Itraconazole Capsules Research Articles

Effects of Food and Omeprazole on a Novel Formulation of Super Bioavailability Itraconazole in Healthy Subjects.

To address the limited bioavailability and intolerance of the conventional itraconazole (ITZ) formulations, a new formulation labeled super bioavailability (SUBA) itraconazole has been developed; however, the specific effects of food and gastric pH are unknown. This study evaluated the pharmacokinetic profile of SUBA itraconazole under fasting and fed conditions, as well as with the concomitant administration of a proton pump inhibitor. First, the effect of food was assessed in an open-label, randomized, crossover bioavailability study of 65-mg SUBA itraconazole capsules (2 65-mg capsules twice a day) in healthy adults (n = 20) under fasting and fed conditions to steady-state levels. Second, an open-label, two-treatment, fixed-sequence comparative bioavailability study in healthy adults (n = 28) under fasted conditions compared the pharmacokinetics of a single oral dose of SUBA itraconazole capsules (2 65-mg capsules/day) with and without coadministration of daily omeprazole delayed-release capsules (1 40-mg capsule/day) under steady-state conditions. In the fed and fasted states, SUBA itraconazole demonstrated similar concentrations at the end of the dosing interval, with modestly lower total and peak ITZ exposure being shown when it was administered under fed conditions than when it was administered in the fasted state, with fed state/fasted state ratios of 78.09% (90% confidence interval [CI], 74.49 to 81.86%) for the area under the concentration-time curve over the dosing interval (14,183.2 versus 18,479.8 ng · h/ml), 73.05% (90% CI, 69.01 to 77.33%) for the maximum concentration at steady state (1,519.1 versus 2,085.2 ng/ml), and 91.53% (90% CI, 86.41 to 96.96%) for the trough concentration (1,071.5 versus 1,218.5 ng/ml) being found. When dosed concomitantly with omeprazole, there was a 22% increase in the total plasma exposure of ITZ, as measured by the area under the concentration-time curve from time zero to infinity (P = 0.0069), and a 31% increase in the peak plasma exposure of ITZ, as measured by the maximum concentration (P = 0.0083).

1354. Novel Formulation SUBA-Itraconazole in Fed and Fasted Healthy Volunteers: Expanding the Clinical Utility of the Established Mold Active Agent

BackgroundItraconazole has been established as an effective mold active agent; however, wide interpatient variability in bioavailability and poor gastrointestinal tolerability have made using the agent challenging. A novel formulation, SUBA-Itraconazole (SUperBioAvailable) has been developed by Mayne Pharma to alleviate these negative properties.MethodsAn open-label, randomized, cross-over study of SUBA–Itraconazole capsules 65 mg (2 × 65 mg BID) in healthy adults under fasting and fed conditions was assessed for steady-state levels. Subjects (n = 20) were administered two capsules of SUBA–Itraconazole twice daily on Days 1–14 and once on the morning of Day 15, either on an empty stomach or with a meal. Safety was monitored by vital signs measurements, electrocardiogram measurements, clinical safety laboratory tests (liver and kidney function tests), and physical examination.ResultsOverall, SUBA–Itraconazole demonstrated similar concentrations at the end of the dosing interval (trough), with modestly lower total and peak exposure when administered under fed conditions compared with the fasted state (fed/fasted ratios of 78.09% for AUCtau [14,183.2 vs. 18,479.8] 73.05% for Cmax,ss [1,519.1 vs. 2,085.2] and 91.53% for Ctrough[1,071.5 vs. 1,218.5]); see Figures 1 and 2. The administration of SUBA–Itraconazole 65 mg capsules was well-tolerated by the healthy subjects participating in this study.ConclusionThe results demonstrate a promising clinical utility for SUBA–Itraconazole in practice. Unlike the conventional capsule formulation which requires a high fat meal for absorption, or the oral solution formulation which requires a fasted administration, SUBA–Itraconazole reached a therapeutic steady state in both fasted and fed states. The similar trough level, however higher peak with fasted state, likely represents a more gradual absorption of drug in the fed state. The slightly higher bioavailability in a fasted state, without gastrointestinal intolerability, is particularly promising for the clinical use of SUBA–Itraconazole in patients unable to have a high fat content meal due to chemotherapy or post-surgery such as hematology patients and transplant recipients.Figure 1.Mean pre-dose plasma itraconazole concentrations.Figure 2:Mean plasma itraconazole concentration–time profile (day 15).Disclosures J. Lindsay, Mayne Pharma: Consultant, Consulting fee. S. Mudge, Mayne Pharma: Employee, Salary.

