Molecular design of conjugated tumor necrosis factor-alpha: synthesis and characteristics of polyvinyl pyrrolidone modified tumor necrosis factor-alpha.

We conjugated tumor necrosis factor-alpha (TNF-alpha) with the synthetic polymeric modifier polyvinyl pyrrolidone (PVP) to facilitate its clinical use for anti-tumor therapy. TNF-alpha was chemically conjugated with the terminal carboxyl-bearing PVP at one end of its main chain, which was radically polymerized via the formation of an amide bond between the lysine amino groups of TNF-alpha and carboxyl group of PVP. In vitro specific bioactivity of PVP-conjugated TNF-alpha (PVP-TNF-alpha) relative to that of native TNF-alpha gradually decreased with increases in the degree of PVP attachment. In contrast, PVP-TNF-alpha in which 40% of TNF-alpha lysine residues were coupled with PVP (MPVP-TNF-alpha) exhibited the highest anti-tumor activity among the conjugated derivatives examined. MPVP-TNF-alpha had more than 200-fold higher anti-tumor efficacy than native TNF-alpha, and the anti-tumor activity of MPVP- TNF-alpha was more than 5-fold stronger than that MPEG- TNF-alpha which had the highest anti-tumor activity among PEG-conjugated TNF-alphas examined. Additionally, a high dose of native TNF-alpha induced toxic side-effects such as body weight reduction, piloerection and tissue inflammation, while no side effects were observed following i.v. administration of MPVP-TNF-alpha. The plasma half-life of MPVP-TNF-alpha (360 min) was about 80 and 3-fold longer than those of native TNF-alpha (4.6 min) and MPEG-TNF-alpha (122 min), respectively. These results suggested that PVP is a useful polymeric modifier for increasing the anti-tumor activity of PVP.

Indonesian medicinal plants. XVII. Characterization of quassinoids from the stems of Quassia indica.

Four new quassinoids named samaderines X (1), Y (2) and Z (3), and indaquassin X (5), and a new C19 quassinoid glycoside, 2-O-glucosylsamaderine C (10), together with five known quassinoids, samaderines B (7), C (8), and E (4), indaquassin C (6), and simarinolide (9), were isolated form the stems of Quassia indica (Simaroubaceae), an Indonesian medicinal plant. The chemical structures of these quassinoids have been elucidated on the bases of their chemical and physiochemical properties. Samaderines X (1), Z (3), E (4), and B (7) were shown to exhibit significant growth-inhibitory activity against the cultured malarial parasite Plasmodium falciparum (a chloroquine- resistant K1 strain), and 1--8 were shown to exhibit in vitro cytotoxicity (IC50: 0.04--100 micrograms/ml) against KB cells. Samaderines X (1), B (7) and C (8), as well s indaquassin X (5), exhibited inhibitory activity in the in vitro endothelial cell-neutrophil leukocyte adhesion assay, whereas samaderines X (1) and B (7) were found to exhibit significant anti-inflammatory activity.

Evaluation of angiogenic inhibitors with an in vivo quantitative angiogenesis method using agarose microencapsulation and mouse hemoglobin enzyme-linked immunosorbent assay.

In the present work, using a previously reported in vivo quantitative tumor-angiogenesis model, we attempted to ascertain whether this animal model is suitable for practical use in monitoring inhibitors of tumor angiogenesis. Mouse sarcoma-180 cells, human A431 cells or rat C6 cells microencapsulated in agarose beads were implanted s.c. into C57BL/6 mice. The level of blood vessel induction at the agarose pellet site was evaluated using mouse hemoglobin enzyme-linked immunosorbent assay on day 10 after implantation. Hydrocortisone, tetrahydro-S, medroxyprogesterone acetate, pentosan polysulfate and suramin inhibited blood vessel growth in our in vivo tumor-angiogenesis assay system, and heparin enhanced the antiangiogenic effects of hydrocortisone and tetrahydro-S. These results are almost entirely consistent with those observed in common assay systems, and suggest that this method may be useful for the identification and quantitative evaluation of inhibitors of tumor angiogenesis.

[Hyperbaric oxygen therapy in the Hokkaido University Hospital].

We surveyed the hyperbaric oxygen therapy during the past seven years in the Hokkaido University Hospital. The mean number of patients was 27 per year. The average number of the therapy was 328 per year. There were neither complications nor accidents attributable to the hyperbaric oxygen therapy. Three representative diseased states hypoxic brain damage, sudden deafness and occlusion of retinal arteries, showed remarkable recovery by this therapeutic modality. A safety standard has been revised in 1991. We have been operating the hyperbaric oxygen therapy according to the revised standard. The inter-departmental approach in this therapeutic modality is mandatory in order to achieve effective outcome.

Acetic acid intoxication by rectal administration.

The enhanced toxicity of acid instilled directly into the rectum, without benefit of dilution and neutralization in the upper intestine, is evident in a case of acetic acid intoxication by accidental rectal administration of 50 mL of 9% acetic acid to a 5-year-old boy. The complications included necrosis of the colon, acute renal failure, acute liver dysfunction, disseminated intravascular coagulopathy (DIC) and sepsis.