SciCombinator

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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

28

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

0

This is an observational-retrospective study comparing the real-world outcomes associated with posaconazole vs. itraconazole as prophylaxis treatments. Two hundred and ninety-three patient admissions attributable to 174 patients were included in the study. Patients were treated with itraconazole (n = 114 admissions; 39%) or posaconazole (n = 179; 61%). Antifungal prophylaxis failure (APF) due to treatment-related adverse events (in 34 out of 293 patient admissions; 11.6%) was more frequent in the posaconazole group (6.1% vs. 15.1%; P = 0.024). There were 9 patient admissions for episodes of APF due to probable/proven breakthrough fungal infection (primary endpoint): 6 and 3 in the itraconazole and posaconazole group, respectively (5.3% vs. 1.7%; P = 0.095). All of them were associated with invasive pulmonary aspergillosis (IPA). APF was more frequent with itraconazole (65% vs. 30%; P < 0.001), along with failure due to possible/probable/proven IPA (25% vs. 10%; P = 0.002) and overall failure by any of the three different causes of prophylaxis failure (70% vs. 38%; P < 0.001). In agreement with clinical trial data, this real-world evidence supports the use of posaconazole over itraconazole in AML or MDS patients undergoing intensive chemotherapy. This article is protected by copyright. All rights reserved.

Concepts: Clinical trial, Leukemia, Acute myeloid leukemia, Aspergillosis, All rights reserved, Copyright, Myelodysplastic syndrome, Itraconazole

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Isavuconazole is a new triazole approved for the treatment of invasive aspergillosis. We investigated isavuconazole MIC distributions, isavuconazole MIC correlations with those of other azoles and pharmacodynamics of isavuconazole in low-level resistant Aspergillus fumigatus isolates.

Concepts: Aspergillosis, Aspergillus, Aspergillus fumigatus, Itraconazole

0

Given the limitations of current antileishmanial drugs and the utility of oral combination therapy for other infections, developing an oral combination against visceral leishmaniasis should be a high priority. In vitro combination studies with DB766 and antifungal azoles against intracellular L. donovani showed that posaconazole and ketoconazole, but not fluconazole, enhanced DB766 potency. Pharmacokinetic analysis of DB766-azole combinations in uninfected Swiss Webster mice revealed that DB766 exposure was increased by higher posaconazole and ketoconazole doses, while DB766 decreased ketoconazole exposure. In L. donovani-infected BALB/c mice, DB766-posaconazole combinations given orally for five days were more effective than DB766 or posaconazole alone. For example, 81 ± 1% (mean ± standard error) inhibition of liver parasite burden was observed for 37.5 mg/kg DB766 + 15 mg/kg posaconazole, while 37.5 mg/kg DB766 and 15 mg/kg posaconazole administered as monotherapy gave 40 ± 5% and 21 ± 3% inhibition, respectively. Combination index (CI) analysis indicated that synergy or moderate synergy was observed in six of nine combined dose groups while the other three were nearly additive. Liver concentrations of DB766 and posaconazole increased in almost all combination groups compared to monotherapy groups, although many increases were not statistically significant. For DB766-ketoconazole combinations evaluated in this model, two were antagonistic, one displayed synergy, and one was nearly additive. These data indicate that the efficacy of DB766-posaconazole and DB766-ketoconazole combinations in vivo is influenced in part by the pharmacokinetics of the combination, and that the former combination deserves further consideration in developing new treatment strategies against visceral leishmaniasis.

Concepts: Pharmacology, Statistics, In vivo, In vitro, Pharmacokinetics, Antifungals, Antifungal drug, Itraconazole

0

Sporotrichosis is an emerging chronic, granulomatous, subcutaneous, mycotic infection caused by Sporothrix species. Sporotrichosis is treated with the azole drug itraconazole as ketoconazole is ineffective. It is a well-known fact that azole drugs act by inhibiting cytochrome P450 monooxygenases (P450s), heme-thiolate proteins. To date, nothing is known about P450s in Sporothrix schenckii and the molecular basis of its resistance to ketoconazole. Here we present genome-wide identification, annotation, phylogenetic analysis and comprehensive P450 family-level comparative analysis of S. schenckii P450s with pathogenic fungi P450s, along with a rationale for ketoconazole resistance by S. schenckii based on in silico structural analysis of CYP51. Genome data-mining of S. schenckii revealed 40 P450s in its genome that can be grouped into 32 P450 families and 39 P450 subfamilies. Comprehensive comparative analysis of P450s revealed that S. schenckii shares 11 P450 families with plant pathogenic fungi and has three unique P450 families: CYP5077, CYP5386 and CYP5696 (novel family). Among P450s, CYP51, the main target of azole drugs was also found in S. schenckii. 3D modeling of S. schenckii CYP51 revealed the presence of characteristic P450 motifs with exceptionally large reductase interaction site 2. In silico analysis revealed number of mutations that can be associated with ketoconazole resistance, especially at the channel entrance to the active site. One of possible reason for better stabilization of itraconazole, compared to ketoconazole, is that the more extended molecule of itraconazole may form a hydrogen bond with ASN-230. This in turn may explain its effectiveness against S. schenckii vis-a-vis resistant to ketoconazole. This article is part of a Special Issue entitled: Cytochrome P450 biodiversity and biotechnology, edited by Erika Plettner, Gianfranco Gilardi, Luet Wong, Vlada Urlacher, Jared Goldstone.

Concepts: DNA, Cytochrome P450, Taxonomic rank, Fungal diseases, Sporothrix schenckii, Azole, Itraconazole, Sporotrichosis