7β-(6-取代-2-喹诺酮-3-乙酰氨基)头孢菌素的合成

以6-取代-2-喹诺酮-3-乙酸为侧链,用CDI法和潘化酯法与7-ADCA,7-ACA,7-ACT,和7-ACD缩合,合成了16个新的7β-(6-取代-2-喹诺酮-3-乙酰氨基)头孢菌素类化合物,通过溶媒转提,葡聚糖凝胶(Sephadex LH-20)柱层析及离心薄层层析分离精制,得到纯品。初步体外抑菌试验表明:新化合物对革兰氏阳性及某些阴性菌具有高度敏感性。大多数化合物对所试试验菌的抗菌活性与头孢唑啉和青霉素G钠相当,有些比它们还强。     

Allergy to laboratory animals: a follow up study of its incidence and of the influence of atopy and pre-existing sensitisation on its development.

OBJECTIVES--To investigate the incidence of allergy to laboratory animals (ALA) during the first two years of employment, and to study the effect on ALA of atopy and sensitisation. METHODS--A follow up prospective study of ALA at the Zeneca (formerly ICI) Research Laboratories. RESULTS--The incidence of the disease during the first year of employment has remained at about 10% since the mid-1980s. This compares with an incidence of 37% in the early 1980s. The reduction in incidence and its maintenance at a lower level is thought to be due to the introduction and management of improved engineering controls, working practices, and educational programmes designed to reduce exposure to allergens from laboratory animals. The underlying incidence of immunological sensitisation to animals (the presence of immunoglobulin E (IgE) antibodies to animal allergens) is much higher (40% after one and 53% after two years of exposure). Both atopic diathesis and presensitisation to laboratory animals increased the likelihood that a person would develop ALA. CONCLUSION--Neither factor predicted the disease accurately so their use should be restricted to the identification of people who may be more susceptible to the development of ALA (and thus who may need to pay particular attention to the use of personal protective equipment) rather than to their exclusion.     

亮氨酸脑啡肽的电子结构及构效关系研究

对亮氨酸脑啡肽进行了量子化学(INDO)计算,研究其电子结构特征,讨论其活性部位、作用机理及构效关系。同吗啡和R31833进行了活性部位的电子结构与空间结构比较,推断它们的活性药效结构具有共同特点,与阿片受体相互作用时作用方式相同,作用部位有对应关系,因而具有相同的药理性质。     

Antagonist binding properties of five cloned muscarinic receptors expressed in CHO-K1 cells

A family of five cholinergic muscarinic receptor genes (m1, m2, m3, m4, and m5) has recently been identified and cloned. In order to investigate the pharmacological properties of the individual muscarinic receptors, we have transfected each of these genes into Chinese hamster ovary cells (CHO-K1) and have established stable cell lines expressing each receptor. In the present study we have examined the antagonist binding properties of each muscarinic receptor. Antagonists were chosen that had previously been proposed to be selective for muscarinic receptor subtypes and included pirenzepine, AF-DX 116, methoctramine, dicyclomine, hexohydrodifenidol, hexahydrosiladifenidol, hexocyclium, and silahexocyclium. m1, m2, and m3 receptors express binding properties similar to those expected of high affinity pirenzepine-type receptors of cerebral cortex ("M1"), low affinity pirenzepine-type receptors of atria ("M2 cardiac type"), and the intermediate affinity pirenzepine-type receptors found in exocrine glands ("M2 glandular type"), respectively. The M1/M2 schema cannot readily accommodate the binding properties of the m4 and m5 receptors. Pirenzepine, methoctramine, and hexahydrosiladifenidol were the most selective agents for the m1, m2, and m3 receptors, respectively. None of the antagonists used in this study were uniquely selective for either the m4 or m5 receptors. The diverse binding profiles of individual cloned receptors and the widespread distribution of m1-m4 mRNAs indicate that radioligand binding studies performed on primary tissues may actually be assessing the composite properties of a heterogeneous mixture of muscarinic receptor subtypes.     

