Current state of interferon (IFN) research is reviewed mainly concerning the properties of IFN molecules and their production in vivo and in vitro. Through the recent upsurge of IFN research, much information has been accumulated on the chemistry of IFN molecules and on the varied actions of IFN at the cellular level, but, to understand the role of IFN in, among others, immune or inflammatory responses of the body, much effort combining different disciplines will still be needed.

View full abstract

Human α and β interferon was evaluated as treatment for viral and malignant diseases.
Lympocytes from patients with chronic hepatitis B have decreased activity to produce interferon stimulating in vitro. Five patients with chronic hepatitis B were injected daily with human α interferon, in doses ranging from 100, 000 to 1, 000, 000 units/day. Total amounts injected were from 15, 400, 000 to 96, 000, 000 units. DNA polymerase activity was measured in three from these five patients. After interferon treatment, DNA activity decreased in all these three cases. Hepatitis B antigen was assayed using RPHA method. In only one case, HBs Antigen became negative. HBc antigen in liver tissue became negative in one case examined immunofluorescence technique. Disappearance of e antigen was observed in two of five cases. Before and after treatment, liver biopsy was done. In two of these five cases, marked improvement (disappearance of cell necrosis) could be recognized. But suppressive effect wa transient. Interferon therapy was tolerated in all patients. Low grade fever developed during course of therapy. All cases had no elevation of transaminase by therapy. All five patients did not show bone marrow suppresion.
Phase I study of human β interferon against malignant tumors (collaborative study) started recently. Eighteen cases already are checking about effect of interferon, only one case injected topically showed very remarkable diminution of size of tumor.

View full abstract

Rats with severe, acute inflammation in a hind foot following the subplantal injection of mycobacterial adjuvant, as well as those with secondarily developed polyarthritis, demonstrated a significant decrease in activity of drug metabolism in vivo and in vitro, and a marked increase in proportion of the rough endoplasmic reticulum (RER) with concomitant decreases of the smooth endoplasmic reticulum (SER) and glycogen granules in hepatocyte. Probably, the increased RER may indicate a stimulated synthesis of specific proteins known as the acute phase proteins (APP) .
Glucocorticoids were significantly effective in preventing these functional and morphologic changes occurring in both acute and chronic inflammation, while non-steroidal anti-inflammatory agents were without effect even in the doses enough to inhibit peripheral inflammation processes. It is assumed that glucocorticoids may act to induce the SER in hepatocyte by stimulating the synthesis of anabolic proteins, instead of APP, and to improve the decreased drug metablism in severely inflamed rats.

View full abstract

During phagocytosis of serum-opsonized zymosan by guinea-pig polymorphonuclear neutrophils, the leucine aminopeptidase activity decreased significantly, whereas 5'-nucleotidase and alkaline phosphodiesterase activities remained unchanged. Inactivation of leucine aminopeptidase activity was not observed by exposure of neutrophils to non-opsonized zymoan, IgG-coated zymosan or polystyrene latex particles. Pretreatment of neutrophils with cytochalasin B, which prevents phagocytosis but not surface binding of particles, did not prevent leucine aminopeptidase from inactivation. On the other hand, the inactivation during phagocytosis was protected by serine protease inhibitors. These findings suggest that loss of leucine aminopeptidase activity from phagocytosing cells may be mediated by certain serine protease inhibitor-sensitive factor (s) which are probably activated by the attachement of an opsonized zymosan particle to a specific membrane recptor, probably the C3b receptor.

View full abstract

A water-inoil emulsion containing a synthetic adjuvant, N-acetylmuramyl-L-alanyl-D-isoglutamine (MDP) induced typical adjuvant-induced arthritis in euthymic rats but not in athymic nude rats. The nude rats as well as euthymic rats, however, developed acute polyarthritis with a 100% incidence after consecutive intravenous injections of 6-O-acyl MDP, such as L₁₈MDP or [B 30] -MDP. This acute polyarthritis rapidly subsided after stopping the injections but flared up within 24 hours after booster injection of 6-O-acyl MDP not of MDP.
The histological features of the acute polyarthritis revealed acute exudative synovitis, subsynovitis and tendinitis.
The present finding that adjuvant active MDP and its derivatives induced transient leukocytosis suggests that this new model of arthritis may result from direct inflammatory reaction to MDP molecules deposited in the diseased joints.

View full abstract

The average TBA value of infectioned jaw cysts fluid was higher, and polyunsaturated fatty acid relative content was lower, than those of non-infected or infection eradicated cysts fluid by irrigation with antibiotic solution. When infection was eradicated by irrigation, the average TBA value and polyunsaturated fatty acid relative content returned to the level of non-infected cysts fluid. Then the average TBA value of infected jaw cyst walls was higher than that of non-infected or infection eradicated jaw cyst walls by irrigation. Indomethacin, added to the homogenate of jaw cyst walls in vitro, lowered the TBA value. The magnitude of indomethacin-effect seemed to correlate positively with the original TBA value. Indomethacin inhibits fatty acid cyclooxyenase, and TBA value could be thought as an indicator of syntheses of PG-endoperoxides. And then its supposed that the syntheses of PG-endoperoxides in infected-jaw-cysts were more stimulated as compared with non-infected ones. Therefore in conclusion the TBA value of jaw cyst walls may reflect the degree of inflammation in the tissue.

