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 Table of Contents  
REVIEW ARTICLE
Year : 2022  |  Volume : 6  |  Issue : 2  |  Page : 164-169

Itraconazole and posaconazole from antifungal to antiviral drugs


Department of Medical Laboratory Technology, College of Medical Technology, The Islamic University, Najaf, Iraq

Date of Submission22-Sep-2021
Date of Acceptance10-Dec-2021
Date of Web Publication17-Jun-2022

Correspondence Address:
Falah Hasan Obayes AL-Khikani
Department of Medical Laboratory Technology, College of Medical Technology, The Islamic University, Najaf
Iraq
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/bbrj.bbrj_242_21

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  Abstract 


The extended spectrum of antifungal triazole such as posaconazole (POS) and itraconazole (ITZ) shows the active efficacy for prophylaxis and treatment of an invasive fungal infection that may cause various infections such as respiratory diseases. Active azoles' derivatives, especially POS and ITZ, with high biological efficacy and low toxicity have made new advances in azoles' compounds as antimicrobials. Recently, some studies focused on the potential antimicrobial action of POS and ITZ against some viruses such as influenza A virus, Ebola virus, and enteroviruses. In general, new treatment research is needed due to the continued expansion of viral diseases and the exponential growth in mortality rates. By discussing the most recent information about the antiviral action of POS and ITZ against certain viral infections, as well as attempting to gain a deep understanding of the major properties, mechanisms of action, immune system responses, and antimicrobial activity of POS and ITZ, this review may serve as an impetus for researchers working in the field of medical microbiology and antiviral drug design. Since the antiviral activity of POS and ITZ against various viruses by different mechanisms of actions including enveloped viral infection, besides its other unique properties such as prophylactic feature and host immunomodulatory effects, as a result of our review, it appears that POS and ITZ, as effective antifungi drugs, may offer the possibility of developing a novel therapeutic alternative or synergistic treatment for certain viruses.

Keywords: Antimicrobial agents, antiviral drugs, itraconazole, posaconazole, viral infections


How to cite this article:
AL-Khikani FH. Itraconazole and posaconazole from antifungal to antiviral drugs. Biomed Biotechnol Res J 2022;6:164-9

How to cite this URL:
AL-Khikani FH. Itraconazole and posaconazole from antifungal to antiviral drugs. Biomed Biotechnol Res J [serial online] 2022 [cited 2022 Jul 7];6:164-9. Available from: https://www.bmbtrj.org/text.asp?2022/6/2/164/347707




  Introduction Top


The widespread therapeutic use of azole-based pharmaceutical drugs has given rise to multiple interest, and their research and development has become a very fast creation of an successful spotlight of infinite space.[1] Itraconazole (ITZ) and posaconazole (POS) belonged to triazoles that have a broad-spectrum antifungal agent, commonly used to prevent and treat several lung fungal infections and other medically significant fungi that cause superficial, subcutaneous, and systemic infections in humans.[2]

Since antifungal drugs are commonly used in patients who are to some extent immunocompromised, it is important to assess the potential effects of these therapies on the immune system.[3],[4],[5],[6] It has been proposed that the efficacy of some antifungal agents may be related to their capacity to induce cytokine production. This also confirmed that some antifungal drugs increase chemokine levels in the supernatants of human mononuclear cell cultures, such as CCL3 and CCL4.[7],[8]

ITZ appears to offer promise for the prevention of opportunistic fungal infections in high-risk individuals, such as women with recurrent vaginal candidiasis, immunodeficient patients with chronic candidiasis, AIDS patients, and patients on immunosuppressive medicines, according to certain research.[9] In patients undergoing chemotherapy for induction remission, POS provided effective prophylaxis against invasive fungal infections and was generally well tolerated.[10]

POS used to treat invasive fungal infections that include chromoblastomycosis, mucormycosis candidiasis, fusariosis, mycetoma, cryptococcosis, aspergillosis, and coccidioidomycosis.[11] Furthermore, ITZ drug has a broad range of activities on fungal infections in humans.[12] Besides the antifungal role of POS and ITZ, they have antiviral efficacy against some viruses by different mechanisms of actions.[13]

This review focuses on understanding challenges in viral infection management in the light by providing a rational and critical discussion on the available knowledge to gain a clear future vision, appropriate solutions, and effective strategies in virus treatment by revealing the possible promising role of POS and ITZ in the prophylactic and therapeutic branch.


  Materials and Methods Top


The databases of Scopus, EMBASE, PubMed, and Google Scholar were searched using the terms posaconazole, itraconazole, antiviral medicines, and the treatment option of viral infections to conduct a review article on the possible effects of POS and ITZ in treating viral infection. We looked over all available published articles till May 2021.


