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At least 19 recordsLinked to original sources
PubMed1988

Activities of fluconazole (UK 49,858) and ketoconazole against ketoconazole-susceptible and -resistant Candida albicans.

We have compared the activities of fluconazole and ketoconazole against ketoconazole-susceptible and -resistant strains of Candida albicans in a neutropenic-site rabbit model. Oral treatment with fluconazole resulted in much higher serum and extravascular concentrations of this antifungal agent than did comparable doses of ketoconazole. Fluconazole had no additional in vivo activity against the ketoconazole-susceptible strains; no fungicidal activity was observed with peak drug levels as high as approximately 75 micrograms/ml in the infection sites. Significant fungistatic activity against the ketoconazole-resistant strains was observed with fluconazole treatment (80 mg/kg), but not with less fluconazole (20 mg/kg) or with ketoconazole (approximately 67 mg/kg). In vitro susceptibility tests separated the ketoconazole-susceptible strains from the ketoconazole-resistant strains, but the results were variable when the resistant strains were tested with fluconazole.

Animals↗
PubMedDate not supplied

Ketoconazole-induced hepatic phospholipidosis in the mouse and its association with de-N-acetyl ketoconazole.

Ketoconazole (KC), an orally effective systemic antifungal agent, has been associated with symptomatic hepatotoxicity with an incidence as low as 1 in 2000. Studies from this laboratory have shown that in the mouse ketoconazole elicit a biphasic effect on drug metabolism and induced phospholipidosis. The pathogenesis of the latter, however, has never been established. Studies in mice demonstrated that ketoconazole administration induced phospholipid accumulation in the liver in a dose and time dependent fashion; and de-N-acetyl ketoconazole (DAKC), a major hepatic metabolite of KC was associated with this biochemical change. A comparative biochemical study following equimolar (0.47 nmol/kg p.o. x 7 days) administration of these two compounds indicated that hepatic phospholipids were elevated to a greater extent by DAKC treatment than by KC. Hepatic profiles of KC, DAKC, and other metabolites at 2, 7.5 and 24 h following single and multiple dosing regimens with either KC or DAKC indicated that KC was readily metabolized to DAKC whereas, DAKC appeared to be recalcitrant to metabolism and accumulated in the liver. In contrast to the biphasic effects of KC on hepatic enzyme activity observed previously following the administration of KC (enzyme inhibition as well as induction), the biological effects of DAKC were consistent with only an enzyme inhibitory effect: liver microsomal protein was not elevated; cytochrome P-450 was depressed; and ethylmorphine N-demethylase and benzphetamine N-demethylase were inhibited. Consequently the induction of phospholipidosis and the inhibition of drug metabolism associated with ketoconazole treatment were attributed to DAKC, whereas the inductive properties of KC were ascribed to the unchanged drug. The dramatic difference in the biological effects of these two compounds was attributed to differences in the orientation of these agents in lipid membranes. These results offer an explanation for the previously observed apparent inhibitory effects of KC on enzyme activities (Whitehouse et al. (1990b) Hepatic effects of ketoconazole in the male Swiss Webster mouse: temporal changes in drug metabolic parameters. Can. J. Physiol. Pharmacol., 68, 1136-1142) and suggest that DAKC may be the chemical entity responsible for the induction of phospholipidosis following ketoconazole administration.

Administration, Oral↗
PubMed1995

Mechanism of ketoconazole-induced elevation of individual serum bile acids in the rat: relationship to the effect of ketoconazole on bile acid uptake by isolated hepatocytes.

