Pre- and post-operative adjuvant chemotherapy in colorectal cancer

A multi-center randomized controlled study was conducted in order to investigate the usefulness of pre- and post-operative adjuvant chemotherapy in colorectal cancer. The patients were stratified into those with colon cancer and those with rectal cancer and divided into 2 groups, Group A and Group B. The patients in Group A received tegafur suppositories (750 mg/day) from 1 to 2 weeks prior to surgery, to 2 weeks following surgery and then oral administration of tegafur and uracil (UFT) (260 mg/m(2)) for 1 year. The patients in Group B, on the other hand, received only UFT (260 mg/m(2)) for 1 year beginning week 2 after surgery. Although there was no significant difference between Groups A and B in the 5-year survival rate, the 5-year disease-free survival rate was significantly higher in Group A, especially for rectal cancer (p<0.05). In addition, remote metastases tended to be suppressed for both colon and rectal cancer in Group A (p=0.08 and p=0.072). There was no serious adverse reaction to tegafur. Pre- and post-operative adjuvant chemotherapy with tegafur had fewer adverse reactions and was convenient to administer. Thus, it was considered useful for suppression of postoperative distant metastasis in colorectal cancer.     

Efficacy of corticosteroids in sarcoidosis presenting with atrioventricular block

BACKGROUND: The usefulness of corticosteroid therapy for cardiac sarcoidosis has not yet been fully clarified. METHODS: Of 40 patients diagnosed with cardiac sarcoidosis, twenty patients complicated by atrioventricular block but normal cardiac function (left ventricular ejection fraction > or = 50%) were divided retrospectively into one group (n = 7) receiving corticosteroids and another (n = 13) not receiving these agents. Over a mean observation period of 79.4 +/- 39.9 months, long-term outcome and laboratory findings were compared between the two groups and side effects also were noted. RESULTS: There were no deaths in the corticosteroid-treated group. In the untreated group, 2 patients died (15.4%). Atrioventricular block resolved in 4 of the 7 patients in the treated group (57.1%), but did not resolve or improve in any of the untreated patients (p < 0.05). Left ventricular ejection fraction did not differ significantly between the treated and untreated groups at the time of initial evaluation (66.7 +/- 6.5% vs. 60.5 +/- 6.4%). In the follow-up period, a marked decline in the ejection fraction had occurred in the untreated group (37.6 +/- 17.3%), but not in the treated group (62.1 +/- 4.4%; p < 0.005). Ventricular tachycardia was not present at the initial assessment in any patient in either group. In the follow-up period, ventricular tachycardia occurred in only 1 of 7 treated patients (14.3%), but was present in 8 of 13 untreated patients (61.5%; p < 0.05). However, side effects of corticosteroid therapy were noted in 6 of the 7 treated patients (85.7%). CONCLUSION: Our findings suggest that corticosteroids are useful in the treatment of cardiac sarcoidosis complicated by atrioventricular block but with normal cardiac function. However, these agents must be used with caution, with the maintenance dose kept as low as possible.     

Intracellular dynamics of sigma-1 receptors (sigma(1) binding sites) in NG108-15 cells

The sigma-1 receptors bind diverse kinds of psychoactive compounds, including cocaine, and translocate upon stimulation by these compounds. However, the exact intracellular localization and dynamics of sigma-1 receptors have been unclear. We recently found that sigma-1 receptors specifically localize on cholesterol-enriched loci on the endoplasmic reticulum (ER) membrane that function as neutral lipid storage sites (i.e., ER lipid droplets or ER-LDs) from which neutral lipids bud out to form cytosolic lipid droplets. By combining immunocytochemistry and real-time monitoring of enhanced yellow fluorescent protein (EYFP)-tagged sigma-1 receptors (Sig-1R-EYFP) in living cells, we characterized the sigma-1 receptor translocation in this study. (+)-Pentazocine, a selective sigma-1 receptor agonist, causes a significant decrease of sigma-1 receptors in ER-LDs and a diffused distribution of sigma-1 receptors over the entire endoplasmic reticulum reticular network in NG108-15 cells. In the presence of sigma-1 receptor agonists, Sig-1R-EYFP move out from ER-LDs and slide along the endoplasmic reticulum network toward nuclear envelope and the tip of neurites. Fluorescence recovery after photobleaching analysis demonstrates that Sig-1R-EYFP on endoplasmic reticulum reticular network are highly mobile compared with those in ER-LDs. A sucrose gradient fractionation study shows that (+)-pentazocine shifts sigma-1 receptors from ER-LD membranes to higher density membranes. These results indicate that sigma-1 receptors localize on ER-LDs and upon stimulation translocate on continuous endoplasmic reticulum reticular network toward peripheries of cells. Because sigma-1 receptors specifically target ER lipid storage sites and compartmentalize neutral lipids therein, these results suggest that sigma-1 receptors' dynamic translocation might affect lipid transport and distribution in neuronal cells.     