  General Features and Mechanisms Action of Posaconazole and Itraconazole Top


The antifungal agents such as ITZ and POS are two of the triazole that inhibits cytochrome P-450 (CYP)-dependent enzymes causing impairment of ergosterol synthesis, [Figure 1];[14] they have been used against blastomycosis, histoplasmosis, aspergillosis, cryptococcal meningitis, and aspergillosis which caused by invasive fungi.[15],[16]
Figure 1: Structure of itraconazole and posaconazole

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POS is produced from ITZ by combining chlorine substituents with phenyl ring flour, as well as hydroxylation of the side chain of triazolone, and these modifications increase the drug's effectiveness and spectrum of activity.[17]

A broad-spectrum POS C37H42F2N8O4 is the second-generation triazole compound with antifungal action against invasive infections by Candida and Aspergillus in severe immunocompromised individuals.[11] When compared to other antifungal drugs, these medicines have less side effects.[18],[19]

ITZ can be delivered intravenously or by mouth.[20] It has been investigated as an anticancer agent in patients with nonsmall cell lung cancer.[21] In nonblinded, randomized trial, in the acute stage of allergic bronchopulmonary aspergillosis, ITZ was effective in a considerable number of patients after 6 weeks and 3 months. The percent decline in IgE and the improvement in lung function after 6 weeks were similar in the two groups.[22] Few resistances reported to POS and ITZ, antibiotic resistance regarding one of the major problems in most common antibiotics.[23],[24],[25]

The mechanism action of systemic triazole antifungal derivate drugs POS and ITZ is inhibiting of fungal essential mediated of ergosterol by interacting with CYP enzymes, via inhibition of particular lanosterol 14α-demethylase that was substantial for biosynthesis in fungal membrane function and growth.[26]


  Effect of Posaconazole and Itraconazole on the Immune System Top


Some medicines, particularly antibiotics, have direct modifying effects on the immune system in addition to their antimicrobial actions, as evidenced by in vitro and in vivo investigations, such as some antifungals on the activities of animal and human macrophages, monocytes, and neutrophils.[27] In healthy male mice, ITZ has a strong immunomodulatory impact at a serum concentration of 1 g/mL (therapeutically attainable concentration), followed by a small pulmonary immunosuppressive tendency, suggesting an alternate, yet unexplored, mechanism of ITZ-mediated immunomodulation.[28]

Besides, ITZ administration in humans has shown an immunomodulatory effect, demonstrated by increasing levels of IL-12p40. ITZ's efficacy in treating the fungal infection may be attributed not only to the direct antifungal action but also to the activation of an immunomodulatory effect on host defense systems by controlling the production of cytokines in macrophages.[29] It should be complemented by a host immune response to remove the infectious agent.[30]

POS, a lipophilic antifungal medication, is absorbed through the membranes of human cells, including neutrophils and other leukocytes.[31] It reaches significant concentrations inside dHL-60 cells.[32] These cells may transmit POS to Aspergillus fumigatus hyphae after being touched, and they have good antifungal activity against A. fumigatus in vitro.

Treatment with POS -charged dHL-60 cells reduced lung fungal load and even eliminated certain mice infections in an invasive pulmonary aspergillosis neutropenic mouse model. These data suggest that neutrophils may be an efficient delivery route for POS.[33]

Various concentrations of POS in varied peripheral blood compartments may play a role in different POS concentrations detected in plasma. The intracellular absorption of the azoles tends to be passive and dependent upon the composition of the extracellular media. Therefore, the intracellular and consequently the extracellular concentrations would automatically adjust upon reaching multiple body compartments with distinct extracellular media compositions. POS intracellular concentrations in mononuclear peripheral blood cells (PBMCs) and polymorphonuclear neutrophils (PMNs) were found to be much higher than the plasma concentration.[34] POS loading at a high intracellular level may aid competent phagocytes in their pathogen-killing duties.[35]


  Posaconazole and Itraconazole as Prophylactic Drugs Top


As for other antifungal drugs, questions exist for respect to the possible development of resistance with POS to broad-spectrum antifungal prophylaxis. Nevertheless, POS and ITZ are valuable emerging options for use in immunocompromised patients as prophylaxis against invasive fungal infections. For prophylaxis against aggressive Aspergillus and Candida infections, oral POS suspension given three times daily is suggested in patients at high risk of contracting such infections due to immunosuppression.[36]

