Safety and tolerability of immune globulin intravenous (human), 10% solution in Japanese subjects with mild to moderate Alzheimer's disease.

BACKGROUND: Immune globulin intravenous (IGIV), 10% is a donor-derived polyclonal human immunoglobulin G antibody mixture that has potent immune modulatory properties and contains conformation selective anti-amyloid antibodies. We evaluated the safety and tolerability of multiple doses of IGIV, 10% in Japanese patients with mild to moderate Alzheimer's disease. METHODS: Among the 16 subjects, 12 subjects were assigned to the IGIV group and 4 subjects to the placebo group. Subjects received a total of six infusions of either IGIV at a dose of 0.2 or 0.4 g/kg, or placebo every 2 weeks. RESULTS: A total of 33 treatment-emergent adverse events (TEAE) occurred in 14 subjects: 13 TEAE in five subjects in both the IGIV 0.2 and 0.4 g/kg groups, and 7 TEAE in four subjects in the placebo group. The most common TEAE in the IGIV subjects were nasopharyngitis, injection-site swelling, and erythema. All 26 TEAE in the IGIV group were considered to be mild. Only one mild TEAE (rash) was considered to be possibly related to the study drug. There were no significant differences in incidence of TEAE between the treatment groups. Four serious TEAE were reported, and all of these were considered to be unrelated to the study treatment. Other assessments related to safety revealed neither clinically significant abnormal values nor findings in the study. CONCLUSION: IGIV is generally safe and well tolerated with multiple intravenous infusions at doses of 0.2 g/kg and 0.4 g/kg in Japanese patients with mild to moderate Alzheimer's disease.

A novel automated method for measuring the effect of analgesics on formalin-evoked licking behavior in rats.

The behavioral assessment of pain is essential for the analysis of pain mechanisms and the evaluation of analgesic drugs. The formalin test is one of such methods widely used as a model of injury-induced pain in rodents. This test is manually demanding and the recording of results is left to the subjectivity of the experimenters. Thus we developed a novel automated method to estimate the pharmacological response in formalin-induced licking behavior in rats using a multicolor detection technique. Two color markers were preliminarily applied to rats-yellow dye on the mouth and fluorescent green tape on the right hind paw. Behaviors of the animals were recorded from both above and below the subject, by a dual-view digital video camera system. After injection with formalin into the hind paw, rats exhibited a biphasic display of licking behavior. Licking time was measured by the sum of frames where the distance between these markers was less than an appropriate threshold of distance (TD). The split-plot analysis of variance demonstrated that the sum of squares of differences in licking time between manual and automated measurement was minimized when TD = 20mm. In addition, frames in which moving velocity of these markers is less than 2.5mm/s was neglected for calculation in order to eliminate sedative effect on the recorded data. On these conditions, subcutaneous administration of morphine in rats dose-dependently decreased formalin-elicited nociceptive responses. These results suggest that under optimal conditions the automated technique when applied to pharmacological studies are more reliable and efficient than if they are manually recorded.

High throughput solubility measurement with automated polarized light microscopy analysis.

As a high throughput solubility assay, the solution-precipitation method using a dimethylsulfoxide (DMSO) sample stock solution (DMSO-SP) has been widely used in drug discovery. However, the solid form of the precipitant has not been investigated. In this study, we investigated the experimental conditions of the DMSO-SP, focusing on the solid form of the precipitant. The final concentration of DMSO was 1% (v/v). The precipitant of more than a half of the model compounds was observed as crystalline by polarized light microscopy analysis. When the incubation time was 20 h and the precipitant was crystalline, the DMSO-SP solubility was similar to the solubility from a powder material (PWD). However, when the incubation time was 10 min and/or the precipitant was not crystalline, the DMSO-SP solubility was higher than the PWD solubility. These results suggested that the information regarding the solid form of the precipitant is important in interpreting the solubility data. In addition, we developed an automated birefringence diagnose system for drug discovery usage.

CJ-15,208, a novel kappa opioid receptor antagonist from a fungus, Ctenomyces serratus ATCC15502.

A novel kappa opioid receptor binding inhibitor CJ-15,208 (I) was isolated from the fermentation broth of a fungus, Ctenomyces serratus ATCC15502. The structure of I was determined to be a cyclic tetrapeptide consisting of one tryptophan, one D-proline, and two L-phenylalanine. Compound I was a selective binding inhibitor for the kappa opioid receptor: 47 nM (IC50) for kappa, 260 nM for mu, and 2,600 nM for delta. In the electrically-stimulated twitch response assay of rabbit vas deferens I recovered the suppression by a kappa agonist asimadoline with an ED50 of 1.3 microM, indicating that it is a kappa antagonist.