Nizoral

Transplant Proc. 2005 Apr;37(3):1574-6.
Hepatotoxicity associated with cyclosporine monitoring using c(2) recommendations in adults renal recipients receiving ketoconazole.
Videla C, Vega J, Borja H.
Nephrology Department, G. Fricke Hospital, Vina del Mar, Chile.

Following the change, in the way we monitored cyclosporine (CsA) levels in January 2000 namely from C(0) to C(2) concentrations, in renal "de novo" allograft recipients, some patients treated with concomitant ketoconazole experienced liver toxicity, a complication that had not been previously seen with CsA monitoring using C(0). Therefore, we decided to compare the outcomes of patients transplanted using CsA levels monitored by C(0) (1998 to 1999) who also had simultaneous C(2) determinations (group A) with those of recipients transplanted after 2000 (group B). All received steroids, azathioprine, and CsA plus ketoconazole. Recipients were followed for at least a year after transplantation. Patients in group B showed higher CsA C(2) levels, AUC concentrations, and drug doses during the immediate postsurgical period, and at 2 weeks as well as 4 and 6 months posttransplantation. Six group B patients (26%) but no group A recipients displayed, severe liver toxicity characterized by jaundice, elevated liver enzymes, with negative serological tests for CMV, HVC, and HVB. There was a correlation between the GOT and the C(2) CsA levels; both normalized 15 to 55 days after CsA dose reduction. High C(2) CsA levels, which have been recommended when the drug is used alone in renal transplantation, cannot be used in patients taking ketoconazole, because C(2) neither represents nor correlates with AUC drug exposure. Thus high C(2) levels may produce liver toxicity.

J Urol. 2005 Jun;173(6):1947-52.
Long-term outcome for men with androgen independent prostate cancer treated with ketoconazole and hydrocortisone.
Scholz M, Jennrich R, Strum S, Brosman S, Johnson H, Lam R.
Prostate Oncology Specialists, Marina del Rey, University of California, Los Angeles, Los Angeles, California, USA. mark@prostateoncology.com

PURPOSE: The combination of high dose ketoconazole and hydrocortisone (HDK) is active against androgen independent prostate cancer (AIPC). Median response times with HDK tend to be brief but a significant minority of AIPC patients benefit with extended responses. Well characterized response and survival information, especially in the cohort of patients who experience these longer, more durable, responses has not been previously reported. Characterization of this subgroup is of particular interest since men with long-term responses derive the greatest benefit from HDK therapy. MATERIALS AND METHODS: The medical records of 78 patients with AIPC treated with HDK between March 1991 and February 1999 were retrospectively reviewed. Baseline clinical and laboratory factors predictive of prolonged response and survival were identified. RESULTS: The median baseline prostate specific antigen (PSA) before the initiation of HDK was 25.1. The number of patients with zero, 1 to 3, and more than 3 lesions on bone scan were 25, 35 and 18, respectively. Median and mean time to PSA progression was 6.7 and 14.5 months. Median and mean survival time was 38.0 and 42.4 months, respectively. Response time and survival were highly correlated (r = 0.799). A total of 34 (44%) men had a greater than 75% decrease in PSA. The median survival times in men with more vs less than a 75% decrease were 60 vs 24 months, respectively. In a Cox proportional hazard regression, prolonged survival was predicted by percent PSA decrease, extent of disease on bone scan and baseline PSA. CONCLUSIONS: Ketoconazole can induce prolonged responses, occasionally lasting for years. Long responses are more likely to occur in men initiating HDK earlier in the course of disease before the cancer burden becomes excessive.

Br J Clin Pharmacol. 2005 Mar;59(3):346-54.
Co-administration of ketoconazole with H-antagonists ebastine and loratadine in healthy subjects: pharmacokinetic and pharmacodynamic effects.
Chaikin P, Gillen MS, Malik M, Pentikis H, Rhodes GR, Roberts DJ.
Kyowa Pharmaceutical Inc., Princeton, New Jersey, USA.

Aims Two studies were conducted to evaluate the effects of coadministration of ketoconazole with two nonsedating antihistamines, ebastine and loratadine, on the QTc interval and on the pharmacokinetics of the antihistamines. Methods In both studies healthy male subjects (55 in one study and 62 in the other) were assigned to receive 5 days of antihistamine (ebastine 20 mg qd in one study, and loratadine 10 mg qd in the other) or placebo alone using a predetermined randomization schedule, followed by 8 days of concomitant ketoconazole 450 mg qd/antihistamine or ketoconazole 400 mg qd/placebo. Serial ECGs and blood sampling for drug analysis were performed at baseline and on study days 5 (at the end of monotherapy) and 13 (at the end of combination therapy). QT intervals were corrected for heart rate using the formula QTc = QT/RR(alpha) with special emphasis on individualized alpha values derived from each subject's own QT/RR relationship at baseline. Results No significant changes in QTc interval from baseline were observed after 5 days administration of ebastine, loratadine or placebo. Ketoconazole/placebo increased the mean QTc (95% CI) by 6.96 (3.31-10.62) ms in the ebastine study and by 7.52 (4.15-10.89) ms in the loratadine study. Mean QTc was statistically significantly increased during both ebastine/ketoconazole administration (12.21 ms; 7.39-17.03 ms) and loratadine/ketoconazole administration (10.68 ms; 6.15-15.21 ms) but these changes were not statistically significantly different from the increases seen with placebo/ketoconazole (6.96 ms; 3.31-10.62 ms), P = 0.08 ebastine study, (7.52 ms; 4.15-10.89 ms), P = 0.26 loratadine study). After the addition of ketoconazole, the mean area under the plasma concentration-time curve (AUC) for ebastine increased by 42.5 fold, and that of its metabolite carebastine by 1.4 fold. The mean AUC for loratadine increased by 4.5 fold and that of its metabolite desloratadine by 1.9 fold following administration of ketoconazole. No subjects were withdrawn because of ECG changes or drug-related adverse events. Conclusions Ketoconazole altered the pharmacokinetic profiles of both ebastine and loratadine although the effect was greater for the former drug. The coadministration of ebastine with ketoconazole resulted in a non significant mean increase of 5.25 ms (-0.65 to 11.15 ms) over ketoconazole with placebo (6.96 ms) while ketoconazole plus loratadine resulted in a nonsignificant mean increase of 3.16 ms (-2.73 to 8.68 ms) over ketoconazole plus placebo (7.52 ms). Changes in uncorrected QT intervals for both antihistamines were not statistically different from those observed with ketoconazole alone. The greater effect of ketoconazole on the pharmacokinetics of ebastine was not accompanied by a correspondingly greater pharmacodynamic effect on cardiac repolarization.

