Prodrugs as drug delivery systems. XXX. 4-Imidazolidinones as potential bioreversible derivatives for the α-aminoamide moiety in peptides

The hydrolysis kinetics of five 4-imidazolidinones derived from acetone and the dipeptides Ala-Gly, Ala-Ala, Phe-Leu, Leu-Gly and Asp-Phe methyl ester were studied to assess their suitability as prodrug forms for the α-aminoamtde moiety occurring in peptides. The imidazolidinyl peptides were found to undergo a complete hydrolysis in the pH range 1–10 at 37°C and most of them showed a sigmoidal pH-rale profile with maximum rates at pH > 4. The stability of the derivatives varied widely, the following half-lives being obtained at pH 7.40 and 37°C: 0.9 h (Asp-Phe methyl ester), 3.4 h (Phe-Leu), 24.6 h (Ala-Ala). 410 h (Ala-Gly) and 530 h (Leu-Gly). The major structural factor influencing the stability appeared to be the stcric properties within the C-terminal amino acid residue. The 4-imidazolidinones are much weaker bases (pK_a about 3.1) than the parent dipeptides and, as determined by partition experiments in octanol-aqueous buffer systems with the Phe-Leu derivative, they are more Hpophilic than the parent compounds. It is suggested that 4-imidazolidinone formation in principle may Become a useful approach to bioreversible dehvatization of dipeptides or other peptides containing an α aminoamide function with the aim of solving delivery problems fur peptide drugs.     

Inclusion complexation of metronidazole benzoate with β-cyclodextrin and its depression of anhydrate-hydrate transition in aqueous suspensions

Metronidazole benzoate was found to form an inclusion complex with β-cyelodextrin (β-CyD) in aqueous solution and in the solid phase. A phase solubility diagram was obtained and an apparent 1:1 formation complex constant of 1.3 × 10³ M^?1 was determined. A microcrystalline inclusion complex was isolated and shown to have the stoichiometric composition of 1:1.5 (drug: β-CyD). By inclusion complexation of the metronidazole ester with β-CyD the phase transition of the clinically used anhydrous form of the compound to the monohydrate occurring in aqueous suspensions was inhibited as was the marked crystal growth resulting from the phase transition. Besides increasing the physical stability of metronidazole benzoate suspensions the complexation with β-CyD protected the drug against photochemical degradation and decreased the rate of hydrolysis.     

Intrapericardial left atrial aneurysm. Report of a case and a review of the literature

A case of intrapericardial left atrial aneurysm successfully removed and presenting clinically with intermittent atrial fibrillation is described. Fourteen other cases are reported in the literature. The first symptom is either palpitation, an arterial embolus, or precordial pain. The diagnosis is confirmed by angiocardiography. The aneurysm should be removed.     

健康成年人静脉血细胞分析参考范围调查

目的:确定Sysmex XE-2100全自动血细胞分析仪检测正常成人静脉血细胞参考值。方法:用Sysmex XE-2100全自动血细胞分析仪及原装试剂对260名健康成年人(男女各半)的空腹静脉血细胞24项参数进行参考范围调查,并将所得数据进行统计学分析。结果:测定参数共有24项,分别是:WBC(×109/L)、RBC(×1012/L)、HGB(g/L)、HCT(%)、MCV(fl)、MCH(pg)、MCHC(g/L)、PLT(×109/L)、NEUT(%)、LYMPH(%)、MONO(%)、EO(%)、BASO(%)、NEUT(#)、LYMPH(#)、MONO(#)、EO(#)、BASO(#)、RDW-CV(%)、RDW-SD(fl)、PDW(fl)、MPV(fl)、P-LCR(%)和PCT(%)。结论:调查结果与《全国临床检验操作规程(第2版)》提供的参考范围存在一定的差异,因此,各实验室有必要根据具体情况建立各自的血细胞参考范围。     

Centralization errors in comparative genomic hybridization array analysis of pituitary tumor samples

Reliable interpretation of comparative genomic hybridization array (aCGH) results requires centralization and normalization of the data. We evaluated the reliability of aCGH centralization by comparing aCGH results (with classical centralization‐normalization steps) to fluorescence in situ hybridization (FISH) results. In addition, we propose a method to correct centralization bias. Sixty‐six pituitary tumors were analyzed (Agilent aCGH + SNP 4 × 180K microarray). For each tumor, the FISH‐based log₂(ratios) of a subset of chromosomes were compared with the corresponding aCGH raw log₂(ratios). With our new normalization‐centralization process, this difference was added to all log₂(ratios), before performing loess regression on non‐altered probes only. Finally, the mean log₂(ratio) and the percentage of normal probes were compared between CGHnormaliter and our new FISH‐based method. For 11 tumors, FISH results and raw CGH log₂(ratios) differed significantly. In addition, nine tumors showed discrepancies between results generated by CGHnormaliter and our new‐method. Such discrepancies seemed to occur with tumours with many abnormalities (0%‐40% normal probes), rather than in those tumours with fewer abnormalities (31%‐100% normal probes). Five tumors had too few normal probes to allow normalization. In these tumors, which can exhibit many changes in DNA copy number, we found that centralization bias was frequent and uncorrected by current normalization methods. Therefore, an external control for centralization, such as FISH analysis, is required to insure reliable interpretation of aCGH data.     

Erroneously elevated immature reticulocyte counts in leukemic patients determined using a Sysmex XE-2100 hematology analyzer

The immature reticulocyte fraction (IRF) in peripheral blood, as determined by automated reticulocyte analysis, is calculated using the sum of medium and highly fluorescent reticulocyte numbers and provides information about erythropoietic activity in bone marrow. The purpose of this study was to investigate erroneously elevated IRF in leukemic patients, as determined using a Sysmex XE-2100 hematology analyzer (Sysmex, Kobe, Japan). Normal reticulocyte scattergram patterns show regions corresponding to reticulocytes located between matured RBCs and an upper particle (UPP) region, which show a continuum of non-separated fraction. The UPP represents erythroblasts and some immature reticulocytes. As a control group, peripheral blood was taken from patients with benign hematologic diseases, and their reticulocyte scattergrams all showed a normal pattern; UPP values were all less than 100. However, the reticulocyte scattergrams of 5 of 11 leukemia patients showed abnormal patterns and displayed a gap between RBC and reticulocyte regions. Three patients showed a flag with a message such as “RET Abn Scattergram”. IRF results were elevated in these five patients, and their UPP values were above 100. For the remaining six leukemia patients with a normal reticulocyte scattergram pattern, immature reticulocytes were not markedly increased, and UPP values were less than 100. The findings of the present study demonstrate that IRF results may be erroneously elevated in leukemia patients and indicate that hematologists should examine reticulocyte scattergrams and UPP values carefully.