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 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 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 The celecoxib derivative AR-12 has broad spectrum antifungal activity in vitro and improves the activity of fluconazole in a murine model of cryptococcosis

2016 ◽  
pp. AAC.01061-16 ◽  
Author(s):  
Kristy Koselny ◽  
Julianne Green ◽  
Louis DiDone ◽  
Justin P. Halterman ◽  
Annette W. Fothergill ◽  
...  
Keyword(s):  
Antifungal Activity ◽  
Small Molecules ◽  
Broad Spectrum ◽  
Murine Model ◽  
Antifungal Drugs ◽  
Dimorphic Fungi ◽  
New Class ◽  
Cancer Agent

Only one new class of antifungal drugs has been introduced into clinical practice in the last thirty years and, thus, the identification of small molecules with novel mechanisms of action is an important goal of current anti-infective research. Here, we describe the characterization of the spectrum of in vitro activity and in vivo activity of AR-12, a celecoxib-derivative which has been tested in a Phase I clinical trial as an anti-cancer agent. AR-12 inhibits fungal acetyl CoA synthetase in vitro and is fungicidal at concentrations similar to those achieved in human plasma. AR-12 has a broad spectrum of activity including active against yeasts (e.g.,C. albicans, non-albicansCandidaspp.,C. neoformans); molds (e.g.,Fusarium,Mucor), and dimorphic fungi (Blastomyces,Histoplasma, andCoccidioides) with minimum inhibitory concentrations of 2-4 μg/mL. AR-12 is also active against azole- and echinocandin-resistantCandidaisolates and sub-inhibitory AR-12 concentrations increase susceptibility of fluconazole- and echinocandin-resistantCandidaisolates. Finally, AR-12 also increases the activity of fluconazole in a murine model of cryptococcosis. Taken together, these data indicate that AR-12 represents a promising class of small molecules with broad spectrum antifungal activity.

scholarly journals Review of the Novel Investigational Antifungal Olorofim

2020 ◽  
Vol 6 (3) ◽  
pp. 122 ◽  
Author(s):  
Nathan P. Wiederhold
Keyword(s):  
Fungal Infections ◽  
Case Reports ◽  
Fusarium Species ◽  
Pharmacokinetic Profile ◽  
Outcome Data ◽  
Dimorphic Fungi ◽  
Key Enzyme ◽  
Endemic Fungi ◽  
Invasive Mold Infections

The incidence of invasive fungal infections caused by molds and endemic fungi is increasing. There is also concern regarding increased rates of reduced susceptibility or frank resistance among Aspergillus and Coccidioides species, while Scedosporium species, Lomentospora prolificans, and Fusarium species are inherently less susceptible or intrinsically resistant to clinically available antifungals. Olorofim (formerly F901318) is the first member of the orotomide class of antifungals to be evaluated clinically for the treatment of invasive mold infections. This agent inhibits dihydroorotate dehydrogenase, a key enzyme in the biosynthesis of pyrimidines. Olorofim has activity against many molds and thermally dimorphic fungi, including species that are resistant to azoles and amphotericin B, but lacks activity against yeasts and the Mucorales. It is currently being developed for both oral and intravenous administration. Although published clinical outcome data have been limited to case reports to date, the results against invasive and refractory infections are promising. This review describes the mechanism of action of olorofim, its in vitro spectrum of activity, and what is currently known about its pharmacokinetic profile and clinical efficacy.

scholarly journals Carrageenans as Broad-Spectrum Microbicides: Current Status and Challenges

Marine Drugs ◽  
2020 ◽  
Vol 18 (9) ◽  
pp. 435
Author(s):  
Choongho Lee
Keyword(s):  
Broad Spectrum ◽  
Red Algae ◽  
Viral Infections ◽  
Ex Vivo ◽  
Antimicrobial Activities ◽  
Current Status ◽  
Sulfated Polysaccharides ◽  
Future Research

