An evaluation of non-clinical animal data from the point of view of a clinical pharmacologist

The development of a new chemical entity for human use is a stepwise process based on an assessment of both animal and human data on efficacy and safety of the drug. Clinical pharmacologists always refer to animal data through an Investigator's Brochure (IB) when planning and performing a clinical trial(s). The IB should provide the investigator(s) with useful information to select doses, dosing intervals, and safety monitoring procedures and also to support the clinical management of subjects during the trial(s). Non-clinical animal studies contained in the IB, however, lack a relationship to the pharmacological and toxicological findings of the investigated product(s). Most of the non-clinical animal studies address the methodology and the results obtained, but are lacking in a discussion of the relevance of the findings. The IB should include not only a summary of the findings in each field of animal study but also relationships of the findings through some indicator(s) such as blood and tissue concentrations of the parent drug and/or metabolites. I do hope Pharmaceutical Companies will provide much useful information about their product(s) through the improvement of their system of research and development.     

Zelkovamycin, a new cyclic peptide antibiotic from Streptomyces sp. K96-0670. II. Structure elucidation

The structure of antibiotic zelkovamycin was elucidated as a cyclic peptide comprising glycyl, 2-aminobutanoyl, 2-amino-2-butenoyl, N-methyl glycyl, alanyl, 1,3-thiazoyl, 7-methoxytryptophanyl and 2-methyldehydrothreonyl residues. The sequence of the amino acids was established by spectroscopic studies including 1H-1H COSY, 13C-1H COSY, 13C-1H HMQC, 13C-1H HMBC, 15N-1H HMQC and 15N-1H HMBC NMR experiments.     

The significance of HLA-DRB1 matching in clinical renal transplantation.

We analyzed the genotype for HLA-DRB1 alleles by digestion of polymerase chain reaction-amplified genes with the restriction endonucleases (PCR-RFLP) method to investigate the influence of HLA-DR antigen "splits" at the DRB1 gene level on the incidence of acute graft rejection in the renal transplant. For all patients, the incidence of acute rejection was proportional to the number of the serological HLA mismatch (0% in patients with two-haplotype match; 18% with HLA-A, -B, and -DR zero mismatch; 33% with HLA-DR zero mismatch; and 48% with HLA-DR one mismatch). For the patients with serological HLA-DR zero mismatch, the incidence of acute rejection in patients with HLA-DRB1 one mismatch (10/13: 77%) was significantly higher than that in those with zero mismatch (2/27: 7%). It was concluded that genotyping for HLA-DRB1 alleles would be beneficial in predicting acute rejection in patients with serological HLA-DR zero mismatch, although no difference was noted in the graft survivals.     

Teratoma of the tongue in neonates: report of a case and review of the literature

A female newborn presented with a huge mass protruding from the mouth. She had no respiratory distress but had difficulty swallowing. The mass originated from the tongue and was completely extirpated on the day of birth. The histologic diagnosis was mature teratoma. Three days later, another mass measuring 1 cm in diameter was found attached to the upper pharyngeal wall and was also completely extirpated 20 days after birth. The histologic diagnosis was also mature teratoma. The infant had a complete cleft palate, but no other malformation was found. Two years after surgery there is no sign of recurrence. Accepted: 22 August 1997     

Guidelines for treatment of ulcerative colitis in children

This paper introduces the guidelines for treatment of ulcerative colitis in children, created by the working group of the Japanese Society for Pediatric Gastroenterology, Hepatology and Nutrition (Chair: Yuichiro Yamashiro) and the Japanese Society for Pediatric Inflammatory Bowel Disease (IBD) (Chair: Akio Kobayashi). The ideas of the working group, with regard to the fundamental differences in medical treatment between children and adults, included: (1) for children, intensive medical treatment including appropriate systemic management is important during the acute phase of illness. (2) Treatment with steroids, which can cause growth disturbances, should not be continued for long periods of time. (3) Pulsed steroid therapy, selective removal of blood cells, and intravenous infusion of cyclosporin should be included in the therapeutic option for severe and fluminant cases.     

Intraoperative management of heart transplantation in Japan--report of two cases

We experienced intraoperative anesthetic management of two cases of heart transplantation in Japan. Both patients were in the end stage of cardiac failure due to dilated cardiomyopathy. One patient had had implantation of left ventricular assist system, and another patient had had implantation of automated cardioveter defibrillator. Transesophageal echocardiography was useful for the monitoring of cardiac function during the operation. Anti-arrythmic therapy including heart pacing and protection of right heart failure are important for the circulatory management of heart transplantation. The anesthesiologist is needed not only for the management of respiration and circulation but also for the prevention of infection and control of the time schedule.     

Hepatitis B Virus Infection Predicts Extrahepatic Metastasis After Hepatic Resection in Patients With Large Hepatocellular Carcinoma

Background Although extrahepatic metastasis occurs rarely after hepatic resection for hepatocellular carcinoma (HCC), the prognosis of these patients is extremely poor. Predictors of extrahepatic metastasis have not been fully investigated. Methods To identify predictors of extrahepatic metastasis after resection, we retrospectively investigated 77 patients with HCC tumors >50 mm in diameter who underwent hepatic resection. We investigated correlations between postoperative extrahepatic metastasis and clinicopathologic factors as well as extrahepatic metastasis-free survival rate by log rank test and predictors of extrahepatic metastasis by univariate and multivariate logistic regression models. Results Hepatitis B surface antigen (HBs-Ag) was found in 25 (32.5%) of 77 patients, and extrahepatic metastasis occurred in 26 (33.8%). Patients with extrahepatic metastasis showed better liver function and a high occurrence of HBs-Ag positivity than those without. The 5-year extrahepatic metastasis-free survival rate was worse in patients with HBs-Ag positivity, larger tumors (≥70 mm), higher alfa-fetoprotein level (≥300 ng/mL), and lower indocyanine green retention rate at 15 minutes (ICGR₁₅) (<15%) than in those without. By univariate logistic regression analysis, HBs-Ag positivity, larger HCC tumor (≥70 mm), lower ICGR₁₅ (<15%), and lower preoperative lymphocyte count (<1000/mm³) were predictors of extrahepatic metastasis (P < .1). By multivariate analysis, HBs-Ag positivity was an independent predictor of postoperative extrahepatic metastasis (P = .04). Conclusions In patients positive for HBs-Ag, radiologic examination of extrahepatic organs should be performed as a part of the postoperative surveillance. Hepatitis B virus infection may promote establishment of extrahepatic metastasis.