Dosage adjustment of quinolone antibiotics and angiotensin-converting enzyme inhibitors in patients with renal dysfunction.

The aim of this study was to verify an approach for calculating pharmacokinetic parameters suitable for adjusting dosage regimens in patients with renal dysfunction. We carried out a retrospective analysis of the pharmacokinetic profiles of 12 new quinolone antibiotics and 11 angiotensin-converting enzyme inhibitors (ACEIs) in patients with normal and impaired renal function to obtain the renal excretion ratio (R(renal)) of each drug. We demonstrated that the pharmacokinetics of each drug in a patient with renal dysfunction can be adequately estimated using the R(renaI) value of each drug together with the creatinine clearance as an index of the individual's renal function. Using the R(renaI) value obtained, we could successfully simulate pharmacokinetic profiles of the drugs in publications other than that used to obtain the R(renal) values. On the other hand, age-related changes in the pharmacokinetics of new quinolone antibiotics are not always adequately predicted using the R(renal) value compared to using creatinine clearance alone as an index, and the reasons for this are not fully understood. These results demonstrate that dosage regimens of quinolone antibiotics and ACEIs in patients with renal dysfunction can be adequately optimized using the R(renal) value for each drug using the present approach.

Pharmacokinetic analysis of felodipine-grapefruit juice interaction based on an irreversible enzyme inhibition model.

UNLABELLED: Aims Ingestion of grapefruit juice (GFJ) alters the pharmacokinetics of various orally administered drugs. Quantitative evaluation of this GFJ-drug interaction is required for the proper clinical management of patients. Methods Using felodipine as a model drug, we constructed a pharmacokinetic model based on irreversible inhibition of intestinal cytochrome P450 3A4 (CYP3A4) by GFJ. We fitted previously published data [5, 6] for felodipine ER (extended release formulation) to the ratio of CLGI,int before and after grapefruit juice ingestion by nonlinear least-squares regression analysis to estimate the reaction rate constant between GFJ and CYP3A4 (K) and the elimination rate constant of CYP3A4 (k ). RESULTS: The model gave a turnover rate of CYP3A4 of 0.0849 h-1, corresponding to a half-life of 8.16 h, in agreement with reported values. The AUC-time profiles of felodipine ER in the case of different amounts and schedules of GFJ ingestion were simulated using the parameter values estimated from the model. CONCLUSIONS: The modelling leads to the important conclusion that GFJ-felodipine interaction increases with increasing frequency and amount of GFJ ingestion, and that an interval of 2-3 days between GFJ intake and felodipine administration is necessary if GFJ-felodipine interaction is to be avoided.

Esophageal carcinoma with high serum parathyroid hormone-related protein (PTHrP) level.

We report two patients with esophageal carcinoma with high levels of serum parathyroid hormone-related protein (PTHrP). Patient 1 was a 66-year-old man in whom the serum calcium level was also high, and patient 2 was an 81-year-old woman. The serum PTHrP level was 411 pM (normal range, 13.8-55.3pM) in patient 1 and 94.5 pM in patient 2 (in whom the serum granulocyte colony-stimulating factor level was also high). We demonstrated PTHrP immunohistologically in esophageal carcinoma cells in both patients. After admission, patient 1 died of pneumonia on the 17th day of hospitalization (the 48th day after he had had an episode of frequent hiccuping) and patient 2 died of acute circulatory failure on the 12th day of hospitalization (the 25th day after she had vomited after a meal). Neither of these patients died of cancer. Pneumonia in patient 1 was believed to be due to weakened body defenses, while the acute circulatory failure in patient 2 was due to emaciation. Since esophageal carcinoma with humoral hypercalcemia of malignancy and leukocytosis is characterized by rapid progression and metastasis, early diagnosis and treatment are mandatory.

Influence of diet on the single-dose pharmacokinetics of isosorbide 5-mononitrate and sustained-release isosorbide dinitrate.

