The misuse and overuse of classic antifungals have accelerated the development of resistance mechanisms,diminishing the efficacy of established therapeutic pathways and necessitating a shift towards alternative target...The misuse and overuse of classic antifungals have accelerated the development of resistance mechanisms,diminishing the efficacy of established therapeutic pathways and necessitating a shift towards alternative targets.Despite this pressing need for new treatments,the antifungal drug pipeline has been largely stagnant for the past three decades,primarily due to the high risks and costs associated with antifungal drug development,compounded by uncertain market returns.Extensive research durations,special patient populations and rigorous regulatory demands pose significant barriers to bringing novel antifungal agents to market.In response,the“push-pull”incentive model has emerged as a vital strategy to invigorate the pipeline and encourage innovation.This editorial critically examines the current clinical landscape and spotlights emerging antifungal agents,such as Fosmanogepix,Ibrexafungerp,and Olorofim,while also unraveling the multifaceted challenges faced in new antifungal drug development.The generation of novel antifungals offers a beacon of hope in the battle against antimicrobial resistance,but it is premature to declare them as definitive solutions.Their future role hinges on thorough clinical validation,costeffectiveness assessments,and continuous post-marketing surveillance.Only through strategic implementation and integration with market strategies we can transform the landscape of antifungal development,addressing both the resistance crisis and the treatment challenges.展开更多
Cardiac toxicity is an uncommon side effect of anti-fungal therapy. Until the recent reports of itraconazole (ITZ) associated cardiac failure, amphotericin was the antifungal most frequently reported with arrhythmias....Cardiac toxicity is an uncommon side effect of anti-fungal therapy. Until the recent reports of itraconazole (ITZ) associated cardiac failure, amphotericin was the antifungal most frequently reported with arrhythmias. We evaluated the cardiac effect of azole antifungals, specifically ITZ, and possible mechanisms of toxicity. Ex vivo live-heart studies were performed utilizing Sprague Dawley rats. Short exposure (<5 minutes), random crossover, dose ranging studies were performed with each pharmacologic agent. ITZ focused trials also included dose ranging utilizing a non-crossover design. The only azole found to have significant toxicity was ITZ. At ITZ ~ ED25 (2 - 2.5 ug/mL) exposures, contractility decreased by 22.2% ± 15.7% and amplitude of left ventricular pressure decreased by 11% ± 0.17%. Electron micrograph and alterations in mitochondrial respiration suggest mitochondrial toxicity as an underlying mechanism. In conclusion, ITZ was associated with reductions in contractility, possibly secondary to mitochondrial dysfunction and dilated cardiomyopathy.展开更多
Aim: Candida, an opportunistic organism is one of the commonest causes of hospital acquired infections among fungi. Currently available antifungal drugs have numerous adverse effects and drug-drug interactions (DDIs) ...Aim: Candida, an opportunistic organism is one of the commonest causes of hospital acquired infections among fungi. Currently available antifungal drugs have numerous adverse effects and drug-drug interactions (DDIs) along with increase in resistance over the time. Therefore, it is highly emergent to consider alternative treatments for candidal infections, having fewer adverse effects and is cost-effective. The current in-vitro study is undertaken to assess and compare the antifungal effects of the herbs, Berberis aristata (B. aristata, Darehald/Darhald) and Punica granatum (P. granatum, Pomegranate) with fluconazole and voriconazole, based on culture and sensitivity of candidal isolates. Materials and Methods: Ethanolic extracts of herbs (Berberis aristata and Punica granatum) and concentrations were formulated as per standard procedure. 130 samples were obtained for the study from in and out patients reported in clinical subsets of Ziauddin Hospital, Karachi from March to May, 2018. Samples were collected and grown according to the standard procedures like, wet mount test and gram’s staining. Species were identified by CHROM agar candida and API 20 C AUX methods. Sensitivity tests were performed by Kirby Bauer’s disc diffusion method according to CLSI guide lines M-44 A2, 2009. Data analysis was done by one-way ANOVA to compare the antifungal activities of drugs and herbs. Results: Mean inhibitory zones of herbs, B. aristata and P. granatum were highly significant against clinical candidal isolates with respective p-values of 0.00 and 0.02. Both of the herbs, B. aristata and P. granatum were found to be more sensitive, 98.5% and 97.7% respectively in comparison to fluconazole showing 42.3% and voriconazole showing 29.2% sensitivity against candidal isolates. The most resistant candidal specie was C. tropicalis that showed resistance against both fluconazole and voriconazole, contrary to that, this specie was highly sensitive to both of the herbs, showing sensitivity of 100% respective for Darehald and Pomeg展开更多
Fungal infection is common in critically ill patients. However, this infection is difficult to diagnose, and alarge proportion of patients receive empirical antifungal treatment without further confirmation of invasiv...Fungal infection is common in critically ill patients. However, this infection is difficult to diagnose, and alarge proportion of patients receive empirical antifungal treatment without further confirmation of invasive fungal disease. Whilst prompt appropriate antifungal treatment is associated with better outcome in patients with confirmed infections, this treatment has several drawbacks. In addition, no clear beneficial effect of empirical antifungal treatment was found in patients without confirmed infection. Reducing antifungal treatment in the intensive care unit(ICU) is feasible, and would allow avoiding drawbacks of this treatment without negative impact on outcome. Antifungal stewardship, preemptive antifungal treatment, based on colonization index and fungal biomarkers; and deescalation of antifungal treatment based on microbiology results and fungal biomarkers could be suggested to reduce antifungal use in the ICU, and are currently under investigation.展开更多
