Dose Of Itraconazole Research Articles

Itraconazole Induced Torsade De Pointes in a Patient Receiving Methadone Substitution Therapy

Issues. Methadone, a pharmacological agent used to treat heroin dependence is relatively safe, but may cause cardiac arrhythmias in the concurrent presence of other risk factors. Approach and Key Findings. This case report highlights the risk of Torsade de Pointes, a life-threatening cardiac arrhythmia, in a heroin-dependent patient receiving methadone substitution therapy who was prescribed itraconazole for vaginal thrush. The patient presented to the accident and emergency department for chest discomfort and an episode of syncope following two doses of itraconazole (200 mg). Electrocardiogram monitoring at the accident and emergency department showed prolonged rate-corrected QT interval leading to Torsade de Pointes. The patient was admitted for cardiac monitoring, and electrocardiogram returned to normal upon discontinuation of methadone. Implication. This cardiac arrhythmia was most likely as a result of a drug interaction between methadone and itraconazole because the patient presented with no other risk factors. Conclusion. Given the benefits of methadone as a substitution treatment for heroin-dependent individuals, the association between methadone and cardiac arrhythmias is of great concern. Physicians treating heroin-dependent patients on methadone substitution therapy should therefore be cautious of the potential risk of drug interactions that may lead to fatal cardiac arrhythmias.

Itraconazole‐induced Torsade de Pointes in a patient receiving methadone substitution therapy

Methadone, a pharmacological agent used to treat heroin dependence is relatively safe, but may cause cardiac arrhythmias in the concurrent presence of other risk factors. APPROACH AND KEY FINDINGS: This case report highlights the risk of torsade de pointes, a life-threatening cardiac arrhythmia, in a heroin-dependent patient receiving methadone substitution therapy who was prescribed itraconazole for vaginal thrush. The patient presented to the accident and emergency department for chest discomfort and an episode of syncope following two doses of itraconazole (200 mg). Electrocardiogram monitoring at the accident and emergency department showed prolonged rate-corrected QT interval leading to torsade de pointes. The patient was admitted for cardiac monitoring, and electrocardiogram returned to normal upon discontinuation of methadone. This cardiac arrhythmia was most likely as a result of a drug interaction between methadone and itraconazole because the patient presented with no other risk factors. Given the benefits of methadone as a substitution treatment for heroin-dependent individuals, the association between methadone and cardiac arrhythmias is of great concern. Physicians treating heroin-dependent patients on methadone substitution therapy should therefore be cautious of the potential risk of drug interactions that may lead to fatal cardiac arrhythmias.

The Role of Itraconazole in Recalcitrant Fungal Sinusitis

Oral itraconazole is an antifungal that has been shown to be of benefit to patients with allergic bronchopulmonary aspergillus (ABPA). It is hypothesized that itraconazole may similarly benefit patients with allergic fungal sinusitis (AFS), a disease similar to ABPA. This study was designed to evaluate the therapeutic response of itraconazole in patients with refractory chronic fungal sinusitis who have failed maximal medical and surgical therapy. A retrospective chart review was performed of 23 patients with AFS and nonallergic eosinophilic fungal sinusitis treated with oral itraconazole. Charts were reviewed for patient demographics, comorbidities, allergies, fungal cultures, type of surgery performed, and amount of oral steroids used before and after itraconazole. All patients were given a 6-month dose of itraconazole (100 mg b.i.d.) when recurrence developed after surgery. Time to next recurrence, change in oral steroid use, and outcomes were noted. Liver function tests were taken at monthly intervals while on itraconazole. Twenty-three patients, 13 men and 10 women, were started on oral itraconazole for recurrent fungal sinusitis. Nineteen patients responded to the medication with a decrease in symptoms and fungal mucin/polyps on endoscopy. Three patients had to stop because of elevated liver enzymes. In the remaining 16 patients a decrease in oral steroid use was noted. In addition, 11 of the 16 patients are disease free to date at a mean follow-up of 15.7 months. No permanent complications occurred from the use of the medication. Oral itraconazole may be of benefit to those patients with recalcitrant fungal sinusitis who have failed maximal medical and surgical therapy. Itraconazole may prolong the time to next recurrence and may enable the patient to significantly decrease or stop oral steroids.

