Nizoral
Clofibrate, a peroxisome-proliferator, enhances reverse cholesterol transport through cytochrome P450 activation and oxysterol generation.

Guan JZ, Tamasawa N, Murakami H, Matsui J, Yamato K, Suda T.

Third Department of Internal Medicine, Hirosaki University School of Medicine, Hirosaki 036-8562, Japan.

Fibrates are widely used hypolipidemic agents that activate the peroxisome proliferator-activated receptor a (PPARalpha) and regulate the expression of many genes involved in lipid metabolism. We studied the mechanism of the effect of clofibrate on cholesterol homeostasis. Rats were fed with chow containing clofibrate, cytochrome P-450 inhibitor ketoconazole, or clofibrate plus ketoconazole. Control rats were fed only with normal chow. The levels of six oxysterols in liver microsome were determined. The levels of mRNAs for liver X receptor alpha (LXRalpha), ATP-binding cassette A1 (ABCA1), PPARalpha and cholesterol 7alpha-hydroxylase (CYP7A) in the liver were analyzed by northern blotting. Clofibrate administration decreased plasma levels of total cholesterol and triglyceride and increased high-density lipoprotein-cholesterol (HDL-C). Clofibrate increased the levels of liver microsomal oxysterols including 25- and 27-hydroxycholesterol, which are potent activators of LXRalpha. Clofibrate also enhanced the expression of mRNAs for PPARalpha, LXRalpha, and ABCA1. Simultaneous administration of ketoconazole suppressed the effects of clofibrate on plasma lipids, hepatic oxysterol levels, and the expression of the genes. Clofibrate increases cytochrome P450 content and the resulting oxysterol generation may partly mediate the clofibrate-induced up-regulattion of LXRa and ABCA1, which are related to reverse cholesterol transport.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14690017&dopt=Abstract ketoconazole Nizoral



Nizoral
Susceptibility of Helicobacter pylori to simethicone and other non-antibiotic drugs.

Ansorg R, von Recklinghausen G, Heintschel von Heinegg E.

Institute of Medical Microbiology, University of Essen, Germany.

The antifoaming agent simethicone (Lefax), the protease inhibitor gabexate mesilate (FOY), the antimycotic ketoconazole, and the hydroxyl scavangers dimethylsulphoxide (DMSO) and allopurinol were investigated for growth inhibition of Helicobacter pylori and representative strains of other bacterial species. H. pylori were selectively inhibited by 64-128 mg/L of simethicone, 64-128 mg/L gabexate mesilate, and 16-64 mg/L ketoconazole. Dimethylsulphoxide and allopurinol showed no antibacterial effect at concentrations used therapeutically. It is concluded that gabexate mesilate, ketoconazole and, particularly, simethicone are candidates for treatment of H. pylori infection.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8647772&dopt=Abstract ketoconazole Nizoral



Nizoral
Inhibition of terfenadine metabolism in vitro by azole antifungal agents and by selective serotonin reuptake inhibitor antidepressants: relation to pharmacokinetic interactions in vivo.

von Moltke LL, Greenblatt DJ, Duan SX, Harmatz JS, Wright CE, Shader RI.

Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, Boston, MA 02111, USA.

Biotransformation of the H-1 antagonist terfenadine to its desalkyl and hydroxy metabolites was studied in vitro using microsomal preparations of human liver. These metabolic reactions are presumed to be mediated by Cytochrome P450-3A isoforms. The azole antifungal agent ketoconazole was a highly potent inhibitor of both reactions, having mean inhibition constants (Ki) of 0.037 and 0.34 microM for desalkyl- and hydroxy-terfenadine formation, respectively. Itraconazole also was a potent inhibitor, with Ki values of 0.28 and 2.05 microM, respectively. Fluconazole, on the other hand, was a weak inhibitor. Six selective serotonin reuptake inhibitor antidepressants tested in this system were at least 20 times less potent inhibitors of terfenadine metabolism than was ketoconazole. An in vitro-in vivo scaling model used in vitro Ki values, typical clinically relevant plasma concentrations of inhibitors, and presumed liver:plasma partition ratios to predict the degree of terfenadine clearance impairment during coadministration of terfenadine with these inhibitors in humans. The model predicted a large and potentially hazardous impairment of terfenadine clearance by ketoconazole and, to a slightly lesser extent, by itraconazole. However, fluconazole and the six selective serotonin reuptake inhibitors (SSRIs) at usual clinical doses were not predicted to impair terfenadine clearance to a degree that would be of clinical importance. Caution is nonetheless warranted with the coadministration of SSRIs and terfenadine when high doses of SSRIs (particularly fluoxetine) are administered. Also, some individuals may be unusually susceptible to metabolic inhibition for a variety of reasons.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8690825&dopt=Abstract ketoconazole Nizoral



