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Refractory anaphylactic shock associated with ketoconazole treatment.

Liu PY, Lee CH, Lin LJ, Chen JH.

Division of Cardiology, Department of Internal Medicine, National Cheng-Kung University Medical Center; Institute of Clinical Medicine, National Cheng-Kung University, Tainan, Taiwan.

OBJECTIVE: To report a rare but severe reaction of refractory anaphylactic shock with ketoconazole treatment-associated hypotensive episodes in an elderly patient. CASE SUMMARY: A 72-year-old woman received antifungal therapy for her almost completely occluded cornea infected with Candida albicans. She was initially prescribed oral ketoconazole 200 mg twice daily. She developed hypotension over the first 2 days of therapy (BP 136/82 mm Hg at baseline; 90/50 mm Hg on day 2). Severe hypotension (BP 90/49 mm Hg) unresponsive to fluid therapy or high-dose dopamine developed on day 4 of therapy. An invasive Swan-Ganz catheterization study showed a very low level of peripheral vascular resistance with high cardiac output index without clinical signs of infection. When laboratory tests showed a high level of plasma tryptase, anaphylactic redistribution shock was diagnosed. Her vital signs became more stable after treatment with hydrocortisone and epinephrine infusion. She was discharged in good condition after 24 hours of observation. DISCUSSION: As of December 2004, refractory anaphylactic shock resulting from ketoconazole use had not been reported. The events of hypotension were strongly associated with the intake of ketoconazole. The hemodynamic results obtained with Swan-Ganz catheterization were compatible with anaphylactic shock. The Naranjo probability scale showed a probable association of the adverse event with ketoconazole. CONCLUSIONS: Ketoconazole may cause severe anaphylactic shock even when taken orally. Invasive catheterization and elevated tryptase levels can provide important information in the management of anaphylactic shock.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15701770&dopt=Abstract ketoconazole Nizoral



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A randomized, phase II trial of ketoconazole plus alendronate versus ketoconazole alone in patients with androgen independent prostate cancer and bone metastases.

Figg WD, Liu Y, Arlen P, Gulley J, Steinberg SM, Liewehr DJ, Cox MC, Zhai S, Cremers S, Parr A, Yang X, Chen CC, Jones E, Dahut WL.

Center for Cancer Research, National Cancer Institute, Warren Grant Magnuson Clinical Center, National Institutes of Health, Bethesda, Maryland 20892, USA. wdfigg helix.nih.gov

PURPOSE: Alendronate (AL), a potent oral bisphosphonate, blocks the secretion of matrix metalloproteinase-2 and the establishment of bone metastases in animal models. Ketoconazole (KT) has demonstrated activity in androgen independent prostate cancer (AIPC). In this study we determined whether KT plus AL produced acceptable disease responses compared with KT alone. As the experimental design, 72 patients with progressive AIPC metastatic to bone were randomized to receive KT (1,200 mg daily) plus hydrocortisone (H) (30 mg daily) with or without AL (40 mg daily). Prostate specific antigen (PSA) consensus criteria and radiographic scans were used to determine the proportion of patients with a PSA decrease, time to progression and response duration. The pharmacokinetics of KT and AL were characterized and changes in circulating angiogenic factors were assessed. RESULTS: At a median potential followup of 23.9 months the proportion of patients with a greater than 50% decrease in PSA was similar in the KT/H/AL and KT/H, groups (50% and 47%, respectively). The median duration of response was 8.9 and 6.3 months in the KT/H/AL and KT/H groups, respectively (p = 0.125). Median progression-free survival was not significantly prolonged in the KT/H/AL group (4.6 vs 3.8 months, p = 0.27). There was no significant difference in overall survival between the 2 treatment arms but there was a trend toward improved survival in the KT/H arm (p = 0.074). Toxicity in the 2 groups was mild and there were no clear associations between changes in circulating angiogenic factor levels and clinical outcomes in either treatment arm. CONCLUSIONS: There were no statistically significant differences in response rate, progression-free survival or overall survival between KT/H alone and KT/H plus AL treatment in patients with AIPC. The addition of AL to KT/H may increase the response duration with an acceptable safety profile compared with treatment with KT/H alone. However, the addition of AL offers no survival benefit in patients with AIPC.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15711271&dopt=Abstract ketoconazole Nizoral



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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.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15725566&dopt=Abstract ketoconazole Nizoral



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[Prophylaxis of fungal infection in patients with hematologic neoplasms and severe neutropenia after high-dose chemotherapy]

[Article in Russian]

[No authors listed]

Infection is one of the main causes of death in patients with hemoblastoses. Within the last years there was observed an increase in the ratio of fungal infections in the structure of mortality among hematologic patients with neutropenia. The present study was aimed at comparative estimation of the efficacy of the prophylactic use of various azole antifungal agents in patients with hematologic neoplasms and severe neutropenia. The trial enrolled 88 patients comparable by the diagnosis and chemotherapy characteristics, in whom severe neutropenia developed after intensive therapy. Antifungal drugs were used prophylactically when the neutrophil count lowered below 1.0 x 10(9)/l until its increasing above 1.0 x 10(9)/l or when the signs of fungal infection were evident. Itraconazole was used in cyclodextrin solution in 30 patients in a dose of 0.2 g orally twice a day and fluconazole was used in capsules in 24 patients in a dose of 0.2 g orally once a day. The results were compared with those of the ketoconazole use in a dose of 0.2 g orally twice a day (n = 34). The frequency of fungal infection proved by the clinical documentation was 20.5% in the ketoconazole group (k) (7 out of 34 patients), 8.3% in the fluconazole group (f) (2 out of 24 patients) and 6.6% in the itraconazole group (i) (2 out of 30 patients), p (k-f) = 0.21, p (k-i) = 0.11 and p (f-i) = 0.74. The frequency of fungal infection proved by the microbiological documentation was statistically much higher in the ketoconazole group (38.2%) vs. the fluconazole group (8.3%) (p = 0.013) and the itraconazole group (6.6%) (p = 0.004). The prophylactic use of itraconazole and fluconazole was efficient in preventing development of invasive mycoses in the patients with hemoblastoses and severe neutropenia. Their efficacy was much higher than that of ketoconazole.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15727147&dopt=Abstract ketoconazole Nizoral



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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.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15737124&dopt=Abstract ketoconazole Nizoral



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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.

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Adsorptive stripping voltammetric determination of ketoconazole in pharmaceutical preparations and urine using carbon paste electrodes.

Shamsipur M, Farhadi K.

Department of Chemistry, Razi University, Kermanshah, Iran.

The oxidation of ketoconazole on a bare carbon paste electrode was studied voltammetrically. The results indicated that the process is irreversible and controlled by an adsorption-extraction process which allows the accumulation of the drug at the electrode surface. After the optimization of solution pH, accumulation variables and instrumental parameters, sensitive differential pulse and linear sweep voltammetric peaks were obtained whose peak currents were linearly proportional to the ketoconazole concentration over the ranges 2.4 x 10(-8)-4.8 x 10(-7) and 9.1 x 10(-7)-1.0 x 10(-5) M, respectively. Based on these findings, a simple procedure was developed for the determination of ketoconazole in human urine and formulations.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11064940&dopt=Abstract ketoconazole Nizoral