Different kinds of red algae are enriched with chemically diverse carbohydrates. In particular, a group of sulfated polysaccharides, which were isolated from the cell walls of red algae, gained a large amount of attention due to their broad-spectrum antimicrobial activities. Within that group, carrageenans (CGs) were expected to be the first clinically applicable microbicides that could prevent various viral infections due to their superior antiviral potency and desirable safety profiles in subclinical studies. However, their anticipated beneficial effects could not be validated in human studies. To assess the value of a second attempt at pharmacologically developing CGs as a new class of preventive microbicides, all preclinical and clinical development processes of CG-based microbicides need to be thoroughly re-evaluated. In this review, the in vitro toxicities; in vivo safety profiles; and in vitro, ex vivo, and in vivo antiviral activities of CGs are summarized according to the study volume of their target viruses, which include human immunodeficiency virus, herpesviruses, respiratory viruses, human papillomavirus, dengue virus, and other viruses along with a description of their antiviral modes of action and development of antiviral resistance. This evaluation of the strengths and weaknesses of CGs will help provide future research directions that may lead to the successful development of CG-based antimicrobial prophylactics.

scholarly journals Determination of Fungicidal Activities against Yeasts and Molds: Lessons Learned from Bactericidal Testing and the Need for Standardization

2004 ◽  
Vol 17 (2) ◽  
pp. 268-280 ◽  
Author(s):  
M. A. Pfaller ◽  
D. J. Sheehan ◽  
J. H. Rex
Keyword(s):  
Antimicrobial Agent ◽  
Bactericidal Activity ◽  
Bacterial Infections ◽  
Fungicidal Activity ◽  
Fungal Infections ◽  
Clinical Care ◽  
Lessons Learned ◽  
Yeasts And Molds

SUMMARY In certain unique clinical settings, the ability of the antimicrobial agent administered to kill the pathogen outright may be quite important. These situations invariably involve infection of a site not easily accessed by host defenses and/or of a structure with essential anatomic or physiologic function such as the heart (endocarditis), central nervous system (meningitis), or bone (osteomyelitis). Likewise, infections in immunosuppressed hosts, especially those who are neutropenic, are often thought to require microbicidal therapy. Proof of the cidal nature of an antimicrobial agent in vitro is tedious, complex, and fraught with error. Although several methods for assessing in vitro bactericidal activity have been standardized (NCCLS M26-A and M21-A), the clinical relevance of these determinations is questionable and the tests are performed infrequently in most laboratories. Most of the clinical data supporting the need for microbicidal therapy and testing have focused on bacterial infections. However, given the fact that most serious fungal infections occur in profoundly immunosuppressed individuals, it is generally assumed that a cidal regimen would be preferable in that setting as well. In view of this clinical concern and the perceived need to assess the fungicidal activity of a variety of agents, we considered that it would be useful to review what is known about the issues and problems in assessing bactericidal activity and the clinical utility of such measurements. Following this review, we discuss the issue of how one defines fungicidal activity in vitro and in vivo and how feasible it might be to determine the fungicidal activity of organism-drug combinations for purposes of both drug development and clinical care. Proposed methods for fungal time-kill determinations and minimal fungicidal concentration determinations are also discussed.

Current Status and Future Perspective for Research on Medicinal Plants with Anticancerous Activity and Minimum Cytotoxic Value

2019 ◽  
Vol 20 (12) ◽  
pp. 1227-1243
Author(s):  
Hina Qamar ◽  
Sumbul Rehman ◽  
D.K. Chauhan
Keyword(s):  
Side Effects ◽  
Medicinal Plants ◽  
Anticancer Agents ◽  
Drug Targets ◽  
Psidium Guajava ◽  
Current Status ◽  
Future Perspective ◽  
Wide Range

Cancer is the second leading cause of morbidity and mortality worldwide. Although chemotherapy and radiotherapy enhance the survival rate of cancerous patients but they have several acute toxic effects. Therefore, there is a need to search for new anticancer agents having better efficacy and lesser side effects. In this regard, herbal treatment is found to be a safe method for treating and preventing cancer. Here, an attempt has been made to screen some less explored medicinal plants like Ammania baccifera, Asclepias curassavica, Azadarichta indica, Butea monosperma, Croton tiglium, Hedera nepalensis, Jatropha curcas, Momordica charantia, Moringa oleifera, Psidium guajava, etc. having potent anticancer activity with minimum cytotoxic value (IC50 >3μM) and lesser or negligible toxicity. They are rich in active phytochemicals with a wide range of drug targets. In this study, these medicinal plants were evaluated for dose-dependent cytotoxicological studies via in vitro MTT assay and in vivo tumor models along with some more plants which are reported to have IC50 value in the range of 0.019-0.528 mg/ml. The findings indicate that these plants inhibit tumor growth by their antiproliferative, pro-apoptotic, anti-metastatic and anti-angiogenic molecular targets. They are widely used because of their easy availability, affordable price and having no or sometimes minimal side effects. This review provides a baseline for the discovery of anticancer drugs from medicinal plants having minimum cytotoxic value with minimal side effects and establishment of their analogues for the welfare of mankind.

