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Sample records for ketoconazole

  1. Ketoconazole

    MedlinePlus

    Ketoconazole comes as a tablet to take by mouth. It is usually taken once a day Take ketoconazole at around the same time every day. ... ranitidine (Zantac); medications to treat tuberculosis such as isoniazid (INH, Nydrazid), rifabutin (Mycobutin), rifampin (Rifadin, Rimactane); methylprednisolone ( ...

  2. Ketoconazole-induced fulminant hepatitis.

    PubMed Central

    Bercoff, E; Bernuau, J; Degott, C; Kalis, B; Lemaire, A; Tilly, H; Rueff, B; Benhamou, J P

    1985-01-01

    We report the cases of two adult patients in whom fulminant hepatitis developed after 17 and 103 days of ketoconazole administration. Histologic administration showed massive, predominantly centrilobular necrosis. Clinical manifestations of hypersensitivity and eosinophilia were absent in both patients, which suggests that ketoconazole hepatotoxicity is not mediated through an immunoallergic mechanism. Images Fig. 2 PMID:4007605

  3. In vivo interaction of ketoconazole and sucralfate in healthy volunteers.

    PubMed Central

    Carver, P L; Berardi, R R; Knapp, M J; Rider, J M; Kauffman, C A; Bradley, S F; Atassi, M

    1994-01-01

    Absorption of ketoconazole is impaired in subjects with an increased gastric pH due to administration of antacids, H2-receptor antagonists, proton pump inhibitors, or the presence of hypochlorhydria. Sucralfate could provide an attractive alternative in patients receiving ketoconazole who require therapy for acid-peptic disorders. Twelve healthy human volunteers were administered a single 400-mg oral dose of ketoconazole in each of three randomized treatment phases. In phase A, ketoconazole was administered orally with 240 ml of water. In phase B, ketoconazole and sucralfate (1.0 g) were administered simultaneously with 240 ml of water. In phase C, ketoconazole was administered with 240 ml of water 2 h after administration of sucralfate (1.0 g) orally with 240 ml of water. A 680-mg oral dose of glutamic acid hydrochloride was administered 10 min prior to and with each dose of ketoconazole, sucralfate, or ketoconazole plus sucralfate. Simultaneous administration of ketoconazole and sucralfate led to a significant reduction in the area under the concentration-time curve and maximal concentration of ketoconazole in serum (78.12 +/- 12.20 versus 59.32 +/- 13.61 micrograms.h/ml and 12.34 +/- 3.07 versus 8.92 +/- 2.57 micrograms/ml, respectively; P < 0.05). When ketoconazole was administered 2 h after sucralfate, the observed ketoconazole area under the concentration-time curve was not significantly decreased compared with that of ketoconazole alone. The time to maximal concentrations in serum and the ketoconazole elimination rate constant were not significantly different in any of the three treatment phases. In patients receiving concurrent administration of ketoconazole and sucralfate, doses should be separated by at least 2 h. PMID:7910724

  4. [Ketoconazole-induced hepatitis. Case report].

    PubMed

    Henning, H; Kasper, B; Lüders, C J

    1983-12-01

    Since Oct. 1981 a new systemic antifungal drug Ketoconazole is available in the Federal Republic of Germany that has proven effective even in severe cases with fungal infections. This case-study will call attention on a rare but important side effect, namely Ketoconazole induced hepatitis. As an acute icteric viral hepatitis, type Non-A-Non-B-hepatitis possibly misdiagnosed only a carefully compiled history of the recent intake of drugs points at the real cause of hepatitis. In our case-report we observed a considerable increase in serum enzymes, especially GOT, GPT and GLDH after a drug-challenge with two tablets. We recommend so-called liver functions tests 2 to 3 weeks after beginning of therapy and further-on in monthly intervals. Histologically at that time toxic hydropic changes of the liver cells and a mesenchymal reaction with portal and intralobular mainly eosinophilic infiltration could be established. The serum enzymes came to normal only after 12 weeks.

