An application of apo(a) isoforms for the clinical assessment of Lp(a).

To examine whether or not Lp(a) is applicable as a diagnostic marker for atherosclerosis, we studied the correlation between Lp(a) levels and molecular weights of apo(a) isoforms in sera from both normal healthy adults and diabetic patients. Serum Lp(a) level was measured by turbidimetric immunoassay (TIA) and the molecular weight of apo(a) isoform was determined by Western blotting analysis. The serum Lp(a) levels of the diabetic patients (25.0 mg/dl +/- 2.2 [mean +/- SE], n = 54) were significantly higher than those of the normal subjects (14.4 mg/dl +/- 0.57, n = 500). With respect to the correlation between serum Lp(a) levels and the molecular weights of apo(a) isoforms, there was an inverse correlation in sera from normal subjects (n = 298), whereas there was no correlation in sera from the diabetic patients. Statistical significant inverse correlation (r = -0.91, y = 224.25 - 3.07x) was especially observed in 50 representative apo(a) isotypes from the normal subjects. By applying a standardized curve based on the significant inverse correlation to serum Lp(a) levels, 40.7% (22/54) of the diabetic patients were revealed to have an abnormally high value of serum Lp(a). Moreover, it was found that the significantly higher mean value of serum Lp(a) in the diabetic group was caused by the 22 patients with higher value of Lp(a). The present findings suggest that determination of apo(a) isoform size provides estimation of the serum Lp(a) value and that the inverse correlation curve between serum Lp(a) level and the molecular weight of apo(a) isoform may be applicable to the clinical use of Lp(a).

Correlation of CT values, iodine concentration, and histological changes in the thyroid.

PURPOSE: We have reported that in the thyroid, there is a linear correlation between iodine concentrations and CT values. However, the slope of the regression line was about three times as large as that in KI solutions. We investigated the factor(s) contributing to the increment of the slope of the regression line in the thyroid. METHOD: Solutions of NH4I and thyroid hormones were used to investigate the regression line. Thirty-six thyroids were evaluated to investigate the correlation between the iodine concentrations and the area ratio of thyroid follicles, which were measured by preoperative CT and from tissue slices, respectively. RESULTS: The slopes of the regression lines in the solutions were almost identical to those in KI solutions. In the thyroid, iodine concentrations were logarithmically correlated with the area ratio of follicles. CONCLUSION: The decrease in CT values not only revealed a decrease of iodine concentration in the thyroid but also represented an increase of follicular cells and/or interstitial structures in the volume ratio secondary to it.

Population pharmacokinetics and pharmacodynamics of cisplatin in patients with cancer: analysis with the NONMEM program.

The population pharmacokinetics and pharmacodynamics of cisplatin (CDDP) were evaluated based on a mixed-effect model using the NONMEM program. Unchanged CDDP in plasma was measured as a biologically active platinum species during CDDP chemotherapy, using high-performance liquid chromatography. Plasma concentration measurements (157) of unchanged CDDP from 26 patients with cancer receiving 80 mg/m2 CDDP by infusion over 2 hours, 3.5 hours, or 4 hours were analyzed according to a one-compartment model. The influences of individual characteristics such as body weight, dose schedule, course, and clinical laboratory values (renal function markers, albumin) on total body clearance (Cl) and volume of distribution (Vd) were examined. In the final pharmacokinetic model, body surface area and dose schedule affected Cl of unchanged CDDP. The Cl of CDDP was increased by 27.3% after the 2-hour infusion schedule compared with Cl after the longer infusions. The Vd was estimated as 13.4 L/m2. The interindividual variability for Cl and Vd and residual variability were 22.9%, 30.9%, and 35.5%, respectively. The relationships between maximum concentration (Cmax) of unchanged CDDP and maximum blood urea nitrogen (BUNmax), or minimum creatinine clearance (ClCr,min) over a 1-month period after CDDP administration were evaluated according to linear, exponential, or maximum response (Emax) models. The linear or Emax model described pharmacodynamics most successfully, with relatively large interindividual variability for both slope and EC50 (more than 25%). Residual variability was 15.3% and 17.1% in BUNmax and Clcrmin, respectively. The population means and interindividual and residual variability of pharmacokinetics and pharmacodynamics of CDDP were evaluated using the NONMEM program. The results of this study show that the population pharmacokinetic and pharmacodynamic approach could be useful to manage CDDP nephrotoxicity using sparse data in a clinical setting.

