Jun Chiba

Discovery of trans-4-[1-[[2,5-Dichloro-4-(1-methyl-3-indolylcarboxamido)phenyl]acetyl]-(4S)-methoxy-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic acid: an orally active, selective very late antigen-4 antagonist.

We have focused on optimization of the inadequate pharmacokinetic profile of trans-4-substituted cyclohexanecarboxylic acid 5, which is commonly observed in many small molecule very late antigen-4 (VLA-4) antagonists. We modified the lipophilic moiety in 5 and found that reducing the polar surface area of this moiety results in improvement of the PK profile. Consequently, our efforts have led to the discovery of trans-4-[1-[[2,5-dichloro-4-(1-methyl-3-indolylcarboxamido)phenyl]acetyl]-(4S)-methoxy-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic acid (14e) with potent activity (IC(50) = 5.4 nM) and significantly improved bioavailability in rats, dogs, and monkeys (100%, 91%, 68%), which demonstrated excellent oral efficacy in murine and guinea pig models of asthma. Based on its overall profile, compound 14e was progressed into clinical trails. In a single ascending-dose phase I clinical study, compound 14e exhibited favorable oral exposure as expected and had no serious adverse events.

2-Fluoro and 2-Methoxycarbonyl Epoxy-β-ionylideneacetic Acids as Abscisic Acid Analogs

Abscisic acid (ABA) is easily isomerized to inactive trans-ABA by light. To solve this problem, two variations of epoxy-ᵚ-ionylideneacetic acid were synthesized as ABA analogs, each of them having a methoxycarbonyl or a fluoric substituent at the 2-position. The 2E-, and 2Z-fluorinated analogs showed moderate growth inhibitory activity toward rice seedlings and lettuce seeds, whereas the methoxycarbonyl analog was inactive toward rice seedling growth and only partially active toward lettuce germination. The 2E-fluorinated analog was extensively isomerized to the 2Z-isomer by UV irradiation. We think that a steric requisite for the 2E-position was high, and that the fluorine substituent was not effective for fixing the 2-double bond in the E-configuration.

Crescentic glomerulonephritis associated with thrombotic microangiopathy

A 71-year-old woman was examined at the department of urology in our hospital, with the chief complaint of macrohematuria. She was diagnosed as having bladder cancer and was hospitalized. After three courses of chemotherapy with cisplatin and epirubicin hydrochloride, total bladder resection and ileostomy were performed. Although the operation was curative, the hematuria persisted. Her renal function rapidly deteriorated. Hemolytic anemia and thrombocytopenia were found, and schistocytes were detected in a peripheral blood smear. Seizures occurred in the patients clinical course. A diagnosis of thrombotic microangiopathy (TMA) was made. The patient died despite receiving treatment. An autopsy was performed, and the renal microscopic findings showed crescentic glomerulonephritis (Cres GN). We present a rare case of Cres GN associated with TMA.

A family with nephronophthisis – medullary cystic disease complex

Abstract We report a family with nephronophthisis-medullary cystic disease complex (NPH-MCD). Case 1 was a 12-year-old girl with normal growth and development, who showed anemia and proteinuria at a health screening. A renal biopsy specimen showed chronic tubulointerstitial nephritis. Her renal function progressively decreased, and maintenance hemodialysis was started in January 1989. Case 2, the 29-year-old elder brother of case 1, had had anemia for 9 years and visited our hospital with symptoms of a common cold. Examination showed that he had chronic renal failure. A renal biopsy specimen showed chronic tublointerstitial nephritis. Case 3, a 27-year-old man, a first cousin of case 1, had had anemia for 1 year and was admitted to our hospital because of acute cardiac failure associated with chronic renal failure. Hemodialysis was started immediately. Two other people in the same family had chronic renal failure. Typing of the histocompatibility leukocyte antigen (HLA) was performed in four members of the family, but the results showed that there was no involvement of HLA in the pathogenesis of NPH-MCD.

Fever of unknown origin deu to sclerosing mediastinitis.

症例は51歳,女性.高熱を主訴に受診.各種抗生物質の投与を受けたが症状は軽快せず,不明熱の原因精査の目的で当科入院した. Gaシンチグラフィーでは前縦隔に著明な集積を認め,胸部CTにおいても同じ部位に腫瘤像を認めた.前縦隔腫瘍として,腫瘍摘出術を施行.病理組織学的にはリンパ球,形質細胞等の非特異的な細胞浸潤を伴う,広範な線維化を主体とした結節構造を認め, Sclerosing mediastinitisと診断した.術後は速やかに解熱し, CRPも徐々に低下した.一般にSclerosing mediastinitisは原因不明の疾患であり,上大静脈症候群等の胸部臓器圧迫症状で発症することが多いとされているが,本症例においては高熱以外の特異的な症状に乏しく,診断に苦慮した症例であり今回報告する.