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Concept: Itraconazole

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Abstract This is a randomized, double-blind study enrolling 70 patients with onychomycosis of the finger and toenails. Clinical and mycological efficacies as well as measures of safety were assessed monthly for a maximum of 6 months of treatment. The treatment regimens were: fluconazole 1% and fluconazole 1% with urea 40%. These results indicated topical treatment of onychomycosis with a combination of fluconazole 1% and urea 40% was more effective (82.8%) than fluconazole 1% (62.8%) nail lacquer alone in treatment of dermatophytic onychomycosis. Fluconazole was well tolerated and side effects were negligible. At the end of therapy and the end of the 6-month follow-up, fluconazole 1% and urea 40% demonstrated statistically significant superiority in clinical and mycological responses compared with fluconazole 1% alone.

Concepts: Medicine, Effectiveness, Finger, Onychomycosis, Nail, Nail disease, Terbinafine, Itraconazole

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An antibacterial is a substance that kills bacteria or slows their growth. An antifungal are the agents that drugs use for treatment of fungal infections. 5- Chloro-1,3-benzoxazol-2(3H)-one (5-Chloro Benzoxazolinone) contains an azole ring structure. Numbers of azole compounds are reported as antibacterial and antifungal agents. Benzoxazolinones naturally occurs in plants. It plays role as defense compounds against bacteria, fungi and insects. Here is synthesis of six Benzoxazolinone derivatives with various substituents. Benzoxazolinone substituted with p-Aminobenzoic acids and sulphanilamide derivatives. The above both substituents are reported as potent antimicrobial agents. Attachment it with azole leads to increase its potency. The other substituents are with 2,4-dichlorobezylchloride. The same rings are found in miconazole and this may lead to increase its antifungal activity. Fluconazole also contains triazole moiety and triazole is having other number of activity like antimicrobial, anti-inflammatory, local anesthetic, antiviral, anticancer, antimalerial etc. Here there is substitution of azole ring at 5-Chloro position in that might increase antibacterial and antifungal activity. Here is the synthesis and interpretation of six final compounds and three intermediates. Synthesis of 5-Chloro Benzoxazolinone derivatives substituted with Halogenated rings, sulphonated and benzylated derivatives and azole derivatives. There was synthesis of P2A, P2B, P4A, P4B, P5A and P6A compounds and their Structures were characterized by UV-Visible, IR, MASS spectroscopy and NMR spectroscopy. The antibacterial activity of all six compounds is measured against various gm+ve and gm-ve bacteria and against fungi.Compound P4A and P4B has good antibacterial and anti fungal activity, half of the Ampicillin and Cephalexin. P4A, P4B, P6A has good activity against S.aureus and E.coli. Compound P2B has good antifungal activity, half of the Miconazole against C.albicans. P2A, P2B, P5A, P6A has almost equal antibacterial activity.

Concepts: Bacteria, Microbiology, Fungus, Meningitis, Antifungals, Antifungal drug, Fluconazole, Itraconazole

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Background: Itraconazole (ITZ), a triazole antifungal agent, is a poorly water-soluble drug that is orally administered for treatment of fungal infections such as allergic bronchopulmonary aspergillosis (ABPA) and invasive aspergillosis (IA). ABPA is relatively well controlled but IA can be fatal, especially in immunosuppressed patients. Aerosolized ITZ delivered to the lung may provide a local treatment and prophylaxis against IA at the primary site of infection in the lungs. Variations of the percent fine particle fraction (FPF), the percent emitted dose, and the physical properties of the aerosol (e.g., crystallinity) can confound consistent delivery. Methods: ITZ NanoClusters were formulated via milling (top-down process) or precipitation (bottom-up process) without using any excipients. Itraconazole formulations (ITZ) were prepared by milling 1 gram of micronized itraconazole in 300 mL of fluid. The suspension was collected at 0.5, 1, and 2 hours milling time. Milled ITZ was compared to ITZ prepared by anti-solvent precipitation and to the stock micronized itraconazole. The aerosolization performance of ITZ formulations was determined using an Andersen Cascade Impactor (ACI). Results: The physicochemical properties and aerosol performance of different ITZ NanoClusters suggested an optimized wet milling was the preferred process compared to precipitation. ITZ NanoClusters prepared by wet milling showed better aerosol performance compared to micronized ITZ as received and ITZ NanoClusters prepared by precipitation. ITZ NanoClusters prepared by precipitation methods also showed an amorphous state, while ITZ milled in 10% EtOH maintained the crystalline character of ITZ throughout a 2 hour milling time. Conclusions: The aerosol performance of milled ITZ NanoClusters was dramatically improved compared to micronized ITZ as received due to the difference of drug particle structures. ITZ NanoCluster formulations represent a potential engineered drug particle approach for inhalation therapy, providing effective aerosol properties and stability due to the crystalline state of the drug powders.