Clinical efficacy of sequential therapy with voriconazole on COPD patients in acute phase with pulmonary aspergillosis and effects on cytokines and pulmonary functions.

To explore the clinical efficacy of sequential therapy with voriconazole on chronic obstructive pulmonary disease (COPD) patients in acute phase with pulmonary aspergillosis and its effects on cytokines and pulmonary functions. A total of 110 COPD patients in acute phase with pulmonary aspergillosis who were admitted to the hospital between February 2015 and November 2016 were enrolled. We divided them randomly into two groups, i.e., the control group (n = 55) and the treatment group (n = 55). Patients in the control group took itraconazole capsules orally (200 mg/time, twice per day for three days followed by once per day). Patients in treatment group underwent sequential treatment with voriconazole through intravenous infusion at a dose of 5 mg/kg/time twice a day for 3 days followed by a dose of 4 mg/kg/time, twice a day for 8 days. Then, patients took voriconazole orally at a dose of 150 mL/time, twice a day for 6 days. Patients in two groups received the treatment for a total of 14 days. After treatment, we evaluated the levels of tumor necrosis factor α (TNF-α), interleukin 6 (IL-6), and IL-8. The total lung capacity (TLC), diffusing capacity of the lung for carbon monoxide (DLco), and arterial oxygen saturation (SaO2), were measured as well. The total effectiveness rates of the treatment group and the control group were 83.63% and 61.82%. The differences had statistical significance (p < 0.01). After treatment, the incidence of chest pain, cough, sputum-coughing, hemoptysis, cyanosis, and dyspnea in the treatment group was significantly fewer than that in the control group (p < 0.05). TCL, DLco, and SaO2 in the two groups were significantly ameliorated by treatment (p < 0.05). The amelioration in the treatment group was more prominent than that in the control group (p < 0.05). The levels of TNF-α, IL-8, and IL-6 in the two groups were decreased dramatically by the treatments. The decrease in the treatment group was significantly lower than those in the control group (p < 0.05). Occurrence of adverse reactions in treatment group and control group were 8.33% and 6.25%, respectively; (p > 0.05). Sequential therapy with voriconazole exhibits promising clinical efficacy in COPD patients in acute phase with pulmonary aspergillosis. The treatment ameliorated the clinical symptoms and vital signs of patients significantly. It also improved the pulmonary functions and inhibited the inflammatory responses of patients with evident clinical efficacy.

Pharmacokinetics and Relative Bioavailability of Orally Administered Innovator-Formulated Itraconazole Capsules and Solution in Healthy Dogs.

BackgroundItraconazole is commonly used for treatment of systemic and cutaneous mycoses in veterinary medicine. Two formulations, capsule and solution, are used interchangeably in dogs. However, marked differences in bioavailability have been reported in other species. Similar investigations have not been performed in dogs.ObjectiveTo determine and compare pharmacokinetics of itraconazole in dogs after oral administration of commercially available capsule and solution formulations intended for use in humans.AnimalsEight healthy, adult, purpose‐bred dogs.MethodsDogs received approximately 10 mg/kg of innovator‐formulated itraconazole solution and capsule PO in randomized, crossover design with a 10‐day washout period. To ensure maximal absorption, solution was administered to fasted dogs, whereas capsules were co‐administered with food. Blood samples were collected at predetermined time points, and plasma drug concentrations were measured using high‐pressure liquid chromatography. Pharmacokinetic parameters were determined with compartmental analysis.ResultsThe mean relative bioavailability of the capsule was 85% that of the solution, but drug absorption was variable, and overall drug concentrations were similar between formulations. Mean elimination half‐lives of both formulations were nearly identical at approximately 33 hours. Regardless of formulation, simulations suggest that a loading dose of 20 mg/kg, followed by 10 mg/kg once every 24 hours, will result in plasma concentrations considered to be adequate in most dogs.Conclusions and Clinical ImportanceContrary to findings reported in other species, overall drug exposures after capsule and solution administration are not substantially different in dogs. Despite some pharmacokinetic differences between itraconazole capsule and solution, formulation‐specific dosages do not appear to be necessary.

The Efficacy and Safety of Miconazole Nitrate Mucoadhesive Tablets versus Itraconazole Capsules in the Treatment of Oral Candidiasis: An Open-Label, Randomized, Multicenter Trial.

