In vitro and in vivo assessment of FK506 analogs as novel antifungal drug candidates.

In this study, we analyzed the cytotoxicity, immunosuppressive activity, and antifungal activity of four FK506 analogs, 31-O-demethyl-FK506, 9-deoxo-FK506, 9-deoxo-31-O-demethyl-FK506, and 9-deoxo-prolyl-FK506, in comparison with FK506. The four FK506 analogs generally possess lower cytotoxicity and immunosuppressive activity than FK506. The FK506 analogs, except for 9-deoxo-prolyl FK506, have strong antifungal activity against Cryptococcus neoformans and Candida albicans, which are two major invasive pathogenic yeasts, due to the inhibition of the calcineurin pathway. Furthermore, the FK506 analogs, except for 9-deoxo-prolyl FK506, have strong antifungal activity against the invasive filamentous fungus Aspergillus fumigatus Notably, 9-deoxo-31-O-demethyl-FK506 and 31-O-demethyl-FK506 exhibited robust synergistic antifungal activity with fluconazole, similar to FK506. Considering the antifungal efficacy, cytotoxicity, immunosuppressive activity, and synergistic effect with commercial antifungal drugs, we selected 9-deoxo-31-O-demethyl-FK506 for further evaluation of in vivo antifungal efficacy in the murine model of systemic cryptococcosis. Although 9-deoxo-31-O-demethyl-FK506 alone was not sufficient to treat the cryptococcal infection, its combination treatment with fluconazole significantly extended the survival of C. neoformans-infected mice, confirming synergistic in vivo antifungal efficacy between these two agents. PMID: 30181374 [PubMed - as supplied by publisher...
Source: Antimicrobial Agents and Chemotherapy - Category: Microbiology Authors: Tags: Antimicrob Agents Chemother Source Type: research

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ConclusionThe proposed multiparametric MRI-based SLICs+MTh method performs noninvasive assessment of NACT response in osteosarcoma that may improve cancer treatment monitoring, planning, and overall prognosis.Key Points• The simple linear iterative clustering supervoxels and Otsu multithresholding-based technique (SLICs+MTh) successfully estimates the proportion of necrosis, viable tumor, and edema in osteosarcoma in the course of chemotherapy.• The proposed technique is noninvasive and uses multiparametric MRI to measure necrosis as an indication of anticancer treatment response.• SLICs+MTh-based necrosis w...
Source: European Radiology - Category: Radiology Source Type: research
Psychologists say anxiety and uncertainty prompt irrational decisions — like turning down a transplant when an organ becomes available.
Source: NYT Health - Category: Consumer Health News Authors: Tags: Transplants Emergency Medical Treatment Coronavirus (2019-nCoV) Liver Fear (Emotion) Anxiety and Stress Cancer Heart your-feed-science your-feed-healthcare Source Type: news
This study, for instance, attributes a patient’s waitlist/transplant outcome to the very last dialysis facility the patient was associated with.  In epidemiology speak, this means the causal inference authors are trying to draw between for-profit status and good transplant outcomes is subject to time-varying confounding. As an example, if one is seeking an association between testosterone levels and risk of a heart attack, using the last testosterone level available would be a poor way of doing this study because testosterone levels are known to vary over time. The same applies to dialysis facilities. Patie...
Source: The Health Care Blog - Category: Consumer Health News Authors: Tags: Medical Practice Physicians Eric Weinhandl JAMA medical research public health Public Policy public policy research Source Type: blogs
Conclusion and Perspectives CYP51 plays a crucial role in fungal invasive growth, hyphae formation and virulence, and inhibitors targeting CYP51 have always been an important component of antifungal agents. Further researches on fungal CYP51s might set about from the following aspects: First, while the detailed crystal structures of several susceptible pathogenic fungi CYP51 have been elaborated, those of drug-resistant variants are still in hypothesis. If those structures were elucidated, targeting at common drug-resistant CYP51 protein variants could probably be promising. Second, it deserves more in-depth researches to...