Chromoblastomycosis: combined treatment with pulsed itraconazole therapy and liquid nitrogen cryotherapy

Three patients with histology- and culture-proven chromoblastomycosis reported to the Colombo South Teaching Hospital, Sri Lanka, in 2005. All three were men (age range, 48-53 years). The duration of symptoms varied from 1 to 8 years and the lesions were on the lower limbs. The patients were treated simultaneously with liquid nitrogen cryotherapy and itraconazole pulses, i.e. 200 mg twice daily for 7 days per month, 1 week on and 3 weeks off. Cryotherapy was given every fortnight using large cotton swabs attached to ekels or the cryogun. Two patients showed a good clinical response within 4 months, with negative histopathology and culture in 4-6 months. The third patient was very resistant to treatment and needed a step-up of the itraconazole dose. A combination of fortnightly liquid nitrogen cryotherapy and pulsed monthly itraconazole is cost-effective and shortens the duration of therapy compared with the use of itraconazole or cryotherapy alone.

Evaluation of Oral Itraconazole Administration in Captive Humboldt Penguins (Spheniscus humboldti)

Aspergillus spp. fungal infections are the most common cause of morbidity and mortality in captive penguins. Itraconazole has been the drug of choice for both therapeutic and prophylactic treatment; however, the pharmacokinetic and pharmacodynamic parameters can be highly variable in different species, and it has not been evaluated in penguins. In this study, four preliminary steady-state trials were performed to compare two oral formulations of itraconazole (commercial capsules compared with generic bulk compounded powder) at two different dosages (6 or 12 mg/kg once a day) administered in fish to small groups of captive Humboldt penguins (Spheniscus humboldti). Building on this data, a final steady-state trial was performed with the use of a 7 mg/kg oral dosage twice a day of commercial capsules given in fish to a group of 15 penguins. With sparse sampling, blood was drawn for testing from small subsets of each treatment group at 4-7 time points in the 24-hr period after the final dose of itraconazole on day 14. Steady-state plasma concentrations of itraconazole and hydroxyitraconazole, the major metabolite, were determined by reverse phase high-performance liquid chromatography with fluorescence detection. Treatment with the generic bulk compounded product resulted in plasma levels of itraconazole that were undetectable for 26 out of 30 blood samples, compared with seven out of 20 blood samples for the commercial product at the same dosage. On the basis of study results, an estimated oral dosage of either 8.5 mg/kg twice a day or 20 mg/kg once a day of the commercial itraconazole capsules given in fish would produce adequate steady-state therapeutic blood levels in Humboldt penguins.

Guidelines for Diagnosis and Treatment of Mucocutaneous Candidiasis

This document summarizes current knowledge about diagnosis and treatment of candidiasis affecting the skin and oral mucosa. Several clinical forms of mucocutaneous candidiasis are distinguished depending on a patient's age and infected site, e.g. Candida intertrigo, erythema mycoticum infantile, erosio interdigitalis blastomycetica, candidal paronychia and onychia, Candida onychomycosis, and oral candidiasis. The diagnosis of candidiasis is confirmed by observation of mycelial forms on microscopic examination. Since Candida yeasts (especially C. albicans) are normal inhabitants of the skin and oral mucosa, it must always be noted that positive culture does not always indicate the presence of candidal infection. The pathogenicity of Candida species is relatively low, and some special conditions are required for tissue invasion by the fungus. Predisposing factors, such as disturbances of the cutaneous and mucosal microenvironment and systemic or local immunosuppression, should be checked in patients with recurrent infection. Therapy for cutaneous candidiasis is dominated by topical antifungal agents. Azole antifungal cream (e.g., bifonazole, ketoconazole, neticonazole hydrochloride, lanoconazole and luliconazole) is most effective. Terbinafine hydrochloride and amorolfine hydrochloride are also useful. Cutaneous candidiasis usually requires a shorter duration of topical treatment (1-2 weeks) than superficial dermatophyte infections. For candidal paronychia and onychomycosis, oral therapy with itraconazole is recommended. The daily dose of itraconazole should be taken for several months, while its pulse therapy for candidiasis is not approved in Japan. Itraconazole oral solution is commonly used for oral candidiasis, and miconazole gel is also effective.

