The Protective Role of Glutathione, Cysteine and Vitamin C against Oxidative DNA Damage Induced in Rat Kidney by Potassium Bromate

The roles of glutathione (GSH), cysteine, vitamin C., liposome-encapsulated superoxide dismutase (L-SOD) and vitamin E in preventing oxidative DNA damage and cytotoxicity in the rat kidney after administration of potassium bromate (KBrO₃) to male F344 rats were investigated by measuring 8-hydroxydeoxyguanosine (8-OH-dG), an oxidative DNA product, lipid peroxidation (LPO) levels and relative kidney weight (RKW). Combined pre- and posttreatment of animals with 2 × 800 mg/kg GSH i.p. inhibited the increase of 8-OH-dG, LPO levels and RKW caused by 80 mg/kg KBrO₃ i.p. administration. In contrast, pretreatment with 0.3 ml/kg diethylmaleate (DEM) i.p., a depletor of tissue GSH, was associated with elevation of 8-OH-dG, LPO levels and RKW after a 20 mg/kg KBrO₃ i.p. treatment, which itself caused no change. Administration of KBrO₃ itself reduced renal non-protein thiol levels, but this was inhibited by the two doses of exogenous GSH. Combined treatment with DEM and KBrO₃ lowered the non-protein thiol level in the kidney more than did DEM treatment alone. Protective effects against the oxidative damage caused by KBrO₃ were also observed for pre- and posttreatment with 400 mg/kg cysteine i.p., another sulfhydryl compound, and daily i.g. application of 200 mg/kg vitamin C for 5 days. However, no influence was evident after pre- and posttreatment with 18,000 U/kg L-SOD i.p. or daily i.g. 100 mg/kg of vitamin E for 5 days. The results suggest that intracellular GSH plays an essential protective role against renal oxidative DNA damage and nephrotoxicity caused by KBrO₃.     

Chemotherapy-induced anemia in patients with primary lung cancer.

To elucidate the factors which influence the value of hemoglobin, the nadir value of hemoglobin, frequency of blood transfusion and prognostic value of blood transfusion in patients with primary lung cancer during intensive chemotherapy, the hematological features of 124 patients entered into a randomized phase III study containing cisplatin were retrospectively analyzed. There was no difference in the percent nadir hemoglobin value of the first course of chemotherapy (% of pretreatment value) in any of the subgroups with respect to sex, body weight loss, performance status, age, stage, number of metastatic sites or treatment arms. The only predictive indicator for the nadir hemoglobin value in the first course of chemotherapy was the pretreatment value of hemoglobin. The equation for the regression line was y = 1.07 + 0.73x (R2 = 0.663, p < 0.001). The lowest nadir hemoglobin value (% of pretreatment value) during all chemotherapy courses was significantly lower in the subgroups older than 60 years and those with body weight loss. There was an inverse correlation between the accumulated dose of cisplatin and the lowest nadir hemoglobin value (p < 0.05). The frequency of blood transfusion in patients with more than two metastatic sites was significantly higher than in those with one or no metastatic sites (p < 0.05). Survival of patients who had required blood transfusion after chemotherapy was significantly shorter than that of patients who had not (p < 0.05).     

Pharmacokinetic Study of Mitomycin C with Emphasis on the Influence of Aging

Mitomycin C (MMC) at a dose of 8 mg/m² was administered by short intravenous infusion to 14 cancer patients. All patients had normal renal, hepatic, cardiac and bone marrow functions. The plasma level of MMC, which was determined by high-performance liquid chromatography over a 24–h period after the infusion, fitted the 2-compartment model curve except for one patient. There was a significant correlation between the area under the time versus concentration curve (AUC) of MMC and the age of patients ( r = 0.558, P < 0.05). Pharmacokinetic parameters in one of the older (a 69-year-old male) patients were extremely different from those of the other 13 patients. This patient experienced severe myelosuppression, probably due to the markedly increased AUC of MMC. Our results suggest that a patient's age has a significant influence on the pharmacokinetics of MMC in patients with normal major organ functions and that in some patients, MMC pharmacokinetics may be altered, possibly due to interpatient variation in the activation or metabolic pathway of MMC.     

Effect of Different Slopes of the Lower Leg during the Nordic Hamstring Exercise on Hamstring Electromyography Activity