Plasma concentrations of (n-3) highly unsaturated fatty acids are good biomarkers of relative dietary fatty acid intakes: a cross-sectional study

A cross-sectional study was conducted to clarify the associations of lifestyle factors (habitual exercise, alcohol intake and smoking habit) and plasma fatty acid (FA) concentrations as biomarkers of dietary FA intakes. We collected 7-d weighed diet records, lifestyle information and blood samples from 15 male and 79 female Japanese dietitians, and estimated dietary FA intakes and analyzed plasma FA concentrations. Plasma concentrations of eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) and (n-3) highly unsaturated FA (HUFA) derived from marine foods, but not linoleic and alpha-linolenic acid from plant origins, demonstrated positive correlations with dietary intakes (r = 0.303-0.602, P < 0.05) in both genders. Multiple linear regression analyses adjusted for age, BMI, total energy intake, fat (or respective FA) consumption and lifestyle factors showed that dietary intakes of EPA, DHA and (n-3) HUFA were positively associated with age in men (P < 0.05) and negatively associated with BMI in women [P < 0.01 for DHA and (n-3) HUFA]. The plasma concentrations of EPA, DHA and (n-3) HUFA in women were found to be positively associated with age and marine oil (or respective FA) intake (P < 0.01), and negatively associated with total energy intake [P < 0.05 for EPA and (n-3) HUFA]. Lifestyle factors were not associated with dietary FA intakes and plasma FA concentrations. These findings suggest that the plasma concentrations of EPA, DHA and (n-3) HUFA might be useful biomarkers for the assessment of relative FA intakes without considering associations with habitual exercise, alcohol intake and smoking habit.     

ZTTA,a Prolyl Endopeptidase Inhibitor,Potentiates the Arginine-Vasopressin-Induced Incorporation of [14C]Leucine in Rat Amygdaloid and Cortical Slices

Pharmaceutical Research -     

Permeation of PEO-PBLA-FITC Polymeric Micelles in Aortic Endothelial Cells

Purpose. To determine aortic endothelial cells permeation ability and mechanisms of the aqueous block copolymeric micelles, poly(ethylene oxide)-poly ((-benzyl L-aspartate) (PEO-PBLA) chemically conjugated with fluroescein isothiocyanate (FITC) by transport study and confocal laser scanning microscopy. Methods. The block copolymers' PEO-PBLA-FITC was first synthesized and characterized by gel permeation chromatography (GPC) reflect index, UV, fluorescence detectors, and critical micelles concentrations (CMC), and atomic force microscopy (AFM). Permeation ability and mechanisms of polymeric micelles in aortic endothelial cells were evaluated by incubating with NaF, NaN₃, wortmannin, cytochalasin B inhibitors, at 20°C, and under reverse conditions. FITC and latex particles (40 nm) were also used for comparison of transport ability. The extent of localization of uptake polymeric micelles was established by confocal laser scanning microscopy. Results. The size of the aqueous PEO-PBLA-FITC polymeric micelles was detected at around 56 nm with unimodal distribution by AFM. The CMC test revealed the fluorescence intensity increased to around 0.01 0.05 mg/ml. NaF, NaN₃, wortmannin, cytochalasin B, 20°C, and reverse experiments inhibited the absorption of polymeric micelles through aortic endothelial cells with apparent permeability coefficients (P) of 18.07 ± 1.03 to 12.98 ± 0.93, 11.31 ± 0.77, 12.44 ±1.23, 6.40 ± 0.23, 11.11 ± 0.46, and 10.22 ± 1.09 X 10^–7 cm/sec, respectively. Also, the permeation of FITC and latex on aortic endothelial cells was 70.02 ±4.71, and 2.05± 0.41 X 10^–7 cm/sec, respectively. Confocal laser microscopy showed that fluorescent compounds were distributed in the intracellular cytoplasm and nucleus. Conclusions. PEO-PBLA-FITC copolymeric micelles in an aqueous system were transported by energy-dependent endocytosis with 18.07 X 10^–7 cm/sec penetrated range and were localized on intracellular and nucleus endothelial cells.     

Reduction of the Side Effects of an Antitumor Agent, KRN5500, by Incorporation of the Drug into Polymeric Micelles

For intravenous (i.v.) injection of a water-insoluble antitumor drug, KRN5500, we have successfully incorporated KRN5500 into polymeric micelles. In the present study, in vitro and in vivo antitumor activity against several human tumor cell lines and toxicity in mice of polymeric micelles incorporating KRN5500 (KRN/m) were evaluated in comparison with those of the prototype KRN5500. KRN/m was found to express similar antitumor activity to KRN5500 in the in vitro and in vivo systems. However, the vascular damage and liver focal necrosis observed with KRN5500 i.v. injection were not seen when KRN/m was administered i.v. Therefore, we expect that KRN/m will be superior to KRN5500 for clinical use and that the methodology of polymeric micelle drug carrier systems can be applied to other water-insoluble drugs.     

Phencyclidine-induced retrograde amnesia in mice

The amnesic action of phencyclidine (PCP) was investigated in mice using a passive avoidance- and escape-learning method. PCP (10–30 mg/kg) administered immediately after the training test dose-dependently shortened and prolonged the step-down latency and escape latency, respectively in the retention test. There was a significant inverse relationship between the step-down and escape latencies, indicating that PCP had induced amnesia. The amnesic actions of PCP were retrograde, being observed when mice were given PCP within 10 min but not more than 30 min after the training test. The amnesic effects of PCP on both variables were antagonized significantly by physostigmine and naloxone, whereas cyproheptadine and haloperidol had no effect. None of these drugs by themselves affected passive avoidance- or escape-learning performance. These results suggest that the retrograde amnesic actions of PCP were produced via either the cholinergic or the opioidergic systems or both, but not through the serotonergic and the dopaminergic systems. Offprint requests to: T. Nabeshima