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2000年から2009年の9年間に当研究所にて，漢方薬による薬物性肝障害と診断した21症例について検討した。平均年齢55.2 ± 13.4歳で，男性5例，女性16例であった。服用3カ月以内には17例（81.0％）が発症していた。発症時，無症状が11例（52.4％）であり，肝細胞障害型と混合型が共に9例（42.9％）であった。起因漢方薬としては19例と9割以上が黄芩を含む処方であった。DLST施行例は5例のみであり，方剤陽性は1例のみであった。治療としては，原因薬の中止のみで肝障害の軽減および肝機能の正常化を認めたのが18例（85.7％）で他2例は同処方去黄芩にて正常化を認めた。今後，特に黄芩を含む処方の場合に無症状でも，薬物性肝障害の早期発見のために3カ月以内の採血が必要と考える。

麗沢通気湯は嗅覚障害を主治とする方剤である。神経性嗅覚障害に対して麗沢通気湯が奏効した症例を経験したので報告する。症例は43歳，男性。主訴は嗅覚脱失である。頭部を打撲して以来，嗅覚が全脱失した。某大学耳鼻咽喉科に通院したが改善しないため，受傷14カ月後に当研究所を受診した。麗沢通気湯を処方したところ4週間後に軽度の自覚症状の改善を認めた。以後，麗沢通気湯を続服し，服薬約2年後に嗅覚は正常化した。麗沢通気湯は神経性嗅覚障害に効果があることが示唆された。

漢方薬を運用する際の臨床的な使用目標の科学的妥当性に関し，消化管機能との関連において記述した報告はほとんどない。我々は以前より，半夏厚朴湯が機能性ディスペプシア（functional dyspepsia＝FD）患者の消化管機能に影響を及ぼし，消化器症状を改善させることを報告してきたが，今回半夏厚朴湯の使用目標の有無と消化管機能，消化器症状の関連について検討した。FD患者における胃排出能は，半夏厚朴湯服用により増加した。このうち，半夏厚朴湯の代表的な使用目標である「咽中炙臠」を有する症例では，「咽中炙臠」のない症例に比べて，胃排出能の有意な増加と消化器症状の有意な改善が認められた。一方腸管ガスについて，腹部単純レントゲン写真から算出した指標gas volume score（GVS）は，FD患者において半夏厚朴湯服用により減少した。このうち，半夏厚朴湯の使用目標のひとつである「腹満」を有する症例においては，「腹満」を認めない症例に比較してGVSの減少が顕著であった。これらの結果から，FD患者における半夏厚朴湯の臨床効果は，「咽中炙臠」や「腹満」といった伝統的に用いられてきた半夏厚朴湯の使用目標の有無と密接に関連すること，またこれらが科学的妥当性に裏付けられた，漢方処方運用における有用な使用目標である可能性が示唆された。

The purpose of this study was to reevaluate the sho of goshuyuto, which has been established in an unscientific manner, and to create a new concept of the sho of goshuyuto. Eighty-four patients suffering from chronic headache were instructed to orally consume 7.5g. day of a spray-dried powder of goshuyuto (TJ-31) for 4 weeks. Before consuming the TJ-31, all subjects underwent Kampo examinations that were based on 43 diagnostic items. After the 4-week period of medication, all the subjects were classified as either responders or nonresponders. After excluding insignificant items from the 43 diagnostic items, discriminant analysis, which discriminated between responders and nonresponders, was conducted. Of the 80 subjects who completed the trial period, 57 were judged to be responders and 23 to be nonresponders. “Cold feet,” “fluid and gas retention in the stomach,” “kyokyo-kuman,” “tenderness at side of navel,” and “pulsation at abdomen” were selected by stepwise selection. The results of the discriminant analysis using these 5 items suggest that 28 subjects were misclassified and that the misclassification rate was 35%. Of the actual 23 nonresponders, 20 were accurately discriminated as nonresponders. The 5 selected items are suggested to be more useful in selecting the nonresponders than the responders. In conclusion, the empirically established sho of goshuyuto seemed to not be abele to completely explain the indication of goshuyuto. However, the inclusion of “tenderness at side of navel” and “pulsation at abdomen,” as new components comprising the sho of goshuyuto, may facilitate a more accurate indication of goshuyuto.