  5. Pharmacology of ketoconazole suspension in infants and children.

    PubMed Central

    Ginsburg, C M; McCracken, G H; Olsen, K

    1983-01-01

    The pharmacokinetics of ketoconazole administered as either a commercially prepared suspension or as a crushed tablet in applesauce were studied in 12 children. The mean peak plasma concentration of ketoconazole and the area under the plasma time-concentration curve were approximately twofold greater with the suspension than with the crushed tablets. PMID:6307138

  6. Enhanced UV protection of ketoconazole using Hyptis suaveolens micro emulsion.

    PubMed

    Khonkarn, Ruttiros; Kittipongpatana, Ornanong S; Boasouna, Vilai; Okonogi, Siriporn

    2018-05-01

    Ketoconazole is photolabile antifungal drug. Photochemical reactions may decrease its therapeutic effect or induce toxic compounds. The aim of this study was to prepare ketoconazole loaded microemulsion containing H. suaveolens oil with antifungal and antioxidant powers in order to obtain effective antifungal formulation. The release study, antifungal activity and photostability test, were then evaluated. The results showed that optimized Hyptis suaveolens microemulsion for ketoconazole loading was selected through construction of pseudo-ternary phase diagrams. It consisted of 12.5% H. suaveolens oil, 12.5% capryol, 25% tween 80, 25% ethanol and 25% water. Mean globule size was 153 nm, as analyzed by photon correlation spectroscopy. Ketoconazole-loaded Hyptis suaveolens microemulsion and Hyptis suaveolens microemulsion had antifungal activity against Candida albican, Microsporum gypseum and Trichophyton mentagrophyte, showing inhibition zone ranged from 28-37 mm and 23-32 mm, respectively. Ketoconazole was released from Hyptis suaveolens microemulsion more than 90% within 5 days. In the results of photostability test, ketoconazole-loaded Hyptis suaveolens microemulsion gave significantly higher remaining ketoconazole than ketoconazole solution. This study demonstrated that Hyptis suaveolens microemulsion could be used to improve the photoprotection of photolabile drug.

  7. Pharmacokinetics of the cyclosporine-ketoconazole interaction in dogs.

    PubMed

    D'mello, A; Venkataramanan, R; Satake, M; Todo, S; Takaya, S; Ptachcinski, R J; Burckart, G J; Starzl, T E

    1989-06-01

    Numerous clinical reports have documented an increase in trough blood concentrations of cyclosporine in transplant recipients treated concomitantly with ketoconazole. The objective of this study was to elucidate the mechanism(s) underlying the cyclosporine-ketoconazole interaction using a choledochoureterostomy dog model. Five male beagle dogs received a 4 mg/kg, i.v. bolus dose of cyclosporine either alone or on day seven of a 10-day, 13 mg/kg/day, oral dosing regimen of ketoconazole. Blood samples were collected prior to and at predetermined times for 60 hrs after the cyclosporine dose, while the bile/urine mixture was collected quantitatively for 96 hours after the cyclosporine dose. Ketoconazole decreased the systemic clearance of cyclosporine from 7.0 ml/min/kg to 2.5 ml/min/kg. The terminal disposition rate constant was also decreased significantly from 0.0794 to 0.0354 hrs-1. Ketoconazole caused no significant changes in cyclosporine steady state volume of distribution, or plasma unbound fraction. Ketoconazole did not significantly alter the excretion of cyclosporine and various cyclosporine metabolites in the bile/urine mixture. Inhibition of hepatic drug metabolizing enzymes appears to be the primary reason for the ketoconazole induced elevation in cyclosporine concentration.

  8. PHARMACOKINETICS OF THE CYCLOSPORINE-KETOCONAZOLE INTERACTION IN DOGS

    PubMed Central

    D'mello, A.; Venkataramanan, R.; Satake, M.; Todo, S.; Takaya, S.; Ptachcinski, R. J.; Burckart, G.J.; Starzl, T.E.

