scholarly journals Comparative Analysis of Pharmacodynamics in the C3HeB/FeJ Mouse Tuberculosis Model for DprE1 inhibitors TBA-7371, PBTZ169 and OPC-167832

2021 ◽  
Author(s):  
Gregory T. Robertson ◽  
Michelle E. Ramey ◽  
Lisa M. Massoudi ◽  
Claire L. Carter ◽  
Matt Zimmerman ◽  
...  
Keyword(s):  
Mouse Model ◽  
Low Dose ◽  
Multiple Drug ◽  
Drug Candidates ◽  
Tuberculosis Model ◽  
Drug Classes ◽  
Significant Efficacy ◽  
Pulmonary Pathology ◽  
Shorten Treatment Duration ◽  
Dose Levels

Multiple drug discovery initiatives for tuberculosis are currently ongoing to identify and develop new potent drugs with novel targets in order to shorten treatment duration. One of the drug classes with a new mode of action are DprE1 inhibitors targeting an essential process in cell wall synthesis of Mycobacterium tuberculosis . In this investigation, three DprE1 inhibitors currently in clinical trials, TBA-7371, PBTZ169 and OPC-167832, were evaluated side-by-side as single agents in the C3HeB/FeJ mouse model presenting with caseous necrotic pulmonary lesions upon tuberculosis infection. The goal was to confirm the efficacy of the DprE1 inhibitors in a mouse tuberculosis model with advanced pulmonary pathology, and perform comprehensive analysis of plasma, lung and lesion-centric drug levels to establish pharmacokinetic-pharmacodynamic (PK-PD) parameters predicting efficacy at the site of infection. Results showed significant efficacy for all three DprE1 inhibitors in the C3HeB/FeJ mouse model after two months of treatment. Superior efficacy was observed for OPC-167832 even at low dose levels, which can be attributed to its low MIC, favorable distribution and sustained retention above the MIC throughout the dosing interval in caseous necrotic lesions where the majority of bacteria reside in C3HeB/FeJ mice. These results support further progression of the three drug candidates through clinical development for tuberculosis treatment.

scholarly journals Sensitivity of Trypanosome Isolates From Pigs In Enugu North Senatorial Zone of Enugu State To Diminazene Aceturate And Isometamidium Chloride

2018 ◽  
Vol 1 (2) ◽  
pp. 152-160
Author(s):  
J.N Omeje ◽  
J.S Akinbobols
Keyword(s):  
Drug Resistance ◽  
Body Weight ◽  
Low Dose ◽  
Multiple Drug Resistance ◽  
Multiple Drug ◽  
High Dose ◽  
Diminazene Aceturate ◽  
Treatment Methods ◽  
Enugu State ◽  
Dose Levels

The sensitivity of trypanosome isolates from naturally infected pigs in Enugu North Senatorial Zone was evaluated in mice at two dose levels each of diminazene aceturate (7 and 28 mg/kg body weight) and isometamidium chloride (0.25 and 2 mg/kg) using the infection and treatment methods. Multiple drug resistance was prevalent in the trypanosome isolates, as all 18 isolates (16 T. brucei and 2 T. congolense) tested were resistant to both diminazene aceturate (7 mg/kg b.w) and isometamidium chloride (0.25 mg/ kg b.w,), at the low dose levels tested. Sixteen of the isolates resisted the high dose levels of diminazene aceturate (28 mg/kg b.w), while six isolates were resistant to isometamidium chloride (2 mg/kg b.w). It was concluded that trypanosome isolates from pigs in the study area exhibited resistance to both diminazene aceturate and isometamidium chloride, the two most commonly used trypanocides in the area. This phenomenon constitutes serious threat to chemotherapeutic control of swine trypanosomosis in particular and animal trypanosomosis in general in Enugu North Senatorial Zone.

scholarly journals Low dose EGCG treatment beginning in adolescence does not improve cognitive impairment in a Down syndrome mouse model

2015 ◽  
Vol 138 ◽  
pp. 70-79 ◽  
Author(s):  
Megan Stringer ◽  
Irushi Abeysekera ◽  
Karl J. Dria ◽  
Randall J. Roper ◽  
Charles R. Goodlett
Keyword(s):  
Down Syndrome ◽  
Cognitive Impairment ◽  
Mouse Model ◽  
Low Dose ◽  
Egcg Treatment

scholarly journals Advantages of Repeated Low Dose against Single High Dose of Kainate in C57BL/6J Mouse Model of Status Epilepticus: Behavioral and Electroencephalographic Studies

