimental tumor transplantable to C3H mice, was used. FM3A, transplanted subcutaneously to the femoral region, was subjected to hyperthermic treatment and 31P-MRS were measured at various times. Because the ATP/Pi ratio indicates the energy status of tumor cells, we conducted measurement of its sequential changes after hyperthermic treatment. With a water bath, hyperthermic treatment was performed at 44 degrees C. Twenty four hours after treatment, the ATP/Pi ratio dropped as the heating time was prolonged, showing an obvious converse correlation to the tumor growth curve on heating. Immediately after hyperthermic treatment, the ATP/Pi ratio fell drastically, began to recover after 18 hrs and remained unchanged up to the 24 hrs. The finding that the ATP/Pi ratio obtained in tumor tissue 24 hrs after hyperthermic treatment was correlated with tumor inhibition suggested that the ratio can be a possible parameter for evaluation of the anti tumor effect by heating. The ATP/Pi ratio obtained by 31P-MRS could be used for non-invasive prediction of tumor tissue damage by heating.

Distribution of pirarubicin in human blood.

We investigated the distribution and stability of pirarubicin in human blood obtained from 12 healthy volunteers. The distribution of pirarubicin into blood cells showed marked temperature- and concentration-dependencies and the Arrhenius plot for pirarubicin uptake in blood was biphasic. Therefore, pirarubicin appears to be taken up into blood cells by a carrier-mediated system. Pirarubicin was mainly enzymatically metabolized to pirarubicinol in blood cells, but pirarubicin was not metabolized into doxorubicin in either blood or plasma. On the other hand, in plasma, pirarubicin was degraded to unknown inactive compounds instead of pirarubicinol. It is therefore suggested that blood cells serve to protect against the degradation of pirarubicin into inactive compounds in blood. Accordingly, when the monitoring of pirarubicin and its active metabolites is carried out in patients, both blood and plasma must be frozen immediately after blood collection.

[Evaluation of thermal damage after hyperthermia on murine experimental tumor by 31P-NMR spectroscopy--correlation between ATP and growth curve].

The possibility of using 31P-NMR spectroscopy (31P-MRS) to estimate the effect of hyperthermic treatment on mouse FM3A tumor was investigated. 1 x 10(6) cells, suspended in saline, were subcutaneously inoculated to the right thigh of C3H mice. For hyperthermic treatment, the tumor-bearing leg was heated by immersing it in a water bath at 44 degrees C for 10, 20 or 30 min. The signal intensities of ATP and Pi of the tumor were measured utilizing the 31P-MRS technique to calculate the ATP/Pi ratio. Immediately after heating, the ATP/Pi ratio decreased markedly. Eighteen hours after hyperthermic treatment, the ratio recovered but was still smaller than the control value, then became almost constant by 24 hours after heating. The ATP/Pi ratio at 24 hours after heating decreased with increased length of heating and was inversely related to tumor regrowth after hyperthermic treatment. We concluded that non-invasive monitoring with 31P-MRS might provide a good indication of the effect of hyperthermic treatment.

[A case of hypertrophic obstructive cardiomyopathy with left atrial giant thrombus during anti-platelet therapy].

A case of a 77-year-old female with hypertrophic obstructive cardiomyopathy having the left atrial "giant" thrombus was reported; the diagnosis of the localization and size of the thrombus was made by employing echocardiography and contrast enhancement computed tomography as well. The clinical record indicated that the thrombus formation, which happened in the course of the antiplatelet therapy, was to be considered due to the complicated condition of the patient, i.e., the combination of atrial fibrillation, low cardiac output, enlargement of left atrium and left ventricular diastolic disfunction, which assumed to predispose the giant thrombus. Avoiding the surgical removal of the thrombus because of the poor conditions of the patient, urokinase treatment was attempted, but not successful, which might be derived from the nature of the thrombus already organized. In general, left atrial giant thrombus is very uncommon status; if any, it is occasionally complicated with mitral stenosis. The case reported deems to be very rare, enough worthy to be reported.