scholarly journals Review of the Novel Echinocandin Antifungal Rezafungin: Animal Studies and Clinical Data

2020 ◽  
Vol 6 (4) ◽  
pp. 192
Author(s):  
Yanan Zhao ◽  
David S. Perlin
Keyword(s):  
Animal Models ◽  
Fungal Pathogens ◽  
Animal Studies ◽  
Fungal Infections ◽  
Wide Spectrum ◽  
Current Status ◽  
Parent Molecule ◽  
Treatment And Prevention

Rezafungin is a novel echinocandin drug being developed as a first-line option for treatment and prevention of invasive fungal infections. As a result of a structural modification in its parent molecule anidulafungin, rezafungin has acquired unique chemical stability conferring prolonged pharmacokinetics, as well as an administration advantage in the clinical setting compared to other drugs in the same class. Rezafungin displays potent in vitro activity against a wide spectrum of fungal pathogens, which is reflected in robust in vivo efficacy and/or pharmacodynamic studies using various animal models as well as in promising clinical trials data. This review describes in vivo characterization of rezafungin using animal models, current status of clinical development and key findings from these studies.

scholarly journals Current status of in vitro and in vivo antifungal activities of posaconazole

2013 ◽  
Vol 1 (1) ◽  
pp. 18-22
Author(s):  
He Sun ◽  
Xin Su ◽  
Yi Shi
Keyword(s):  
Animal Models ◽  
Broad Spectrum ◽  
Fungal Infections ◽  
Current Status ◽  
Dimorphic Fungi ◽  
Antifungal Activities ◽  
Endemic Fungi ◽  
Yeasts And Molds

Abstract Posaconazole (POS) is a new triazole drug with broad-spectrum in vitro activity against most yeasts and molds such as Candida, Cryptococcus neoformans, Aspergillus, Fusarium and Zygomycetes, as well as certain species of dimorphic fungi and endemic fungi. In immunocompetent or immunocompromised animal models with invasive fungal infections, POS has demonstrated highly effective, broad-spectrum antifungal activities. In vitro and in vivo antifungal activities of POS were superior to those of other azoles against Candida glabrata, Candida krusei, Aspergillus terrus, Fusarium and Zygomycetes. In vivo susceptibility studies have shown promising efficacy of POS against life-threatening fungal infections in animal models with different immune status and infection sites.

scholarly journals Techniques for the Assessment of In Vitro and In Vivo Antifungal Combinations

2021 ◽  
Vol 7 (2) ◽  
pp. 113
Author(s):  
Anne-Laure Bidaud ◽  
Patrick Schwarz ◽  
Guillaume Herbreteau ◽  
Eric Dannaoui
Keyword(s):  
Animal Models ◽  
Fungal Infections ◽  
Acquired Resistance ◽  
Adequate Treatment ◽  
Combination Treatments ◽  
Target Organs ◽  
Fungal Load ◽  
Time Kill

Systemic fungal infections are associated with high mortality rates despite adequate treatment. Moreover, acquired resistance to antifungals is increasing, which further complicates the therapeutic management. One strategy to overcome antifungal resistance is to use antifungal combinations. In vitro, several techniques are used to assess drug interactions, such as the broth microdilution checkerboard, agar-diffusion methods, and time-kill curves. Currently, the most widely used technique is the checkerboard method. The aim of all these techniques is to determine if the interaction between antifungal agents is synergistic, indifferent, or antagonistic. However, the interpretation of the results remains difficult. Several methods of analysis can be used, based on different theories. The most commonly used method is the calculation of the fractional inhibitory concentration index. Determination of the usefulness of combination treatments in patients needs well-conducted clinical trials, which are difficult. It is therefore important to study antifungal combinations in vivo, in experimental animal models of fungal infections. Although mammalian models have mostly been used, new alternative animal models in invertebrates look promising. To evaluate the antifungal efficacy, the most commonly used criteria are the mortality rate and the fungal load in the target organs.

scholarly journals Current and Emerging Azole Antifungal Agents

1999 ◽  
Vol 12 (1) ◽  
pp. 40-79 ◽  
Author(s):  
Daniel J. Sheehan ◽  
Christopher A. Hitchcock ◽  
Carol M. Sibley
Keyword(s):  
Fungal Pathogens ◽  
Antifungal Agents ◽  
Susceptibility Testing ◽  
Fungal Infections ◽  
Mechanisms Of Action ◽  
Current Status ◽  
In Vitro Susceptibility ◽  
Clinical Resistance ◽  
In Vitro Susceptibility Testing