Biochemical characterisation of para-aminophenol-induced nephrotoxic lesions in the F344 rat

The acute biochemical effects of the nephrotoxin p-aminophenol (PAP) were studied in detail using a combination of conventional bioanalytical and ¹H-NMR spectroscopic methods. Dosing PAP (25–100 mg/kg) to male F344 rats resulted in a dose-related proximal nephropathy with consequent elevations in urinary enzymes, glucose, and urine total protein as shown by conventional methodology. ¹H-NMR spectroscopy at 400 MHz of urine from PAP-treated rats also revealed a characteristic glycosuria, with concomitant amino aciduria. The increased excretion of these compounds indicates functional defects in the proximal tubule and reduced solute reabsorption efficiency. In addition, ¹H-NMR urinalysis and conventional enzymatic analysis showed a dose-related lactic aciduria. Other changes detected by ¹H-NMR included a dose-related reduction in the excretion of citrate (confirmed by a conventional biochemical method) and an increase in the excretion of acetate. The degree of abnormalities shown by ¹H-NMR urinalysis agreed well with histopathological observations and conventional biochemical indices of nephrotoxicity. ¹H-NMR urinalysis therefore serves to highlight changes in the excretion of low MW urine components not routinely studied by conventional biochemical analysis.Abbreviations ALP alkaline phosphatase - APAP paracetamol - BUN blood urea nitrogen - GFR glomerular filtration rate - GOT glutamate oxaloacetate transaminase - LAP leucine aminopeptidase - LDH lactate dehydrogenase - MW molecular weight - NAG N-acetyl--D-glucosaminidase - PAP p-aminophenol - ppm parts per million - TMAO trimethylamine N-oxide - UFR urine flow rate     

Expression microdissection: operator-independent retrieval of cells for molecular profiling.

Tissue microdissection is an important method for the study of disease states. However, it is difficult to perform high-throughput molecular analysis with current techniques. We describe here a prototype version of a novel technique (expression microdissection) that allows for the procurement of desired cells via molecular targeting. Expression microdissection (xMD) offers significant advantages over available methods, including an increase in dissection speed of several orders of magnitude. xMD may become a valuable tool for investigators studying cancer or other disease states in patient specimens and animal models.     

Contractile activity of neonatal heart cells in culture derived from offspring of exercised pregnant rats

Summary 5-day-old neonatal offspring of exercised or non-exercised pregnant Sprague Dawley rats were used to prepare primary cultures of beating myocardial cells. The cells from the exercise group exhibited a slower beating rate for both single and aggregate cells; a larger cell size; an increased percentage of contracting cells; a greater capacity to form confluent monolayers, and a greater viability. It was concluded that exercise during the period of pregnancy produced morphological alterations in the myocardium of the progeny.     

Susceptibility of cyclooxygenase-2-deficient mice to pulmonary fibrogenesis

The cyclooxygenase (COX)-2 enzyme has been implicated as an important mediator of pulmonary fibrosis. In this study, the lung fibrotic responses were investigated in COX-1 or COX-2-deficient (-/-) mice following vanadium pentoxide (V(2)O(5)) exposure. Lung histology was normal in saline-instilled wild-type and COX-deficient mice. COX-2(-/-), but not COX-1(-/-) or wild-type mice, exhibited severe inflammatory responses by 3 days following V(2)O(5) exposure and developed pulmonary fibrosis 2 weeks post-V(2)O(5) exposure. Western blot analysis and immunohistochemistry showed that COX-1 protein was present in type 2 epithelial cells, bronchial epithelial cells, and airway smooth muscle cells of saline or V(2)O(5)-exposed wild-type and COX-2(-/-) mice. COX-2 protein was present in Clara cells of wild-type and COX-1(-/-) terminal bronchioles and was strongly induced 24 hours after V(2)O(5) exposure. Prostaglandin (PG) E(2) levels in the bronchoalveolar lavage (BAL) fluid from wild-type and COX-1(-/-) mice were significantly up-regulated by V(2)O(5) exposure within 24 hours, whereas PGE(2) was not up-regulated in COX-2(-/-) BAL fluid. Tumor necrosis factor-alpha was elevated in the BAL fluid from all genotypes after V(2)O(5) exposure, but was significantly and chronically elevated in the BAL fluid from COX-2(-/-) mice above wild-type or COX-1(-/-) mice. These findings indicate that the COX-2 enzyme is protective against pulmonary fibrogenesis, and we suggest that COX-2 generation of PGE(2) is an important factor in resolving inflammation.