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Drug Delivery Dec 2021We examined formulating a new antifungal agent, posaconazole (POS) and its derivatives, with different molecular vehicles. Several combinations of drug and carrier...
We examined formulating a new antifungal agent, posaconazole (POS) and its derivatives, with different molecular vehicles. Several combinations of drug and carrier molecules were synthesized, and their antifungal activities were evaluated against . Posaconazole and four of its derivatives were conjugated to either generation 5 (G5) dendrimers or partially modified G5 dendrimers. The antifungal activities of these compounds suggest that conjugates with specific chemical linkages showed better fungistatic activity than direct conjugates to POS. In particular, a polyethylene glycol (PEG)-imidazole modified G5 dendrimer demonstrated improved antifungal efficacy relative to the parent G5 molecule. Further studies were then conducted with POS derived molecules coupled to PEG-imidazole modified G5 dendrimers to achieve a highly soluble and active conjugate of POS. This conjugated macromolecule averaged 23 POS molecules per G5 and had a high solubility with 50 mg/mL, which improved the molar solubility of POS from less than 0.03 mg/mL to as high as 16 mg/mL in water. The primary release profile of the drug in human plasma was extended to over 72 h, which is reflected in the inhibition of growth of over 96 h. These POS-polymer conjugates appear to be novel and efficient antifungal agents.
Topics: Antifungal Agents; Aspergillus fumigatus; Chemistry, Pharmaceutical; Dendrimers; Dose-Response Relationship, Drug; Drug Carriers; Drug Liberation; Imidazoles; Nanoparticles; Polyethylene Glycols; Triazoles
PubMed: 34617850
DOI: 10.1080/10717544.2021.1986605 -
Annals of Hematology Jul 2020With the advent of new targeted drugs in hematology and oncology patient prognosis is improved. Combination with antifungal prophylaxis challenges clinicians due to... (Review)
Review
With the advent of new targeted drugs in hematology and oncology patient prognosis is improved. Combination with antifungal prophylaxis challenges clinicians due to pharmacological profiles prone to drug-drug interactions (DDI). Midostaurin is a novel agent for FLT3-TKD/-ITD-acute myeloid leukemia (AML) and metabolized via cytochrome P450 3A4 (CYP3A4). Posaconazole is a standard of care antifungal agent used for prophylaxis during induction treatment of AML and a strong CYP3A4 inhibitor. Concomitant administration of both drugs leads to elevated midostaurin exposure. Both drugs improve overall survival at low numbers needed to treat. The impact of CYP3A4-related DDI remains to be determined. Severe adverse events have been observed; however, it remains unclear if they can be directly linked to DDI. The lack of prospective clinical studies assessing incidence of invasive fungal infections and clinical impact of DDI contributes to neglecting live-saving antifungal prophylaxis. Management strategies to combine both drugs have been proposed, but evidence on which approach to use is scarce. In this review, we discuss several approaches in the specific clinical setting of concomitant administration of midostaurin and posaconazole and give examples from everyday clinical practice. Therapeutic drug monitoring will become increasingly important to individualize and personalize antineoplastic concomitant and antifungal treatment in the context of DDI. Pharmaceutical companies addressing the issue in clinical trials may take a pioneer role in this field. Other recently developed and approved drugs for the treatment of AML likely inhere potential of DDI marking a foreseeable issue in future treatment of this life-threatening disease.
Topics: Antifungal Agents; Chemoprevention; Drug Interactions; Drugs, Investigational; Humans; Invasive Fungal Infections; Leukemia, Myeloid, Acute; Prognosis; Staurosporine; Triazoles
PubMed: 32514626
DOI: 10.1007/s00277-020-04107-1 -
Journal of Foot and Ankle Research Oct 2023Dermatophytes are group of filamentous fungi which have adapted to living on the skin of humans and other animals. In the last decade, reports have emerged from Asia of...
Dermatophytes are group of filamentous fungi which have adapted to living on the skin of humans and other animals. In the last decade, reports have emerged from Asia of new dermatophyte strains showing resistance to the commonly used antifungal agent terbinafine and others. The spread of these resistant strains has been noted in many other countries globally. Little is known about the mechanisms or management of this emerging problem. Urgent research and changes to current practice are required if the spread of the infection is to be contained and managed effectively.
