Nagoya Journal of Medical Science

Although a number of antipsychotics have been introduced for the treatment of schizophrenia, inter-individual differences of in antipsychotic response and the number of refractory schizophrenic patients have become two of the most challenging problems in clinical psychiatry. Thus, the pharmacogenetics of antipsychotics have been aimed at providing genetic components of this inter-individual variability in antipsychotic response in order to establish an individually-based pharmacotherapy for schizophrenia and to elucidate the mechanism of antipsychotic response so as to solve the refractoriness of schizophrenia. Pharmacogenetics, which is defined as the science of pharmacological response and its modification by hereditary influence can be divided into two categories: the genetic background of pharmacokinetics, i.e. the absorption, distribution, tissue localization, biotransformation and excretion of drugs, and pharmacodynamics, i.e. the biochemical and physiological consequences of a drug and its mechanism of action. Pharmacokinetics of antipsychotics has been focused mainly on the association between genetic polymorphisms in CYP genes, including CYP2D6, and the metabolism of these drugs. Polymorphism in CYP2D6 enables a division of individuals within a given population into at least two groups, i.e. poor metabolizers (PMs), extensive metabolizers (EMs), and ultrarapid metabolizers (UMs) of certain drugs. PMs have higher plasma concentrations of and more adverse effects from antipsychotics. UMs could be one of the important factors that induce treatment-refractoriness to antipsychotics. Genetic polymorphisms in serotonin and dopamine receptors that have a high affinity for antipsychotics have so far been extensively investigated in the pharmacodynamics of this type of drug. Not just one gene but multiple genes play a role in complex phenotypes, including the clinical response to medication. Thus, a multiple candidate genes approach has recently been adopted in the pharmacogenetics of antipsychotics. The new field of pharmacogenomics using DNA microarray analysis, which focuses on the genetic determinants of drug response at the level of the entire human genome, is important for development and prescription of safer and more effective individually-tailored antipsychotics.

Background: To improve quality of life cytostatic effect of serially changed chemotherapy was investigated. Materials and Methods: Nonrandomized controlled trial in 17 patients with diagnosis of metastasis or recurrence following primary colorectal carcinoma was conducted from 1996 through 2001. Patients underwent low-dose CDDP+5-FU monitoring continual CEA level. Whenever uninterrupted increase for minimally 3 times of CEA level was observed, the next chemotherapy was chosen from the following chemotherapy: l-Leucovorin+5-FU, low-dose CPT-11. RESULTS: Six were died of carcinoma. Median survival time from primary surgery and those from the day of diagnosis of metastasis were 48.6 and 23.3 months, respectively. Most of the patients experienced decrease in CEA level after continuous increase. No severe side effects were observed in them except one who died of hyperosmolar diabetic syndrome. CONCLUSIONS: Although the present trial should await further follow-up to confirm the clinical relevance of its modality, longer survival attained by the serially exchanged chemotherapy would implicate future chemotherapeutic strategy.

We examined three intervention methods for their efficacy in preventing aspiration in 25 patients with Parkinson’s disease (PD) and 23 patients with degenerative cerebellar ataxia (CA). On videofluoroscopic examination, 13 patients with PD (52%) and 7 patients with CA (30.4%) showed aspiration. In all PD patients and 5 patients with CA, no aspiration was observed after changing the food form. With the chin down posture and supraglottic swallow techniques, no aspiration was observed in only l PD patient. Among 7 patients with CA, the chin down posture and supraglottic swallow techniques resulted in the disappearance of aspiration in 4 patients. This indicates that changing the food form (ex. jelly) was effective in preventing aspiration in both PD and CA patients with a history of aspiration. In addition, the chin down posture and suprag1ottic swallow techniques were effective in preventing aspiration in CA patients with good sittingposition balance and cervical control.

