Severe vincristine toxicity in combination with itraconazole

We report two patients with acute lymphoblastic leukaemia (ALL) who were entered into the current MRC adult ALL trial (UKALL XII) in whom unusually severe vincristine induced neurotoxicity developed. This appeared to be the result of an interaction with itraconazole suspension.     

Liver failure and transplantation after itraconazole treatment for toenail onychomycosis

Three weeks after completing a 4-pulse course of itraconazole for toenail onychomycosis, a 25-year-old woman patient developed severe liver crisis and required an emergency liver transplant. We report the case and discuss the use of itraconazole in onychomycosis and dermatomycoses.     

Visceral paracoccidioidomycosis in a gold miner from Brazil

Zusammenfassung: Es wird über einen 49-jährigen Deutschen berichtet, der nach 15-jährigem Aufenthalt in Südameri-ka an einer Paracoccidioidomykose er-krankte. Er litt an einer Cheilitis, einer erosiven Stomatitis, einer Laryngitis und einer beidseitigen Pilzpneumonie; außer-dem bestand der Verdacht auf ein Pilzgra-nulom des Gehirns. Die Diagnose wurde kulturell und serologisch gesichert. Die Ausbildung typischer Hefeformen mit mul-tiplen Sprossungen (“Steuerradformen”) benötigt oft länger als einen Monat (in die-sem Fall 6 Wochen), was die Diagnostik bei unklaren Krankheitsbildern erschwert. Der Patient wurde zunächst mit Amphotericin B und Sulfamethoxazol/Trimethoprim behandelt. Beide Medikamente muß-ten wegen Nebenwirkungen abgesetzt wer-den, obwohl Amphotericin B gut wirksam war. Ketoconazol war bei unserem Patien-ten weniger gut wirksam, während unter Itraconazol eine weitere deutliche Besse-rung eintrat. Nebenwirkungen wurden unter den beiden letztgenannten Medika-menten nicht beobachtet. Summary: We report on a 49 years old patient who developed paracoccidioidomycosis after working in a gold mine in South America. The patient suffered from cheilitis, stomatitis, laryngitis, and bilateral pneumonia. Additionally, there was evidence for cerebral granuloma. The diagnosis was confirmed by culture and serologic methods. Paracoccidioides brasilien-sis grows slowly and more than a month may elapse (in this case 6 weeks) before typical yeast-like forms with multiple buds (steering-wheel fungus cells) appear in culture, which often complicates the diagnosis if there is no typical clinical picture. The patient was treated with amphotericin B and sulfamethoxazole/trimethoprim, and a clinical response to therapy was observed. However, therapy had to be stopped because of severe side effects. Ketoconazole was less effective, but further clinical improvement was achieved under itraconazole without untoward side effects.     

Oral and Gastrointestinal Candidosis: Prophylaxis During Immunosuppressive Therapy.

Summary: Patients with acute leukaemia and malignant lymphomas often are severely affected by fungal infections. There is in particular growing concern about disseminated candidosis. Oral, gastrointestinal and systemic candidosis seem to be closely linked. Predisposing factors are damaged mucosal barriers due to chemotherapy, protracted periods of neutropenia, and prolonged use of antibiotics and steroids.
Oropharyngeal candidosis is very frequent. This can be prevented or controlled by the application of topical antifungals such as nystatin. The systemic application of antifungals is an alternative for patients who do not respond. Both oral ketoconazole and intravenous amphotericin B have been proven effective. Candida oesophagitis is also an important problem. Oral nystatin suspension can be helpful in mild cases. In others oral ketoconazole and intravenous amphotericin B have to be used. A whole range of measures has to be taken to prevent spread of the disease, i.e. H,-antagonists should be used only if definitely needed. Specific antifungal prophylaxis has also been discussed. Oral amphotericin B seems to be helpful. The azole itraconazole might be especially promising.     

Treatment with Itraconazole of Experimental Coccidioidomycosis in the Wistar Rat/Itraconazol-Behandlung der experimentellen Coccidioidomykose an Wistar-Ratten