Nizoral
Cardiotoxic and drug interaction profile of the second generation antihistamines ebastine and terfenadine in an experimental animal model of torsade de pointes.

Hey JA, del Prado M, Kreutner W, Egan RW.

Schering-Plough Research Institute, Allergy, Kenilworth, New Jersey, USA.

Second generation antihistamines are widely used because of their efficacy in treating allergic disorders without significant sedative side effects. Recent clinical evidence shows that some of the early prototypes in this class, namely terfenadine and astemizole, have the potential for producing torsade de pointes, a rare form of ventricular arrhythmia that is life-threatening. Important questions have been raised as to whether this is a property shared by newer, recently-introduced second generation antihistamines. The objective of this study was to characterize and compare the ECG and cardiovascular effects of terfenadine (CAS 50679-08-8) and ebastine (CAS 90729-43-4), a new second generation antihistamine, in an experimental animal model predictive of the cardiotoxic proclivity of these agents. Also, the drug interaction effect of the antifungal drug ketoconazole (CAS 65277-42-1) was evaluated, which blocks hepatic first-pass biotransformation of ebastine and terfenadine leading to increased cardiotoxity of terfenadine in man, on the ECG effects of terfenadine and ebastine in this animal model. Terfenadine (10 mg/kg) and ebastine (50 mg/kg) were administered intravenously to anesthetized guinea pigs. Electrocardiographic (ECG) and cardiovascular parameters (blood pressure and heart rate) were measured during the course of the experiment. The ECG wave form was analyzed to determine QTc interval, PR interval, QRS interval and heart rate. In separate studies in conscious guinea pigs, the effect of oral ketoconazole (200 mg) on the ECG effects of oral terfenadine (60 mg) and ebastine (10 mg) was studied. Terfenadine (10 mg/kg) and ebastine (50 mg/kg) produced significant prolongation of the QTc interval and disruption of the ECG signal when given intravenously to anesthetized guinea pigs. The ECG effects were characterized by large amplitude, morphologically aberrant T-waves, and instances of arrhythmogenic activity. Both drugs produced pronounced bradycardia and hypotension. In conscious animals, pretreatment with oral ketoconazole significantly enhanced the QTc interval prolongation effects of terfenadine and ebastine. Oral terfenadine and ebastine, when given alone at the doses tested, were devoid of adverse QTc interval prolongation effects in the conscious guinea pig. In separate studies in conscious guinea pigs, oral loratadine (10 mg; CAS 79794-75-5) given alone or in animals pretreated with ketoconazole did not affect ECG parameters. The present studies show that terfenadine and ebastine share similar cardiotoxic properties characterized by QTc interval prolongation, bradycardia, hypotension and proarrhythmogenic activity in the anesthetized guinea pig. In addition, pretreatment with ketoconazole enhances the QTc interval effect of both drugs, most likely due to the accumulation of parent compound that occurs after blockade of hepatic metabolism by CYP3A4. In conclusion, our findings indicate that ebastine and terfenadine display similarities in their inherent potential for cardiotoxic and adverse drug interaction effects. In contrast, loratadine is devoid of adverse ECG and drug interaction effects.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8720305&dopt=Abstract ketoconazole Nizoral



Nizoral
In-vitro antifungal activity of sertaconazole, bifonazole, ketoconazole, and miconazole against yeasts of the Candida genus.

Carrilo-Munoz AJ, Tur C, Torres J.