SUMMARY Major developments in research into the azole class of antifungal agents during the 1990s have provided expanded options for the treatment of many opportunistic and endemic fungal infections. Fluconazole and itraconazole have proved to be safer than both amphotericin B and ketoconazole. Despite these advances, serious fungal infections remain difficult to treat, and resistance to the available drugs is emerging. This review describes present and future uses of the currently available azole antifungal agents in the treatment of systemic and superficial fungal infections and provides a brief overview of the current status of in vitro susceptibility testing and the growing problem of clinical resistance to the azoles. Use of the currently available azoles in combination with other antifungal agents with different mechanisms of action is likely to provide enhanced efficacy. Detailed information on some of the second-generation triazoles being developed to provide extended coverage of opportunistic, endemic, and emerging fungal pathogens, as well as those in which resistance to older agents is becoming problematic, is provided.

scholarly journals Replacement Strategies for Animal Studies in Inhalation Testing

Sci ◽  
2021 ◽  
Vol 3 (4) ◽  
pp. 45
Author(s):  
Eleonore Fröhlich
Keyword(s):  
Animal Models ◽  
In Silico ◽  
Particle Deposition ◽  
Drug Testing ◽  
Animal Studies ◽  
Inhalation Exposure ◽  
Animal Testing ◽  
The Future

Animal testing is mandatory in drug testing and is the gold standard for toxicity and efficacy evaluations. This situation is expected to change in the future as the 3Rs principle, which stands for the replacement, reduction, and refinement of the use of animals in science, is reinforced by many countries. On the other hand, technologies for alternatives to animal testing have increased. The need to develop and use alternatives depends on the complexity of the research topic and also on the extent to which the currently used animal models can mimic human physiology and/or exposure. The lung morphology and physiology of commonly used animal species differs from that of human lungs, and the realistic inhalation exposure of animals is challenging. In vitro and in silico methods can assess important aspects of the in vivo effects, namely particle deposition, dissolution, action at, and permeation through, the respiratory barrier, and pharmacokinetics. This review discusses the limitations of animal models and exposure systems and proposes in vitro and in silico techniques that could, when used together, reduce or even replace animal testing in inhalation testing in the future.

scholarly journals Heat Shock Protein 72 Expressing Stress in Sepsis: Unbridgeable Gap between Animal and Human Studies—A Hypothetical “Comparative” Study

2014 ◽  
Vol 2014 ◽  
pp. 1-17 ◽  
Author(s):  
George Briassoulis ◽  
Efrossini Briassouli ◽  
Diana-Michaela Fitrolaki ◽  
Ioanna Plati ◽  
Kleovoulos Apostolou ◽  
...  
Keyword(s):  
Heat Shock ◽  
Animal Models ◽  
Heat Shock Protein ◽  
Comparative Study ◽  
Protective Effect ◽  
Animal Studies ◽  
Human Studies ◽  
Heat Shock Protein 72

Heat shock protein 72 (Hsp72) exhibits a protective role during times of increased risk of pathogenic challenge and/or tissue damage. The aim of the study was to ascertain Hsp72 protective effect differences between animal and human studies in sepsis using a hypothetical “comparative study” model. Forty-one in vivo (56.1%), in vitro (17.1%), or combined (26.8%) animal and 14 in vivo (2) or in vitro (12) human Hsp72 studies (P<0.0001) were enrolled in the analysis. Of the 14 human studies, 50% showed a protective Hsp72 effect compared to 95.8% protection shown in septic animal studies (P<0.0001). Only human studies reported Hsp72-associated mortality (21.4%) or infection (7.1%) or reported results (14.3%) to be nonprotective (P<0.001). In animal models, any Hsp72 induction method tried increased intracellular Hsp72 (100%), compared to 57.1% of human studies (P<0.02), reduced proinflammatory cytokines (28/29), and enhanced survival (18/18). Animal studies show a clear Hsp72 protective effect in sepsis. Human studies are inconclusive, showing either protection or a possible relation to mortality and infections. This might be due to the fact that using evermore purified target cell populations in animal models, a lot of clinical information regarding the net response that occurs in sepsis is missing.

scholarly journals Self-similar synchronization of calcium and membrane potential transitions during AP cycles predict HR across species

2020 ◽  
Author(s):  
Syevda Tagirova Sirenko ◽  
Kenta Tsutsui ◽  
Kirill Tarasov ◽  
Dongmei Yang ◽  
Ashley N Wirth ◽  
...  
Keyword(s):  
Heart Rate ◽  
Animal Models ◽  
Animal Studies ◽  
Power Laws ◽  
Single Species ◽  
Cellular Mechanisms ◽  
Wide Range ◽  
Self Similar

