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Japanese scallops Patinopecten yessoensis are one of the main marine products of Hokkaido, Japan. In addition to adductor muscle, scallop mantle tissue is also eaten in Japan. We fed Wistar rats diets containing the scallop mantle epithelial cell layer for 3-8 weeks and compared the outcomes with a control group. No differences in general appearance or behavior were observed between the groups for the first 2 weeks. Thereafter, a significant decrease in food consumption was observed, and the treated rats died between 6 and 8 weeks. Serum biochemistry and histological studies revealed nephrotoxicity and hepatotoxicity in rats fed scallop mantle epithelial cells. Glucose tolerance tests showed that feeding scallop mantle epithelial cells to rats causes a glucose metabolism disorder. A diet containing a water extract from scallop mantle epithelial cells caused toxicity in mice, but a diet containing a methanol extract, which dissolves diarrhetic shellfish poisoning (DSP) toxin, or an extract in heated 0.1 M HCl, which dissolves paralytic shellfish poisoning (PSP) toxin, did not cause toxicity. Mice fed a diet containing pronase-treated water extract neither showed a decrease in their food intake nor death. These results suggest that a water-soluble component other than DSP or PSP toxin causes toxicity. [ABSTRACT FROM AUTHOR]

Quantitative systems pharmacology (QSP) models are increasingly used in drug development to provide a deep understanding of the mechanism of action of drugs and to identify appropriate disease targets. Such models are, however, not suitable for estimation purposes due to their high dimensionality. Based on any desired and specific input-output relationship, the system may be reduced to a model with fewer states and parameters. However, any simplification process will be a trade-off between model performance and complexity. In this study, we develop a weighted composite criterion which brings together the opposing indices of performance and dimensionality. The weighting factor can be determined by qualification of the simplified model based on a visual predictive check (VPC) using the precision of each parameter. The weighted criterion and model qualification techniques were illustrated with three examples: a simple compartmental pharmacokinetic model, a physiologically based pharmacokinetic (PBPK) example, and a semimechanistic model for bone mineral density. When considering the PBPK example, this automated search identified the same reduced model which had been detected in a previous report, as well as a simpler model which had not been previously identified. The simpler bone mineral density model provided an adequate description of the response even after 1 year from the initiation of treatment. The proposed criterion together with a VPC provides a natural way for model order reduction that can be fully automated and applied to multiscale models. [ABSTRACT FROM AUTHOR]

Background: ONO-5334 is a cathepsin K inhibitor that induced bone mineral density (BMD) gain in a phase II study in postmenopausal osteoporosis patients. Even though the antiresorptive effect could only be monitored in the morning during the study, simulation can allow the antiresorptive effect to be assessed over 24 h, with assessment of the relationship to BMD gain.Methods: Inhibition of the serum C-telopeptide of type I collagen (sCTX) level at doses of ONO-5334 of 100 mg once daily (QD), 300 mg QD, and 50 mg twice daily (BID) was simulated using plasma ONO-5334 pharmacokinetic (PK) data for repeated dose administration in a phase I study and corresponding sCTX inhibition from the PK-pharmacodynamic (PK/PD) relationship. sCTX was selected because it has a high signal-to-noise ratio compared to other telopeptides. A negative sigmoidal shape for the PK/PD relationship between plasma ONO-5334 and sCTX levels was obtained in our previous study.Results: The simulated sCTX inhibition reached >99% of the maximal inhibitory effect (Emax) at 0.5 h in all treatment groups, and decreased to <80% Emax at 8 and 12 h at 50 mg BID and 100 mg QD, respectively. However, sCTX inhibition at 300 mg QD was maintained at ≥82% Emax over 24 h. The mean sCTX inhibition rates for 24 h at 100 mg QD, 300 mg QD and 50 mg BID were 63, 95 and 80% Emax, respectively. There was a positive linear relationship by treatment group between mean sCTX inhibition over 24 h and observed BMD gain in the phase II study.Conclusion: The dose response for BMD with ONO-5334 at 100 and 300 mg QD and higher BMD gain at 50 mg BID vs. 100 mg QD can be explained by sCTX inhibition over 24 h. The simulation gave the antiresorptive effect of ONO-5334 over 24 h and allowed prediction of BMD gain due to ONO-5334.Trial Registration: The registration number in The European Union Clinical Trials Register is 2007-002417-39 . The date of registration was August 31, 2007. [ABSTRACT FROM AUTHOR]