scholarly journals Whole-mouse in vivo bioluminescence imaging applied to drug screening against Leishmania infantum: a reliable method to evaluate efficacy and optimize treatment regimens

2018 ◽  
Author(s):  
David M. Costa ◽  
Pedro Cecílio ◽  
Nuno Santarém ◽  
Anabela Cordeiro-da-Silva ◽  
Joana Tavares
Keyword(s):  
Leishmania Infantum ◽  
Treatment Options ◽  
Treatment Regimens ◽  
Axenic Amastigotes ◽  
Bioluminescent Signal ◽  
Target Organs ◽  
In Vivo Bioluminescence Imaging ◽  
Vector Borne ◽  
Visceral Infection

ABSTRACTLeishmaniasis is an important vector-borne neglected tropical disease caused by Leishmania parasites. Current anti-Leishmania chemotherapy is unsatisfactory, justifying the continued search for alternative treatment options. Herein, we propose the use of a minimally invasive bioluminescence-based murine model for preliminary in vivo screening of compounds against visceral infection by Leishmania infantum. We demonstrate that luciferase-expressing axenic amastigotes, unlike promastigotes, are highly infectious to BALB/c mice and generate a robust bioluminescent signal in the main target organs, such as the liver and spleen. Finally, we validate the use of this technique to evaluate in vivo treatment efficacy using reference drugs amphotericin B and miltefosine.

scholarly journals Murine infection with bioluminescent Leishmania infantum axenic amastigotes applied to drug discovery

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
David Mendes Costa ◽  
Pedro Cecílio ◽  
Nuno Santarém ◽  
Anabela Cordeiro-da-Silva ◽  
Joana Tavares
Keyword(s):  
Treatment Efficacy ◽  
Leishmania Infantum ◽  
Treatment Options ◽  
Non Invasive ◽  
Axenic Amastigotes ◽  
Large Numbers ◽  
Infection Treatment ◽  
Target Organs ◽  
Invasive Method ◽  
Vector Borne

AbstractLeishmaniasis is an important vector-borne neglected tropical disease caused by Leishmania parasites. Current anti-Leishmania chemotherapy is unsatisfactory, justifying the continued search for alternative treatment options. Herein, we demonstrate that luciferase-expressing Leishmania infantum axenic amastigotes, unlike promastigotes, are highly infectious to BALB/c mice and thus generate a robust bioluminescent signal in target organs, such as the liver and the spleen, as early as two weeks after infection. Treatment with the reference drugs amphotericin B and miltefosine was effective at reducing parasite burdens. This model allows the assessment of treatment efficacy using whole-mouse bioluminescence imaging without the need to wait several weeks for spleen infections to be detectable by this non-invasive method. In conclusion, we propose the use of this model in an initial approach to evaluate the treatment efficacy of promising chemical entities without having to sacrifice large numbers of animals or to wait several days for a readout.

scholarly journals In Vitro and In Vivo Effectiveness of Carvacrol, Thymol and Linalool against Leishmania infantum

Molecules ◽  
2019 ◽  
Vol 24 (11) ◽  
pp. 2072 ◽  
Author(s):  
Mohammad Reza Youssefi ◽  
Elham Moghaddas ◽  
Mohaddeseh Abouhosseini Tabari ◽  
Ali Akbar Moghadamnia ◽  
Seyed Mohammad Hosseini ◽  
...  
Keyword(s):  
Mtt Assay ◽  
Leishmania Infantum ◽  
Standard Drug ◽  
In Vivo Test ◽  
Causative Agents ◽  
Ic50 Values ◽  
Vector Borne ◽  
Effective Drugs

