Plasma Concentrations Of Itraconazole Research Articles

Increasing the oral bioavailability of the poorly water soluble drug itraconazole with ordered mesoporous silica

This study aims to evaluate the in vivo performance of ordered mesoporous silica (OMS) as a carrier for poorly water soluble drugs. Itraconazole was selected as model compound. Physicochemical characterization was carried out by SEM, TEM, nitrogen adsorption, DSC, TGA and in vitro dissolution. After loading itraconazole into OMS, its oral bioavailability was compared with the crystalline drug and the marketed product Sporanox in rabbits and dogs. Plasma concentrations of itraconazole and OH-itraconazole were determined by HPLC-UV. After administration of crystalline itraconazole in dogs (20mg), no systemic itraconazole could be detected. Using OMS as a carrier, the AUC0-8 was boosted to 681+/-566 nM h. In rabbits, the AUC0-24 increased significantly from 521+/-159 nM h after oral administration of crystalline itraconazole (8 mg) to 1069+/-278 nM h when this dose was loaded into OMS. Tmax decreased from 9.8+/-1.8 to 4.2+/-1.8h. No significant differences (AUC, Cmax, and Tmax) could be determined when comparing OMS with Sporanox in both species. The oral bioavailability of itraconazole formulated with OMS as a carrier compares well with the marketed product Sporanox, in rabbits as well as in dogs. OMS can therefore be considered as a promising carrier to achieve enhanced oral bioavailability for drugs with extremely low water solubility.

Drug-Drug Interaction between Itraconazole and Efavirenz in a Patient with AIDS and Disseminated Histoplasmosis

Although there is a presumed drug-drug interaction between itraconazole and nonnucleoside reverse-transcriptase inhibitors, the medical literature lacks such documentation. We describe a drug-drug interaction between itraconazole and efavirenz in a patient with disseminated histoplasmosis and acquired immunodeficiency syndrome (AIDS). The drug combination resulted in persistently elevated urinary Histoplasma antigen levels and subtherapeutic plasma itraconazole concentrations. Changing treatment from efavirenz to a protease inhibitor was accompanied by improvements in the desired urinary Histoplasma antigen level and plasma itraconazole concentration.

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.

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.

Determination of itraconazole in human plasma by high-performance liquid chromatography with solid-phase extraction

A practical, simple, high-performance liquid chromatographic (HPLC) method is needed for the determination of itraconazole in clinical plasma samples. Itraconazole and bifonazole (internal standard) were extracted from plasma using a C8-bonded solid-phase cartridge, separated by C8 reversed-phase HPLC, and quantified by ultraviolet absorption at 263 nm. This new method enabled the determination of itraconazole in the concentration range of 10.0-500.0 microg/L. The detection limit of itraconazole was 5.0 microg/L. The mean recovery of itraconazole added to plasma was more than 89.1%, with a coefficient of variation of less than 6.9%. We applied this method for the determination of plasma itraconazole in volunteers treated daily with a 200 mg oral capsule of itraconazole for four days. We monitored the plasma level of itraconazole for the following 24 h and obtained the mean area under the plasma concentration-time curve from 0 to 24 h (AUC(0-24) ) value of 4358.9 +/- 1933.4 microg h/L. Our new method will be clinically useful for accurately monitoring the plasma concentration of itraconazole in patients under treatment.

In vitro metabolism of quazepam in human liver and intestine and assessment of drug interactions

1. The study was carried out to identify and characterize kinetically the cytochrome P450 (CYP) enzymes responsible for the major metabolite formation of quazepam.2. In in vitro studies using human liver and intestinal microsomes and cDNA-expressed human CYP and FMO isoenzymes, quazepam was rapidly metabolized mainly by CYP3A4 and to a minor extent by CYP2C9, CYP2C19 and FMO1 to 2-oxoquazepam (OQ), which was then further biotransformed to N-desalkyl-2-oxoquazepam (DOQ) and to 3-hydroxy-2-oxoquazepam (HOQ) mainly by CYP3A4 and CYP2C9. CYP3A4 is the enzyme predominantly responsible for all the metabolic pathways of quazepam.3. Itraconazole inhibited the formation of OQ from quazepam, HOQ from OQ and DOQ from OQ in human liver microsomes with Ki values of 8.40, 0.08 and 0.39 μM, respectively. However, the Ki for OQ formation was greater than the peak plasma itraconazole concentration following a clinically relevant 200-mg oral dose to healthy volunteers. In addition, CYP2C9 and CYP2C19 inhibitors failed to inhibit OQ formation from quazepam.4. In conclusion, clinically relevant drug interaction with CYP inhibitors seem unlikely for the major metabolic pathway of quazepam to OQ.