Ketoconazole, an imidazole derivative, has been implicated in a number of hepatic dysfunctions. The aim of the present study was to determine the effect of in vivo treatment of rats with ketoconazole on individual serum bile acid levels and the in vitro effects of ketoconazole on the hepatocellular uptake of two bile acids and two other model substrates transported by liver cells. Male Sprague-Dawley rats were treated i.p. with a single injection of ketoconazole of 25 mg/kg (n = 4) or 50 mg/kg (n = 4); the control group (n = 4) received the vehicle only at a dose of 1 ml/kg. Blood samples were collected at 4 hr after dosing. With high-performance liquid chromatography, the serum was assayed for individual serum bile acids. At the higher dose, ketoconazole produced a significant increase in serum levels of cholic acid, taurocholic acid, chenodeoxycholic acid, glycocholic acid, glycochenodeoxycholic acid, glycodeoxycholic acid, deoxycholic acid and taurochenodeoxycholic acid compared with the control group (P < .05). Cholic acid, taurocholic acid and chenodeoxycholic acid levels were significantly raised in rats treated with the lower dose. In vitro, ketoconazole strongly inhibited the hepatocellular uptake of [14C]cholic acid, [14C]taurocholic acid and [3H]ouabain but not [14C]2-aminoisobutyric acid, which indicated that the effect is relatively specific. The kinetics of inhibition were competitive and the inhibition constants for taurocholate and ouabain were 6 and 1 microM, respectively. Ketoconazole inhibited by both Na(+)-dependent taurocholate uptake and stimulated bile acid countertransport of preloaded hepatocytes.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMedDate not supplied

Comparison of itraconazole and ketoconazole in HIV-positive patients with oropharyngeal or esophageal candidiasis. Human Immunodeficiency Virus Itraconazole Ketoconazole Project Group.

The efficacy of oral itraconazole and ketoconazole in the treatment of oropharyngeal and/or esophageal candidiasis, and the rate of post-treatment relapse, were compared in a multicenter, prospective, double-blind, double-dummy, randomized, parallel-group trial. A total of 143 adult HIV-positive patients with oropharyngeal and/or esophageal candidiasis were assigned to receive either itraconazole or ketoconazole (200 mg/day). Patients with oropharyngeal and esophageal candidiasis were treated for 2 and 4 weeks, respectively. Patients were evaluated clinically and mycologically after 1, 2 and 4 (for esophageal patients) weeks of therapy, and relapses were compared in a 6-week post-treatment follow-up period. Of 129 evaluable patients, 98 had oropharyngeal candidiasis and 31 esophageal infection. CDC classification, CD4+ cell counts, and number of previous episodes of oropharyngeal or esophageal candidiasis were comparable in both groups. Oropharyngeal infection was cleared clinically at 21 days in 71% of patients receiving itraconazole and 60% receiving ketoconazole, and esophageal candidiasis was cleared at 41 days in 100% of patients receiving itraconazole and 91% receiving ketoconazole. Marginally significant differences were found between itraconazole and ketoconazole in rates of clearing of infection clinically in patients with oropharyngeal and esophageal candidiasis (p = 0.0614 and 0.0781, respectively). Mean rates of infection relapse were not statistically different in the two treatment groups. Adverse events were generally mild and not considered drug related. Itraconazole is marginally more efficacious than ketoconazole in the treatment of oropharyngeal and esophageal candidiasis in HIV-positive patients and both drugs appear safe and well tolerated.

AIDS-Related Opportunistic Infections↗
PubMed1983

Mode of insertion of miconazole, ketoconazole and deacylated ketoconazole in lipid layers. A conformational analysis.

The conformation of three imidazole derivatives, miconazole, ketoconazole and deacylated ketoconazole (R 39 519) inserted in a lipid layer was calculated using a procedure of conformational analysis. For each imidazole derivative all probable conformers were inserted into a dipalmitoyl phosphatidylcholine (DPPC) monolayer. Miconazole maintains its two dichlorophenyl groups in the hydrophobic phase whereas the imidazole moiety is orientated in the hydrophilic phase. Ketoconazole orientates its dichlorophenyl group in the hydrophobic phase whereas its acylated piperazine moiety is orientated towards the hydrophobic region. Deacylation inverses completely the orientation of the compound. The most probable conformer of R 39 519 is inserted in the lipid layer with its piperazine moiety orientated towards the aqueous phase. The inversion increases the area occupied per drug molecule from 30 A2 for ketoconazole to 90 A2 for R 39 519 equal to the mean area occupied per miconazole molecule and higher than that occupied per DPPC molecule (60 A2). Such a conformation should result in a destabilizing effect of miconazole and R 39 519; this was proved using differential scanning calorimetry.