    2010-01-01

    Numerous clinical reports have documented an increase in trough blood concentrations of cyclosporine in transplant recipients treated concomitantly with ketoconazole. The objective of this study was to elucidate the mechanism(s) underlying the cyclosporine-ketoconazole interaction using a choledochoureterostomy dog model. Five male beagle dogs received a 4 mg/kg, i.v. bolus dose of cyclosporine either alone or on day seven of a 10-day, 13 mg/kg/day, oral dosing regimen of ketoconazole. Blood samples were collected prior to and at predetermined times for 60 hrs after the cyclosporine dose, while the bile/urine mixture was collected quantitatively for 96 hours after the cyclosporine dose. Ketoconazole decreased the systemic clearance of cyclosporine from 7.0 ml/min/kg to 2.5 ml/min/kg. The terminal disposition rate constant was also decreased significantly from 0.0794 to 0.0354 hrs−1. Ketoconazole caused no significant changes in cyclosporine steady state volume of distribution, or plasma unbound fraction. Ketoconazole did not significantly alter the excretion of cyclosporine and various cyclosporine metabolites in the bile/urine mixture. Inhibition of hepatic drug metabolizing enzymes appears to be the primary reason for the ketoconazole induced elevation in cyclosporine concentration. PMID:2781141

  9. Treatment of systemic candidiasis in neutropenic dogs with ketoconazole.

    PubMed

    Weber, M J; Keppen, M; Gawith, K E; Epstein, R B

    1985-09-01

    The present study evaluated the activity of ketoconazole in neutropenic dogs with systemic candidiasis. Five dog pairs were made neutropenic by intravenous cyclophosphamide (50 mg/kg) and challenged with either 10(6) or 10(7) colony-forming units (CFU) of Candida albicans. Half of the dogs received ketoconazole (10 mg/kg) daily beginning 24 h after challenge. All were killed at 96 h and liver, spleen, and kidney were cultured. Of four dogs given 10(6) CFU, two untreated dogs had 9 X 10(3) to 1 X 10(5) CFU/g wet tissue, compared to 0 CFU in ketoconazole-treated dogs. With inoculum increased to 10(7) CFU, three untreated dogs had 2 X 10(4) to 3 X 10(5) CFU/g wet tissue, while three ketoconazole dogs had 0-5 X 10(3) CFU/g wet tissue. The effect of ketoconazole on autologous marrow reconstitution in dogs with systemic candidiasis was examined by infusing autologous cryopreserved marrow into four dogs one day after lethal whole body irradiation (800 rad). Once neutropenic, they were challenged with 10(7) CFU of C. albicans. Two dogs received no ketoconazole and died of disseminated candidiasis, without marrow reconstitution. Two dogs received ketoconazole for 25 days. Prompt marrow recovery occurred and they remained healthy. There was no evidence of infection at death. These studies quantitatively demonstrate the in vivo effectiveness of ketoconazole in reducing tissue infection with C. albicans in neutropenic dogs. They provide in vivo evidence that ketoconazole can prevent or cure systemic candidiasis in the bone marrow transplant setting without significant inhibition of marrow recovery.

  10. Interaction between tolbutamide and ketoconazole in healthy subjects.

    PubMed Central

    Krishnaiah, Y S; Satyanarayana, S; Visweswaram, D

    1994-01-01

    A possible interaction between tolbutamide and ketoconazole was studied in seven healthy volunteers. Treatment for 1 week with 200 mg oral ketoconazole increased the elimination half-life (from mean +/- s.d. 3.7 +/- 0.4 to 12.3 +/- 1.9 h) and AUC(0.12 h) of tolbutamide (from 309 +/- 27 to 546 +/- 20 micrograms ml-1 h) by 25 +/- 64 and 66 +/- 15%, respectively. The percentage blood glucose reduction was also increased when tolbutamide and ketoconazole were coadministered. PMID:8186066

  11. A successful case of Cushing's disease pregnancy treated with ketoconazole.

    PubMed

    Costenaro, Fabíola; Rodrigues, Ticiana C; de Lima, Paula B; Ruszczyk, Juliana; Rollin, Guilherme; Czepielewski, Mauro A