It is a favorable antifungal agent to be used prophylactically in hematologic patients aged 13 years or less, administering as an oral suspension in a dosage of 120 mg/m2 tid results in sufficient POS plasma exposure, without significant reverse status,[37] also it has been tried as prophylactic agent following lung transplantation to avoid the incidence of invasive fungal infections.[38]

Otherwise, experiments found a modification in the glycosylation of FcπR in monocytes and neutrophils from Gram-negative-infected persons.[39] Since phagocytosis plays a crucial role in the elimination of pathogens, apoptotic cells, and tumor cells, these indicating an importance for ITZ use, especially in vulnerable populations such as those undergoing chemotherapy and who are already immunocompromised.[40]

Administration of POS oral solution has been observed to result in considerably higher intracellular concentrations in PBMCs and PMNs compared with those in plasma, and POS is found in red blood cells, but to a lesser degree. Such intracellular concentrations will affect POS's distribution, likely explaining in part its superior prophylactic efficacy.[35]

According to clinical evidence, POS is effective for prophylaxis against many invasive fungal diseases, particularly aspergillosis, in high-risk individuals, 200 mg three times daily for prophylaxis, 800 mg in two or four separated doses for the treatment of invasive fungal infections, and 100 mg daily for the treatment of oropharyngeal candidiasis.[41],[42]


  Posaconazole and Itraconazole as Antiviral Drug Top


Since viral infections are common in the world, which is difficult to control, especially RNA viruses with constantly changing, so some studies have conducted a series of experiments on some of the treatments available for re-use to treatment or prevention of viruses.[43],[44],[45],[46]

Both medicines suppress the growth of the influenza A virus (IAV) in a cell culture model without causing cytotoxicity. The method of action might be dependent on a variety of targets, including cellular induction imbalance and priming of the interferon (IFN) response.[47] Both antifungals are inhibitors of Niemann–Pick C1 (NPC1), a lysosome membrane protein required for the export of cholesterol from Low density lipoprotein (LDL) cells via receptor mediated endocytosis to lysosomes.[48] Indeed, there has been a significant increase in LE/L cholesterol rates in cells treated with ITZ and POS, and the acidic pH present in elevated LE/L rates is a key factor in the fusion of the viral envelope with endosomal membranes and the subsequent transition of the viral genome to the cytoplasm of the host cell[49].Other implication stages are activated by pH 6.0 and K + ion influx when exposure to pH below 6.5 causes a conformation change in the linker sequence and the C-terminal region of M1 protein. It induces further alterations in M1 and a loss of stability in the bundle of viral ribonucleoproteins, both of which are required for effective uncoating and infection of prime IAV cores.[50]

Mechanistically, the potential specificity of the antiviral effect of ITZ which possesses high antiviral effect compared with POS may due to the releasing high amounts of IFNs. Generally speaking, IFN-induced gene products are predominantly virus-selective despite picomolar concentrations of IFN but are already adequate to induce priming and thus an improved immune response to microbial challenges, providing protection against a wide range of unrelated RNAs at least in macrophages at that time.[51] ITZ and POS are thus attractive prospective therapeutics in the treatment of influenza and other enveloped viruses.

In the case of enteroviruses (which are nonenveloped icosahedral RNA viruses), ITZ, which was discovered to be an effective inhibitor of EV71 replication in the low micromolar range, also inhibited other enteroviruses such as coxsackievirus B3, coxsackievirus A16, enterovirus 68, and poliovirus 1. Time-of-addition and transient-replicon assays revealed that ITZ targeted a step involved in RNA replication or polyprotein processing.[52]

Another study showed that ITZ is a novel inhibitor of a wide range of viruses, including hepatitis C virus (HCV) and poliovirus, targeting a novel protein (oxysterol-binding protein) that plays a key role in lipid transfer. ITZ also inhibited replication of the Saffold virus, a human cardiovirus, and ITZ does not inhibit the translation of the virus genome because luciferase levels were not affected. However, at later points, the production of luciferase by both replicates decreased, demonstrating that ITZ significantly affects RNA replication.[53]

ITZ is also a leading contender for the development of antiviral medicines against Echovirus 30 that may be employed in the early phases of the virus's replication. Echovirus 30 is a picornaviridae virus with a lot of genomic diversity.[54]

Two sets of combinations of three medicines, toremifene–mefloquine–POS and toremifene–clarithromycin–POS, efficiently blocked Ebola virus (EBOV) entrance and further validated to suppress live EBOV infection, according to the Food and Drug Administration -approved pharmaceuticals. The functional inhibitions of (NPC1), acid sphingomyelinase, and lysosomal calcium release established the mechanisms of action of these medicines. POS provides a viable synergistic drug candidate for clinical development within the combination of three treatments, inhibiting EBOV entrance with a more powerful impact than other medicines at the late endosome and POS lysosome phases.[55]

