Prevention of Mycosis in Granulocytopenic Patients with Prophylactic Ketoconazole Treatment/Prophylaktische Mykose-Behandlung mit Ketoconazol bei granulozytopenischen Patienten

Summary: 38 patients with acute leukemia were randomly allocated to receive ketoconazole 400 mg daily p. o. or placebo in a double-blind fashion. Ketoconazole did neither prevent the patients from being colonized with Candida species, nor eradicate the fungi in patients already colonized, but only 2 ketoconazole patients developed clinical mycosis against 9 placebo patients (p = 0.03). The cumulative risk of developing clinical mycosis was significantly different in the two treatment groups (p = 0.003 at day 14). Prophylactic treatment with ketoconazole prevents or postpones the develepment of clinical mycosis in highly predisposed patients and has very few side effects.
Zusammenfassung: 38 Patienten mit akuter Leukämie wurden in einer randomisierten Doppelblindstudie mit Ketoconazol 400 mg pro die gegen Placebo untersucht. Ketoconazol vermochte weder die Kolonisierung von Candida-Spezies zu verhindern, noch beim Patienten bereits kolonisierte Pilze zu vernichten. Klinische Mykosen entwickelten sich bei 2 Ketoconazol-Patienten, gegenüber 9 Placebo-Patienten (p = 0,03). Das kumulative Risiko, eine Mykose zu entwickeln, war deshalb signifikant verschieden in den beiden Behandlungsgruppen (p = 0,003 am 14. Tag). Die prophylaktische Behandlung mit Ketoconazol verhindert oder verzögert die Entwicklung von Mykosen bei hochdisponierten Patienten und weist wenige Nebenwirkungen auf.     

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     

Effect of Ketoconazole on the Initial Stages of Germ Tube Formation by Strains of Candida albicans

Summary: The effect of therapeutic concentrations of ketoconazole on the initial stages of germ tube formation of asynchronous cells of three Candida albicans strains was compared in Eagles Minimal Essential Medium (EMEM) and human serum. Germ tube formation after incubation for 3h at 37°C in drug free medium was found to be strain and incubation medium dependent. Ketoconazole did not influence conversion from the blastospore to the hyphal form of cells in human serum. In EMEM, marked variation in germination among strains was evident although not influenced by ketoconazole. Individual strains demonstrated similar patterns of byphal formation in all serum specimens obtained over 48h from human subjects who had received either 200 or 400 mg ketoconazole as single oral doses. Zusammenfassung: Drei verscbiedene Candida albimns-Stämme, zwei wurden von Patienten mit einer Candidose isoliert, wurden auf ihre Fähigkeit Keimschläuche zu bilden, und zwar sowohl auf “Eagles minimal essential medium (EMEM)” als auch in “menschlichem Serum“, untersucht. Die Keimschlauchbildung war in antimykotikafreien Nährböden nach 3 Stunden bei 37°C stamm- und nährbodenabhängig. Hingegen beeinflußte Ketokonazol die Keimschlauchbildung bei einer therapeutischen Konzentration von 8 γ/ml Medium in keiner Weise. Die zahlenmäßig unterschiedlich zu beobachtende Keimschlauchbildung auf EMEM der drei C. albicans-Stämme war stammbedingt und wurde durch die Ketokonazolkonzentration (8 γ/ml) nicht beeinflußt. Probanden erhielten oral eine Einzeldosis von 200 oder 400 mg Ketokonazol. Vor dieser Einzeldosis sowie 1,2,3,4,6,8,12,24 und 48 Stunden nach der Medikamentengabe wurde ihnen Blut abgenommen. Keine der Serumproben ließ eine signifikante Verminderung der Keimschlauchbildung erkennen. Es wurden nur pilzstammbedingte Unterschiede beobachtet. Die Ketokonazolkonzentration wurde in diesen Serumproben mit einer mikrobiologischen Agardiffusionsmethode bestimmt. Die höchsten Ketokonazolkonzentrationen wurden jeweils nach 2 Stunden gemessen, und mar 2,44 γ/ml (200 mg) und 7,5 γ/ml (400 mg).     

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.     