View full abstract

No useful profiling analyses of prostaglandins (PGs) in biological matrix have been reported. We present here a quantitative profiling analysis of urinary PGs determined by GC or GC-MS using a new simple extraction method. In both cases ODS silica column (Sep-Paks, Waters) was used for extraction of PGs from human urine. This column was pretreated with 20 mlethanol followed by 20 mlwater before use. The 20 mlsample was acidified with formic acid to pH 3.0 and passed through a ODS silica column using a glass syringe. The column was eluted successively with 20 mlethanol/water (15/85), 20 mlpetroleum ether and 10 mlmethyl formate. The recovery rate estimated using³H-PGs in methyl formate fraction was as follows. 6-keto-PGF_1α: 68%, PGE₂: 60%, PGF_2α: 65%. The samples were derevatized to 6-keto-PGF_1α-MOX-TMS-Bz, PGE₂-MOX-TMS-Bz and PGF_2α-TMS-Bz after extractive alkylation using THAH and benzyl bromide. GC peaks of the PG derivatives appeared at the same retention time as external standards. The quantitative determination of endogenous PGs were thus achieved by GC. d₇-6-keto-PGF_1α, d₇-PGE₂and d₈-PGF_2αwere added as internal standards to the human urine, which was treated with the same procedure as above. PGs in the methyl formate fraction were derivatized to 6-keto-PGF_1αMOX-Me-TMS, PGE₂-Me-TMS and PGF_2α-Me-TMS. The sample was analysed by GC-MS (JEOL D-300) using selected ion monitoring.
In conclusion, we have developed a new simple extraction method for PGs using a convenient ODS silica column chromatography in combination with the extractive alkylation. It seems to be very useful for the quantitative profiling analysis of urinary PGs.

View full abstract

Liposomes have been used in animals as a good carrier for several drugs. However, problems with liposomal therapy are instability of liposome and lack in clinical use. Lipid particles, which are very stable and in widespread use for parenteral nutrition in man (intralipid), are also taken up readily by phagocytic cells like liposome. The present study was undertaken to investigate whether or not both IgG coated and non-coated lipid particles can be a good carrier for various drugs. The tissue distribution of lipid particles was studied by electromictoscopy and fluorescent microscopy. The lipid particles were easily phagocytized by macrophage of the liver, spleen and abdominal cavity, but not by neutrophils. On the other hand, IgG coated lipid particles were phagocytized by both of macrophage and neutrophils. Free dexamethasone phosphate exerted little influence on phagocytosis of IgG coated latex by macrophage, while lipid particles containing dexamethasone palmitate markedly suppressed the phagocytosis. This study suggests that IgG coated and non-coated lipid particles can be used as a drug carrier for various fat-soluble drugs.

View full abstract

In the in vitro studies of murine lymphocytes, CCA showed a tendency to increase the viability of spleen cells and an activity to enhance the mitogenic responses of those cells by LPS, B-mitogen. Enhancing effects of CCA on T-mitogen-induced lymphocytes reaction have also been reported in other papers. These results were considered in connection with a phenomenon that CCA increased the RNA polymerase activity of nucleus from rat lymphnode cells. CCA also enhanced thein vivo mitogenic reaction by Con A. CCA was not mytogenic by itself.
As for the activities of macrophages, CCA did not almost show any effects inin vitrostudies while it did in the carbon clearance test using both normal and tumor-bearing animals.

View full abstract

CS-600, sodium 2- (4- (2-oxocyclopentan-l-yl methyl) phenyl) propionate, which has potent anti-inflammatory and analgesic activities, showed a weak inhibitory activity to thein vitroPG synthesis with bovine seminal vesicle microsomes (IC₅₀: 760μM) . Its main metabolite, which was produced by stereospecific reduction of the cyclopentanone moiety to hydroxy cyclopentane, exhibited a potent inhibitory activity (IC₅₀: 9 μM) to the enzyme. The stereospecific configuration (trans-OH, SRS) was essential for the inhibitory activity. Oral administration of CS-600 to rats markedly decreased the urinary PGE₂and F₂α levels, suggesting that the active metabolite was produced and inhibited PG synthesisin vivo. In a culture system of 3T6 fibroblasts, CS-600 was effectively converted to the active metabolite and inhibited the PGE₂production of the fibroblasts.

View full abstract

The effect of pranoprofen (PPF), indomethacin (IM) and acetylsalicylic acid (ASA) on acute and chronic inflammation, inflammatory pain and gastro-intestinal organ in mice was investigated. The inhibitory effect of PPF on carrageenin- or concanavalin A-induced paw edema, phenylquinone writhing and cotton pellet granuloma formation was as potent as that of IM and more active than that of ASA. In contrast, PPF was about 15 times less active than IM in the production of gastric ulcers in mice. Furthermore, PPF was less active than IM in the inhibition of stomach prostaglandins synthesis and arachidonic acid-induced diarrhea in mice. These results suggest that the less potent activity in inhibiting the gastro-intestinal prostaglandins synthesis of PPF with the potent anti-inflammatory activity contributes to its weak ulcerative effect in mice.

View full abstract