Design, Synthesis, and Pharmacokinetic Evaluation of O-Carbamoyl Tizoxanide Prodrugs

2020 ◽  
Vol 16 ◽  
Author(s):  
Xi He ◽  
Wenjun Hu ◽  
Fanhua Meng ◽  
Xingzhou Li
Keyword(s):  
Plasma Concentration ◽  
Broad Spectrum ◽  
Plasma Concentrations ◽  
Antiviral Drug ◽  
Systemic Exposure ◽  
Pharmacokinetic Profile ◽  
Hydroxyl Group ◽  
First Pass

Background: The broad-spectrum antiparasitic drug nitazoxanide (N) has been repositioned as a broad-spectrum antiviral drug. Nitazoxanide’s in vivo antiviral activities are mainly attributed to its metabolitetizoxanide, the deacetylation product of nitazoxanide. In reference to the pharmacokinetic profile of nitazoxanide, we proposed the hypotheses that the low plasma concentrations and the low system exposure of tizoxanide after dosing with nitazoxanide result from significant first pass effects in the liver. It was thought that this may be due to the unstable acyloxy bond of nitazoxanide. Objective: Tizoxanide prodrugs, with the more stable formamyl substituent attached to the hydroxyl group rather than the acetyl group of nitazoxanide, were designed with the thought that they might be more stable in plasma. It was anticipated that these prodrugs might be less affected by the first pass effect, which would improve plasma concentrations and system exposure of tizoxanide. Method: These O-carbamoyl tizoxanide prodrugs were synthesized and evaluated in a mouse model for pharmacokinetic (PK) properties and in an in vitro model for plasma stabilities. Results: The results indicated that the plasma concentration and the systemic exposure of tizoxanide (T) after oral administration of O-carbamoyl tizoxanide prodrugs were much greater than that produced by equimolar dosage of nitazoxanide. It was also found that the plasma concentration and the systemic exposure of tizoxanide glucuronide (TG) were much lower than that produced by nitazoxanide. Conclusion: Further analysis showed that the suitable plasma stability of O-carbamoyl tizoxanide prodrugs is the key factor in maximizing the plasma concentration and the systemic exposure of the active ingredient tizoxanide.

Transplantation of Adipose-derived Cells for Periodontal Regeneration: A Systematic Review

2019 ◽  
Vol 14 (6) ◽  
pp. 504-518 ◽  
Author(s):  
Dilcele Silva Moreira Dziedzic ◽  
Bassam Felipe Mogharbel ◽  
Priscila Elias Ferreira ◽  
Ana Carolina Irioda ◽  
Katherine Athayde Teixeira de Carvalho
Keyword(s):  
Systematic Review ◽  
Animal Models ◽  
Platelet Rich Plasma ◽  
Periodontal Regeneration ◽  
In Vitro Studies ◽  
In Vivo Studies ◽  
Cell Sources ◽  
Study Designs

This systematic review evaluated the transplantation of cells derived from adipose tissue for applications in dentistry. SCOPUS, PUBMED and LILACS databases were searched for in vitro studies and pre-clinical animal model studies using the keywords “ADIPOSE”, “CELLS”, and “PERIODONTAL”, with the Boolean operator “AND”. A total of 160 titles and abstracts were identified, and 29 publications met the inclusion criteria, 14 in vitro and 15 in vivo studies. In vitro studies demonstrated that adipose- derived cells stimulate neovascularization, have osteogenic and odontogenic potential; besides adhesion, proliferation and differentiation on probable cell carriers. Preclinical studies described improvement of bone and periodontal healing with the association of adipose-derived cells and the carrier materials tested: Platelet Rich Plasma, Fibrin, Collagen and Synthetic polymer. There is evidence from the current in vitro and in vivo data indicating that adipose-derived cells may contribute to bone and periodontal regeneration. The small quantity of studies and the large variation on study designs, from animal models, cell sources and defect morphology, did not favor a meta-analysis. Additional studies need to be conducted to investigate the regeneration variability and the mechanisms of cell participation in the processes. An overview of animal models, cell sources, and scaffolds, as well as new perspectives are provided for future bone and periodontal regeneration study designs.

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