Sandbox 123456

Introduction

Noxafil, also known as posaconazole, was developed by Schering-Plough in the mid-2000s ^[1], and is a broad spectrum antifungal drug mainly used to treat fungal infections caused by Candida and Aspergillus species and derived from a similar triazole antifungal agent, Itraconazole. It is especially effective against filamentous fungi. Noxafil is also often used when other antifungal medicines are not able to be tolerated or if the patient is immunocompromised. Noxafil falls under the triazole class of antifungal drugs and thus works through inhibiting the biosynthesis of ergosterol in the fungal cell membrane, an essential factor that if inhibited, will lead to prevention of cell growth and ultimately death ^[2].

Function/Structure

• Chemical Formula: C₃₇H₄₂F₂N₈O₄
• Molecular Weight: 700.792 g/mol
• IUPAC name: 4-[4-[4-[4-[[(3R,5R)-5-(2,4-difluorophenyl)-5-(1,2,4-triazol-1-ylmethyl)oxolan-3-yl]methoxy]phenyl]piperazin-1-yl]phenyl]-2-[(2S,3S)-2-hydroxypentan-3-yl]-1,2,4-triazol-3-one

The primary component of Noxafil, is a potent, broad-spectrum antifungal drug. It was derived from a similar triazole antifungal agent, Itraconazole. The differences in structure are that the chlorine substituents in the aromatic ring on the left-hand side of the images are replaces with fluorines and that the triazolone sidechain is hydroxylated in the posaconazole structure^[3]. The extended side chain residues and hydrophobic contacts enhances antifungal activity by allowing tighter binding affinities to the in the active site of the CYP450-dependent enzyme lanosterol alpha-demthylase () ^[4][5]. The tighter binding affinity of posaconazole makes it less susceptible to be affected by mutations in the enzyme resulting in resistance of fungi ^[6]. The scene shows the crystal of sterol 14-alpha demethylase (CYP51) from a pathogenic yeast Candida albicans in complex with the antifungal drug posaconazole

Mechanism

When administered, posaconazole acts as a potent and broad-spectrum antifungal drug by binding to the heme cofactor through an ionic bond between a neutral nitrogen atom on posaconazole and an iron atom on heme (make green link) located in the active site of CYP450-dependent enzyme lanosterol alpha-demethylase (CYP51). This prevents biosynthesis of ergosterol and causes accumulation of toxic methylated sterol precursor, 14-alpha-methylsterol ^[4]. Ergosterol is an essential performs in fungal cells how cholesterol does in animal cells, making the cell membrane less permeable. Without it, the cells can no longer proliferate and eventually die because the cell membranes become “leaky”, releasing essential organic components from the cell’s interior and preventing it from performing normal cellular functions (citation?). In this way, posaconazole acts as a fungistatic against "Candida" species, and a fungicidal against "Asperigillus" species ^[6].

Pharmaceutical Information

Noxafil is available in several forms, such as an oral suspension, gastro resistant tablets, and a concentrate (EMA). The pharmacokinetics and pharmacodynamics of Noxafil, specifically posaconazole, have been studied extensively and continue to be studied today to further improve the overall effectivenes of the drug (link to https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4896980/ ). Some of the most commonly reported side effects include nausea, diarrhea, mild headaches, tiredness, and dizziness. Posaconazole has not been found to be have significant dose-limiting toxicity and has more reduced drug-drug interactions than many other antifungals (formularyjournal)

Relevance

Invasive fungal infections, commonly caused by "Candida" or "Aspergillus" species affect patients that are immunocompromised such as those with different pre-existing infections or more seriously for those with immunologically suppressing diseases like HIV/AIDS. "Candida" (thrush/Candidiasis) is the most common yeast pathogen that typically grows in human mucosal surfaces like the intestinal tract and causes pathology when it becomes overgrown. "Aspergillus" is the most common mold pathogen leading to invasive fungal infections, termed Aspergillosis, when it is acquired from the surrounding environment ^[7]. Noxafil oral suspension is the best form of treatment for invasive Candida and Aspergillus infections in patients 13 years and older who are severely immunocompromised. Noxafil is also more effective at preventing invasive fungal infections in immunocompromised patients when compared to other antifungal treatments (fluconazole and itraconazole)^[8] . Overall, Noxafil displays fewer cases of invasive fungal infections and is also a more affordable treatment for immunocompromised patients. (Add more & add citations). There has been a noticeable increase in the incidence of invasive fungal infections particularly within patients receiving chemotherapy and transplant recipients. These patients are extremely susceptible because of their compromised immune system and the pressures from antibiotic usage, which is why invasive fungal infections are on the rise with these medical advances. (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3155160/)

References

1. ↑ Posaconazole. (2011, December 12). Retrieved from https://www.acs.org/content/acs/en/molecule-of-the-week/archive/p/molecule-of-the-week-posaconazole.html?_ga=1.240614083.1136742914.1490798730
2. ↑ National Center for Biotechnology Information. PubChem Compound Database; CID=468595, https://pubchem.ncbi.nlm.nih.gov/compound/468595
3. ↑ Posaconazole. (n.d.). Retrieved from https://www.drugbank.ca/drugs/DB01263 Accession Number: DB01263
4. ↑ ^{4.0 4.1} Groll AH, Walsh TJ. Posaconazole: clinical pharmacology and potential for management of fungal infections. Expert Rev Anti Infect Ther. 2005 Aug;3(4):467-87. PMID:16107193 doi:http://dx.doi.org/10.1586/14787210.3.4.467
5. ↑ Nagappan V, Deresinski S. Reviews of anti-infective agents: posaconazole: a broad-spectrum triazole antifungal agent. Clin Infect Dis. 2007 Dec 15;45(12):1610-7. doi: 10.1086/523576. PMID:18190324 doi:http://dx.doi.org/10.1086/523576
6. ↑ ^{6.0 6.1} Sircar-Ramsewak,, F., Nicolau, D. P., & Kuti, J. L. (2005). Focus on posaconazole: A novel triazole antifungal for the treatment of invasive fungal infections. Formulary Journal - Modern Medicine Network
7. ↑ Soysal A. Prevention of invasive fungal infections in immunocompromised patients: the role of delayed-release posaconazole. Infect Drug Resist. 2015 Sep 9;8:321-31. doi: 10.2147/IDR.S65592. eCollection, 2015. PMID:26392781 doi:http://dx.doi.org/10.2147/IDR.S65592
8. ↑ Dekkers BG, Bakker M, van der Elst KC, Sturkenboom MG, Veringa A, Span LF, Alffenaar JC. Therapeutic Drug Monitoring of Posaconazole: an Update. Curr Fungal Infect Rep. 2016;10:51-61. Epub 2016 May 7. PMID:27358662 doi:http://dx.doi.org/10.1007/s12281-016-0255-4