Concepts: Crystal, Physical chemistry, Particulate, Aerosol, Aspergillosis, Allergic bronchopulmonary aspergillosis, Amorphous solid, Itraconazole

2

Patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT) are at increased risk of invasive fungal infections, especially during the early neutropenic phase and severe graft-versus-host disease. Mold-active prophylaxis should be limited to the highest risk groups. Empiric antifungal therapy for HSCT with persistent febrile neutropenia is associated with unacceptable response rates, unnecessary antifungal therapy, increased risk of toxicity, and inflated costs. Empiric therapy should not be a substitute for detailed work up to identify the cause of fever in such patients. The improved diagnostic performance of serum biomarkers such as galactomannan and β-D-glucan, as well as polymerase chain reaction assays has allowed the development of diagnostic-driven antifungal therapy strategies for high risk patients. Diagnostic-driven approaches have resulted in reduced unnecessary antifungal exposure, improved diagnosis of invasive fungal disease, and reduced costs without increased risk of mortality. The appropriateness of diagnostic-driven antifungal strategy for individual HSCT centers depends on the availability and turnaround times for diagnostics, multidisciplinary expertise, and the local epidemiology of invasive fungal infections. Echinocandins are the treatment of choice for invasive candidiasis in most HSCT recipients. Fluconazole may be used for the treatment of invasive candidiasis in hemodynamically stable patients with no prior azole exposure. The primary treatment of choice for invasive aspergillosis is voriconazole. Alternatives include isavuconazole and lipid formulations of amphotericin. Currently available evidence does not support routine primary combination antifungal therapy for invasive aspergillosis. However, combination salvage antifungal therapy may be considered in selected patients. Therapeutic drug monitoring is recommended for the majority of HSCT recipients on itraconazole, posaconazole, or voriconazole.

Concepts: Infectious disease, Graft-versus-host disease, Hematopoietic stem cell transplantation, Fever, Antifungals, Candidiasis, Fungal diseases, Itraconazole

2

Isavuconazole is a new extended spectrum triazole with activity against yeasts, molds, and dimorphic fungi. It is approved for the treatment of invasive aspergillosis and mucormycosis. Advantages of this triazole include the availability of a water-soluble IV formulation, excellent bioavailability of the oral formulation, and predictable pharmacokinetics in adults. A randomized, double-blind comparison clinical trial for treatment of invasive aspergillosis found that the efficacy of isavuconazole was non-inferior to that of voriconazole. An open-label trial that studied primary, as well as salvage therapy of invasive mucormycosis showed efficacy with isavuconazole that was similar to that reported for amphotericin B and posaconazole. In patients in these studies, as well as in normal volunteers, isavuconazole was well tolerated, appeared to have few serious adverse effects, and had fewer drug-drug interactions than those noted with voriconazole. As clinical experience increases, the role of this new triazole in the treatment of invasive fungal infections will be better defined.

Concepts: Pharmacology, Effectiveness, Aspergillosis, Antifungals, Flucytosine, Ergosterol, Triazole, Itraconazole

2

Case reports suggest that long-term, high-dose fluconazole treatment for severe fungal infections during pregnancy causes a pattern of birth defects. It is unclear whether commonly used lower doses increase the risk of specific birth defects.

Concepts: Childbirth, Itraconazole

1

Mortality and morbidity due to invasive fungal infections have increased over the years. Posaconazole is a second-generation triazole agent with an extended spectrum of activity, which shows a high interindividual variability in its plasma levels, rendering dosing in many patients inconsistent or inadequate. Hence, posaconazole therapeutic drug monitoring, which is easily available in clinical practice, may improve treatment success and safety. The aim of the study was to describe posaconazole pharmacokinetics, and to evaluate the utility of therapeutic drug monitoring for therapy and prophylaxis in a cohort of adult patients. A fully validated chromatographic method was used to quantify posaconazole concentration in plasma collected from adult patients at the end of the dosing interval. Associations between variables were tested using the Pearson test. The Mann-Whitney test was used to probe the influence of categorical variables on continuous ones. A high inter-individual variability was shown. Of the 172 enrolled patients, among those receiving the drug by the oral route (N = 170), gender significantly influenced drug exposure: males showed greater posaconazole concentration than females (p = 0.028). This study highlights the importance of therapeutic drug monitoring in those with invasive fungal infections and its significant clinical implications; moreover we propose, for the first time, the possible influence of gender on posaconazole exposure.