Steady-state plasma concentrations of itraconazole after oral administration in Kemp's ridley sea turtles, Lepidochelys kempi.

Pharmacokinetic studies of antifungal agents in reptiles are uncommon. Itraconazole, which has been used prophylactically in juvenile sea turtles suffering from hypothermia (cold stunning) on a regular basis, was evaluated for steady-state plasma concentrations. Five Kemp's ridley sea turtles (Lepidochelys kempi) receiving itraconazole at several dosages in a rehabilitation program had blood collected within 24 hr to estimate dosing frequency. Subsequently, serial blood samples of Kemp's ridley sea turtles that were given itraconazole at several dosages for 30 days to treat cold stunning were collected at various intervals to evaluate itraconazole plasma concentrations. Tissue samples were collected from one Kemp's ridley that died during rehabilitation. Plasma concentrations of itraconazole (and of hydroxyitraconazole [OH-ITRA], one of its major bioactive metabolites) were determined using a modified, validated reverse-phase high-performance liquid chromatography technique. Itraconazole concentrations in tissues were determined by bioassay to be far greater than the plasma concentrations measured in any of the turtles. At a 15-mg/kg dosage, the half-life (t1/2) was 75 hr for itraconazole and 55 hr for OH-ITRA. All dosages produced adequate concentrations in some turtles, but consistent therapeutic concentrations were produced only at 15 mg/kg q72hr and 5 mg/kg s.i.d., with the latter producing the highest plasma concentrations.

Effects of Single and Repeated Treatment with Itraconazole on the Pharmacokinetics of Midazolam in Rats

To estimate the influence of repeated administration of drug metabolism inhibitors on the extent of drug interaction, we investigated the effects of single intravenous or repeated oral administration of itraconazole on the pharmacokinetics of midazolam in rats. In the single administration study, the plasma concentration of itraconazole was maintained by intravenous infusion, and midazolam was administered into the portal vein to investigate its kinetics. In the repeated administration study, the kinetics of midazolam was investigated after seven-day oral treatment with itraconazole. The in vitro metabolism of midazolam and the contents of cytochrome P450 were investigated using liver microsomes from the itraconazole-treated rats. The area under the curve (AUC) of midazolam was increased by 1.45- or 1.44-fold after single or repeated itraconazole treatment, respectively. Meanwhile, the liver concentrations of itraconazole after single administration and repeated administration were 38.2 and 20.3 (nmol/g), respectively. In vitro maximum metabolic reaction velocity (V(max)) and Michaelis-Menten constant (K(m)) of midazolam were increased from 2.26 to 3.84 (nmol/min/mg protein) and from 8.28 to 13.0 (microM) by single itraconazole treatment, respectively, and decreased from 2.23 to 1.17 (nmol/min/mg protein) and from 7.86 to 4.47 (microM) by repeated treatment, respectively. Correspondingly, the content of CYP3A2 was significantly altered by single or repeated itraconazole administration. The increases in AUC could be predicted only when the changes in V(max) and K(m) were taken into consideration, in addition to the hepatic unbound concentration of itraconazole. In conclusion, changes in enzyme kinetics should be taken into account to predict the extent of drug interaction after repeated treatment with inhibitors.

Abnormalities in liver enzymes during simultaneous therapy with itraconazole and amphotericin B in leukaemic patients