BackgroundOral candidiasis (OC) is a common oral fungal infection. Recently, miconazole mucoadhesive tablets have been gaining attention for OC treatment. Despite trials in patients with human immunodeficiency virus and cancer, evidence of its application in the large-scale, general population with OC is lacking. This study aimed to evaluate the efficacy and safety of miconazole nitrate mucoadhesive tablets in comparison with itraconazole capsules for OC treatment.MethodsThe study was a randomized, open-label, parallel-armed, multicenter clinical trial. Totally, 343 patients diagnosed with OC, who met the inclusion criteria, were randomly assigned to either a treatment group that received miconazole nitrate mucoadhesive tablets (10 mg) once daily or a control group that received itraconazole capsules (100 mg QD) for 2 weeks, and were followed up for 2 weeks. The clinical cure, improvement of clinical symptoms/signs, mycologic cure, and safety were evaluated.ResultsThe mucoadhesive tablets (n = 171) did not show inferiority to itraconazole (n = 172) in the treatment of OC. At the end of the 14-day treatment, the clinical cure rates were 45.29% and 41.76% in the miconazole and itraconazole groups, respectively (P = 0.3472). At the end of the 14-day follow-up, the clinical cure rates were 51.18% and 41.76% in the miconazole and itraconazole groups, respectively (P = 0.0329). Adverse events occurred in 53 subjects (33 in the miconazole group and 20 in the itraconazole group). There was no statistical difference in the safety profile between miconazole and itraconazole (P = 0.0533). Thrombocytopenic purpura, although rare, occurred in one patient in the miconazole group and was considered a drug-related, severe adverse event.ConclusionMiconazole nitrate mucoadhesive tablets may be as effective as systemic itraconazole capsule for OC treatment. Physicians should be cautious about thrombocytopenic purpura occurring as a rare and serious adverse event of miconazole nitrate.Trial RegistrationChinese Clinical Trial Register ChiCTR-TRC-13003935

A case of cutaneous Arthrinium phaeospermum infection after lower limb amputation

A 59-year-old female patient, who received bilateral lower limb amputation 39 years ago, presented with eczematoid changes in both lower limbs for over 20 years, and with chronic granuloma-like lesions complicated by verrucous hyperplasia for more than 10 years. There were large areas of infiltrative and proliferative lesions with exudation and peripheral erythema at the amputation sites in both knee joints. The lesions were hard with tenderness on palpation. Microscopic examination of lesional scales with 10% KOH showed negative results for fungi. However, three times of culture on the Sabouraud dextrose agar (SDA) medium all grew the same kind of fungus, and the front side and reverse side of its filamentous colony were white and orange yellow respectively. Microculture showed that linear hyaline conidiophores came out from lageniform mother cells with conidia ascending alongside. The conidia looked like dark brown eye lens, with an equatorial germ slit. Based on these findings, this fungus was identified as Arthrinium phaeospermum. Periodic acid-Schiff (PAS) staining showed scattered hyphae in the stratum corneum. The internal transcribe spacer (ITS) sequence of the isolated fungus showed 99% consistency with that of Arthrinium phaeospermum. The patient was diagnosed with cutaneous Arthrinium phaeospermum infection, and treated with oral itraconazole capsules 200 mg/d for 16 days. One month later, follow-up showed satisfactory outcomes. Key words: Dermatomycoses; Amputation stumps; Infection; Itraconazole; Arthrinium phaeospermum

Development of a Physiologically Based Pharmacokinetic Model for Itraconazole Pharmacokinetics and Drug-Drug Interaction Prediction.

Physiologically based pharmacokinetic (PBPK) modeling for itraconazole has been challenging due to highly variable in vitro d ata used for 'bottom-up' model building. Under-prediction of pharmacokinetics and drug-drug interactions (DDIs) following multiple doses of itraconazole has limited the use of PBPK model simulation to aid an itraconazole clinical DDI study design. The aim of this work is to develop an itraconazole PBPK model predominantly using a 'top-down' approach to enable a more accurate pharmacokinetic and DDI prediction. An itraconazole PBPK model describing itraconazole and hydroxyl-itraconazole (OH-ITZ) was constructed in Simcyp(®). The key parameters that govern the pharmacokinetic profile, including non-linear clearance (i.e., maximum rate of reaction [V max] and the Michaelis-Menten constant [K m]) and volume of distribution for both itraconazole and OH-ITZ, were redefined by leveraging existing in vivo data. Model verification was performed by comparing the simulated itraconazole and OH-ITZ pharmacokinetic profiles with the observed clinical data. Finally, the model was used to simulate clinical DDIs between itraconazole and midazolam. The developed PBPK model well-described the pharmacokinetics of itraconazole and OH-ITZ, and particularly captured their accumulation after repeated doses of itraconazole. This was verified with the observed data from 29 clinical studies where itraconazole solution or capsule was given as a single or multiple dose. The predicted DDI between itraconazole and midazolam was within 1.25-fold of the observed data for seven of ten studies and within 1.5-fold for nine of ten studies. The improvement of the itraconazole PBPK model increased our confidence in using PBPK model simulations to optimize clinical itraconazole DDI study design.

