FIRST-ORDER VERSUS MICHAELIS-MENTEN PHARMACOKINETIC MODEL SELECTION USING A MIXTURE MODEL. S. P. Riley, PharmD, T. M. Lndden, PhD, GloboMax, LLC, Hanover, MD. Population pharmacokinetic (PK) modeling involves fitting a model of specific compartmental form to data from many individuals to estimate PK parameters and their variability. The purpose of this study was to evaluate the utility of using a mixture model to permit data from different individuals to be described by different models. Simulated data sets (500 replications) containing various combinations of t-compartment (1CM) [clearance (CL) = 0.693, volume of distribution (Vc) = 1.0] and Michaelis-Menten (MM) [Vmax = 0.59, Km 0.35, Vc = 1.0] data were fitted (NONMEM V, First-Order Conditional Estimation with Interaction) with ICM and MM models, and a mixture (MIX) model that allowed for a choice between the two models. The ICM and MIX models provided accurate estimates of CL and Vc (82.2% to 113% of true values) in all cases where 1CM data were present in the dataset. When the data were analyzed using the MM model, Vma ~ and K m estimates became upwardly biased (12.9% to 603% relative prediction error (RPE)) and less precise (13.7% to 600% root mean squared error (RMSE)) as the 1CM fraction of the data increased from 20% to 80%. Parameter estimates from the MIX model remained comparatively unbiased (-2.19% to -0.730% RPE) and precise (2.72% to 7.46% RMSE). Individual model selection was correct for >96% of the individuals in the simulated datasets. Using a mixtnre model improved the accuracy and precision of pharmacokiuetic parameter estimates in the presence of a mixture of 1CM and MM data. PII-84

Crizotinib treatment for refractory pediatric acute myeloid leukemia with RAN-binding protein 2-anaplastic lymphoma kinase fusion gene

A mobile mass spectrometer to measure He concentrations has been developed by the U.S. Geological Survey. This instrument has been tested in areas of known uranium deposits, and He anomalies have been found in both soil gas and water. A gas sample is collected in a hypodermic syringe, injected into the spectrometer, and analyzed for He. Over 100 analyses a day can be performed with a sensitivity of 10 parts per billion (ppb). One detailed study conducted in Weld County, Colorado, shows that values for He in soil gas can be contoured to outline an anomalous area and that the anomaly is displaced from the deposit in the direction of groundwater flow. Other studies include the Schwartzwalder uranium mine, Jefferson County, Colorado, where He anomalies may be related to geologic structure; near Ambrosia Lake, New Mexico, where the location of He anomalies are related to groundwater movement; and tests for diurnal effects showing only slight variations probably related to soil-moisture content.

背景:糖尿病患者は年々増加しており,成人の5人に1人は糖尿病と言われている.糖尿病は膵癌のリスクファクターであるが,さらにその中から膵癌のハイリスク群を見分けることができれば,早期発見,治療につながると考えられる.目的:糖尿病患者における膵癌の予測因子を明らかにする.対象および方法:当科で経験した39例の糖尿病合併膵癌症例についてカルテ調査にて臨床的特徴を検討した.結果:糖尿病患者における膵癌予測因子として,喫煙と癌の家族歴があげられた.膵癌診断までの1年間で血糖コントロールは悪化し体重は減少していた.糖尿病の罹病期間が2年未満の症例および糖尿病と膵癌同時診断症例では,糖尿病の家族歴を認めず,膵性糖尿病であったと考えられた.結語:糖尿病患者における血糖悪化および体重減少,糖尿病家族歴のない新規発症糖尿病患者に対しては,膵癌を疑って迅速にスクリーニングするべきと考えられた.