Antifungal Agents↗
PubMed1985

Treatment of systemic mycoses with ketoconazole: in vitro susceptibilities of clinical isolates of systemic and pathogenic fungi to ketoconazole.

Ketoconazole was tested in vitro in three different media against 69 isolates of pathogenic fungi by using a macro-broth dilution procedure. The dimorphic systemic pathogens were highly susceptible, with most isolates of Blastomyces dermatitidis and Histoplasma capsulatum being inhibited and killed by concentrations less than or equal to 0.39 micrograms of ketoconazole/ml. Most isolates of Coccidioides immitis were also inhibited or killed by 0.39 micrograms of ketoconazole/ml; however, several were not killed by 100 micrograms/ml. Isolates of Cryptococcus neoformans and Sporothrix schenckii appeared to be less susceptible, with many isolates being resistant to less than or equal to 1.56 micrograms of ketoconazole/ml. There were 19 isolates of B. dermatitidis, C. immitis, and H. capsulatum recovered from 12 patients either during or following treatment with ketoconazole. Evidence for selection of secondary resistance to ketoconazole in these isolates was not observed. Results of these in vitro studies correlated poorly with the clinical responses to ketoconazole observed in the patients from whom the isolates were recovered.

Blastomyces↗
PubMed1987

Treatment of seborrhoeic dermatitis with ketoconazole: II. Response of seborrhoeic dermatitis of the face, scalp and trunk to topical ketoconazole.

A randomized, double-blind, placebo-controlled study was made of 2% ketoconazole cream and shampoo in 20 patients with seborrhoeic dermatitis of the face. Sixteen also had seborrhoeic dermatitis of the scalp and five had seborrhoeic dermatitis of the chest or back. Responses were measured by clinicians and patients independently using a grading system and linear analogue scales, respectively. Face and scalp lesions, assessed by both patient and clinician, showed a significant improvement or complete clearance in the group treated with ketoconazole. The patients who had seborrhoeic dermatitis of the chest or back and were treated with ketoconazole also improved. There was no improvement with placebo. This study provides further evidence for the aetiological role of pityrosporon yeasts in seborrhoeic dermatitis and of the efficacy of topical ketoconazole in its treatment.

Administration, Topical↗
PubMed1987

Treatment of seborrhoeic dermatitis with ketoconazole: I. Response of seborrhoeic dermatitis of the scalp to topical ketoconazole.

A randomized, double-blind, placebo-controlled cross-over study was made of ketoconazole shampoo in the treatment of 20 subjects with seborrhoeic dermatitis of the scalp. Responses were measured by clinicians using clinical gradings, and by the patients using a linear analogue scale. Scaling and itching of the scalp improved significantly with ketoconazole and no response was seen with placebo. Topical ketoconazole appears to be an effective therapy for seborrhoeic dermatitis of the scalp, and more suitable for long-term treatment than the oral preparation.

Administration, Topical↗
PubMed1983

Successful ketoconazole treatment of protothecosis with ketoconazole-associated hepatotoxicity.

A 46-year-old woman had a chronic, unresponsive wrist infection that was proved to be due to the algaelike organism Prototheca wickerhamii. Treatment with ketoconazole resulted in prompt improvement and ultimate healing. Therapy was complicated by hepatitis that was ketoconazole-related. Ketoconazole may be effective and easily administered therapy for this generally unresponsive infection.

Chemical and Drug Induced Liver Injury↗
PubMed1997

Metabolism of ketoconazole and deacetylated ketoconazole by rat hepatic microsomes and flavin-containing monooxygenases.

