Plasma itraconazole concentrations during treatment of feline sporotrichosis.

Itraconazole (ITZ) is the most used drug to treat feline sporotrichosis; however, little is known about its pharmacokinetics in cats with this mycosis. The aim of this study was to determine plasma ITZ concentrations in cats with sporotrichosis treated with ITZ as monotherapy or in combination with potassium iodide (KI). Cats diagnosed with sporotrichosis received orally ITZ (100 mg/cat/day) or combination therapy with ITZ (100 mg/cat/day) and KI (2.5-5 mg/kg/day) in the case of worsening or stagnation of the clinical condition. At each monthly visit, blood samples were collected at an interval of 4 h for analysis of trough and peak plasma ITZ concentrations by HPLC. Clinical features and laboratory parameters were evaluated during follow-up. Sixteen cats were included in the study. The median plasma ITZ concentration of all cats was 0.75 µg/mL. The median plasma ITZ concentration was 0.5 µg/mL in cats that received ITZ monotherapy (n = 12) and 1.0 µg/mL in those treated with ITZ + KI (n = 4). The clinical cure rate was 56.3% (n = 9) and the median treatment duration was 8 weeks. Nine cats (56.3%) developed adverse clinical reactions, and hyporexia was the most frequent (n = 8; 88.9%). Serum alanine aminotransferase was elevated in four cats (25%). The median plasma ITZ concentration detected in cats was considered to be therapeutic (>0.5 µg/mL) and was reached after 4 weeks of treatment. Plasma ITZ concentrations were higher in cats that received ITZ + KI compared to those treated only with ITZ, suggesting pharmacokinetic synergism between these drugs.

Itraconazole is the most common therapy for feline sporotrichosis, and combination therapy with potassium iodide is used in nonresponsive cases. Our study showed that all cats achieved a therapeutic plasma concentration of itraconazole, with higher levels in cats treated with the combination therapy.

Itraconazole encapsulated PLGA-nanoparticles covered with mannose as potential candidates against leishmaniasis.

Leishmaniasis is a neglected disease threatening over 350 million people. Antimonials are first-line drugs due to resistance and side effects there is a demand for alternative chemotherapy. Itraconazole (ITZ) is an antimycotic. It was encapsulated into poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) and covered with mannose. The NPs were 250 nm and -1.1 mV ± 0.7. PLGA-ITZ-mannose NPs presented a toxicity of 20.7% for J774 cells, and no toxicity for THP 1. The J774 cells were infected with three Leishmania promastigotes strains and treated with ITZ loaded PLGA NPs with/without mannose. The parasite percentage of L.(V.) panamensis intracellular amastigotes significantly (p < 0.01) decreased from 34.4% to 13.7% and 5.7% for PLGA-ITZ-mannose NPs and PLGA-ITZ NPs, respectively. For L.(L.) infantum there was a reduction (p < 0.001) from 18.1% to 4.8% and 8.3% for PLGA-ITZ-mannose NPs and PLGA-ITZ NPs, respectively. Further with L.(L.) braziliensis amastigotes there was a significant reduction (p < 0.001) from 54.9% to 28% and 21.1% for PLGA-ITZ-mannose NPs and PLGA-ITZ NPs, respectively. Adding mannose increased the efficacy PLGA-ITZ NPs against L.(L.) infantum, while it had no effect against L(V.) panamensis and L.(L.) braziliensis amastigotes. We recommend further investigation of PLGA-ITZ-mannose NPs in animal models to evaluate their potential. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater 00B: 000-000, 2018. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater 107B: 680-687, 2019.

[Efficacy of the treatment and secondary antifungal prophylaxis in AIDS-related histoplasmosis. Experience at the Francisco J. Muñiz Infectious Diseases Hospital in Buenos Aires]. / Eficacia del tratamiento y de la profilaxis antifúngica secundaria en la histoplasmosis asociada al sida. Experiencia del Hospital de Infecciosas Francisco J. Muñiz, de la ciudad de Buenos Aires.

