Orungal Review Article
Orungal (Itraconazole) also known as Sporanox is a drug used in the treatment of fungal infections, such as aspergillosis, blastomycosis, histoplasmosis, and fungal infection localized to the toenails and fingernails (onychomycosis).
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Orungal has a wider spectrum of activity than Ketoconazole. It is useful for the treatment of tinea versicolor, a superficial infection caused by Malassezia furfur; for the treatment of cutaneous ringworm infections caused by Epidermophyton, Trichophyton and Microsporum species; for the treatment of sporotrichosis, a subcutaneous infection caused by Sporothrix shenckii; for the treatment of primary systemic fungal infections (those that cause disease on healthy individuals) like valley fever caused by Coccidioides immitis, histoplasmosis or spelunkerís disease caused by Histoplasma capsulatum, North and South American Blastomycoses caused by Blastomyces dermatitidis and Paracoccidioides brasiliensis respectively; and opportunistic systemic mycoses (those that only cause disease if the patient is immunocompromised) caused Aspergillus, Candida, and Cryptococcus neoformans. Aside from that, it is also effective for the treatment of leishmaniasis, caused by Leishmania spp.
Orungal (Itraconazole) is an antifungal drug belonging to the triazole drug class. It is the most potent among all azole type antifungal agent. Its molecular formula is C35H38Cl2N8O4 and its structural formula is:
Orungal is the azole of choice for dimorphic fungi like Histoplasma capsulatum, Blastomyces dermatitidis, and Sporothrix shenckii. It is used extensively for dermatophytes and onchomycoses.
The Triazoles: Mechanism of Action
Azole is an antifungal drug class. The term azole pertains to the azole ring common to the structures of the drugs belonging to this class. They can be further classified into two, according to the number of Nitrogen substitution on the azole ring Ė the imidazoles which contain 2 N atoms, and the triazoles which contain 3 N atoms.
Imidazole (left) vs Triazole (right)
Azoles exert their antifungal activity by inhibiting the synthesis of ergosterol of fungi. Ergosterol is a fungal sterol (human counterpart is cholesterol), which is an integral part of their cell membrane. Azoles halt ergosterol synthesis by inhibiting a fungal cytochrome P450 (CYP450) enzyme called C14-α-sterol demethylase.
When ergosterol levels are depleted, the fungal cell membrane becomes more permeable, leading to disruption and eventual cell death. Aside from that, ergosterol precursors like 14-α-methylsterols accumulate. These methyl sterols are highly toxic to fungi, disrupting the packing of acylchains of phospholipids and impairing membrane bound enzyme systems. This leads to the inhibition of fungal cell growth.
Triazoles have two distinct advantages over imidazoles. First, they are metabolized more slowly, making them longer acting than imidazoles. Second, triazoles have higher selectivity for human CYP450 enzymes, resulting to lesser side effect and interaction.
For example, ketoconazole, a widely used imidazole, is known to affect steroid synthesis. Orungal does not affect steroid synthesis. Aside from that, interaction with other drugs is much lesser with Orungal than ketoconazole due to higher selectivity for fungal CYP450 enzymes. Triazoles are considered superior to imidazoles. Drugs currently under development are mostly triazole types.
Orungal is the most potent among all azoles. It is an effective drug that even its metabolite, hydroxyl-itraconazole, is biologically active. Several studies have proven the effectiveness of this drug clinically. In a study made by Grant and Clissold (1989), it was found that Orungal was extremely effective in treating a wide variety of fungal infections. They also stated that more than 80% of patients with dermatophyte or yeast infections are cured with Orungal. This was supported by Haria, Bryson and Goa (1996).
Orungal is frequently compared to Amphotericn B, another antifungal agent. In a study by Denning, et al., (1993) they found that Orungal is effective as an alternative treatment for aspergillosis, where Amphotericin B was only approved. In a study by Boogaerts, et al. (2001), they found that Orungal has atleast equally efficacy as empirical treatment for neutropenic patients with cancer.
In a study done by Chong and colleagues (2007), they found that Orungal has a strong inhibitory effect on angiogenesis. They found that Orungal inhibits endothelial cell cycle progression in animal models by blocking the vascular endothelial growth factor and basic fibroblast growth factor-dependent angiogenesis. This two growth factors are necessary for cancer progression. Chong and colleagues proposes that C14-α-sterol demethylase is necessary for cancer, and its inhibition by Orungal is responsible for its anti cancer effects.
In a recent study made by Kim et al., (2010), they found that Orungal also act on a different mechanism aside from C14-α-sterol demethylase inhibition. In their study, they found that Orungal is a potent antagonist of the Hedgehog signaling pathway. This signaling pathway is a mechanism that directs the growth of cells. One of the etiologies of cancer is the malfunctioning of the Hedgehog signaling pathway. Thus, antagonizing or inhibiting this pathway is a rational approach to treating cancer. Kim and colleagues had found in animal models that Orungal can potentially be used for cancer. Aftab and colleagues (2011) had found that Orungal, in vivo, is effective in inhibiting non small cell lung cancer cells.