Fungal infections of the skin are one of the often faced with dermatological diseases in worldwide. Topical therapy is an attractive choice for the treatment of the cutaneous infections due to its advantageous such as...Fungal infections of the skin are one of the often faced with dermatological diseases in worldwide. Topical therapy is an attractive choice for the treatment of the cutaneous infections due to its advantageous such as targeting of drugs to the site of infection and reduction of the risk of systemic side effects. Currently, antifungal drugs are generally used as conventional cream and gel preparations in topical treatment. The efficiency of that treatment depends on the penetration of drugs through the target layers of the skin at the effective concentrations. However, stratum corneum, the outermost layer of the skin, is an effective barrier for penetration of drugs into deeper layers of the skin. The physicochemical characteristics of drug molecules and the types of the formulations are effective factors in topical drug delivery. Therefore, a number of formulation strategies have been investigated for delivering antifungal compounds through targeted site of the skin. This review article focuses on the new alternative formulation approaches to improve skin penetration of antifungal drugs.展开更多
The Genisteae tribe belongs to the Fabaceae family.The wide occurrence of secondary metabolites,explicitly high-lighting the quinolizidine alkaloids(QAs),characterizes this tribe.In the present study,twenty QAs(1-20),...The Genisteae tribe belongs to the Fabaceae family.The wide occurrence of secondary metabolites,explicitly high-lighting the quinolizidine alkaloids(QAs),characterizes this tribe.In the present study,twenty QAs(1-20),including lupanine(1-7),sparteine(8-10),lupanine(11),cytisine and tetrahydrocytisine(12-17),and matrine(18-20)-type QAs were extracted and isolated from leaves of three species(i.e.,Lupinus polyphyllus(’rusell’hybrid),Lupinus muta-bilis,and Genista monspessulana)belonging to the Genisteae tribe.These plant sources were propagated under greenhouse conditions.The isolated compounds were elucidated by analyzing their spectroscopical data(MS,NMR).The antifungal effect on the mycelial growth of Fusarium oxysporum(Fox)of each isolated QA was then evaluated through the amended medium assay.The best antifungal activity was found to be for compounds 8(IC_(50)=16.5μM),9(IC_(50)=7.2μM),12(IC_(50)=11.3μM),and 18(IC_(50)=12.3μM).The inhibitory data suggest that some QAs could effi-ciently inhibit Fox mycelium growth depending on particular structural requirements deduced from structure-activity relationship scrutinies.The identified quinolizidine-related moieties can be involved in lead structures to develop further antifungal bioactives against Fox.展开更多
文摘The misuse and overuse of classic antifungals have accelerated the development of resistance mechanisms,diminishing the efficacy of established therapeutic pathways and necessitating a shift towards alternative targets.Despite this pressing need for new treatments,the antifungal drug pipeline has been largely stagnant for the past three decades,primarily due to the high risks and costs associated with antifungal drug development,compounded by uncertain market returns.Extensive research durations,special patient populations and rigorous regulatory demands pose significant barriers to bringing novel antifungal agents to market.In response,the“push-pull”incentive model has emerged as a vital strategy to invigorate the pipeline and encourage innovation.This editorial critically examines the current clinical landscape and spotlights emerging antifungal agents,such as Fosmanogepix,Ibrexafungerp,and Olorofim,while also unraveling the multifaceted challenges faced in new antifungal drug development.The generation of novel antifungals offers a beacon of hope in the battle against antimicrobial resistance,but it is premature to declare them as definitive solutions.Their future role hinges on thorough clinical validation,costeffectiveness assessments,and continuous post-marketing surveillance.Only through strategic implementation and integration with market strategies we can transform the landscape of antifungal development,addressing both the resistance crisis and the treatment challenges.
文摘Cardiac toxicity is an uncommon side effect of anti-fungal therapy. Until the recent reports of itraconazole (ITZ) associated cardiac failure, amphotericin was the antifungal most frequently reported with arrhythmias. We evaluated the cardiac effect of azole antifungals, specifically ITZ, and possible mechanisms of toxicity. Ex vivo live-heart studies were performed utilizing Sprague Dawley rats. Short exposure (<5 minutes), random crossover, dose ranging studies were performed with each pharmacologic agent. ITZ focused trials also included dose ranging utilizing a non-crossover design. The only azole found to have significant toxicity was ITZ. At ITZ ~ ED25 (2 - 2.5 ug/mL) exposures, contractility decreased by 22.2% ± 15.7% and amplitude of left ventricular pressure decreased by 11% ± 0.17%. Electron micrograph and alterations in mitochondrial respiration suggest mitochondrial toxicity as an underlying mechanism. In conclusion, ITZ was associated with reductions in contractility, possibly secondary to mitochondrial dysfunction and dilated cardiomyopathy.