Summary: The results obtained in a comparative study between ketoconazole and itraconazole in the treatment of the experimental coccidioidomycosis of the Wistar rat are presented. Animals weighing 250 g were inoculated intracardiacally with 200 arthrospores of Coccidioides immitis. Both drugs were administered once a day by gavage 16 mg/kg for itraconazole and 80 mg/kg for ketoconazole. Two therapeutic schedules of 14 days were used. The first one was set up 3 d before the infecting inoculation (earlier treatment) and the second one 7 d after it (later treatment). The control group of animals received only the solvent of both drugs (PEG 200). 98 animals which received the earlier treatment were evaluated. Only 3/30 rats that received itraconazole showed lung granulomas without spherules and the cultures were negative in all cases. From the 31 animals belonging to the ketoconazole group, 15 showed granulomas, 11 showed spherules and in 10 C. immitis developed in cultures. From the 37 rats used as controls, 35 had lung granulomas, 34 of them with spherules, and the cultures were positive in 35 cases. The later starting scheme was used on 30 rats, 8/10 of the animals treated with ketoconazole showed granulomas with spherules and the cultures were positive in 3 rats with 256 C.F.U./g of the lung; 9/10 of the itraconazole treated rats showed pulmonary granulomas with sporangia, with positive cultures in 2 cases and an average of 231 CF.U./g of the lung. The whole population of the control animals showed granulomas with sporangia and positive cultures, with an average of 18.247 C.F.U./g of the lung. All the treated animals exhibited very small sporangia without endospores. It was concluded that itraconazole was better in the treatment of the earlier schedule and showed similar efficacy to ketoconazole in the later schedule with doses 5 times lower. Zusammenfassung: Die Resultate einer Vergleichsstudie zwischen Ketoconazol and Itraconazol in der Behandlung der experimentellen Coccidioidomykose der Wistar-Ratte werden dargestellt. Es wurden Tiere mit einem Gewicht von 250 g verwendet und 200 Arthrosporen von Coccidioides immitis intrakardial inokuliert. Die Verabreichung beider Medikamente erfolgte 1 x/d in einer Dosierung von 16 mg/kg Itraconazol sowie 80 mg/kg Ketoconazol. Es kamen zwei therapeutische Schemata von 14-tägiger Dauer zur Anwendung, das erste begann 3 d vor der Infektion (Frühtherapie), das zweite 7 d danach (Spättherapie). Die Kontroll-gruppe erhielt ausschlißlich das Lösungsmittel beider Medikamente (PEG 200): 98 Versuchstiere mit Frühtherapie wurden ausgewertet. Nur 3/30 Ratten, denen Itraconazol appliziert wurde, zeigten pulmonale Granulome ohne Spherulen, und die Kulturen waren in allen Fällen negativ. Von 31 mit Ketoconazol behandelten Tieren wiesen 15 Granulome, 11 Spherulen auf, und bei 10 wuchs C. Immitis in Kulturen. Von den 37 Ratten der Kontrollgruppe zeigten 35 Lungengranulome, 34 davon mit Spherulen, und in 35 Fällen waren die Kulturen positiv. Die Spättherapie wurde bei 30 Ratten ange-wandt; 8/10 dieser Tiere, behandelt mit Ketoconazol, zeigten Granulome mit Spherulen, und bei drei Ratten waren die Kulturen positiv mit 256 KfE/g Lunge. 9/10 der mit Itraconazol therapierten Ratten wiesen pulmonale Granulome mit Spherulen auf mit positiven Kulturen in zwei Fällen und einem Durchschnitt von 231 KfE/g Lunge. Die gesamte Kontrollgruppe zeigte Granulome mit Spherulen und positive Kulturen mit einem Durchschnitt von 18.247 KfE/g Lunge. Alle behandelten Tiere wiesen sehr kleine Spherulen ohne Endosporen auf, die Kontrollgruppe hingegen reife Spherulen mit Endosporen. Daraus wird geschlossen, daß Itraconazol in der Friihtherapie besser wirkt und in der Spättherapie dem Ketoconazol vergleichbare Wirksamkeit mit einer fünffach niedrigeren Dosis erzielt     

Treatment of Pityriasis versicolor with Itraconazole: A Double-Blind Placebo Controlled Study

