Our library of drug research abstracts drawn from the medical literature is updated on a regular schedule, and you can be assured that new nizoral research articles will be listed here shortly after becoming available to us.
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Medical research on nizoral
J Pharm Biomed Anal. 2008 May 17;
Youdim KA, Lyons R, Payne L, Jones BC, Saunders K
The current study focused on the development of an automated IC(50) cocktail assay in a miniaturized 384 well assay format. This was developed in combination with a significantly shorter high pressure liquid chromatography (HPLC) separation and liquid chromatography-mass spectrometry (LC-MS/MS) run-time; than those currently reported in the literature. The 384-well assay used human liver microsomes in conjunction with a cocktail of probe substrates metabolized by the five major CYPs (tacrine for CYP1A2, diclofenac for CYP2C9, (S)-mephenytoin for CYP2C19, dextromethorphan for CYP2D6 and midazolam for CYP3A4). To validate the usefulness of the automated and analytical methodologies, IC(50) determinations were performed for a series of test compounds known to exhibit inhibition across these five major P450s. Eight compounds (sertraline, disulfuram, ticlopidine fluconazole, fluvoxamine, ketoconazole, miconazole, paroxetine, flunitrazepam) were studied as part of a cocktail assay, and against each CYPs individually. The data showed that the IC(50)s generated with cocktail incubations did not differ to a great extent from those obtained in the single probe experiments and hence unlikely to significantly influence the predicted clinical DDI risk. In addition the present method offered a significant advantage over some of the existing cocktail analytical methodology in that separation can be achieved with run times as short as 1min without compromising data integrity. Although numerous studies have been reported to measure CYP inhibition in a cocktail format the need to support growing discovery libraries not only relies on higher throughput assays but quicker analytical run times. The current study reports a miniaturized high-throughput cocktail IC(50) assay, in conjunction with a robust, rapid resolution LC-MS/MS end-point offered increased sample throughput without compromising analytical sensitivity or analyte resolution.
Bioorg Med Chem Lett. 2008 Jun 10;
Das BC, Madhukumar AV, Anguiano J, Kim S, Sinz M, Zvyaga TA, Power EC, Ganellin CR, Mani S
PXR, pregnane X receptor, in its activated state, is a validated target for controlling certain drug-drug interactions in humans. In this context, there is a paucity of inhibitors directed toward activated PXR. Using prior observations with ketoconazole as a PXR inhibitor, the target compound 3 was synthesized from (s)-glycidol with overall 56% yield. (+)-Glycidol was reacted with 4-bromophenol and potassium carbonate in DMF to yield the ring opened compound 6. This was then heated to reflux in benzene along with 2', 4'-difluoroacetophenone and catalytic amount of para-toluene sulfonic acid to yield 8. The resultant acetal 8 was then functionalized using Palladium chemistry to yield the target compound 3. The activity of the compound was compared with ketoconazole and UCL2158H. However, in contrast with ketoconazole (IC(50) approximately 0.020muM; approximately 100% inhibition), 3 has negligible effects on inhibition of microsomal CYP450 (maximum approximately 20% inhibition) at concentrations >40muM. In vitro, micromolar concentration of ketoconazole is toxic to passaged human cell lines, while 3 does not exhibit cytotoxicity up to concentrations approximately 100muM (viability >85%). This is the first demonstration of a chemical analog of a PXR inhibitor that retains activity against activated PXR. Furthermore, in contrast with ketoconazole, 3 is less toxic in human cell lines and has negligible CYP450 activity.
J Invest Dermatol. 2008 Jun 26;
Hong SP, Kim MJ, Jung MY, Jeon H, Goo J, Ahn SK, Lee SH, Elias PM, Choi EH
Whereas high-dose ultraviolet B (UVB) is detrimental to the epidermal permeability barrier, suberythemal doses of UVB are used to treat atopic dermatitis (AD), which is characterized by defective permeability barrier and antimicrobial function. As epidermal permeability barrier and antimicrobial peptide (AMP) expression are coregulated and interdependent functions, we hypothesized that suberythemal doses of UVB exposure could regulate AMP expression in parallel with permeability barrier function. Hairless mice were exposed to 40 mJ cm(-2) UVB (about 1/2 minimal erythema dose) daily for 1 or 3 days. Twenty-four hours after the last exposure, epidermal barrier function was assessed and skin specimens were taken for western blotting, immunohistochemistry, and quantitative reverse transcription-PCR for mouse beta-defensin (mBD)-2, mBD3 and cathelin-related antimicrobial peptide (CRAMP). mRNA levels of the vitamin D receptor (VDR), 1alpha-hydroxylase and key epidermal lipid synthetic enzymes were also quantified. After 3 days of UVB exposure, acceleration of barrier recovery and augmentation in expression of epidermal differentiation markers (for example, involucrin and filaggrin) occurred in parallel with increased mBD2, mBD3, and CRAMP expression at both the mRNA and protein level. VDR, 1alpha-hydroxylase, and the major epidermal lipid synthetic enzymes were also upregulated. When an inhibitor of 1alpha, 25 dihydroxyvitamin D(3) formation, ketoconazole, was applied immediately after UVB exposure, the cutaneous vitamin D system was inhibited, which in turn blocked epidermal lipid synthesis, AMP expression, and permeability barrier homeostasis, suggesting that the beneficial effect of low-dose UVB depends, at least in part, on activation of the cutaneous vitamin D system. Our results provide new insights into the mechanisms whereby low-dose UVB comprises effective therapy for AD.Journal of Investigative Dermatology advance online publication, 26 June 2008; doi:10.1038/jid.2008.169.