Network Meta-analysis and Pharmacoeconomic Evaluation of Fluconazole, Itraconazole, Posaconazole, and Voriconazole in Invasive Fungal Infection Prophylaxis.

Invasive fungal infections (IFIs) are associated with high mortality rates and large economic burdens. Triazole prophylaxis is used for at-risk patients with hematological malignancies or stem cell transplants. We evaluated both the efficacy and the cost-effectiveness of triazole prophylaxis. A network meta-analysis (NMA) of randomized controlled trials (RCTs) evaluating fluconazole, itraconazole capsule and solution, posaconazole, and voriconazole was conducted. The outcomes of interest included the incidences of IFIs and deaths. This was coupled with a cost-effectiveness analysis from patient perspective over a lifetime horizon. Probabilities of transitions between health states were derived from the NMA. Resource use and costs were obtained from the Singapore health care institution. Data on 5,505 participants in 21 RCTs were included. Other than itraconazole capsule, all triazole antifungals were effective in reducing IFIs. Posaconazole was better than fluconazole (odds ratio [OR], 0.35 [95% confidence interval [CI], 0.16 to 0.73]) and itraconazole capsule (OR, 0.25 [95% CI, 0.06 to 0.97]), but not voriconazole (OR, 1.31 [95% CI, 0.43 to 4.01]), in preventing IFIs. Posaconazole significantly reduced all-cause deaths, compared to placebo, fluconazole, and itraconazole solution (OR, 0.49 to 0.54 [95% CI, 0.28 to 0.88]). The incremental cost-effectiveness ratio for itraconazole solution was lower than that for posaconazole (Singapore dollars [SGD] 12,546 versus SGD 26,817 per IFI avoided and SGD 5,844 versus SGD 12,423 per LY saved) for transplant patients. For leukemia patients, itraconazole solution was the dominant strategy. Voriconazole was dominated by posaconazole. All triazole antifungals except itraconazole capsule were effective in preventing IFIs. Posaconazole was more efficacious in reducing IFIs and all-cause deaths than were fluconazole and itraconazole. Both itraconazole solution and posaconazole were cost-effective in the Singapore health care setting.

Alternate-day dosing of itraconazole in healthy adult cats.

The current available formulations of itraconazole are not ideal for dosing in cats. The capsular preparation often does not allow for accurate dosing, the oral solution is difficult to administer and poorly tolerated, and the bioavailability of compounded formulations has been shown to be poor in other species. The aim of this study was to evaluate every other day dosing of 100 mg itraconazole capsule in healthy adult cats. Ten healthy adult cats received a 100 mg capsule of itraconazole orally every 48 h for 8 weeks. Peak and trough serum concentrations of itraconazole were measured weekly using high-performance liquid chromatography (HPLC). Physical examination, complete blood count (CBC), and chemistry profiles were performed weekly. The dosage regimen achieved average therapeutic trough concentrations (>0.5 μg/mL) within 3 weeks. The protocol yielded no adverse effects in 8 of the 10 study cats, with affected cats recovering fully with discontinuation of the drug and supportive care. At 8 weeks, an average peak concentration of 1.79 ± 0.952 μg/mL (95% CI: 0.996-2.588) and an average trough concentration of 0.761 ± 0.540 μg/mL (95% CI: 0.314-1.216) were achieved. Overall, a 100 mg every other day oral dosage regimen for itraconazole in cats yielded serum concentrations with minimal fluctuation and with careful monitoring may be considered for treatment of cats with systemic fungal disease.

Unrelated Cord Blood Does Not Increase An Overall Risk Of Invasive Fungal Infections Compared To Unrelated Bone Marrow: A Single Center Retrospective Analysis For 749 Recipients

