Structure-activity relationships of alkylxanthines: alkyl chain elongation at the N1- or N7-position decreases cardiotonic activity in the isolated guinea pig heart

Relationships between the alkyl substitutions (C1-C6) and cardiac inotropic activities of xanthine derivatives were studied in isolated guinea pig heart muscles. Most of the alkylxanthines exhibited positive inotropic activity on the left atrium, which was increased with an elongation of alkyl chain at the N3-position but decreased by substitution of a long alkyl group at the N1- or N7-position of the xanthine skeleton. Although positive inotropic activity in the right ventricular papillary muscle was also increased by longer alkyl groups at the N3-position, the inotropic activity became negative with an increment in alkyl chain length at the N1- or N7-position. The positive inotropic activity of alkylxanthines was correlated with their inhibitory activity on the phosphodiesterase (PDE) III isoenzyme. Adenosine A1 antagonism and PDE IV inhibitory activity were also partly associated with the inotropic activity because H-89, an inhibitor of cyclic AMP-dependent protein kinase, diminished the positive inotropic action and potentiated the negative inotropic action. These results indicate that the positive inotropic activity of alkylxanthines becomes weak with elongation of alkyl chains at the N1- and N7-positions; In particular, xanthines having two long alkyl chains show a negative inotropic activity on the right ventricular papillary muscle, an effect that could not be elucidated from their cyclic AMP-dependent action.     

Functioning survival rate of fixtures and superstructures of osseointegrated implants: ten years of progress in Tokyo Dental College Hospital (second report)

Endoglucanase production was measured in culture filtrates of four species of Saccobolus growing in media containing glucose or crystalline cellulose as the only carbon sources. Enzyme activity was four to seven times higher in the presence of cellulose than glucose. S. saccoboloides showed maximal growth and enzyme production. The extracellular proteins secreted during growth on cellulose were separated by polyacrylamide gel electrophoresis and stained for proteins. A zymogram technique was used to visualize bands with endoglucanase activity. The four species showed different protein and isoenzyme patterns.     

Differential chemosensitivity in oncogene-transformed cells

The effects of anticancer drugs on cell growth have been investigated by MTT colorimetric assay using mouse and rat cultured cells transformed by various oncogenes and tumor viruses. Aclarubicin, mitomycin C and 1-hexylcarbamoyl-5-fluorouracil showed higher growth-inhibitory activities toward transformed cells than those toward the normal counterparts. Nimustine, bleomycin and 5-fluorouracil also showed selective growth-suppressive activities toward transformed cells except for a few cell lines. ras-oncogene-transformed cells were more sensitive toward 5-fluorouracil and 1-hexylcarbamoyl-5-fluorouracil than the normal parent cells and other transformed cells. These drugs would thus be effective in the chemotherapy of ras-induced cancer.     

Hepatoblastoma in an adult associated with c-met proto-oncogene imbalance

A rare case of hepatoblastoma in a 61-year-old Japanese housewife is described. This liver tumor mainly consisted of two tissue components: embryonal hepatocytes and primitive mesenchymal tissue. Fetal hepatocytes with alpha-fetoprotein production, gland formation, cartilage and osteoid were also found in a small portion. Molecular analysis by slot blot method revealed increased copy numbers of c-met and K-sam proto-oncogenes and cyclin D1 genes. These findings suggest that alterations of these oncogenes might play a role in the development of adult hepatoblastoma.     

Diarrhea in young children associated with Escherichia coli non-O157 organisms that produce Shiga-like toxin

The aim of this study was to evaluate the way in which short-term protection declines and is eventually lost in preconditioning and to determine the efficacy of a second preconditioning at various reperfusion intervals. Male rabbits were divided into six groups. Forty-five minutes (sustained) ischemia followed by 120 minutes reperfusion was applied 60, 65, 70, 75, and 80 minutes after a 5 minute preconditioning (groups A, B, C, D, and E) and in a control group (F) after no preconditioning. The infarct to risk ratio (I/R) was 38.3 +/- 3.5% in group A, 46.0 +/- 7.8% in B, 61.6 +/- 9.7% in C, 68.1 +/- 4.2% in D, 64.5 +/- 7.8% in E, and 61.0 +/- 7.7% in F. Group A had a smaller I/R compared with groups C, D, E, and F (p < 0.05). In another series, groups G, H, and I were exposed to two 5-minute preconditioning stimuli, separated, respectively, by 45, 60, and 75 minutes of reperfusion; 10 minutes after the last preconditioning, the animals were exposed to 45-minutes ischemia and 120 minutes reperfusion. Groups A and D (with the smaller and higher I/R ratio) were also incorporated into this protocol in order to compare the effect of the additional preconditioning with the single one. The I/R ratio was 25.4 +/- 8.5% in group G, 22.8 +/- 7.0% in group H, and 14.7 +/- 4.0% in group I (p = NS). Group D showed a higher I/R compared with groups G, A, and H (p < 0.01), and group I had a smaller I/R compared with groups A (p < 0.01) and D (p < 0.001). Cardioprotection after a first preconditioning declines gradually and is eventually lost. An additional preconditioning is always effective, and the longer the interval from the first preconditioning, the more potent is the effect.     

Multiple coronary artery aneurysm

Co-Cinobufotalin Oral Liquor (CCOL) was studied for its ability to inhibit hepatitis B virus DNA replication, HBsAg and HBeAg expression in a HBV-transfected cell line (2.2.15 cell). The result showed that ID50 (the drug concentration that inhibits HBsAg or HBeAg secretion by 50%) was 0.08 mg/ml and 0.07 mg/ml on HBsAg and HBeAg respectively. CD50 (the drug concentration that reduces cell growth by 50%) was 2.5 mg/ml. TI (therapeutic index) was 31.3 and 35.7 respectively. The present data suggest that CCOL could exert a potent antiviral activity against HBV in vitro. Southern blot showed that CCOL inhibited HBV-DNA repication in a dose-dependent manner.