In vitro susceptibilities of clinical yeast isolates to the new antifungal eberconazole compared with their susceptibilities to clotrimazole and ketoconazole. (9/766)

The antifungal activity of eberconazole, a new imidazole derivative, against 124 clinical isolates of Candida comprising eight different species and to 34 isolates of Cryptococcus neoformans was compared to those of clotrimazole and ketoconazole. MICs of eberconazole, determined by the National Committee for Clinical Laboratory Standards standardized microbroth method, were equal to or lower than those of other azoles, especially for Candida krusei and Candida glabrata, which are usually resistant to triazoles.  (+info)

Comparison of the toxicity of fluconazole and other azole antifungal drugs to murine and human granulocyte-macrophage progenitor cells in vitro. (10/766)

We studied the inhibitory effects on colony formation by granulocyte-macrophage colony forming units (cfu-gm) of eight azole antifungal agents in vitro. All agents, except fluconazole, inhibited colony formation dose-dependently with 50% inhibitory concentrations (IC50) in the range of 0.78-49 micromol/L in cultures of murine and human bone marrow. For human cells, the IC50 values were 0.553 mg/L for itraconazole, 1.24 mg/L for saperconazole, 2.58 mg/L for clotrimazole, 5.33 mg/L for miconazole, 6.17 mg/L for econazole, 6.27 mg/L for ketoconazole and 8.38 mg/L for oxiconazole. The IC50 of itraconazole for human cfu-gm in vitro was similar to the plasma level of this drug recommended for systemic antifungal therapy (>0.5 mg/L) thus indicating the potential clinical relevance of our data. The IC50 of ketoconazole for human cfu-gm in vitro may be exceeded by plasma levels produced in vivo by high (> or =400 mg) doses, whereas fluconazole failed to reduce colony formation by 50% even at 100 mg/L, a concentration not reached in vivo even after extremely high doses (2000 mg/day). To most of the drugs studied, murine progenitor cells seemed to be less sensitive than the human ones. There was, however, a close correlation between the murine and human log IC50 values of the drugs (r2 = 0.964, P< 0.001), suggesting that cultures of murine bone marrow may be suitable to predict the in-vitro toxicity of azole antifungals to human cfu-gm.  (+info)

Zolpidem metabolism in vitro: responsible cytochromes, chemical inhibitors, and in vivo correlations. (11/766)

AIMS: To determine the human cytochromes mediating biotransformation of the imidazopyridine hypnotic, zolpidem, and the clinical correlates of the findings. METHODS: Kinetic properties of zolpidem biotransformation to its three hydroxylated metabolites were studied in vitro using human liver microsomes and heterologously expressed individual human cytochromes. RESULTS: The metabolic product termed M-3 accounted for more than 80% of net intrinsic clearance by liver microsomes in vitro. Microsomes containing human cytochromes CYP1A2, 2C9, 2C19, 2D6, and 3 A4 expressed by cDNA-transfected human lymphoblastoid cells mediated zolpidem metabolism in vitro. The kinetic profile for zolpidem metabolite formation by each individual cytochrome was combined with estimated relative abundances based on immunological quantification, yielding projected contributions to net intrinsic clearance of: 61% for 3 A4, 22% for 2C9, 14% for 1A2, and less than 3% for 2D6 and 2C19. These values were consistent with inhibitory effects of ketoconazole and sulfaphenazole on zolpidem biotransformation by liver microsomes. Ketoconazole had a 50% inhibitory concentration (IC50 ) of 0.61 microm vs formation of the M-3 metabolite of zolpidem in vitro; in a clinical study, ketoconazole coadministration reduced zolpidem oral clearance by approximately 40%, somewhat less than anticipated based on the IC50 value and total plasma ketoconazole levels, but much more than predicted based on unbound plasma ketoconazole levels. CONCLUSIONS: The incomplete dependence of zolpidem clearance on CYP3A activity has clinical implications for susceptibility to metabolic inhibition.  (+info)

Isoforms of cytochrome P450 on organic nitrate-derived nitric oxide release in human heart vessels. (12/766)

Glutathione S-transferases and the cytochrome P450 system have been proposed for the vascular biotransformation systems in the metabolic activation of organic nitrates. The present study was designed to elucidate the role of human cytochrome P450 isoforms on nitric oxide formation from organic nitrates using lymphoblast microsomes transfected with human CYP isoforms cDNA. CYP3A4-transfected microsomes had the most effective potential of nitric oxide formation from isosorbide dinitrate. Anti-CYP3A2 antibody (which cross-reacts with CYP3A4) or ketoconazole (an inhibitor of the CYP3A superfamily) inhibited nitric oxide formation from isosorbide dinitrate in rat heart microsomes. Immunohistochemistry of human heart also showed intense bindings of CYP3A4 antibody in the endothelium of the endocardium and coronary vessels. These results suggest that the CYP3A4-NADPH-cytochrome P450 reductase system specifically participates in nitric oxide formation from isosorbide dinitrate.  (+info)

Infectious keratitis in leprosy. (13/766)