    2015-03-01

    The association of pregnancy and Cushing's disease (CD) is rare. Treatment of Cushing's syndrome (CS) is imperative to reduce maternal and fetal morbidity. Ketoconazole is a widely used drug for CS control when the woman is not pregnant but concerns about its teratogenicity and embryotoxicity restricted its use during pregnancy. We describe a case of a CD patient managed with Ketoconazole during the first and second trimester and other cares for her metabolic CS aspects during pregnancy. She delivered a normal female baby. It is supposed that even with treatment the relatively hypercortisolemic mother could protect her child from the embryotoxicity of ketoconazole as proved in rat fetuses and we suggest that ketoconazole could be an emergency pharmacological therapeutic option for CS management during pregnancy.

  12. Multiple oral dosing of ketoconazole increases dog exposure to ivermectin.

    PubMed

    Hugnet, Christophe; Lespine, Anne; Alvinerie, Michel

    2007-01-01

    The parasiticide ivermectin and the antimicrobial drug ketoconazole are macrolides that interact with P-glycoprotein. We investigated the effects of ketoconazole at a clinical dose on the pharmacokinetics of ivermectin, a CYP3A substrate with low hepatic clearance. Beagle dogs received a single subcutaneous injection of ivermectin at 0.05 mg/kg alone (n=6) or in combination with a daily oral dose of ketoconazole 10 mg/kg over 5 days before and after ivermectin administration (n=6). The plasma kinetics of ivermectin and its metabolite were followed over 15 days by HPLC analysis. Co-administered ketoconazole induced a higher plasma concentration and longer residence time of ivermectin in dogs, leading to a substantial increase in the overall exposure of the animal to the drug. Ketoconazole does not interfere with the production of the ivermectin metabolite but it may rather inhibit the elimination of the parental drug by interfering with P-gp transport. Multiple oral dosing of ketoconazole dramatically altered the pharmacokinetics of ivermectin in dogs leading to an increase in systemic exposure to the drug. Neurotoxicity of ivermectin means that inhibition of the P-gp function at the blood-brain barrier during polytherapy using P-gp inhibitors must be taken into consideration.

  13. Ketoconazole attenuates radiation-induction of tumor necrosis factor

    SciT

    Hallahan, D.E.; Virudachalam, S.; Kufe, D.W.

    1994-07-01

    Previous work has demonstrated that inhibitors of phospholipase A2 attenuate ionizing radiation-induced arachidonic acid production, protein kinase C activation, and prevent subsequent induction of the tumor necrosis factor gene. Because arachidonic acid contributes to radiation-induced tumor necrosis factor expression, the authors analyzed the effects of agents which alter arachidonate metabolism on the regulation of this gene. Phospholipase A2 inhibitors quinicrine, bromphenyl bromide, and pentoxyfylline or the inhibitor of lipoxygenase (ketoconazole) or the inhibitor of cycloxygenase (indomethacine) were added to cell culture 1 h prior to irradiation. Radiation-induced tumor necrosis factor gene expression was attenuated by each of the phospholipase A2more » inhibitors (quinicrine, bromphenylbromide, and pentoxyfylline). Furthermore, ketoconazole attenuated X ray induced tumor necrosis factor gene expression. Conversely, indomethacin enhanced tumor necrosis factor expression following irradiation. The finding that radiation-induced tumor necrosis factor gene expression was attenuated by ketoconazole suggests that the lipoxygenase pathway participates in signal transduction preceding tumor necrosis factor induction. Enhancement of tumor necrosis factor expression by indomethacin following irradiation suggests that prostaglandins produced by cyclooxygenase act as negative regulators of tumor necrosis factor expression. Inhibitors of tumor necrosis factor induction ameliorate acute and subacute sequelae of radiotherapy. The authors propose therefore, that ketoconazole may reduce acute radiation sequelae such as mucositis and esophagitis through a reduction in tumor necrosis factor induction or inhibition of phospholipase A2 in addition to its antifungal activity. 25 refs., 2 figs.« less