Sir, Systemic mycoses, such as invasive aspergillosis, are usually treated with antifungal drugs such as iv amphotericin B or itraconazole capsules. The plasma concentrations of itraconazole observed in patients are sometimes much higher than the minimal therapeutic level (1000 ng/mL), and the potential hepatic toxicity of the drug needs to be evaluated. A retrospective study on the effect of itraconazole on liver enzyme levels was conducted after checking bioavailability by plasma assays. Twenty patients, hospitalized between 1 January 1993 and 1 February 1998 were studied. Fourteen had leukaemia, four chronic respiratory insufficiency and one cystic fibrosis, while one had a lung transplant, all complicated by fungal ‘infections’ (12 definitely or probably had invasive aspergillosis, seven were colonized with an Aspergillus sp. and one had Scedosporium sp. sinusitis). Inclusion criteria were: a curative treatment by itraconazole followed by at least one serum concentration (out of three to six assays) 2500 ng/mL of unchanged itraconazole and of its active metabolite (total 5000 equivalent ng/mL). Patients with known hepatic illness before the start of itraconazole therapy, and those with a history of alcohol abuse, were excluded. Patients were treated for 44–455 days (median 143 days with itraconazole 200–600 mg/day (900 mg/day in two patients for 8 days). Twelve patients, all with leukaemia, received itraconazole and amphotericin B for 10–54 days (median 28 days). None of these patients received a bone marrow transplant. No disorders were observed in eight patients, even during the period of high plasma itraconazole concentration. One patient with liver dysfunction presented with cholecystitis at the onset of itraconazole therapy, which was resolved by surgery, but no subsequent hepatic disorders were seen. The 11 other patients, all with leukaemia, had increases in -glutamyltranspeptidase ( GT) and alkaline phosphatase (AP) (median value of 6.5 and 2.5 higher than the normal limit). In nine of these patients, ALT levels were also increased. In three patients such abnormalities were only seen during the period of high plasma itraconazole concentration, with a decrease following a decrease of itraconazole treatment. Different co-drugs were given to these 11 patients and their possible interactions were analysed by a causality assessment. Amphotericin B was the only drug administered, in addition to itraconazole, to all these 11 patients with hepatic disorders. Another leukaemic patient was also treated with itraconazole and amphotericin B, with no hepatic disorders. For the 12 patients treated with itraconazole and amphotericin B, the GT, AP and ALT concentrations were measured at three times: (i) before the beginning of antifungal therapy (period A), during administration of amphotericin B plus itraconazole (and within 21 days after amphotericin B treatment was ended, a time corresponding to seven halflives of the drug) (period B) and 2 months after the end of amphotericin B treatment (period C) (Figure). For each patient, hepatic enzyme concentrations were greatest during period B (Friedman test: P 0.001 for GT and AP, P 0.0015 for ALT). In seven patients, these abnormalities disappeared when amphotericin B was discontinued, although itraconazole therapy was continued. In three other patients, hepatic enzyme abnormalities were observed 5–19 days after the end of amphotericin B therapy. For one patient, the data for period C were not available. A significant increase in hepatic enzyme values, in 11 (92%) out of 12 leukaemic patients was seen. This increase appeared not to be related to the period of high plasma itraconazole concentration for eight of the patients but it was observed during simultaneous treatment with itraconazole plus amphotericin B or a few days after amphotericin B treatment ended.

Overview of aspergillosis: Pathogenesis and treatment options

Aspergillosis is a common fungal infection in a wide range of birds. Although free-living birds tend to be negative for Aspergillus , captive environments or stress may play a role in this fungal disease. Recent data suggest that gross and histopathologic lesions common in Aspergillus infections may be caused by the presence of Pasteurella multocida lipopolysaccharide (LPS). In fact, LPS by itself may produce lesions similar to those produced by conidia. Studies exploring the pathogenesis are reviewed, and two important antifungal drugs are discussed: amphotericin B and itraconazole. The nature and use of these two antifungals are explored. Acidification of itraconazole resulted in increased concentrations of the antifungal metabolite hydroxyitraconazole, allowing it to reach physiologically privileged sites such as the brain. Plasma concentrations of itraconazole vary with the type of bird, possibly because of differences in plasma protein binding between species. Pharmacokinetic considerations are important in developing treatment regimens for mycotic pneumonias.

