Success rate and risk factors for failure of empirical antifungal therapy with itraconazole in patients with hematological malignancies: a multicenter, prospective, open-label, observational study in Korea.

We assessed the success rate of empirical antifungal therapy with itraconazole and evaluated risk factors for predicting the failure of empirical antifungal therapy. A multicenter, prospective, observational study was performed in patients with hematological malignancies who had neutropenic fever and received empirical antifungal therapy with itraconazole at 22 centers. A total of 391 patients who had abnormal findings on chest imaging tests (31.0%) or a positive result of enzyme immunoassay for serum galactomannan (17.6%) showed a 56.5% overall success rate. Positive galactomannan tests before the initiation of the empirical antifungal therapy (P=0.026, hazard ratio [HR], 2.28; 95% confidence interval [CI], 1.10-4.69) and abnormal findings on the chest imaging tests before initiation of the empirical antifungal therapy (P=0.022, HR, 2.03; 95% CI, 1.11-3.71) were significantly associated with poor outcomes for the empirical antifungal therapy. Eight patients (2.0%) had premature discontinuation of itraconazole therapy due to toxicity. It is suggested that positive galactomannan tests and abnormal findings on the chest imaging tests at the time of initiation of the empirical antifungal therapy are risk factors for predicting the failure of the empirical antifungal therapy with itraconazole. (Clinical Trial Registration on National Cancer Institute website, NCT01060462).

Lack of drug interaction between the migraine drug MAP0004 (orally inhaled dihydroergotamine) and a CYP3A4 inhibitor in humans.

BACKGROUND: Dihydroergotamine (DHE), a proven migraine treatment, currently has product labeling warning against concomitant use of CYP3A4 inhibitors because of potential drug interactions. However, no reported studies of such interactions with DHE administered by any route are available. METHODS: The pharmacokinetics (PK) of MAP0004, an investigative inhaled DHE formulation, were assessed in human subjects with and without CYP3A4 inhibition by ketoconazole to evaluate the potential for drug interaction, elevation of DHE levels, and increased adverse effects. RESULTS: After MAP0004 alone vs. MAP0004 plus ketoconazole, the DHE maximum concentrations (C(max)) and area-under-the-curve (AUC(0-48) and AUC(0-∞)) were not statistically significantly different nor was the C(max) of the primary metabolite, 8'-OH-DHE. A difference in 8'-OH-DHE AUCs was observed between MAP0004 with and without ketoconazole; however, the concentrations were very low. MAP0004 was well tolerated after both treatments. CONCLUSIONS: This study demonstrated that CYP3A4 inhibition had little to no effect on DHE PK after MAP0004 administration, apparently because of its high systemic and low gastrointestinal bioavailability. CYP3A4 inhibition slowed elimination of the metabolite 8'-OH-DHE, but concentrations were too low to be pharmacologically relevant.

Successful outcome of pregnancy in a patient with Cushing's disease under treatment with ketoconazole during the first trimester of gestation.

BACKGROUND: Ketoconazole is the most widely used medical treatment for Cushing's syndrome, but, because of its potential to cause birth defects, it is not recommended during pregnancy. Specifically, due to its antiandrogenic effects, ketoconazole entails theoretical risks of interfering with the development of external genitalia in male fetuses. CASE: A pregnancy was diagnosed at 13 weeks of gestation in a 26-year-old woman with Cushing's disease under treatment with ketoconazole. The drug was withdrawn and the patient underwent transsphenoidal surgery at 16 weeks of pregnancy. She did not develop postsurgical adrenal insufficiency and was treated with metyrapone during the second and third trimesters of gestation. Partum was induced at 34 weeks of pregnancy. The patient delivered a healthy male infant with normal external genitalia. CONCLUSION: Treatment with ketoconazole during the critical period of organogenesis did not cause congenital birth defects to the male fetus of a woman with Cushing's disease. This report should be taken into account for future cases of unplanned pregnancies in women with Cushing's syndrome treated with ketoconazole, as well in those cases in which other therapeutic options are not feasible.

