Efficacy of Long-Acting Bedaquiline Regimens in a Mouse Model of Tuberculosis Preventive Therapy

2021 ◽  
Author(s):  
Amit Kaushik ◽  
Nicole C Ammerman ◽  
Rokeya Tasneen ◽  
Sophie Lachau-Durand ◽  
Koen Andries ◽  
...  
Keyword(s):  
Mouse Model ◽  
Preventive Therapy ◽  
Long Acting

scholarly journals Analysis of Rifapentine for Preventive Therapy in the Cornell Mouse Model of Latent Tuberculosis

1999 ◽  
Vol 43 (9) ◽  
pp. 2126-2130 ◽  
Author(s):  
Eishi Miyazaki ◽  
Richard E. Chaisson ◽  
William R. Bishai
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Drug Therapy ◽  
Mouse Model ◽  
Latent Tuberculosis Infection ◽  
Latent Tuberculosis ◽  
Preventive Therapy ◽  
Load Reduction ◽  
Short Course ◽  
Drug Regimens ◽  
Long Acting

ABSTRACT Rifapentine is a long-acting rifamycin which may be useful for intermittent drug therapy against tuberculosis. In this study we measured the efficacies of rifapentine-containing intermittent drug regimens for preventive therapy using the Cornell mouse model of latent tuberculosis. We infected groups of mice intravenously withMycobacterium tuberculosis and then treated them with isoniazid and pyrazinamide for 12 weeks according to the Cornell latency development protocol. After a 4-week interval of no treatment, experimental preventive therapy was administered by esophageal gavage for 12 or 18 weeks. After equilibration and dexamethasone amplification treatment, mouse organs were analyzed by quantitative colony counts to measure the effectiveness of therapy. Our results showed that once-weekly isoniazid plus rifapentine combination therapy for 18 weeks was an effective preventive regimen with sterilizing potency and bacillary load reduction comparable to those of daily isoniazid therapy for 18 weeks. Monotherapy with rifapentine weekly or fortnightly or with rifampin twice weekly for up to 18 weeks did not offer advantages in reducing bacillary load or in sterilizing organs compared to the effects of a placebo. These results with the Cornell mouse model indicate that once-weekly, short-course preventive therapy with isoniazid plus rifapentine is effective and may warrant investigation in humans with latent tuberculosis infection.

scholarly journals Long-lasting rescue of schizophrenia-relevant cognitive impairments via risperidone-loaded microPlates

2022 ◽  
Author(s):  
Elena Bellotti ◽  
Gabriella Contarini ◽  
Federica Geraci ◽  
Sebastiano Alfio Torrisi ◽  
Cateno Piazza ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
Mouse Model ◽  
Sustained Release ◽  
Temporal Order ◽  
Single Injection ◽  
Chronic Administration ◽  
Psychotic Symptoms ◽  
Residual Rate ◽  
Long Acting

AbstractSchizophrenia is a disorder characterized by cognitive impairment and psychotic symptoms that fluctuate over time and can only be mitigated with the chronic administration of antipsychotics. Here, we propose biodegradable microPlates made of PLGA for the sustained release of risperidone over several weeks. Two microPlate configurations – short: 20 × 20 × 10 μm; tall: 20 × 20 × 20 μm – are engineered and compared to conventional ~ 10 μm PLGA microspheres in terms of risperidone loading and release. Tall microPlates realize the slowest release documenting a 35% risperidone delivery at 100 days with a residual rate of 30 ng/ml. Short microPlates and microspheres present similar release profiles with over 50% of the loaded risperidone delivered within the first 40 days. Then, the therapeutic efficacy of one single intraperitoneal injection of risperidone microPlates is compared to the daily administration of free risperidone in heterozygous knockout mice for dysbindin-1, a clinically relevant mouse model of cognitive and psychiatric liability. In temporal order object recognition tasks, mice treated with risperidone microPlates outperform those receiving free risperidone up to 2, 4, 8, and 12 weeks of observation. This suggests that the sustained release of antipsychotics from one-time microPlate deposition can rescue cognitive impairment in dysbindin mice for up to several weeks. Overall, these results demonstrate that risperidone-loaded microPlates are a promising platform for improving cognitive symptoms associated to schizophrenia. Moreover, the long-term efficacy with one single administration could be of clinical relevance in terms of patient’s compliance and adherence to the treatment regimen. Graphical abstract Single injection of long-acting risperidone-loaded µPL ameliorates the dysbindin-induced deficit in a clinically relevant mouse model of cognitive and psychiatric liability for up to 12 weeks

scholarly journals Activity of a long-acting injectable bedaquiline formulation in a paucibacillary mouse model of latent tuberculosis infection