BACKGROUND: Classic histoplasmosis is a systemic endemic mycosis due to Histoplasma capsulatum var. capsulatum. A significant reduction in the morbidity and mortality of AIDS-related histoplasmosis has been observed since the introduction of highly active antiretroviral therapy (HAART) and secondary antifungal prophylaxis. AIMS: The aim of this study was to determine the current state of prognosis and treatment response of HIV-positive patients with histoplasmosis in the Francisco J. Muñiz Infectious Diseases Hospital in Buenos Aires City. METHODS: A retrospective study was conducted using the demographic, clinical, immunological and treatment data of 80 patients suffering from AIDS-related histoplasmosis. RESULTS: Of the 80 cases studied 65 were male, the median age was 36 years, with 73.7% of the patients being drug addicts, 82.5% of the patients was not receiving HAART at diagnosis, and 58.7% of the cases had less than 50 CD4+ cells/µl at the beginning of the treatment. The initial phase of treatment consisted of intravenous amphotericin B and/or oral itraconazole for 3 months, with 78.7% of the cases showing a good clinical response. Only 26/63 patients who were discharged from hospital continued with the follow-up of the HAART, secondary prophylaxis with itraconazole or amphotericin B. Secondary prophylaxis was stopped after more than one year of HAART if the patients were asymptomatic, had two CD4+ cell counts greater than 150cells/µl, and undetectable viral loads. No relapses were observed during a two-year follow up after prophylaxis was stopped. CONCLUSIONS: The treatment of histoplasmosis in HIV-positive patients was effective in 78.8% of the cases. The combination of HAART and secondary antifungal prophylaxis is safe, well tolerated, and effective. The low adherence of patients to HAART and the lack of laboratory kits for rapid histoplasmosis diagnosis should be addressed in the future. The usefulness of primary antifungal prophylaxis for cryptococcosis and histoplasmosis HIV-positive patients should be studied.

Preclinical monitoring of drug association in experimental chemotherapy of Chagas' disease by a new HPLC-UV method.

A combination of drugs in experimental chemotherapy of Chagas' disease may increase the effectiveness of treatment. To evaluate the possible mechanisms that influence the improvement of therapy, we investigated the pharmacokinetic interaction between benznidazole and itraconazole in a murine model treated orally with single doses of 5 mg of each compound separately or together. Blood samples from treated mice were collected at different intervals for 48 h, and a high-performance liquid chromatography (HPLC)-UV method was used to quantify both drugs in the plasma. A decrease of 1.5-fold in the maximum drug concentration in the plasma (C(max)) and an increase of 2.66-fold in the volume of distribution (V) and 7.5-fold in the elimination half-life (t(1/2ß)) of benznidazole when coadministered with itraconazole were observed. The parameters area under the curve (AUC(0-t)), area under the curve extrapolated to infinity (AUC(0-∞)), time to maximum concentration of drug in serum (T(max)), and clearance (CL) for benznidazole were not significantly different in this therapeutic regime. None of the evaluated parameters for ITC demonstrated a significant difference between isolated and associated administration. These results suggest that the main effect of this interaction leads to accumulation of benznidazole in the biological system. This effect may contribute to the improved therapeutic efficacy of this combination of drugs, in addition to synergism of the different mechanisms of action of benznidazole and itraconazole against Trypanosoma cruzi in vivo.

Bioequivalence study of two formulations of 100 mg capsule of itraconazole. Quantification by tandem mass spectrometry.

The purpose of this study is to compare the bioavailability of two itraconazole (CAS 84625-61-6) capsule formulations. An open, randomized, two-period crossover study with a 7-day washout interval was conduced in 32 healthy volunteers. The plasma samples were obtained up to 96 h after drug administration. A sensitive and specific liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated for the determination of itraconazole in human plasma. Itraconazole and ketoconazole (internal standard) were extracted from the plasma by liquid-liquid extraction using diethylether : dichloromethane (70 : 30) as extraction solvent and separated on a C8 analytical column (150 mm x 4.6 mm I.D.) maintained at 40 degrees C. The elution was performed by a constant flow rate of 1.2 mL/min and the mobile phase consisted of acetonitrile and acetic acid 0.1% (85 :15 v/v). The mass spectrometer equipped with an electrospray source in positive mode, was set up in multiple reaction monitoring, to detect parent --> production 705.0 392.0 (itraconazole) and 531.0 --> 81.70 (ketoconazole). The chromatographic separation was obtained within 3.5 min and was linear in the concentration range of 5 to 600 ng/mL. Bioequivalence between the products was determined by calculating 90% confidence intervals for the ratio of C(max) (95.02%-109.48%), AUC(0-t) (81.41%-107.77%) and AUC(0-inf) (80.85%-106.86%). These values for the test and reference products are within the 80-125% interval, proposed by FDA and EMEA. It was concluded that the proposed method was successfully applied to a pharmacokinetic study in healthy human volunteers, and results showed that the two itraconazole formulations are bioequivalent in their rate and extent of absorption.

