Oxidative bioactivation of the lactol prodrug of a lactone cyclooxygenase-2 inhibitor.

The lactol derivative of a lactone cyclooxygenase-2 inhibitor (DFU) was evaluated in vivo and in vitro for its potential suitability as a prodrug. DFU-lactol was found to be 10 to 20 times more soluble than DFU in a variety of aqueous vehicles. After administration of DFU-lactol at 20 mg kg-1 p.o. in rats, a Cmax of 7.5 microM DFU was reached in the plasma. After oral administration, the ED50s of DFU-lactol in the carrageenan-induced paw edema and lipopolysaccharide-induced pyresis assays in rats are comparable with the ED50s observed when dosing with DFU. Incubations of DFU-lactol with rat and human hepatocytes demonstrated that the oxidation of DFU-lactol can be mediated by liver enzymes and that a competing pathway is direct glucuronidation of the DFU-lactol hydroxyl group. Assays with subcellular fractions from rat liver indicated that most of the oxidation of DFU-lactol occurs in the cytosolic fraction and requires NAD(P)+. Human liver cytosol can also support the oxidation of DFU-lactol to DFU when NAD(P)+ is added to the incubations. Fractionation of human liver cytosolic proteins showed that at least three enzymes are capable of efficiently effecting the oxidation of DFU-lactol to DFU. Incubations with commercially available dehydrogenases suggest that alcohol and hydroxysteroid dehydrogenases are involved in this oxidative process. These data together suggest that lactols may represent useful prodrugs for lactone-containing drugs.     

DA1 receptor activity opposes anorectic responses to amino acid-imbalanced diets

The serotonin3 (5-HT3) receptor plays an important role in the aminoprivic feeding model. Other neurochemical systems, including cholecystokinin (CCK) and dopamine (DA), are known to affect food intake. We pretreated rats systemically with tropisetron, a 5-HT3 receptor antagonist, alone and combined with antagonists of DA1 and DA2 receptors, and measured intake of an amino acid-imbalanced diet (IMB). As expected, tropisetron significantly increased intake of IMB. SCH-23390, a DA1 antagonist, increased IMB anorexia. When combined with tropisetron, DA2 antagonism with eticlopride reduced short-term intake of both the basal diet (BAS) and IMB. In the IMB model, specificity of 5-HT3-DA2 interactions, and of 5-HT3-CCK(A) interactions from previous studies, prompted investigation of CCK(A)-DA2 interactions; there appeared to be none. SKF-38393, a DA1 agonist, combined with the CCK(A) receptor antagonist, devazepide, increased BAS and tended to increase IMB intake. Thus, CCK(A)-DA1 interactions were not specific for IMB. These data suggest that DA1 receptor activity opposes IMB anorexia, possibly via an interaction with the 5-HT3 receptor.     

一叶秋碱诱导人白血病HL—60细胞凋亡

目的 研究一叶秋碱能否诱导ＨＬ－６０细胞凋亡,方法 用ＭＴＴ法检测一叶秋碱对细胞增殖影响;应用流式细胞仪检测凋亡细胞数;采用琼脂糖凝胶电泳法观测ＤＮＡ碎片,透射电镜观察凋亡的形态改变,结果：一叶秋碱５－８０ｍｇ．Ｌ＾－１能诱导ＨＬ－６０细胞凋亡,电镜观察到典型的凋亡形态学改变,电泳呈现出阶梯状条带,流式细胞仪检测到凋亡率随剂量的增高而升高,ＭＴＴ法示一叶秋碱抑制ＨＬ－６０细胞增殖,并且呈时间,剂量     

Monoamine oxidase-dependent metabolism of dopamine in the striatum and substantia nigra of

The autors presented two typical cases of patients who were infected with Propionibacterium acnes (P. acnes) after intraocular lens implantation. The patients were treated successfully by the removal of the intraocular lens and the residual lens capsule, and the administration of intravitreal vacomycin. The histopathology illustrated numerous prokaryote bacilli surrounding the lens material without inflammatory reaction. The thickened bacterial cell wall structure may relate to the resistance of P. acnes killing and degradation by the host neutrophils and macrophages. Complete removal of the lens material which may sequester the bacterial growth in the eye is important to eradicate P. acnes endophthalmitis.     