Topics: Animals; Humans; Arthrodermataceae; Naphthalenes; Microbial Sensitivity Tests; Antifungal Agents; Terbinafine
PubMed: 37794415
DOI: 10.1186/s13047-023-00665-5 -
Paediatric Drugs Apr 2020Neonates and immunosuppressed/immunocompromised pediatric patients are at high risk of invasive fungal diseases. Appropriate antifungal selection and optimized dosing... (Review)
Review
Neonates and immunosuppressed/immunocompromised pediatric patients are at high risk of invasive fungal diseases. Appropriate antifungal selection and optimized dosing are imperative to the successful prevention and treatment of these life-threatening infections. Conventional amphotericin B was the mainstay of antifungal therapy for many decades, but dose-limiting nephrotoxicity and infusion-related adverse events impeded its use. Despite the development of several new antifungal classes and agents in the past 20 years, and their now routine use in at-risk pediatric populations, data to guide the optimal dosing of antifungals in children are limited. This paper reviews the spectra of activity for approved antifungal agents and summarizes the current literature specific to pediatric patients regarding pharmacokinetic/pharmacodynamic data, dosing, and therapeutic drug monitoring.
Topics: Antifungal Agents; Child; Child, Preschool; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Infant; Infant, Newborn; Male
PubMed: 31974859
DOI: 10.1007/s40272-020-00379-2 -
Revista Chilena de Pediatria Feb 2020Onychomycosis (OM) is a fungal infection of the nails, whose main etiologic agent is Trichophytum rubrum. Although, it is an unusual pathology in children, in the last... (Review)
Review
Onychomycosis (OM) is a fungal infection of the nails, whose main etiologic agent is Trichophytum rubrum. Although, it is an unusual pathology in children, in the last years an increase in its preva lence has been observed. To date, there are several studies and clinical guidelines for OM in adults. However, literature in children is scarce, which makes pediatric treatment difficult. The objective of this publication was to review the current literature in order to establish diagnostic methods for OM, national and international epidemiological data, and to provide treatment options taking into account their efficiency and safety profile in the pediatric population.
Topics: Adolescent; Antifungal Agents; Child; Child, Preschool; Global Health; Humans; Infant; Onychomycosis; Pediatrics
PubMed: 32730424
DOI: 10.32641/rchped.v91i1.1309 -
Revista Da Sociedade Brasileira de... 2023There is a consensus that the antifungal repertoire for the treatment of cryptococcal infections is limited. Standard treatment involves the administration of an... (Review)
Review
There is a consensus that the antifungal repertoire for the treatment of cryptococcal infections is limited. Standard treatment involves the administration of an antifungal drug derived from natural sources (i.e., amphotericin B) and two other drugs developed synthetically (i.e., flucytosine and fluconazole). Despite treatment, the mortality rates associated with fungal cryptococcosis are high. Amphotericin B and flucytosine are toxic, require intravenous administration, and are usually unavailable in low-income countries because of their high cost. However, fluconazole is cost-effective, widely available, and harmless with regard to its side effects. However, fluconazole is a fungistatic agent that has contributed considerably to the increase in fungal resistance and frequent relapses in patients with cryptococcal meningitis. Therefore, there is an unquestionable need to identify new alternatives or adjuvants to conventional drugs for the treatment of cryptococcosis. A potential antifungal agent should be able to kill cryptococci and "bypass" the virulence mechanism of the yeast. Furthermore, it should have fungicidal action, low toxicity, high selectivity, easily penetrate the central nervous system, and widely available. In this review, we describe cryptococcosis, its conventional therapy, and failures arising from the use of drugs traditionally considered to be the reference standard. Additionally, we present the approaches used for the discovery of new drugs to counteract cryptococcosis, ranging from the conventional screening of natural products to the inclusion of structural modifications to optimize anticryptococcal activity, as well as drug repositioning and combined therapies.
Topics: Humans; Antifungal Agents; Amphotericin B; Flucytosine; Fluconazole; Cryptococcosis; Cryptococcus neoformans
PubMed: 37493736
DOI: 10.1590/0037-8682-0121-2023 -
Antimicrobial Agents and Chemotherapy Jun 2023Fungal infections, which commonly occur in immunocompromised patients, can cause high morbidity and mortality. Antifungal agents act by disrupting the cell membrane,... (Review)
Review
Fungal infections, which commonly occur in immunocompromised patients, can cause high morbidity and mortality. Antifungal agents act by disrupting the cell membrane, inhibiting nucleic acid synthesis and function, or inhibiting β-1,3-glucan synthase. Because the incidences of life-threatening fungal infections and antifungal drug resistance are continuously increasing, there is an urgent need for the development of new antifungal agents with novel mechanisms of action. Recent studies have focused on mitochondrial components as potential therapeutic drug targets, owing to their important roles in fungal viability and pathogenesis. In this review, we discuss novel antifungal drugs targeting mitochondrial components and highlight the unique fungal proteins involved in the electron transport chain, which is useful for investigating selective antifungal targets. Finally, we comprehensively summarize the efficacy and safety of lead compounds in clinical and preclinical development. Although fungus-specific proteins in the mitochondrion are involved in various processes, the majority of the antifungal agents target dysfunction of mitochondria, including mitochondrial respiration disturbance, increased intracellular ATP, reactive oxygen species generation, and others. Moreover, only a few drugs are under clinical trials, necessitating further exploration of possible targets and development of effective antifungal agents. The unique chemical structures and targets of these compounds will provide valuable hints for further exploiting new antifungals.