BMC Bioinformatics. 2008; 9 Suppl 6: S11
Arikuma T, Yoshikawa S, Azuma R, Watanabe K, Matsumura K, Konagaya A
BACKGROUND: In accordance with the increasing amount of information concerning individual differences in drug response and molecular interaction, the role of in silico prediction of drug interaction on the pathway level is becoming more and more important. However, in view of the interferences for the identification of new drug interactions, most conventional information models of a biological pathway would have limitations. As a reflection of real world biological events triggered by a stimulus, it is important to facilitate the incorporation of known molecular events for inferring (unknown) possible pathways and hypothetic drug interactions. Here, we propose a new Ontology-Driven Hypothetic Assertion (OHA) framework including pathway generation, drug interaction detection, simulation model generation, numerical simulation, and hypothetic assertion. Potential drug interactions are detected from drug metabolic pathways dynamically generated by molecular events triggered after the administration of certain drugs. Numerical simulation enables to estimate the degree of side effects caused by the predicted drug interactions. New hypothetic assertions of the potential drug interactions and simulation are deduced from the Drug Interaction Ontology (DIO) written in Web Ontology Language (OWL). RESULTS: The concept of the Ontology-Driven Hypothetic Assertion (OHA) framework was demonstrated with known interactions between irinotecan (CPT-11) and ketoconazole. Four drug interactions that involved cytochrome p450 (CYP3A4) and albumin as potential drug interaction proteins were automatically detected from Drug Interaction Ontology (DIO). The effect of the two interactions involving CYP3A4 were quantitatively evaluated with numerical simulation. The co-administration of ketoconazole may increase AUC and Cmax of SN-38(active metabolite of irinotecan) to 108% and 105%, respectively. We also estimates the potential effects of genetic variations: the AUC and Cmax of SN-38 may increase to 208% and 165% respectively with the genetic variation UGT1A1*28/*28 which reduces the expression of UGT1A1 down to 30%. CONCLUSION: These results demonstrate that the Ontology-Driven Hypothetic Assertion framework is a promising approach for in silico prediction of drug interactions. The following future researches for the in silico prediction of individual differences in the response to the drug and drug interactions after the administration of multiple drugs: expansion of the Drug Interaction Ontology for other drugs, and incorporation of virtual population model for genetic variation analysis, as well as refinement of the pathway generation rules, the drug interaction detection rules, and the numerical simulation models.
NATURAL SESQUITERPENE LACTONES ARE ACTIVE AGAINST LEISHMANIA MEXICANA.
J Parasitol. 2008 Mar 11; 1
Barrera P, Verónica JO, Tonn C, Giordano O, Galanti N, Sosa M
In this paper, the effects of three natural sesquiterpene lactones - helenalin (Hln), mexicanin (Mxc) and dehydroleucodine (DhL) - were evaluated on cultured Leishmania mexicana promastigotes and it was observed that the compounds inhibited the in vitro growth of the parasites at relatively low concentrations. The effect was rapid and irreversible with an estimated IC50 2-4 muM, while all the lactones were more effective than ketoconazole. Moreover, these compounds exhibited low cytotoxicity on mammalian cells. Hln induced strong vacuolization of the parasite cytoplasm, although pericellular microtubules were preserved. The three lactones induced DNA fragmentation as judged by the high labeling with the fluorescent TUNEL method, and confirmed by electrophoresis on agarose gels. The ability of the parasites to invade Vero cells was also decreased by exposure to low concentrations of the compounds. We conclude that these compounds can affect the parasite life cycle, possibly through multiple mechanisms. Identification of the molecular targets of these natural products and studies of their effects on amastigotes should be carried out to evaluate the possible therapeutic use of the compounds against Leishmania mexicana.