Efficacy of Itraconazole in the Treatment of Patients with Chronic Cough Whose Sputa Yield Basidiomycetous Fungi—Fungus-Associated Chronic Cough (FACC)

Objectives. This controlled study was performed to clarify the therapeutic benefit of itraconazole for the treatment of patients with chronic cough, wherein a sputum culture yielded basidiomycetous (BM) fungi. Methods. Of the 171 patients who visited our hospital for the diagnosis and treatment of chronic cough, BM was detected in the sputum of 39 patients. Informed consents were obtained from 21 patients who were subsequently enrolled in this trial. After the administration of the standard therapy, all the patients were enrolled in a randomized placebo-controlled study with 2 weeks of treatment with a low dose of itraconazole (50 mg/day) (n = 10) in comparison with a corresponding period of treatment with matched placebo (ambroxol hydrochloride 45 mg/day) (n = 11). Coughing was assessed using subjective cough symptom scale and capsaicin cough challenging. Results. The treatment with itraconazole, but not placebo (p = 0.17), was associated with a significant improvement in the cough scale (p = 0.0051); moreover, the improvement achieved with itraconazole was significant (p < 0.001) when compared with that of the placebo. Conclusions. Low-dose itraconazole was shown to be an effective antitussive in patients with chronic cough in which sputum examination yielded BM fungi. The 21 patients described here entailed the following manifestations: (1) chronic cough; (2) the presence of environmental fungi, particularly basidiomycetous (BM) fungi, in the sputum; and (3) good clinical response to antifungal drugs. These clinical features may constitute a unique disease concept called fungus-associated chronic cough (FACC).

Coccidioidomycosis

Coccidioidomycosis is a common infectious disease in the southwestern United States. Although Coccidioides species are not endemic in other areas of the country, the rapid population growth in the southwestern United States in recent decades and the increase in tourism mean that many people travel to the Southwest and return home before developing the clinical syndrome of coccidioidomycosis. In this respect, coccidioidomycosis is a disease of national importance. It can occur in various manifestations: acute pneumonia, chronic progressive pneumonia, pulmonary nodules and cavities, extrapulmonary nonmeningeal disease, and meningitis. The diagnosis is often made on the basis of serologic findings. Treatment is usually with an azole or amphotericin B, depending on the clinical manifestations and the immune status of the host. We discuss the most common clinical manifestations, the best way to make the diagnosis, and the treatment of common infections.

Single-Dose Pharmacokinetics of Intravenous Itraconazole and Hydroxypropyl-β-Cyclodextrin in Infants, Children, and Adolescents

