The effects of multiple ketoconazole administration on emedastine kinetics were evaluated by comparing values obtained for pharmacokinetic parameters at steady state, with and without ketoconazole. C(ss,max), C(ss,min), tmax, AUCss, t(1/2) and Cl(ss)/F values, obtained after both treatments, were compared. Significant difference was defined as p < 0.05. QTc intervals from ECGs at baseline, after emedastine treatment and after emedastine-ketoconazole co-treatment were statistically compared.
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The oxidative metabolism of irbesartan, a new nonpeptide angiotensin II receptor antagonist, was investigated on 12 human fully characterized hepatic microsomes and purified cytochrome P-450 (CYP) isoforms. After incubation of microsomes with irbesartan and NADPH, four main hydroxy metabolites were formed, as confirmed by liquid chromatography-mass spectrometry analysis. Irbesartan oxidation follows Michaelis-Menten kinetics, consistent with the involvement of a single CYP isoform in these hydroxylation processes. Only a low interindividual variability (2-fold difference) was observed in drug oxidation, even in preparations lacking CYP2D6. Km and Vmax for irbesartan oxidation were 54 +/- 6.5 microM and 0.62 +/- 0.18 nmol/min/mg, respectively. Irbesartan oxidation correlated (r2 = 0. 769) with tolbutamide (CYP2C9 substrate) 4-methyl-hydroxylation. Oxidation of irbesartan was markedly inhibited by sulfaphenazole (CYP2C9 inhibitor), but not by any of several other CYP inhibitors. In the same manner, both tolbutamide and warfarin (CYP2C9 substrates), were competitive-type inhibitors of irbesartan oxidation with Ki values of 500 and 30 microM, respectively. Moreover, irbesartan was a competitive-type inhibitor of tolbutamide 4-methylhydroxylation (Ki = 317 microM). Nifedipine also potentially decreased irbesartan oxidation, whereas neither ketoconazole and triacetyloleandomycin (CYP3A inhibitors), nor diltiazem and verapamil, (CYP3A4 substrates), exhibited an inhibitory effect. Additional studies demonstrated that nifedipine was an inhibitor of irbesartan (Ki = 20 microM) and tolbutamide oxidation processes, whereas irbesartan had no effect at all on nifedipine dehydrogenation. Enzyme kinetics suggest that nifedipine is a noncompetitive-type inhibitor of CYP2C9-mediated catalytic activities. Finally, only microsomes containing recombinant human liver CYP2C9 were capable of oxidizing irbesartan. These results provide evidence that CYP2C9 plays a major role in irbesartan oxidation.
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The permeability of three imidazole antimycotics (miconazole nitrate, ketoconazole, and itraconazole) through the free edge of healthy human nail was evaluated in vitro using side-by-side diffusion cells. The influence of keratolytic substances (papain, urea, and salicylic acid) on the permeability of the antimycotics was also studied. The results suggested that the nail constituted an impermeable barrier for these antimycotics; it could be considered that the nail behaved as a hydrophilic gel membrane, through which drugs of low solubility could not permeate. The use of ethanol did not promote the passage of any of the antimycotic drugs. Although scanning electron microscopy indicated that the keratolytic substances had a significant effect on the nail surface (papain > salicylic acid > urea), the passage of the three antimycotics was not improved by pretreatment with salicylic acid alone (20% for 10 days), or by the application of the drug in a 40% urea solution. It was found that only the combined effects of papain (15% for 1 day) and salicylic acid (20% for 10 days) were capable of enhancing the permeability of the antimycotic.
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The levels of haloperidol (HP) and its pyridinium metabolite HPP+ were estimated in plasma and brain tissues of rats treated i.p. with HP (10 mg/kg). HP and HPP+ levels in plasma decreased linearly during the 0-3 hour period following drug administration. On the other hand, HPP+ levels in brain tissues increased gradually during the same period. HPP+ levels in brain tissues increased further when HP (10 mg/kg) was injected for three consecutive days. The formation of HPP+ also was studied in rat brain mitochondrial and liver microsomal preparations. Enzyme activity responsible for the conversion of HP to HPP+ was not found in brain mitochondria. Liver microsomal enzymes catalyzed the oxidation of HP and its tetrahydropyridine dehydration product HPTP to HPP+ with about the same efficiency. Studies employing several cytochrome P450 inhibitors and anti-cytochrome P450 antibodies were carried out in an effort to identify the forms of cytochrome P450 that are responsible for catalyzing the oxidation of HP and HPTP to HPP+. The formation of HPP+ in liver microsomes was strongly inhibited by ketoconazole and nifedipine and by an anti-CYP3A antibody. These results suggest that formation of HPP+ from HP and HPTP in rat liver microsomes is catalyzed mainly by CYP3A although the participation of other P450 forms cannot be ruled out.