Pharmacokinetic Disposition of Itraconazole in Red-Tailed Hawks (Buteo jamaicensis)

The pharmacokinetic disposition of itraconazole in plasma and tissues was evaluated in a multiple dose study using 11 nonreleasable red-tailed hawks (Buteo jamaicensis). An itraconazole solution was administered by gavage at a dosage of 5 mg/kg in 4 hawks and 10 mg/kg in 7 hawks once daily for 15 days. On days 1 and 14, blood samples were obtained at 1, 8, 16, and 24 hours after itraconazole administration. The hawks were killed on day 15, and samples of air sac, brain, kidney, liver, lung, and small intestine were retrieved. High-pressure liquid chromatography was used to measure the concentration of the parent drug, itraconazole, and its active metabolite, hydroxyitraconazole, in plasma and tissues of each hawk. Concentrations represent point-in-time values. Results suggest that hawks gavaged with itraconazole at 10 mg/kg once daily will reach steady state plasma concentrations of itraconazole and hydroxyitraconazole within 2 weeks. Although plasma concentrations were lower than those reported in parrots and pigeons, concentrations of both itraconazole and hydroxyitraconazole in organs other than the brain were comparable among species of birds.

Plasma concentration of itraconazole and its antifungal prophylactic efficacy in patients with neutropenia after chemotherapy for acute leukemia

Patients with acute leukemia are at high risk of fungal infection, suggesting that a preventive strategy is required. Fourteen patients receiving intensive chemotherapy for acute leukemia were studied to evaluate antifungal prophylaxis using itraconazole, and the plasma concentration of the drug was measured to determine its relationship to clinical efficacy. The median age of the patients was 50 years (range, 25 to 79 years), and all patients had neutropenia (less than 500 neutrophils/íl) which had lasted a median of 16 days (range, 4 to 30 days). Itraconazole was given orally at a dose of 200mg (four capsules of 50mg) once daily for at least 14 days. An H2-receptor antagonist was also given to prevent chemotherapy-induced gastrointestinal toxicity. Trough plasma concentrations of itraconazole and its metabolite, hydroxyitraconazole, were determined by reversephase high-performance liquid chromatography. The mean concentrations of itraconazole and hydroxyitraconazole on day 10 were 300 6 96ng/ml (range, 131–428ng/ml) and 776±369ng/ml (range, 320–1582ng/ml), respectively. There were marked inter-patient variations in both concentrations. No side effects were observed in the patients, and there was no definite fungal infection episode during this study. Daily oral administration of 200mg of itraconazole appears to be effective as prophylaxis against fungal infection in neutropenic patients with acute leukemia. However, there were marked individual variations in the itraconazole plasma concentrations, which suggests that the plasma concentration should be monitored in patients with a risk of low absorption of this drug to adjust the dose given to an adequate level.

P-glycoprotein-mediated transport of itraconazole across the blood-brain barrier.

The mechanism for the accumulation of itraconazole (ITZ) in its elimination from the brain was studied in rats and mice. The concentration of ITZ in liver tissue declined in parallel with the plasma ITZ concentration until 24 h after intravenous injection of the drug (half-life, 5 h); however, the ITZ in brain tissue rapidly disappeared (half-life, 0.4 h). The time profiles of the brain/plasma ITZ concentration ratio (Kp value) showed a marked overshooting, and the Kp value increased with increasing dose; these phenomena were not observed in the liver tissue. This finding indicates the occurrence of a nonlinear efflux of ITZ from the brain to the blood. Moreover, based on a pharmacokinetic model which hypothesized processes for both nonlinear and linear effluxes of ITZ from the brain to the blood, we found that the efflux rate constant in the saturable process was approximately sevenfold larger than that in the nonsaturable process. The Kp value for the brain tissue was significantly increased in the presence of ketoconazole or verapamil. The brain Kp value for mdr1a knockout mice was also significantly increased compared with that of control mice. Moreover, the uptake of vincristine or vinblastine, both of which are substrates of the P glycoprotein (P-gp), into mouse brain capillary endothelial cells was also significantly increased by ITZ or verapamil. In conclusion, P-gp in the brain capillary endothelial cells participates in a process of active efflux of ITZ from the brain to the blood at the blood-brain barrier, and ITZ can be an inhibitor of various substrates of P-gp.

Plasma concentration of itraconazole in patients receiving chemotherapy for hematological malignancies: the effect of famotidine on the absorption of itraconazole

Plasma concentration of itraconazole in patients receiving chemotherapy for hematological malignancies: the effect of famotidine on the absorption of itraconazole

Optimisation of itraconazole therapy using target drug concentrations.