Concepts: Pharmacology, Clinical trial, Male, Female, Biology, Gender, Sex, Itraconazole

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OBJECTIVE To determine the clinical manifestations of histoplasmosis in a large sample of dogs, compare outcomes achieved with fluconazole versus itraconazole, and identify variables available at the time of diagnosis with prognostic value. DESIGN Retrospective case series with nested cohort study. ANIMALS 79 dogs with confirmed histoplasmosis evaluated at 2 veterinary teaching hospitals from 1999 through 2015. PROCEDURES Medical records were reviewed and data extracted regarding clinical signs at evaluation, physical examination findings, clinical laboratory values, other diagnostic test results, treatments, and outcomes. Data were compared between antifungal agents used (fluconazole or itraconazole) and between other variables. RESULTS Various breeds were represented. Working and herding breeds had mostly disseminated histoplasmosis, and toy breeds had mostly the gastrointestinal form. The diagnosis was often achieved with noninvasive techniques, such as cytologic evaluation of rectal scrape samples (n = 24) or blood films (15). Clinical remission was achieved in 16 of 25 (64%) dogs receiving fluconazole and 17 of 24 (71%) dogs receiving itraconazole. No differences were identified between antifungal agents in survival, clinical remission, or disease relapse rates. Identified negative prognostic factors included Great Pyrenees breed, dyspnea, need for oxygen supplementation, icterus, palpable abdominal organomegaly, anemia, thrombocytopenia, hypercalcemia, high serum alkaline phosphatase activity, and hyperbilirubinemia, whereas diarrhea was a positive prognostic factor. CONCLUSIONS AND CLINICAL RELEVANCE Findings suggested that histoplasmosis should be considered in a sick dog of any breed in an endemic area. Clinical signs may be nonspecific. Diagnosis may often be possible with noninvasive and inexpensive tests. Either fluconazole or itraconazole may be an effective treatment option.

Concepts: Alkaline phosphatase, Medical diagnosis, Physical examination, Antifungals, Dog breed, Antifungal drug, Fluconazole, Itraconazole

0

Invasive fungal infections are an increasing cause of mortality and morbidity in high risk patient populations such as those on immunosuppressive therapy. Triazole antifungals are recommended for the prevention and treatment of such infections. The aim of this study was to develop and validate a simple, sensitive and robust LCMS/MS method for the simultaneous analysis in human plasma of three frequently used antifungal drugs: voriconazole, posaconazole, and itraconazole.

Concepts: Antifungals, Antifungal drug, Athlete's foot, Fluconazole, Griseofulvin, Triazole, Triazoles, Itraconazole

0

The fungistatic nature and toxicity concern associated with the azole drugs currently on the market have resulted in an increased demand for new azole antifungal agents for which these problematic characteristics do not exist. The extensive use of azoles has resulted in fungal strains capable of resisting the action of these drugs. Herein, we report the synthesis and antifungal activity of novel fluconazole (FLC) analogues with alkyl-, aryl-, cycloalkyl-, and dialkyl-amino substituents. We evaluated their antifungal activity by MIC determination and time-kill assay as well as their safety profile by hemolytic activity against murine erythrocytes as well as cytotoxicity against mammalian cells. The best compounds from our study exhibited broad-spectrum activity against most of the fungal strains tested, with excellent MIC values against a number of clinical isolates. The most promising compounds were found to be less hemolytic than the least hemolytic FDA-approved azole antifungal agent voriconazole (VOR). Finally, we demonstrated that the synthetic alkyl-amino FLC analogues displayed chain-dependent fungal membrane disruption as well as inhibition of ergosterol biosynthesis as possible mechanisms of action.

Concepts: Antifungals, Candidiasis, Ergosterol, Antifungal drug, Fluconazole, Azole, Azoles, Itraconazole