Background Invasive fungal infections (IFIs) are of great concern after allogeneic hematopoietic stem cell transplantation (HSCT), the risk of which is considered to be particularly prominent among cord blood transplantation (CBT) recipients. Patients and Methods We retrospectively analysed the records of 749 adult patients who underwent CBT or unrelated bone marrow transplantation (uBMT) for the first time at the Toranomon Hospital between 2002 and 2012, and who had neither prior history nor suspicious findings of IFIs. As prophylaxis for IFIs, fluconazole (FLCZ) or itraconazole (ITCZ) capsules were conventionally used until around 2006, which were then changed to newer mold-active agents including ITCZ oral solution, voriconazole or micafungin after their approval in Japan, the choice of which was subjected to physician's discretion. Results Engraftment achieved in 418 CBT patients and 198 uBMT patients with a significantly longer neutropenic period in CBT patients (median 20 days vs 18 days, P&lt;0.001), whereas 37 patients underwent re-transplantation and 96 died before engraftment. The incidences of grade II-IV acute graft-versus-host disease (GVHD) and extensive chronic GVHD were significantly less frequent after CBT compared to uBMT (40% vs 54% and 17% vs 46%, both P&lt;0.001). Systemic corticosteroids at ≥0.5mg/kg/day was given in fewer CBT patients compared to uBMT patients (59% vs 66%, P=0.07). The median durations of immunosuppressants and antifungal prophylaxis were significantly shorter in CBT patients compared to uBMT patients (118 days vs 302 days and 315 days vs 491 days, both P&lt;0.001). As prophylaxis for IFIs, 194 CBT patients and 91 uBMT patients received FLCZ/ITCZ capsules, while 341 CBT patients and 123 uBMT patients received newer mold-active agents. Seventy-nine patients (57 in CBT and 22 in uBMT) developed IFIs with a cumulative incidence of 12.2%, at a median of 27 (1-1646) days after HSCT. About 60% of the patients developed IFIs by day 50 and the percentage reached more than 90% until 1 year. The median onset was significantly earlier in CBT patients compared to uBMT patients (day 19 vs day 61, P=0.007). The cumulative incidence of IFIs was significantly higher in CBT patients compared to uBMT patients during 50 days after HSCT (7.9% vs 3.8%, P=0.04), but became significantly lower thereafter until 1 year (2.7% vs 6.9%, P=0.02), and an overall incidence was almost similar between the 2 groups (12.6% vs 11.6%, P=0.58) (Figure 1). Four patients had 2 infectious episodes caused by different fungal species, and a total of 83 infectious episodes were documented. Eighty-one cases were breakthrough infection during antifungal prophylaxis (FLCZ/ITCZ capsules in 28, and newer mold-active agents in 53). Invasive aspergillosis (IA) was the most common, accounting for 67.9% (proven in 11, probable in 46), followed by invasive candidiasis (IC), (19.3%; candidemia in 15, encephalitis in 1). Although the incidences of IA and IC were comparable between CBT and uBMT patients, relatively rare type of IFIs caused by Trichosporon (4 cases), Mucor (2 cases) and Rodotorula (1 case) exclusively occurred in CBT patients, except one case of Fusarium infection in a patient who relapsed after uBMT. Grade II-IV acute GVHD, extensive chronic GVHD and systemic corticosteroids at ≥0.5mg/kg/day were identified as significant risk factors of IFIs for both groups (HR 1.89, P=0.01, HR 4.16, P=0.006, and HR 1.83, P=0.02). However, the impact of all these were not apparent in CBT patients (HR 1.59, P=0.16, HR 2.18, P=0.29 and HR 1.48, P=0.22), in contrast with the powerful impact in uBMT patients (HR 2.51, P=0.049, HR 10.23, P=0.03 and HR 2.87, P=0.03). Although the cessation of antifungal prophylaxis significantly increased the risk of IFIs in uBMT patients (HR 5.95, P=0.01), it showed no impact in CBT patients (HR 0.87, P=0.89). IFIs were main causes of death in 21 patients, which significantly affected non-relapse mortality in both CBT and uBMT patients (HR 3.93 and HR 6.08, both P&lt;0.001). Conclusion Unrelated cord blood did not increase an overall incidence of IFIs, because higher risk in the early post-transplant period was counterbalanced by the dramatically decreased risk due to lower frequencies of GVHD and its treatment in the later period. Particular attention might be required to the early-onset IFIs due to fungi other than Aspergillus or Candida species, in order to further decrease the risk of IFIs after CBT. Disclosures: No relevant conflicts of interest to declare.

Ultra-performance liquid chromatography electrospray ionization–tandem mass spectrometry method for the simultaneous determination of itraconazole and hydroxy itraconazole in human plasma

A highly sensitive, selective, and precise ultra-performance liquid chromatography tandem mass spectrometry method was developed and validated for simultaneous quantification of itraconazole and hydroxy itraconazole in human plasma by a single liquid–liquid extraction step. The precursor to product ion transitions of m/z 705.3/392.3, m/z 721.2/408.3 and m/z 708.2/435.4 were used to detect and quantify itraconazole, hydroxy itraconazole and itraconazole-d3 respectively. The lower limit of quantitation was found to be 0.500ng/mL for itraconazole and 1.00ng/mL for hydroxy itraconazole. The mean recoveries for itraconazole and hydroxy itraconazole were found to be 100.045% and 100.021%, respectively. This developed method with a chromatographic run time of 2.0min was successfully applied to a bioequivalence study of 100mg itraconazole capsule.