Comparison of the oral pharmacokinetics of fluconazole and itraconazole in Mexicans.

Fluconazole and itraconazole are antimycotics widely used in Mexico. However, limited information about their pharmacokinetics is available. It has been reported that physicochemical characteristics of these compounds are disparate, leading to different pharmacokinetic profiles. Moreover, it has been suggested that pharmacokinetics of some drugs may vary in Mexicans when compared with Caucasians due to reduced metabolism by CYP3A4. Based on these distinctions, it is important to carry out local studies in order to establish dosage regimens according the characteristics of each population. The purpose of this study was to compare the oral pharmacokinetics of fluconazole and itraconazole in Mexicans and to compare our results with those reported in other populations. Two groups of 16 subjects volunteered for this study that was approved by the Institutional Research and Ethics Committees. All subjects gave written informed consent for participation. After an overnight fast, volunteers received an oral dose of 100 mg fluconazole or itraconazole and blood samples were obtained at selected times over 96 hr. Plasma was obtained and analyzed by HPLC and pharmacokinetic parameters were obtained. As expected, fluconazole plasma levels were higher than itraconazole due to a lower volume of distribution. Additionally, less variability was observed for fluconazole. When data obtained in Mexicans was compared with those obtained in other populations, no differences were observed, suggesting that there are not interethnic differences in the pharmacokinetics of fluconazole and itraconazole.

Simultaneous itraconazole bioequivalence assessment and CYP3A phenotyping in South American subjects.

OBJECTIVE: The present study evaluates the acute effect of a single-dose itraconazole administration on CYP3A phenotype, as measured by cortisol MR ratio in urine. METHODS: Twenty-four healthy Uruguayan subjects recruited according to strict inclusion criteria participated in an open-label, randomized, two-period, crossover study designed to evaluate the bioequivalence of an itraconazole formulation (Traconal 100 mg, Achê Labs, São Paulo, Brazil). The study comprised two treatment periods separated by a wash-out period of 14 days. In each period a series of venous blood samples were drawn over 48 hours. Three urine samples were obtained for CYP3A phenotyping: pre-dose, 24 and 48 hours after dosing. Blood and urine samples were assayed for itraconazole, beta-hydroxycortisol and cortisol using a validated chromatographic method. RESULTS: The ratio of the mean AUC0-inf. T/AUC0-inf. R was included in the bioequivalence range, however, due to high variability, the CI90% was not. It was found that the cortisol metabolic ratio (MR) showed inhibition relative to basal activity in a proportion of subjects 24 hours (68 +/- 6.1%, mean +/- CI95%) and 48 hours (80 +/- 7.3%, mean +/- CI95%) after ingestion of itraconazole. A significant correlation was found between itraconazole AUC0-inf. and normalized basal CYP3A MR for the reference (r = 0.62, t = 3.72, p = 0.001) and the test product (r = 0.74, t = 5.22, p = 0.00003). A good correlation existed between basal cortisol MR and the elimination half-life of itraconazole. CONCLUSIONS: The findings are in line with the hypothesis that the determination of the bioavailability of highly variable CYP3A substrates might be improved by simultaneous non-interfering phenotyping. If this is confirmed, a new methodological paradigm may need to be developed in order to take account of metabolic variability in bioequivalence evaluation of this group of drugs.

