[Mesenteric venous thrombosis complicating acute appendicitis]. / Thrombose veineuse mésentérique compliquant une appendicite aiguë.

Common primary surgical sources of thrombophlebitis of the mesenteric vein are diverticulitis and appendicitis. This is an acute ascending infection with septic thrombophlebitis. C.T. imaging can diagnose this complication at an early stage. Broad spectrum antibiotic therapy and heparin should be started. Surgery is performed electively to eradicate the primary inflammatory process. Early detections of septic ascending pylephlebitis and adequate treatment have decreased the mortality rate. We report a clinical case of thrombophlebitis of the mesenteric vein in acute appendicitis.

[Small bowel obstruction secondary to ischemic stenosis due to cholesterol crystal embolism]. / Occlusion du grêle secondaire à une sténose ischémique par embolie de cristaux de cholestérol.

Cholesterol crystal embolization is a well-known disorder resulting from release of cholesterol crystals from ulcerous atherosclerotic plaques. Gastrointestinal involvement occurs in about a third of cases, but it is usually asymptomatic. We report a case of an old woman with small bowel obstruction secondary to atheromatous embolism. She was treated by acenocoumarol for atrial fibrillation and pulmonary embolism. Two weeks before admission for small bowel obstruction, she had a watery diarrhea. After 3 weeks of parenteral nutrition, she underwent resection of the involved ileum. Pathological examination showed a small bowel stricture secondary to atheromatous embolism. Cholesterol emboli should be considered as a potential cause of small bowel obstruction in old patient who has taken anticoagulant therapy or after vascular invasive procedure.

Comparative metabolism of tosufloxacin and BMY 43748 in hepatocytes from rat, dog, monkey and man.

Metabolism of two broad spectrum quinolones in advanced preclinical development-tosufloxacin and BMY 43748-was compared in hepatocyte cultures derived from rat, dog, monkey and humans. The drugs were added at the first medium renewal and incubated for 4 or 24 hr in serum-free medium. Metabolites were analysed by HPLC. Marked species differences were found in both the metabolic rates and pathways of the two quinolones. BMY 43748 was found to be more actively metabolized than tosufloxacin in cultured hepatocytes from the three animal species. Human hepatocytes were totally ineffective, thereby indicating that they were metabolically different from monkey cells. Comparison with available in vivo data demonstrated a good but not perfect qualitative in vivo/in vitro correlation.

Relationships among antibacterial activity, inhibition of DNA gyrase, and intracellular accumulation of 11 fluoroquinolones.

A series of 11 fluoroquinolone antibacterial agents, including 8 newly synthesized molecules and 3 reference compounds (pefloxacin, ciprofloxacin, and sparfloxacin), were tested for their MICs against Escherichia coli, Staphylococcus aureus, and Pseudomonas aeruginosa. The intracellular accumulation of fluoroquinolones by these microorganisms was measured by centrifugation through silicone oil and a fluorescence assay. The minimal effective dose (MED) was determined for all agents in a supercoiling assay with E. coli DNA gyrase. The hydrophobicities of the quinolones were determined and expressed as the logarithm of the coefficient of distribution (log D) between 1-octanol and phosphate buffer (pH 7.2). No correlation was found between MICs and cell accumulation for the quinolones studied. A correlation was found between log D and accumulation by S. aureus (r = 0.71, n = 11), and an inverse correlation was found between log D and accumulation by E. coli (r = 0.73, n = 11) and P. aeruginosa (r = 0.64, n = 10). The correlation coefficients between MICs and MED for E. coli, which were 0.60, 0.64, and 0.74 (n = 11) for E. coli, P. aeruginosa, and S. aureus, respectively, rose to 0.85, 0.74, and 0.74 (n = 11) for the same microorganisms, respectively, when the accumulation of the drug by the cell was taken into account. It was concluded that the inhibitory activity against DNA gyrase remains the most important parameter for quinolone potency, but that intracellular accumulation must be taken into account, since, for a given organism, both parameters are under the control of the physicochemical properties of the quinolones.

Fluoronaphthyridines and -quinolones as antibacterial agents. 5. Synthesis and antimicrobial activity of chiral 1-tert-butyl-6-fluoro-7-substituted-naphthyridones.

A series of novel 7-substituted-1-tert-butyl-6-fluoronaphthyridone-3- carboxylic acids has been prepared. These derivatives are characterized by chiral aminopyrrolidine substituents at the 7 position. In this paper we report the full details of the asymmetric synthesis of this series of compounds. Structure-activity relationship studies indicate that the absolute stereochemistry at the asymmetric centers of the pyrrolidine ring is critical for maintaining good activity. Compounds 60 and 61 (3-amino-4-methylpyrrolidine enantiomers) were selected for preclinical evaluation.

Fluoronaphthyridines as antibacterial agents. 6. Synthesis and structure-activity relationships of new chiral 7-(1-, 3-, 4-, and 6-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)naphthyridine analogues of 7-[(1R,4R)-2,5- diazabicyclo[2.2.1]heptan-2-yl]-1-(1,1-dimethylethyl)-6-fluoro-1,4-dihy dro-4-oxo-1,8-naphthyridine-3-carboxylic acid. Influence of the configuration on blood pressure in dogs. A quinolone-class effect.