Background: One of the most important causative agents of visceral leishmaniasis (VL) is Leishmania infantum, which is mainly spread by Phlebotomus and Lutzomyia sandflies in the Old and New World, respectively. Novel and effective drugs to manage this neglected vector-borne disease are urgently required. In this study, we evaluated the toxicity of carvacrol, thymol and linalool, three common essential oil constituents, on amastigotes and promastigotes of L. infantum. Methods: in vitro experiments were performed by 24 h MTT assay. Carvacrol, thymol and linalool at concentrations ranging from 1.3 to 10 μg/mL were tested on promastigotes of L. infantum. For in vivo test, two groups of hamsters (Mesocricetus auratus) received 100 mg/kg of body weight/day of carvacrol and thymol as intraperitoneal injection on day 7 post-infection, followed by a 48 h later injection. The third group was treated with the glucantime as standard drug (500 mg/kg) and the last group (control) just received normal saline. On the 16th day, the number of parasites and histopathological changes in liver and spleen were investigated. Results: 24 h MTT assay showed promising antileishmanial activity of thymol and carvacrol, with IC50 values of 7.2 (48 μM) and 9.8 μg/mL (65 μM), respectively. Linalool at all concentrations did not affect L. infantum promastigote viability. In vivo toxicity data of carvacrol and thymol showed that the former at 100 mg/kg was the safest and most effective treatment with little side effects on the liver. Conclusions: Overall, thymol and carvacrol are highly promising candidates for the development of effective and safe drugs in the fight against VL.

scholarly journals Toll-Like Receptor 9 Signaling in Dendritic Cells Regulates Neutrophil Recruitment to Inflammatory Foci following Leishmania infantum Infection

2015 ◽  
Vol 83 (12) ◽  
pp. 4604-4616 ◽  
Author(s):  
Laís Sacramento ◽  
Silvia C. Trevelin ◽  
Manuela S. Nascimento ◽  
Djalma S. Lima-Jùnior ◽  
Diego L. Costa ◽  
...  
Keyword(s):  
Leishmania Infantum ◽  
Critical Role ◽  
Costimulatory Molecule ◽  
Protozoan Parasite ◽  
Neutrophil Recruitment ◽  
Content Type ◽  
Target Organs ◽  
Myd88 Signaling

Leishmania infantumis a protozoan parasite that causes visceral leishmaniasis (VL). This infection triggers dendritic cell (DC) activation through the recognition of microbial products by Toll-like receptors (TLRs). Among the TLRs, TLR9 is required for DC activation by differentLeishmaniaspecies. We demonstrated that TLR9 is upregulatedin vitroandin vivoduring infection. We show that C57BL/6 mice deficient in TLR9 expression (TLR9−/−mice) are more susceptible to infection and display higher parasite numbers in the spleen and liver. The increased susceptibility of TLR9−/−mice was due to the impaired recruitment of neutrophils to the infection foci associated with reduced levels of neutrophil chemoattractants released by DCs in the target organs. Moreover, both Th1 and Th17 cells were also committed in TLR9−/−mice. TLR9-dependent neutrophil recruitment is mediated via the MyD88 signaling pathway but is TIR domain-containing adapter-inducing interferon beta (TRIF) independent. Furthermore,L. infantumfailed to activate both plasmacytoid and myeloid DCs from TLR9−/−mice, which presented reduced surface costimulatory molecule expression and chemokine release. Interestingly, neutrophil chemotaxis was affected bothin vitroandin vivowhen DCs were derived from TLR9−/−mice. Our results suggest that TLR9 plays a critical role in neutrophil recruitment during the protective response againstL. infantuminfection that could be associated with DC activation.

scholarly journals BioluminescentFrancisella tularensisSCHU-S4 enables non-invasive tracking of bacterial dissemination and the evaluation of antibiotics in an inhalational mouse model of tularemia

2016 ◽  
pp. AAC.01586-16
Author(s):  
Charlotte A. Hall ◽  
Helen C. Flick-Smith ◽  
Sarah V. Harding ◽  
Helen S. Atkins ◽  
Richard W Titball
Keyword(s):  
Real Time ◽  
Bioluminescence Imaging ◽  
Infection Model ◽  
Treatment Cessation ◽  
Treatment Regimens ◽  
Non Invasive ◽  
Bioluminescent Signal ◽  
Bacterial Dissemination ◽  
Schu S4