  14. Effect of ketoconazole on cyclosporine dose in healthy dogs.

    PubMed

    Dahlinger, J; Gregory, C; Bea, J

    1998-01-01

    To determine the degree to which the dose of oral cyclosporine (CyA), in healthy dogs, can be decreased by concurrent oral administration of ketoconazole. Dogs in this study were observed for physical or biochemical side effects that might have been caused by the administration of CyA and ketoconazole. Prospective research study. Five healthy, intact female Beagle dogs. CyA was administered orally twice daily to achieve stable whole blood trough levels of 400 to 600 ng/mL. Ketoconazole was added at a low therapeutic dose (average dose: 13.6 mg/kg/d) then at a subtherapeutic dose (average dose: 4.7 mg/kg/d). CyA whole blood trough levels were monitored every 3 to 4 days and maintained at 400 to 600 ng/mL by adjusting CyA doses accordingly. Physical examination, CBC, biochemical profile, and urinalysis were performed at 2-week intervals throughout the study period. The initial mean dose of CyA required to achieve target blood levels was 14.5 mg/ kg/d. With concurrent ketoconazole (low therapeutic dose, average dose: 13.6 mg/kg/d) and CyA administration, the CyA dose declined to 3.4 mg/kg/day (range: 1.2 to 5.2 mg/kg/d), representing a 75% reduction in CyA dose and monetary savings of 57.8%. At a subtherapeutic dose of ketoconazole (average dose: 4.7 mg/kg/d), combination therapy resulted in a CyA dose of 10.1 mg/kg/day (4.9 to 10.6 mg/kg/d), representing a 38% reduction in CyA dose and monetary savings of 23.8%. Weight loss and transient hypoalbuminemia of unknown clinical significance were observed. Other physical and biochemical evaluations were unremarkable over the 12-week study period. The oral administration of ketoconazole can be used to reduce substantially the oral CyA dose needed to maintain selected blood levels in healthy dogs. The oral administration of ketoconazole can result in substantial cost savings to owners of dogs receiving CyA after renal allograft transplantation or for the treatment of autoimmune disease.

  15. Adverse effects of ketoconazole in dogs--a retrospective study.

    PubMed

    Mayer, Ursula K; Glos, Katharina; Schmid, Matthias; Power, Helen T; Bettenay, Sonya V; Mueller, Ralf S

    2008-08-01

    Although ketoconazole has been used extensively in dogs for the treatment of various fungal infections, information about adverse effects is mainly anecdotal. Common adverse effects in humans include dose-dependant anorexia, nausea and vomiting, allergic rashes and pruritus. Drug-induced hepatitis is very rare, but potentially fatal. The aim of this study was to evaluate the type and frequency of adverse effects associated with ketoconazole therapy in dogs treated for skin diseases and any possible influence of dosage, duration of therapy, signalment or concurrent medication. The medical records of 632 dogs treated with ketoconazole (2.6-33.4 mg/kg) were reviewed. Adverse effects occurred in 14.6% (92 dogs) and included vomiting (7.1%), anorexia (4.9%), lethargy (1.9%), diarrhea (1.1%), pruritus (0.6%), erythema (0.3%) and other adverse effects (2.5%). Of the dogs with other adverse effects, four of 16 (25%) were ataxic and three of these received concurrent ivermectin. Adverse effects were significantly more often recorded in dogs concurrently treated with ciclosporin (P = 0.034) or ivermectin (P = 0.007). Increased liver enzyme levels were reported rarely, and icterus was not seen in any of the dogs. However, monitoring liver enzymes during therapy is recommended, although this might not necessarily prevent severe idiosyncratic hepatotoxicity.