AIM: To describe leprosy characteristics, ocular features, and type of organisms that produce infective corneal ulcers in leprosy patients. METHOD: The records of all leprosy patients admitted for treatment of corneal ulcers between 1992 and 1997 were reviewed. RESULTS: 63 leprosy patients, 53 males and 10 females, are described. 16 were tuberculoid and 47 lepromatous. 25 patients had completed multidrug therapy. 10 patients had face patches, eight had type I reaction, and 10 had type II reaction. 43 (68%) patients had hand deformities. In 54% of patients pain was absent as a presenting symptom. 19 patients gave a history of trauma. In 15 patients ulcers had also occurred on the other eye, five of them having occurred during the study period and the rest before 1992. Of the 68 eyes with corneal ulcers, 28 had madarosis, 34 had lagophthalmos, nine had ectropion, three had trichiasis, six had blocked nasolacrimal ducts, and 39 decreased corneal sensation. In 14 eyes, a previous lagophthalmos surgery had been done. 16 patients were blind at presentation. 32% of ulcers were located centrally. After treatment only 18% of the eyes showed visual improvement. Five types of fungus were cultured, two of them rare ocular pathogens. CONCLUSIONS: Corneal ulcers occur more in males and in the lepromatous group of patients. Decreased corneal sensation, lagophthalmos and hand deformity are closely associated. Indigenous treatment and late presentations were notable in many patients. Visual outcome is not good. There is increased risk of developing an ulcer in the other eye. Fungal corneal ulcers are not uncommon.  (+info)

In-vitro resistance to azoles associated with mitochondrial DNA deficiency in Candida glabrata. (14/766)

A commercially available disk diffusion procedure was used in a large-scale study to evaluate the susceptibility of a wide range of Candida isolates to polyenes and azoles. With almost all isolates of C. glabrata resistant colonies were present within the inhibition zones for the azole compounds fluconazole, ketoconazole and miconazole, and less frequently for isoconazole, econazole and clotrimazole. Ten randomly selected isolates were cloned by limiting dilution and the susceptibility of the resulting strains to polyenes and azoles was determined. All strains presented a similar susceptibility pattern with sensitivity to polyenes and the presence of resistant colonies for all azole compounds except tioconazole. For each strain and each antifungal agent, one of these resistant colonies was subcultured and studied for antifungal susceptibility. All these colonies showed similar properties regardless of which antifungal agent allowed their selection, with increased sensitivity to polyenes and cross-resistance to the azole compounds except tioconazole. Similar results were obtained on Shadomy's modified medium and on synthetic medium. Likewise, determination of MICs by the Etest method confirmed the resistance to fluconazole. Comparative growth studies revealed a respiratory deficiency in the mutants caused by mitochondrial DNA (mtDNA) deletions. In addition, 'petite' mutants were obtained from a wild-type strain by exposure to ethidium bromide, and these respiratory mutants were shown to be resistant to azoles. These results demonstrate the relationship between mtDNA deficiency and resistance to azoles, and provide an interesting model to study the mechanisms of action of these antifungal agents.  (+info)

Effect of raised plasma beta endorphin concentrations on peripheral pain and angina thresholds in patients with stable angina. (15/766)

OBJECTIVE: To determine whether changes in plasma concentrations of beta endorphins alter angina threshold and peripheral pain threshold in patients with stable angina. DESIGN: Latin square design comparison of angina thresholds by exercise treadmill test and peripheral pain thresholds using a radiant heat source in eight patients with stable angina under control conditions, after stimulation of pituitary beta endorphin release by ketoconazole, after suppression of pituitary beta endorphin release by dexamethasone, and after blockade of opioid receptors by intravenous naloxone. RESULTS: An approximately fivefold increase in circulating concentrations of beta endorphins was found after administration of ketoconazole (mean (SEM): 13.9 (1.2) v 73.8 (6.2) pg/ml; p < 0.05), which was associated with an increase in peripheral pain threshold to a radiant heat source (time to onset of pain perception 72 (19) v 123 (40) seconds; p < 0.05), but no significant difference in angina threshold. A reduction in circulating concentrations of beta endorphins after pretreatment with dexamethasone was statistically non-significant (13.9 (1.2) v 9.0 (1.5) pg/ml; NS) and was not associated with any change in either peripheral pain or angina thresholds. No effects were seen after blockade of opioid receptors by previous administration of intravenous naloxone. CONCLUSIONS: Increased plasma concentrations of beta endorphins alter peripheral pain threshold but not angina threshold in patients with stable angina pectoris.  (+info)

The effect of ketoconazole on the jejunal permeability and CYP3A metabolism of (R/S)-verapamil in humans. (16/766)

AIMS: The purpose of this human intestinal perfusion study was to investigate the effect of ketoconazole on the jejunal permeability and first-pass metabolism of (R)- and (S)-verapamil in humans. METHODS: A regional single-pass perfusion of the jejunum was performed using a Loc-I-Gut(R) perfusion tube in six healthy volunteers. Each perfusion lasted for 200 min and was divided into two periods of 100 min each. The inlet concentration of (R/S)-verapamil was 120 mg l-1 in both periods, and ketoconazole was added at 40 mg l-1 in period 2. (R/S)-verapamil was also administered as a short intravenous infusion of 5 mg, over a period of 10 min. The appearance ratios of the CYP3A formed metabolites (R)- and (S)-norverapamil were also estimated in the outlet jejunal perfusate. RESULTS: The effective jejunal permeability (Peff) of both (R)- and (S)-verapamil was unaffected by the addition of ketoconazole in period 2 suggesting that ketoconazole had no effect on the P-glycoprotein mediated efflux. However, the appearance ratio of both (R)- and (S)-norverapamil in the outlet jejunal perfusate decreased in the presence of ketoconazole. The rate of absorption into plasma of (R)- and (S)-verapamil increased despite the low dose of ketoconazole added, indicating an inhibition of the gut wall metabolism of (R/S)-verapamil by ketoconazole. CONCLUSIONS: Ketoconazole did not affect the jejunal Peff of (R/S)-verapamil, but it did increase the overall transport into the systemic circulation (bioavailability), probably by inhibition of the gut wall metabolism of verapamil. This might be due to ketoconazole being less potent as an inhibitor of P-glycoprotein than of CYP3A4 in vivo in humans.  (+info)