Ketoconazole (KT) has been reported to cause hepatotoxicity, which is probably not mediated through an immunoallergic mechanism. Although KT is extensively metabolized by hepatic microsomal enzymes, the nature, route of formation, and toxicity of suspected metabolites are largely unknown. Recent reports indicate that N-deacetyl ketoconazole (DAK) is a major initial metabolite in mice, which, like lipophilic 4-alkylpiperazines, is susceptible to successive oxidative attacks on the N-1 position producing ring-opened dialdehydes. The rate of formation of DAK from hepatic rat microsomal incubations of KT was determined by HPLC. The rate of disappearance for KT was almost equal to the rate of DAK formation: 5.96 and 5.88 microM/hr, respectively. Also, the potential bioactivation of DAK was evaluated by measuring substrate activity of DAK with purified pig liver flavin-containing monooxygenase (FMO) and rat liver microsomes. Activity was measured by following DAK-dependent oxygen uptake polarographically at 37 degrees C in pyrophosphate buffer (pH 8.8) containing the glucose-6-phosphate NADPH-generating system. The K(M)'s of DAK were 34.6 and 77.4 microM for the purified FMO and rat microsomal FMO, respectively. Lastly, DAK was found to be metabolized by an NADPH-dependent rat liver microsomal monooxygenases at pH 8.8 to two metabolites as determined by HPLC. Heat inactivation of rat liver microsomal FMO abolished the formation of these metabolites from DAK. SKF-525A and anti-rat NADPH cytochrome P450 reductase did not inhibit this reaction. These results suggest that deacetylation of KT yields a major product, DAK, for further metabolism by microsomal monooxygenases that seem to be FMO-related.

Animals↗
PubMed1994

In vitro analysis of the interaction between sucralfate and ketoconazole.

In healthy volunteers, the bioavailability of ketoconazole is significantly decreased during simultaneous administration with sucralfate. In an effort to address this problem, we examined the interaction between sucralfate and ketoconazole in aqueous solutions and in simulated gastric fluid (SGF) at various initial pHs (1, 2, 3, and 6) in the presence or absence of glutamic acid hydrochloride (GA). Samples from each solution were taken 30 min and 2 h after the addition of ketoconazole to evaluate the solubility of ketoconazole over the usual time period of maximal absorption of ketoconazole in humans. The addition of GA to SGF leads to an increase in solution acidity, while the pHs of SGF at a pH of 1, 2, or 3 are markedly increased by the addition of sucralfate. There is a net decrease in acidity from initial pHs for the pH 1, 2, and 3 solutions when GA and sucralfate are combined. The concentration of ketoconazole in SGF at pHs of 1, 2, 3, 4, and 6 was evaluated in order to assess the pH-dependent solubility properties of the drug in the absence of other interacting species. Regardless of the initial pH, combinations of GA plus ketoconazole showed high concentrations of ketoconazole (approximately 100%) in solution. In contrast, significant decreases in the concentration of soluble ketoconazole were observed when sucralfate was mixed with ketoconazole, and, in some cases, soluble ketoconazole was not detectable. The addition of GA to a mixture of sucralfate and ketoconazole leads to a significant increase in the concentration of solubilized ketoconazole. Nonetheless, important sucralfate-ketoconazole interactions are still observed. After 2 h, approximately 35% of the maximal ketoconazole concentration remained in solution. Comparison of the ketoconazole concentrations at different pHs with the predicted concentrations of the three protonation species of ketoconazole [H2(ketoconazole)(2+), H(ketoconazole)(+), or ketoconazole] showed no correlation. Therefore, the decrease in ketoconazole solubility is not simply a reflection of pH perturbation associated with the dissolution of sucralfate. The observed data are most consistent with a model that has H2(ketoconazole)(2+) or H(ketoconazole)(+) forming an electrostatic interaction with the sucralfate polyanion. The findings of this study suggest that the coadministration of sucralfate with other azole antifungal agents should be investigated.