Congenit Anom (Kyoto). 2005 Mar;45(1):5-8.
Population-based case-control study of oral ketoconazole treatment for birth outcomes.
Kazy Z, Puho E, Czeizel AE.
Foundation for the Community Control of Hereditary Diseases, Budapest, Hungary.

ABSTRACT The objective of the study presented here was to check the effect of oral ketoconazole treatment on fetal development. Ketoconazole has been given a teratogenic classification of C by the US Food and Drug Administration, but human controlled epidemiological studies of the treatment's effects have not been reported. The occurrence of ketoconazole use in the second to third months of gestation was compared between cases with congenital abnormalities and their matched controls in the large population-based data set of the Hungarian Case-Control Surveillance of Congenital Abnormalities, 1980-1996. Birth weight and gestational age were evaluated in control newborn infants born to mothers with or without ketoconazole treatment. The case group comprised 22 843 cases with congenital abnormalities, while the control group contained 38 151 newborn infants without any defects. Six infants (0.03%) and 12 controls (0.03%) had mothers who had received oral ketoconazole treatment (prevalence odds ratio: with 95% confidence interval: 0.8, 0.3-2.2). No group of infants with congenital abnormalities had mothers with a higher incidence of use of the drug. The mean gestational age was somewhat longer while birth weight was somewhat larger in controls with ketoconazole treated mothers. Our study failed to demonstrate a higher rate of congenital abnormalities in infants with mothers who had received oral ketoconazole treatment during pregnancy.

Int J Pharm. 2005 Mar 23;292(1-2):195-9. Epub 2005 Jan 20.
Microbiological assay of ketoconazole in shampoo.
Staub I, Schapoval EE, Bergold AM.
Programa de Pos-Graduacao em Ciencias Farmaceuticas, UFRGS, Av. Ipiranga 2752 Porto Alegre CEP 90610-000, Brasil.

Ketoconazole, an anti-fungal agent, is often incorporated in several pharmaceutical forms and in shampoo formulation it is known to be effective against fungal infection on the scalp. This paper describes a method to quantify ketoconazole in shampoo by comparing the cylinder plate assay and the HPLC method. The test organism used for the agar diffusion assay was Candida albicans ATCC 10231. Three different concentrations of ketoconazole were used for the diffusion assay. A mean zone diameter was obtained for each concentration. A standard curve was obtained by plotting the three values derived from the zone diameters. A prospective validation of the method showed that the method was linear (r=0.9982), precise (R.S.D.=2.57%) and accurate. The results obtained by the two methods were statistically evaluated by analysis of variance (ANOVA) and the results obtained indicate that there is no significant difference between these two methods.

Cancer Chemother Pharmacol. 2004 Oct;54(4):290-4. Epub 2004 May 08.
Pharmacokinetic interaction between ketoconazole and imatinib mesylate (Glivec) in healthy subjects.
Dutreix C, Peng B, Mehring G, Hayes M, Capdeville R, Pokorny R, Seiberling M.
Novartis Pharma AG, 4002 Basel, Switzerland. catherine.dutreix@pharma.novartis.com

The study under discussion was a drug-drug interaction study in which the effect of ketoconazole, a potent CYP450 3A4 inhibitor, on the pharmacokinetics of Glivec (imatinib) was investigated. A total of 14 healthy subjects (13 male, 1 female) were enrolled in this study. Each subject received a single oral dose of imatinib 200 mg alone, and a single oral dose of imatinib 200 mg coadministered with a single oral dose of ketoconazole 400 mg according to a two-period crossover design. The treatment sequence was randomly allocated. Subtherapeutic imatinib doses and a short exposure were tested in order not to overexpose the healthy volunteers. There was a minimum 7-day washout period between the two sequences. Blood samples for determination of plasma concentrations were taken up to 96 h after dosing. Imatinib and CGP74588 (main metabolite of imatinib) concentrations were measured using LC/MS/MS method and pharmacokinetic parameters were estimated by a non-compartmental analysis. Following ketoconazole coadministration, the mean imatinib C(max), AUC((0-24)) and AUC((0- infinity )) increased significantly by 26% ( P<0.005), 40% ( P<0.0005) and 40% ( P <0.0005), respectively. There was a statistically significant decrease in apparent clearance (CL/f) of imatinib with a mean reduction of 28.6% ( P<0.0005). The mean C(max) and AUC((0-24)) of the metabolite CGP74588 decreased significantly by 22.6% ( P<0.005) and 13% ( P<0.05) after ketoconazole treatment, although the AUC((0- infinity )) of CGP74588 only decreased by 5% ( P=0.28). Coadministration of ketoconazole and imatinib caused a 40% increase in exposure to imatinib in healthy volunteers. Given its previously demonstrated safety profile, this increased exposure to imatinib is likely to be clinically significant only at high doses. This interaction should be considered when administering inhibitors of the CYP3A family in combination with imatinib.