4-aminopyridyl-based lead compounds targeting CYP51 prevent spontaneous parasite relapse in a chronic model and improve cardiac pathology in an acute model of Trypanosoma cruzi infection.

BACKGROUND: Chagas disease, caused by the protozoan Trypanosoma cruzi, is the leading cause of heart failure in Latin America. The clinical treatment of Chagas disease is limited to two 60 year-old drugs, nifurtimox and benznidazole, that have variable efficacy against different strains of the parasite and may lead to severe side effects. CYP51 is an enzyme in the sterol biosynthesis pathway that has been exploited for the development of therapeutics for fungal and parasitic infections. In a target-based drug discovery program guided by x-ray crystallography, we identified the 4-aminopyridyl-based series of CYP51 inhibitors as being efficacious versus T.cruzi in vitro; two of the most potent leads, 9 and 12, have now been evaluated for toxicity and efficacy in mice. METHODOLOGY/PRINCIPAL FINDINGS: Both acute and chronic animal models infected with wild type or transgenic T. cruzi strains were evaluated. There was no evidence of toxicity in the 28-day dosing study of uninfected animals, as judged by the monitoring of multiple serum and histological parameters. In two acute models of Chagas disease, 9 and 12 drastically reduced parasitemia, increased survival of mice, and prevented liver and heart injury. None of the compounds produced long term sterile cure. In the less severe acute model using the transgenic CL-Brenner strain of T.cruzi, parasitemia relapsed upon drug withdrawal. In the chronic model, parasitemia fell to a background level and, as evidenced by the bioluminescence detection of T. cruzi expressing the red-shifted luciferase marker, mice remained negative for 4 weeks after drug withdrawal. Two immunosuppression cycles with cyclophosphamide were required to re-activate the parasites. Although no sterile cure was achieved, the suppression of parasitemia in acutely infected mice resulted in drastically reduced inflammation in the heart. CONCLUSIONS/SIGNIFICANCE: The positive outcomes achieved in the absence of sterile cure suggest that the target product profile in anti-Chagasic drug discovery should be revised in favor of safe re-administration of the medication during the lifespan of a Chagas disease patient. A medication that reduces parasite burden may halt or slow progression of cardiomyopathy and therefore improve both life expectancy and quality of life.

[Clinical usefulness of triazole derivatives in the management of fungal infections]. / La utilidad clínica de los derivados triazólicos en el tratamiento de las infecciones fúngicas.

Current therapy for mycoses is limited to the use of a relative reduced number of antifungal drugs. Although amphotericin B still remains considered as the "gold standard" for treatment, acute and chronic toxicity, such as impairment of renal function, limits its use and enhances the investigation and clinical use other chemical families of antifungal drugs. One of these chemical class of active drugs are azole derivatives, discovered in 70s and introduced in clinical practice in 80s. Being the most prolific antifungal class, investigation about more molecules, with a safer and better pharmacological profile, active against a wide spectrum of fungi, with a wide range of administration routes gives us some azole representatives.

Efinaconazole (Jublia) for the treatment of onychomycosis.

Efinaconazole 10% nail solution (Jublia(®)) is a new topical triazole antifungal designed for the topical treatment of distal and lateral subungual onychomycosis. It inhibits ergosterol biosynthesis enzyme sterol 14α-demethylase. Efinaconazole has lower minimum inhibitory concentrations than terbinafine, ciclopirox, itraconazole and amorolfine in Trichophyton rubrum, Trichophyton mentagrophytes and Candida albicans. The solution based formula has low surface tension and keratin binding properties that increase penetrance through the nail plate. Safety studies have shown that this formulation is not associated with atopic dermatitis or contact sensitivity. Duplicate Phase III clinical trials in adults with mild to moderate distal and lateral subungual onychomycosis indicate that efinaconazole 10% solution is an effective therapy with a pooled complete cure rate of 17% and a pooled mycological cure rate of 54%. Efinaconazole 10% nail solution is a safe and effective new topical therapy for onychomycosis, which will fill a pressing need for more effective topical therapy in this disease.