Chemistry, Pharmaceutical↗
PubMed1991

Effects of ranitidine and sucralfate on ketoconazole bioavailability.

Ketoconazole is an oral imidazole antifungal agent useful in the treatment of opportunistic fungal infections. Gastrointestinal absorption of this agent is variable and dependent on the presence of gastric acid. This study compared the effects of concomitant sucralfate administration with ranitidine administration on the pharmacokinetic disposition of a 400-mg ketoconazole dose. Six healthy male volunteers were randomized to receive 400 mg of ketoconazole alone, 1.0 g of sucralfate concomitantly with a 400-mg ketoconazole dose, or ranitidine, administered 2 h prior to a 400-mg ketoconazole dose to titrate to a gastric pH of 6. All subjects received all three regimens in crossover fashion. Gastric pH was measured continuously for 4 h after ketoconazole administration in all subjects by using a Heidelberg radiotelemetry pH capsule. Relative ketoconazole bioavailability was compared between treatments. With sucralfate, five of six subjects demonstrated a decrease in the peak drug concentration in serum as well as an increase in the time to peak concentration, indicating a delay in ketoconazole absorption. The mean area under the concentration-time curve from 0 to 12 h for ketoconazole following gastric alkalinization was significantly different from that of either ketoconazole alone or ketoconazole with sucralfate (P less than 0.01). Continuous gastric pH monitoring allowed correlation between the decrease in ketoconazole bioavailability observed with ranitidine and the increase in gastric pH. The apparent decrease in ketoconazole bioavailability observed with sucralfate appears to be caused by an alternative mechanism since a change in gastric pH was not observed. On the basis of these findings, separating the administration of ketoconazole and sucralfate should be considered to decrease the potential for interaction of sucralfate on ketoconazole bioavailability.

Adult↗
PubMed1994

In vivo interaction of ketoconazole and sucralfate in healthy volunteers.

Absorption of ketoconazole is impaired in subjects with an increased gastric pH due to administration of antacids, H2-receptor antagonists, proton pump inhibitors, or the presence of hypochlorhydria. Sucralfate could provide an attractive alternative in patients receiving ketoconazole who require therapy for acid-peptic disorders. Twelve healthy human volunteers were administered a single 400-mg oral dose of ketoconazole in each of three randomized treatment phases. In phase A, ketoconazole was administered orally with 240 ml of water. In phase B, ketoconazole and sucralfate (1.0 g) were administered simultaneously with 240 ml of water. In phase C, ketoconazole was administered with 240 ml of water 2 h after administration of sucralfate (1.0 g) orally with 240 ml of water. A 680-mg oral dose of glutamic acid hydrochloride was administered 10 min prior to and with each dose of ketoconazole, sucralfate, or ketoconazole plus sucralfate. Simultaneous administration of ketoconazole and sucralfate led to a significant reduction in the area under the concentration-time curve and maximal concentration of ketoconazole in serum (78.12 +/- 12.20 versus 59.32 +/- 13.61 micrograms.h/ml and 12.34 +/- 3.07 versus 8.92 +/- 2.57 micrograms/ml, respectively; P < 0.05). When ketoconazole was administered 2 h after sucralfate, the observed ketoconazole area under the concentration-time curve was not significantly decreased compared with that of ketoconazole alone. The time to maximal concentrations in serum and the ketoconazole elimination rate constant were not significantly different in any of the three treatment phases. In patients receiving concurrent administration of ketoconazole and sucralfate, doses should be separated by at least 2 h.

Absorption↗
PubMedDate not supplied

Evaluation of ketoconazole.