Effects of cytochrome P450 3A modulators ketoconazole and carbamazepine on quetiapine pharmacokinetics

AIMS: To explore the potential for drug interactions on quetiapine pharmacokinetics using in vitro and in vivo assessments. METHODS: The CYP enzymes responsible for quetiapine metabolite formation were assessed using recombinant expressed CYPs and CYP-selective inhibitors. P-glycoprotein (Pgp) transport was tested in MDCK cells expressing the human MDR1 gene. The effects of CYP3A4 inhibition were evaluated clinically in 12 healthy volunteers that received 25 mg quetiapine before and after 4 days of treatment with ketoconazole 200 mg daily. To assess CYP3A4 induction in vivo, 18 patients with psychiatric disorders were titrated to steady-state quetiapine levels (300 mg twice daily), then titrated to 600 mg daily carbamazepine for 2 weeks. RESULTS: CYP3A4 was found to be responsible for formation of quetiapine sulfoxide and N- and O-desalkylquetiapine and not a Pgp substrate. In the clinical studies, ketoconazole increased mean quetiapine plasma C(max) by 3.35-fold, from 45 to 150 ng ml(-1) (mean C(max) ratio 90% CI 2.51, 4.47) and decreased its clearance (Cl/F) by 84%, from 138 to 22 l h(-1) (mean ratio 90% CI 0.13, 0.20). Carbamazepine decreased quetiapine plasma C(max) by 80%, from 1042 to 205 ng ml(-1) (mean C(max) ratio 90% CI 0.14, 0.28) and increased its clearance 7.5-fold, from 65 to 483 l h(-1) (mean ratio 90% CI 6.04, 9.28). CONCLUSIONS: Cytochrome P450 3A4 is a primary enzyme responsible for the metabolic clearance of quetiapine. Quetiapine pharmacokinetics were affected by concomitant administration of ketoconazole and carbamazepine, and therefore other drugs and ingested natural products that strongly modulate the activity or expression of CYP3A4 would be predicted to change exposure to quetiapine.     

The Effect of Ketoconazole on the Phagocytosis and Intracellular Killing of Candida albicans by Polymorphonuclear Granulocytes

Summary: The synergism between the polymorphonuclear granulocytes and ketoconazole was studied in vitro. The phagocyte index proved to be 87.3 + 8.1. while the Candida killing index was 20.8 + 4.8. Treatment of granulocytes with ketoconazole did not influence their activity. However, the treatment of Candida albicans with ketoconazole led to unchanged phagocytosis, but a significantly higher killer activity. The results indicate that not the immunomodulating effect of the imidazole derivative, but its antimycotic effect, is responsible for the synergism observed between ketoconazole and the host defence mechanisms.
Zusammenfassung: Der Synergismus zwischen polymorphonukleären Granulozyten und Ketoconazol wurde in der vorliegenden Studie in vitro untersucht. Die Bestimmung des Phagozytosenindex ergab einen Wert von 87,3 + 8,1. und beim Candida-Abtötungsindex 20,8 + 4,8. Die Behandlung der Granulozyten mit Ketoconazol ließ die Aktivität dieser Zellen unbeeinflußt. Wird der Candida-Suspension Ketoconazol zugesetzt, beeinflußt es die Phagozytose der Candida-Zellen nicht, sondern erhöht signifikant die candidacide Aktivität. Die Ergebnisse weisen darauf bin, daß der zwischen dem Arzneimittel und dem Abwehrsystem des Wirtes bestehende Synergismus sich nicht aus einem immunomodulierenden Effekt der Imidazol-Derivate erklärt, sondern auf die antimykotische Wirkung von Ketoconazol zurückgeht.     

Comparison of Ketoconazole Suspension and Nystatin in the Treatment of Newborns and Infants with Oral Candidosis: Vergleich von Ketoconazol-Suspension und Nystatin in der Behandlung der oralen Candidose bei Neugeborenen und Kleinkindern

Ketoconazole suspension (20 mg per ml) was compared with nystatin (100,000 units per ml) in the treatment of oral candidosis in newborns and infants. In all patients Candida infection was proven by culture. Twenty patients were treated with ketoconazole and 15 patients with nystatin. Treatment was discontinued 2 days after clinical cure, or after 3 weeks. The investigator assessed the severity of the thrush and accompanying symptoms at the start of the study and at weekly controls. After one week all 20 patients on ketoconazole (100%) and 8 (53%) patients on nystatin were cured clinically. At the end of the treatment 12 patients on nystatin (80%) were cured. Clinical cure was confirmed by negative culture in 94% of the patients on ketoconazole and in 73% of the patients on nystatin. No side-effects were observed in the patients on ketoconazole. Only in the case of one patient on nystatin, was vomiting observed. This study shows that ketoconazole cures thrush faster and more effectively than nystatin.     

