Nodulisporic acid A synthetic studies. 1. Overall strategy and construction of a western hemisphere subtarget.

In this, the first of two Letters, we outline our overall strategy for the construction of (+)-nodulisporic acid A (1), a representative member of a new class of indole diterpenes. In addition, we describe the efficient assembly of (-)-6, an advanced western hemisphere subtarget, comprising the ABC rings of (+)-nodulisporic acid A (1). The synthesis proceeded in 9% overall yield (longest linear sequence, 11 steps), exploiting a Shibasaki-Mori tandem transmetalation-cyclization to construct ring B. [reaction: see text]

Design and synthesis of new orally active inhibitors of human neutrophil elastase.

To identify new orally active inhibitors, further modification of 1 (ONO-6818) was performed. Peptidic derivatives 4b, 4c and 4n showed more potent inhibitory activity than nonpeptidic derivatives 3a-c. As a result, a series of peptidic inhibitors, 4a-s and 5a-v, were discovered. Among these N-aryl derivatives 5a-g, 5i, 5m and 5o-v showed oral activity. Their oral activity showed good correlation with their metabolic stability. Compounds 5h and 5j-l, which were extremely metabolically unstable in hamster plasma, did not show oral activity. Oral activity was considered to be determined by a combination of at least two factors: oral absorption and metabolic stability.

The crystal structure of the complex of non-peptidic inhibitor of human neutrophil elastase ONO-6818 and porcine pancreatic elastase.

The crystal structure of a new inhibitor of human neutrophil elastase (HNE), N-[2-[5-(tert-butyl)-1,3,4-oxadiazol-2-yl]-(IRS)-1-(methylethyl)-2-oxoethyl]-2-(5-amino-6-oxo-2-phenyl-6H-pyrimidin-1-ly)acetamide (ONO-6818, 1) complexed to porcine pancreatic elastase (PPE) has been determined at 1.86 A resolution. Analytical results provided evidence of a 1:1 complex in which the electrophilic ketone of 1 covalently bound to O gamma of Ser195 at the active site of PPE. The role of the unique electron-withdrawing ketone of 1 has been elucidated.

Development of orally active nonpeptidic inhibitors of human neutrophil elastase.

5-Amino-2-phenylpyrimidin-6-ones, some of their desamino derivatives, and miscellaneous derivatives were synthesized and biologically evaluated on both in vitro activity and oral activity in an acute hemorrhagic assay. These compounds contained an alpha-keto-1,3,4-oxadiazole moiety to bind covalently to the Ser-195 hydroxy group of human neutrophil elastase (HNE). Among those tested, compounds 11a-c,e,i-l(F), 11d,e,k(H), 21d,e,k(F), and 21d,e(H) showed a good oral profile. RS-Mixture 3(H) was selected for clinical evaluation based on its oral potency, duration of action, enzyme selectivity, safety profile, and ease of synthesis. Structure-activity relationships (SARs) are discussed.

CT appearance of hepatic parenchymal changes after percutaneous microwave coagulation therapy for hepatocellular carcinoma.

PURPOSE: The purpose of this study was to evaluate the changes in the CT appearance of the hepatic parenchyma surrounding the necrotic area in the early period after percutaneous microwave coagulation therapy (PMCT) for hepatocellular carcinoma (HCC). METHOD: We reviewed enhanced CT scans obtained before and within 2 weeks, at 1 month, and at 3 months after PMCT of 61 lesions in 47 patients with HCC. RESULTS: On dynamic CT, early enhancement of the hepatic parenchyma around the treated area was a frequent finding within 1 (87%) or 2 (68%) weeks after PMCT, but such enhancement disappeared on follow-up. Arterioportal shunts were also demonstrated by enhanced CT after treatment (21% at < or =2 weeks), and these shunts tended to persist for >1 month. CONCLUSION: We should evaluate the effect of PMCT by performing dynamic enhanced CT not only within 2 weeks to determine the end-point of treatment but also at 1 month or more after finishing treatment for definite assessment of tumor necrosis.

Intraperitoneal hemorrhage as a major complication of percutaneous ethanol injection therapy for hepatocellular carcinoma.

Two cases of intraperitoneal hemorrhage, which is one of the major complications of percutaneous ethanol injection therapy for hepatocellular carcinoma, are reported. A 70-year-old man was hospitalized for treatment of a small recurrent hepatocellular carcinoma located on the surface of the left lobe of the liver. Acute hemoperitoneum developed after percutaneous ethanol injection therapy, but he was treated conservatively with blood transfusion, and recovered. The other patient was a 72-year-old man who was admitted for treatment of a solitary superficial hepatocellular carcinoma on the dome of the liver. Immediately after percutaneous ethanol injection, he suffered the sudden onset of severe abdominal pain with shock and massive hemoperitoneum. His bleeding was successfully controlled by emergency transcatheter arterial embolization. Our experience suggests that care must be taken when using percutaneous ethanol injection to treat patients with superficial hepatocellular carcinomas located on the surface of the liver. Moreover, transcatheter arterial embolization should be considered the treatment of choice for the management of uncontrollable intraperitoneal hemorrhage after percutaneous ethanol injection therapy.

Hepatic angiosarcoma with early central enhancement and arterioportal shunt on dynamic CT.

We report a case of hepatic angiosarcoma that is usually difficult to differentiate from cavernous hemangioma on computed tomography. The present case suggests that early central enhancement and arterioportal shunting on dynamic computed tomography might be helpful for distinguishing hepatic angiosarcoma with a solid growth pattern from benign vascular neoplasms of the liver such as cavernous hemangioma.

[Factors leading to home care of patients in the terminal stage of malignant diseases--a study of 10 cases].

In order to clarify the factors that lead patients in the terminal stage of malignant diseases to home care, we interviewed ten families of such patients. Among factors involving patients, a strong desire to stay at home and to spend time at home with the family were initially required. Adequate understanding of the patients and their diseases was also needed by families. Other factors include guaranteed medical services in emergencies and/or 24 hours/day 7 days/week care. Patients requested referrals to family physicians, visiting nurses or community health services to cover outpatient clinic functions. It is concluded that a strong desire to stay at home, adequate understanding by the family and guaranteed medical services in emergencies were three significant factors leading to home care of patients in the terminal stage of malignant diseases.

Mercury evaporation from amalgams with varied mercury contents.

This study examined the relationship between mercury content and mercury evaporation from amalgams during setting. Two different types of commercial high-copper amalgams (single composition and admixed types) were used. Cylindrical specimens of each amalgam were prepared with five different mercury contents according to ADA Specification No.1. Specimens were also prepared by hand condensation. Mercury evaporation from amalgam specimens maintained at 37 degrees C was measured using a gold film mercury analyzer from 10 min after the end of trituration until the mercury concentration in air reached an undetectable level. The mercury content more clearly influenced the mercury evaporation from the admixed type amalgam specimens when the mercury content decreased below the manufacturers' recommended trituration conditions. Triturating with less mercury than the manufacturers' recommended amount cannot lower the evaporation of mercury from freshly made amalgam. Proper condensing procedures can minimize the mercury evaporation from the amalgam surface.