Simulation for population analysis of Michaelis-Menten elimination kinetics

A simulation study was conducted to compare the cost and performance of various models for population analysis of the steady state pharmacokinetic data arising from a one-compartment model with Michaelis-Menten elimination. The usual Michaelis-Menten model (MM) and its variants provide no estimate of the volume of distribution, and generally give poor estimates of the maximal elimination rate and the Michaelis-Menten constant. The exact solution to the Michaelis-Menten differential equation (TRUE) requires a precise analysis method designed for estimation of population pharmacokinetic parameters (the first-order conditional estimation method) and also considerable computational time to estimate population mean parameters accurately. The one-compartment model with dose-dependent clearance (DDCL), in conjunction with the first-order conditional estimation or Laplacian method, ran approximately 20-fold faster than TRUE and gave accurate population mean parameters for a drug having a long biological half-life relative to the dosing interval. These findings suggest that the well-known MM and its variants should be used carefully for the analysis of blood concentrations of a drug with Michaelis-Menten elimination kinetics, and that TRUE, in conjunction with a precise analysis method, should be considered for estimating population pharmacokinetic parameters. In addition, DDCL is a promising alternative to TRUE with respect to computation time, when the dosing interval is short relative to the biological half-life of a drug. This work was supported in part by the Epilepsy Research Foundation, the Nakatomi Foundation, and a Grant-in-Aid for Scientific Research from the Ministry of Education, Science, and Culture of Japan.     

AUGMENTED ENDOGENOUS NITRIC OXIDE PRODUCTION IN PARTIAL PORTAL VEIN-LIGATED RATS

1. Endothelium-derived nitric oxide (NO) is a potent vasodilator. Because the body oxidizes it to nitrate ions, NO₃-, measurement of the serum concentration and the urinary excretion of NO₃- may be an index for endogenous NO. We investigated the role of NO on hyperdynamic circulation in cirrhotic and partial portal vein-ligated rats by measuring NO₃. 2. Liver cirrhosis was induced by administration of thioacetamide. Systemic and splanchnic haemodynamics and splenic-systemic shunting were determined by tracer microspheres. The concentration of NO₃- was measured by using high-performance liquid chromatography with an anion-column. 3. We found that systemic and splanchnic hyperdynamic circulation existed to almost the same extent in cirrhotic and in portal vein-ligated rats as compared to the controls and sham-operated rats, respectively. Splenic-systemic shunting was markedly greater in portal vein-ligated rats than in cirrhotic rats. 4. Serum NO₃- levels and urinary excretion of NO₃- in cirrhotic rats tended to increase as compared to the controls. On the other hand, the levels in portal vein-ligated rats were significantly increased as compared to those of the sham-operated rats, and were significantly and negatively correlated to the splanchnic arterial resistance and total vascular resistance. The amount of urinary excretion of NO₃- significantly correlated to splenic-systemic shunting (r = 0.61, P<0.05) only in portal vein-ligated rats. 5. We suggest that these high levels of NO₃- in portal vein-ligated rats relate to the extensive formation of porto-collateral vasculature or acute changes in systemic and splanchnic haemodynamics due to portal vein-ligation.     

Zebrafish protocadherin 10 is involved in paraxial mesoderm development and somitogenesis.

Here, we present the first report of the molecular cloning of zebrafish protocadherin 10 (Pcdh10, OL-protocadherin) and describe its functional analyses in the development of segmental plate. Epitope-tagged Pcdh10 expressed in embryos was localized on cell peripheries of adjacent cells. In situ hybridization showed that pcdh10 was expressed in the paraxial mesoderm (PAM) and developing somites, and in the pineal body, the diencephalon, and the vicinity of otocysts. Expression in PAM increased in the last few presumptive somites, reached the maximum level in the latest segmenting somites, and decreased thereafter during somite maturation. These expression patterns suggested that Pcdh10 is involved in development of PAM and somites. This was confirmed by morpholino knockdown and dominant-negative inhibition of Pcdh10 in embryos, which disturbed movements of PAM cells and somite segmentation. Comparative studies showed that pcdh10 expression lasted up to approximately three times longer in maturing somites than that of paraxial protocadherin (pcdh8). They also indicated that the adaxial cells expressed pcdh8 but not pcdh10. We propose that Pcdh10 is involved in the morphogenic movements of PAM cells and somite segmentation and that differential adhesion of Pcdh8 and Pcdh10 plays a role in the morphogenic machinery of somites and adaxial cells.     

Hemodynamic and volume changes by recombinant human erythropoietin (rHuEPO) in the treatment of anemic hemodialysis patients

Hemodynamic and volume changes induced by recombinant human erythropoietin (rHuEPO) treatment were investigated in 12 chronic hemodialysis patients with refractory anemia. After rHuEPO administration for 49 to 151 days, hematocrit (Ht) significantly improved from 19.4 +/- 2.3 to 30.1 +/- 1.1% (Mean +/- SD). Mean blood pressure (MBP) increased slightly but significantly from 78.8 +/- 13.2 to 88.9 +/- 16.9 mmHg. Hemodynamically, total peripheral resistance index (TPRI) increased significantly from 1,444 +/- 367 to 2,146 +/- 470 dynes.sec.cm-5.m2, while cardiac index (CI) decreased significantly from 4.49 +/- 0.85 to 3.37 +/- 0.60 l/min/m2. Both pulse rate (PR) and stroke volume index (SVI) also decreased significantly, but blood volume (BV) remained unchanged. Plasma renin activity and plasma norepinephrine decreased significantly. There were positive correlations between the change of MBP and that of CI, and between the change in CI and that of BV, respectively (p less than 0.05 or less). In conclusion the improvement of anemia using rHuEPO is hemodynamically associated with an increase in TPRI and a decrease in CI as well. Blood pressure elevation seems to be caused by an inappropriately minor reduction of CI. The contribution of humoral factors is not suggested.     

