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Serum 4β-hydroxycholesterol increases during fluconazole treatment.
Lütjohann, D, Stellaard, F, Kerksiek, A, Lötsch, J, Oertel, BG
European journal of clinical pharmacology. 2021;(5):659-669
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PURPOSE The antifungal drugs ketoconazole and itraconazole reduce serum concentrations of 4β-hydroxycholesterol, which is a validated marker for hepatic cytochrome P450 (CYP) 3A4 activity. We tested the effect of another antifungal triazole agent, fluconazole, on serum concentrations of different sterols and oxysterols within the cholesterol metabolism to see if this inhibitory reaction is a general side effect of azole antifungal agents. METHODS In a prospective, double-blind, placebo-controlled, two-way crossover design, we studied 17 healthy subjects (nine men, eight women) who received 400 mg fluconazole or placebo daily for 8 days. On day 1 before treatment and on day 8 after the last dose, fasting blood samples were collected. Serum cholesterol precursors and oxysterols were measured by gas chromatography-mass spectrometry-selected ion monitoring and expressed as the ratio to cholesterol (R_sterol). RESULTS Under fluconazole treatment, serum R_lanosterol and R_24,25-dihydrolanosterol increased significantly without affecting serum cholesterol or metabolic downstream markers of hepatic cholesterol synthesis. Serum R_4β-, R_24S-, and R_27-hydroxycholesterol increased significantly. CONCLUSION Fluconazole inhibits the 14α-demethylation of lanosterol and 24,25-dihydrolanosterol, regulated by CYP51A1, without reduction of total cholesterol synthesis. The increased serum level of R_4β-hydroxycholesterol under fluconazole treatment is in contrast to the reductions observed under ketoconazole and itraconazole treatments. The question, whether this increase is caused by induction of CYP3A4 or by inhibition of the catabolism of 4β-hydroxycholesterol, must be answered by mechanistic in vitro and in vivo studies comparing effects of various azole antifungal agents on hepatic CYP3A4 activity.
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Correlation of In Vitro Susceptibility Based on MICs and Squalene Epoxidase Mutations with Clinical Response to Terbinafine in Patients with Tinea Corporis/Cruris.
Khurana, A, Masih, A, Chowdhary, A, Sardana, K, Borker, S, Gupta, A, Gautam, RK, Sharma, PK, Jain, D
Antimicrobial agents and chemotherapy. 2018;(12)
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Recalcitrant dermatophytoses are on the rise in India. High MICs of terbinafine (TRB) and squalene epoxidase (SQLE) gene mutations conferring resistance in Trichophyton spp. have been recently documented. However, studies correlating laboratory data with clinical response to TRB in tinea corporis/cruris are lacking. For this study, we investigated the clinicomycological profile of 85 tinea corporis/cruris patients and performed antifungal susceptibility testing by CLSI microbroth dilution and SQLE mutation analysis of the isolates obtained and correlated these with the responses to TRB. Patients confirmed by potassium hydroxide (KOH) mounting of skin scrapings were started on TRB at 250 mg once a day (OD). If >50% clinical clearance was achieved by 3 weeks, the same dose was continued (group 1). If response was <50%, the dose was increased to 250 mg twice a day (BD) (group 2). If the response still remained below 50% after 3 weeks of BD, the patients were treated with itraconazole (ITR; group 3). Overall, skin scrapings from 64 (75.3%) patients yielded growth on culture. Strikingly, all isolates were confirmed to be Trichophyton interdigitale isolates by internal transcribed spacer (ITS) sequencing. Thirty-nine (61%) of the isolates had TRB MICs of ≥1 µg/ml. Complete follow-up data were available for 30 culture-positive patients. A highly significant difference in modal MICs to TRB among the three treatment response groups was noted (P = 0.009). Interestingly, 8 of the 9 patients in group 3 harbored isolates exhibiting elevated TRB MICs (8 to 32 µg/ml) and SQLE mutations. The odds of achieving cure with TRB MIC < 1 µg/ml strains were 2.5 times the odds of achieving cure with the strain exhibiting MIC ≥1 µg/ml.
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Antifungal treatment in sarcoidosis--a pilot intervention trial.