Antifungal susceptibility testing: Progress and future developments

The establishment of a standardized broth reference method for antifungal susceptibility testing of yeastshas opened the door to a number of interesting and useful developments. The adaptation of the reference macrodilution method to a microdilution method has significantly increased the clinical utility of antifungal susceptibility testing, and both methods are now included in the NCCLS document M27-A. The publication of quality control limits for five antifungal agents, coupled with the estabilisment of interpretive MIC breakpoints for three agents, provides useful parameters to survey clinical isolates of Candida and other yeast species. Adaptations of the M27 microdilution method for testing molds has also proved feasible. These developments have made it possible for a number of recent studies designed to expand the capabilities of laboratories to perform antifungal susceptibility testing and to enhance our understanging of trends in antifungal susceptibility. The availability of reference methods also provides a useful touchstone for the development of commercial products that promise to be more user friendly and to further improve test standartization. Products in varying stages of development include two colorimetric microdilution methods (Sensititre and KPI) and the Etest stable gradient MIC method. Preliminary data indicate that these methods are viable alternatives to the reference method for testing of yeasts. Furthermore, Etest may also prove useful for testing molds. Future expectations for antifungal susceptibility testing includes improved ability to detect amphotericin B resistence, development of an NCCLS document for susceptibility testing of molds, and application of these methods for testing dematophytes. Incorporation of antifungal susceptibility testing methods into the clinical trials of new antifungal agents will facilitate the establishment of clinical correlates and further enhance the clinical utility of antifungal susceptibility testing.

Limited-sampling strategy models for itraconazole and hydroxy-itraconazole based on data from a bioequivalence study.

The extensive interindividual variability in oral bioavailability of itraconazole prompted an assessment of the bioequivalence of two formulations marketed in Brazil, namely, Sporanox (reference) and Traconal (test). Eighteen healthy volunteers received single 200-mg oral doses of each formulation at 2-week intervals in a randomized, crossover protocol. The concentrations of itraconazole and hydroxy-itraconazole in plasma were measured by high-performance liquid chromatography, and the datum points (n = 396) were subsequently used to develop limited-sampling strategy models for estimation of the areas under the curve (AUCs) for both compounds. The 90% confidence intervals for individual percent ratios (test/reference formulations) of the maximum concentration of drug in serum, the AUC from 0 to 48 h and the AUC from time zero to infinity (AUC0-infinity) for itraconazole and hydoxy-itraconazole were below the range of 80 to 125%, suggesting that these formulations are not bioequivalent. Linear regression analysis of the AUC0-infinity against time and a "jackknife" validation procedure revealed that models based on three sampling times accurately predict (R2, >0.98; bias, <3%; precision, 3 to 7%) the AUC0-infinity for each of the four formulation-compound pairs tested. Increasing the number of sampling points to more than three adds little to the accuracy of the estimates of AUC0-infinity. The three-point models developed for the reference formulation were validated retrospectively and were found to predict within 2% the AUC0-infinity reported in previous studies performed under similar protocols. In conclusion, the data in this study indicate (i) that the tested formulations are not bioequivalent when single doses are compared and (ii) that limited-sampling strategy models based on three points predict accurately the AUC0-infinitys for itraconazole and hydroxy-itraconazole and could be a valuable tool in pharmacokinetic and bioequivalence studies of single oral doses of itraconazole.

Seguimiento post-terapia en pacientes con paracoccidioidomicosis tratados con itraconazol

De 80 pacientes con paracoccidioidomicosis (PCM) que, a partir de 1985, fueran diagnosticados en los laboratorios de la Corporación para Investigaciones Biológicas (CIB) y que recibieran tratamiento con itraconazol (ITZ), fue posible hacer un seguimiento post-terapia prolongado (promedio de 30 meses, rango 1-8 años) en 53 de ellos. Al momento del diagnóstico, 50 presentaban la forma crónica pulmonar del adulto y los 3 restantes, la forma juvenil. Cuatro de los enfermos estudiados habían recaído después de tratamiento con Ketoconazol. La mayoría de los pacientes (92.4 por ciento) recibieron 100 mgs diarios de ITZ, con una duración promedio de 6 meses de tratamiento en el 62 por ciento de los casos. Ninguno de los pacientes seguidos post-terapia presentó recaída durante el período de observación. Los sítomas más importantes a la terminación de la terapia fueron tos, expertoración y disnea, presentes al final de la terapia en 38.3 por ciento, 22.6 por ciento y 26.4 por ciento de los casos, respectivamente. Su frecuencia, sin embargo, disminuyó durante la observación post-terapia, persistiendo sólo la disnea en 35 por ciento de los casos. El seguimiento radiológico permitió observar la desaparición de los infiltrados retículo-nodulares presentes durante la terapia; sin embargo, la fibrosis fue permanente en 7 de los 11 pacientes que fueron seguidos por más de 4 años. En el 85 por ciento de los pacientes se notó un importante descenso en los títulos de anticuerpos contra el agente causal, P brasiliensis. Los anteriores hallazgos revelan la eficacia del ITZ en el tratamiento de la PCM; se comprueba que este triazol es superior a las drogas para administración oral o intravenosa anteriormente utilizadas ya que no se acompaña de recaídas.