The purpose of this clinical trial was to assess the efficacy of goshuyuto, a typical Kampo formula, in preventing episodes of headache in chronic headache patients.Because the treatment target of a Kampo formula is decided on a basis different to that of Western medicine, we first selected patients belonging to a subgroup that responded to goshuyuto before conducting the usual randomized controlled trial. During stage 1, the subjects were instructed to orally consume goshuyuto for 4 weeks. Only those subjects judged as responders advanced to stage 2, during which a double-blind, randomized, placebo-controlled study was conducted. The subjects consumed the same dose of goshuyuto or placebo for 12 weeks.Of the 91 subjects enrolled in stage 1, 60 were judged as responders. Of these, 53 advanced to stage 2; 28 were assigned to the goshuyuto group and 25 to the placebo group. The decrease in the number of days on which headache episodes occurred was greater in the goshuyuto group than in the placebo group (2.6 +/- 3.7 vs. 0.3 +/- 4.0 days, p = 0.034); no difference was observed with regard to the reduction in the frequency of consuming reliever medications (2.2 +/- 4.0 vs. 1.4 +/- 8.2, p = 0.672). Improvement in the associated symptoms was observed in more than 50% of the subjects in the goshuyuto group.Goshuyuto is useful in preventing episodes of headache in chronic headache patients. Responder-limited design is a candidate for evaluating Kampo medicine.

The majority of research for the calcitonin gene-related peptide (CGRP) in the stomach has been devoted to the submucosal blood flow, and only slight attention has been paid to its involvement in the gastric epithelial function. In this study, we examined the age-related change in the CGRP-containing nerves and its effects on the mucus metabolism. We compared the immunoreactivity for CGRP in the gastric mucosa of 7-week-old rats (young) to that of 52-week-old animals (middle-aged). The effects of CGRP on the mucin biosynthesis were compared using the stomachs from both young and middle-aged rats. The nitric oxide synthase (NOS) activity was measured in the surface and deep mucosa of the gastric corpus. The density of the CGRP nerve fibers was reduced in both the lamina propria and submucosa of the middle-aged rats compared to the young rats. CGRP stimulated the mucin biosynthesis in the cultured corpus mucosa from the 7-week-old rats, but not from the 52-week-old rats. The total NOS activity of the surface layer in the corpus mucosa was markedly reduced in the middle-aged rats compared to the young rats. These findings demonstrate the age-dependent reduction in the CGRP-induced mucin biosynthesis, as well as in the density of the CGRP fibers in the rat stomach. The decreased NOS activity in the surface layer of the oxyntic mucosa in the aged rats may also be a principal cause for the lack of regulation of the mucin biosynthesis by CGRP.

The abundance of substance P (SP)-, calcitonin gene-related peptide (CGRP)-, vasoactive intestinal polypeptide (VIP)-, and neuropeptide Y (NPY)-immunoreactive nerve fibers in the carotid body was compared between normoxic and chronically hypoxic rats (10% O 2 and 3.0–4.0% CO 2 for 3 months). The immunoreactive fibers appeared as thin processes with many varicosities, and were distributed mainly around the vasculatures. In the normoxic control carotid body, NPY fibers were more numerous than VIP, CGRP, and SP fibers. In the chronically hypoxic rats, the carotid body was enlarged several fold, and the mean absolute number of VIP and NPY fibers was 3.88 and 2.22 times higher than in the normoxic carotid body, respectively, although that of SP and CGRP fibers was not changed. When expressed as density per unit area of the parenchyma, the density of SP and CGRP fibers in the chronically hypoxic carotid body decreased significantly to under 50%, the density of VIP fibers increased significantly 1.80 times, and the density of NPY fibers were unchanged. Immunoreactivity for four neuropeptides was not found in the glomus cells of normoxic or chronically hypoxic carotid bodies. These results suggest that altered peptidergic innervation of the chronically hypoxic carotid body is one feature of hypoxic adaptation. Because these neuropeptides are vasoactive in nature, altered carotid body circulation may contribute to modulation of the chemosensory mechanisms by chronic hypoxia.