Unitat de Micologia, Institut Municipal D'investigacio (IMIM), Universitat Autonoma de Barcelona, Spain. ajcm.acia bcn.servicom.es

The in-vitro antifungal activity of sertaconazole against 110 strains of Candida yeasts (50 Candida albicans, 15 Candida glabrata, 2 Candida guilliermodii, 8 Candida krusei, 1 Candida kefyr, 8 Candida parapsilosis and 26 Candida tropicalis) was assessed in comparison with bifonazole, ketoconazole, econazole and miconazole. The majority of the strains were clinical isolates; some reference strains were included. A commercial agar diffusion method (NeoSensitabs, Rosco, Taastrup, Denmark) in Shadomy's modified medium pH 7 was used. Using the manufacturer's criteria, 86.4% of the strains were classified as "sensitive" to sertaconazole. The only strain classified as "resistant" to sertaconazole was the control reference strain of C. albicans. The remaining strains were classified as "moderately sensitive". The sensitivity/resistance percentages for the other antifungals tested were 75.5/1.8 for ketoconazole, 71.8/2.7 for miconazole, 63.7/13.6 for econazole, and 59.1/5.5 for bifonazole. Sertaconazole showed a higher antifungal activity than that of the other antimycotics, tested in vitro which was statistically significant (P < 0.001), as well as a lower resistance rate than that of econazole, bifonazole and ketoconazole.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8722548&dopt=Abstract ketoconazole Nizoral



Nizoral
Comparisons of the susceptibilities of planktonic and adherent Candida albicans to antifungal agents: a modified XTT tetrazolium assay using synchronised C. albicans cells.

Hawser S.

Lepetit Research Center, Marion Merrell Dow Research Institute, Gerenzano (Varese), Italy.

Adhesion of synchronised yeast-phase Candida albicans cells to tissue culture plastic, and the susceptibility of planktonic and adherent cells to antifungal agents, was investigated using a modified tetrazolium (XTT) assay. MIC data demonstrated that ketoconazole and amphotericin B were highly active against planktonic C. albicans yeast-phase cells. XTT tetrazolium assays permitted comparisons of MIC values with XTT formazan IC50 and IC80 (percentage inhibitory concentrations); IC50 and IC80 values for amphotericin B and ketoconazole were similar. Furthermore, IC50 and IC80 values for 24 h incubation with antifungal agent were typically higher than corresponding IC50 and IC80 values for 48 h incubation. Furthermore, in comparison to values for planktonic Candida cells, adherent cells were typically less susceptible to amphotericin B and ketoconazole. For example, with increasing incubation time following the initial adhesion period, cells became progressively less susceptible to amphotericin B and ketoconazole: 24 h (P < 0.05) and 48 h (P < 0.001). Furthermore, other azoles showed the same activities compared with ketoconazole against both planktonic and adherent cells. Overall, the data demonstrate the usefulness of the XTT tetrazolium assay in describing comparisons of the susceptibility profiles for both planktonic and adherent synchronous yeast phase C. albicans in vitro.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8732362&dopt=Abstract ketoconazole Nizoral



Nizoral
Comparison of ketoconazole and fluconazole as cytochrome P450 inhibitors. Use of steady-state infusion approach to achieve plasma concentration-response relationships.

Ervine CM, Matthew DE, Brennan B, Houston JB.

Department of Pharmacy, University of Manchester, UK.

The ability of two azole antifungal agents, ketoconazole and fluconazole, to inhibit hepatic cytochrome P450 activity in vivo in the rat has been determined. To make a valid comparison, differences in pharmacokinetic properties between the azoles were accounted for by using an infusion approach to maintain steady-state plasma concentrations over a range of 1-48 mg/liter. Both compounds showed a maximum inhibitory effect, assessed by a reduction in antipyrine clearance, of approximately 75%. The relationship between steady-state plasma concentration and the degree of inhibition of antipyrine clearance was nonlinear for both azoles. However, the inhibitory effect resulted at lower concentrations for ketoconazole than for fluconazole. Analysis of these data provided Ki values of 3 and 10 microM, for ketoconazole and fluconazole, respectively, based on plasma concentration of azole. This difference in activity is 2 orders of magnitude greater when Ki values are expressed in terms of unbound concentration in the blood, which may be more representative of hepatic tissue concentrations. Ki values based on unbound drug concentration are 0.07 and 8.7 microM for ketoconazole and fluconazole, respectively. These data confirm the conclusions based on in vitro findings that ketoconazole is a more inhibitory of mammalian cytochrome P450 isoenzymes than fluconazole.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8742233&dopt=Abstract ketoconazole Nizoral