ABSTRACT
Perturbation of hydroxyl radical accumulation by subinhibitory concentrations of 2,2'-bipyridyl plus thiourea protects Escherichia coli from being killed by 3 lethal antimicrobial classes. Here, we show that 2,2'-bipyridyl plus thiourea delays and/or reduces antimicrobial killing of Staphylococcus aureus by daptomycin, moxifloxacin, and oxacillin. While the protective effect of 2,2'-bipyridyl plus thiourea varied among strains and compounds, the data support the hypothesis that hydroxyl radical enhances antimicrobial lethality.
Subject(s)
Anti-Bacterial Agents/pharmacology , Aza Compounds/pharmacology , Daptomycin/pharmacology , Oxacillin/pharmacology , Quinolines/pharmacology , Reactive Oxygen Species/metabolism , Staphylococcus aureus/drug effects , 2,2'-Dipyridyl/pharmacology , Anti-Bacterial Agents/antagonists & inhibitors , Aza Compounds/antagonists & inhibitors , Daptomycin/antagonists & inhibitors , Fluoroquinolones , Microbial Sensitivity Tests , Moxifloxacin , Oxacillin/antagonists & inhibitors , Quinolines/antagonists & inhibitors , Reactive Oxygen Species/antagonists & inhibitors , Staphylococcus aureus/growth & development , Thiourea/pharmacology , Time FactorsABSTRACT
BACKGROUND: The long duration of the current tuberculosis (TB) treatment is demanding and warrants the development of new drugs. Moxifloxacin shows promising results and may be combined with rifampicin to shorten the duration of TB treatment. Rifampicin induces the phase II metabolic enzymes that are involved in the biotransformation of moxifloxacin. Therefore, the interaction between rifampicin and moxifloxacin should be investigated. PATIENTS AND METHODS: Nineteen Indonesian patients with pulmonary TB who were in the last month of their TB treatment completed a 1-arm, 2-period, fixed-order pharmacokinetic study. In phase 1 of the study, they received 400 mg of moxifloxacin every day for 5 days in addition to 450 mg of rifampicin and 600 mg of isoniazid 3 times per week. In phase 2 of the study, after a 1-month washout period, patients received moxifloxacin for another 5 days (without rifampicin and isoniazid). A 24-h pharmacokinetic curve for moxifloxacin was recorded on the last day of both study periods, and its pharmacokinetic parameters were evaluated for an interaction with rifampicin, using a bioequivalence approach. RESULTS: Coadministration of moxifloxacin with rifampicin and isoniazid resulted in an almost uniform decrease in moxifloxacin exposure (in 18 of 19 patients). The geometric means for the ratio of phase 1 area under the curve to phase 2 area under the curve and for the ratio of phase 1 peak plasma concentration to phase 2 peak plasma concentration were 0.69 (90% confidence interval, 0.65-0.74) and 0.68 (90% confidence interval, 0.64-0.73), respectively. The median time to reach peak plasma concentration for moxifloxacin was prolonged from 1 h to 2.5 h when combined with rifampicin and isoniazid (P=.003). CONCLUSIONS: Coadministration of moxifloxacin with intermittently administered rifampicin and isoniazid results in reduced moxifloxacin plasma concentrations, which is most likely the result of induced glucuronidation or sulphation by rifampicin. Further studies are warranted to evaluate the impact of the interaction on the outcome of TB treatment.
Subject(s)
Antibiotics, Antitubercular/pharmacokinetics , Antibiotics, Antitubercular/therapeutic use , Aza Compounds/antagonists & inhibitors , Aza Compounds/pharmacokinetics , Plasma/chemistry , Quinolines/antagonists & inhibitors , Quinolines/pharmacokinetics , Rifampin/therapeutic use , Tuberculosis, Pulmonary/drug therapy , Adolescent , Adult , Aza Compounds/administration & dosage , Drug Interactions , Female , Fluoroquinolones , Humans , Indonesia , Isoniazid/therapeutic use , Male , Middle Aged , Moxifloxacin , Quinolines/administration & dosage , Rifampin/administration & dosageABSTRACT
Two 3,8 diazabicyclo (3.2.1.) octane derivates, namely DBO 17 and DBO 11, were studied for the opioid-like activity. In the rat brain membrane preparation binding studies, DBO 17 and DBO 11 showed a high affinity and selectivity for the mu opioid receptor (Ki's: 5.1 and 25 nM, respectively). DBO 17 and DBO 11 inhibited the nociceptive response in the hot-plate test of mice with ED50 values of 0.16 mg/kg and 0.44 mg/kg, respectively. The antinociceptive action of both DBO 17 and DBO 11 was blocked by naloxone. Tolerance to the antinociceptive action of DBO 17 and DBO 11 was present after 13 and 7 days of repeated treatment, respectively. Both DBO 17 and DBO 11 were ineffective in morphine-tolerant mice and vice versa. Chronic treatments (three times daily for seven consecutive days) of DBO 17 and DBO 11 induced a naloxone-precipitated withdrawal syndrome in DBO 17 treated mice similar to that in morphine treated mice, whereas in DBO 11 treated mice abstinence signs were virtually absent. These results indicate an interesting pharmacological profile that suggests these compounds as possible new candidates for the clinical treatment of pain.