Itraconazole is a new triazole compound with a broad spectrum of activity against a number of fungal pathogens, including Aspergillus species. The drug is being used increasingly as prophylaxis in patients with immunodepression. Itraconazole is highly lipophilic and only ionised at low pH. The absolute availability of capsules in healthy volunteers under fasting conditions is about 55% and is increased after a meal. Itraconazole is 99.8% bound to human plasma proteins and its apparent volume of distribution is about 11 L/kg. The drug is extensively metabolised by the liver. Among the metabolites, hydroxy-itraconazole is of particular interest because its antifungal activity measured in vitro is similar to that of the parent drug and its plasma concentration is 2 to 3 times higher than that of itraconazole. Mean total itraconazole blood clearance determined in healthy volunteers following a single intravenous infusion was 39.6 L/h. After a single oral dose, the terminal elimination half-life of itraconazole is about 24 hours. The drug exhibits a dose-dependent pharmacokinetic behaviour. Renal failure does not affect the pharmacokinetic properties of itraconazole; however, little is known about the effects of hepatic insufficiency. In immunocompromised patients the absorption of itraconazole is affected by gastrointestinal disorders caused by diseases and cytotoxic chemotherapy. The pharmacokinetics of itraconazole may be significantly altered when the drug is coadministered with certain other agents. Itraconazole is a potent inhibitor of cytochrome P450 (CYP) 3A4 and, thus, can also considerably change the pharmacokinetics of other drugs. Such changes may have clinically relevant consequences. Itraconazole appears to be well tolerated. Gastrointestinal disturbances and dizziness are the most frequently reported adverse effects. Clinical studies in patients with haemotological malignancies suggest that plasma concentrations [measured by high performance liquid chromatography (HPLC)] > or = 250 micrograms/L itraconazole, or 750 to 1000 micrograms/L for itraconazole plus hydroxy-itraconazole, are required for effective prophylactic antifungal activity. It seems that a curative effect may be enhanced by ensuring that itraconazole plasma concentrations exceed 500 micrograms/L. The marked intra- and inter-patient variability in the pharmacokinetics of the drug, and the fact that it is impossible to predict steady-state plasma concentrations from the initial dosage are major factors obscuring any clear relationship between dose and plasma concentrations and clinical efficacy. Thus, in patients with life-threatening fungal infections treated with itraconazole drug, plasma concentrations should be regularly monitored to ensure sufficient drug exposure for antifungal activity.

The effect of coadministration of a cola beverage on the bioavailability of itraconazole in patients with acquired immunodeficiency syndrome

This open-label, randomized, two-way crossover study was conducted to determine whether coadministration of an acidic beverage would affect the bioavailability of itraconazole capsules in fasted patients with acquired immunodeficiency syndrome (AIDS). Eighteen men who had been diagnosed with AIDS based on criteria established by the Centers for Disease Control and Prevention and a CD4 cell count <300/μL received single oral doses of itraconazole 200 mg (two 100-mg capsules) with either 8 oz of water (ITR/H 2O) or 8 oz of a cola beverage (ITR/COLA). There was a 2-week washout period between treatments. Gastric pH was monitored continously by pH probe for 6 hours after dosing. Blood samples were taken before itraconazole dosing and for 72 hours postdose; plasma concentrations of itraconazole and its main active metabolite, hydroxyitraconazole, were determined by using high-performance liquid chromatography. In the fasted AIDS patients, the bioavailability of itraconazole was enhanced by the coadministration of a cola beverage compared with coadministration of itraconazole and water; the mean values for peak plasma concentration of the drug and the area under the plasma concentration—time curve from 0 to 24 hours increased 55% and 38%, respectively, while the mean time to peak plasma concentration decreased by 12%. Results were similar for hydroxyitraconazole. This study demonstrated that the bioavailability of itraconazole is increased in fasted AIDS patients when itraconazole is coadministered with a cola beverage.

A High-Performance Liquid Chromatographic Assay for the Determination of Itraconazole Concentration Using Solid-Phase Extraction and Small Sample Volume

Itraconazole has been shown to be highly effective against a broad spectrum of fungi, particularly aspergillus. In order to achieve the desired pharmacological effect, the itraconazole plasma concentration should be > 250 ng/ml. We developed a high-performance liquid chromatography assay for the rapid determination of plasma itraconazole concentration using solid-phase extraction and small sample volume. The assay possessed linearity up to 5,000 ng/ml, sensitivity of 50 ng/ml, average recovery of 100.8%, and run-to-run precision (n = 10) for concentrations of 100, 200, and 500 ng/ml of 12, 6.6, and 5.8%, respectively. Furthermore, the assay proved to be free of interference from 48 commonly prescribed and some over-the-counter medications. We conclude that the method described here is ideally suited for the therapeutic monitoring of itraconazole.