The route and three dimensional distribution of nerve terminals in the submandibular gland were investigated in rats using immunohistochemistry for the protein gene product (PGP) 9.5, as a marker of neuronal elements. Thick fiber bundles were found along the wall of the excretory duct. Many fine fibers from these thick bundles were distributed each lobule of the submandibular gland. A large number of single fibers terminated in the area around the striated, intercalated ducts and the acini. The densities of PGP 9.5 immunoreactive terminals were measured by a computer aided analysis system in the three areas: the striated duct, the intercalated duct, and the acini, whose densities (μm/μm2) were 0.23, 0.39 and 0.05 respectively. The relatively high density of nerve terminals in the intercalated duct suggests that the duct system probably plays an unexpectedly important role in the functional aspects.

Human neuroblastomas and gliomas express high levels of GD2 ganglioside. Mechanisms for the re-expression of GD2 after the incorporation of an exogenous precursor structure were analyzed using a human heterophilic monoclonal antibody (mAb) together with mouse anti-GD3 and mouse anti-GD2 mAbs. First, mouse anti-GD2 mAb 220-51 was generated and its reactivity was confirmed to be almost identical with that of the well-known mAb 3F8 antibody. As reported previously for GD3 variants, new ganglioside antigens reactive with human mAb 32-27 were analyzed by culturing an astrocytoma cell line AS in the presence of NeuGc-GM3. Analysis of the extracted gangliosides from AS thus cultured revealed a new component detected with mAb 32-27, migrating similarly to GD2. Incorporated NeuGc-GM3 seemed to be converted to NeuAc-NeuGc-type GD3, and then to NeuAc-NeuGc-type GD2 with α2,8-sialyltransferase and β1,4-GalNAc transferase, respectively. In addition, AS was inoculated into nude mice, and glycolipids were extracted from generated tumors. Analysis of the ganglioside components using mAbs indicated that NeuAc-NeuGc-type GD2 was generated in the xenogeneic tumors by incorporating NeuGc-GM3 from mouse blood. These results indicated the presence of a pathway for utilization of exogenous gangliosides for remodeling and re-expression in vivo.

On June 9, 2003, we started free genetic tests of eight polymorphisms for health checkup examinees who attended a basic course at Nagoya University Hospital. They were informed of their genotypes within four weeks after blood donation for research purposes. The genotypes were those of alcohol dehydrogenase 2 (ADH2) Arg47His, aldehyde dehydrogenase 2 (ALDH2) Glu487Lys, NAD(P)H: quinone oxidoreductase (NQO1) C609T, glutathione S transferase M1 (GSTM1), glutathione S-transferase T1 (GSTT1), interleukin- 1B (IL-1B) C-31T, and tumor necrosis factor A (TNF-A) T-1031C, angiotensin-converting enzyme (ACE) Ins/ Del. In the first three months, 227 (89.4%) out of 254 examinees participated in the free tests, having been informed of the research aims, after which they consented to our use of research data. To date, there have been no complaints from the participants, indicating that the announcement of polymorphism genotypes may be accepted differently from that of hereditary disease genotypes.

Genetic polymorphisms have the potential to predict disease susceptibility. This may be especially useful among individuals with a high-risk lifestyle, so that the genotyping could be adopted for disease prevention through modifications toward a lower-risk lifestyle. We started a program of free genotype announcements in a polymorphism study aming health checkup examinees at the Nagoya University Hospital on June 9, 2003. Since such announcements remain controversial for fear of unexpected harmful effects and counseling system, the accumulated evidence on the association between disease risk and genotypes announcements in our study was reviewed in this article. The genotypes used were those of alcohol dehydrogenase 2 (ADH2) Arg47His, aldehyde dehydrogenase 2 (ALDH2) Glu487Lys, NAD(P)H: quinone oxidoreductase (NQO1) C609T, glutathione S transferase M1 (GSTM1), glutathione S-transferase T1 (GSTT1), interleukin-1B (IL- 1B) C-31T, and tumor necrosis factor A (TNF-A) T-1031C, angiotensin converting enzyme (ACE) Ins/Del. Since showed a potential for widespread use in health checkups, the information on the above polymorphisms seems worth documenting. Although there have been no complaints from the participants to date, careful treatments are requested.