Clin Pharmacol Ther. 2004 Aug;76(2):154-66.
Ketoconazole, a cytochrome P450 3A4 inhibitor, markedly increases concentrations of levo-acetyl-alpha-methadol in opioid-naive individuals.
Moody DE, Walsh SL, Rollins DE, Neff JA, Huang W.
Center for Human Toxicology, Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, Utah 84112-9437, USA. dmoody@alanine.pharm.utah.edu

BACKGROUND: Levo-acetyl-alpha-methadol (LAAM) exerts most of it mu-agonist activity through the action of its 2 N-demethylation metabolites, norLAAM and dinorLAAM. The N-demethylation of LAAM to norLAAM and norLAAM to dinorLAAM is primarily performed by cytochrome P450s (CYP) in the 3A family. No previous studies have been conducted to determine the effect of in vivo inhibition of CYP3A on the pharmacokinetics and pharmacodynamics of LAAM. METHODS: Oral LAAM (5 mg/70 kg) was administered on 2 occasions in a single-blind, randomized crossover design to 13 opioid-naive subjects (6 women and 7 men) 1 hour after pretreatment with 400 mg ketoconazole or placebo. Blood and urine samples were collected at defined intervals over 240- and 96-hour periods, respectively; LAAM, norLAAM, and dinorLAAM concentrations were determined by liquid chromatography-tandem mass spectrometry. Physiologic and subjective measures were collected for up to 72 hours. RESULTS: Results are presented as the geometric mean with 90% confidence intervals of individual ratios of ketoconazole to placebo sessions. Coadministration of ketoconazole and LAAM resulted in a 3.22-fold (2.53-4.10, P <.001) and 5.29-fold (4.24-6.61, P <.001) increase in the maximum plasma concentration (Cmax) and area under the curve (AUC) of LAAM. The values for time to Cmax (tmax) of norLAAM and dinorLAAM were increased 2.43-fold (1.92-3.08, P <.001) and 11.6-fold (8.36-16.1, P <.001), with 0.77-fold (0.67-0.87, P <.005) and 0.55-fold (0.49-0.60, P <.001) decreases in their respective Cmax values. The AUCs of norLAAM and dinorLAAM were increased 2.25-fold (1.96-2.58, P <.001) and 1.21-fold (1.12-1.32, P <.005), respectively. Pupil diameter was significantly decreased by LAAM after both placebo and ketoconazole pretreatment; ketoconazole increased the tmax for miosis 2.92-fold (2.01-4.25, P <.001). Other physiologic measures and numerous subjective effects measures were significantly affected by LAAM; however, few significant effects of ketoconazole pretreatment were observed on these outcomes. CONCLUSION: A single dose of ketoconazole causes a significant pharmacokinetic drug interaction with a single dose of LAAM that results in increased LAAM concentrations relative to norLAAM and dinorLAAM at early time points. Coadministration also results in prolongation of the appearance of its active metabolites and a concomitant prolongation of miosis, a sensitive dynamic index of mu-opioid action. The clinically relevant increase in LAAM concentrations and prolongation of plasma LAAM metabolites may affect physiologic function, such as QT intervals, suggesting that coadministration of LAAM and CYP3A4 inhibitors should be contraindicated.

J Feline Med Surg. 2004 Aug;6(4):271-7.
Concurrent Fusarium chlamydosporum and Microsphaeropsis arundinis infections in a cat.
Kluger EK, Della Torre PK, Martin P, Krockenberger MB, Malik R.
Kirrawee Veterinary Hospital, 540 Princes Highway, Kirrawee, NSW 2232, Australia. ekluger@optusnet.com.au
A 7-year-old cat was presented initially with multiple draining sinuses on the metatarsal region of its right hindlimb. Another lesion had appeared at the same time on the fifth proximal interphalangeal joint of the left forelimb. Histopathological examination of a biopsy from the right hindlimb lesion revealed chronic pyogranulomatous inflammation associated with yeast-like bodies and septate mycelia; a fungus was cultured on conventional media but not identified further. Culture of a swab collected from the left forelimb lesion demonstrated a pigmented fungus, also not characterised further. Although there was initially a favourable response to ketoconazole (Nizoral, Janssen-Cilag Pty. Ltd) and beta-lactam therapy, the infection in the hind limb relapsed subsequently, and Fusarium chlamydosporum was cultured from deep biopsy specimens. Clinical improvement followed debridement and itraconazole (Sporanox, Janssen-Cilag Pty. Ltd; 100 mg orally once daily), however amputation of the limb represented the best chance for a cure. The cat made an uncomplicated recovery following surgery and remained well for five months until the lesion on the left forelimb recurred. Amputation of the distal fourth digit was then performed, and the resected tissue submitted for culture. The dematiaceous fungus Microsphaeropsis arundinis was subsequently cultured. The cat remained well for several months, until a further F. chlamydosporum infection developed on the body wall. This was excised 7 months ago, and no lesions have recurred in this area. Importantly, this is the first reported case of M. arundinis infection in a mammalian host.