2019 ◽  
Author(s):  
Amit Kaushik ◽  
Nicole C. Ammerman ◽  
Sandeep Tyagi ◽  
Vikram Saini ◽  
Iwan Vervoort ◽  
...  
Keyword(s):  
Mouse Model ◽  
Latent Tuberculosis Infection ◽  
Latent Tuberculosis ◽  
Positive Control ◽  
Negative Control ◽  
Tuberculosis Infection ◽  
Sustained Activity ◽  
Short Course ◽  
Long Acting ◽  
Aerosol Infection

ABSTRACTThe potent anti-tuberculosis activity and long half-life of bedaquiline make it an attractive candidate for long-acting/extended release formulations for treatment of latent tuberculosis infection (LTBI). Our objective was to evaluate a long-acting injectable (LAI) bedaquiline formulation in a validated paucibacillary mouse model of LTBI. Following immunization with Mycobacterium bovis rBCG30, BALB/c mice were challenged by aerosol infection with M. tuberculosis H37Rv. Treatment began 13 weeks after challenge infection with one of the following regimens: untreated negative control; positive controls of daily rifampin (10 mg/kg), once-weekly rifapentine (15 mg/kg) and isoniazid (50 mg/kg), or daily bedaquiline (25 mg/kg); test regimens of one, two, or three monthly doses of LAI bedaquiline at 160 mg/dose (BLAI-160); and test regimens of daily bedaquiline at 2.67 (B2.67), 5.33 (B5.33), or 8 (B8) mg/kg to deliver the same total bedaquiline as one, two, or three doses of BLAI-160, respectively. All drugs were administered orally, except for BLAI-160 (intramuscular injection). The primary outcome was the decline in M. tuberculosis lung CFU counts during 12 weeks of treatment. The negative and positive control regimens performed as expected. One, two, and three doses of BLA-160 resulted in decreases of 2.9, 3.2, and 3.5 log10 CFU/lung, respectively by week 12. Daily oral dosing with B2.67, B5.33, and B8 decreased lung CFU counts by 1.6, 2.8, and 4.1 log10, respectively. One dose of BLAI-160 exhibited activity for at least 12 weeks. The sustained activity of BLAI-160 indicates promise as a short-course LTBI treatment requiring few patient encounters to ensure treatment completion.

Formoterol, a Long-Acting β2 Adrenergic Agonist, Improves Cognitive Function and Promotes Dendritic Complexity in a Mouse Model of Down Syndrome

2014 ◽  
Vol 75 (3) ◽  
pp. 179-188 ◽  
Author(s):  
Van Dang ◽  
Brian Medina ◽  
Devsmita Das ◽  
Sarah Moghadam ◽  
Kara J. Martin ◽  
...  
Keyword(s):  
Down Syndrome ◽  
Cognitive Function ◽  
Mouse Model ◽  
Adrenergic Agonist ◽  
Long Acting ◽  
Dendritic Complexity

638-P: A Novel, Long-Acting Dual Agonist for GIPR/GLP-1R, HISHS-2001, Demonstrates Effects on HbA1c and Weight Loss in the db/db Mouse Model of Type 2 Diabetes

Diabetes ◽  
2021 ◽  
Vol 70 (Supplement 1) ◽  
pp. 638-P
Author(s):  
VINOD S. BURADE ◽  
ADOLFO GARCIA-OCANA ◽  
RICHARD E. PRATLEY ◽  
GUY A. RUTTER ◽  
TINA VILSBØLL ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Weight Loss ◽  
Mouse Model ◽  
Long Acting ◽  
Dual Agonist

scholarly journals The long-term actions of etonogestrel and levonorgestrel on decidualized and non-decidualized endometrium in a mouse model mimic some effects of progestogen-only contraceptives in women

