| 2021 | Rifapentine Polylactic Acid Sustained-Release Microsphere Complex for Spinal Tuberculosis Therapy: Preparation, in vitro and in vivo Studies. | Infect Drug Resist | Spinal tuberculosis has been a common clinical extrapulmonary tuberculosis in recent years. The general anti-tuberculosis drug treatment cycle is long, with unsatisfactory efficacy. This study focused on the preparation and evaluation of rifapentine polylactic acid sustained-release microsphere complex for spinal tuberculosis therapy.Rifapentine polylactic acid sustained-release microspheres (RPSMs) were prepared through the double emulsion solvent evaporation method, and RPSMs were combined with hydroxyapatite/β-tricalcium phosphate (HA/β-TCP) composite material to obtain drug-loaded, sustained-release complex. We evaluated the complex for dynamics of drug release and osteogenic ability using in vitro release test, alkaline phosphatase and alizarin red staining, real-time PCR and Western blot. A rabbit model of a spinal tuberculosis defect was established and repaired using HA/β-TCP or complex. The ability of anti-tuberculosis and tissue repair effects of the complex were evaluated through in vivo experiments.The complex constructed of RPSMs and HA/β-TCP demonstrated a long drug release time, with no significant inhibition of cell osteogenic differentiation in vitro experiments. Postoperative macroscopic observation, immunohistochemical staining and Nilsson histological scores showed that the complex has good effects on the tissue repair. Moreover, the erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), important indexes of inflammation, decreased to normal levels in the complex group.In vitro and in vivo experiments demonstrated that the complex constructed of RPSMs and HA/β-TCP effectively treated spinal tuberculosis. Therefore, the complex represents a promising approach for the treatment of spinal tuberculosis. |
| 2018 | Cytokine-Mediated Systemic Adverse Drug Reactions in a Drug-Drug Interaction Study of Dolutegravir With Once-Weekly Isoniazid and Rifapentine. | Clin Infect Dis | Once-weekly isoniazid and rifapentine for 3 months is a treatment option in persons with human immunodeficiency virus and latent tuberculosis infection. This study aimed to examine pharmacokinetic drug-drug interactions between this regimen and dolutegravir, a first-line antiretroviral medication.This was a single-center, open-label, fixed-sequence, drug-drug interaction study in healthy volunteers. Subjects received oral dolutegravir 50 mg once daily alone (days 1-4) and concomitantly with once-weekly isoniazid 900 mg, rifapentine 900 mg, and pyridoxine 50 mg (days 5-19). Dolutegravir concentrations were measured on days 4, 14, and 19, and rifapentine, 25-desacetyl-rifapentine, and isoniazid concentrations were measured on day 19. Cytokines and antidrug antibodies to isoniazid and rifapentine were examined at select time points.The study was terminated following the development of flu-like syndrome and elevated aminotransferase levels in 2 of 4 subjects after the third isoniazid-rifapentine dose. Markedly elevated levels of interferon-γ, CXCL10, C-reactive protein, and other cytokines were temporally associated with symptoms. Antidrug antibodies were infrequently detected. Dolutegravir area under the curve (AUC) was decreased by 46% (90% confidence interval, 27-110%; P = .13) on day 14. Rifapentine and 25-desacetyl rifapentine levels on day 19 were comparable to reference data, whereas isoniazid AUCs were approximately 67%-92% higher in the subjects who developed toxicities.The combined use of dolutegravir with once-weekly isoniazid-rifapentine resulted in unexpected and serious toxicities that were mediated by endogenous cytokine release. Additional investigations are necessary to examine the safety and efficacy of coadministering these medications.NCT02771249. |