Effect of thermosensitive liposomal doxorubicin with hyperthermia on primary tumor and lung metastases in hamster osteosarcoma.

We evaluated the effect of intravenous thermosensitive liposomal doxorubicin (TL-DOX) together with local hyperthermia on primary tumors in highly metastatic hamster osteosarcoma. This combination resulted in higher DOX concentrations in plasma, primary tumors and lungs than standard DOX under the same conditions. Tumor growth and lung metastasis were also inhibited more by TL-DOX and hyperthermia than by hyperthermia alone, DOX with or without hyperthermia, and TL-DOX without hyperthermia. In addition, gains in hamster body weight were not suppressed. These results suggest that the combination of TL-DOX and hyperthermia can control primary tumors and suppress lung metastasis in hamsters.

Intrahypothalamic perfusion of KP102 stimulates growth hormone release in goats.

The hypothalamic actions of KP102 (also called GHRP-2) on the release of GH were studied in female goats. KP102 (10(-5) M) was perfused into the goat hypothalamus through a microdialysis probe (CMA/10 probe with a 4 mm membrane length) at a rate of 4 microl/min for 90 min, and plasma GH concentrations before and after perfusion were measured. The intrahypothalamic perfusion of 10(-5) M KP102 significantly stimulated GH release in goats (P<0.05). The GH levels began to rise after commencement of perfusion, and reached a maximum mean value at 180 min. The concentrations of GH at 165, 180, 195, 210, 225 and 240 min after commencement of perfusion of KP102 were significantly higher than the corresponding values for control animals (P<0.05). KP102 had no effect on GH pulse frequency, but it significantly increased the GH pulse amplitude after the perfusion (P<0.05). In contrast to KP102, intrahypothalamic perfusion of 10(-5) M GHRH had no effect on the stimulation of GH release in goats even if intravenous injection of 10(-5) M GHRH significantly stimulated GH release (P<0.05). These results suggest that KP102 may act partly on the hypothalamus to stimulate GH release in goats.

Improvement of thrombocytopenia following bone marrow transplantation by pegylated recombinant human megakaryocyte growth and development factor in mice.

We examined whether pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF) is capable of improving thrombocytopenia and promoting thrombopoietic reconstitution following lethal irradiation and bone marrow transplantation (BMT) in mice. Immediately after receiving 10 Gy whole body irradiation (day 0), male C3H/HeN mice were inoculated with 10(6) bone marrow cells obtained from syngeneic mice. Circulating platelet counts decreased to below 4% of the normal counts with a nadir on day 10, and then returned to the normal level on day 28 in the control mice undergoing BMT. Subcutaneous consecutive treatment with PEG-rHuMGDF at doses from 10 to 300 micrograms/kg/day from day 1 for 13 days significantly improved the platelet nadir and promoted platelet recovery. The white blood cell counts and hemoglobin concentration following BMT were not influenced by the PEG-rHuMGDF. PEG-rHuMGDF-injection starting from day 5 did not improve the platelet nadir following BMT. Furthermore, administration with PEG-rHuMGDF on alternate days at 55.7 micrograms/kg/day for 7 days or at an interval of 3 days at 78 micrograms/kg/day for 4 days (twice a week for 2 weeks) had a significant efficacy, but these administration regimens had less efficacy than consecutive administration at 30 micrograms/kg/day for 13 days. The numbers of megakaryocytes and megakaryocyte progenitor cells decreased to 5 and 0.2% of normal level, respectively, in the control mice. Consecutive administration of PEG-rHuMGDF enhanced the recovery of the mean number of these cells compared to those in vehicle-treated mice, although such effects were not statistically significant except for the number of megakaryocyte progenitors on day 12. These results suggest that consecutive treatment with PEG-rHuMGDF beginning from the day after BMT may be effective in improving thrombocytopenia following BMT.

Microdialysis measurement of intracerebral somatostatin in the goat.

A microdialysis sampling technique for the intracerebral measurement of somatostatin (SS) in extracellular fluid was examined in the goat. The microdialysis probe (70-mm shaft, 0.5 mm outer diameter) contained at its tip a 4-mm length of copolymer dialysis membrane (20 kDa cut-off). Artificial cerebrospinal fluid (artificial CSF) was pumped through the probe tip at a rate of 4 microliters/min with a batter-driven syringe pump, and effluent fractions of dialysate (120 microliters) were collected every 30 min. An in vitro recovery test showed that changes in the SS concentration in dialysate were highly correlated (r = 0.95, P < 0.01) with those in the external medium, and the relative recovery averaged 2.0%. As a validation for in vivo microdialysis, trails were conducted with conscious behaving goats wherein the inflow dialysate was changed transiently from artificial CSF with low potassium (2.5 mM) to a solution of 300 mM KCl. Potassium-induced depolarization around the probe tip located in the preoptic area and in the hypothalamus induced an increase in SS concentrations in dialysate at each location. In the most remarkable response, the concentrations of SS were increased 6-fold and 11-fold in the first and second 30-min fractions, respectively, compared with prepotassium concentrations. These results suggest that intracerebral SS levels in extracellular fluid could be estimated from conscious behaving goats by the use of our intracerebral microdialysis system.

