The past, present and future of antimycotic combination therapy

Polak, Annemarie

doi:10.1046/j.1439-0507.1999.00475.x

Cited by 100 publications

(29 citation statements)

References 127 publications

(157 reference statements)

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“…Amphotericin B, developed in the 1950s, still remains as a widely used antifungal drug, most recently gaining renewed applications through lipid based formulations. According to Polak [6] ideal drugs to cure fungal infections have not been discovered yet. In the meantime, resistance to currently available antifungal agents continues to grow [7].…”

Section: Introductionmentioning

confidence: 99%

“…In the meantime, resistance to currently available antifungal agents continues to grow [7]. Although combination therapy has emerged as a good alternative to bypass these disadvantages [6,8], there is an urgent need for a next generation of safer and more potent antifungal agents [1,8]. These explorations have resulted in the identification of novel molecules, which could prove promising for further future development.…”

Section: Introductionmentioning

confidence: 99%

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Penetratin and derivatives acting as antifungal agents

Masman

Rodrı́guez

Raimondi

et al. 2009

European Journal of Medicinal Chemistry

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The synthesis, in vitro evaluation, and conformational study of RQIKIWFQNRRMKWKKeNH 2 (penetratin) and related derivatives acting as antifungal agents are reported. Penetratin and some of its derivatives displayed antifungal activity against the human opportunistic pathogenic standardized ATCC strains Candida albicans and Cryptococcus neoformans as well as clinical isolates of C. neoformans. Among the compounds tested, penetratin along with the nonapeptide RKWRRKWKKeNH 2 and the tetrapeptide RQKKeNH 2 exhibited significant antifungal activities against the Cryptococcus species. A comprehensive conformational analysis on the peptides reported here using three different approaches, molecular mechanics, simulated annealing and molecular dynamics simulations, was carried out. The experimental and theoretical results allow us to identify a topographical template which may provide a guide for the design of new compounds with antifungal characteristics against C. neoformans.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Penetratin and derivatives acting as antifungal agents

Masman

Rodrı́guez

Raimondi

et al. 2009

European Journal of Medicinal Chemistry

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“…Regarding the behavior of compound 4a against yeasts, it is worthwhile to take into account its selective activity against C. neoformans which is the cause of the fatal cryptococcosis in immunocompromised hosts [24]. It is important to keep in mind that, for a long time, the treatment of fungal infections with the same broad-spectrum antifungal agent sometimes leads to a high resistance against the available antifungal agents [25].…”

Section: Antifungal Activitymentioning

confidence: 99%

Fungicide Activity of 5‐(4‐Chlorobenzylidene)‐(Z)‐2‐dimethylamino‐1,3‐thiazol‐4‐one against Cryptococcus Neoformans

Insuasty¹,

Gutiérrez²,

Quiroga³

et al. 2010

Archiv der Pharmazie

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The present work describes the synthesis and antifungal evaluation of new 5-arylidene-(Z)-2-dimethylamino-1,3-thiazol-4-ones 4a-f, obtained by the reaction of aromatic aldehydes 1 and rhodanine 2 followed by treatment with DMF. All compounds were tested against a panel of yeasts, hialohyphomycetes, and dermatophytes using the microbroth dilution method. Compounds 4a and 4c showed antifungal activity, with compound 4a being the most active one. Compound 4a demonstrated to be fungicidal rather than fungistatic and selective activity against Cryptococcus neoformans and dermatophytes. MIC(100), MIC(80), and MIC(50) of 4a were determined against a panel of clinical isolates of C. neoformans showing ranges of MICs between 2 and 16 microg/mL.

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“…Amphotericin B (amB) has been the drug of choice for decades [7,8,9,10]; however, treatment is limited by associated toxic effects. Despite the introduction of newer antifungal agents with better tolerability, like itraconazole, voriconazole, posaconazole and caspofungin, and despite long-term combination therapy, the effectiveness may still prove unsatisfactory especially in patients with large infiltrates and prolonged neutropenia [8, 9,11,12,13,14]. IPA is considered highly lethal in the immunocompromised host despite ongoing therapy.…”

Section: Introductionmentioning

confidence: 99%

“…Furthermore, considering the critical clinical condition of affected patients, a rapid, tolerable and effective therapy is mandatory, not only to prevent an aggravation by life-threatening complications like haemoptysis or further spread of the infection, but also to allow the continuation of cytotoxic chemotherapy to fight the primary disease. The concentration levels of antifungal agents in affected lung tissue achieved by intravenous (IV) or oral treatment is often too low to allow a therapeutic effect [9, 16]. Therapeutic bronchoscopy has become an alternative and minimally invasive procedure able to reduce morbidity and mortality in selected critically ill patients [17].…”

Section: Introductionmentioning

confidence: 99%

Treatment of Invasive Pulmonary Aspergillosis in Neutropenic Patients by Additional Bronchoscopic Amphotericin B Instillation

Winkler¹,

Müller²,

Nenoff³

et al. 2007

Respiration

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Background: Invasive pulmonary aspergillosis (IPA) remains a life-threatening condition despite systemic antifungal therapy. Objectives: This retrospective analysis investigated whether additional bronchoscopic instillation of amphotericin B (amB) would improve efficacy of antifungal treatment in patients with haematological malignancies suffering from IPA. Methods: Twenty patients (40.6 ± 14.2 years, 14 male) with preceding chemotherapy, bone marrow or stem cell transplantation complicated by severe IPA who did not respond sufficiently to systemic antifungal therapy were additionally treated by repeated bronchoscopic instillations of amB solution (91 instillations, on average 4.6 ± 2.2 instillations per patient over a period of 24.1 ± 21.0 days). Therapeutic response to this combined treatment regimen was monitored by chest X-ray and CT scan. Results: The mean infiltration sizes during systemic antifungal therapy alone (mean duration 11.9 ± 9.9 days) did not change significantly. However, after additional bronchoscopic instillation of amB solution infiltration sizes were reduced significantly (p < 0.05). A total resolution of infiltrates was seen in 3 and a partial reduction in 13 of 20 patients. Mean duration of total antifungal treatment was 50.1 ± 24.0 days. The mean follow-up period was 34.1 ± 31.2 months. The IPA-related mortality rate was 18.8% (3 of 16 patients). Conclusions: Additional bronchoscopic instillation of amB may improve the efficacy of systemic antifungal therapy in patients with haematological malignancies complicated by severe IPA. Bronchoscopic instillation of amB should be considered as an additional treatment option in cases with IPA unresponsive to systemic therapy.

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The past, present and future of antimycotic combination therapy

Cited by 100 publications

References 127 publications

Penetratin and derivatives acting as antifungal agents

Penetratin and derivatives acting as antifungal agents

Fungicide Activity of 5‐(4‐Chlorobenzylidene)‐(Z)‐2‐dimethylamino‐1,3‐thiazol‐4‐one against Cryptococcus Neoformans

Treatment of Invasive Pulmonary Aspergillosis in Neutropenic Patients by Additional Bronchoscopic Amphotericin B Instillation

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