Differential biologic effects resulting from bimodal binding of recombinant human tumor necrosis factor to myeloid leukemia cells

Human recombinant tumor necrosis factor (rTNF) bound to ML-1 and HL-60 human myeloid leukemia cells in a bimodal manner. Saturable high- affinity binding was maximal at approximately 3 nmol/L rTNF, whereas saturable low-affinity binding reached its maximum at approximately 30 nmol/L. As analyzed by computer program, the observed data fit a two- receptor site model, with p less than .05. High-affinity binding concentrations of rTNF caused the differentiation of both cell lines, whereas low-affinity binding concentrations abolished this effect in a concentration-dependent manner. Thus, the type of biologic response elicited with rTNF in these cells is a function of the concentration at which the factor is applied. If generally applicable, this bimodal effect may require consideration when rTNF is to be used therapeutically.     

Role of β2 integrins in glomerular leucocytes in Henoch-Schoenlein purpura nephritis: an age-matched comparative study with immunoglobulin A nephropathy

SUMMARY: A comparative immunohistological study was performed for the glomerular deposition of complements (C1q and C3c), fibrin/fibrinogen‐related antigen (FRA), the expression of intercellular adhesion molecule‐1 (ICAM‐1), and the infiltration of leucocytes bearing β₂ integrins (leucocyte function associated antigen‐1 (LFA‐1), complement receptor 3 (CR3) and complement receptor 4 (CR4)) on renal biopsy specimens from 49 cases with Henoch‐Schoenlein purpura nephritis (HSPN), and 49 age‐matched cases with immunoglobulin A nephropathy (IgAN). the glomerular expression of ICAM‐1 was signifcantly correlated with the glomerular infiltration of leucocyte function associated antigen (LFA)‐1⁺ leucocytes in both diseases, and with that of CR3⁺ leucocytes in HSPN. the expression of ICAM‐1 was closely localized with the infiltration of LFA‐1⁺ leucocytes in the study with double immunostaining. the incidence and intensity of glomerular deposition of FRA were significantly higher in HSPN than in IgAN (P< 0.001), and those of C3c were significantly lower in HSPN than in IgAN (P< 0.001). the glomerular deposition of FRA was significantly correlated with the glomerular infiltration of CR4⁺ leucocytes in HSPN (P<0.05) but not in IgAN. In contrast, the glomerular deposition of C3c was significantly correlated with the glomerular infiltration of CR4⁺ leucocytes in IgAN (P<0.05), but not in HSPN. Studies with double immunostaining revealed a close association of CR4⁺ leucocytes with FRA deposition in HSPN and with C3c deposition in IgAN, respectively. the number of glomerular leucocytes bearing β₂ integrins was significantly correlated with urinary protein at the time of renal biopsy in both diseases. These results suggested the differential roles of β₂ integrins in the induction of glomerular injury in HSPN and IgAN. the ICAM‐1/LFA‐1 interaction may commonly be involved in the glomerular infiltration of leucocytes in both diseases. the ICAM‐1/CR3 interaction may be involved only in HSPN. Complement receptor 4 may function as a fibrin/fibrinogen receptor in HSPN, while CR4 may function as a complement receptor in IgAN.     

Clinical studies on the transabdominal resection of esophagocardial cancer and cervical anastomosis using bypass methods. Analysis of data on 76 patients

Transabdominal resection for esophagocardial cancer and reestablishment of alimentary continuity using bypass methods were performed in 76 patients. Thirteen underwent a bypass with a gastric tube and in 30, a colonic segment was prepared. In the remaining 33, a jejunal segment was used as a bypass organ, with considerable success. The 5 year survival rates were 68.8 per cent in those with stages (I+II), 16.5 per cent in those with stage III, 12.6 per cent in those with stage IV and 22.5 per cent in all cases, indicating similar results compared to those with cancer located in the upper third of the stomach with the limited proximal extension within the esophagocardial junction and operated on during the same period.     

Video-assisted thoracoscopic wedge resection of solitary pulmonary metastasis from hepatocellular carcinoma

We report a metastatic pulmonary tumor resected by video-assisted thoracoscopic surgery. A 63-year-old female was found to have four nodules of hepatocellular carcinoma (HCC) in January 1991; after non-surgical treatment, the tumors had become necrotic. In June 1992, a new HCC nodule was found. After infusion chemotherapy, it became necrotic. In September 1993, a solitary lung tumor, 2.4 cm in diameter, appeared at the periphery of the right lung. Because the tumor was considered to be a metastatic HCC rather than a primary lung cancer, it was removed by thoracoscopic wedge resection. Although whether metastasectomy contributes to prolongation of survival is still controversial, thoracoscopic pulmonary resection may be indicated for solitary peripheral metastasis, if the primary HCC is well controlled by multidisciplinary treatment.