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A 27-year-old man presented due to severe ocular pain in his left eye caused by a corneal ulcer. The patient was injured 7 days before presentation by metallic thread contaminated by sewage. Corneal scrapping and deep stromal biopsy were obtained and stained for microscopic evaluation with periodic acid-Schiff, Giemsa, and Gomori's methenamine silver stains. Samples were sent for aerobic and anaerobic bacterial and fungal cultures.
Research into the pathogenesis and treatment of chronic recurrent candidosis vaginalis did not come up with a clear answer of curing this phenomenon. In this investigation, data are presented of a therapy with a new antifungal agent, itraconazole. After a therapeutic treatment course, 17 patients received a prophylaxis for CRCV over 6 months. The treatment schedule for prophylaxis consisted of 4 capsules of 50 mg itraconazole on day 5 and 6 of the menstrual cycle. Eleven remained symptom-free in this period. Although there is no explanation for recurrence in most cases of CRCV, intermittent treatment schedules can be used to treat but not to cure these patients. Data of this investigation and data mentioned in the literature prove the necessity to discriminate between a sympatomtic and a mycological cure.
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The effects of some novel steroidal compounds were evaluated against both human C17,20-lyase and 5alpha-reductase in vitro and also against androgen synthesis in normal male rats. L-2, L-36, L-37, and I-41 showed potent inhibition of human testicular C17,20-lyase, with IC50s of 43, 39, 42, and 58 nM, respectively. In contrast, ketoconazole, a competitive inhibitor of C17,20-lyase, had an IC50 of 76 n.M. L-36 also showed potent inhibitory activity against 5a-reductase in human prostatic microsomes, with an IC50 of approximately 31 nM. The inhibitory activities of L-2 and 1-41 on 5alpha-reductase were moderate, with IC50s of 75 and 151 nM, respectively, whereas L-37 showed little inhibitory activity against this enzyme. In comparison, finasteride, a potent inhibitor of 5alpha-reductase, had an IC50 of 33 nM. When normal male rats were treated with these novel compounds (50 or 100 mg/kg/day) for 14 consecutive days, the wet weight of the prostate was significantly reduced by L-36, L-37, and I-41, compared to the control group. Testosterone levels in rat serum were also reduced by L-36 (55%), L-37 (86%), and I-41 (53%). The concentrations of testosterone in rat testes were reduced by these novel compounds by 13-74%. The compounds also reduced the concentration of testosterone in rat prostates by 35-75%. Similarly, dihydrotestosterone (DHT) concentration in rat serum was reduced 30-89% by these compounds, compared to the control group. Prostatic DHT levels were also lower in rats treated with L-36 (48%), L-37 (54%), or I-41 (26%). In contrast, L-2 enhanced serum testosterone and prostatic DHT concentrations by >50%. These findings suggest that the dual activities of several of these novel inhibitors of C17,20-lyase and 5alpha-reductase accounts for the diminished levels of circulating androgens in vivo.
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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.
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We have investigated the growth-inhibitory effects of two ergosterol biosynthesis inhibitors, the dioxolane imidazole ketoconazole and the allylamine SF 86-327, alone and in combination, on the proliferative stages of Trypanosoma (Schizotrypanum) cruzi, the causative agent of Chagas' disease. Proliferation of epimastigotes in liver infusion-tryptose medium at 28 degrees C was immediately arrested by any of these drugs at greater than or equal to 3 x 10(-5) M; cell lysis occurred 24 h later. Below that concentration, SF 86-327 at concentrations down to 1 x 10(-6) M stopped growth after 48 h. In contrast, ketoconazole slowed cell growth only moderately, but proliferation finally stopped and cell lysis occurred after 120 h at 3 x 10(-6) M. Synergistic effects could be observed when the two drugs were used in combination: the concentration of SF 86-327 required to reduce the cell growth to 25% of controls in 144 h was reduced 33-fold in the presence of 1 x 10(-6) M ketoconazole, which by itself reduced growth only by 30%. Amastigotes, proliferating in Vero cells at 37 degrees C, were much more susceptible to both drugs, but ketoconazole was definitely a more potent antiparasitic agent than the allylamine in this system: whereas the concentration of SF 86-327 required to reduce the number of infected cells to 50% of controls was 1 x 10(-7) M and that required to completely eradicate the parasite was 3 x 10(-6) M, for ketoconazole these concentrations were 1 x 10(-10) M and 1 x 10(-8) M, respectively. Again, strong synergistic effects were observed when the drugs were used in combination: the concentration of SF 86-327 required to reduce the number of infected cells to 50% of controls was 100-fold lower in the presence of 10(-11) M ketoconazole, which by itself had no effects on amastigote proliferation. The parasite was completely eradicated when the drugs were used in combination at concentrations as low as 10(-9) M. Synergy of the antiproliferative effects of the drugs on both froms of the parasite was further demonstrated by concave isobolograms. On the other hand, SF 86-327 at 10(-5) M had no effects on the proliferation of Vero cells, whereas ketoconazole at 10(-7) M reduced the proliferation of these cells by 50%.