Microbes Infect. 2004 Aug;6(10):882-91.
Invasion of epithelial mammalian cells by Paracoccidioides brasiliensis leads to cytoskeletal rearrangement and apoptosis of the host cell.
Mendes-Giannini MJ, Hanna SA, da Silva JL, Andreotti PF, Vincenzi LR, Benard G, Lenzi HL, Soares CP.
Departamento de Analises Clinicas, Faculdade de Ciencias Farmaceuticas-UNESP, Rua Expedicionarios do Brasil, 1621-CEP, 14801-902 Araraquara, SP, Brazil. giannini@fcfar.unesp.br
Paracoccidioides brasiliensis (Pb) yeast cells can enter mammalian cells and probably manipulate the host cell environment to favor their own growth and survival. We studied the uptake of strain Pb 18 into A549 lung and Vero epithelial cells, with an emphasis on the repercussions in the cytoskeleton and the apoptosis of host cells. Cytoskeleton components of the host cells, such as actin and tubulin, were involved in the P. brasiliensis invasion process. Cytochalasin D and colchicine treatment substantially reduced invasion, indicating the functional participation of microfilaments (MFs) and microtubules (MTs) in this mechanism. Cytokeratin could also play a role in the P. brasiliensis interaction with the host. Gp43 was recognized by anti-actin and anti-cytokeratin antibodies, but not by anti-tubulin. The apoptosis induced by this fungus in infected epithelial cells was demonstrated by various techniques: TUNEL, DNA fragmentation and Bak and Bcl-2 immunocytochemical expression. DNA fragmentation was observed in infected cells but not in uninfected ones, by both TUNEL and gel electrophoresis methods. Moreover, Bcl-2 and Bak did not show any differences until 24 h after infection of cells, suggesting a competitive mechanism that allows persistence of infection. Overexpression of Bak was observed after 48 h, indicating the loss of competition between death and survival signals. In conclusion, the mechanisms of invasion of host cells, persistence within them, and the subsequent induction of apoptosis of such cells may explain the efficient dissemination of P. brasiliensis.

Biopharm Drug Dispos. 2004 Jul;25(5):203-9.
Bioequivalence evaluation of two brands of ketoconazole tablets (Onofin-K and Nizoral) in a healthy female Mexican population.
Marcelin-Jimenez G, Hernandez J, Angeles AP, Contreras L, Hinojosa M, Rivera L, Martinez-Rossier L, Amancio O, Fernandez A.
Servicio de Investigacion de Farmacologia Clinica, Hospital General de Mexico, Mexico City, Mexico. gabmarcelin@hotmail.com
A randomized, crossover study was conducted in 24 healthy female volunteers to compare the bioavailability of two brands of ketoconazole (200 mg) tablets; Onofin-K (Farmacéuticos Rayere S.A., Mexico) as the test and Nizoral (Janssen-Cilag, Mexico) as the reference products. The study was performed at the Clinical Pharmacology Research Center of the Hospital General de Mexico in Mexico City. Two tablets (400 mg) were administered as a single dose with 250 ml of water after a 12 h overnight fast on two treatment days separated by a 1 week washout period. After dosing, serial blood samples were collected for a period of 12 h. Plasma harvested was analysed for ketoconazole by a modified and validated HPLC method with UV detection in the range 400-14000 ng/ml, using 200 microl of plasma in a full-run time of 2.5 min. The pharmacokinetic parameters AUC(0-t), AUC(0-alpha), Cmax, Tmax and t(1/2) were determined from plasma concentrations of both formulations and the results discussed. AUC(0-t), AUC(0-alpha) and Cmax were tested for bioequivalence after log transformation of data, and no significant differences were found either in 90% classic confidence interval or in the Anderson and Hauck test (p < 0.05). Based on statistical analysis, it is concluded that Onofin-K is bioequivalent to Nizoral. Copyright 2004 John Wiley & Sons, Ltd.