The influence of diet on the single-dose pharmacokinetics of isosorbide 5-mononitrate (IS-5-MN) and sustained-release isosorbide dinitrate (ISDN) was studied in 8 healthy male volunteers. The subjects received either a low-calorie/low-fat diet (LCFD) or a high-calorie/high-fat diet (HCFD) according to a cross-over schedule and were administered the drug in tablet form after breakfast. The study was conducted first in 8 subjects who received a 20 mg IS-5-MN tablet and then in 6 of these individuals who received a 20 mg sustained-release ISDN tablet. After oral doses of IS-5-MN, the plasma drug levels declined monoexponentially and could be described by a one-compartment open model. There were no significant differences in the pharmacokinetic parameters for IS-5-MN between the LCFD and the HCFD. After administration of sustained-release ISDN, the plasma ISDN levels showed marked variations both between and within individuals. The increase in the mean AUC0-12 values for ISDN with the HCFD was found to exceed 60%, although there was no significant difference between the two diets.

Oesophageal carcinoma with humoral hypercalcaemia of malignancy and leucocytosis.

We report a case of oesophageal carcinoma with humoral hypercalcaemia of malignancy and leucocytosis in a 66-year-old man. We also demonstrate parathyroid hormone-related protein, by immunohistology. After admission, calcitonin was administered for the hypercalcaemia but the patient died of pneumonia on the 17th day of hospitalization. As oesophageal carcinoma with humoral hypercalcaemia of malignancy and leucocytosis is characterized by rapid progression and metastasis, earlier diagnosis and treatment is mandatory.

Pushing exercise program to correct glottal incompetence.

A voice therapy program using pushing exercises to correct glottal incompetence is described. The program utilizes various types of instrumentation to determine whether or not a given patient is likely to benefit from the treatment. The program also provides feedback of target voices. Three cases with incomplete glottal closure and subsequent vocal dysphonia characterized by an asthenic breathy quality are used to illustrate the program. Details of the program, termination criteria, and problems and precautions learned from treating 29 patients over a 3-year period are presented.

The effects of recombinant interleukin 2 on HBe antigen positive chronic hepatitis B.

Recombinant interleukin (IL-2) was administered to 16 patients with HBe antigen-positive chronic active hepatitis in which the diagnosis was ascertained histologically. In 7 of the 16 patients, a decrement of the serum HBe antigen value was observed (Group A). In group A, the findings showed an increment of peripheral Leu 11-positive cells and NK and LAK cell activity, an acute exacerbation during and after IL-2 administration, disappearance of HBc antigen observed in liver biopsy histology, and decrement of serum DNA-p activity. However, seroconversion of HBs antigen was not observed and no case showed the elimination status of continuous HB virus infection. On the other hand, in the other 9 patients (Group B), these changes were not observed and the existence of a HLA type difference between Group A and B was shown by HLA analysis. These results indicated that the immune responses mediated by IL-2 may play an important role in the development of chronic hepatitis B, and these results may be regulated genetically.

Cloning and expression of raw-starch-digesting alpha-amylase gene from Bacillus circulans F-2 in Escherichia coli.

The raw potato-starch-digesting alpha-amylase gene of Bacillus circulans F-2 was cloned for the first time in Escherichia coli C600, using plasmid pYEJ001. The recombinant plasmid, named pYKA3, has a 5.4 kb insert from a chromosome of the donor bacterium. Subcloning of this amylase gene gave plasmid pHA300 which carried 3.15 kb of the inserted DNA. The transformed bacterium, E. coli C600 (pYKA3), produced the amylase in the periplasmic space, whereas it is secreted outside the cell in the donor bacterium. The cloned raw-starch-digesting alpha-amylase has a molecular weight of 93,000 on SDS-PAGE, and its action pattern was absolutely the same as that of the potent raw-starch-digestible amylase produced by B. circulans F-2. The periplasmic amylase produced by the transformed E. coli (pHA300) could digest raw starch granules such as potato, corn and barley raw starch granules, indicating that the raw-starch-digesting amylase is active in E. coli. Furthermore, this amylase crossreacted with the rabbit antiserum raised against the raw potato-digesting alpha-amylase of B. circulans F-2. From these results it was concluded that the cloned amylase is the same amylase protein as B. circulans F-2 amylase, which has a potent raw-starch digestibility. Thus, this paper is to our knowledge the first describing the molecular cloning of raw-starch-digesting alpha-amylase from Bacillus species and its successful expression in E. coli.

Immunoreactive corticotropin-releasing hormone, adrenocorticotropin and cortisol in human plasma during pregnancy and delivery and postpartum.

