Dysthymia and Apathy: Diagnosis and Treatment

Dysthymia is a depressive mood disorder characterized by chronic and persistent but mild depression. It is often difficult to be distinguished from major depression, specifically in its partially remitted state because “loss of interest” or “apathy” tends to prevail both in dysthymia, and remitted depression. Apathy may also occur in various psychiatric and neurological disorders, including schizophrenia, stroke, Parkinson's disease, progressive supranuclear palsy, Huntington's disease, and dementias such as Alzheimer's disease, vascular dementia, and frontotemporal dementia. It is symptomatologically important that apathy is related to, but different from, major depression from the viewpoint of its causes and treatment. Antidepressants, especially noradrenergic agents, are useful for depression-related apathy. However, selective serotonin reuptake inhibitors (SSRIs) may be less effective for apathy in depressed elderly patients and have even been reported to worsen apathy. Dopaminergic agonists seem to be effective for apathy. Acetylcholine esterase inhibitors, methylphenidate, atypical antipsychotics, nicergoline, and cilostazol are another choice. Medication choice should be determined according to the background and underlying etiology of the targeting disease

塩基性薬物の脂溶性に基づく細胞内分布機構に関する研究

取得学位：博士(薬学)，学位授与番号：博乙第183号，学位授与年月日：平成11年3月25日,学位授与年：199

A case of eosinophilic chronic rhinosinusitis associated with optic neuropathy

We report a case of eosinophilic chronic rhinosinusitis (ECRS) associated with optic neuropathy. The visual acuity in the right eye was suddenly reduced to no light perception on awakening in the morning. Fundus examination of both eyes on the same day showed no remarkable changes. Emergency computed tomography showed pan-sinusitis bilaterally and a partial defect of the sphenoid bone on the right side. From the clinical findings, the case was diagnosed as optic neuropathy associated with chronic sinusitis. Endoscopic sinus surgery (ESS) was performed on the same day, and all of the major sinuses were found to be filled with highly viscous fluid. Part of the optic canal had a defect probably due to inflammatory invasion from the adjacent sphenoid bone. Steroid therapy was started immediately postoperatively. Histopathological examination of excised polyps showed that numerous eosinophils had invaded the polyps but no hyphae were present. The patient reported that he had bronchial asthma and had had nasal polypectomy. Six months after the ESS and steroid therapy, the patient had a recurrence of the sinusitis. At that time, laboratory examination showed an elevation of total IgE and eosinophil numbers. From the clinical findings and course, this case was diagnosed as ECRS accompanied by optic neuropathy. Although ECRS rarely has ocular complications, the inflammation can spread and the optic nerve can be affected

Studies on the mechanism of subcellular distribution of basic drugs based on their lipophilicity

金沢大学医学部附属病院薬剤部This paper described the studies on the mechanism of subcellular distribution of lipophilic weak bases. Although the tissue distribution of basic drugs appeared to decrease with time simply in parallel with their plasma concentration, their subcellular distribution in various tissues exhibited a variety of patterns. Basic drugs were distributed widely in various tissues, but were concentrated in lung granule fraction, where their accumulation was dependent on their lipophilicity and lysosomal uptake. As the plasma concentration of drugs decreased after maximum level, the contribution of lysosomes to their subcellular distribution increased. The uptake of the basic drugs into lysosomes depended both on their intralysosomal pH and on the drug lipophilicity. As the lipophilicity of the basic drugs increased, they accumulated more than the values predicted from the pH-partition theory and raised the intralysosomal pH more potently, probably owing to their binding with lysosomal membranes with or without additional intralysosomal aggregation. These phenomena should be considered as a basis of drug interaction in clinical treatments

Consideration of mouth opening when using positioning stents during radiotherapy for tongue cancer: a retrospective study

Background: The aim was to clarify the range of mouth opening required to minimize the development of oral mucositis on the palate while using a positioning stent during radiotherapy in patients with tongue cancer. A positioning stent is used to reduce the severity of oral mucositis; however, requirements for fabricating the device have not been standardized. In particular, the range of mouth opening required while using a stent to prevent radiation-induced oral mucositis has not been determined. Material and methods: We retrospectively analyzed medical records and computed tomography (CT) images of nine patients who had undergone radiotherapy for tongue cancer. Irradiation dose for the palate and range of mouth opening while using the positioning stent was calculated from CT images and the radiotherapy treatment planning program. Results: The irradiation dose presented as medians and interquartile range (IQR) for the palate was 1.6 (IQR: 1.1–2.2) Gy with the use of the positioning stent and 37.2 (IQR: 17.5–44.1) Gy without the use of the positioning stent. The was 19–37 [mean ± standard deviation (SD): 26 ± 5.6] mm, and it attenuation amount of irradiation dose to the palate (r = 0.673, p = 0.0467). Regression equation was y = 0.21x + 19. Conclusions: Our study may be useful for deriving the relationship between the attenuation amount of irradiation of the palate with the positioning stent and the amount of mouth opening required for this attenuation.

