Camsonne R, Bigot M C, Fusibet H, Moulin M A
Service de Pharmacologie et des Explorations Fonctionnelles B, CHRU, Caen.
Therapie. 1993 Mar-Apr;48(2):105-7.
Ro 5-3335 is a new benzodiazepine highly active in vitro (IC50 = 0.1-1.0 microM [corrected]) against HIV-1 viruses of AIDS resistant or non-resistant to zidovudine (AZT). It is also active against HIV-2. Ro 5-3335 is original by its mechanism of action, acting on the trans-activation factor of transcription (TAT) and non on the reverse transcriptase. Such as, it could prevent proviral DNA to express in both evolutive and silent AIDS resistant or non-resistant to AZT or to other anti-reverse transcriptase series. In addition, in antagonizing extracellular TAT's actions, Ro 5-3335 could alleviate the syndrome commonly associated with AIDS as Kaposi's syndrome. In rodent test, Ro 5-3335 has no diazepam-like central effects and presents in comparison to AZT a more favorable therapeutic index. In dog, the elimination half-life, peak concentration and availability are 2 h, 0.8 microM and 85% respectively, after a 1 mg.kg-1 oral dose of Ro 5-3335. Theoretically, Ro 5-3335 and now its analogue Ro 24-7429 seem to possess all virtues to antagonize evolutive and latent AIDS. Its arrival is timely to cope with the ever increasing resistance phenomena, lengthy development of AIDS vaccines, exponential contamination of populations worldwide and last but not least possibly to impede evolutions of the disease. Ability to manipulate TAT-mediated activation of HIV-1 genes paves the ways to study conceivable corrections of abnormal gene expressions of neurotransmitters, hormones, oncogenes and key enzymes.
Ro 5-3335是一种新型苯二氮䓬类药物，在体外具有高活性（IC50 = 0.1 - 1.0微摩尔[校正后]），对齐多夫定（AZT）耐药或不耐药的艾滋病HIV-1病毒均有效。它对HIV-2也有活性。Ro 5-3335的作用机制独特，作用于转录反式激活因子（TAT）而非逆转录酶。因此，它可以阻止前病毒DNA在进化型和潜伏型的对AZT耐药或不耐药的艾滋病病毒中表达，也能阻止其在对其他抗逆转录酶药物系列耐药或不耐药的病毒中表达。此外，通过拮抗细胞外TAT的作用，Ro 5-3335可以缓解通常与艾滋病相关的综合征，如卡波西肉瘤。在啮齿动物试验中，Ro 5-3335没有类似地西泮的中枢作用，与AZT相比，其治疗指数更有利。在犬类中，口服1毫克/千克剂量的Ro 5-3335后，消除半衰期、峰值浓度和生物利用度分别为2小时、0.8微摩尔和85%。从理论上讲，Ro 5-3335及其类似物Ro 24-7429似乎具备对抗进化型和潜伏型艾滋病的所有优点。它的出现恰逢其时，可应对不断增加的耐药现象、艾滋病疫苗研发的漫长过程、全球人口的指数级感染，以及最后但同样重要的是可能阻止疾病的演变。操纵TAT介导的HIV-1基因激活的能力为研究神经递质、激素、癌基因和关键酶异常基因表达的可能校正方法铺平了道路。