Orungal is well tolerated. Some of the well known adverse effects of the drug are elevation of liver enzymes, fever, shortness of breath, edema, weight gain, decreased hearing, numbing sensation, painful urination, nausea and other gastrointestinal disturbances. Allergic reactions like swelling of the face, lips, tongue, hives, or difficulty in breathing may also occur. These reactions require immediate medical attention.
Though it has a higher selectivity for fungal CYP450, Orungal still has an effect human CYP450 enzymes, resulting to an increase on the concentration of another drug. Orungal itself is metabolized by different class of CYP450 enzyme, and drugs inhibting or inducing the said enzyme results to an increase or decrease in its plasma concentration, respectively. Below shown the list of drugs with known interaction with Orungal.
Drugs that increase their concentration: Alfentanil, Alprazolam, Amprenavir, Atorvastatin, Buspirone, Busulfan, Cerivastatin, Cisapride, Cyclophosphamide, Cyclosporine, Delavirdine, Diazepam, Digoxin, Dihydropyridine, Calcium, Channel, Blockers, Docetaxel, Haloperidol, Indinavir, Loratidine, Lovastatin, Methylprednisolone, Midazolam, Phenytoin, Pimozide, Quinidine, Ritonavir, Saquinavir, Sildenafil, Simvastatin, Sirolimus, Sulfonylureas, Tacrolimus, Triazolma, Trimetrexate, Verapamil, Vinca, alkaloids, Warfarin.
Orungal Concentration Decreased: H2-receptor blockers, Proton Pump Inhibitors, Carbamazepine, Isoniazid, Nevirapine, Phenobarbital, Phenytoin, Rifampin, Rifabutin, St. Johnís wort.
Orungal Concentration Increased: Amprenavir, Clarithromycin, Grapefruit Juice, Indinavir, Lopinavir, Ritonavir.
A positive interaction between terbinafine, an allylamine antifungal which also acts on ergosterol synthesis (but on a different enzyme), and Orungal was found in vitro. It was found to be effective against Candida albicans (Barchiesi, et al., 1997) and Scedosporium prolificans (Meletiadis, et al., 2000). Clinical significance is yet to be proven.
Aftab, B. T., Dobromilskaya, I., Liu, J. O., et al., 2011, Itraconazole inhibits angiogenesis and tumor growth in non-small cell lung cancer
Barchiesi, F., et al., 1997, In vitro activities of terbinafine in combination with fluconazole and itraconazole against isolates of Candida albicans with reduced susceptibility to azoles, Antimicrob Agents Chemother. 41:1812-14
Boogaerts, M., Winston, D. J., Bow, E. J., et al., Intravenous and Oral Itraconazole versus Intravenous Amphotericin B Deoxycholate as Empirical Antifungal Therapy for Persistent Fever in Neutropenic Patients with Cancer Who Are Receiving Broad-Spectrum Antibacterial Therapy
A Randomized, Controlled Trial
Chong, C. R., Xu, J., Lu, J., et al., 2007, Inhibition of angiogenesis by the antifungal drug itraconazole
Denning, D. W., Lee, J. Y., et al., 1993, NIAID mycoses study group multicenter trial of oral itraconazole therapy for invasive aspergillosis
Grant, S. M., and Clissold, S. P., Itraconazole. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in superficial and systemic mycoses
Haria, M., Bryson, H. M., and Goa, K. L., 1996, Itraconazole. A reappraisal of its pharmacological properties and therapeutic use in the management of superficial fungal infections
Kim, J., Tanq, J. Y., Kim, J., et al., 2010, Itraconazole, a commonly used antifungal that inhibits Hedgehog pathway activity and cancer growth
Meletiadis, J., et al., 2000, In vitro interaction of terbinafine with itraconazole against clinical isolates of Scedosporium prolificans, Antimicrob Agents Chemother. 44:470-472
Olkkola, K. T., Backman, J. T., and Neuvonen, P. J., 1994, Midazolam should be avoided in patients receiving the systemic antimycotics ketoconazole or itraconazole
Sweetman, S. C. ed., 2009, Martindale, The complete drug reference 36th ed, London: Pharmaceutical Press, p. 536-538
Teemu, K., Kivisto, K. T., and Neuvonen, P. J., 1998, Effect of itraconazole on the pharmacokinetics of atorvastatin
Varhe, A., Olkkola, K. T., and Neuvonen, P. J., 1994, Oral triazolam is potentially hazardous to patients receiving systemic antimycotics ketoconazole or itraconazole
Orungal Review Article