Clinical pathologic findings of Propionibacterium acnes endophthalmitis

The autors presented two typical cases of patients who were infected with Propionibacterium acnes (P. acnes) after intraocular lens implantation. The patients were treated successfully by the removal of the intraocular lens and the residual lens capsule, and the administration of intravitreal vacomycin. The histopathology illustrated numerous prokaryote bacilli surrounding the lens material without inflammatory reaction. The thickened bacterial cell wall structure may relate to the resistance of P. acnes killing and degradation by the host neutrophils and macrophages. Complete removal of the lens material which may sequester the bacterial growth in the eye is important to eradicate P. acnes endophthalmitis.     

The eyes of transforming growth factor-sZ1 (TGF-sZ1) transgenic mice Morphology and the development of endotoxin-induced uveitis

Transforming growth factor-beta (TGFsZ) is a potent regulator of cellular growth and immune function. The authors studied ocular histology and endotoxin-induced uveitis in a TGF-sZ(1) transgenic (Tg) murine model. TGF-sZ(1) Tg mice were generated by micro injecting a gene constructed by fusing the mouse albumin enhancer/promoter and porcine TGF-sZ(1) cDNA. The eyes of Tg mice from two to 14 weeks of age were studied histologically. Tg mice, two to five weeks of age exhibited mild fragmentation of the lens fibers and retinal edema. No pathology was found from six to ten weeks of age, however, a progressive increased frequency of cataract was observed from 11 to 14 weeks of age. Plasma TGF-sZ(1) levels were much higher in Tg mice than age-matched wild type control littermates (wt). Endotoxin-induced uveitis (EIU) in six-to eight-week-old Tg and wt mice was induced by footpad injection of lipopolysaccharide (LPS). Mice were euthanized 24 hr after LPS injection, the eyes were collected for histology and serum assayed for IL-6 and TGF-sZ(1). There was a decrease in the mean numbers of infiltrating cells in Tg mice compared to wt mice. Serum IL-6 and TGF-sZ(1) were much higher in Tg mice. The authors concluded that expression of the TGF-sZ(1) transgene in the eyes may have effect on lens growth. Overexpression of TGF-sZ(1) results in little or no effect on the development of EIU.     

Synthesis andin vitro antitumor activity of isoazamitosene and isoiminoazamitosene derivatives

Seven isoazamitosene derivatives, mitomycin analogues, were synthesized and tested for cytotoxicities against leukemia and gastric cancer cell lines. Preparation of a pyrrolo[1,2-a]benzimidazole (3) (azamitosene ring system) was completed by utilizing the Lewis acid-catalized cyclization, witho-chloronitrotoluene as the starting material. Nitration of3 produced a mixture of two isomers (5-nitro isomer (4) and 7-nitro isomer (5)) in product ratio of 36∶52.4 was directly converted into quinone (7) by reduction and Fremy oxidaton. Finally, quinone derivatives (8, 9, 10, and11) were synthesized by 1,4-addition of7 with cyclic secondary amines. From above-mentioned5, 8-nitro compound (15) was prepared in 4 steps. At pH 3, Fremy oxidation of15 produced quinone (16), whereas iminoquinone derivatives (17a and17b) at pH 7. Isoazamitosene derivatives (8, 9, 10, and11), containing cyclic amino groups at the 7-position, showed potent cytotoxicity on P388, SNU-1, and KHH tumor cell lines. Among them,8 had stronger cytotoxicity against SNU-1 cell line than mitomycin and adriamycin. Considering these results, isoazamitosene derivatives may had unique cytotoxicity profiles. However, isoiminoazamitosene derivatives (17a and17b) revealed very weak cytotoxicity.     

Aminopyrine-induced blood dyscrasias--still a problem in many parts of the world

The aminopyrines were introduced about a century ago as analgesics and antipyretics, but it was not until the 1930s that agranulocytosis, their major adverse reaction, was recognized. In patients receiving aminopyrines, although agranulocytosis is the most frequent blood dyscrasia, aplastic anaemia has also been reported. For these reasons, these drugs have been banned or withdrawn from the market in most industrialized countries. However, aminopyrines are still available in many parts of the world, including the Far East, Africa and Latin and South America and can be found as adulterants in some 'herbal' patent preparations. Their continuing availability in the Far East may have contributed in part to the higher incidence of aplastic anaemia, compared with the West.