This investigation was designed to evaluate the single-dose pharmacokinetics of itraconazole, hydroxyitraconazole, and hydroxypropyl-beta-cyclodextrin (HP-beta-CD) after intravenous administration to children at risk for fungal infection. Thirty-three children aged 7 months to 17 years received a single dose of itraconazole (2.5 mg/kg in 0.1-g/kg HP-beta-CD) administered over 1 h by intravenous infusion. Plasma samples for the determination of the analytes of interest were drawn over 120 h and analyzed by high-pressure liquid chromatography, and the pharmacokinetics were determined by traditional noncompartmental analysis. Consistent with the role of CYP3A4 in the biotransformation of itraconazole, a substantial degree of variability was observed in the pharmacokinetics of this drug after IV administration. The maximum plasma concentrations (C(max)) for itraconazole, hydroxyitraconazole, and HP-beta-CD averaged 1,015 +/- 692 ng/ml, 293 +/- 133 ng/ml, and 329 +/- 200 mug/ml, respectively. The total body exposures (area under the concentration-time curve from 0 to 24 h) for itraconazole, hydroxyitraconazole, and HP-beta-CD averaged 4,922 +/- 6,784 ng.h/ml, 3,811 +/- 2,794 ng.h/ml, and 641.5 +/- 265.0 mug.h/ml, respectively, with no significant age dependence observed among the children evaluated. Similarly, there was no relationship between age and total body clearance (702.8 +/- 499.4 ml/h/kg); however, weak associations between age and the itraconazole distribution volume (r(2) = 0.18, P = 0.02), C(max) (r(2) = 0.14, P = 0.045), and terminal elimination rate (r(2) = 0.26, P < 0.01) were noted. Itraconazole infusion appeared to be well tolerated in this population with a single adverse event (stinging at the site of infusion) deemed to be related to study drug administration. Based on the findings of this investigation, it appears that intravenous itraconazole can be administered to infants beyond 6 months, children, and adolescents using a weight-normalized approach to dosing.

Pharmacokinetic study of the interaction between itraconazole and nevirapine

To investigate the drug interaction potential between itraconazole and nevirapine. Our study was conducted in 12 healthy volunteers in two phases. In phase 1 (from days 1-28), all subjects were randomly assigned to a two-way crossover study of a nevirapine regimen (nevirapine 200 mg once daily for 7 days) and an itraconazole regimen (itraconazole 200 mg once daily for 7 days) with a 14-day wash-out period between. Phase 2 (from days 43-49) was performed 14 days after phase 1 ended, and all subjects received a combination regimen (nevirapine 200 mg combined with itraconazole 200 mg once daily for 7 days). Nevirapine pharmacokinetic studies were carried out starting with the seventh dose of nevirapine in the nevirapine regimen (on days 7-10 or 28-31) and the combination regimen (on days 49-52). Itraconazole pharmacokinetic studies were carried out starting with the seventh dose of itraconazole in the itraconazole regimen (on days 7-10 or 28-31) and the combination regimen (on days 49-52). There was no significant difference in nevirapine pharmacokinetic parameters between the nevirapine and combination regimens. Itraconazole plasma concentrations were lower when it was administered in the combination regimen than when it was administered in the itraconazole regimen. The mean C(max), AUC(0-96) and t (1/2) of itraconazole were significantly reduced by 38, 61 and 31%, respectively. Nevirapine had a strong inducing effect on the metabolism of itraconazole, but there was no significant effect of itraconazole on the pharmacokinetics of nevirapine. However, a higher daily dosage of itraconazole might have an inhibitory effect.

In vitro susceptibility of Madurella mycetomatis, prime agent of Madura foot, to tea tree oil and artemisinin

Eumycetoma caused by Madurella mycetomatis is treated with surgery and high doses of itraconazole and ketoconazole. These agents are toxic, and new therapies are required. MICs were determined for artemisinin and tea tree oil, two natural herbal compounds. Artemisinin was not active against M. mycetomatis, but tea tree oil did inhibit its growth. Since tea tree oil's prime component easily penetrates the skin, tea tree oil could be a useful agent in the treatment of eumycetoma. Tea tree oil is active in vitro against M. mycetomatis.

