Investigating the treatment shortening potential of a combination of bedaquiline, delamanid and moxifloxacin with and without sutezolid, in a murine tuberculosis model with confirmed drug exposures

Article

作者: Svensson, Elin M ; Hoelscher, Michael ; Walter, Kerstin ; Hölscher, Christoph ; Heinrich, Norbert ; te Brake, Lindsey H M ; Lemm, Ann-Kathrin

AbstractBackgroundNew and shorter regimens against multi-drug resistant tuberculosis (TB) remain urgently needed. To inform treatment duration in clinical trials, this study aimed to identify human pharmacokinetic equivalent doses, antimycobacterial and sterilizing activity of a novel regimen, containing bedaquiline, delamanid, moxifloxacin and sutezolid (BDMU), in the standard mouse model (BALB/c) of Mycobacterium tuberculosis (Mtb) infection.MethodsTreatment of mice with B25D0.6M200U200, B25D0.6M200, B25D0.6M200(U2003) or H10R10Z150E100 (isoniazid, rifampicin, pyrazinamide, ethambutol, HRZE), started 3 weeks after Mtb infection. Bactericidal activity was assessed after 1, 2, 3 and 4 months of treatment and relapse rates were assessed 3 months after completing treatment durations of 2, 3 and 4 months.ResultsB25D0.6M200U200 generated human equivalent exposures in uninfected BALB/c mice. After 1 month of treatment, a higher bactericidal activity was observed for the B25D0.6M200U200 and the B25D0.6M200 regimen compared to the standard H10R10Z150E100 regimen. Furthermore, 3 months of therapy with both BDM-based regimens resulted in negative lung cultures, whereas all H10R10Z150E100 treated mice were still culture positive. After 3 months of therapy 7% and 13% of mice relapsed receiving B25D0.6M200U200 and B25D0.6M200, respectively, compared to 40% for H10R10Z150E100 treatment showing an increased sterilizing activity of both BDM-based regimens.ConclusionsBDM-based regimens, with and without sutezolid, have a higher efficacy than the HRZE regimen in the BALB/c model of TB, with some improvement by adding sutezolid. By translating these results to TB patients, this novel BDMU regimen should be able to reduce treatment duration by 25% compared to HRZE therapy.

2024-09-01·Journal of Behavior Therapy and Experimental Psychiatry

Transitioning to college: Testing cognitive bias modification for interpretations as an inoculation tool for social anxiety in college first-years

Article

作者: Fite, Robert E ; Geyer, Rachel B ; Das, Akanksha ; Kiel, Elizabeth J ; Dreyer-Oren, Sarah E ; Clerkin, Elise M

BACKGROUND AND OBJECTIVESReducing social anxiety development among incoming college students may improve college adjustment and mental health outcomes. This study tested whether cognitive bias modification for interpretations (CBM-I) reduces social anxiety and increases adjustment during the transition to college, and whether changes in outcomes would be mediated by changes in interpretation biases.METHODSParticipants (N = 73) were randomly assigned to a 3-session weekly CBM-I condition or symptom tracking (ST) control condition. Multilevel models were used to estimate within-person trajectories from baseline to one week post-intervention and to test whether trajectories differed by condition.RESULTSThose in the CBM-I condition (vs. ST) reported higher increases in social adjustment across time. There were not significant differences between conditions for changes in social anxiety, academic adjustment, and personal adjustment. CBM-I was indirectly linked to improvements in outcome variables via more adaptive interpretation biases.LIMITATIONSCBM-I was administered in a laboratory setting, requiring more resources than some computerized interventions.CONCLUSIONSData tentatively support CBM-I for first-year students to increase social adjustment. Further, mediation findings provide support for targeting interpretation biases to improve social anxiety and adjustment outcomes. Yet, CBM-I did not outperform ST in improving social anxiety symptoms or other areas of college adjustment, and effect sizes were small, suggesting that more work is needed to amplify the potential of CBM-I as a therapeutic tool.

2024-07-25·The Journal of Infectious Diseases

Steroid Drugs Inhibit Bacterial Respiratory Oxidases and Are Lethal Toward Methicillin-Resistant Staphylococcus aureus

Article

作者: Jobson, Mary-Elizabeth ; Wass, Mark N ; Torres, Nathanial J ; Henry, Samantha A ; Robinson, Gary K ; Webster, Calum M ; Shepherd, Mark ; Totzke, Brendan C ; Shaw, Lindsey N ; Jackson, Jessica K ; McGreig, Jake E

AbstractBackgroundCytochrome bd complexes are respiratory oxidases found exclusively in prokaryotes that are important during infection for numerous bacterial pathogens.MethodsIn silico docking was employed to screen approved drugs for their ability to bind to the quinol site of Escherichia coli cytochrome bd-I. Respiratory inhibition was assessed with oxygen electrodes using membranes isolated from E. coli and methicillin-resistant Staphylococcus aureus strains expressing single respiratory oxidases (ie, cytochromes bd, bo′, or aa3). Growth/viability assays were used to measure bacteriostatic and bactericidal effects.ResultsThe steroid drugs ethinylestradiol and quinestrol inhibited E. coli bd-I activity with median inhibitory concentration (IC50) values of 47 ± 28.9 µg/mL (158 ± 97.2 µM) and 0.2 ± 0.04 µg/mL (0.5 ± 0.1 µM), respectively. Quinestrol inhibited growth of an E. coli “bd-I only” strain with an IC50 of 0.06 ± 0.02 µg/mL (0.2 ± 0.07 µM). Growth of an S. aureus “bd only” strain was inhibited by quinestrol with an IC50 of 2.2 ± 0.43 µg/mL (6.0 ± 1.2 µM). Quinestrol exhibited potent bactericidal effects against S. aureus but not E. coli.ConclusionsQuinestrol inhibits cytochrome bd in E. coli and S. aureus membranes and inhibits the growth of both species, yet is only bactericidal toward S. aureus.

100 项与 BDM-I 相关的药物交易

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