特比萘芬与萘替芬酮康唑联合治疗外耳道真菌病的疗效分析

目的观察口服特比萘芬联合外用萘替芬酮康唑治疗外耳道真菌病的疗效、安全性。方法将66例外耳道真菌病患者随机分为两组：治疗组34例,口服特比萘芬联合外用萘替芬酮康唑,疗程1月;对照组32例,局部外用萘替芬酮康唑,疗程1月。结果治疗组1月后有效率为94.1%,高于对照组的53.1%,有显著性差异。结论联合疗法和单一外用药物治疗外耳道真菌病均有效,但联合疗法起效快、疗程短、效果好。     

Abiraterone acetate for castration resistant prostate cancer

Importance of the field: Androgen deprivation therapy has been the standard of care in advanced prostate cancer for >?50 years. Although castration is initially effective, most patients eventually develop progressive disease despite low levels of testosterone (termed castration resistant prostate cancer, CRPC). Intratumor and extra-gonadal androgens (specifically adrenal androgens) represent a means for continued androgen receptor-mediated growth in CRPC and have thus become therapeutic targets. One novel therapeutic is abiraterone acetate (AA): an inhibitor of CYP17, an enzyme that catalyzes two key serial reactions in androgen and estrogen biosynthesis. Data from Phase I and II trials suggest that clinically important antitumor activity is seen in up to 70% of castrate patients with advanced prostate cancer resistant to currently available endocrine therapies. The toxicity profile has also been found to be acceptable. Two large Phase III clinical trials are currently open to accrual and will hopefully validate the impressive Phase II data.

Areas covered in the review: The chemistry, pharmacodynamics, pharmacokinetics, clinical efficacy and safety/tolerability of AA.

What the reader will gain: Readers will understand the function of non-gonadal androgens, the importance of continued androgen deprivation in advanced prostate cancer and the role/clinical efficacy of AA.

Take home message: The recent realization that non-gonadal sources of androgens (adrenal and intracrine de novo synthesis) may be a major mediator of disease progression forms the biological rationale behind the development of abiraterone acetate and related drugs. Abiraterone acetate is an orally administered, specific inhibitor of CYP17A1, a rate-limiting enzyme in androgen biosynthesis. Preliminary data from Phase I and II trials suggest that prostate specific antigen declines occur in a large proportion of patients and that the toxicity profile is acceptable. Two large Phase III clinical trials are currently open to accrual and, if proven to be efficacious, will result in widespread use of a drug specifically developed to suppress adrenal androgens.     

Ketoconazole enantiomer for the treatment of diabetes mellitus

The impact of hypercortisolism on multiple metabolic conditions is well recognized; the metabolic manifestations of Cushing's syndrome overlap with those seen in type 2 diabetes and the metabolic syndrome. Ketoconazole (KTZ), a widely used antifungal agent that inhibits various enzymes in adrenal cortisol synthesis, is effective in treating hypercortisolemia, but its use is limited by toxicities. KTZ is a racemic compound of two cis-enantiomers: (2R,4S)-(+)-KTZ and (2S,4R)-(-)-KTZ. The consideration of an enantiomer with selective effect but minimal metabolic toxicity has driven the development of DIO-902 ([2S,4R]-[-]-KTZ) for the treatment of patients with type 2 diabetes and the metabolic syndrome. To evaluate the safety profile and effect of KTZ enantiomer, (2S,4R)-(-)-KTZ, on cortisol production, glycemia, and lipid profiles in patients with type 2 diabetes. Review of multiple published studies and examination of preliminary results from a Phase IIb clinical trial. Twelve weeks of treatment with DIO-902 resulted in reduced levels of HbA1c, FPG, total and LDL cholesterol as well as weight loss and decreased BP. In a previously conducted Phase IIa study, C-reactive protein levels decreased with DIO-902 treatment. Unfortunately, the development of this agent has been terminated due to unacceptable safety profiles.