PLoS ONE ◽  
2014 ◽  
Vol 9 (5) ◽  
pp. e96622 ◽  
Author(s):  
Karen Tse ◽  
Sreekanth Puttachary ◽  
Edward Beamer ◽  
Graeme J. Sills ◽  
Thimmasettappa Thippeswamy
Keyword(s):  
Status Epilepticus ◽  
Mouse Model ◽  
Low Dose ◽  
High Dose ◽  
Single High Dose

scholarly journals A Mouse Model of Acute Q Fever Following Infection Via A Non-Invasive Intratracheal Inoculation Method

2019 ◽  
Author(s):  
Xueyuan Hu ◽  
Yonghui Yu ◽  
Junxia Feng ◽  
Mengjiao Fu ◽  
Lupeng Dai ◽  
...  
Keyword(s):  
Mouse Model ◽  
Low Dose ◽  
Q Fever ◽  
Pulmonary Delivery ◽  
Delivery Device ◽  
Inflammatory Infiltration ◽  
Pathological Lesions ◽  
Non Invasive ◽  
Therapeutic Drugs ◽  
Acute Q Fever

Abstract Background: Q fever is a worldwide zoonosis caused by Coxiella burnetii and mainly transmitted by aerosols. This study aims at establishing a systematic and efficient mouse model of acute Q fever via intratracheal (IT) inoculation of aerosolized C. burnetii. Methods: BALB/c mice were infected with C. burnetii via IT route using a non-invasive aerosol pulmonary delivery device to directly place the living C. burnetii organisms into their tracheas. The bacterial loads, pathological lesions, and serological responses were analyzed in mice, and compared with those of mice infected via intraperitoneal (IP) route. Results: As early as at day three post-infection (pi) with a low dose of C. burnetii (1×10⁴ per mouse), a large amount of C. burnetii organisms were determined in blood, lungs, hearts, livers, and spleens of the mice. The inflammatory infiltration was observed in hearts and lungs of mice. Compared with mice infected via IP route, the mice infected via IT route exhibited a higher level of bacterial loads and more severe pathological lesions in hearts and lungs at day 3 and day 7 pi. Conclusions: These data indicated that IT route is more efficient than IP route to cause acute C. burnetii infection in mice. Overall, we successfully established a mouse model of C. burnetii infection via IT route, which is useful for investigations of pathogenesis and immunity of acute C. burnetii infection as well as evaluation of therapeutic drugs and preventive vaccines of Q fever.

scholarly journals Intravenous Infusion Tests Have Limited Utility for Selecting Long-term Drug Therapy in Patients with Chronic Pain

2009 ◽  
Vol 111 (2) ◽  
pp. 416-431 ◽  
Author(s):  
Steven P. Cohen ◽  
Shruti G. Kapoor ◽  
James P. Rathmell
Keyword(s):  
Systematic Review ◽  
Drug Therapy ◽  
Intravenous Infusion ◽  
Multiple Drug ◽  
Poor Responders ◽  
Intravenous Lidocaine ◽  
Temporary Relief ◽  
Drug Classes ◽  
Convincing Data

Since the first description in the early 1990s, the scope of intravenous infusions tests has expanded to encompass multiple drug classes and indications. Purported advantages of these tests include elucidating mechanisms of pain, providing temporary relief of symptoms, and usefulness as prognostic tools in guiding drug therapy. In an attempt to discern the value of these tests, the authors conducted a systematic review to explore the rationale and evidence behind the following intravenous infusion tests: lidocaine, ketamine, opioid, and phentolamine. The studies evaluating all intravenous infusion tests were characterized by lack of standardization, wide variations in outcome measures, and methodological flaws. The strongest evidence found was for the intravenous lidocaine test, with the phentolamine test characterized by the least convincing data. Whereas intravenous opioid infusions are the most conceptually appealing test, their greatest utility may be in predicting poor responders to sustained-release formulations.

scholarly journals Using the Apolipoprotein E Knock-Out Mouse Model to Define Atherosclerotic Plaque Changes Induced by Low Dose Arsenic

2018 ◽  
Vol 166 (1) ◽  
pp. 213-218 ◽  
Author(s):  
Kiran Makhani ◽  
Christopher Chiavatti ◽  
Dany Plourde ◽  
Luis Fernando Negro Silva ◽  
Maryse Lemaire ◽  
...  
Keyword(s):  
Mouse Model ◽  
Apolipoprotein E ◽  
Atherosclerotic Plaque ◽  
Low Dose ◽  
Knock Out ◽  
Knock Out Mouse

Abstract 14648: Interleukin-18 Blockade Prevents Diastolic Dysfunction in a Mouse Model of Heart Failure With Preserved Ejection Fraction