Prevention of Relapse of Histoplasmosis with Itraconazole in Patients with the Acquired Immunodeficiency Syndrome

To assess the efficacy and safety of itraconazole in preventing relapse of histoplasmosis after induction therapy with amphotericin B in patients with the acquired immunodeficiency syndrome (AIDS) and disseminated histoplasmosis. A prospective, multicenter, open-label clinical trial, with follow-up for at least 52 weeks. Tertiary care hospitals participating in a clinical investigation sponsored by the National Institutes of Allergy and Infectious Diseases (AIDS Clinical Trial Group and Mycoses Study Group). Forty-two patients with AIDS who had successfully completed induction therapy for disseminated histoplasmosis amphotericin B, at least 15 mg/kg body weight given over 4 to 12 weeks. Itraconazole, 200 mg given orally twice daily. Response to therapy, specifically prevention of histoplasmosis relapse, was the main outcome measure. Secondary end points were survival and the effect of therapy on Histoplasma capsulatum variety capsulatum antigen levels in urine and serum. Plasma itraconazole concentrations were measured to document drug absorption and compliance with therapy. The median follow-up was 109 weeks, and median survival was 98 weeks. Two relapses occurred (5%; 95% CI, 0.5% to 16%), one in a patient withdrawn from the study 18 weeks earlier and one in a patient who did not comply with the study therapy. Patients with elevated antigen levels at study entry showed clearance of antigen from urine and serum; urine specimens became negative in 43% of patients (CI, 26% to 59%), and serum specimens became negative in 75% of patients (CI, 56% to 94%). Only one patient discontinued treatment because of itraconazole toxicity (hypokalemia). Itraconazole, 200 mg twice daily, is safe and effective in preventing relapse of disseminated histoplasmosis in patients with AIDS. Antigen clearance from blood and urine correlates with clinical efficacy.

Aspergillose invasive en réanimation chirurgicale

Aspergillosis is a rare event in intensive care patients. Three cases of invasive aspergillosis due to Aspergillus fumigatus were diagnosed in a surgical critical care unit. Risk factors for aspergillosis were found in two liver transplanted patients. One of them had a primitive cutaneous aspergillosis, and the other, treatment difficulties due to the unavailability of an injectable preparation of itraconazole, a new triazole antifungal agent efficient against Aspergillus species. The third case occurred in a patient who had had surgery for gastric carcinoma with liver metastasis. The mycological examination of the air and workbench in the patients' rooms disclosed between 2 and 13 CFU · mm −3 of different Aspergillus species. Plasma itraconazole concentrations were measured in one patient only. They were below the therapeutic range, probably because of intestinal disturbances. The oral administration of itraconazole capsules through gastro-intestinal feeding tubes results in a poor availability of the drug. Such a technique of administration should therefore be undertaken with larger doses than those commonly recommended. Moreover, itraconazole plasma concentrations should be monitored. The association with amphotericin B is recommended until normal intestinal absorption has been obtained.

Plasma itraconazole concentrations in neutropenic patients after repeated high-dose treatment

Two different treatments with repeated oral high doses of itraconazole were tested for 10 days in 20 neutropenic patients, 10 receiving 400 mg per day and 10 receiving 600 mg per day. In each group 5 patients were treated for acute leukaemia and 5 patients were recipients of autologous bone-marrow transplantation (ABMT). Itraconazole plasma concentrations were assayed by high-performance liquid chromatography. Statistical analysis disclosed a significant interaction between the dispensed dose and the patient types. The difference between the two doses of itraconazole was greater in the ABMT than in the leukaemia patients. After 10 days at 600 mg per day all the ABMT patients had an itraconazole plasma concentration higher than 250 μg/l. Therefore, 600 mg per day seems more efficient to obtain a therapeutic level of itraconazole in ABMT patients but this needs to be confirmed for all the neutropenic patients.