Comparison of Itraconazole and Fluconazole Treatments in a Murine Model of Coccidioidal Meningitis

Coccidioidal meningitis (CM) is a devastating disease that requires long-term therapy and for which there is little hope of a cure. A model was used to compare the efficacies of itraconazole and fluconazole. CD-1 mice were infected intrathecally with 30 to 36 viable arthroconidia of Coccidioides. Oral therapy with cyclodextrin (control) or itraconazole or fluconazole at 10, 25, or 50 mg/kg of body weight twice daily (BID) was given for 12 days, from day 3 of infection. Treatment with both antifungals at all doses prolonged survival compared with that of the control treatment (P < 0.01 to 0.0001). At 50 mg/kg, itraconazole and fluconazole were equivalent, whereas itraconazole at 10 or 25 mg/kg prolonged survival compared to that achieved with fluconazole at these dosages (P < 0.05 and 0.01, respectively). Early histologic analysis (10 days of treatment) with 50 mg/kg BID itraconazole or fluconazole showed suppression of CM in all five animals per group; in quantitative cultures, three of three animals from each group had no detectable infection in the brain, spinal cord, or a site of secondary infection, the lungs. In contrast, four of seven controls showed mild to severe meningitis, with arteritis detected in three animals. In a short-term organ clearance study, 5 days of treatment with 10 or 50 mg/kg BID itraconazole or fluconazole reduced the tissue burdens in the brain and spinal cord compared to the tissue burdens in the controls (P < 0.02 to 0.0003). Fluconazole at 10 mg/kg did not reduce the fungal burden in secondary sites, the lungs and kidneys, whereas this itraconazole dose was more effective in clearing the fungi from both organs (P < 0.05 and P < 0.001, respectively). At 50 mg/kg, itraconazole and fluconazole were equivalent in clearing the fungi from the brain and kidney, but itraconazole was superior to fluconazole in clearing the fungi from the spinal cord and lungs (P < 0.05). Thus, both itraconazole and fluconazole were effective at controlling CM, but neither eliminated Coccidioides from tissues. Overall, itraconazole was more efficacious on an mg/kg basis; at high doses they were similarly effective.

Comparative analysis of the effects of rice and bread meals on bioavailability of itraconazole using NONMEM in healthy volunteers

The objectives of this retrospective study were to examine the relationship between the bioavailability of itraconazole and the type of food consumed and to determine the effects of food consumption on the pharmacokinetic parameters following a single oral dose of itraconazole in healthy volunteers. The plasma itraconazole concentration-time data were pooled from four pharmacokinetic studies in 144 healthy subjects. Individual pharmacokinetic values were estimated as model-independent (AUC, C (max), and T (max)) and model-dependent (T (lag), K (a), K (cp), K (pc), K (el), and V (d)/F; two-compartment open model with lag time) parameters using the WinNonlin software program. We estimated the population characteristics of the food effects using NONMEM. The consumption of a bread meal before the administration of itraconazole caused a significant increase in its bioavailability, as well as increases in the peak plasma concentration and lag time for itraconazole absorption. On the contrary, consumption of a rice meal before the administration of itraconazole caused a significant decrease in its bioavailability. Therefore, although a dose of itraconazole is normally administered immediately after a meal to increase its bioavailability, this is not an effective strategy after a rice meal.

Pharmacokinetics of Itraconazole and Hydroxyitraconazole in Healthy Subjects after Single and Multiple Doses of a Novel Formulation

Originally, itraconazole for parenteral administration was licensed in a 40% hydroxypropyl-beta-cyclodextrin (HPBCD) solution for intravenous administration. A novel formulation, the NanoCrystal formulation (NCF), was prepared. NCF consists of drug particles of approximately 200 to 300 nm. The pharmacokinetics of itraconazole and its hydroxy metabolite in healthy subjects were evaluated after single and multiple doses of itraconazole as NCF. In the single-ascending-dose (SAD) study, itraconazole doses were planned to range from 50 to 500 mg, while in the multiple-ascending-dose (MAD) study, itraconazole doses of 100, 200, and 300 mg as NCF were studied, as was one dose level (200 mg) as an HBPCD solution. Samples were collected in heparinized tubes at various time points and were analyzed by high-performance liquid chromatography to allow full pharmacokinetic analysis both after the first dose and on day 7. The results of both the SAD and the MAD studies indicated that there was a dose dependency in the half-life of itraconazole from the novel formulation, increasing from 44 h (100 mg) to more than 150 h (300 mg) once steady state was achieved. Similar dose-dependent effects were observed for the hydroxy metabolite. The areas under the concentration-time curves for itraconazole and hydroxyitraconazole were also dose dependent. The pharmacokinetic profiles after 200-mg doses of itraconazole as NCF and HPBCD formulations were comparable with respect to the terminal half-life, both after a single dose and at steady state. NCF may provide an alternative to the HPBCD solution for the further optimization of antifungal treatment with itraconazole.