Summary:  Thirtythree patients with pityriasis versicolor were treated in a double-blind placebo controlled study with intraconazole. 17 patients received 100 mg capsules once daily of itraconazole and 16 patients received one placebo capsule once daily, 2 patients in the itraconazole and 2 patients in the placebo group did not fulfill the treatment. 10 of 15 patients (66.7%) were cured in the itraconazole group and one of 14 (7.2%) in the placebo group (p < 0.01). Patients who were not cured after 2 weeks received itraconazole 100 mg o.d. in an open study. Here 11 of 18 patients (61.1%) cleared after two weeks and the other 7 patients (38.9%) after 4 weeks. No side-effects were seen. Due to the few reported side-effects of itraconazole this drug may be used both for the treatment and as prophylaxis in patients with pityriasis versicolor.
Zusammenfassung:  Dreiunddreißig Patienten mit Pityriasis versicolor wurden in einer Placebo-kontrollierten Doppelblindstudie mit Itraconazol behandelt. 17 Patienten erhielten einmal täglich eine Kapsel mit 100 mg Itraconazol, 16 Patienten einmal täglich eine Placebo-Kapsel. Je 2 Patienten in der Itraconazol- wie in der Placebo-Gruppe erfüllten das Therapieregime nicht. In der Itraconazol-Gruppe wurden 10 von 15 Patienten (66,7%) und in der Placebo-Gruppe einer von 14 (7,2%) geheilt (p < 0,01). Patienten, die nach 2 Wochen nicht geheilt waren, erhielten weiterhin 100 mg Itraconazol einmal täglich in einer offenen Studie. Hierbei heilten 11 von 18 (61.1%) nach weiteren 2 Wochen und die übrigen 7 Patienten (38.9%) nach 4 Wochen ab. Nebenwirkungen wurden nicht beobachtet. Wegen der geringen, bis jetzt berichteten Nebenwirkungsrate ist Itraconazol offensichtlich für die Behandlung wie für die Prophylaxe der Pityriasis versicolor geeignet.     

中国志愿受试者多剂量口服伊曲康唑后血液和指甲药代动力学研究

目的：对９例中国健康志愿者多剂量口服西安扬森公司生产的伊曲康唑后的血液和指甲药代动力学进行研究。方法：用高效液相色谱法测定血清和指甲中药物浓度，以３ｐ８７实用药代动力学程序计算稳态后，一次给药的药代动力学参数。结果：血中药物消除半衰期（ｔ１／２）平均为４１．５６ｈ；血中药物最高浓度（Ｃｍａｘ）平均为１２３０．８３ｎｇ／ｍｌ；血中药物达最高浓度的时间（Ｔｍａｘ）平均为４．３８ｈ；血药浓度－时间曲线下面积（ＡＵＣ）平均为６６３９６．５２ｎｇ·ｈ／ｍｌ。停药后ｄ７和９个月，受试者指甲中伊曲康唑的平均浓度分别为（９５７±１００９）ｎｇ／ｇ和（２３１±４１８）ｎｇ／ｇ。     

Fluconazole and itraconazole susceptibilities of Candida spp. isolated from oropharyngeal specimens and blood cultures of paediatric haematology/oncology patients

This study examined the in vitro susceptibilities to fluconazole and itraconazole of isolates of Candida spp. from surveillance oropharyngeal specimens and blood cultures from paediatric patients with malignancy. The species distribution of 100 isolates from oropharyngeal specimens was C. albicans 86%, C. glabrata 7%, C. lusitaniae 4%, C. parapsilosis 2% and C. tropicalis 1%. From a total of nine isolates from blood cultures the species distribution was C. albicans 33.3%, C. parapsilosis 33.3 % and C. guilliermondii 33.3%. Only three of the oropharyngeal isolates were resistant to fluconazole (MIC > or = 64 mg l(-1)) and only two were resistant to itraconazole (MIC > or = 1 mg l(-1)). None of the blood culture isolates was resistant to either agent. At this centre, C. albicans is the predominant species from oropharyngeal specimens, but non-albicans Candida species predominate in blood cultures. Although resistance to fluconazole and itraconazole is rare at present, continued surveillance is warranted to monitor trends in species distribution and antifungal susceptibility.     

Factors influencing the magnitude and clinical significance of drug interactions between azole antifungals and select immunosuppressants

The magnitude of drug interactions between azole antifungals and immunosuppressants is drug and patient specific and depends on the potency of the azole inhibitor involved, the resulting plasma concentrations of each drug, the drug formulation, and interpatient variability. Many factors contribute to variability in the magnitude and clinical significance of drug interactions between an immunosuppressant such as cyclosporine, tacrolimus, or sirolimus and an antifungal agent such as ketoconazole, fluconazole, itraconazole, voriconazole, or posaconazole. By bringing similarities and differences among these agents and their potential interactions to clinicians' attention, they can appreciate and apply these findings in a individualized patient approach rather than follow only the one-size-fits-all dosing recommendations suggested in many tertiary references. Differences in metabolism and in the inhibitory potency of cytochrome P450 3A4 and P-glycoprotein influence the onset, magnitude, and resolution of drug interactions and their potential effect on clinical outcomes. Important issues are the route of administration and the decision to preemptively adjust dosages versus intensive monitoring with subsequent dosage adjustments. We provide recommendations for the concomitant use of these agents, including suggestions regarding contraindicated combinations, those best avoided, and those requiring close monitoring of drug dosages and plasma concentrations.