Itraconazole intravenous

Future Antimycotics for Systemic Treatment. Two new antimycotics for systemic use have now reached the stage of clinical development. The first is a triazole and fluoride analogue of itraconazole. This compound (saperconazole) is extremely active 2i 2cm.%. Jisperpillus spp. and slightly more soluble. Consequentiy, intravenous adruinistration might be possible (34). The second molecule is terbinafine [91161 -71 -6] an aHylamine, C21H25N, that appears to be particularly active against dermatophytes, just like topical naftifine (35). 

Twenty percent of HIV-infected patients develop fluconazole-resistant Candida albicans isolates after repeated exposure to fluconazole.33 To treat fluconazole-resistant oropharyngeal candidiasis, daily itraconazole for 2 to 4 weeks may be used. Oral itraconazole solution exhibits a mycological cure rate of 88% and a clinical cure rate of 97% in immunocompromised patients.34 Fluconazole-resistant esophageal candidiasis should be treated with intravenous amphotericin B or caspofungin. 

Mucocutaneous candidiasis is generally not life-threatening nor invasive and can be treated with topical azoles (clotrimazole troches), oral azoles (fluconazole, ketoconazole, or itraconazole), or oral polyenes (such as nystatin or oral amphotericin B). Orally administered and absorbed azoles (ketoconazole, fluconazole, or itraconazole solution), amphotericin B suspension, intravenous caspofungin, or intravenous amphotericin B are recommended for refractory or recurrent infections.20... 

Although more invasive, esophageal candidiasis does not typically evolve into a life-threatening infection. However, topical therapy is ineffective. Azoles (fluconazole, itraconazole solution, or voriconazole), echinocandins, or intravenous amphotericin B (in cases of unresponsive infections) are effective treatment options. Parenteral therapy should be used in patients who are unable to take oral medications.20... 

Itraconazole 200 mg/day orally for 4 days markedly reduced the clearance and increased the half-life of intravenous methylprednisolone from 2.1 to 4.8 hours in a double-blind, randomized, two-phase, crossover study in nine healthy volunteers (SEDA-23,430 480). The volume of distribution was not affected. The mean morning plasma cortisol concentration during the itraconazole phase, measured 24 hours after methylprednisolone, was only 9% of that during the placebo phase (11 versus 117 ng/ml). 

Itraconazole, given orally increased oral prednisolone concentrations by only 24% (481) but increased intravenous dexamethasone concentrations 3.3-fold and oral dexamethasone 3.7-fold (482). 

Varis T, Kivisto KT, Backman JT, Neuvonen PJ. Itraconazole decreases the clearance and enhances the effects of intravenously administered methylprednisolone in healthy volunteers. Pharmacol Toxicol 1999 85(l) 29-32. 

Slain D, Rogers PD, Cleary JD, Chapman SW. Intravenous itraconazole. Ann Pharmacother. 2001 35 720-729. 

Voriconazole is the newest triazole to be licensed in the USA. It is available in intravenous and oral formulations. The recommended dosage is 400 mg/d. The drug is well absorbed orally, with a bioavailability exceeding 90%, and exhibits less protein binding than itraconazole. Metabolism is predominantly hepatic, but the propensity for inhibition of mammalian P450 appears to be low. Observed toxicities include rash, elevated hepatic enzymes, and transient visual disturbances. 

Olkkola KT, Ahonen J, Neuvonen PJ. The effect of systemic antimycotics, itraconazole and fluconazole, on the pharmacokinetics and pharmacodynamics of intravenous and oral midazolam. Anesth Analg 1996 82 511-516. 

Donnelly, J.P. Mouton, J.W. Blijlevens, N.M.A. Smiets, A. Verweij, P.E. Depauw, B.E. Pharmacokinetics of a 14 day course of itraconazole nanocrystals given intravenously to allogenic haematopoietic stem cell transplant (HSCT) recipients. Abstr. Intersci. Conf Antimicrob. Agents Che-mother. 2001, 41, 5. 

Hydroxypropyl-p-cyclodextrin is also a water-soluble cyclodextrin. Itraconazole is water insoluble and is solubilized in Sporanox to lOmg/ml in an aqueous pH 4.5 solution with 40% hydroxypropyl-p-cyclodextrin, and is administered by IV infusion after a two-fold dilution with saline. The dose of Sporanox is up to 20 ml, which is 8,000 mg of hydroxypropyl-p-cyclodextrin per dose, representing the estimated maximum amount administered intravenously. 

Boogaerts M, Winston DJ, Bow EJ, Garber G, Reboli AC, Schwarer AP, Novitzky N, Boehme A, Chwetzoff E, De Beule K Itraconazole Neutropenia Study Group. 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. Ann Intern Med 2001 135(6) 412-22. 

Oral itraconazole solution has been compared with intravenous/oral fluconazole for the prevention of fungal infections in a randomized, controlled trial in adult hver transplant recipients, who were randomized to receive... 

The interaction of itraconazole 200 mg orally od for 4 days with a single intravenous dose of racemic bupivacaine (0.3 mg /kg given over 60 minutes) has been examined in a placebo-controlled crossover study in 10 healthy volunteers (65). Itraconazole reduced the clearance of i -bupivacaine by 21% and that of 5-bupivacaine by 25%, but had no other significant effects on the pharmacokinetics of the enantiomers. Reduction of bupivacaine clearance by itraconazole is likely to increase steady-state concentrations of bupivacaine enantiomers by 20-25%, and this should be taken into account in the concomitant use of itraconazole and bupivacaine. 

Itraconazole markedly increases both systemic exposure to dexamethasone and its effects. This interaction has been investigated in a randomized, double-blind, placebo-controlled, crossover study (94). Eight healthy volunteers took either oral itraconazole 200 mg od or placebo for 4 days. On day 4, each subject was given oral dexamethasone 4.5 mg or intravenous dexamethasone sodium phosphate 5.0 mg. Itraconazole reduced the systemic clearance of intravenous dexamethasone by 68%, and increased its AUC and prolonged its half-life more than three-fold the AUC of oral dexamethasone was increased nearly four-fold and its half-life nearly three-fold. Morning plasma cortisol concentrations at 47 and 71 hours after dexamethasone were significantly lower after itraconazole than placebo. 

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