  16. Formulation and evaluation of Ketoconazole niosomal gel drug delivery system

    PubMed Central

    Shirsand, SB; Para, MS; Nagendrakumar, D; Kanani, KM; Keerthy, D

    2012-01-01

    Purpose: Niosomes play an increasingly important role in drug delivery as they can reduce toxicity and modify pharmacokinetic and bio-availability. Topically applied niosomes can increase the residence time of drugs in the stratum corneum and epidermis, while reducing the systemic absorption of the drug. It can act as drug containing reservoirs and the modification of the vesicular compositions or surface properties can adjust the drug release rate and the affinity for the target site. Ketoconazole is a broad spectrum Imidazole derivative useful in the treatment of superficial and systemic fungal infections. Materials and Methods: In order to improve the low skin penetration and to minimize the side effects associated with topical conventional drug administration, Ketoconazole niosomes were prepared by a thin film hydration method using different ratios of non-ionic surfactants (Span 40, 60 and Tween 60) along with cholesterol (CHO). The formulations were evaluated for size, shape, entrapment efficiency and in vitro drug release. Results: Niosomes appeared spherical in shape and size range was found to be 4.86 ± 1.24-7.38 ± 3.64 μm. The entrapment efficiency was found in the range of 55.14 ± 2.29-78.63 ± 0.91% and in vitro drug release in the range of 46.63 ± 0.95-72.37 ± 0.59% in 24 h. Ketoconazole niosomes formulated with Span 60 and CHO in the ratio of 1:0.2 were found to be promising and were incorporated into 1% Carbopol gel. The formulated gel was evaluated for various physicochemical parameters and antifungal activity. The in vitro drug release study was carried out using phosphate buffer saline pH 7.4 and was found to be 36.18 ± 1.50% in 12 h. Conclusion: Gel formulation containing niosomes loaded with Ketoconazole showed prolonged action than formulations containing Ketoconazole in non-niosomal form and it can be developed successfully to improve the antifungal activity. PMID:23580936

  17. The pharmacokinetics of ketoconazole and its effects on the pharmacokinetics of midazolam and fentanyl in dogs.

    PubMed

    KuKanich, B; Hubin, M

    2010-02-01

    Ketoconazole inhibits the Cytochrome P450 3A12 (CYP3A12) metabolizing enzyme as well as the p-glycoprotein efflux pump. The extent and clinical consequence of these effects are poorly understood in dogs. The objective was to assess the pharmacokinetics of ketoconazole after single and multiple doses and the effect of multiple doses of ketoconazole on midazolam (a known CYP3A12 substrate) and the opioid fentanyl. Six greyhound dogs were studied. The study consisted of three phases. Phase 1 consisted of i.v. midazolam (0.23 mg/kg base) and fentanyl (15.71 microg/kg base). Phase 2 consisted of a single oral dose of ketoconazole (mean dose 12.34 mg/kg). Phase 3 consisted of i.v. midazolam (0.23 mg/kg) and fentanyl (10 microg/kg) after 5 days of oral ketoconazole (12.25 mg/kg/day). Ketoconazole significantly inhibited its own elimination with the mean residence time (MRT) increasing from 6.24 h in Phase 1 to 12.54 h in Phase 3. Ketoconazole significantly decreased the elimination of midazolam, as expected, with the MRT increasing from 0.81 to 1.49 h. The elimination of fentanyl was not significantly altered by co-administration of ketoconazole with the MRT being 3.90 and 6.35 h. The MRT was the most robust estimate of decreased drug elimination.

  18. Use of ketoconazole to treat dogs with pituitary-dependent hyperadrenocorticism: 48 cases (1994-2007).

    PubMed

    Lien, Yu-Hsin; Huang, Hui-Pi

    2008-12-15

    To evaluate the effectiveness of ketoconazole as a treatment for dogs with pituitary-dependent hyperadrenocorticism (PDH). Retrospective case series. 48 client-owned dogs in which PDH was diagnosed. Medical records of dogs with PDH that were treated with ketoconazole were examined. Data collected from each record included signalment, clinical signs, results of ACTH stimulation tests before and after treatment with ketoconazole, serum alkaline phosphatase (ALP) and alanine aminotransferase (ALT) activities, dosage of ketoconazole, clinical response, and survival time. 43 of 48 (90%) dogs had evidence of clinical improvement during the treatment period. In all dogs, treatment with ketoconazole resulted in significantly lower serum cortisol concentrations as measured before and after ACTH stimulation testing; 69% (33/48) of serum cortisol concentrations measured after ACTH stimulation were within the reference range. Serum ALP and ALT activities significantly decreased after treatment with ketoconazole. Survival time after diagnosis of PDH ranged from 2 to 61 months (mean, 26.9 months; median, 25 months). Ketoconazole was a safe and effective option for treating dogs with PDH. Additional research is needed to evaluate the effects of long-term treatment with ketoconazole on adrenal glands.