Ketoconazole in Cushing's disease: is it worth a try?

BACKGROUND: The use of ketoconazole has been recently questioned after warnings from the European Medicine Agencies and the Food and Drug Administration due to potential hepatotoxicity. However, ketoconazole is frequently used as a drug to lower circulating cortisol levels. Several pharmacological agents have recently been approved for the treatment of Cushing's disease (CD) despite limited efficacy or significant side effects. Ketoconazole has been used worldwide for more than 30 years in CD, but in the absence of a large-scale study, its efficacy and tolerance are still under debate. PATIENTS AND METHODS: We conducted a French retrospective multicenter study reviewing data from patients treated by ketoconazole as a single agent for CD, with the aim of clarifying efficacy and tolerance to better determine the benefit/risk balance. RESULTS: Data from 200 patients were included in this study. At the last follow-up, 49.3% of patients had normal urinary free cortisol (UFC) levels, 25.6% had at least a 50% decrease, and 25.4% had unchanged UFC levels. The median final dose of ketoconazole was 600 mg/d. Forty patients (20%) received ketoconazole as a presurgical treatment; 40% to 50% of these patients showed improvement of hypertension, hypokalemia, and diabetes, and 48.7% had normal UFC before surgery. Overall, 41 patients (20.5%) stopped the treatment due to poor tolerance. Mild (<5N, inferior to 5-fold normal values) and major (>5N, superior to 5-fold normal values) increases in liver enzymes were observed in 13.5% and 2.5% of patients, respectively. No fatal hepatitis was observed. CONCLUSIONS: Ketoconazole is an effective drug with acceptable side effects. It should be used under close liver enzyme monitoring. Hepatotoxicity is usually mild and resolves after drug withdrawal.

Safety and efficacy of maintenance therapy with a nonspecific cytochrome P17 inhibitor (CYP17i) after response/stabilization to docetaxel in metastatic castration-resistant prostate cancer.

BACKGROUND: Frontline treatment of metastatic castration-resistant prostate cancer (mCRPC) consists of docetaxel-based chemotherapy. The median time to progression (TTP) from chemotherapy initiation is 6 to 8 months. Ketoconazole, a nonspecific cytochrome P17 inhibitor (CYP17i), blocks adrenal androgen synthesis. Low-dose ketoconazole (LDK), (200 mg three times daily [t.d.s]) has shown activity in mCRPC after progression to androgen deprivation. The role of a CYP17i after docetaxel treatment in the maintenance setting has been unexplored. METHODS: We identified 38 patients with mCRPC who showed progression to luteinizing hormone releasing-hormone agonists (LHRHa) and who were treated with a median of 7 cycles of frontline three-weekly docetaxel (75 mg/m(2)) plus prednisone (10 mg/d) and LHRHa. Medical charts of 20 patients who showed no progression to docetaxel were reviewed. After the last docetaxel cycle, 10 patients received LDK maintenance treatment plus prednisone (10 mg/d) and LHRHa, whereas 10 patients received LHRHa alone. TTP was the primary endpoint. RESULTS: After a follow-up of 27 months, disease in all patients receiving LHRHa alone progressed, whereas 8/10 patients progressed to maintenance therapy. Median TTP from docetaxel initiation was 11.5 months (95% confidence interval [CI], 6.3-16.6) for maintenance therapy and 9.2 months (95% CI, 8.5-9.9) for LHRHa alone (P = .047). The maintenance treatment was well tolerated. Only 1 patient experienced a grade 4 adverse event due to a nonsymptomatic pulmonary embolism. CONCLUSION: This is the first study evaluating a CYP17i for maintenance therapy after docetaxel therapy. We showed a 2-month significant benefit in TTP for patients with mCRPC treated with LDK maintenance therapy after docetaxel, with a favorable toxicity profile. A large prospective randomized study using a CYP17i is warranted.

