Antimalarial activity of radicicol, heptelidic acid and other fungal metabolites.

In the course of our screening program for artemisinin-like antimalarial compounds from microorganisms, seven fungal metabolites such as radicicol and heptelidic acid were identified as active compounds. Some of them exhibited antimalarial activity in vitro against the human malaria parasite Plasmodium falciparum to the extent of approximately 1/10 as potent as artemisinin. Radicicol was moderately active in vivo against Plasmodium berghei in mice.

Quantitative determination of domperidone in rat plasma by high-performance liquid chromatography with fluorescence detection.

A sensitive and selective analytical method for the determination of domperidone in rat plasma is described. The procedure involves liquid-liquid extraction followed by reversed-phase high-performance chromatographic analysis with fluorometric detection at 282 nm for excitation and 328 nm for emission. The detection limit was 1 ng ml(-1) using 1 ml of plasma. This assay procedure should be useful for the pharmacokinetic study of domperidone in small animals such as rats.

Effect of acute renal failure on the distribution of iomeprol, a nonionic contrast agent, to cerebrospinal fluid in rats.

The effect of acute renal failure on the pharmacokinetics concerning the cerebrospinal fluid (CSF) distribution of iomeprol, a nonionic contrast agent, was studied. The concentrations of iomeprol in the plasma and CSF were measured after intravenous (i.v.) administration at the dose of 50 or 500 mg/kg body weight. The time courses of plasma and CSF concentration were linear within the dose studied. Influx and efflux clearances estimated by simultaneous fitting were 4.6 x 10(-5) ml/min and 8.8 x 10(-4) ml/min, respectively, which suggested that the distribution of iomeprol to CSF low and linear. The distribution volume at steady state was 300-500 ml/kg, suggesting that iomeprol was readily distributed to the extracellular space but hardly distributed to the intercellular space. Total body clearance (9-13 ml/min/kg) indicated that iomeprol was mainly excreted by glomerular filtration. In the rat with acute renal failure induced by ligating the binary ureters, the concentration of iomeprol in CSF after i.v. administration of 500 mg/kg dose was much higher than that in the intact rat according to the delay of elimination from plasma (CLtot = 0.07 ml/min/kg). However, the time course of iomeprol concentration in CSF was predictable using the values of the influx clearance to CSF and the efflux clearance from CSF determined by intact rats. In conclusion, renal failure is one risk factor for central nervous system toxicity because of decreased total body clearance, while acute renal failure may not affect the transport of iomeprol to CSF.

[Inhibitory effects of prostaglandin E1.alpha-cyclodextrin (PGE1.CD) on dimethylnitrosamine-induced acute liver damage in rats].

The effects of PGE1.CD on dimethylnitrosamine (DMN)-induced acute liver damage with intravascular coagulation in rats were biochemically and histopathologically investigated. PGE1.CD was administered i.v. from 30 min before to 24 hr after DMN-intoxication (pretreatment) and from 30 min after or from 4 hr after to 24 hr after DMN-intoxication (post-treatment). Pretreatment with PGE1.CD (0.2-2 micrograms/kg/min) dose-dependently suppressed the decrease of platelet counts and the elevation of blood biochemical parameters (PT, HPT, GOT, GPT, LDH, LAP, T-Bil) caused by DMN-intoxication. PGE1.CD (0.5 microgram/kg/min and over) significantly suppressed the DMN-induced histopathological changes (occurrence of hemorrhage and necrosis). Post-treatment with PGE1.CD (2 micrograms/kg/min) also suppressed the liver damage. Furthermore, pretreatment with PGE1.CD (2 micrograms/kg/min) not only suppressed the disruption of hepatocytes, but also prevented the damages of sinusoidal endothelial cells and lysosomal membrane, and it reduced the increase of lipid peroxidation. PGE1.CD (1 microgram/kg/min and over) significantly suppressed the decrease of hepatic tissue blood flow caused by DMN-intoxication. These results demonstrate that PGE1.CD has therapeutically efficacy against DMN-induced acute liver damage in rats; Therefore, it will be clinically useful for the treatment of severe hepatitis such as fulminant hepatitis with intravascular coagulation in the sinusoid.

[Mucosubstance and lectin histochemistry of DMH induced colonic tumor in rats].

Histo-pathological appearances of DMH-induced colonic tumor in Wistar rats were sequentially observed upto the 35th week after the drug administration. In our series, 28 tumors were successfully induced in the colonic mucosa of 19 out of 64 rats treated with DMH, and they were histologically diagnosed as adenocarcinoma. However, there were differences in the histo-pathological findings of the carcinoma between the distal colon and the proximal colon in rats. That is, the slowly growing type of well differentiated adenocarcinoma was likely to originate from the proper mucosa in the distal colon, while in the proximal colon the rapidly growing type of tumor did from atypical glands in the lymphoid follicles. Therefore, it was suggested that histogenesis and growing processes of the carcinoma were differed in the distal colon from that in the proximal colon in rats. Second, epithelial mucosubstances and lectin-binding properties of these lesions were examined histochemically. There were differences in the lectin-binding patterns of UEA-I and PNA between carcinomas and/or atypical glands in the lymphoid follicle and normal background mucosa in rat colon. In the UEA-I staining, almost all tumors were positively stained except for one case, and in the well differentiated type a positive staining was discernible at the cell apex and secretory product in tumors, while in the undifferentiated type, it was seen at the cytoplasma and secretory product. From these histopathological and histochemical studies it may be concluded that these lectins is likely to be useful as tumor markers for the large bowel, and also effective for a diagnosis of minute carcinoma in the large bowel.

Study of response to naproxen in patients with hepatocellular carcinoma who developed fever following transcatheter arterial embolization.

Good antipyretic response was obtained when naproxen was given at 600 mg/day for about one week to patients who developed fever after transcatheter arterial embolization (TAE). Fever recurred in several patients, but subsided again when naproxen was given at 300 mg/day. No patients developed gastric mucosal lesions of clinical concern that seemed to be related to naproxen.