Bioluminescence imaging (BLI) enables real-time, non-invasive tracking of infectionin vivoand longitudinal infection studies. In this study, a bioluminescentF. tularensisSCHU S4-luxstrain was used to develop an inhalational infection model in BALB/c mice. Mice were infected intranasally and the progression of infection was monitored in real time using BLI. A bioluminescent signal was detectable from 3 days post-infection (dpi), initially in the spleen, then in the liver and lymph nodes before finally becoming systemic. The level of bioluminescent signal correlated with bacterial numbersin vivoenabling non-invasive quantification of bacterial burden in tissues. Treatment with levofloxacin (commencing at 4 dpi) significantly reduced the BLI signal. Furthermore, BLI was able to non-invasively distinguish between different levofloxacin treatment regimens and identify sites of relapse following treatment cessation. These data demonstrate that BLI and SCHU S4-luxare suitable for the study ofF. tularensispathogenesis and the evaluation of therapeutics for tularemia.

scholarly journals Quantification of bacteria by in vivo bioluminescence imaging in comparison with standard spread plate method and reverse transcription quantitative PCR (RT-qPCR)

2021 ◽  
Author(s):  
Katarína Briestenská ◽  
Miriam Mikušová ◽  
Karolína Tomčíková ◽  
František Kostolanský ◽  
Eva Varečková
Keyword(s):  
Quantitative Pcr ◽  
Reverse Transcription ◽  
Bioluminescence Imaging ◽  
Accurate Determination ◽  
Photon Flux ◽  
Plate Method ◽  
Bioluminescent Signal ◽  
Reverse Transcription Quantitative Pcr ◽  
In Vivo Bioluminescence Imaging

AbstractIn vivo bioluminescence imaging (BLI) offers a unique opportunity to analyze ongoing bacterial infections qualitatively and quantitatively in intact animals over time, leading to a reduction in the number of animals needed for a study. Since accurate determination of the bacterial burden plays an essential role in microbiological research, the present study aimed to evaluate the ability to quantify bacteria by non-invasive BLI technique in comparison to standard spread plate method and reverse transcription quantitative PCR (RT-qPCR). For this purpose, BALB/c mice were intranasally infected with 1 × 105 CFU of bioluminescent Streptococcus pneumoniae A66.1. At day 1 post-infection, the presence of S. pneumoniae in lungs was demonstrated by spread plate method and RT-qPCR, but not by in vivo BLI. However, on the second day p.i., the bioluminescent signal was already detectable, and the photon flux values positively correlated with CFU counts and RT-qPCR data within days 2–6. Though in vivo BLI is valuable research tool allowing the continuous monitoring and quantification of pneumococcal infection in living mice, it should be kept in mind that early in the infection, depending on the infective dose, the bioluminescent signal may be below the detection limit.

scholarly journals Improving the Drug Development Pipeline for Mycobacteria: Modelling Antibiotic Exposure in the Hollow Fibre Infection Model

Antibiotics ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 1515
Author(s):  
Arundhati Maitra ◽  
Priya Solanki ◽  
Zahra Sadouki ◽  
Timothy D. McHugh ◽  
Frank Kloprogge
Keyword(s):  
Drug Discovery ◽  
Drug Development ◽  
Market Failure ◽  
Treatment Options ◽  
Effective Means ◽  
Hollow Fibre ◽  
Infection Model ◽  
Bacterial Killing ◽  
Treatment Regimens

Mycobacterial infections are difficult to treat, requiring a combination of drugs and lengthy treatment times, thereby presenting a substantial burden to both the patient and health services worldwide. The limited treatment options available are under threat due to the emergence of antibiotic resistance in the pathogen, hence necessitating the development of new treatment regimens. Drug development processes are lengthy, resource intensive, and high-risk, which have contributed to market failure as demonstrated by pharmaceutical companies limiting their antimicrobial drug discovery programmes. Pre-clinical protocols evaluating treatment regimens that can mimic in vivo PK/PD attributes can underpin the drug development process. The hollow fibre infection model (HFIM) allows for the pathogen to be exposed to a single or a combination of agents at concentrations achieved in vivo–in plasma or at infection sites. Samples taken from the HFIM, depending on the analyses performed, provide information on the rate of bacterial killing and the emergence of resistance. Thereby, the HFIM is an effective means to investigate the efficacy of a drug combination. Although applicable to a wide variety of infections, the complexity of anti-mycobacterial drug discovery makes the information available from the HFIM invaluable as explored in this review.