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We studied mefloquine metabolism in cells and microsomes isolated from human and animal (monkey, dog, rat) livers. In both hepatocytes and microsomes, mefloquine underwent conversion to two major metabolites, carboxymefloquine and hydroxymefloquine. In human cells and microsomes these metabolites only were formed, as already demonstrated in vivo, while in other species several unidentified metabolites were also detected. After a 48 hr incubation with human and rat hepatocytes, metabolites accounted for 55-65% of the initial drug concentration, whereas in monkey and dog hepatocytes, mefloquine was entirely metabolized after 15 and 39 hrs, respectively. The consumption of mefloquine was less extensive in microsomes, and unchanged drug represented 60% (monkey) to 85-100% (human, dog, rat) of the total radioactivity after 5 hr incubations. The involvement of the cytochrome P450 3A subfamily in mefloquine biotransformation was suggested by several lines of evidence. Firstly, mefloquine metabolism was strongly increased in hepatic microsomes from dexamethasone-pretreated rats, and also in human and rat hepatocytes after prior treatment with a cytochrome P450 3A inducer. Secondly, mefloquine biotransformation in rifampycin-induced human hepatocytes was inhibited in a concentration-dependent manner by the cytochrome P450 3A inhibitor ketoconazole and thirdly, a strong correlation was found between erythromycin-N-demethylase activity (mediated by cytochrome P450 3A) and mefloquine metabolism in human microsomes (r=0.81, P < 0.05, N=13). Collectively, these findings concerning the role of cytochrome P450 3A in mefloquine metabolism may have important in vivo consequences especially with regard to the choice of agents used in multidrug antimalarial regimens.
Bone marrow transplants experience severe immuno-deficiency as a consequence of pretransplant radiation and chemotherapy, transient granulocytopenia before marrow engraftment, and post-transplant prevention and treatment of graft-versus-host disease with immuno-suppressive agents. During periods of granulocytopenia, chemoprophylaxis with the oral fluorinated quinolones can prevent colonization and infection with gram-negative bacilli, is better tolerated than oral non-absorbable antibiotics or trimethoprim-sulfamethoxazole and is more cost-effective than laminar-air-flow isolation or prophylactic granulocyte transfusions. Antifungal prophylaxis with oral nystatin, ketoconazole or amphotericin B, however, has not been consistently effective; empiric intravenous amphotericin B therapy is still the most reliable way to prevent fatal fungal infections. Following marrow engraftment, cytomegalovirus infection and interstitial pneumonia can be prevented in cytomegalovirus-seronegative patients by the use of cytomegalovirus-seronegative blood products and cytomegalovirus immune globulin. In cytomegalovirus-seropositive patients, prophylactic DHPG (ganciclovir) is currently being evaluated in a controlled clinical trial. Herpes simplex and varicella-zoster infections can be treated effectively with intravenous acyclovir, but routine acyclovir prophylaxis is not cost-effective. Trimethoprim-sulfamethoxazole is used for prophylaxis of Pneumocystis carinii pneumonia and may be continued in patients with chronic graft-versus-host disease for prevention of late post-transplant bacterial infections.
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Since its discovery in 1970, and introduction into clinical practice in 1978, cyclosporin has become the most important immunosuppressive drug used to prevent organ transplant rejection. This has been achieved by virtue of the improved graft survival rates and adverse effect profiles in patients when compared with that of the older agents. Cyclosporin is substantially more expensive (both to provide and to monitor) however, and the magnitude of these costs may preclude its use, particularly where the transplant recipient is required to pay. Cyclosporin has a complex pharmacokinetic profile with poor absorption, extensive metabolism to more than 30 metabolites and considerable inter- and intrapatient variability. Many transplant centres routinely use drugs ("cyclosporin-sparing agents') to allow a reduction in the dosage of cyclosporin while maintaining therapeutic blood cyclosporin concentrations. The use of a second drug to affect the pharmacokinetic profile of a primary drug is not new, but the use of cyclosporin-sparing agents is a departure from previous practices in that this coprescription is primarily for economic reasons. The decision to use these agents (and the choice of agent) is based upon economic and other factors including the extent of the cyclosporin-sparing effect, the potential for additional therapeutic benefit and/or adverse effects. The coprescription of cyclosporin-sparing agents is ethically more acceptable where the transplant recipient is the economic beneficiary but where the savings accrue to a third party it is more difficult. Benefits to the community at large must be balanced against the risk of adverse effects to the patient. The use of cyclosporin-sparing agents may reduce compliance and hence, jeopardise transplant and/or recipient outcomes. The transplant recipient must be informed about the reasons for their use and advised to consult an experienced physician or pharmacist before altering the established drug regimen.