Drug-induced gynecomastia: an evidence-based review.

INTRODUCTION: Drugs are estimated to cause about 10 - 25% of all cases of gynecomastia. Over the course of several decades, multiple medications have been implicated in the development of gynecomastia mostly in the form of case reports and case series. However, these reports suffer from a multitude of deficiencies, including poor quality of evidence. AREAS COVERED: Studies were selected for this review by performing an extensive electronic and hand-search using BIOSIS, EMBASE and Medline, from 1940 to present, for all reported drug associations of gynecomastia and their possible pathophysiology. Quality of evidence was assessed on a three-point scale: good, fair and poor, and each of the drugs reported to cause gynecomastia was assigned a level of strength. The pathophysiology of gynecomastia is also discussed in detail for each of the drugs found to have a good or fair evidence of association with gynecomastia. EXPERT OPINION: Most of the reported drug-gynecomastia associations were based on poor quality evidence. The drugs definitely associated with the onset of gynecomastia are spironolactone, cimetidine, ketoconazole, hGH, estrogens, hCG, anti-androgens, GnRH analogs and 5-α reductase inhibitors. Medications probably associated with gynecomastia include risperidone, verapamil, nifedipine, omeprazole, alkylating agents, HIV medications (efavirenz), anabolic steroids, alcohol and opioids.

Voriconazole in clinical practice.

Invasive fungal diseases are associated with significant morbidity and mortality in immunocompromized patients. Voriconazole is the first line treatment of invasive aspergillosis, and has been successfully used in other invasive fungal infections, such as candidiasis, fusariosis or scedosporidiosis. Voriconazole has non-linear pharmacokinetics and undergoes extensive hepatic metabolism by the cytochrome P450 system that depends on age, genetic factors, and interactions with other drugs. Thus, significant interpatient variability is observed after administration of the same dose. Additionally, the therapeutic window is narrow, with high risk of side effects at serum levels 3-5 times higher than the minimal threshold for efficacy. Therefore, the knowledge of pharmacological properties, metabolism, interactions, dosage indications in various populations and side effects is crucial. Therapeutic drug monitoring can help maximize the efficacy and minimize the risk of toxicity. Pharmacological, mycological and clinical aspects of the treatment with voriconazole are summarized in order to optimize its use in daily clinical practice.

Success Rate and Risk Factors for Failure of Empirical Antifungal Therapy with Itraconazole in Patients with Hematological Malignancies: A Multicenter, Prospective, Open-Label, Observational Study in Korea

We assessed the success rate of empirical antifungal therapy with itraconazole and evaluated risk factors for predicting the failure of empirical antifungal therapy. A multicenter, prospective, observational study was performed in patients with hematological malignancies who had neutropenic fever and received empirical antifungal therapy with itraconazole at 22 centers. A total of 391 patients who had abnormal findings on chest imaging tests (31.0%) or a positive result of enzyme immunoassay for serum galactomannan (17.6%) showed a 56.5% overall success rate. Positive galactomannan tests before the initiation of the empirical antifungal therapy (P=0.026, hazard ratio [HR], 2.28; 95% confidence interval [CI], 1.10-4.69) and abnormal findings on the chest imaging tests before initiation of the empirical antifungal therapy (P=0.022, HR, 2.03; 95% CI, 1.11-3.71) were significantly associated with poor outcomes for the empirical antifungal therapy. Eight patients (2.0%) had premature discontinuation of itraconazole therapy due to toxicity. It is suggested that positive galactomannan tests and abnormal findings on the chest imaging tests at the time of initiation of the empirical antifungal therapy are risk factors for predicting the failure of the empirical antifungal therapy with itraconazole. (Clinical Trial Registration on National Cancer Institute website, NCT01060462)