Tercelj, M, Rott, T, Rylander, R
Respiratory medicine. 2007;(4):774-8
Abstract
BACKGROUND Sarcoidosis is generally treated with corticosteroids that are not always an effective therapy. OBJECTIVES To assess if treatment with antifungal drugs would improve the clinical status of patients with sarcoidosis. METHODS Patients (n=18) with sarcoidosis grades II and III according to established criteria and without clinical and immunological signs of fungal infection, were treated with antifungal medication together with corticosteroids for 3-6 months. Pulmonary X-ray infiltration, lung function, and severity of symptoms were registered before and after the treatment and at follow up 9-58 months later. RESULTS The treatment resulted in statistically significant decreases in the degree of pulmonary infiltration with an average decrease in the group from 2.0 to 1.0. There were also significant increases in diffusion capacity and decreases in the severity of symptoms. CONCLUSION It is suggested that treatment with antifungal drugs may be useful, at least in certain cases of sarcoidosis.
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Pharmacokinetic effect of ketoconazole on solifenacin in healthy volunteers.
Swart, PJ, Krauwinkel, WJ, Smulders, RA, Smith, NN
Basic & clinical pharmacology & toxicology. 2006;(1):33-6
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Solifenacin succinate (YM905) is a new, once-daily, orally administered muscarinic receptor antagonist designed to treat overactive bladder. The metabolism of solifenacin involves hepatic cytochrome P450 (CYP) 3A4; therefore, the pharmacokinetics of solifenacin may be affected by drugs that inhibit CYP3A4. This study aimed to examine the effects of co-administration of ketoconazole, a potent CYP3A4 inhibitor, on the pharmacokinetics of solifenacin in healthy volunteers. In a single-site, open-label, monosequence, crossover study, 17 healthy men and women aged 18 to 65 years received a single 10 mg oral dose of solifenacin, which is is the highest available dose. After a 14-day wash-out period, they began 20 days of oral ketoconazole at a dose of 200 mg once daily. A single 10 mg dose of solifenacin was administered again on day 7 of ketoconazole treatment. Pharmacokinetics was assessed using the standard measurements of maximum plasma concentration (Cmax), time to Cmax, area under the curve (AUC), and elimination half-life (t1/2). Co-administration of ketoconazole resulted in a 1.43 times increase in the C(max) of solifenacin and an approximately 2 times increase in AUC. The mean t1/2 of solifenacin was extended from 49.3 to 77.5 hr whereas time to Cmax did not change. No substantial increase in the overall rate of adverse events, and no significant effects on vital signs, electrocardiography, clinical laboratory values, or physical examinations were noted. Administration of 200 mg ketoconazole once daily in healthy male volunteers resulted in a 2 times increase in exposure of a single 10 mg dose of solifenacin. Since ketoconazole is one of the strongest inhibitors of CYP3A4, it is expected that co-administration of other CYP3A4 inhibitors will not result in a stronger increase in solifenacin exposure.
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Effect of ketoconazole on the pharmacokinetics of rosiglitazone in healthy subjects.
Park, JY, Kim, KA, Shin, JG, Lee, KY
British journal of clinical pharmacology. 2004;(4):397-402
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AIMS: Fungal infection is a significant comorbidity in patients with diabetes mellitus, and ketoconazole, an antifungal agent, causes a number of drug interactions with coadministered drugs. Rosiglitazone is a novel thiazolidinedione antidiabetic drug, mainly metabolized by CYP2C8 and to a lesser extent CYP2C9. We investigated the possible effect of ketoconazole on the pharmacokinetics of rosiglitazone in humans. METHODS Ten healthy Korean male volunteers were treated twice daily for 5 days with 200 mg ketoconazole or with placebo, using a randomized, open-label, two-way crossover study. On day 5, a single dose of 8 mg rosiglitazone was administered orally, and plasma rosiglitazone concentrations were measured. RESULTS Ketoconazole increased the mean area under the plasma concentration-time curve for rosiglitazone by 47%[P = 0.0003; 95% confidence interval (CI) 23, 70] and the mean elimination half-life from 3.55 to 5.50 h (P = 0.0003; 95% CI in difference 1.1, 2.4). The peak plasma concentration of rosiglitazone was increased by ketoconazole treatment by 17% (P = 0.03; 95% CI 5, 29). The apparent oral clearance of rosiglitazone decreased by 28% after ketoconazole treatment (P = 0.0005; 95% CI 18, 38). CONCLUSIONS This study revealed that ketoconazole affected the disposition of rosiglitazone in humans, probably by the inhibition of CYP2C8 and CYP2C9, leading to increasing rosiglitazone concentrations that could increase the efficacy of rosiglitazone or its adverse events.