Lack of Dose-Dependent Effects of Itraconazole on the Pharmacokinetic Interaction with Fexofenadine

The aim of this study was to determine the inhibitory effect of itraconazole at different coadministered doses on fexofenadine pharmacokinetics. In a randomized four-phase crossover study, 11 healthy volunteers were administered a 60-mg fexofenadine hydrochloride tablet alone on one occasion (control phase) and with three different doses of 50, 100, and 200 mg of itraconazole simultaneously on the other three occasions (itraconazole phase). Although the elimination half-life and the renal clearance of fexofenadine remained relatively constant, a single administration of itraconazole with fexofenadine significantly increased mean area under the plasma concentration-time curve (AUC(0-infinity)) of fexofenadine (1701/3554, 4308, and 4107 ng h/ml for control; 50 mg, 100 mg, and 200 mg of itraconazole, respectively). Although mean itraconazole AUC(0-48) from 50 mg to 200 mg increased dose dependently from 214 to 772 ng h/ml (p = 0.003), no significant difference was noted in the three parameters, AUC (p = 0.423), C(max) (p = 0.636), and renal clearance (p = 0.495), of fexofenadine among the three doses of itraconazole. Itraconazole exposure at a lower dose (50 mg) compared with the clinical dose (200 mg once or twice daily) had the maximal effect on fexofenadine pharmacokinetics, even though itraconazole plasma concentrations gradually increased after higher doses. These findings suggest that the interaction may occur at the gut wall before reaching the portal vein circulation, and the inhibitory effect must be saturated by substantial local concentrations of itraconazole in the gut lumen after 50-mg dosing.

Effects of single and multiple doses of itraconazole on the pharmacokinetics of fexofenadine, a substrate of P‐glycoprotein

We determined whether or not the extent of drug interaction of fexofenadine by itraconazole is time-dependent. In a randomized two-phase crossover study, itraconazole was administered orally for 6 days, and, on days 1, 3 and 6, fexofenadine was administered simultaneously. On another occasion, fexofenadine was administered alone. Itraconazole increased fexofenadine AUC(0, infinity), and the % change for difference was 178% (95% CI 1235, 3379), 205% (95% CI 1539, 3319) and 169% (95% CI 1128, 2987) on days 1, 3 and 6 of the 6 day treatment, respectively. The extent of drug interaction by itraconazole was not time-dependent.

Involvement of Phenobarbital and SKF 525A in the Hepatotoxicity of Antifungal Drugs Itraconazole and Fluconazole in Rats