Pruebas de sensibilidad in vitro para levaduras: evaluación de un micrométodo / In vitro susceptibility tests for yeasts: evaluation of a micromethod

Se evaluó un micrométodo para la realización de pruebas de sensibilidad de levaduras frente a antifúngicos, basado en el macrométodo en medio líquido estandarizado por el National Committee for Clinical Laboratory Standards (NCCLS) Subcommittee on Antifungal Susceptibility Testing. En este trabajo se compararon ambos métodos utilizando 6 cepas de referencia de diferente sensibilidad a los siguientes antifúngicos, anfotericina B (AMB), flucitosina (5FC), fluconazol (FCZ), itraconazol (ITZ), ketoconazol (KTZ) y miconazol (MCZ). Se observaron variaciones de sólo 1 ó 2 diluciones entre los resultados de las concentraciones inhibitorias mínimas (CIM) obtenidas con las dos técnicas. Asimismo, se compararon las lecturas visuales de CIM por micrométodo con las mediciones turbidimétricas del crecimiento en distintas concentraciones de antifúngicos frente a 47 aislamientos de Candida albicans. Existió una correlación significativa (p<0.001) entre CIM visual y la inhibición del 80 por ciento de crecimiento determinada por turbidimetría con AMB, 5FC, FCZ, ITZ y MCZ; en cambio no hubo correlación alguna para KTZ (p=1.00)

Pruebas de sensibilidad in vitro para levaduras: evaluación de un micrométodo / In vitro susceptibility tests for yeasts: evaluation of a micromethod

Se evaluó un micrométodo para la realización de pruebas de sensibilidad de levaduras frente a antifúngicos, basado en el macrométodo en medio líquido estandarizado por el National Committee for Clinical Laboratory Standards (NCCLS) Subcommittee on Antifungal Susceptibility Testing. En este trabajo se compararon ambos métodos utilizando 6 cepas de referencia de diferente sensibilidad a los siguientes antifúngicos, anfotericina B (AMB), flucitosina (5FC), fluconazol (FCZ), itraconazol (ITZ), ketoconazol (KTZ) y miconazol (MCZ). Se observaron variaciones de sólo 1 ó 2 diluciones entre los resultados de las concentraciones inhibitorias mínimas (CIM) obtenidas con las dos técnicas. Asimismo, se compararon las lecturas visuales de CIM por micrométodo con las mediciones turbidimétricas del crecimiento en distintas concentraciones de antifúngicos frente a 47 aislamientos de Candida albicans. Existió una correlación significativa (p<0.001) entre CIM visual y la inhibición del 80 por ciento de crecimiento determinada por turbidimetría con AMB, 5FC, FCZ, ITZ y MCZ; en cambio no hubo correlación alguna para KTZ (p=1.00) (AU)

Long-term itraconazole prophylaxis against Aspergillus infections in thirty-two patients with chronic granulomatous disease.