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Influence of ketoconazole on azimilide pharmacokinetics in healthy subjects.
El Mouelhi, M, Worley, DJ, Kuzmak, B, Destefano, AJ, Thompson, GA
British journal of clinical pharmacology. 2004;(6):641-7
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AIM: To assess the influence of ketoconazole on azimilide pharmacokinetics. METHODS A two-period randomized crossover study was conducted in healthy male and female subjects (19-45 years). Placebo or 200 mg ketoconazole were administered orally every 24 h for 29 days. On day 8, a single oral dose of 125 mg azimilide dihydrochloride was coadministered following an overnight fast. Blood samples were obtained prior to and for 22 days following azimilide dihydrochloride administration. The plasma protein binding of azimilide was also assessed at 6 h after dosing. RESULTS Following ketoconazole administration, a 16% increase in azimilide AUC (90% confidence interval (CI) 112%, 120%), a 12% increase in C(max) (95% CI 107%, 116%), a 13% increase in t(1/2,z) (95% CI 107%, 120%) and a 14% decrease in CL(o) (95% CI 82%, 90%) were observed. CONCLUSIONS The changes in azimilide pharmacokinetics following ketoconazole treatment are not clinically important since the 90% CI for the AUC fell within the prespecified range of 80-125%. Thus, no clinically important drug interactions are expected when azimilide dihydrochloride is coadministered with CYP3A4 inhibitors.
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Coping with mild inflammatory catamenial acne: a clinical and bioinstrumental split-face assessment.
Petit, L, Piérard- Franchimont, C, Uhoda, E, Vroome, V, Cauwenbergh, G, Piérard, GE
Skin research and technology : official journal of International Society for Bioengineering and the Skin (ISBS) [and] International Society for Digital Imaging of Skin (ISDIS) [and] International Society for Skin Imaging (ISSI). 2004;(4):278-82
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BACKGROUND Acne is a multifactorial disease exhibiting distinct clinical presentations. Among them, the catamenial type is a matter of concern for young women. Some oral contraceptives may help without, however, clearing the skin condition. AIM: The present open study aimed at evaluating the effect of overnight applications of a paste made of petrolatum,15% zinc oxide and 0.25% miconazole nitrate. METHOD The split-face trial was conducted in 35 women. A non-medicated cream was used as control. Clinical evaluations and biometrological assessments on cyanoacrylate follicular biopsies were performed monthly for 3 months. Comedometry and the density in autofluorescent follicular casts were used as analytical parameters. In addition, the five most severe cases at inclusion were tested at the completion of the study for follicular bacterial viability using dual flow cytometry. RESULTS Compared with baseline and to the control hemi-face, the medicated paste brought significant improvement of acne. The number of papules and their redness were reduced beginning with the first treatment phase. A reduction in the follicular fluorescence was yielded beginning with the second treatment phase. The ratios between injured and dead bacteria, on the one hand, and live bacteria, on the other hand were significantly increased at completion of the study. CONCLUSION A miconazole paste applied for 1 week at the end of the ovarian cycle has a beneficial effect on catamenial acne.
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Pharmacokinetics of posaconazole coadministered with antacid in fasting or nonfasting healthy men.
Courtney, R, Radwanski, E, Lim, J, Laughlin, M
Antimicrobial agents and chemotherapy. 2004;(3):804-8
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Posaconazole is a potent broad-spectrum azole antifungal agent in clinical development for the treatment of invasive fungal infections. This study evaluated the potential for a pH-dependent pharmacokinetic interaction between posaconazole and an antacid (Mylanta), under fasting and nonfasting conditions. Twelve men completed this randomized, four-period crossover, single-dose study. Subjects received 200 mg of posaconazole following a 10-h fast, with 20 ml of Mylanta and a 10-h fast, with 20 ml of Mylanta and a high-fat breakfast, and with a high-fat breakfast alone. Antacid coadministration had no statistically significant effects on posaconazole bioavailability under fasting or nonfasting conditions. In the fasting state, antacid slightly increased the relative oral bioavailability of posaconazole by 15% (P = 0.296); in the nonfasting state, antacid decreased the relative bioavailability of posaconazole by 12% (P = 0.352). Food increased the relative oral bioavailability of posaconazole by 400% (P = 0.001). In conclusion, the effect of antacid on posaconazole exposure in the fasting or nonfasting state was small and is not considered clinically significant.