The purpose of this study was to examine whether the NHE with an increased lower leg slope angle would enhance hamstring EMG activity in the final phase of the descend. The hamstring EMG activity was measured, the biceps femoris long head (BFlh) and the semitendinosus (ST). Fifteen male volunteers participated in this study. Subjects performed a prone leg curl with maximal voluntary isometric contraction to normalize the hamstring EMG activity. Subsequently, subjects performed the NHE, with the help of a certified strength and conditioning specialist, while the lower leg slope angle were randomly set at 0° (NH), 20° (N20), and 40° (N40). To compare hamstring EMG activity during the NHE variations, the knee flexion angle was set in the range from 0° to 50°, divided into five phases (0–10°, 10–20°, 20–30°, 30–40° and 40–50°), where 0° indicated that the knee was fully extended. To calculate the knee extension angular velocity, the knee flexion angle divided by time, and break point angle (BPA) was the angle at which 10°/s was exceeded. In the statistical analysis, a two-way repeated measures ANOVA was used for the hamstring EMG activity and a one-way repeated measures ANOVA was used for the BPA. The EMG activity of the BFlh and the ST in N20 and N40 was significantly higher than in NH at knee flexion angle of 0–20° (p < 0.05). For the BPA, NH (57.75° ± 13.28°), N20 (36.27° ± 9.89°) and N40 (16.26° ± 9.58°) were significantly higher in that order (p < 0.05). The results of this study revealed that the NHE with an increased lower leg slope angle shifted the BPA to the lower knee flexion angle and enhanced the hamstring EMG activity in the final phase of the descent.Key points

• The NHE with an increased lower leg slope angle enhances the hamstring EMG activity in the final phase of the descent.
• The NHE with an increased lower leg slope angle shifts the BPA to the lower knee flexion angle.
• The NHE with an increased lower leg slope angle may be an important rehabilitation exercise to prevent recurrence of HSIs.

Key words: Sports injuries, injury recurrence, hamstring muscles, electromyography, rehabilitation exercise, resistance training     

A Randomized Cross-over Study of High-dose Metoclopramide plus Dexamethasone versus Granisetron plus Dexamethasone in Patients Receiving Chemotherapy with High-dose Cisplatin

We carried out a randomized, single-blind, cross-over trial to compare the antiemetic effect, for both acute and delayed emesis, of granisetron plus dexamethasone (GRN+Dx) with that of high-dose metoclopramide plus dexamethasone (HDMP + Dx). Fifty-four patients with primary or metastatic lung cancer, given single-dose cisplatin (> 80 mg/m²) chemotherapy more than twice, were enrolled in this study. They were treated with both HDMP+Dx and GRN+Dx in two consecutive chemotherapy courses. On day 1, patients experienced a mean of 2.5 (SD=4.3) and 0,1 (SD = 0.4) episodes of vomiting in the HDMP+Dx and the GRN + Dx groups, respectively ( P =0.0008). Complete response rate on day 1 was 45 and 90% in the HDMP+Dx and the GRN+Dx groups, respectively ( P = 0.0001). Patients treated with GRN+Dx had a tendency to suffer more episodes of vomiting than the HDMP+Dx group on days 2–5, but it was not statistically significant. Twenty-four patients (57%) preferred the GRN+Dx treatment and 14 patients (33%), HDMP + Dx. In the HDMP + Dx group, nine patients (21%) had an extrapyramidal reaction, and 5 patients (12%) had constipation that lasted for at least two days. In contrast, no patients had extrapyramidal reactions, and IS patients (43%) had constipation in the GRN+Dx group ( P < 0.01). GRN+Dx was more effective than HDMP+Dx only in preventing the acute emesis induced by cisplatin. An effective treatment for delayed emesis is still needed.     

CPT-11: Population Pharmacokinetic Model and Estimation of Pharmacokinetics Using the Bayesian Method in Patients with Lung Cancer

In this study, we aimed to develop a population pharmacokinetic model for CPT-11 and to use the Bayesian method to estimate CPT-11 pharmacokinetic parameters in each of 43 patients who received combined therapy consisting of CPT-11 and etoposide. The group was divided into first and second data sets of 30 and 13 patients, respectively. We developed a population pharmacokinetic model of CPT-11 based on the first data set. The individual pharmacokinetic parameters [area under the concentration curve (AUC) and clearance (CD] were subsequently estimated by using the Bayesian method on the second data set. Plasma CPT-11 concentrations were measured by high-performance liquid chromatography, and compartmental pharmacokinetic models were fitted by the Bayesian method. The population pharmacokinetic model was developed by using the nonlinear mixed effect model. We selected the volume of the central compartment (Vc), CL, and distribution rate constants (K12, K21) as population pharmacokinetic parameters. The population mean values (CV%) of Vc, CL, K12, and K21 were, respectively, 31.8 (15.7%) liter/m²,14.1 (27.8%) liter/h/m²,1.1 (8.4%)/h, and 0.41 (30.3%)/h. Residual intraindivirtual variability was 22.9%. The optimal sampling regime for estimation of the AUC and CL in using the Bayesian method was the two time points of 1 and 8 h post infusion. The mean predictive error, the mean absolute predictive error, and the root mean squared error were -3.3, 9.4, 3.2% (AUC) and 6.3, 10.0, 3.5% (CL), respectively. We concluded that the AUC and CL of CPT-11 could be estimated from plasma concentrations at two times by using the Bayesian method.     