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The prevention of fungal infections in granulocytopenic patients seems necessary to improve the final outcome of neoplastic patients. In particular, aspergillosis and candidiasis represent common life-threatening infections among the patients with acute hematological malignancies. Despite extensive investigations during this last decade, the optimal approaches to prevent these complications are still controversial. This situation probably reflects and stresses the numerous factors which predispose to these opportunistic fungal infections. Therefore, the effective prophylaxis of candidiasis and aspergillosis should result from the use of basic and specific approaches. General and simple measures including well trained personnel (physicians, nurses but also individuals in charge of the housekeeping, etc.), careful patient teaching of personal hygiene and control of the food intake (limited to cooked food diet), will reduce the acquisition of potential fungal pathogens. Moreover, the isolation in a laminar air flow room seems to be the optimal specific technique to prevent the colonization as well as the development of pulmonary aspergillosis. The meticulous evaluation of the respiratory sinus status as well as surveillance cultures obtained from the nose have been shown to be helpful to predict patients at high risks. Until now, there is no systemic chemoprophylaxis available to decrease the incidence of invasive aspergillosis. However, the topical application of antifungal agent using nasal spray or aerosols should be further investigated. Exogenous candidiasis such as catheter or TPN products related yeast infections can be avoided by aseptic manipulations. Endogenous candidiasis, resulting from the dissemination of the yeasts from the gastro-intestinal tract (which represents the major reservoir), are still much more difficult to prevent.(ABSTRACT TRUNCATED AT 250 WORDS)
Prediction of clinically important drug-drug interaction with SimCYP using in vitro human metabolism data can be a powerful tool during early clinical development to ensure safe administration of anticancer drugs, which are often co-administered at maximum tolerated doses with other drugs as part of a palliative treatment regimen.
Pituitary adenomas may hypersecrete hormones or cause mass effects. Therefore, early diagnosis and treatment are important.
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Our objective was to critically review the published literature on topical treatments for facial SD.
To assess the effect of strong and moderate cytochrome P450 (CYP) 3A4 inhibition on exposure of bitopertin, a glycine reuptake inhibitor primarily metabolized by CYP3A4, and to compare the results with predictions based on physiologically based pharmacokinetic (PBPK) modelling.
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Wild-type hERG and SCN5A/hNa(v) 1.5 Na(+) channels or the Y652A and F656C mutated forms of the hERG were stably expressed in HEK293 cells. The K(+) and Na(+) currents were recorded in these cells by using the whole-cell patch-clamp technique (23 degrees C). Protein trafficking of the hERG was evaluated by Western blot analysis and flow cytometry.
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In the present study we describe the isolation and functional analysis of a sphingolipid biosynthetic gene, IPT1, of Candida albicans. The functional consequence of the disruption of both alleles of IPT1 was confirmed by mass analysis of its sphingolipid composition. The disruption of both alleles or a single allele of IPT1 did not lead to any change in growth phenotype or total sphingolipid, ergosterol, or phospholipid content of the mutant cells. The loss of mannosyl diinositol diphosphoceramide [M(IP)(2)C] in the ipt1 disruptant, however, resulted in increased sensitivity to drugs like 4-nitroquinoline oxide, terbinafine, o-phenanthroline, fluconazole, itraconazole, and ketoconazole. The increase in drug susceptibilities of ipt1 cells was linked to an altered sphingolipid composition, which appeared to be due to the impaired functionality of Cdr1p, a major drug efflux pump of C. albicans that belongs to the ATP binding cassette superfamily. Our confocal and Western blotting results demonstrated that surface localization of green fluorescent protein-tagged Cdr1p was affected in ipt1 disruptant cells. Poor surface localization of Cdr1p resulted in an impaired ability to efflux fluconazole and rhodamine 6G. The effect of mannosyl inositol phosphoceramide accumulation in the ipt1 mutant and the absence of M(IP)(2)C from the ipt1 mutant on the efflux of drug substrates was very selective. The efflux of methotrexate, a specific substrate of CaMdr1p, another major efflux pump of major facilitator superfamily, remained unaffected in ipt1 mutant cells. Interestingly, changes in sphingolipid composition affected the ability of mutant cells to form proper hyphae in various media. Taken together, our results demonstrate that an altered composition of sphingolipid, which is among the major constituents of membrane rafts, affects the drug susceptibilities and morphogenesis of C. albicans.