We conducted a prospective, open study of oral itraconazole therapy (5 and then 10 mg/kg per day) to assess tolerance and potential efficacy in preventing fungal infections in patients with chronic granulomatous disease. Thirty-two patients were enrolled in one center between 1985 and 1991. Tolerance was excellent in all cases. Poor compliance was suspected in three cases. Two patients were excluded from efficacy analysis because itraconazole was used as part of therapy for pulmonary aspergillosis. Of 30 patients, 3 developed a fungal (Aspergillus) lung infection, an incidence 3.4/100 patient-years versus 11.5 in a historical control group that did not receive any prophylaxis (p = 0.13) and 9.55 in a historical group of patients who received daily ketoconazole prophylaxis (p = 0.19). The percentage of patients infected with Aspergillus was significantly different: 10% in the itraconazole group versus 34.4% in the untreated group (p = 0.013). These results require further evaluation through a comparative randomized trial to assess the possible benefit of itraconazole prophylaxis in patients with chronic granulomatous disease.

Administration of the antimycotic agents fluconazole and itraconazole to leukaemia patients: a comparative pharmacokinetic study.

This report presents the results of a randomized parallel design comparative study of the serum concentrations of fluconazole and itraconazole after administration of 100 mg orally to patients with leukaemia. Each group consisted of ten patients. The antimycotic drugs were administered with a standard breakfast immediately before the start of chemotherapy (day one) and on days eight and fifteen. No significant differences (p > 0.05; ANOVA) in the pharmacokinetic parameters of fluconazole (AUC, Cmax, Tmax) were found during the three days of the trial. It is concluded that there is no clinically important pharmacokinetic interaction between fluconazole and the chemotherapeutic agents given to this group of patients. A pharmacokinetic interaction between fluconazole and the fever suffered by some of the patients also seems unlikely. No significant differences (p < 0.05; ANOVA) in the pharmacokinetic parameters of itraconazole (AUC, Cmax, Tmax) were found during the three days of the trial, although the statistical power of the data was low. The significantly greater variability of all pharmacokinetic parameters for itraconazole than for fluconazole and the sharp increases and decreases in AUC during the course of the trial found for some patients in the itraconazole group suggest the need for caution in this group of patients.

Itraconazole: pharmacokinetics and indications.

Itraconazole is a highly lipophilic triazolic compound, scarcely soluble in acidified polyethylene glycol, and soluble in hydroxypropyl-beta-cyclodextrin. It possesses an excellent digestive adsorption and its peak plasma level after oral administration of 100 mg is 0.16 microgram/ml at 3 or 4 h after drug intake. Half-life of itraconazole ranges between 17 to 21 h and 99.8% binds to plasmatic proteins, especially albumin. Metabolization is mainly done in the liver where inactive metabolites are formed with the exception of hydroxy-itraconazole, which exhibits a discrete antifungal activity. Stabilization of blood levels with repeated drug administration is reached at day 14, showing an increase both in plasma concentrations and in its half-life. Tissue levels of itraconazole are 3- to 20-fold higher than plasmatic concentrations, whereas only negligible concentrations are in CSF and urine. In the skin and particularly nails, itraconazole persists for a long time after discontinuation of therapy. Its mechanism of action is similar to other azolic compounds, inhibiting the alpha-14-demethylase of lanosterol which interferes with the synthesis of ergosterol. This drug behaves as a wide spectrum antifungal agent, acting against most pathogenic fungi with the exception of the Zygomycetes. Daily doses vary, according to indications, from 100 to 400 mg. The efficacy and results obtained in dermatomycosis, candidiasis, paracoccidioidomycosis, keratomycosis, sporotrichosis, chromoblastomycosis, coccidioidomycosis, blastomycosis, cryptococcosis, phaeohyphomycosis and maduromycotic mycetomas are detailed.

Sporanox en la candidiasis vaginal

Pacientes con candidiasis vagial fueron seleccionadas a participar en un estudio multicéntrico abierto para evaluar el SPORANOX (ITRACONAZOL Janssen) un día de tratamiento(dos cápsulas 100 mgr tomadas en la mañana y en la noche del mismo día) para evaluar el flujo y la sintomatología vulvar y vaginal(eritema, edema, prurito); se realizó test de KOH y cultivo a la admisión, una semana después del tratamiento y a las cuatro semanas. Los resultados indican una mejoría significativa de la sintomatología del flujo en la primera semana de observación y 96.5 por ciento en la última semana. Al final de la observación clínica hecha en 266 pacientes incluían cultivos de control de los cuales 240 fueron negativos, indicando una rata de curación del 92 por ciento. No se detectaron efectos colaterales