The pharmacology, microbiology, pharmacokinetics, clinical use, adverse effects, dosage and administration, and drug interactions of ketoconazole are reviewed. Ketoconazole, a new orally active antifungal agent, is an imidazole derivative structurally related to miconazole and clotrimazole. It impairs the synthesis of ergosterol (the main sterol in fungal cell membranes) in susceptible organisms, including yeast (Candida and Cryptococcus spp.), fungi, and dermatophytes. Ketoconazole is absorbed from the gastrointestinal tract; it is better absorbed from acidic aqueous solutions, so drugs that alter the pH of the stomach affect ketoconazole absorption. Therapeutic plasma concentrations are maintained for several hours following ketoconazole administration. Ketoconazole distributes readily into blood, urine, saliva, joint fluid, sebum, and cerumen; recent data indicate it may penetrate into cerebrospinal fluid as well. Elimination is biphasic, with a half-life of two hours during the first 10 hours following a dose, and a half-life of eight hours thereafter. Ketoconazole is metabolized by the hepatic microsomal oxidation system; metabolites are excreted renally. Ketoconazole is effective in treatment of several local and systemic fungal infections. It is approved by FDA for treating candidiasis, chronic mucocutaneous candidiasis, oral thrush, candiduria, coccidioidomycosis, histoplasmosis, chromomycosis, and paracoccidioidomycosis. Ketoconazole has also shown promise in other conditions not yet approved by FDA, including dermatophytosis, pityriasis versicolor, and vaginal candidosis. Controlled, comparative, double-blind trials of ketoconazole versus older agents are generally unavailable. Nausea and vomiting are the most common adverse effects encountered with ketoconazole. Transient elevations in serum liver enzymes have been noted occasionally. Initial daily ketoconazole dosage is 200 mg taken with a meal; 400 mg daily has been used for some conditions. Ketoconazole is a promising new drug, especially when one considers other available antifungal agents. However, large-scale comparative studies are not yet available; a more definitive evaluation of efficacy and safety, especially when the drug is used for long periods of time, must await more widespread use of ketoconazole.

Fungi↗
PubMed1995

Ketoconazole to reduce the need for cyclosporine after cardiac transplantation.

BACKGROUND: Because ketoconazole can markedly reduce the need for cyclosporine and because it also has antimicrobial properties, it may offer benefits in the treatment of patients after cardiac transplantation. METHODS: We randomly assigned 43 patients at the time of cardiac transplantation to receive ketoconazole (200 mg per day) (23 patients) or no ketoconazole (20 patients). The main end points were the dose of cyclosporine required and the incidence of cardiac rejection and infection. RESULTS: Ketoconazole reduced the dose of cyclosporine needed to maintain target levels by 62 percent at one week and by 80 percent at one year. The cost savings per patient (in U.S. dollars, inclusive of the cost of ketoconazole) was about $5,200 in the first year and about $3,920 in each subsequent year. The mean (+/- SD) rate of rejection in the first month was lower in the ketoconazole group than in the controls (4.2 +/- 0.8 vs 5.7 +/- 1.0 episodes per 100 patient-days, P < 0.001), and the average number of days to the first rejection was higher (30 +/- 29 vs. 15 +/- 8, P = 0.03). In the first year, 22 percent of the ketoconazole group required cytolytic therapy, as compared with 35 percent of the controls, and 9 percent of the ketoconazole group required total lymphoid irradiation, as compared with 15 percent of the controls (P = 0.07). The incidence of infection was lower in ketoconazole-treated patients than in controls in the second month (1.4 +/- 0.5 vs. 2.8 +/- 0.7 episodes per 100 patient-days, P < 0.001) and in the third month (0.8 +/- 0.3 vs. 2.3 +/- 0.6 episodes per 100 patient days, P < 0.001). Transient, asymptomatic cholestasis was observed in the ketoconazole group. CONCLUSIONS: After cardiac transplantation, ketoconazole greatly reduced the need for cyclosporine, resulting in substantial cost savings. Ketoconazole also reduced the rates of rejection and infection, without persistent toxic effects. We now use ketoconazole routinely in cardiac-transplant recipients.

Actuarial Analysis↗