RATIONALE: The objectives of our study are to clarify the clinical features and to characterize the allergens in 7 patients with allergic reactions after ingestion of fermented soybeans, which were recently hypothesized to cause IgE-mediated, late-onset anaphylaxis due to delayed absorption or release of allergens into the bowel rather than an immunologic phenomenon. METHODS: Seven patients with suspected hypersensitivity to fermented soybeans, who gave informed consent, underwent skin test and challenge test with fermented soybeans. Specific IgE against fermented soybeans and the allergens of fermented soybeans were detected by ELISA and IgE-immunoblotting, respectively. RESULTS: Seven male patients, aged 26 to 42 years, were participated. All patients reported generalized urticaria and dyspnea; five, loss of consciousness; two, collapse; two, vomiting; and two, diarrhea after fermented soybeans ingestion. The interval between fermented soybeans ingestion and onset of symptoms was 5 to 14 hours (mean, 9.6 hours). The results of prick-prick test with fermented soybeans were positive, whereas the results of SPT with soybean extract and a saline solution containing Bacillus natto were negative in all patients. In two patients, the oral challenge with fermented soybeans was positive 5.5 and 13 hours after ingestion. In ELISA, all five patients tested showed elevated IgE levels to the fermented soybeans extract. Furthermore, IgE-immunoblotting using 5 patients' sera showed six bands, of which three bands at 38, 28, and 26-kd were bound to sera from four patients. CONCLUSION: Cases with hypersensitivity after ingestion of fermented soybeans could mostly correspond to IgE-mediated, late-onset anaphylaxis.

BACKGROUND:Late-onset anaphylactic reactions without early-phase reactions are rarely reported. The hypothesized mechanism of late-onset anaphylaxis to fermented soybeans is delayed absorption or release into the bowel rather than an immunologic phenomenon.OBJECTIVES:To investigate the mechanisms of late-onset anaphylaxis to fermented soybeans in 2 patients and to characterize the allergens involved in anaphylaxis caused by fermented soybeans.METHODS:Two patients underwent skin prick-by-prick tests with fermented soybeans as is. We used an open challenge for the provocation test of anaphylaxis and measured changes in plasma histamine, plasma tryptase, serum eosinophil cationic protein, and plasma leukotriene B4 levels in 1 patient. In addition, specific IgE against fermented soybeans and the allergens of fermented soybeans were detected by enzyme-linked immunosorbent assay and immunoblotting, respectively.RESULTS:The results of the prick-by-prick tests with fermented soybeans as is were positive in both patients and negative in control subjects. The challenge with 50 g of fermented soybeans caused generalized urticaria and dyspnea 13 hours after ingestion of fermented soybeans in 1 patient. In addition, his plasma histamine and tryptase levels transiently elevated during the anaphylactic event. In enzyme-linked immunosorbent assay, the patients showed elevated IgE levels to the proteins of fermented soybeans. Serum IgE antibodies of patients 1 and 2 were bound to approximately 5- and 26-kDa proteins in immunoblotting of fermented soybeans, respectively.CONCLUSION:To our knowledge, this is the first report of late-onset anaphylaxis provoked by the challenge test half a day after ingestion of fermented soybeans.

We recently demonstrated that squalene synthase (SQS) inhibitors reduce plasma triglyceride through an LDL receptor-independent mechanism in Watanabe heritable hyperlipidemic rabbits (Hiyoshi et al. 2001. Eur. J Pharmacol. 431: 345-352). The present study deals with the mechanism of the inhibition of triglyceride biosynthesis by the SQS inhibitors ER-27856 and RPR-107393 in rat primary cultured hepatocytes. Atorvastatin, an HMG-CoA reductase inhibitor, had no effect on triglyceride biosynthesis, but reversed the inhibitory effect of the SQS inhibitors. A squalene epoxidase inhibitor, NB-598, affected neither triglyceride biosynthesis nor its inhibition by ER-27856 and RPR-107393. The reduction of triglyceride biosynthesis by ER-27856 and RPR-107393 was potentiated by mevalonolactone supplementation. Treatment of hepatocytes with farnesol and its derivatives reduced triglyceride biosynthesis. In addition, we found that ER-27856 and RPR-107393 significantly reduced the incorporation of [1-C-14]acetic acid into oleic acid, but not the incorporation of [1-C-14]oleic acid into triglyceride. Though ER-27856 and RPR-107393 increased mitochondrial fatty acid beta-oxidation, the inhibition of beta-oxidation by RS-etomoxir had little effect on their inhibition of triglyceride biosynthesis. These results suggest that SQS inhibitors reduce triglyceride biosynthesis by suppressing fatty acid biosynthesis via an increase in intracellular farnesol and its derivatives.