Topics: Humans; Antifungal Agents; Mycoses; Mitochondria; Drug Delivery Systems; Fungal Proteins
PubMed: 37195189
DOI: 10.1128/aac.00003-23 -
Archives of Oral Biology Mar 2021To determine the phytochemical composition of Byrsonima gardneriana (A. Juss) leaf extract (BGE) and its antifungal activity against Candida spp., antioxidant potential...
OBJECTIVE
To determine the phytochemical composition of Byrsonima gardneriana (A. Juss) leaf extract (BGE) and its antifungal activity against Candida spp., antioxidant potential and in vitro cytotoxicity.
MATERIAL AND METHODS
BGE was obtained and submitted to Gas Chromatography Coupled to Mass Spectrometry for phytochemical analysis. The ethanolic extract was tested for its antifungal activity against C. albicans and non-albicans reference strains and clinical isolates in addition to inhibition of C. albicans growth kinetics. It was also tested for antioxidant potential in the presence of phenylhydrazine and reactive oxygen species (ROS). And cytoxicity in human erythrocytes. The data were analyzed by one-way Analysis of Variance (ANOVA) followed by Tukey's or Dunnett's post-hoc test, with α = 0.05.
RESULTS
Pyroglutamic acid (90.77 %), eucalyptol (89.61 %) and octanoic acid (76.22 %) were the major compounds detected in BGE, P (%) is the percent probability of compound identification, according to the mass spectra library. The extract showed fungistatic activity, with MIC of 125 μg/mL against most tested strains. While BGE showed low hemolytic activity on all blood types tested herein, it could not prevent osmotic stress in human erythrocytes. The extract did not have oxidizing effects in the presence of phenylhydrazine, but it showed antioxidant potential against ROS when tested at 31 μg/mL and 62 μg/mL.
CONCLUSION
B. gardneriana extract showed antifungal activity against Candida spp., demonstrated low hemolytic potential, no oxidant activity in human erythrocytes and antioxidant activity against ROS. This study opens avenues for the study of BGE as a promising biocompatible antifungal agent.
Topics: Antifungal Agents; Antioxidants; Candida; Erythrocytes; Gas Chromatography-Mass Spectrometry; Hemolysis; Humans; Malpighiaceae; Microbial Sensitivity Tests; Phytochemicals; Plant Extracts
PubMed: 33472099
DOI: 10.1016/j.archoralbio.2020.104994 -
Drug Discovery Today Jul 2022Although fungal diseases are a major and growing public health concern, there are only four major classes of drug to treat primary fungal pathogens. The pipeline of new... (Review)
Review
Although fungal diseases are a major and growing public health concern, there are only four major classes of drug to treat primary fungal pathogens. The pipeline of new antifungals in clinical development is relatively thin compared with other disease classes. One approach to rapidly identify and provide novel treatment options is to repurpose existing drugs as antifungals. However, such proposed drug-repurposing candidates often suffer suboptimal efficacy and pharmacokinetics (PK) for fungal diseases. Herein, we briefly review the current antifungal drug pipeline and recent approaches to optimize existing drugs into novel molecules with unique modes of action relative to existing antifungal drug classes.
Topics: Antifungal Agents; Drug Repositioning; Humans; Mycoses
PubMed: 35489676
DOI: 10.1016/j.drudis.2022.04.021 -
Medical Mycology Journal 2021Treatment of Candidemia has become increasingly complicated as more and more non-albicans Candida species are being isolated in recent years.We launched an investigation...
Treatment of Candidemia has become increasingly complicated as more and more non-albicans Candida species are being isolated in recent years.We launched an investigation of the species, the MIC value, and the state of administration of antifungal drugs for all the cases with Candida spp. confirmed by blood cultures for the 7-year period from 2012 to 2018 at our hospital. In total, 192 cases were found and 206 strains of Candida species were isolated. Overall, 49.5% of the 206 isolated strains were Candida albicans (102 strains), followed by Candida glabrata (40 strains, 19.4%), and Candida parapsilosis (38 strains, 18.4%). The most frequently used antifungal drug for the initial dose was MCFG (120 cases, 59.2%), while the most frequently switched antifungal agent was L-AMB. Cases with an inappropriate end-of-treatment time represented 58.7% of all the cases.We investigated the Candidemia situation at our hospital for a period of seven years. We believe that it is important for medical institutions to gather detailed data on candidemia at their own hospitals. Likewise, the hospital's Infection Control Team/Antimicrobial Stewardship Team should inform the physicians-in-charge about the appropriate diagnosis and treatment based on the data obtained.
Topics: Antifungal Agents; Candida; Candidemia; Hospitals; Humans; Microbial Sensitivity Tests
PubMed: 34053977
DOI: 10.3314/mmj.20-00013