AbstractBackgroundTranslation of knowledge of sinoatrial nodal “SAN” automaticity gleaned from animal studies to human dysrhythmias, e.g. “Sick Sinus” Syndrome (SSS) requiring electronic pacemaker insertion has been sub-optimal, largely because heart rate (HR) varies widely across species.ObjectivesTo discover regulatory universal mechanisms of normal automaticity in SAN pacemaker cells that are self-similar across species.MethodSub-cellular Ca2+ releases, whole cell AP-induced Ca2+ transients and APs were recorded in isolated mouse, guinea-pig, rabbit and human SAN cells. Parametric Ca2+ and Vm Kinetic Transitions (PCVKT) during phases of AP cycles from their ignition to recovery were quantified.ResultsAlthough both action potential cycle lengths (APCL) and PCVKT during AP cycles differed across species by ten-fold, trans-species scaling of PCVKT during AP cycles and scaling, of PCVKT to APCL in cells in vitro, EKG RR intervals in vivo, and BM were self-similar (obeyed power laws) across species. Thus, APCL in vitro, HR in vivo, and BM of any species can be predicted by PCVKT during AP cycles in SAN cells measured in any single species in vitro.ConclusionsIn designing optimal HR to match widely different BM and energy requirements from mice to humans, nature did not “reinvent pacemaker cell wheels”, but differentially scaled kinetics of gears that regulate the rates at which the “wheels spin”. This discovery will facilitate the development of novel pharmalogic therapies and biologic pacemakers featuring a normal, wide-range rate regulation in animal models and the translation of these to humans to target recalcitrant human SSS.Condensed AbstractStudies in animal models are an important facet of cardiac arrhythmia research. Because HR differs by over ten-fold between some animals and humans, translation of knowledge about regulatory mechanisms of SAN normal automaticity gleaned from studies in animal models to target human SSS has been sub-optimal. Our findings demonstrating that trans-species self-similarity of sub-cellular and cellular mechanisms that couple Ca2+ to Vm during AP cycles can predict heart rate in vivo from mice to humans will inform on the design of novel studies in animal models and facilitate translation of this knowledge to target human disease.

scholarly journals Replacement Strategies for Animal Studies in Inhalation Testing

2021 ◽  
Author(s):  
Eleonore Fröhlich
Keyword(s):  
Animal Models ◽  
In Silico ◽  
Particle Deposition ◽  
Drug Testing ◽  
Animal Studies ◽  
Inhalation Exposure ◽  
The Future ◽  
In Silico Models

Testing in animals is mandatory in drug testing and the gold standard for evaluation of toxicity. This situation is expected to change in the future because the 3Rs principle, which stands for replacement, reduction and refinement of the use of animals in science, is reinforced by many countries. On the other hand, technologies for alternatives to animals experiments have increased. The necessity to develop and use of alternatives is influenced by the complexity of the research topic and also by the fact, to which extent the currently used animal models can mimic human physiology and/or exposure. Rodent lung morphology and physiology differs markedly for that of humans and inhalation exposure of the animals are challenging. In vitro and in silico methods can assess important aspects of the in vivo action, namely particle deposition, dissolution, action at and permeation across the respiratory barrier and pharmacokinetics. Out of the numerous homemade in vitro and in silico models some are available commercially or open access. This review discusses limitations of animal models and exposure systems and proposes a panel of in vitro and in silico techniques that, in the future, may replace animal experimentation in inhalation testing.

scholarly journals Enhanced immunogenicity of leukemia-derived exosomes via transfection with lentiviral vectors encoding costimulatory molecules

2020 ◽  
Vol 43 (5) ◽  
pp. 889-900 ◽  
Author(s):  
Weiwei Hu ◽  
Fang Huang ◽  
Liuxin Ning ◽  
Jun Hao ◽  
Jiangbo Wan ◽  
...  
Keyword(s):  
Animal Models ◽  
Immune Responses ◽  
Animal Studies ◽  
Lentiviral Vector ◽  
Cytotoxic T Lymphocyte ◽  
Leukemia Cell ◽  
Costimulatory Molecules ◽  
Leukemia Cells