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Jessica A Regan ◽  
Adolofo G Mauro ◽  
Salvatore Carbone ◽  
Carlo Marchetti ◽  
Eleonora Mezzaroma ◽  
...  
Keyword(s):  
Heart Failure ◽  
Blood Pressure ◽  
Ejection Fraction ◽  
Mouse Model ◽  
Diastolic Dysfunction ◽  
Diastolic Function ◽  
Low Dose ◽  
Preserved Ejection Fraction ◽  
Interleukin 18 ◽  
Lv Diastolic Function

Background: Heart failure with preserved ejection fraction (HFpEF) is characterized by elevated left ventricular (LV) filling pressures due to impaired LV diastolic function. Low-dose infusion of angiotensin 2 (AT2) in the mouse induces a HFpEF phenotype without increasing blood pressure. AT2 infusion induces expression of Interleukin-18 (IL-18) in the heart. We therefore tested whether IL-18 mediated AT2-induced LV diastolic dysfunction in this model. Methods: We infused subcutaneously AT2 (0.2 mg/Kg/day) or a matching volume of vehicle via osmotic pumps surgically implanted in the interscapular space in adult wild-type (WT) male mice and IL-18 knock-out mice (IL-18KO). We also treated WT mice with daily intraperitoneal injections of recombinant murine IL-18 binding protein (IL-18bp, a naturally occurring IL-18 blocker) at 3 different doses (0.1, 0.3 and 1.0 mg/kg) or vehicle for 25 days starting on day 3. We performed a Doppler-echocardiography study before implantation and at 28 days to measure LV dimensions, mass, and systolic and diastolic function in all mice. LV catheterization was performed prior to sacrifice to measure LV end-diastolic pressure (LVEDP) using a Millar catheter. Results: AT2 induces a significant increase in isovolumetric relaxation time (IRT) and myocardial performance index (MPI) at Doppler echocardiography and elevation of LVEDP at catheterization, indicative of impaired LV diastolic function, in absence of any measurable effects on systolic blood pressure nor LV dimensions, mass, or systolic function. Mice with genetic deletion of IL-18 (IL-18 KO) or WT mice treated with IL-18bp had no significant increase in IRT, MPI or LVEDP with AT2 infusion. Conclusion: Genetic or pharmacologic IL-18 blockade prevent diastolic dysfunction in a mouse model of HFpEF induced by low dose AT2 infusion, suggesting a critical role of IL-18 in the pathophysiology of HFpEF.

Effect of parenteral energy or amino acid doses on in-hospital mortality, among patients with aspiration pneumonia: a cohort medical claims database study

2021 ◽  
Author(s):  
Keisuke Maeda ◽  
Kenta Murotani ◽  
Satoru Kamoshita ◽  
Yuri Horikoshi ◽  
Akiyoshi Kuroda
Keyword(s):  
Amino Acid ◽  
Hospital Mortality ◽  
Aspiration Pneumonia ◽  
Low Dose ◽  
Oral Intake ◽  
Reference Level ◽  
Claims Database ◽  
Medical Claims ◽  
Dose Levels ◽  
Medical Claims Database

Abstract Background This study examined the association between parenteral energy/amino acid doses and in-hospital mortality among inpatients on long-term nil per os (NPO) status, using a medical claims database in Japan. Methods Hospitalized patients with aspiration pneumonia, aged ≥65 years and on >7-days NPO status, were identified in a medical claims database between January 2013 and December 2018. Using multivariate logistic regression and regression analyses, we examined the association between mean parenteral energy/amino acid doses and in-hospital mortality, and secondarily the association between prognosis (in-hospital mortality, inability to receive full oral intake, re-admission, hospital stay length) among four groups classified by mean amino acid dose (No dose: 0 g/kg/day; Very low dose: >0, ≤0.3 g/kg/day; Low dose: >0.3, ≤0.6 g/kg/day; Moderate dose: >0.6 g/kg/day). Results The analysis population included 20,457 inpatients (≥80 years: 78.3%). In total, 5,920 mortalities were recorded. Increased amino acid doses were significantly associated with reduced in-hospital mortality (p <0.001). With a No dose reference level, the odds ratios (95% confidence interval) of in-hospital mortality adjusted for potential confounders, were 0.78 (0.72–0.85), 0.74 (0.67–0.82), and 0.69 (0.59–0.81) for Very low, Low, and Moderate amino acid doses, respectively. Additionally, patients prescribed amino acid dose levels >0.6 g/kg/day had shorter hospitalization periods than those prescribed none. Conclusions Increased amino acid doses were associated with reduced in-hospital mortality. Sufficient amino acid administration is recommended for patients with aspiration pneumonia requiring NPO status.

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