Exp Parasitol. 2004 Jul-Aug;107(3-4):115-9.
Resistance reversal action of ketoconazole against mefloquine resistance of Plasmodium yoelii nigeriensis.
Awasthi A, Dutta GP, Bhakuni V, Tripathi R.
Division of Parasitology, Central Drug Research Institute, Chattat Manzil, PO Box No. 173, Lucknow 226 001, India.
Ketoconazole at 200 mg/kg dose has been found to exert marginal antimalarial action against multidrug resistant (MDR) Plasmodium yoelii nigeriensis (P. yoelii nigeriensis) in Swiss mice with 25% protection (2/8 mice) while at lower Ketoconazole dose i.e., 75-100 mg/kg, 14.28% mice were protected. Mefloquine (MFQ) (at 8 and 16 mg/kg) exerted suppressive action against MDR P. yoelii nigeriensis resulting in 25 and 14.28% protection of mice respectively. Combined treatment with Ketoconazole and mefloquine resulted in protection of 5/6 mice (83.33%) at MFQ 4 mg/kg + Ketoconazole 100 mg/kg dose, 7/8 (87.5%) mice at MFQ 8 mg/kg + Ketoconazole 20 mg/kg dose and 5/7 (71.42%) mice at MFQ 16 mg/kg + Ketoconazole 25 mg/kg dose and 5/6 (83.33%) mice at MFQ 16 mg/kg + Ketoconazole 100 mg/kg dose. Ketoconazole has been found to enhance the protective effect of mefloquine against MFQ resistant P. yoelii nigeriensis resulting in 66-88% protection of the mice treated with the appropriate combinations. The combination also increased suppression of parasitaemia at different times. The Ketoconazole combination with MFQ significantly increased the mean survival time of the treated mice compared to individual drugs alone. The study shows that Ketoconazole when administered with MFQ exerts bio-enhancing action against mefloquine resistance of MDR P. yoelii nigeriensis.

Eur J Clin Pharmacol. 2004 Jun;60(4):237-46. Epub 2004 Apr 28.
Oral administration of a low dose of midazolam (75 microg) as an in vivo probe for CYP3A activity.
Eap CB, Buclin T, Cucchia G, Zullino D, Hustert E, Bleiber G, Golay KP, Aubert AC, Baumann P, Telenti A, Kerb R.
Unit of Biochemistry and Clinical Psychopharmacology, Centre of Psychiatric Neurosciences, University Department of Adult Psychiatry, Prilly-Lausanne, Switzerland. Chin.Eap@inst.hospvd.ch
OBJECTIVE: We investigated whether the oral administration of a low dose (75 micro g) of midazolam, a CYP3A probe, can be used to measure the in vivo CYP3A activity. METHODS: Plasma concentrations of midazolam, 1'OH-midazolam and 4'OH-midazolam were measured after the oral administration of 7.5 mg and 75 micro g midazolam in 13 healthy subjects without medication, in four subjects pretreated for 2 days with ketoconazole (200 mg b.i.d.), a CYP3A inhibitor, and in four subjects pretreated for 4 days with rifampicin (450 mg q.d.), a CYP3A inducer. RESULTS: After oral administration of 75 micro g midazolam, the 30-min total (unconjugated + conjugated) 1'OH-midazolam/midazolam ratios measured in the groups without co-medication, with ketoconazole and with rifampicin were (mean+/-SD): 6.23+/-2.61, 0.79+/-0.39 and 56.1+/-12.4, respectively. No side effects were reported by the subjects taking this low dose of midazolam. Good correlations were observed between the 30-min total 1'OH-midazolam/midazolam ratio and midazolam clearance in the group without co-medication (r(2)=0.64, P<0.001) and in the three groups taken together (r(2)=0.91, P<0.0001). Good correlations were also observed between midazolam plasma levels and midazolam clearance, measured between 1.5 h and 4 h. CONCLUSION: A low oral dose of midazolam can be used to phenotype CYP3A, either by the determination of total 1'OH-midazolam/midazolam ratios at 30 min or by the determination of midazolam plasma levels between 1.5 h and 4 h after its administration.

Mycoses. 2004 Jun;47(5-6):216-21.
Susceptibility of sequential Fonsecaea pedrosoi isolates from chromoblastomycosis patients to antifungal agents.
Andrade TS, Castro LG, Nunes RS, Gimenes VM, Cury AE.
Departamento de Analises Clinicas, Laboratorio de Micologia Clinica, Faculdade de Ciencias Farmaceuticas, Universidade de Sao Paulo, Sao Paulo, Brazil. tsandrad@zaz.com.br
Fourteen Fonsecaea pedrosoi isolates from six chromoblastomycosis patients were submitted to susceptibility testing. Some patients were undergoing treatment with itraconazole (ITZ) and/or cryosurgery with liquid nitrogen. The antifungal agents amphotericin B (AMB), ITZ, fluconazole (FCZ), ketoconazole (KCZ), 5-fluorocytosine (5-FC), and terbinafine (TBF) were tested. AMB and FCZ showed less activity for all isolates. The most active agents were KCZ and TBF. Sequentially isolates from four patients presented ITZ minimal inhibitory concentration (MIC) higher than the previous ones; for two of these patients, response to therapy with this agent was not observed. These results suggest development of microbiologic resistance to ITZ in four instances, two of them coinciding with lack of clinical response to this drug.

Nephrol Dial Transplant. 2004 Jun;19(6):1613-7. Epub 2004 Mar 19.
Co-administration of ketoconazole to tacrolimus-treated kidney transplant recipients: a prospective randomized study.
el-Dahshan KF, Bakr MA, Donia AF, Badr Ael-S, Sobh MA.
Nephrology Department, Urology and Nephrology Center, Mansoura University, Mansoura, Egypt.
BACKGROUND: Since the introduction of calcineurin inhibitors, there has been a significant improvement in the results of solid organ transplantation, including graft and patient survival. However, high cost, chronic nephrotoxicity and other side effects stand as major challenges for long-term use of these drugs. The long-term safety and financial benefits of the combination ketoconazole-cyclosporine previously studied. However, data about the effect of the addition of ketoconazole addition to tacrolimus-treated patients are scarce. Therefore, this study was conducted to evaluate the safety and financial impact of that combination. METHODS: The subjects of this work included 70 live-donor stable kidney transplant recipients receiving tacrolimus. Their age ranged from 16 to 45 years. Among them, 54 were males and 16 were females. All of them were 6 months or more post-transplantation. Patients were randomly divided into two equal groups. Group I patients initially received ketoconazole 100 mg/day in addition to their usual treatment, while group II patients were considered a control. Patients were followed-up for 6 months. RESULTS: Concomitant ketoconazole-tacrolimus resulted in marked reduction of tacrolimus dose (by 58.7%) and cost (by 56.9%). It also resulted in significant improvement in graft function and fungal skin infection, in addition to a decrease of gastrointestinal episodes and hospitalization. CONCLUSION: We conclude that ketoconazole-tacrolimus combination in kidney transplant recipients is safe, has outstanding impact on treatment costs and improves patient and graft outcome.

