Search

A novel series of bacterial topoisomerase (3-aminoquinazolinediones) inhibitors are described. The side-chain SAR against Gram-positive and Gram-negative organisms as well as DNA gyrase activity is reported.

A series of 3-aminoquinazolinediones was synthesized and evaluated for its antibacterial and DNA gyrase activity. The SAR around the quinazolinedione core was explored and the optimal substitutions were combined to give two compounds, 2r and 2s, with exceptional enzyme potency (IC50 = 0.2 microM) and activity against gram-positive organisms (MIC's = 0.015-0.06 microg/mL).

The 3-aminoquinzolinediones represent a new series of antibacterial agents structurally related to the fluoroquinolones. They are inhibitors of bacterial gyrase and topoisomerase IV and demonstrate clinically useful antibacterial activity against fastidious Gram-negative and Gram-positive organisms, including multidrug- and fluoroquinolone-resistant organisms. These agents also demonstrate in vivo efficacy in murine systemic infection models.

Objective: To evaluate the efficiency on the vertigos and the impact on the audition of the vestibular neurotomy (VN) and the chemical labyrinthectomy (CL) in patients with severe Menière's disease, in order to determine the precise place for each technique in treatment algorithm., Method: Retrospective study of 71 VN (performed between 1986 and 2003) and 35 CL (performed between 1997 and 2003). These two treatments both aim at obtaining a vestibular deafferentation in order to free definitely the patient of vertigo manifestations. Vestibular results have been assessed by caloric tests performed before and 6 months after treatment. Subjective success was evaluated by searching for recurrent attacks of vertigo and by the AAO-HNS (American Academy of Otolaryngology-Head and Neck Society) scale of subjective evaluation of vertigos (follow-up of 6.4 years after VN and 2.4 years after CL). Pure tone audiometry before treatment and then 6 months later was performed. Complications of two types of treatment were recorded and evaluated., Results: In 90% of the cases after VN and 86% of the cases after CL, caloric tests indicated a strong vestibular hyporeflexy (hypovalence > 90%). Attacks of vertigo reoccurred in 5.6% of the cases when the hyporeflexy was strong and 85.7% of the cases when it was weak. The quality of the vestibular results on vertigo depends on the degree of hypovalence after treatment. An improvement of the AAO-HNS scale have been obtained in 93% of the cases in the NV group and in 81% of the cases in the LC group. Attacks of vertigo were recurrent in 7% of the patients operated on by VN and 11.4% of the patients treated by CL. Mean pure tone auditory thresholds changed from 50.24 dB HL to 55.64 dB HL (p=0.003) in the VN group and from 69.11 dB HL to 74.51 dB HL (p=0.41) in the CL group. Comparison of the variations of the mean pure tone auditory thresholds before treatment and 6 months after the end of the treatment doesn't show any significant difference between the 2 groups (p > 0.05). Impairment of the audition superior to 20 dB HL was observed in 8.5% of the patients of each group. The auditive results are similar in the 2 groups., Conclusion: These two methods of treatment can not be strictly compared due to several bias in this study. Indeed more patients were treated by VN with a longer follow-up and only the patients with a class C or D audition according to the criteria of the AAO-HNS could be treated by CL. The VN provides a better control of the vertigos than the CL which is an efficient method of treatment in invalidating Meniere's disease. In all the cases, the quality of the results on vertigos depends on the degree of hypovalence after treatment. The auditive results are similar. Since the results of the two treatments are similar, the simplicity of CL encourages us to broaden the indications and to modify the place of the VN in the therapeutic algorithm of Menière's disease.