Itraconazole and fluconazole are potent wide spectrum antifungal drugs. Both of these drugs induce hepatotoxicity clinically. The mechanism underlying the hepatotoxicity is unknown. The purpose of this study was to investigate the role of phenobarbital (PB), an inducer of cytochrome P450 (CYP), and SKF 525A, an inhibitor of CYP, in the mechanism of hepatotoxicity induced by these two drugs in vivo. Rats were pretreated with PB (75 mg/kg for 4 days) prior to itraconazole or fluconazole dosing (20 and 200 mg/kg for 4 days). In the inhibition study, for 4 consecutive days, rats were pretreated with SKF 525A (50 mg/kg) or saline followed by itraconazole or fluconazole (20 and 200 mg/kg) Dose-dependent increases in plasma alanine aminotransferase (ALT), γ-glutamyl transferase (γ-GT), and alkaline phosphatase (ALP) activities and in liver weight were detected in rats receiving itraconazole treatment. Interestingly, pretreatment with PB prior to itraconazole reduced the ALT and γ-GT activities and the liver weight of rats. No changes were observed in rats treated with fluconazole. Pretreatment with SKF 525A induced more severe hepatotoxicity for both itraconazole and fluconazole. CYP 3A activity was inhibited dose-dependently by itraconazole treatment. Itraconazole had no effects on the activity of CYP 1A and 2E. Fluconazole potently inhibited all three isoenzymes of CYP. PB plays a role in hepatoprotection to itraconazole-induced but not fluconazole-induced hepatotoxicity. SKF 525A enhanced the hepatotoxicity of both antifungal drugs in vivo. Therefore, it can be concluded that inhibition of CYP may play a key role in the mechanism of hepatotoxicity induced by itraconazole and fluconazole.

Oral Antifungal-Exacerbated Inflammatory Flare-Up Reactions of Dermatomycosis

Inflammatory flare-up reactions of some dermatomycoses, particularly those caused by zoophilic fungi, are typical and potentially severe adverse effects following the intake of some oral antifungals. However, this condition has not previously been reported with the most frequently used antifungals in dermatology, namely fluconazole, itraconazole, and terbinafine. In this report, we describe five patients, observed over a 10-year period, who presented with inflammatory exacerbations following oral antifungal therapy for dermatomycoses. We also review the literature on inflammatory reactions exacerbated by oral antifungal agents. Details of the patients' age, sex, occupation, and atopic background; the site of the lesion, its clinical and histologic features, and any systemic signs; the identity of the fungal pathogen; the antifungal agent taken by the patient; the time between drug intake and occurrence of the flare-up; the approach to management; and the outcome were documented for each patient. A PubMed literature search was also conducted, focusing on inflammatory exacerbations induced by griseofulvin, ketoconazole, itraconazole, fluconazole, and terbinafine. The patients were four farmers and one veterinarian (all male). All primary lesions were inflammatory dermatophytoses, including one kerion. Inflammatory exacerbation of the skin lesions started 12-24 hours after the intake of oral antifungals. Mild systemic changes, including slight fever and malaise, occurred in two cases. Itraconazole 400 mg/day was implicated as the causative agent in four cases and terbinafine 250 mg/day in one case. Mycologic cultures grew Trichophytonverrucosum in four cases. Antifungal treatment was discontinued in all patients. Oral and topical corticosteroids were administered to the two patients with systemic changes; the other three patients were treated with topical corticosteroids only. Two days after the onset of corticosteroids, lower doses of itraconazole (100 mg/day) and terbinafine (125 mg/day) were reintroduced. All lesions healed after 4-5 weeks. The PubMed search did not identify any articles that described inflammatory exacerbations of dermatomycoses induced by oral antifungals. Inflammatory flare-up of dermatomycoses is a rare but potentially severe cutaneous complication of oral antifungal use. Occupational contact with animals, inflammatory dermatomycoses, and zoophilic fungi represent common features in these patients. Although evidence-based data are not available, clinical experience shows that, in addition to antifungal therapy, topical and/or systemic corticosteroids are helpful to reduce the inflammatory reactions. The cases described in this article represent the first published report of oral antifungal-exacerbated inflammatory flare-up reactions of dermatomycosis in patients taking itraconazole or terbinafine.