Source: Frontiers in Microbiology - Category: Microbiology Source Type: research
In this study they also showed PTX3 localized in NETs formed after neutrophil activation (5). Proteomics analysis revealed that PTX3 forms complexes with two anti-microbial proteins [azurocidin (AZU1) and myeloperoxidase (MPO)] associated to NETs (30). More recently, PTX3 localization in NETs has been confirmed, and the colocalization with AZU1 and MPO has been defined more accurately (31). Further investigation will be needed to understand the involvement of PTX3 interaction with AZU1 and MPO in their antibacterial role during NET formation. Regulation of Complement Activation PTX3 interaction with microorganisms is not...
Source: Frontiers in Immunology - Category: Allergy & Immunology Source Type: research
Conclusion In conclusion, F. keratoplasticum and F. petroliphilum were the most frequent species in this study. Amphotericin B showed lower MICs against Fusarium species whereas the antifungal azoles and the fungicide difenoconazole exhibited higher MICs against FSSC. Ethics Statement Samples were collected during routine patient care and the study was retrospective, therefore it was determined by the local Institutional Review Board of the Hospital de Clínicas, Federal University of Paraná and CAPES that ethical clearance was not indicated. Author Contributions PH, AA-H, FQ-T, and JM designed the study....
Source: Frontiers in Microbiology - Category: Microbiology Source Type: research
Conclusion: Patterns of invasive fungal infections are changing in many ways. In the midst of these evolving trends, IFI of the respiratory tractcontinue to remain important causes of morbidity and mortality. Diagnostic tools can be adequately used only if the treating physician is aware of the propensity of patients to acquire a fungal infection. Thus, continuous awareness and education is crucial for successful management of patients. Judicious use of antifungal medications as prophylactic measures must be employed, particularly in the critically ill and patients of HIV.
Source: Indian Journal of Medical Microbiology - Category: Microbiology Authors: Source Type: research
LITFL • Life in the Fast Lane Medical Blog LITFL • Life in the Fast Lane Medical Blog - Emergency medicine and critical care medical education blog aka Tropical Travel Trouble 009 The diagnosis of HIV is no longer fatal and the term AIDS is becoming less frequent. In many countries, people with HIV are living longer than those with diabetes. This post will hopefully teach the basics of a complex disease and demystify some of the potential diseases you need to consider in those who are severely immunosuppressed. While trying to be comprehensive this post can not be exhaustive (as you can imagine any patient with ...
Source: Life in the Fast Lane - Category: Emergency Medicine Authors: Tags: Clinical Cases Tropical Medicine AIDS art cryptococcoma cryptococcus HIV HIV1 HIV2 PEP PrEP TB toxoplasma tuberculoma Source Type: blogs
QIDP Designation Granted for Treatment of Cryptococcosis Provides Priority Review, Fast-Track Status and Five Additional Years of Market Exclusivity SAN DIEGO, March 19, 2018 -- (Healthcare Sales &Marketing Network) -- Amplyx Pharmaceuticals, a compan... Biopharmaceuticals, FDA Amplyx Pharmaceuticals, Candida, Aspergillus
Source: HSMN NewsFeed - Category: Pharmaceuticals Source Type: news
Abstract Every year, Candida, Aspergillus, Cryptococcus and Pneumocystis infect an estimated two million individuals worldwide. Most are immunocompromised or critically ill. Candida is the most common fungal pathogen of the critically ill and of recipients of transplanted abdominal organs. In high-risk haemato-oncological patients, in contrast, the introduction of antifungal prophylaxis with fluconazole and later with mould-active posaconazole has led to a remarkable reduction of invasive candidiasis and is likely to have a similar effect on invasive aspergillosis. Invasive aspergillosis remains the dominant invas...
Source: Swiss Medical Weekly - Category: Journals (General) Authors: Tags: Swiss Med Wkly Source Type: research
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