A size of error in observed data for fitting curves and an estimation problem due to multiple solutions in a two-compartment model were studied by using two different non-linear least-squares regression programs, SALS and NONLIN. It was found that bolus intravenous data have generally 5-10 per cent errors and oral data contain 10-25 per cent errors against the fitted data with respect to total 151 data sets of 11 different drugs. Parameters of five drugs reported in references were used to obtain simulated concentrations at the sampling times, and five different data sets containing 25 per cent normally distributed random errors as a coefficient of variation were generated using each data set of these simulated concentration. In the two-compartment model with tri-exponential equations, unreasonable estimates were occasionally observed, resulting in reversed relative values to the theoretical ones of L/M, L/N, M/N or Ka/alpha, which are analogous to the well-known flip-flop phenomenon in the one-compartment model, when number of parameters to be estimated is not less than five or errors of data exceed about 10 per cent. In an attempt to avoid such unreasonable values, initial estimates for curve fitting was successfully obtained by using a microcomputer program SIMPLEX based on a simplex method. On the basis of these results, some problems in curve fitting of plasma drug concentration data are discussed.

Models, Statistical↗

PubMedDate not supplied

Nonlinear least-squares regression analysis by a simplex method using differential equations containing Michaelis-Menten type rate constants.

Computer curve fittings were carried out to observed data as well as theoretically generated plasma concentrations of several drugs, using differential equations which contained nonlinear Michaelis-Menten type rate constants to discuss problems of initial parameter estimation in pharmacokinetic analysis. Calculation based on two different algorithms, each carried out by using SIMP (simplex method) and NONLIN (modified Gauss-Newton method) produced similar results. However, occasional divergence or unreasonable solutions occurred in a later case, when assumed values of Km and Vmax were used as initial parameters. A combined use of SIMP and NONLIN in which calculated values by SIMP were used as initial values for NONLIN, was shown to be effective to analyse plasma concentration data of indocyanine green bearing difficulty in estimating initial values. It is suggested that the successive method is useful for the curve fitting of plasma concentration with nonlinear pharmacokinetic rate processes.

Models, Statistical↗

PubMedDate not supplied

Simultaneous exposure to interleukin-18 and interleukin-10 in vitro synergistically augments murine spleen natural killer cell activity.

Interleukin-18 (IL-18) enhances interferon gamma (IFNgamma) production and natural killer (NK) cell activity, and elicits protective antitumor effects in vivo. IL-18 and IL-12 synergistically augment IFNgamma production reportedly because IL-12 enhances IL-18 receptor (IL-18R) expression. We now show that IL-18 also synergizes with IL-10 to augment murine splenic NK activity against Yac-1 cells in a standard 4-h chromium-release assay, but IFNgamma production is only slightly enhanced. This pattern of NK activity was also observed with severe combined immunodeficient (SCID) mouse spleen cells indicating that the cytokines were not acting on T or B cells. The cytokines had no priming activity on the spleen cells and, when cells were left unstimulated for 24 h in culture, little NK activity was induced when IL-18 was added for the next 24 h. The reverse transcriptase/polymerase chain reaction revealed that IL-18 receptor (IL-18R) mRNA was expressed early during in vitro spleen cell culture but none was expressed after culture for 24 h regardless of the stimulus. Binding of 125I-labeled IL-18 revealed that exposure to IL-10 only slightly increased IL-18R expression. Expression of perforin mRNA was constitutive and was unaffected by the cytokines; however, Fas ligand (FasL) mRNA expression was strong in cultures with IL-18 alone or combined with IL-10. When Fas-expressing cells and their parental cells were used as targets, weak Fas-mediated cytolytic activity was observed after exposure to IL-18, and this was further enhanced by combination with IL-10. Finally, the augmentation of NK activity was abrogated by the inhibitor concanamycin A, indicating that the enhanced NK activity is perforin-dependent.

Animals↗

PubMedDate not supplied

Rupture of brain stem abscess into fourth ventricle: MR demonstration.

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Aged↗

PubMedDate not supplied

Early detection of cerebral ischemic lesion using diffusion-weighted MRI.

We performed serial diffusion-weighted imaging (DWI) in a patient with right middle cerebral arterial occlusion using 1.0 T MRI. The initial DWI demonstrated suppression of water diffusion in the gray matter in the ischemic lesion as a high signal area 4 h after stroke onset, when T2-weighted imaging failed to detect any parenchymal injury. Repeat DWI 9 h after onset demonstrated the whole infarct, whereas it was not demonstrated by T2-weighted imaging until 48 h. Furthermore, the regional apparent diffusion coefficient (ADC) had already decreased significantly in both the gray and white matters of the ischemic lesion 4 h after onset, even though hyperintensity was not visible in the white matter on the DWI. The features in this case indicate that DWI in conjunction with the assessment of regional ADC can provide important information regarding the evolving infarct at a very early stage even when a relatively low tesla clinically available MRI unit is used.

Brain Ischemia↗

PubMedDate not supplied

Enhanced expression of the multidrug resistance gene in vindesine-resistant human esophageal cancer cells.

We developed and characterized a new series of low- and high-grade multi-drug-resistant (MDR) cell lines of human esophageal carcinoma. Eight vindesine-resistant clones, SH-1-V1, SH-1-V2, SH-1-V3, SH-1-V4, SH-1-V5, SH-1-V6, SH-1-V7, and SH-1-V8 were isolated from the human esophageal cancer cell line, SH-1, by stepwise selection on exposure to increasing doses of vindesine. SH-1-V1 to SH-1-V8 acquired resistance to vindesine, in a stepwise manner, from 3- to 115-fold over findings in the parental SH-1 cells. The most resistant clone, SH-1-V8, was cross-resistant to other anticancer agents such as vincristine, actinomycin D, and daunomycin, thereby suggesting acquisition of the MDR phenotype. In SH-1-V8 cells, cellular accumulation of vincristine decreased and an MDR reversal agent, cepharanthine, potentiated the cytocidal action of vindesine. The expression of MDR1 mRNA was enhanced and amplification of the MDR1 gene was observed in clones SH-1-V4, SH-1-V5, SH-1-V6, SH-1-V7 and SH-1-V8; expression of MDR1 mRNA was detectable without gene amplification in the remaining 3 clones. The enhanced expression of the MDR1 gene may be involved in the acquisition of vindesine resistance in human esophageal cancer cells.

Alkaloids↗