Selective drug delivery to bone using acidic oligopeptides

金沢大学附属病院薬剤

Immunogenicity and Antigenicity of Allogeneic Amniotic Epithelial Transplants Grafted to the Cornea, Conjunctiva, and Anterior Chamber

PURPOSE. To determine the immunogenic characterization of amniotic epithelium (AE), by examining the fate of allogeneic AE grafts heterotopically transplanted in the eye. METHODS. Intact AE from enhanced green fluorescence protein (EGFP) transgenic mice (C57BL/6 background) and wild-type C57BL/6 mice were transplanted onto cornea or conjunctiva, or inserted into the anterior chamber (AC) of normal BALB/c mice, C57BL/6 mice, or BALB/c mice presensitized to donor antigens. For repeated AE transplantation experiments, AE was grafted in the other eye 7 days after the first grafting. Graft fate was assessed clinically and histologically at selected intervals after grafting. Infiltrating inflammatory cells were examined immunohistochemically. Sensitization to alloantigens by AE was assessed by the delayed hypersensitivity (DH) response. RESULTS. In normal recipients, GFP ϩ cells were absent in EGFP donor-derived AE grafts by day 21 on cornea and by day 7 on conjunctiva. AE grafts implanted in the AC survived for Ͼ8 weeks. In presensitized recipients and recipients that underwent repeated AE implantation, graft survival was markedly shorter than in normal recipients. DH was induced at 2 weeks, but failed to be induced at 4 weeks after grafting on cornea or at 8 weeks after grafting on conjunctiva and in the AC of normal recipients. CONCLUSIONS. Fresh allogeneic AE expressed immunogenicity when placed on the ocular surface, although no memory of allospecific DH was acquired. Allogeneic AE is clearly vulnerable to immune rejection in specifically sensitized recipients

Influence of chronic hepatic failure on disposition kinetics of valproate excretion through a phase II reaction in rats treated with carbon tetrachloride

The influence of chronic hepatic failure on the disposition kinetics of valproate (VPA) excretion via a phase II reaction was examined in rats treated with carbon tetrachloride (1.0 mg/kg, s.c., 3 times a week) for 2 or 3 months. There was no significant difference in the plasma concentration-time courses of VPA among the control and two treated groups up to 120 min after i.v. administration of VPA (75 mg/kg), but subsequently the plasma concentrations of the treated groups declined significantly below the control levels. Expression of Mrp2 mRNA in the liver of the treated groups was significantly lower than in the control group; conversely that in the kidney was significantly higher. The enzyme activity of UGTs in the liver of the treated groups decreased significantly, but UGT1A8 mRNA expression in the duodenum was increased about 3-fold. Cumulative excretion of VPA glucuronide (VPA-G) in bile of the treated groups was reduced significantly, while that in urine was markedly increased. In conclusion, the area under the VPA plasma concentration-time curve was decreased significantly in rats with chronic hepatic failure owing to increased excretion of VPA-G via the kidney as a result of induction of Mrp2, and inhibition of enterohepatic circulation of VPA-G. Copyright © 2007 John Wiley & Sons, Ltd

Mnagement of Information about Advarse Events in Clinical Trials

金沢大学医学部附属病院薬剤

Change in pharmacokinetics of mycophenolic acid as a function of age in rats and effect of coadministered amoxicillin/clavulanate

Changes of mycophenolic acid (MPA) pharmacokinetics with aging were investigated in rats. We also compared the effect of concomitant amoxicillin/clavulanate combination (CVA/AMPC) on the pharmacokinetics of MPA in 4-week-old and 12-week-old rats (the package insert of CVA/AMPC warns of possible interaction with MPA). Four-week-old rats showed a 1.4-fold higher total body clearance of MPA and a lower volume of distribution of MPA (65%), compared to the values in 12-week-old rats. However, the difference in MPA pharmacokinetics disappeared when enterohepatic circulation was eliminated by bile duct cannulation (BDC). Concomitant CVA/AMPC significantly reduced plasma MPA concentration in intact rats of both age groups, and the age-dependent difference of MPA pharmacokinetics was no longer apparent. The effect of CVA/AMPC was not seen in rats that had undergone BDC, suggesting that the drug-drug interaction can be attributed to inhibition of enterohepatic circulation by CVA/AMPC. These results indicate that the aging-related alteration of MPA pharmacokinetics is a consequence of immature enterohepatic circulation in 4-week-old rats. Higher doses of MPA may be necessary in juveniles. © 2012 The Pharmaceutical Society of Japan