Invest New Drugs. 2008 Jun 24;
Lorusso P, Heath EI, McGreivy J, Sun YN, Melara R, Yan L, Malburg L, Ingram M, Wiezorek J, Chen L, Pilat MJ
Motesanib diphosphate is a novel angiogenesis inhibitor selectively targeting vascular endothelial growth factor receptors 1, 2, and 3; platelet-derived growth factor receptor and stem cell factor receptor. The purpose of this phase 1b, drug-drug interaction study was to investigate the effect of ketoconazole, a strong inhibitor of the cytochrome P450 3A4 isoenzyme, on the pharmacokinetics and tolerability of motesanib diphosphate. Fourteen patients with advanced solid tumors refractory to standard treatment were enrolled and received motesanib diphosphate 50 mg once daily from day 1 through 15. Patients were randomized to receive a single oral dose of ketoconazole 400 mg either on day 8 (Sequence 1; n = 7) or day 15 (Sequence 2; n = 7), while pharmacokinetic samples were collected. After completion of this part (day 16), 13 patients received an escalated once-daily dose of motesanib diphosphate 125 mg. Evaluable pharmacokinetic data (n = 12) suggest that ketoconazole modestly increased motesanib exposure. The motesanib area under the concentration-time curve (AUC) from 0 to 24 h increased by 86% (90% CI, 1.50-2.29; P < 0.001) and the maximum plasma concentration (C (max)) by 35% (90% CI, 1.12-1.64; P = 0.02), compared with motesanib diphosphate administration alone. The tolerability profile (with or without ketoconazole coadministration) was consistent with that from other motesanib diphosphate monotherapy studies. Treatment-related adverse events were mild to moderate and commonly included fatigue (50% of patients), hypertension (43%), diarrhea (21%), dizziness (14%), paresthesia (14%), and vomiting (14%). Hypertension was the most common related grade 3 event (21%). No grade 4 or 5 treatment-related adverse events occurred.
Drug Metab Dispos. 2008 Jun 23;
Sharma S, Ou J, Strom SC, Mattison D, Caritis S, Venkataramanan R
Preterm delivery, that is delivery before 37 completed weeks of gestation, is the major determinant of neonatal morbidity and mortality. Until recently no effective therapies for prevention of preterm birth existed. In a recent multicentered trial, 17alpha- hydroxyprogesterone caproate (17-OHPC) reduced the rate of preterm birth by 33% in a group of high risk women. Limited pharmacologic data exist for this drug. The recommended dose is empiric, the metabolic pathways are not well defined especially in pregnant women and the fetal exposure has not been quantified. In order to define the metabolic pathways of 17-OHPC we used human liver microsomes, fresh human hepatocytes and expressed enzymes. Human liver microsomes (HLM) in the presence of NADPH generated 3 major metabolites (M1, M2, and M3); whereas 2 major metabolites (M1, M2) were observed with fresh human hepatocytes (FHH). Metabolism of 17-OHPC was significantly inhibited by the CYP3A4 inhibitors ketoconazole and troleandomycin in HLM and FHH. Metabolism of 17-OHPC was significantly greater in FHH treated with the CYP3A inducers, rifampin and phenobarbital. Further, studies with expressed enzymes demonstrated that 17-OHPC is metabolized exclusively by CYP3A4 and CYP3A5. The caproic acid ester was intact in the major metabolites generated indicating that 17-OHPC is not converted to the primary progesterone metabolite, 17-alpha hydroxyprogesterone (HP). In summary, this study demonstrates that 17-OHPC is metabolized by CYP3A. Since, CYP3A is involved in the oxidative metabolism of numerous commonly used drugs; 17-OHPC may be involved in clinically relevant metabolic drug interactions with co-administered CYP3A4 inhibitors or inducers.