Abstract Background: Tumor cell-derived exosomes (TEXs) have been widely used to induce antitumor immune responses in animal models and clinical trials. Similarly, leukemia cell-derived exosomes (LEXs) can induce antileukemia immune responses in animal models. However, the antileukemia immunity induced by LEXs is less effective, which may be due to an inadequate costimulatory capacity. Methods: In this study, we transduced L1210 leukemia cells with a lentiviral vector encoding two B7 costimulatory molecules (CD80, CD86) and obtained LEXs that highly expressed CD80 and CD86. The antileukemia immune response derived from these LEXs was examined in vitro and in vivo in animal models. Results: We found that B7 gene-modified LEXs, including LEX-CD80, LEX-CD86, and LEX-8086, could significantly boost the expression of CD80 and CD86 in dendritic cells (DCs) and promote the secretion of functional cytokines such as TNF-α and IL-12. Moreover, these B7 gene-modified LEXs, particularly LEX-CD8086, could effectively induce CD4+ T cell proliferation, Th1 cytokine secretion, and an antigen-specific anti-leukemia cytotoxic T lymphocyte (CTL) response. Additional animal studies indicated that immunization with B7 gene-modified LEXs, in particular LEX-CD8086, could significantly retard tumor growth compared to the control LEXnull group. Conclusions: This study sheds light on the feasibility of obtaining LEXs that overexpress costimulatory molecules via genetically modified leukemia cells, thereby enhancing their anti-leukemia immunity and providing a potential therapeutic strategy that contributes to leukemia immunotherapy.

scholarly journals Amphotericin B, the Wonder of Today’s Pharmacology Science: Persisting Usage for More Than Seven Decades

2020 ◽  
Author(s):  
Falah Hasan Obayes AL-Khikani
Keyword(s):  
Adverse Effects ◽  
Fungal Infection ◽  
Amphotericin B ◽  
Antimicrobial Agents ◽  
Fungal Infections ◽  
Wide Spectrum ◽  
Antifungal Drugs ◽  
Systemic Fungal Infection

Background: Despite several available topical and systemic antifungal drugs for the treatment of fungal infections, Amphotericin B (AmB) is still one of the most common first-line choices in treating systemic fungal infection for more than seven decades after its discovery.  Objectives: Amphotericin B which belongs to the polyene group has a wide spectrum of in vitro and in vivo antifungal activity. Its mechanism of antifungal action is characterized by creating a pore in the fungal plasma membrane leading to cell death. Methods: In addition to the old formula of deoxycholate-Amphotericin B (D-AmB), three lipid formulas have been developed to reduce the adverse effects of conventional AmB (D-AmB) in the human body and increase its therapeutic efficacy. All of the known available formulas of AmB are administrated via intravenous injection to treat severe systemic fungal infections, while the development of the topical formula of AmB is still under preliminary research. Numerous pharmaceutical formulas of systemic and topical applications with clinical uses of AmB in just humans, not in vitro or animals model, against various fungal infections are discussed in this review. Topical AmB formulas are a promising way to develop effective management and to reduce the adverse effects of intravenous formulas of AmB without laboratory monitoring. Results: The wonderful pharmacological properties of AmB with its prolonged use for about seven decades may help researchers to apply its unique features on other various antimicrobial agents by more understanding about the AmB mechanisms of actions. Conclusion: Amphotericin B is widely used intravenously for the treatment of systemic fungal infection, while the topical formula of AmB is still under experimental study. 

scholarly journals Current Status and Future Perspectives on Therapeutic Potential of Apigenin: Focus on Metabolic-Syndrome-Dependent Organ Dysfunction

Antioxidants ◽  
2021 ◽  
Vol 10 (10) ◽  
pp. 1643
Author(s):  
Waqas Alam ◽  
Carmine Rocca ◽  
Haroon Khan ◽  
Yaseen Hussain ◽  
Michael Aschner ◽  
...  
Keyword(s):  
Metabolic Syndrome ◽  
Organ Dysfunction ◽  
Therapeutic Potential ◽  
Current Status ◽  
Protective Effects ◽  
Treatment And Prevention ◽  
Medicinal Plant Extracts ◽  
Vegetables And Fruits

Metabolic syndrome and its associated disorders such as obesity, insulin resistance, atherosclerosis and type 2 diabetes mellitus are globally prevalent. Different molecules showing therapeutic potential are currently available for the management of metabolic syndrome, although their efficacy has often been compromised by their poor bioavailability and side effects. Studies have been carried out on medicinal plant extracts for the treatment and prevention of metabolic syndrome. In this regard, isolated pure compounds have shown promising efficacy for the management of metabolic syndrome, both in preclinical and clinical settings. Apigenin, a natural bioactive flavonoid widely present in medicinal plants, functional foods, vegetables and fruits, exerts protective effects in models of neurological disorders and cardiovascular diseases and most of these effects are attributed to its antioxidant action. Various preclinical and clinical studies carried out so far show a protective effect of apigenin against metabolic syndrome. Herein, we provide a comprehensive review on both in vitro and in vivo evidence related to the promising antioxidant role of apigenin in cardioprotection, neuroprotection and renoprotection, and to its beneficial action in metabolic-syndrome-dependent organ dysfunction. We also provide evidence on the potential of apigenin in the prevention and/or treatment of metabolic syndrome, analysing the potential and limitation of its therapeutic use.

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