Peculiarities of the course of type I allergic reactions in patients with blood diseases

2020 ◽  
pp. 40-50
Author(s):  
A. Nikitina
Keyword(s):  
Search Engines ◽  
Anaphylactic Shock ◽  
Type I ◽  
Allergic Reactions ◽  
Common Cause ◽  
Blood Diseases ◽  
Treatment Regimens ◽  
Modern Methods

Analysis of literature data presented in search engines — Elibrary, PubMed, Cochrane — concerning the risk of developing type I allergic reactions in patients with blood diseases is presented. It is shown that the most common cause of type I allergic reactions is drugs included in the treatment regimens of this category of patients. The article presents statistics on the increase in the number of drug allergies leading to cases of anaphylactic shock in patients with blood diseases. Modern methods for the diagnosis of type I allergic reactions in vivo and in vitro are considered.

Current Challenges in the Development of Vaccines and Drugs Against Emerging Vector-borne Diseases

2019 ◽  
Vol 26 (16) ◽  
pp. 2974-2986 ◽  
Author(s):  
Kwang-sun Kim
Keyword(s):  
New Host ◽  
In Vivo Models ◽  
Vector Borne Diseases ◽  
Novel Drugs ◽  
Huge Impact ◽  
Tick Borne Disease ◽  
Vector Borne ◽  
Living Organisms

Vectors are living organisms that transmit infectious diseases from an infected animal to humans or another animal. Biological vectors such as mosquitoes, ticks, and sand flies carry pathogens that multiply within their bodies prior to delivery to a new host. The increased prevalence of Vector-Borne Diseases (VBDs) such as Aedes-borne dengue, Chikungunya (CHIKV), Zika (ZIKV), malaria, Tick-Borne Disease (TBD), and scrub typhus has a huge impact on the health of both humans and livestock worldwide. In particular, zoonotic diseases transmitted by mosquitoes and ticks place a considerable burden on public health. Vaccines, drugs, and vector control methods have been developed to prevent and treat VBDs and have prevented millions of deaths. However, development of such strategies is falling behind the rapid emergence of VBDs. Therefore, a comprehensive approach to fighting VBDs must be considered immediately. In this review, I focus on the challenges posed by emerging outbreaks of VBDs and discuss available drugs and vaccines designed to overcome this burden. Research into promising drugs needs to be upgraded and fast-tracked, and novel drugs or vaccines being tested in in vitro and in vivo models need to be moved into human clinical trials. Active preventive tactics, as well as new and upgraded diagnostics, surveillance, treatments, and vaccination strategies, need to be monitored constantly if we are to manage VBDs of medical importance.

Considering a Potential Role of Linalool as a Mood Stabilizer for Bipolar Disorder

2020 ◽  
Vol 26 (40) ◽  
pp. 5128-5133
Author(s):  
Kate Levenberg ◽  
Wade Edris ◽  
Martha Levine ◽  
Daniel R. George
Keyword(s):  
Bipolar Disorder ◽  
Treatment Options ◽  
Mood Stabilizer ◽  
Well Being ◽  
Epidemiologic Studies ◽  
Treatment Regimens ◽  
Bipolar Spectrum Disorders ◽  
Short And Long Term

Epidemiologic studies suggest that the lifetime prevalence of bipolar spectrum disorders ranges from 2.8 to 6.5 percent of the population. To decrease morbidity and mortality associated with disease progression, pharmacologic intervention is indicated for the majority of these patients. While a number of effective treatment regimens exist, many conventional medications have significant side effect profiles that adversely impact patients’ short and long-term well-being. It is thus important to continue advancing and improving therapeutic options available to patients. This paper reviews the limitations of current treatments and examines the chemical compound Linalool, an alcohol found in many plant species, that may serve as an effective mood stabilizer. While relatively little is known about Linalool and bipolar disorder, the compound has been shown to have antiepileptic, anti-inflammatory, anxiolytic, anti-depressive, and neurotrophic effects, with mechanisms that are comparable to current bipolar disorder treatment options.

Sign in / Sign up

Export Citation Format

Share Document