Epidemiological characteristics of Malassezia folliculitis and use of the May-Grünwald-Giemsa stain to diagnose the infection

Various bacterial, fungal, parasitic, and viral pathogens can cause folliculitis, which is often mistakenly treated with antibiotics for months or even years. A laboratory diagnosis is required before therapy can be planned. Here, we describe the prevalence and risk factors, as well as the clinical, cytological, and mycological characteristics, of patients with Malassezia folliculitis (MF) in Adana, Turkey. We also report the treatment responses of the MF patients and describe the Malassezia spp. using culture-based molecular methods. Cytological examinations were performed in 264 folliculitis patients, 49 of whom (18.5%) were diagnosed with MF. The positivity of the May-Grünwald-Giemsa (MGG) smear was higher (100%) than that of the potassium hydroxide test (81.6%). Using Wood's light, yellow-green fluorescence was observed in 66.7% of the MF patients. Identification using the rDNA internal transcribed spacer region revealed that Malassezia globosa was the most common species, followed by Malassezia sympodialis, Malassezia restricta, and Malassezia furfur. The MF patients were treated with itraconazole capsules (200 mg/d) for 2 weeks. Complete recovery was observed in 79.6% of the patients. These novel findings help improve our current understanding of the epidemiological characteristics of MF and establish MGG as a practical tool for the diagnosis of MF.

Intraocular penetration of itraconazole in patient with fungal endophthalmitis

The purpose of this study was to determine the penetration of itraconazole, a type of azole antifungal agent, into the aqueous humor and vitreous after repeated oral administrations. Fungal endophthalmitis developed bilaterally in a 21-year-old man who had a history of intravenous hyperalimentation following abdominal surgery. Itraconazole capsules (200 mg/day) were taken orally for 12 consecutive days. Vitrectomy was performed on the left eye 30 h after the last oral itraconazole. Samples of blood, aqueous, and vitreous were collected during the vitrectomy. The concentration of itraconazole was determined by high performance liquid chromatography. The concentration of itraconazole was 0.492 μg/mL in the plasma, 0.020 μg/mL in the vitreous, and none in the aqueous of the left eye. Although no fungal organisms were isolated from the plasma and vitreous samples from both eyes, fungal DNA was detected in the vitreous from the left eye. Our findings indicate that oral itraconazole has limited penetration in eyes with fungal endophthalmitis.

Efficacy of Oral Itraconazole in the Treatment of Seborrheic Dermatitis

Background: Seborrheic dermatitis is a common papulosquamous dermatosis and occurring in 2% to 5% of the population. The prevalence of seborrheic dermatitis among HIV-positive and AIDS patients between 34% and 83%. The anti-inflammatory activity of oral itraconazole and efficacy on Malessezia suggests that itraconazole capsule will be the first oral treatment option in future in seborrheic dermatitis. Unfortunately there is no data base study with the efficacy of oral itraconazole for the treatment of seborrheic dermatitis over Bangladeshi people.Objectives: To evaluate the efficacy of itraconazole in the treatment of Seborrheic dermatitis.Methods: This was an interventional type of study and total thirty seven patients of seborrheic dermatitis from department of Dermatology and Venereology, Bangabandhu Sheikh Mujib Medical University (BSMMU) was enrolled. The study was carried out for a period of two years from January 2008 to December 2009 and purposive type non-probability sampling technique was followed in this study.Results: The scoring of seborrhea was 6.33±1.15 before treatment and 4.33 ±3.21 after treatment, scoring of itching was 6.66 ±1.49 before treatment and 3.61 ±2.70 after treatment and scoring of greasy crust was 7.12 ±2.70 before treatment and 4.00 ±3.16 after treatment. It was observed that before treatment, erythema was severe in 43.2% cases, moderate in 51.4% cases and mild type erythema was present in 5.4% cases. And after treatment, 29.7% had severe type erythema, no patient had moderate type erythema, only 43.2% had mild type and 27% cases had no erythema at all. Before treatment, papular eruption was severe in 27% cases, moderate in 54.1% cases and only 18.9% had mild type papular eruption. But after treatment, 10.8% had severe type, 18.9% had moderate, 51.4% had mild and 18.9% had no papular eruption at all. It was observed that before treatment, squamation was severe in 37.8% cases and moderate in 62.2% cases. But after treatment, 18.9% had severe type squamation, 10.8% had moderate, 45.9% had mild and 24.3% had no squamation. Improvement was shown in 26(70.27%) cases and 11(29.73%) cases shown no improvement at all.Conclusion: The study suggests that oral itraconazole has significant efficacy profile for treatment option of seborrheic dermatitis. DOI: http://dx.doi.org/10.3329/jbcps.v29i4.11326 J Bangladesh Coll Phys Surg 2011; 29: 201-206