[Bacteriological and clinical studies of panipenem/betamipron in pediatrics].

We carried out bacteriological and clinical studies of panipenem/betamipron (PAPM/BP), a newly-developed carbapenem antibiotic, in pediatrics, and the following results were obtained: 1. When antibacterial activities of panipenem (PAPM) were determined, it was found that MICs against such Gram-positive cocci as Staphylococcus aureus and Streptococcus pneumoniae and against such Gram-negative rods as Escherichia coli, Haemophilus influenzae, Pseudomonas aeruginosa, and Branhamella catarrhalis were all sufficiently low. 2. PAPM showed better MIC-correlated antibacterial activities against 215 subcultured strains of methicillin-resistant S. aureus (MRSA) than imipenem. 3. Clinical efficacies were evaluated to be excellent in 23 of 34 patients treated with PAPM/BP, excluding 3 patients from the efficacy evaluation. In addition, good responses were obtained in 10 patients but poor response in one, showing the overall efficacy rate of 97.1%. As for bacteriological efficacies, the eradication rate was also determined to be high, 92.6%. 4. As for side effects, rash appeared in 2 patients, and soft stool and diarrhea occurred in one each. The overall incidence of side effects was calculated to be 10.8%. As for abnormal laboratory findings, increases of eosinophiles in 4 patients, thrombocytes in 2, total bilirubin in 1, and GOT in 1 were observed. From these results, PAPM/BP was thought to be a highly useful drug in pediatrics.

Induction of transplantable tumors by repeated subcutaneous injections of natural and synthetic vitamin E in mice and rats.

Natural vitamin E and synthetic vitamin E (dl-alpha-tocopheryl acetate) were tested for their tumorigenicity in rodents. Transplantable tumors, at the site of injection, were induced by repeated injections of these compounds in two strains of mice, NFS/N and C57BL/6N x C3H/He F1, and in a strain of rats, Fischer 344. Natural vitamin E was tumorigenic in both strains of female mice only when injected with soya oil. In contrast, dl-alpha-tocopheryl acetate alone was capable of inducing tumors in Fischer 344 rats. Only one out of 5 male NFS/N mice given dl-alpha-tocopheryl acetate developed a tumor. Therefore, Fischer 344 rats were more susceptible to tumor formation by dl-alpha-tocopheryl acetate than NFS/N mice. dl-alpha-Tocopheryl acetate with soya oil or with palm oil also resulted in the formation of transplantable tumors in NFS/N mice and Fischer 344 rats. There was no difference in the tumor incidence between mice treated with dl-alpha-tocopheryl acetate alone and dl-alpha-tocopheryl acetate plus soya oil or palm oil. However, in rats, the incidence was lower for a group treated with dl-alpha-tocopheryl acetate plus palm oil than for those with dl-alpha-tocopheryl acetate alone and with dl-alpha-tocopheryl acetate plus soya oil.

[Clinical trial of T-3262 on acute enteritis. Japan Research Committee of T-3262, Research Group for Acute Infectious Enteritis].

For the purpose of evaluation of clinical efficacy, safety and usefulness on acute infectious enteritis (bacillary dysentery, and enteritis caused by Salmonella spp., Campylobacter spp., enteropathogenic E. coli, and so on), T-3262, a newly developed pyridone-carboxylic acid derivative, was administered to a total of 136 patients and carriers. In addition, in vitro antibacterial activity of T-3262 was determined against the clinical isolates, and compared with those of nalidixic acid (NA), pipemidic acid (PPA), enoxacin (ENX), norfloxacin (NFLX) and ofloxacin (OFLX). The daily dose of 450 mg of T-3262 was administered orally three times after meals for 5 days, with the exception of 7 day administration against Salmonella enteritis. A total of 89 cases were evaluated; 23 with Shigella spp., 30 with Salmonella spp., 15 with Campylobacter spp., 6 with enteropathogenic E. coli, and 15 cases with the other pathogens or pathogen-negative. The efficacy on clinical symptoms judging from duration of fever, and duration of diarrhea and abnormal stool character was 100% in all the enteritis except enteropathogenic E. coli enteritis, in which it was 50% (n = 2). Concerning bacteriological response, elimination of the causative organisms from the feces was 100% in Shigella spp. (n = 19), Salmonella spp. (n = 30), and enteropathogenic E. coli (n = 6), although 64.3% in Campylobacter spp. (n = 14). As an adverse effect, epigastric discomfort was observed in one (0.8%) of 130 cases. Deteriorations in laboratory findings were seen in five (6.2%) of 81 cases, consisting of two with elevated GOT and GPT, two with elevated GPT, and one with increased eosinophils count, although they were all slight in degree. MICs of T-3262 which inhibited 90% of the isolates of Shigella spp, Salmonella spp., and Campylobacter spp., were 0.025, 0.05, and 0.78 microgram/ml, respectively. These values were lowest among the quinolone derivatives tested, except that the MIC90 against Campylobacter spp. was the same as that of ofloxacin.