Relationship between pharmacokinetics of unchanged cisplatin and nephrotoxicity after intravenous infusions of cisplatin to cancer patients.

PURPOSE: The relationships between pharmacokinetic parameters of unchanged cisplatin (CDDP) and several markers for nephrotoxicity after CDDP infusion (80 mg/m2) over 2 and 4 h were quantitated in patients with various cancers (lung, stomach and colon cancers and mediastinal tumor). METHODS: Plasma and urinary levels of unchanged CDDP were measured using a specific high-performance liquid chromatography method. Pharmacokinetic parameters were calculated according to the model-independent method. The nephrotoxicity markers, blood urea nitrogen (BUN), serum creatinine (SCr), plasma and urinary beta2-microglobulin (BMGp and BMGu), urinary N-acetyl-beta-D-glucosaminidase (NAG) and creatinine clearance (CCR) were monitored for 30 days following CDDP administration. RESULTS: The maximum plasma concentration (Cmax), maximum urinary excretion rate (dAe/dt(max)), area under the plasma concentration-time curve from time zero to infinity (AUC), cumulative amount excreted in urine from time zero to infinity (Ae), total clearance (Clt), renal clearance (Clr) and plasma half-life (t1/2) of unchanged CDDP were not significantly different between the 2-h and 4-h infusion schedules. The values of the nephrotoxicity markers changed significantly following CDDP administration, suggesting that CDDP chemotherapy (80 mg/m2) caused nephrotoxicity. The Cmax of unchanged CDDP was the most informative pharmacokinetic parameter for nephrotoxicity. Cmax was related to maximum BUN, maximum SCr and minimum CCR levels in 27 CDDP treatments according to an exponential model. CONCLUSION: In order to attain more effective CDDP chemotherapy with minimum nephrotoxicity, the present pharmacokinetic and pharmacodynamic studies suggest that the Cmax or steady-state plasma level of unchanged CDDP should be maintained between 1.5 and 2 microg/ml in a standard continuous infusion schedule over 2 h and 4 h.

13C-UBT using an infrared spectrometer for detection of Helicobacter pylori and for monitoring the effects of lansoprazole.

The stable isotope [13C]-labeled urea breath test (13C-UBT) is very useful for detecting Helicobacter pylori. Conventionally, a mass spectrometer is used to measure the presence of 13CO2 in breath. However, this technique is complex and expensive. Therefore, we carried out the 13C-UBT using an easy-to-operate infrared spectrometer, and we studied its usefulness. The 95 subjects included 35 patients with gastric ulcers, 32 with duodenal ulcers, 13 with gastroduodenal ulcers, some patients with nonulcer gastroduodenal disease, and normal controls. The 13C-UBT was negative in normal controls and positive in 86 of 91 (95%) patients with illness. Peaks appeared 15 to 30 min after [13C]urea administration. The 33 patients who were 13C-UBT-positive were then given lansoprazole 30 mg/day and the 13C-UBT was repeated after 8 to 16 weeks. Lansoprazole was found to be effective in patients who exhibited peak 13CO2 values that were at least two-thirds less than the pretreatment values. This effect was seen in 16 patients (48%), 13 of whom (81%) had gastric ulcers. Thirteen of the 17 patients (76%) who exhibited no effect had duodenal ulcers, and there were clear treatment response differences between the two types of ulcers.

Measurement of thyroid iodine by CT.

For evaluation of thyroidal iodine kinetics and thyroid nodules, we carried out quantitative in vivo measurement of thyroid iodine concentration by CT. Neuron activation analysis of iodine content was conducted on 48 thyroid fragments without calcification operatively obtained from 18 patients who had undergone CT of the thyroid without contrast enhancement. The CT attenuation values were obtained from the regions of interest in the CT image that corresponded to the analyzed fragment. When iodine concentration in the thyroid tissue was greater than 0.02 mg/g, the CT values correlated linearly with the iodine concentrations in thyroid nodules, thyroids with diffuse thyroid disease, and normal thyroids. The relationship is represented by the following formula: iodine concentration (mg/g) = (CT value-65)/104. The relationship between iodine concentration and CT value in diffuse thyroid disease, thyroid nodules, and normal thyroids was not significantly different.