Preparation and cyclodextrin assisted dissolution rate enhancement of itraconazolium dinitrate salt

The poor solubility of itraconazole (ITR) results in its variable oral absorption and bioavailability and has also proven to be a major setback in developing an efficient oral delivery system. To improve its solubility and dissolution profile, itraconazolium dinitrate salt (ITRDNT) was prepared and characterized using various spectral and thermal techniques. The morphology of the salt was studied using optical and scanning electron microscopy (SEM). Broth microdilution assay demonstrated antifungal efficacy of ITRDNT similar to ITR against four different fungal strains namely, Asparagillus fumigatus, Microsporum canis, Microsporum gypsum and Trichophyton rubrum. The salt exhibited better solubility profile than ITR in water and a number of pharmaceutical solvents. Dissolution studies revealed the total amount of drug released from ITRDNT in 3 h was four times greater than that of ITR. To further improve dissolution characteristics, the physical mixtures of ITR and ITRDNT with two cyclodextrins, β-cyclodextrin (β-CD) and HP-β-cyclodextrin (HP-β-CD) were prepared and their molar ratios were optimized. It was observed that about 75% of drug was released in 30 min from 1:3 molar ratio of ITRDNT and HP-β-CD physical mixture, which was distinctly higher than ITR commercial capsules (70%). Owing to its facile and economical preparation and substantially better in vitro release profile, the ITRDNT and its CD physical mixtures could be better and cost effective alternatives to ITR and commercial ITR capsules.

Clinical characteristics and outcome of Penicillium marneffei infection among HIV-infected patients in northern Vietnam

ObjectiveThis study reports the clinical characteristics and outcome of HIV-associated Penicilliummarneffei infection in northern Vietnam.MethodsWe conducted a retrospective chart review of all patients with laboratory confirmed Penicilliummarneffei infection admitted to the National Hospital for Tropical Diseases in Hanoi, Vietnam, between July 2006 and September 2009.Results127 patients with P. marneffei infection were identified. All were HIV-infected; median CD4+ T-cell count was 24 cells/μl (IQR:12-48); 76% were men. Common clinical features were fever (92.9%), skin lesions (82.6%), hepatomegaly (61.4%), lymphadenopathy (40.2%), weight loss (59.1%) and cough (49.6%). Concurrent opportunistic infections were present in 22.0%; half of those had tuberculosis. Initial treatment regimens were: itraconazole or ketoconazole capsule (77.2%), amphotericin B (20.5%), and fluconazole (1.6%). In-hospital mortality was 12.6% and showed no significant difference in patients treated with itraconazole (or ketoconazole) and amphotericin B (p = 0.43). Dyspnea, ascites, and increased LDH level were independent predictors of mortality. No seasonality was observed.ConclusionThe clinical features, treatments and outcomes of HIV-associated P. marneffei infection in northern Vietnam are similar to those reported in other endemic regions. Dyspnea was an important predictor of mortality. More patients were treated with itraconazole than amphotericin B and no significant difference in treatment outcome was observed. It would be of clinical value to compare the efficacy of oral itraconazole and amphotericin B in a clinical trial.

Bioequivalence study of two formulations of 100 mg capsule of itraconazole

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.

Early Diagnostic Procedure and Treatment for Invasive Fungal Infection Centered on Invasive Aspergillosis in Patients with Myelodysplastic Syndrome or Acute Myeloid Leukemia