文摘Aim: Candida, an opportunistic organism is one of the commonest causes of hospital acquired infections among fungi. Currently available antifungal drugs have numerous adverse effects and drug-drug interactions (DDIs) along with increase in resistance over the time. Therefore, it is highly emergent to consider alternative treatments for candidal infections, having fewer adverse effects and is cost-effective. The current in-vitro study is undertaken to assess and compare the antifungal effects of the herbs, Berberis aristata (B. aristata, Darehald/Darhald) and Punica granatum (P. granatum, Pomegranate) with fluconazole and voriconazole, based on culture and sensitivity of candidal isolates. Materials and Methods: Ethanolic extracts of herbs (Berberis aristata and Punica granatum) and concentrations were formulated as per standard procedure. 130 samples were obtained for the study from in and out patients reported in clinical subsets of Ziauddin Hospital, Karachi from March to May, 2018. Samples were collected and grown according to the standard procedures like, wet mount test and gram’s staining. Species were identified by CHROM agar candida and API 20 C AUX methods. Sensitivity tests were performed by Kirby Bauer’s disc diffusion method according to CLSI guide lines M-44 A2, 2009. Data analysis was done by one-way ANOVA to compare the antifungal activities of drugs and herbs. Results: Mean inhibitory zones of herbs, B. aristata and P. granatum were highly significant against clinical candidal isolates with respective p-values of 0.00 and 0.02. Both of the herbs, B. aristata and P. granatum were found to be more sensitive, 98.5% and 97.7% respectively in comparison to fluconazole showing 42.3% and voriconazole showing 29.2% sensitivity against candidal isolates. The most resistant candidal specie was C. tropicalis that showed resistance against both fluconazole and voriconazole, contrary to that, this specie was highly sensitive to both of the herbs, showing sensitivity of 100% respective for Darehald and Pomeg
文摘Fungal infection is common in critically ill patients. However, this infection is difficult to diagnose, and alarge proportion of patients receive empirical antifungal treatment without further confirmation of invasive fungal disease. Whilst prompt appropriate antifungal treatment is associated with better outcome in patients with confirmed infections, this treatment has several drawbacks. In addition, no clear beneficial effect of empirical antifungal treatment was found in patients without confirmed infection. Reducing antifungal treatment in the intensive care unit(ICU) is feasible, and would allow avoiding drawbacks of this treatment without negative impact on outcome. Antifungal stewardship, preemptive antifungal treatment, based on colonization index and fungal biomarkers; and deescalation of antifungal treatment based on microbiology results and fungal biomarkers could be suggested to reduce antifungal use in the ICU, and are currently under investigation.
文摘Fungal infections of the skin are one of the often faced with dermatological diseases in worldwide. Topical therapy is an attractive choice for the treatment of the cutaneous infections due to its advantageous such as targeting of drugs to the site of infection and reduction of the risk of systemic side effects. Currently, antifungal drugs are generally used as conventional cream and gel preparations in topical treatment. The efficiency of that treatment depends on the penetration of drugs through the target layers of the skin at the effective concentrations. However, stratum corneum, the outermost layer of the skin, is an effective barrier for penetration of drugs into deeper layers of the skin. The physicochemical characteristics of drug molecules and the types of the formulations are effective factors in topical drug delivery. Therefore, a number of formulation strategies have been investigated for delivering antifungal compounds through targeted site of the skin. This review article focuses on the new alternative formulation approaches to improve skin penetration of antifungal drugs.
基金the Vicerrectoría de Investigaciones at the Universidad Militar Nueva Granada(UMNG)through the project IMP-CIAS-2924,validity 2020.
文摘The Genisteae tribe belongs to the Fabaceae family.The wide occurrence of secondary metabolites,explicitly high-lighting the quinolizidine alkaloids(QAs),characterizes this tribe.In the present study,twenty QAs(1-20),including lupanine(1-7),sparteine(8-10),lupanine(11),cytisine and tetrahydrocytisine(12-17),and matrine(18-20)-type QAs were extracted and isolated from leaves of three species(i.e.,Lupinus polyphyllus(’rusell’hybrid),Lupinus muta-bilis,and Genista monspessulana)belonging to the Genisteae tribe.These plant sources were propagated under greenhouse conditions.The isolated compounds were elucidated by analyzing their spectroscopical data(MS,NMR).The antifungal effect on the mycelial growth of Fusarium oxysporum(Fox)of each isolated QA was then evaluated through the amended medium assay.The best antifungal activity was found to be for compounds 8(IC_(50)=16.5μM),9(IC_(50)=7.2μM),12(IC_(50)=11.3μM),and 18(IC_(50)=12.3μM).The inhibitory data suggest that some QAs could effi-ciently inhibit Fox mycelium growth depending on particular structural requirements deduced from structure-activity relationship scrutinies.The identified quinolizidine-related moieties can be involved in lead structures to develop further antifungal bioactives against Fox.