The distribution of nitric oxide synthase (NOS) immunoreactive nerve fibers in the carotid body was compared between normoxic and chronically hypoxic rats (10% O2 and 3.0–4.0% CO2 for 3 months). NOS immunoreactive fibers appeared as thin processes with many varicosities. They were distributed predominantly around small arteries and arterioles, and around clusters of glomus cells. When expressed by the density of varicosities per unit area in the parenchyma, the density of NOS fibers associated with the vasculature and with the glomus cells in the chronically hypoxic carotid bodies was significantly decreased. Because nitric oxide (NO) is an inhibitory neuronal messenger in the normoxic carotid body, the present findings suggest that the sensory mechanisms in the hypoxic carotid body may be involved in `disinhibition' resulting from reduced NO synthesis.

The time of appearance and distribution of substance P (SP)-like immunoreactivity in the granular convoluted tubule cells of the developing male mouse submandibular glands were examined, and the subcellular localization of SP-like immunoreactivity was investiagted by electron microscopy. At 25 days of age, SP-like immunoreactivity was first detected in the supranuclear cytoplasm of the granular convoluted tubule cells, which occurred either singly or in small clusters. At 30 and 35 days of age, granular convoluted tubule cells with SP-like immunoreactivity were more numerous than in the earlier stages, as the volume ratio of the cells increased. Not all granular convoluted tubule cells demonstrated SP-like immunoreactivity. The number of cells with SP-like immunoreactivity decreased at 60 days of age, and these cells had completely disappeared at 90 days of age. Most, but not all, secretory granules in the granular convoluted tubule cells were strongly labeled with gold particles, indicating that the subcellular site of SP-like substance is in the secretory granules within the cells. The findings suggest that the physiological role of the SP-like substance secreted from the GCT cells is restricted to the early postnatal stages, and that it may be involved in the development of the oral mucosa or digestive tract as a trophic factor.

The occurrence and distribution of neuropeptide-containing nerve fibres in the human circumvallate papillae were examined by the peroxidase-antiperoxidase immunolocalisation method using surgical specimens that had not been subjected to radiotherapy, and the abundance of neuropeptide-containing fibres was expressed as the percentage of total nerve fibres demonstrated by protein gene product (PGP) 9.5 immunoreactivity for a quantitative representation of these peptidergic fibres. Substance P (SP) and calcitonin gene-related peptide (CGRP) immunoreactive (IR) nerve fibres were densely distributed in the connective tissue core of the circumvallate papillae, and some SP and CGRP-IR fibres were associated with the taste buds. A moderate number of vasoactive intestinal polypeptide (VIP)-IR fibres and a few galanin (GAL)-IR fibres were also seen in the connective tissue core and subepithelial layer. There were, however, no VIP-IR or GAL-IR fibres associated with the taste buds. Neuropeptide Y (NPY)-IR fibres were few and were associated with the blood vessels. Within the epithelium of the circumvallate papillae, no peptidergic fibres were found, although a number of PGP 9.5-IR fibres were detected. The abundance of SP, CGRP, VIP, and GAL-IR fibres expressed as the percentage of total PGP 9.5 IR fibres was 25.35+/-3.45%, 22.18+/-3.26%, 10.23+/-1.18%, and 4.12+/-1.05%, respectively. The percentage of NPY-IR fibres was below 3%. In a deeper layer of the papillae, a few VIP, GAL, and NPY-IR ganglion cells were found, and VIP immunoreactivity was detected in a few cells of the taste buds. There was no somatostatin, leucine enkephalin, or methionine enkephalin immunoreactivity in the circumvallate papillae. These results suggest that the dense SP and CGRP-IR fibres within the connective tissue core of the human circumvallate papillae may be involved in the deep sensation of the tongue.