Antimycotic 2-alkyldithio, 2-aralkyldithio, 2-aryldithiobenzamides

Some 2-alkyldithio, 2-aralkyldithio, 2-aryldithio benzoic acids, their methyl esters and N-monosubstituted amides were prepared and tested in vitro against Candida albicans and Trichophyton mentagrophytes. Some N-monosubstituted amides displayed activities similar to those of clotrimazole and pyrrolnitrin. Against Candida albicans, N-monosubstituted amides exhibited a generally higher activity than the corresponding N-monosubstituted amides of 2,2'-dicarboxydiphenyldisulfide.     

Reference Datasets for 2-Treatment, 2-Sequence, 2-Period Bioequivalence Studies

It is difficult to validate statistical software used to assess bioequivalence since very few datasets with known results are in the public domain, and the few that are published are of moderate size and balanced. The purpose of this paper is therefore to introduce reference datasets of varying complexity in terms of dataset size and characteristics (balance, range, outlier presence, residual error distribution) for 2-treatment, 2-period, 2-sequence bioequivalence studies and to report their point estimates and 90% confidence intervals which companies can use to validate their installations. The results for these datasets were calculated using the commercial packages EquivTest, Kinetica, SAS and WinNonlin, and the non-commercial package R. The results of three of these packages mostly agree, but imbalance between sequences seems to provoke questionable results with one package, which illustrates well the need for proper software validation.     

PS2、COX2、CerbB2在乳腺癌中表达的研究

目的研究ER、PR与PS2、COX2、CerbB2在乳腺癌组织中的表达,探讨与病理类型、淋巴转移、内分泌治疗及预后的关系。方法采用免疫组化SP检测54例乳腺癌组织中COX2、CerbB2、PS2、ER、PR的表达。结果COX2、CerbB2在乳腺癌组织的表达的阳性率与肿瘤的大小、发病年龄肿瘤分级及淋巴转移有关,（P〈0.05）,在高分化癌中低表达,在低分化癌中高表达,在淋巴结转移组织中两者都高表达。PS2在ER、PR阳性的癌组织中高表达,与肿瘤的大小、发病年龄、淋巴结转移无明显的关系,但与肿瘤的分化程度有关,在高分化癌中高表达,在低分化癌中低表达。结论PS2、ER、PR三项指标全阳性可预测乳腺癌患者辅助内分泌治疗疗效的可靠指标;COX2、CerbB2可作为判断预后的指标。     

Stability of T-2, HT-2, and T-2 tetraol in biological fluids

The stabilities of tritium-labeled T-2, HT-2, and T-2 tetraol were studied in blood and urine at -70 degrees, 4 degrees, and 23 degrees C for 6 months in the presence of EDTA or NaF. Samples were counted with a radiochromatographic scanner and results indicated the stability of T-2 tetraol greater than T-2 greater than HT-2. Toxins were most stable when stored at -70 degrees C, in the presence of NaF, and in urine (pH 6). They were less stable in saline (control, pH 7) and least stable in blood (pH 8). These results suggest that urine and T-2 tetraol are the biological fluid and metabolite of choice for diagnostic purposes.     

Subunit-specific agonist activity at NR2A-, NR2B-, NR2C-, and NR2D-containing N-methyl-D-aspartate glutamate receptors

The four N-methyl-d-aspartate (NMDA) receptor NR2 subunits (NR2A-D) have different developmental, anatomical, and functional profiles that allow them to serve different roles in normal and neuropathological situations. Identification of subunit-selective NMDA receptor agonists, antagonists, or modulators could prove to be both valuable pharmacological tools as well as potential new therapeutic agents. We evaluated the potency and efficacy of a wide range of glutamate-like compounds at NR1/NR2A, NR1/NR2B, NR1/NR2C, and NR1/NR2D receptors. Twenty-five of 53 compounds examined exhibited agonist activity at the glutamate binding site of NMDA receptors. Concentration-response relationships were determined for these agonists at each NR2 subunit. We find consistently higher potency at the NR2D subunit for a wide range of dissimilar structures, with (2S,4R)-4-methylglutamate (SYM2081) showing the greatest differential potency between NR2A- and NR2D-containing receptors (46-fold). Analysis of chimeric NR2A/D receptors suggests that enhanced agonist potency for NR2D is controlled by residues in both of the domains (Domain1 and Domain2) that compose the bilobed agonist binding domain. Molecular dynamics (MD) simulations comparing a crystallography-based hydrated NR1/NR2A model with a homology-based NR1/NR2D hydrated model of the agonist binding domains suggest that glutamate exhibits a different binding mode in NR2D compared with NR2A that accommodates a 4-methyl substitution in SYM2081. Mutagenesis of functionally divergent residues supports the conclusions drawn based on the modeling studies. Despite high homology and conserved atomic contact residues within the agonist binding pocket of NR2A and NR2D, glutamate adopts a different binding orientation that could be exploited for the development of subunit selective agonists and competitive antagonists.     