Reproduction ◽  
2007 ◽  
Vol 133 (1) ◽  
pp. 309-321 ◽  
Author(s):  
Naomi B Morison ◽  
Jin Zhang ◽  
Tu’uhevaha J Kaitu’u-Lino ◽  
Ian S Fraser ◽  
Lois A Salamonsen
Keyword(s):  
Mouse Model ◽  
Morphological Changes ◽  
Luminal Epithelium ◽  
Tissue Remodelling ◽  
Breakthrough Bleeding ◽  
Functional Studies ◽  
Tissue Integrity ◽  
Uterine Natural Killer Cells ◽  
Long Acting

Breakthrough bleeding (BTB), a major side effect of long-acting progestogen (p)-only contraceptives in women, is the main reason for discontinuation of their use. To understand the mechanisms of BTB, a mouse model of endometrial breakdown and repair was adapted to evaluate the effects of long-term progestogens on the endometrium. Appropriately prepared mice received either an etonogestrel (ENG)- or levonorgestrel (LNG)-releasing subdermal implant. Forty eight hours after decidualization was induced in one uterine horn the majority of tissues were highly decidualized, designated 0 day (0d). Uteri were collected subsequently at 5-day intervals (to 45d) and both decidualized and non-decidualized horns were analysed for morphological changes, leukocyte infiltration and matrix metalloproteinase expression (MMP). In decidualized horns, large blood vessels (BV) developed and disturbance of tissue integrity was observed at 5d with substantial stromal breakdown by 10d, progressing until 25d when re-epithelialization was initiated. By 45d, the tissue was restored to its pre-decidualized state but with considerable tortuosity of the luminal epithelium. Tissue remodelling was not apparent in the non-decidualized horns before 35d, when hyperproliferation of the luminal epithelium resulted in tortuosity. Changes in morphology were similar with the two progestogens, but occurred more rapidly with LNG. Apart from macrophages, few leukocytes were present in non-decidualized horns but large infiltrates of neutrophils and uterine natural killer cells (uNK) were associated with tissue breakdown in decidualized tissue, many of these cells were MMP9-positive. MMP7 was primarily associated with tissue repair. Therefore, this model mimics some of the changes observed in endometria of women using p-only contraceptives and provides an opportunity for functional studies.

scholarly journals Dulaglutide Alone and in Combination with Empagliflozin Attenuate Inflammatory Pathways and Microbiome Dysbiosis in a Non-Diabetic Mouse Model of NASH

Biomedicines ◽  
2021 ◽  
Vol 9 (4) ◽  
pp. 353
Author(s):  
Katharina Luise Hupa-Breier ◽  
Janine Dywicki ◽  
Björn Hartleben ◽  
Freya Wellhöner ◽  
Benjamin Heidrich ◽  
...  
Keyword(s):  
Mouse Model ◽  
Glucose Homeostasis ◽  
Diabetic Mouse ◽  
Significant Weight Loss ◽  
High Fat ◽  
Beneficial Effects ◽  
High Fructose ◽  
Patients With Diabetes ◽  
Anti Inflammatory ◽  
Long Acting

Dysregulation of glucose homeostasis plays a major role in the pathogenesis of non-alcoholic steatohepatitis (NASH) as it activates proinflammatory and profibrotic processes. Beneficial effects of antiglycemic treatments such as GLP-1 agonist or SGLT-2 inhibitor on NASH in patients with diabetes have already been investigated. However, their effect on NASH in a non-diabetic setting remains unclear. With this aim, we investigated the effect of long-acting GLP1-agonist dulaglutide and SGLT-2 inhibitor empagliflozin and their combination in a non-diabetic mouse model of NASH. C57BL/6 mice received a high-fat-high-fructose (HFHC) diet with a surplus of cholesterol for 16 weeks. After 12 weeks of diet, mice were treated with either dulaglutide, empagliflozin or their combination. Dulaglutide alone and in combination with empagliflozin led to significant weight loss, improved glucose homeostasis and diminished anti-inflammatory and anti-fibrotic pathways. Combination of dulaglutide and empagliflozin further decreased MoMFLy6CHigh and CD4+Foxp3+ T cells. No beneficial effects for treatment with empagliflozin alone could be shown. While no effect of dulaglutide or its combination with empaglifozin on hepatic steatosis was evident, these data demonstrate distinct anti-inflammatory effects of dulaglutide and their combination with empagliflozin in a non-diabetic background, which could have important implications for further treatment of NASH.

Sign in / Sign up

Export Citation Format

Share Document