Changes in repolarization properties with long-term cardiac memory modify dispersion of repolarization in patients with Wolff-Parkinson-White syndrome

INTRODUCTION: Transient T wave changes after cessation of preexcitation have been attributed to cardiac memory. However, there have been no reports on the effects of long-term cardiac memory on repolarization dispersion before and after catheter ablation in patients with Wolff-Parkinson-White (WPW) syndrome. METHODS AND RESULTS: We investigated 47 patients with an accessory pathway (AP; 24 manifest left-sided, 14 manifest right-sided, and 9 concealed left-sided). Repolarization dispersion was analyzed by two methods, recovery time (RT) dispersion and newly proposed T wave width (WT), from 87-lead body surface maps before, 1 day after, and 7 days after catheter ablation. RT dispersion and WT were significantly correlated before, 1 day after, and 7 days after catheter ablation (r = 0.78). In patients with preexcitation, RT dispersion and WT increased significantly (P < 0.05) 1 day after catheter ablation (178 +/- 32 msec and 172 +/- 30 msec) compared with those before (154 +/- 24 msec and 156 +/- 18 msec) and 7 days after catheter ablation (147 +/- 19 msec and 156 +/- 16 msec), respectively. However, there were no significant changes in RT dispersion and WT before and after catheter ablation in concealed WPW syndrome. CONCLUSION: The findings suggest that the abrupt changes in activation sequence increase repolarization dispersion in the presence of previous cardiac memory, and that the dispersion decreases days or weeks after alteration of activation sequence by catheter ablation, with development of new cardiac memory in patients with manifest WPW syndrome.     

Detection of hypervascular hepatocellular carcinoma by dynamic magnetic resonance imaging with double-echo chemical shift in-phase and opposed-phase gradient echo technique: comparison with dynamic helical computed tomography imaging with double arterial phase

PURPOSE: The technique of double-echo chemical shift gradient echo magnetic resonance imaging (MRI) with the fast low-angle shot (double-echo FLASH) sequence provides in-phase and opposed-phase images in a single breath hold. The purpose of this study was to evaluate the efficacy of dynamic MRI with double-echo FLASH imaging for the detection of hypervascular hepatocellular carcinoma by comparing it with dynamic helical computed tomography (CT) imaging with double arterial phase. MATERIALS AND METHODS: Twenty-nine patients with 67 hypervascular hepatocellular carcinoma nodules who underwent both dynamic MRI with double-echo FLASH imaging (repetition time/echo time/flip angle: 160/3.6, 7.0/80 degrees ) and dynamic helical CT imaging with double arterial phase were enrolled in the study. For dynamic MRI, precontrast, arterial, portal venous, and equilibrium phase images were obtained before and approximately 19, 60, and 120 seconds, respectively, after intravenous injection of 0.1 mmol/kg of gadopentetate dimeglumine at a rate of 2 ml/s. For dynamic CT imaging, quadraphase images, including early arterial, late arterial, portal venous, and equilibrium phases, were obtained serially approximately 20, 30, 70, and 180 seconds, respectively, after intravenous administration of 2 ml/kg of 300 mgI/ml of nonionic contrast medium at a rate of 5 ml/s. Three masked observers independently interpreted images obtained with each technique in random order, separately and without patient identifiers. Sensitivity and positive predictive values as well as the area below the alternative-free response receiver operating characteristic curve (Az) for each imaging technique were calculated and compared statistically. RESULTS: Mean sensitivity and positive predictive values of MRI for hypervascular hepatocellular carcinoma were 48% and 94%, respectively, and those of CT imaging were 47% and 91%, respectively. In 11 (38%) of the 29 patients, at least one observer judged dynamic MRI to be superior, whereas in 5 patients (17%), dynamic CT was judged to be superior. There was no significant difference in the sensitivity and positive predictive values between these techniques (p > 0.05). There was no significant difference either in mean Az values between CT (0.55) and MRI (0.57) (p = 0.61). CONCLUSION: Dynamic MRI with double-echo FLASH imaging can detect hypervascular hepatocellular carcinoma as well as dynamic helical CT imaging with double arterial phase.     

High dose rate endovascular brachytherapy in aorto-iliac lesion for the prevention of restenosis

This study examined the applicability of endovascular brachytherapy to larger del arteries such as the abdominal aorta and iliac artery. Endovascular brachytherapy using an Ir-192 HDR source was administered 11 times to nine patients who had undergone percutaneous transluminal angioplasty (PTA) between 1995 and 1999. The follow-up lasted 13 to 55 months after treatment (median, 24 months). Eight of the 11 lesions have been controlled so far. Although one case developed thrombus inside the stent five months later, recanalization was achieved by means of retreatment. One patient who underwent low-dose irradiation (6 Gy) without stent implantation showed restenosis five months after treatment. We used a centering catheter that did not block the blood stream for exact centering of the radiation source in larger vessels such as the abdominal aorta. Although endovascular brachytherapy is a promising and safe procedure, careful follow-up is needed to detect untoward reactions such as thrombosis.