Banyu Pharmaceutical Co. Ltd.

The aim of this study was to investigate whether in vivo drug distribution in brain in monkeys can be reconstructed by integrating four factors: protein expression levels of P-glycoprotein (P-gp)/multidrug resistance protein 1 at the blood-brain barrier (BBB), in vitro transport activity per P-gp molecule, and unbound drug fractions in plasma and brain. For five P-gp substrates (indinavir, quinidine, loperamide, paclitaxel, and verapamil) and one nonsubstrate (diazepam), in vitro P-gp transport activities were determined by measuring transcellular transport across monolayers of cynomolgus monkey P-gp-transfected LLC-PK1 and parental cells. In vivo P-gp functions at the BBB were reconstructed from in vitro P-gp transport activities and P-gp expression levels in transfected cells and cynomolgus brain microvessels. Brain-to-plasma concentration ratios (Kp,brain) were reconstructed by integrating the reconstructed in vivo P-gp functions with drug unbound fractions in plasma and brain. For all compounds, the reconstructed Kp,brain values were within a 3-fold range of observed values, as determined by constant intravenous infusion in adult cynomolgus monkeys. Among four factors, plasma unbound fraction was the most sensitive factor to species differences in Kp,brain between monkeys and mice. Unbound brain-to-plasma concentration ratios (Kp,uu,brain) were reconstructed as the reciprocal of the reconstructed in vivo P-gp functions, and the reconstructed Kp,uu,brain values were within a 3-fold range of in vivo values, which were estimated from observed Kp,brain and unbound fractions. This study experimentally demonstrates that brain distributions of P-gp substrates and nonsubstrate can be reconstructed on the basis of pharmacoproteomic concept in monkeys, which serve as a robust model of drug distribution in human brain.

The liver plays an important role in maintaining glucose homeostasis in the body. In the prandial state, some of the glucose which is absorbed by the gastrointestinal tract is converted into glycogen and stored in the liver. In contrast, the liver produces glucose by glycogenolysis and gluconeogenesis while fasting. Thus, the liver contributes to maintaining blood glucose level within normoglycemic range. Glycogenesis and glycogenolysis are regulated by various mechanisms including hormones, the sympathetic and parasympathetic nervous systems and the hepatic glucose content. In this study, we examined a rat model in which the celiac superior mesenteric ganglion (CSMG) was resected. We attempted to elucidate how the celiac sympathetic nervous system is involved in regulating glucose homeostasis by assessing the effects of CSMG resection on glucose excursion during an oral glucose tolerance test, and by examining hepatic glycogen content and hepatic glycogen phosphorylase (GP) activity. On the oral glucose tolerance test, CSMG-resected rats demonstrated improved glucose tolerance and significantly increased GP activity compared with sham-operated rats, whereas there were no significant differences in insulin, glucagon or catecholamine levels between the 2 groups. These results suggest that the celiac sympathetic nervous system is involved in regulating the rate of glycogen consumption through GP activity. In conclusion, the examined rat model showed that the celiac sympathetic nervous system regulates hepatic glucose metabolism in conjunction with vagal nerve innervations and is a critical component in the maintenance of blood glucose homeostasis.

A review.Schizophrenia is a psychiatric disorder whose symptoms the many show in adolescence or adolescence, and it is known that incidence ratio is comparatively as high as about 1% of overall population.Although the condition of schizophrenia is variegated and it is not the most important, there is cognitive dysfunction, such as neg. symptoms, such as pos. symptoms, such as a hallucination and delusion, flattening of affect, volition decline, and social withdrawal, an attentiveness fall, and executive dysfunction, as cardinal symptoms.Although the existing schizophrenia curative medicine mainly has the antagonism to D₂ receptor and a 5-HT_2A receptor and it succeeds in a pos. symptom, an improvement action on neg. symptoms or cognitive dysfunction is not yet enough, and about 30% of schizophrenia patients still show drug resistance nature.Moreover, the necessity for development of the schizophrenia curative medicine which has a new mechanism from revealing side effects, such as extrapyramidal system condition, high prolactin symptom and weight gain, etc. has recited strongly.As one of them, the drug design what is called based on a glutamic acid hypothesis (NMDA receptor function fall hypothesis) that the abnormalities in glutamatergic neurotransmission of a frontal cortex are mainly the causes is activating.Now, glycine transporter-inhibitory drug, metabotropic glutamate receptor 2/3 type (mGluR2/3) agonist, a mGluR2 pos. allosteric modulator, etc. are during a clin. test.The metabotropic glutamate receptor 1 type (mGluR1) as a baguette, and have advanced drug design of the antagonistic drug.In this paper, new mGluR1 antagonistic it gives an outline focusing on a relation with the evaluation and the receptor share about the validity and the side effects in the feature and its schizophrenia animal model of drug and possibility as a new schizophrenia curative medicine of mGluR1 antagonistic drug is considered.