Int J Pharm. 2008 May 14;
Ujie K, Oda M, Kobayashi M, Saitoh H
It has been shown that fexofenadine, a selective non-sedating histamine H(1)-receptor antagonist, is a substrate for P-glycoprotein (P-gp) and an organic anion transporting peptide (OATP). This study was undertaken to investigate the relative contribution of these absorptive and secretory transporters to the intestinal absorption of fexofenadine in rats. When 0.1mM fexofenadine was introduced into duodenal, jejunal, and ileal loops, its disappearance was around 10% over 30min. Cyclosporine A, but not ketoconazole, probenecid or mitoxantron, significantly increased fexofenadine disappearance in the ileal loops. The serosal-to-mucosal permeation of fexofenadine across the rat ileal segments was approximately 18-fold greater than its mucosal-to-serosal permeation. The secretory orientation of the ileal permeation of fexofenadine was weakened significantly in the presence of cyclosporine A, moderately in the presence of ketoconazole, but was unchanged in the presence of probenecid. When fexofenadine (0.1 or 0.5mM) was administered to rats intraluminally, plasma concentrations increased linearly up to 120min. The magnitude of the increase in plasma fexofenadine concentrations in the presence of cyclosporine A was more remarkable at 0.5mM than at 0.1mM. The results obtained in this study suggest that the intestinal absorption of fexofenadine is relatively small in rats even if OATP functions as an absorptive transporter for fexofenadine. Low absorption of fexofenadine in rats is attributed to potent secretory transport mediated by P-gp.
Planta Med. 2008 Jun 18;
Yoo HH, Lee SH, Jin C, Kim DH
The purpose of this investigation is to characterize the inhibition of CYP3A4 by methylenedioxyphenyl lignans isolated from ACANTHOPANAX CHIISANENSIS. Inhibition of CYP3A4 by three methylenedioxyphenyl lignans, avinin, helioxanthin, and 3-(3'',4''-dimethoxybenzyl)-2-(3',4'-methylenedioxybenzyl)butyrolactone was time-, concentration-, and NADPH-dependent and characterized by K(I) values of 2.4, 1.6, and 2.2 muM and K(inact) values of 0.030, 0.043, and 0.047 min (-1), respectively. The inhibition of CYP3A4 activity by these lignans was suppressed in the presence of a competitive CYP3A4 substrate, ketoconazole. Addition of nucleophiles or reactive oxygen scavenger and dialysis did not prevent inactivation of CYP3A4 by the ACANTHOPANAX lignans. The loss of CYP3A4 enzymatic activity resulting from incubation with the ACANTHOPANAX lignans was accompanied with a spectral loss of CYP3A4. These results collectively demonstrate that savinin, helioxanthin and 3-(3'',4''-dimethoxybenzyl)-2-(3',4'-methylenedioxybenzyl)butyrolactone from A. CHIISANENSIS inactivate CYP3A4 in a mechanism-based mode. CYP: cytochrome P450 CAP3A4: cytochrome P450 3A4 K (I): inhibitor concentration required for a half-maximal inactivation K (inact): maximal rate constant of the inactivation P450: cytochrome P450.
Blood monocyte derived Neo-Hepatocytes as in vitro test system for drug-metabolism.
Drug Metab Dispos. 2008 Jun 16;
Ehnert S, Nussler AK, Lehmann A, Dooley S
The gold standard for human drug metabolism studies is primary hepatocytes. However, availability is limited by donor organ scarcity. Therefore, efforts have been made to provide alternatives, e.g. the hepatocyte-like (NeoHep) cell type, which was generated from peripheral blood monocytes (PBMCs). In this study, expression and activity of phase I and phase II drug-metabolizing enzymes were investigated during trans-differentiation of NeoHep cells and compared to primary human hepatocytes. Important drug metabolizing enzymes are cytochrome P450 (CYP) iso-forms (1A1, 1A2, 2A6, 2B6, 2C8, 2C9, 2D6, 2E1, 3A4), microsomal epoxide hydrolase 1 (EPHX1), glutathione-S-transferase (GST) A1 and M1, N-acetyltransferase 1 (NAT1), NAD(P)H menadione oxidoreductase 1 (NMO1), Sulfotransferase 1A1 (SULT1A1) and UDP-glucoronosyltransferase 1A6 (UGT1A6). Monocytes and programmable cells of monocytic origin (PCMOs) expressed only a few of the investigated enzymes. Throughout differentiation, NeoHep cells showed a continuously increasing expression of all drug-metabolizing enzymes investigated, resulting in a stable basal activity after approximately 15 days. Fluorescence based activity assays indicated that NeoHep cells and primary hepatocytes have similar enzyme kinetics, although the basal activities were significantly lower in NeoHep cells. Stimulation with 3-Methylcholanthrene (3-MC) and Rifampicin (RIF) markedly increased CYP1A1/2 or CYP3A4 activities, which could be selectively inhibited by Nifedipine (NIF), Verapamil (VER), Ketoconazole (KET) and Quercetin (QUE). Our data reveal similarities in expression, activity, induction and inhibition of drug-metabolizing enzymes between NeoHep cells and primary human hepatocytes and hence suggest that NeoHep cells are useful as an alternative to human hepatocytes for measuring bio-activation of substances.