Transplantation. 2004 May 15;77(9):1371-6.
A prospective, randomized study of coadministration of ketoconazole and cyclosporine a in kidney transplant recipients: ten-year follow-up.
el-Agroudy AE, Sobh MA, Hamdy AF, Ghoneim MA.
Urology and Nephrology Center, Mansoura University, Mansoura, Egypt. amgadelbaz@ahram0505.net
BACKGROUND: In a prospective, randomized study, we previously proved the safety and financial benefits of the coadministration of ketoconazole (keto) and cyclosporine A (CsA) in patients. We report the 10-year follow-up of these patients and the controls. PATIENTS AND METHODS: In January 1992, 100 living-related kidney transplant recipients were randomized into two groups: Group 1 (51 patients) received 100 mg/day keto, and group 2 (49 patients) did not receive keto (control). Both groups were evaluated regarding graft function, CsA dose and levels, liver function tests, serum calcium and phosphorus, bone mineral density, and histopathologic assessment. RESULTS: Follow-up for 10 years showed that CsA dose reduction was maximum after 1 month (76.5%) and decreased gradually after 10 years (64.6%). Acute rejection was diagnosed in 22% and 27% in the keto and control groups, respectively (P =0.27). In the control group, the acute rejection episodes were more frequent with poorer response to treatment. Chronic allograft nephropathy was statistically significantly less in the keto group. Hepatotoxicity and metabolic complications were similar in both groups. The annual cost saving of CsA was 60% after 1 year and 50% at the end of the study. CONCLUSIONS: We conclude that the long-term use of keto for CsA dose reduction in kidney transplant recipients is safe, tolerable, and cost-sparing and is associated with stable graft function.

Clin Pharmacol Ther. 2004 May;75(5):448-54.
Effect of cytochrome P450 3A4 inhibition on the pharmacokinetics of docetaxel.
Engels FK, Ten Tije AJ, Baker SD, Lee CK, Loos WJ, Vulto AG, Verweij J, Sparreboom A.
Department of Medical Oncology, Erasmus Medical Center-Daniel den Hoed Medical Center, Rotterdam, The Netherlands.
OBJECTIVE: In vitro studies indicate that the anticancer drug docetaxel is primarily eliminated by cytochrome P450 (CYP) 3A4-mediated metabolism. Coadministration of drugs that modulate the activity of CYP3A4 is, therefore, likely to have undesirable clinical consequences. We investigated the effects of the potent CYP3A4 inhibitor ketoconazole on the pharmacokinetics of docetaxel in patients with cancer. METHODS: Seven patients were treated in a randomized crossover design with docetaxel (100 mg/m(2)), followed 3 weeks later by docetaxel (10 mg/m(2)) given in combination with orally administered ketoconazole (200 mg once daily for 3 days), or the reverse sequence. Plasma concentration-time data were analyzed by noncompartmental analysis. RESULTS: Ketoconazole coadministration resulted in a 49% decrease in clearance of docetaxel (P =.018). The mean (+/-SD) clearance values were 35.0 +/- 11.8 L/h (95% confidence interval, 24.1-45.9 L/h) for docetaxel alone and 18.2 L/h (95% confidence interval, 9.22-27.1 L/h) in the presence of ketoconazole, respectively. The docetaxel clearance ratio in the presence and absence of ketoconazole was weakly related to the area under the curve of ketoconazole (R(2) = 0.529, P =.064). CONCLUSION: Inhibition of CYP3A4 by ketoconazole in vivo results in docetaxel clearance values that have previously been shown to be associated with a several-fold increase in the odds for febrile neutropenia at standard doses. Caution should be taken and substantial dose reductions are required if docetaxel has to be administered together with potent inhibitors of CYP3A4.