Potent inhibitors of Parechovirus A3 activity have been discovered as ITZ and POS. ITZ and POS may target a different pathway than recognized EV inhibitors enviroxime and 25-hydroxycholesterol. Par A3 is an emerging viral illness of the juvenile central nervous system. POS might be a useful tool in the development of PeV-A3 antiviral treatment. By directly targeting the capsid and interfering with virus–cell interactions, POS prevents PeV-A3 infection. The activity effect of these both drugs POS and ITZ may give an abroad antiviral effective on the single strand genomic virus.[56]

A combination of antiviral drugs also has a role in inhibition replication of multiple serotypes of Dengue virus and the related Flavivirus Zika virus, leads to reduced viral single-strand RNA replication, and not a translation of the viral genome.[57]

Nucleoside analogs in the form of adenine or guanine derivatives that block viral RNA synthesis in a broad range of RNA viruses, including human coronaviruses, by targeting RNA-dependent polymerase, are currently being studied as potential repurposing candidates for 2019-nCoV for the management of viral infection.[58] Remdesivir (an adenosine analog) causes EBOLA and other RNA viruses, including coronavirus, to terminate prematurely.[59] Remdesivir and chloroquine are highly successful in regulating in vitro 2019-nCoV infection, chloroquine is known to prevent viral infection by growing the endosomal pH needed for virus/cell fusion and by interacting with the glycosylation of severe acute respiratory syndrome coronavirus cell receptors.[60],[61],[62],[63],[64] As ITZ and POS have been reported, cholesterol exports from lysosomes have increased rates of LE/L cholesterol in cells and acidic pH, resulting in inhibiting uncoating and host cell infection.[47],[48]

IFN alfa-2a and-2b may be used to induce endogenous antiviral responses in patients diagnosed with 2019-nCoV, and experiments involving IFN initiated comparative efficacy and protection of ribavirin + IFN-alpha, such as an accepted anti-HCV combination study for IFN plus ribavirin in patients with mild-to-moderate coronavirus pneumonia.[65] In noninfected cells, the cholesterol imbalance promotes the expression of both IFN and IFN-stimulated genes the greatest.[51] Furthermore, the current review mentioned that cholesterol levels may increase in cells that treated by ITZ and POS.[47]

From previous studies, ITZ and POS could be an effective drug against many RNA viral infections multiple mechanisms, including inhibitions of Nicotinic acid adenine dinucleotide phosphate (NAADP)-stimulated lysosomal calcium release, NPC1 protein function, increased cholesterol level, acidic pH, and stimulating IFN.


  Conclusions Top


Viral infections in human are a continuous threat as a global public health emergency, which requires a collaborative higher level of responsive measures from all countries. Efficient communication, collaboration, and cooperation in implementing scientific evidence-based measures on the personal, national, and international levels are crucial. Urgent clinical trials on potential drugs for these infections are required; more research is urgently needed to better understand the better treatment.

ITZ and POS are ready for use and accessible. We noticed that some viruses that they targeted have envelopes and RNA nucleic acid; however, all may be similar in complexity and contain specific virus proteins that can be targeted by the medication protocol. Since ITZ and POS are promising antifungal agents with limited resistance, as well as broad-spectrum action against various microbial illnesses, their use in modern branches and novel applications is required.

As is well known, the immune system plays a critical role in viral elimination and body defense during viral infection, so using an antibiotic that can enhance immune response, activate innate immunity, and stimulate pro-inflammatory responses, such as ITZ and POS, can help protect against viral invasion. It has significant immunomodulatory properties through inducing pro-inflammatory responses, which has been linked to protective benefits. During infection, ITZ and POS act not only on the pathogen but also on the host. This issue is of particular interest because patients affected by viral infections may be immunocompromised. As well as prophylactic properties of these drugs can be utilized for previous protection against viral infections by providing high intracellular concentrations in PBMCs and PMNs. These intracellular concentrations can influence the distribution of drugs, enhancing prophylactic effectiveness.

According to the previous findings regarding the efficacy of ITZ and POS to various viral infection besides unique properties of ITZ and POS as prophylactic therapy and treating a viral infection, thus, using these drugs instead of some current therapeutic options in patients with certain viral infections may give reduced side effects and may be promising branch to be evaluated clinically, this finding demands more studies in medical laboratories and clinical trials.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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