The activity of the hypothalamo-pituitary adrenal axis was examined, by measuring the levels of immunoreactive (IR) corticotropin-releasing hormone (CRH), adrenocorticotropin (ACTH) and cortisol (F) in human plasma during normal pregnancy and after delivery with or without complications and during normal postpartum using a specific RIA. The level of IR-CRH in maternal plasma increased progressively during pregnancy, increased further at delivery and declined rapidly to the non-pregnant level on the 1st day postpartum. The level of IR-F in maternal plasma also increased progressively during pregnancy, increased further at delivery, but decreased slowly postpartum, not returning to the non-pregnant level within 5 days. Significant correlations were found between the level of IR-CRH and IR-ACTH, IR-CRH and IR-F, and IR-ACTH and IRF in maternal plasma both during pregnancy and after delivery. It is noteworthy that the concentration of IR-CRH in the maternal plasma at delivery was higher in multiple pregnancy than in normal pregnancy, and that the level of IR-CRH in the umbilical cord in uncomplicated cases was much lower than that in the maternal plasma, and was significantly lower than those in the umbilical cord plasma in cases of asphyxia, IUGR or premature delivery. The level of IR-F, not IR-CRH and IR-ACTH, at normal vaginal delivery was significantly higher than that at elective cesarean section. On these results, we investigated the feto-maternal-hypothalamo-pituitary adrenal axis during pregnancy and delivery, in which CRH plays an important role.

The pathogenesis of graft-versus-host reaction in the intrahepatic bile duct. An immunohistochemical study.

Although intrahepatic bile duct injury following bone marrow transplantation is considered to be one feature of graft-versus-host disease, its developmental mechanism has not been clarified. In order to elucidate this aspect, an immunohistochemical study of the liver following human allogeneic bone marrow transplantation was made. Cytotoxic T lymphocytes (Tc) and natural killer cells (NK) were found in contact with intrahepatic bile duct epithelial cells showing degeneration and necrotic changes. These findings suggested a cytotoxic effect of these cells on bile duct epithelial cells. Abnormal expression of HLA class II (DR) antigen was recognized in intrahepatic bile duct epithelial cells following bone marrow transplantation. Cell injury was prominent in cells with weak DR antigen expression, whereas the cells demonstrating conspicuous expression appeared almost normal. There results suggest that abnormal expression of DR antigen plays an important role in the development of GVHD of the intrahepatic bile duct.

[A case of recurrence of gastric cancer with an abdominal wall tumor responding to intratumoral OK-432 administration].

Intratumoral administration of 5 K.E. OK-423 was given every other day for a patient with an abdominal wall recurrence of gastric cancer. After a total dose of 465 K.E. the abdominal tumor turned necrotic and its demarcation was monitored. Finally, the tumor separated and fell from the abdominal wall. Histologically, marked infiltration of neutrophils, lymphocytes, and macrophages were observed in the cancerous tissue. Clinically, local pain lessened and the serum CEA level decreased. PPD and PHA skin tests were markedly stimulated. A long term small-dose intratumoral administration of OK-432 seemed to be effective for a local recurrence of gastric cancer.

[Clinical experience of vaginal contraceptive film containing the spermicide, polyoxyethylene nonylphenyl ether (c-film study group) (authors' transl)].

PIP: A new vaginal contraceptive in the form of a film containing the spermicide, polyoxyethylene nonylphenyl ether (C-Film) was put into clinical trials. To evaluate spermicidal activity of C-film, an in vitro test was performed. After 1 minute, no motile sperm could be seen in the C-film solution which was diluted 32 times by a 5% glucose solution. When the sperm contacted the C-film solution diluted 8 times, the sperm stopped moving. C-film was used by 168 women for 1 and one-half years from December 1977 to May 1979 for a total period of 2161 months. Only 1 pregnancy occurred, thus giving a pregnancy rate of 0.56/100 women-years. During the use of C-film, 16 cases (9.5%) complained about an increase of vaginal discharge, 8 cases (4.8%) felt unfamiliar with the insertion, and 7 cases (4.2%) complained about unusual feelings caused by the presence of the C-film. A total of 9 cases (5.4%) stopped using C-film; 3 due to irritation, 2 due to troublesome use; and others due to vaginal discharge, burning sensation, pregnancy, and reasons unknown. No significant changes were observed in the vaginal bacteriology, cervical cytology, liver function, or renal function. The study indicates that C-film is very effective, well-tolerated, and has a low incidence of side effects. (Authors' modified)^ieng