[Clinical evaluation of immunoscintigraphy with 131I anti-CEA and 131I anti-CA 19-9 monoclonal antibody cocktail (IMACIS-1)--report of the phase II study].

The clinical trials of immunoscintigraphy with a cocktail of 131I anti CEA monoclonal antibody F(ab')2 and 131I anti CA 19-9 monoclonal antibody F(ab')2 (IMACIS-1) were performed to evaluate the safety and clinical usefulness. Thirty-five patients with proven cancer in six hospitals were examined in the phase two study. No significant changes of the heart rates, temperature, blood pressure, respiratory rates and clinical laboratory data were observed after i.v. IMACIS-1. Significant elevation of HAMA and IgE values in serum were not shown. Positive scintigrams which were interpreted by each hospital were obtained in 31/35 (89%) patients and in 39/53 (74%) lesions. The safety and clinical usefulness of immunoscintigraphy with IMACIS-1 were proven in the phase two study.

[Clinical evaluation of radioimmunoscintigraphy using a I-131 anti CEA and CA 19-9 monoclonal antibodies cocktail (IMACIS-1)].

The clinical usefulness of a I-131 anti CEA F(ab')2 MoAB and CA 19-9 F(ab')2 MoAB cocktail(IMACIS-1) for the localization of a cancer has been studied in 35 patients (Lung Ca. 10, Pancreas Ca. 7, Gastric Ca. 6, Colon Ca. 5, Hepatoma 2, Cholangio Ca. 2, Esophageal Ca. 1, Uterus Ca. 1, and, Retroperitoneal tumor 1). Of these 28 patients (80%) had an abnormal accumulation of radioactivity in the tumor sites (Lung Ca. 5, Pancreas Ca. 7, Gastric Ca. 6, Colon Ca. 5, Hepatoma 2, Esophageal Ca. 1, Uterus Ca. 1, and, Retroperitoneal tumor 1). Eighteen cases (56.3%) in 32 cases in which the primary site was known showed an abnormal radioactive accumulation and, similarly, 20 metastatic sites (71.4%) in 16 cases with 28 metastatic sites also showed an abnormal accumulation of radioimmunoscintigraphy showed no correlation with the serum CEA or CA 19-9 concentration. Further, no side effect was observed.

[Evaluation of measuring serum trypsin by radioimmunoassay and clinical application for the study on the exocrine function in diabetics (author's transl)].

Measurement of serum concentration of trypsin by RIA-Gnost Trypsin kit (Hoechst-Japan) was evaluated. The clinical usefulness of measuring serum trypsin level in diabetic patients was assessed. The measurement of trypsin using the radioimmunoassay (RIA) kit revealed good precision and reproducibility with intraassay error ranging from 3.6 to 5.5% in C.V. corresponding to mean trypsin concentration of 236.5-838.7 ng/ml and interassay error ranging from 8.1 to 11.1%. Tests for recovery and dilution were satisfactory for clinical use. Clinical materials included 35 normal subjects, 88 diabetics, 22 patients with liver diseases, 3 with acute pancreatitis, 7 with chronic pancreatitis and 3 with chronic renal failure. Serum trypsin concentration in normal controls was 157.6 +/- 59.9 ng/ml (m + 1 S.D.). Diabetic patients treated with diet therapy alone revealed serum trypsin level of 203.6 +/- 74.8 ng/ml (n = 50). In diabetics treated with sulfonil urea serum trypsin was 171.3 +/- 83.0 ng/ml (n = 25). In patients receiving insulin serum trypsin level was 90.5 +/- 49.0 ng/ml (n = 13). In patients with liver diseases, acute pancreatitis, chronic pancreatitis and chronic renal failure serum trypsin concentration were 236.9 +/- 88.0, 520.1 +/- 80.0, 113.0 +/- 75.6, and 2557 +/- 2771 respectively. Our results may indicate impaired pancreatic exocrine function in patients with severe diabetes mellitus. Increased serum trypsin level in diabetics treated with diet therapy may be due to stimulated excretion of trypsin resulted from restricted food intake. However, further study in larger number of patients is needed.