The effect of the CYP3A4 inhibitor, itraconazole, on the pharmacokinetics of ZD6474 in healthy subjects

3124 Background: ZD6474 selectively targets two key pathways in tumor growth by inhibiting VEGF receptor-2 and EGFR tyrosine kinase activity. ZD6474 is orally active and shows antitumor activity in a range of human tumor xenografts. Because the CYP3A4 isoenzyme is likely to contribute to the metabolism of ZD6474, this study assessed the effect of itraconazole (IT), a potent inhibitor of CYP3A4, on the pharmacokinetics (PK) of ZD6474. Methods: Sixteen healthy male volunteers (mean age 30.2 years, range 20–44) were enrolled in a randomized, open-label, two-period, cross-over study. Subjects were randomized into two groups of eight. One group received 24 daily doses of IT (200 mg, days 1–24) plus a single oral dose of ZD6474 (300 mg, day 4), and the other received a single oral dose of ZD6474. After a 3-month washout period, subjects were crossed-over to receive the alternative regimen. Blood sampling for PK was performed regularly throughout the study. Subjects were also assessed for tolerability, including ECG monitoring. Results: Compared with ZD6474 alone, IT treatment increased ZD6474 AUC0–504 by 9% (90% CI: 1.01–1.18). This increase was statistically significant, but was not considered to be clinically relevant. There was also a trend for an increased t1/2 of ZD6474 in the presence of IT (mean 235.5 h, CV 19.39%) compared with ZD6474 alone (mean 209.2 h, CV 25.86%). Cmax was not significantly different between treatments (mean difference -4%; 90% CI: 0.83–1.11). Tmax was similar for ZD6474 alone (median 5 h, range 3–7) vs ZD6474 with IT (median 5 h, range 3–12). ZD6474 in the presence and absence of IT was well tolerated in this study. Conclusions: The increase in ZD6474 AUC0–504 during administration of IT, a potent CYP3A4 inhibitor, is a relatively minor PK interaction. This increase was considered to be due to a reduction in the systemic clearance of ZD6474 (indicated by the trend for an increased t1/2) caused by IT-mediated inhibition of CYP3A4, rather than because of a change in bioavailability. ZD6474 was well tolerated in this population and its concomitant use with CYP3A4 inhibitors is not expected to result in a PK interaction. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration AstraZeneca AstraZeneca

Effects of Combined Treatment with Sildenafil and Itraconazole on the Cardiovascular System in Telemetered Conscious Dogs

Sildenafil, a potent PDE5 inhibitor, is widely prescribed as a treatment of erectile dysfunction. Itraconazole is an inhibitor of CYP3A4, a metabolic enzyme of sildenafil. In the current study, we investigated the effects of single treatment with sildenafil and combined treatment with sildenafil and itraconazole on blood pressure, heart rate, and QT interval in conscious beagle dogs. After a transmitter was implanted to beagle dogs for conscious state experiments, a single oral dose of sildenafil was administered to the beagle dogs at dose levels of 3, 15, and 30 mg/kg. Blood pressure, heart rate, and lead II ECG were measured prior to dosing and at 0.5, 1, 2, 4, 6, and 24 h postdosing. In the study of combined treatment with sildenafil and itraconazole, the 100 mg/kg dose of itraconazole was orally administered 1 h prior to oral administration of sildenafil. No changes in blood pressure were observed at any doses in animals receiving either single treatment with sildenafil or combined treatment with sildenafil and itraconazole. Increased heart rate from 0.5 h to 6 h postdosing and decreased QT interval were observed in animals receiving single treatment with sildenafil at 15 or 30 mg/kg. When 30 mg/kg of sildenafil was coadministered with 100 mg/kg of itraconazole, drug-related effects such as increased heart rate and decreased QT interval were significantlyenhanced as compared to sildenafil-alone administration at 6 h postadministration. These results demonstrated that increased heart rate and decreased QT interval, the adverse effects of sildenafil, were enhanced and prolonged when sildenafil was coadministered with itraconazole. Therefore, caution should be taken when sildenafil is coadministered with itraconazole, a CYP3A4 inhibitor, or when administered to elderly patients or patients with hepatic or renal impairment who cannot metabolize and excrete sildenafil normally.