Environ Toxicol Chem. 2004 May;23(5):1326-34.
Effects of the antifungal imidazole ketoconazole on CYP1A and CYP3A in rainbow trout and killifish.
Hegelund T, Ottosson K, Radinger M, Tomberg P, Celander MC.
Goteborg University, Department of Zoophysiology, Box 463, SE 405 30 Goteborg, Sweden.
The use of N-substituted imidazoles is widespread, and imidazole and triazole fungicides have been detected in the aquatic environment and shown to bioaccumulate in fish. We have investigated effects of the model imidazole, ketoconazole, on drug-metabolizing cytochrome P450 (CYP) forms. We focused on cytochrome P4501A (CYP1A) and cytochrome P4503A (CYP3A) expression and activities in juvenile rainbow trout and in adult killifish. The CYP1A expression (mRNA, protein) and activity was induced in rainbow trout, whereas in killifish no effect of ketoconazole on CYP1A protein expression was observed. A biphasic dose-response relationship was observed between ketoconazole exposure and hepatic CYP1A-mediated ethoxyresorufin O-deethylase (EROD) activity in rainbow trout in vitro and in vivo, implying that higher doses of ketoconazole inhibit CYP1A activities. Slight induction of CYP3A protein levels was observed in rainbow trout exposed in vivo to ketoconazole. However, the CYP3A-mediated benzyloxy-4-[trifluoromethyl]-coumarin (BFC) O-debenzyloxylase activity was reduced in rainbow trout and killifish treated with ketoconazole. In vitro inhibition studies confirmed that ketoconazole was a potent inhibitor of both CYP3A and CYP1A enzyme activities in these species. This study showed that ketoconazole induced CYP1A and CYP3A expression in rainbow trout. However, the most pronounced effect of ketoconazole was a 60 to 90% decrease in CYP3A catalytic activities in rainbow trout and in killifish.

Eur Urol. 2004 May;45(5):581-4; discussion 585.
An evaluation of intermediate-dose ketoconazole in hormone refractory prostate cancer.
Wilkinson S, Chodak G.
The Midwest Prostate and Urology Health Center, Weiss Memorial Hospital, 4646 North Marine Drive, Chicago, IL 60640, USA. simonmwilkinson@hotmail.com
OBJECTIVES: The management of hormone refractory prostate cancer remains controversial. Among the options, second-line hormonal therapy is commonly used. We investigated the efficacy of ketoconazole, an inhibitor of testicular and adrenal androgen biosynthesis, for treating patients with advanced hormone refractory prostate cancer. METHODS: The study comprised 38 patients with progressive disease despite combined androgen blockade. Treatment consisted of intermediate-dose ketoconazole (300mg three times daily) and replacement hydrocortisone. Patients were monitored clinically and with serial psa measurements every 3 months. the principal endpoint was psa response. RESULTS: Of the 38 patients, 21 (55.3%) showed a decrease in PSA >50% (95% confidence interval 38.3%-71.4%) with a median duration of 6 months (range 3-48 months). A PSA reduction >50% was seen in 21 of 34 patients (61.8%) with established metastases. Thirteen patients (34.2%), all of whom had metastases, exhibited a PSA decrease >80% (95% confidence interval 19.6%-51.4%) with a median duration of 9 months (range 3-48 months). Age, PSA at diagnosis, Gleason score and bone scan result were not significantly associated with response to ketoconazole treatment in univariate or multivariate analyses. For the entire study group, the median time to progression was 5 months (range 0-27 months) and the median survival was 12 months (range 3-48 months). Overall, 12 patients (31.6%) reported toxicity related to intermediate-dose ketoconazole but only 6 patients (15.8%) discontinued therapy due to intolerable side effects. CONCLUSION: It is apparent from this study that a reasonable percentage of patients failing standard hormonal therapy respond favourably to intermediate-dose ketoconazole and that toxicity is mild. In the absence of studies demonstrating better survival with chemotherapy, we believe that a trial of ketoconazole should be considered when progression occurs on hormone therapy.

J Small Anim Pract. 2004 May;45(5):259-62.
Multicentric lymphoma in a dog after cyclosporine therapy.
Blackwood L, German AJ, Stell AJ, O'Neill T.
Small Animal Hospital, Department of Veterinary Clinical Science, University of Liverpool, Crown Street, Liverpool L7 7EX.
An 11-year-old, neutered male German shepherd dog was presented with perianal ulceration and fistulas. A clinical diagnosis of anal furunculosis was made, and the dog was treated with cyclosporine and ketoconazole. The perianal lesions resolved. However, after four weeks of therapy the dog developed multicentric lymphoma. Complete remission was achieved with combination chemotherapy (Wisconsin-Madison protocol). Cyclosporine administration is associated with an increased risk of development of lymphoma in humans and a similar increased risk might be expected in dogs. Although a causative relationship between cyclosporine administration and the development of lymphoma cannot be proven in this case, it is possible that cyclosporine therapy may have contributed to lymphomagenesis. As the use of cyclosporine in small animals is increasing, further work is required to substantiate and quantify the proposed increased risk.

Dermatol Clin. 2003 Jul;21(3):469-79, vi.
The use of oral antifungal agents to treat onychomycosis.
Gupta AK, Ryder JE.
Division of Dermatology, Department of Medicine, Sunnybrook and Women's College Health Science Center (Sunnybrook Site), University of Toronto, 2075 Bayview Avenue, Toronto, Ontario M4N 3M5, Canada.
Onychomycosis has been treated for years with oral antifungal agents, and more recently in the United States with a topical nail lacquer. Griseofulvin was the first significant oral agent available to manage onychomycosis. The introduction of the azoles (ketoconazole, itraconazole, and fluconazole) and the allylamine, terbinafine, led to improved cure rates and a broad spectrum of activity. Pharmacokinetic studies have shown that the newer oral agents penetrate the nail within approximately one to two weeks after the start of therapy and remain for several months after the end of treatment. This article reviews the oral antifungal agents used to treat onychomycosis.