Abstract 1544Since myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) are more prevalent in the elderly, intensive chemotherapy is difficult. However, recent progress in supportive therapy, especially with anti-fungal agents, and diagnostic procedures for invasive fungal infection (IFI) such as β-D glucan (β-D), galactomannan antigen (GM) and computed tomography (CT), have resulted in dramatically enhanced safety of post-chemotherapy control of elderly patients.To evaluate the efficacy and safety of our diagnosis and treatment strategy for IFI, we examined 112 consecutive episodes in 110 patients who received remission induction therapy from December 15, 2009 to June 18, 2011, including new or recurrent patients with MDS related AML (MDS-AML) and those with AML without a history of invasive aspergillosis (IA). Diagnosis was MDS-AML in 88 episodes (relapse 18) and AML in 24 (M1 5,M2 9,M4 9,M6 1).The median age was 70 (range: 21–88).Remission induction therapy consisted of behenoyl-ara-C for 10 days and idarubicin for 4 days (For further details, please refer to 51st ASH abstract #1052; Taiichi Kyo et al). Patients were always admitted to a clean room until neutrophil recovery, and were routinely administered macrophage-colony stimulating factor (CSF) and granulocyte-CSF. Amphotericin-b syrup and itraconazole capsules were given as antifungal prophylaxis. IFI diagnostic procedures consisted of CT, GM, β-D and surveillance culture (SC). At the time of admission a control CT was taken. CT was repeated within 24 hours when pyrexia of ≥38.0°C occurred. If fever showed no improvement, CT was repeated every 3 days (X-ray was also taken). If any change suggesting infection was noted, treatment against IA was considered. GM, β-D and SC were all conducted twice a week from the time of admission until discharge. ≥0.5 GM was regarded as positive and the treatment against IA was started even if there was only one positive result. At present there is no worldwide consensus concerning β-D, thus we considered a value exceeding the cut-off value of the reagent as positive. Treatment was started when there were both a positive result and increasing fever; and treatment against IA or candidiasis depended on imaging findings. Even if β-D was negative, candida detected by SC or diarrhea combined with increasing fever was also an indication for treatment against candidiasis. IA was treated with voriconazole (VRCZ) and candidiasis with micafungin (MCFG). VRCZ and MCFC were administered at 200–300 mg/twice/day and 100–300 mg/day, respectively. When no sufficient effect was observed with VRCZ alone, MCFG was added.Complete remission (CR) and partial remission (PR) were achieved in 81/112 (72%) and 9/112 (8%) episodes, while in 19/112 (17%) no response was obtained and 3/112 (2.7%) episodes resulted in death during chemotherapy. CR rate was comparable among de novo MDS-AML (49/70, 70%), MDS-AML relapse (9/18, 50%) and AML (23/24, 96%). The cause of death associated with chemotherapy was bacteremia 1, bacteremia or IA 1, and cerebral hemorrhage 1. GM was positive in 48 (43%) episodes. The reason for this large number was probably the advanced age of the patients and the long term neutropenia [absolute neutrophil count <500 (median) 27 days]. In spite of higher IA morbidity, mortality rates seemed very low. Furthermore, although GM >2.5 indicates an unfavorable prognosis and >5.0 no hope of survival, none of our patients with GM >2.5 (10 patients) died of IA (2 died of other causes) and all patients with GM >5.0 (4 patients) survived. Candidemia was found in 2 patients (krusei 1, guilliermondii 1) and were treated succesfully. β-D was positive in 46 /112 (41%) episodes and 28/112 (25%) were also positive for GM. As for GM and β-D, GM positivity preceded that of β-D in 9/28 (32%); regarding GM and CT, GM positivity preceded the observation of CT findings in 13/30 (43%).At the beginning of this study, no control CT was obtained. But in the course of the study we found some patients who presented CT findings indicating IA, such as nodular lesions, but with no infection. Thus, we realized the need for a control CT to detect IA more accurately. Each diagnostic procedure has excellent characteristics but it is not sufficient by itself. The results of this single-center clinical study indicate that an improvement of antifungal therapy combined with a battery of diagnostic procedures may allow safe, intensive chemotherapy for many patients with MDS or AML. Disclosures:No relevant conflicts of interest to declare.

7 Candidiasis

7 Candidiasis

Impact of the efficacy of HAART for AIDS combined of oral fungal infections

Objective To explore the efficacy of HAART for AIDS combined of oral fungal infection. Methods 60 AIDS patients combined with fungal infection were selected and divided into therapy group (n =30) and control group (n = 30) by HAART criteria. Individuals in control group were treated with routine care, including washing mouth by 2％ sodium bicarbonate, Smearing glycerol reducing mold on local skin, and taking fluconazole or itraconazole capsules 100 mg orally, and all above were taken twice a day, meanwhile nutrition therapy and oral nursing were strengthened. Therapy group were treated with HAART on the base of routine care. Results Effect rate between the two groups was significantly different (X2 = 6. 667, P ＜ 0. 05). Cure rate and recurrence rate were also different (X2 = 4. 286,4. 356; P ＜ 0. 05). Conclusions Application of HAART on the basis of routine care for AIDS combined of oral fungal infections has better efficacy and lower recurrence rate and improve the clinical symptom and raise the life quality of the patients. Key words: HAART; Highly effect; AIDS; Fungal; Infection control