Studies on the Development of Novel Antileprous Chemotherapeutics Using Nude Mice With Special Reference to a New Quinolone Carboxylic Acid, AT-4140

Clinical trial of sparfloxacin for lepromatous leprosy

“…Sparfloxacin (AT-4140) was found to be the most active clinically relevant quinolone; its in vitro activity surpassed those of both pefloxacin and ofloxacin. Comparative studies (versus ofloxacin) in both nude mice (10,20) and healthy immune-competent mice (6,9) confirmed the in vitro observations. Considering its favorable plasma half-life of 17 h (13) and efficacy against other intracellular infections, sparfloxacin was chosen for a clinical trial in the treatment of patients with leprosy.…”

“…Considering the relative data obtained to date with sparfloxacin and ofloxacin with respect to toxicity (equivalent 50% lethal doses for mice [12,15]), pharmacokinetics (13), and bactericidal activity in vitro (7,14,16), in vivo (9,20), and in humans (with 200 mg of sparfloxacin given daily in the present study and 400 mg of ofloxacin given daily in a previous study [11]), a comparison of the longer-term therapeutic effects and potential toxicities of these two quinolones should be determined before choosing one for inclusion in a multidrug regimen for the treatment of leprosy.…”

Activities of various quinolone antibiotics against Mycobacterium leprae in infected mice

“…We utilized the kinetic method of of the quinolones five times weekly by gavage at doses of 50, 150, and 300 mg/kg. Additionally, because sparfloxacin previously had been found to inhibit the growth of M. leprae in nude mice at 15 mg/kg (36), in the present study, sparfloxacin was also evaluated at 15 and 30 mg/kg given five times weekly. At day 154 and at intervals of 2 to 3 months thereafter, generally up to 9 to 12 months, the number of M. leprae organisms from pools of four hind feet (from two mice) was determined microscopically until growth of M. leprae was considered to have occurred, the number of acid-fast bacilli per footpad equalling or exceeding 105 (33).…”

In vitro activities of aminoglycosides, lincosamides, and rifamycins against Mycobacterium leprae

“…It was radiorespirometric systems which initially demonstrated the antileprosy activity of macrolides and further identified clarithromycin as the most active drug in this class (4); the latter has been confirmed in the mouse footpad system by my colleague and me (4) and others (17). Likewise, they identified sparfloxacin (AT-4140) as being more active than other clinically relevant fluoroquinolones, including ofloxacin, against M. leprae (6), a finding which was subsequently confirmed in mice (26) and will soon be tested in humans. Overall, in vitro radiorespirometric systems appear to be predictive of the in vivo response in experimental and clinical leprosy.…”