鬼臼酰肼-2,2,6,6-四甲基哌啶腙的抗肿瘤作用

目的研究鬼臼酰肼-2，2，6，6-四甲基哌啶腙的抗肿瘤作用。方法：K(562)及L(1210)细胞体外培养24h台盼蓝染色计数、小鼠单次腹腔注射LD(50)测定、小鼠移植性肿瘤S(180)、EAC及HepA皮下接种及测瘤重。结果：鬼臼酰肼-2，2，6，6-四甲基哌啶腙及鬼臼乙叉甙用0．1714、0．0857、0.0171、0.0086及0.0017mmol·L(－1)浓度对体外培养的K(562)及L(1210)细胞有杀伤及增殖抑制作用，鬼臼酰肼-2，2，6，6-四甲基哌啶腙的抑制率为60．55％、45．38％、18．68％、15．93％、11．57％；61．88％、47．59％、24．28％、16．55％、12．85％。鬼臼乙叉甙抑制率为64．73％、49．15％、22．94％、15．37％、10．44％；66．37％、52．43％、36.32％、19．37％、9．07％，给药组与对照组比较差别有显著性。两药品相同剂量比较无明显的差异，鬼臼酰肼-2,2，6，6-四甲基哌啶腙小鼠单次腹腔注射LD(50)为288．6～413．1mg·kg(-1)。鬼臼乙叉甙LD50为72.3～102.9mg·kg(-1)，对小鼠移植性肿瘤S(180)、EAC及HepA有抑制作用，瘤重抑制率鬼臼酰肼-2，2，6，6-四甲基哌啶腙为41．6％、43．3％、40．3％、（70．0mg·kg(－1)），32．2％、34．6％、35．1％（35．0mg·kg(-1)），26.2％、32.3％、28．6％（14．5mg·kg(－1)）;鬼臼乙叉?     

Reaction of glyoxal with 2'-deoxyguanosine, 2'-deoxyadenosine, 2'-deoxycytidine, cytidine, thymidine, and calf thymus DNA: identification of DNA adducts

Glyoxal (ethanedial) is an increasingly used industrial chemical that has been found to be mutagenic in bacteria and mammalian cells. In this study, the reactions of glyoxal with 2'-deoxyguanosine, 2'-deoxyadenosine, 2'-deoxycytidine, cytidine, thymidine, and calf thymus DNA have been studied in aqueous buffered solutions. The nucleoside adducts were isolated by reversed-phase liquid chromatography and characterized by their UV absorbance and 1H and 13C NMR spectroscopic and mass spectrometric features. The reaction with 2'-deoxyguanosine gave one adduct, the previously known 3-(2'-deoxy-beta-D-erythro-pentofuranosyl)-5,6,7-trihydro-6,7-dihydroxyimidazo[1,2-a]purine-9-one adduct. The reaction of 2'-deoxyadenosine with glyoxal resulted in the formation of a previously not reported N6-(hydroxyacetyl)-2'-deoxyadenosine adduct. In the reaction of glyoxal with 2'-deoxycytidine and cytidine at neutral conditions and 37 degrees C, 5-hydroxyacetyl pyrimidine derivatives were obtained. When the cytidine reaction was performed at pH 4.5 and 50 degrees C, the 5-hydroxyacetyl derivative of uridine was formed through deamination of cytidine-glyoxal. Adducts in the thymidine reaction could not be detected. In the reaction of glyoxal with calf thymus DNA, the 2'-deoxyguanosine-glyoxal and 2'-deoxyadenosine-glyoxal adducts were obtained, the former being the major adduct.     

Multiple column peptide synthesis,Part 2 (1, 2)

A manually operated apparatus for parallel multiple column soli-phase peptide synthesis is described. It employs Fmoc-amino acid-O-Dhbt or -Pfp esters in the continuous flow version of the polyamide method on small packed columns of kieselguhr supported resin in a reaction block of Teflon. The solvents and deprotecting reagents are dispensed from two washers in a parallel fashion and reagent consumption is low. Activated and protected amino acids are transferred from a dispenser tray as solutions, eight at a time. The use of the method is demonstrated by the synthesis of overlapping peptides from a protein structure and of analogous protease substrates. The products have been characterized by HPLC, FAB mass spectroscopy and amino acid analysis.     

Aflatoxins, B1, B2, G1, G2 in primary liver cell carcinoma

Aflatoxin B1, B2, G1, G2 levels were determined in sera of 20 patients with primary liver cell carcinoma (CC). Values of B1 above 0.15 microgram/ml were obtained in sera of three patients. Hepatitis B surface antigen (HBsAg) was detected in only 35% of patients. 50-90% of serum levels were cleared in 24 h in three patients studied. Although it is inconclusive as to the carcinogenic potential of aflatoxins in adult man, foodstuffs should be protected from excessive aflatoxin contamination.