J Vet Pharmacol Ther. 2003 Feb;26(1):5-29.
Antifungal agents of use in animal health--chemical, biochemical and pharmacological aspects.
Vanden Bossche H, Engelen M, Rochette F.
Steenweg op Gierle 68, B-2300 Turnhout, Belgium. hugo.
A limited number of antifungal agents is licensed for use in animals, however, many of those available for the treatment of mycoses in humans are used by veterinary practitioners. This review includes chemical aspects, spectra of activity, mechanisms of action and resistance, adverse reactions and drug interactions of the antifungals in current use.

Fertil Steril. 2003 Nov;80(5):1151-5.
Parsanezhad ME, Alborzi S, Pakniat M, Schmidt EH.
Shiraz University of Medical Sciences, Shiraz, Iran. parsame@sums.ac.ir
A double-blind, randomized, placebo-controlled study to assess the efficacy of ketoconazole for reducing the risk of ovarian hyperstimulation syndrome.
To evaluate the role of ketoconazole in prevention of ovarian hyperstimulation syndrome (OHSS) in women with the polycystic ovary syndrome (PCOS) undergoing ovarian stimulation with gonadotropins. DESIGN: Prospective, randomized, double-blind, placebo-controlled study. University hospitals.One hundred nine women with PCOS who were referred for treatment with gonadotropins. Fifty patients were randomly assigned to receive two ampoules of hMG beginning on day 2 or 3 of the cycle and ketoconazole (50 mg every 48 hours) starting on the first day of hMG treatment. Fifty-one patients received the same amount of hMG plus one tablet of placebo every 48 hours. Follicular development, E(2) level, and pregnancy rate. The total number of hMG ampoules and duration of treatment to attain ovarian stimulation were higher among ketoconazole recipients. The serum E(2) level and number of patients with dominant follicles on day 9 of the cycle were greater in placebo recipients. Serum E(2) level and total number of follicles at the time of hCG administration did not differ between the two groups. The cancellation rate and OHSS rate were similar in the two groups. Ketoconazole does not prevent OHSS in patients with PCOS who are undergoing ovarian stimulation. It may reduce the rate of folliculogenesis and steroidogenesis.

Cancer. 2003 Nov 1;98(9):1855-62.
Van Veldhuizen PJ, Reed G, Aggarwal A, Baranda J, Zulfiqar M, Williamson S.
Department of Medicine, Section of Hematology/Oncology, Kansas City Veterans Affairs Medical Center, University of Kansas Medical Center, Missouri, USA.
Docetaxel and ketoconazole in advanced hormone-refractory prostate carcinoma: a phase I and pharmacokinetic study.
BACKGROUND: Docetaxel has significant single-agent activity in patients with prostate carcinoma, and ketoconazole has activity as a second-line hormonal agent. In vitro, ketoconazole exhibits synergy with several chemotherapeutic agents. A potential drug interaction exists, however, because both docetaxel and ketoconazole are metabolized hepatically by the cytochrome p450 system (CYP3A4). The authors performed a Phase I study and a pharmacokinetic study evaluating the both tolerability of a docetaxel/ketoconazole combination as well as this potential drug interaction. METHODS: For all initial patients, docetaxel was administered intravenously at a dose of 55 mg/m(2) over 1 hour every 21 days. Starting on Day 8 after their first docetaxel dose, cohorts of at least 3-5 new patients were enrolled to receive escalating doses of ketoconazole. When the maximally tolerated dose (MTD) of ketoconazole was reached, the subsequent cohort of patients received an escalating dose of docetaxel. Pharmacokinetic studies were performed after docetaxel infusions on Day 1 (prior to ketoconazole) and Day 22 (after starting ketoconazole). RESULTS: Twenty-six patients were enrolled and completed at least 2 cycles of treatment. The MTD was ketoconazole 400 mg twice daily and docetaxel 55 mg/m(2). Dose-limiting toxicities included neutropenia and fatigue. Ketoconazole did not cause a consistent effect on docetaxel pharmacokinetics, although there was significant intrapatient and interpatient variability in serum levels. CONCLUSIONS: The recommended Phase II dose for this combination is ketoconazole 400 mg twice daily and docetaxel 55 mg/m(2) every 21 days.

J Clin Pharmacol. 2003 Sep;43(9):996-1002.
Hurwitz A, Ruhl CE, Kimler BF, Topp EM, Mayo MS.
Department of Internal Medicine, Division of Clinical Pharmacology, Room 4016 Wescoe, University of Kansas Medical Center, KS USA.
Gastric function in the elderly: effects on absorption of ketoconazole.
The authors studied effects of age-related changes in gastric function on absorption of ketoconazole. Eighteen men and women age 65 years or older swallowed 200 mg ketoconazole on two occasions, once as tablets with water and once as tablets crushed in acidic juice. The sequence was randomly determined. Gastric pH was measured by radiotelemetry and gastric emptying rate by radiolabeled technetium with a gamma camera. Plasma ketoconazole was assayed by high-performance liquid chromatography (HPLC). Subjects with gastric pH less than or equal to 4.5 absorbed ketoconazole equally well from intact tablets and tablets crushed in acid. When pH was 5.0 or higher, ketoconazole was absorbed well from acid-crushed tablets but not from intact tablets. Gastric emptying was shown to be rapid in all subjects. Since the prevalence of such hypoacivity is approximately 5% in the elderly, and other parameters of gastric function are usually normal, impaired absorption of drugs such as ketoconazole should be uncommon with normal aging.