A series of novel chiral 7-(1-, 3-, 4-, and 6-methyl-[(1R,4R)-2,5- diazabicyclo[2.2.1]heptan-2-yl]-substituted naphthyridines has been prepared with the aim of obtaining good in vitro and in vivo antibacterial agents with a decrease of the pseudoallergic type reaction when compared to that observed with 7[(1R,4R)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-1-(1,1-dimethylethyl )1,4- dihydro-6-fluoro-4-oxo-1,8-naphthyridine-3-carboxylic acid (1a) (BMY 40062). The derivatives 7-[(1R,4R,6S)-6-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl]- 1-(1,1-dimethylethyl)-6-fluro-1,4-dihydro-4-oxo-1,8-naphthyridine- 3-carboxylic acid (41) and 7-[(1R,4R,6S)-6-methyl-2,5-diazabicyclo[2.2.1]heptan-2- yl]-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxy lic acid (49) showed potent in vitro and in vivo antibacterial activity against Gram-positive and Gram-negative bacteria. The derivative 49 displayed a less marked decrease in blood pressure (MAP), compared to that of 1a, after intravenous infusion in dogs and was selected as a potential candidate for preclinical trials.

Fluoronaphthyridines as antibacterial agents. 4. Synthesis and structure-activity relationships of 5-substituted-6-fluoro-7-(cycloalkylamino)-1,4-dihydro-4-oxo-1,8- naphthyridine-3-carboxylic acids.

A series of 5-substituted-6-fluoro-7-(cycloalkylamino)-1,4-dihydro-4-oxo-1,8- naphthyridine-3-carboxylic acids have been prepared and tested for their in vitro and in vivo antibacterial activities. The 5-methyl group gave better in vitro activity with the 1-cyclopropyl appendage, but poorer activity with the 1-tert-butyl moiety. With the 1-(2,4-difluorophenyl) substitution, the influence of the 7-cycloalkylamino group was determinant: a (3S)-3-amino-pyrrolidine was shown to enhance greatly the in vitro and in vivo activity of the 5-methyl derivative. Compound 33 (BMY 43748) was selected as a promising candidate for an improved therapeutic agent.

In vitro and in vivo evaluation of BMY 45243, a new 5-amino-naphthyridone derivative.

BMY 45243 is the first representative of 5-amino naphthyridone derivatives prepared following a new methodology developed by the authors. BMY 45243 is a highly lipophilic compound, very active in vitro and in vivo on S. aureus and was found to be as potent as ciprofloxacin on Gram-negative organisms with identical in vivo activity against Pseudomonas aeruginosa. Pharmacokinetics in mice showed better AUC and Cmax and longer t1/2 for BMY 45243 than for sparfloxacin and ciprofloxacin.

["Pouchitis" after ileo-anal anastomosis with reservoir]. / "Pochite" après anastomose iléo-anale avec réservoir.

Pouchitis is the most poorly understood complication of ileoanal anastomosis. The incidence reported in the literature ranges from 7 to 42% as there are no diagnostic criteria. The various clinical symptoms and endoscopic findings raise the possibility that pouchitis is a heterogenous disease, in which the role of bacterial overgrowth and recurrence of inflammatory bowel disease must be clarified.

Fluoronaphthyridines and -quinolones as antibacterial agents. 3. Synthesis and structure-activity relationships of new 1-(1,1-dimethyl-2-fluoroethyl), 1-[1-methyl-1-(fluoromethyl)-2-fluoroethyl], and 1-[1,1-(difluoromethyl)-2-fluoroethyl] substituted derivatives.

A series of novel N-1-(mono-,-(di- and -(trifluoro-tert-butyl)quinolones and -naphthyridines has been prepared. Structure-activity relationship (SAR) studies indicated that the in vitro antibacterial potency was the following order: 1-(1,1-dimethyl-2-fluoroethyl) greater than 1-[1-methyl-1-(fluoromethyl)-2-fluoroethyl] greater than 1-[1,1-(difluoromethyl)-2-fluoroethyl] substituents. In the quinolone series the monofluoro-tert-butyl derivatives were found to possess better in vitro antibacterial activity than the nonfluorinated-tert-butyl equivalents. In vivo PD50 values of the 1-fluoro-tert-butyl-substituted derivatives reflect pharmacokinetic behavior and incomplete oral absorption.

Fluoronaphthyridines and quinolones as antibacterial agents. 2. Synthesis and structure-activity relationships of new 1-tert-butyl 7-substituted derivatives.

A number of 7-substituted-1-tert-butyl-6-fluoroquinolone-3-carboxylic acids and 7-substituted-1-tert-butyl-6-fluoro-1,8-naphthyridine-3-carboxylic acids have been prepared and tested for antibacterial activities. Among those the 7-aminopyrrolidinyl 20b and the 7-diazabicyclo naphthyridine 18b are the most potent compounds in vitro and in vivo. Physicochemical data and acute toxicity are also discussed. Compound 18b, BMY 40062, exhibits the most favorable overall properties, considering in vitro and in vivo microbiological activity, its low toxicity, and pharmacokinetic profile, and was selected for clinical evaluation.

Fluoronaphthyridines and quinolones as antibacterial agents. 1. Synthesis and structure-activity relationships of new 1-substituted derivatives.

A series of novel 7-piperazinyl-1-substituted-6-fluoroquinolones and naphthyridines have been prepared and their antibacterial activities evaluated. These derivatives are characterized by having alkyl, alkenyl, arylalkyl, cycloalkyl, and cycloalkenyl groups at the 1-position. As a result of this study, derivatives 7 and 26, which are substituted with tert-butyl groups at N-1, were found to possess excellent in vitro and in vivo potency, particularly against Staphylococcus aureus, comparable to that of norfloxacin or ciprofloxacin. Structure-activity relationships of N-1 substituted alkyls and cycloalkyls are also discussed.