  19. Putative contact ketoconazole shampoo-triggered pemphigus foliaceus in a dog.

    PubMed

    Sung, Hyun-Jeong; Yoon, In-Hwa; Kim, Jung-Hyun

    2017-09-01

    A 10-year-old spayed female cocker spaniel dog was referred for an evaluation of acute-onset generalized pustular cutaneous lesions following application of ketoconazole shampoo. Cytologic and histopathologic examinations of the lesions revealed intra-epidermal pustules with predominantly neutrophils and acantholytic cells. This is the first description of putative contact ketoconazole shampoo-triggered pemphigus foliaceus in a dog.

  20. Plasma cortisol response to ketoconazole administration in dogs with hyperadrenocorticism.

    PubMed

    Feldman, E C; Bruyette, D S; Nelson, R W; Farver, T B

    1990-07-01

    The effect of orally administered ketoconazole on plasma cortisol concentration in dogs with hyperadrenocorticism was evaluated. Every 30 minutes from 0800 hours through 1600 hours and again at 1800 hours, 2000 hours, and 0800 hours the following morning, 15 clinically normal dogs and 49 dogs with hyperadrenocorticism had plasma samples obtained and analyzed for cortisol concentration. The mean (+/- SD) plasma cortisol concentration for the initial 8-hour testing period was highest in 18 dogs with adrenocortical tumor (5.3 +/- 1.6 micrograms/dl), lowest in 15 control dogs (1.3 +/- 0.5 micrograms/dl), and intermediate in 31 dogs with pituitary-dependent hyperadrenocorticism (PDH; 3.4 +/- 1.2 micrograms/dl). Results in each of the 2 groups of dogs with hyperadrenocorticism were significantly (P less than 0.05) different from results in control dogs, but not from each other. The same cortisol secretory experiment was performed, using 8 dogs with hyperadrenocorticism (5 with PDH; 3 with adrenocortical tumor) before and after administration at 0800 hours of 15 mg of ketoconazole/kg of body weight. Significant (P less than 0.05) decrease in the 8-hour mean plasma cortisol concentration (0.9 +/- 0.2 microgram/dl) was observed, with return to baseline plasma cortisol concentration 24 hours later. Twenty dogs with hyperadrenocorticism (11 with PDH, 9 with adrenocortical tumor) were treated with ketoconazole at a dosage of 15 mg/kg given every 12 hours for a half month to 12 months. The disease in 2 dogs with PDH failed to respond to treatment, but 18 dogs had complete resolution of clinical signs of hyperadrenocorticism and significant (P less than 0.05) reduction in plasma cortisol responsiveness to exogenous adrenocorticotropin (ACTH).(ABSTRACT TRUNCATED AT 250 WORDS)

  1. Ketoconazole in paracoccidioidomycosis: efficacy of prolonged oral therapy.

    PubMed

    Restrepo, A; Stevens, D A; Leiderman, E; Fuentes, J; Arana, A; Angel, R; Mejía, G; Gómez, I

    1980-08-29

    Ketoconazole, a new oral imidazole derivative, was employed for the treatment of five patients with paracoccidioidomycosis. The response was excellent, with objective clinical improvement and healing of both mucocutaneous and pulmonary lesions. Mycological and serological tests, as well as delayed hypersensitivity, were assessed and found to correlate with clinical improvement. Therapy was conducted for 12 months with a dose of 200 mg day in 2 patients; in the remainder the dose was reduced (100 mg day) after the first 6 months and maintained as such for an equal period. No side-effects or toxicity were noted despite prolonged treatment. The advantages of the new therapeutic approach are discussed.

  2. Ketoconazole treatment in Cushing's syndrome: experience in 34 patients.

    PubMed

    Sonino, N; Boscaro, M; Paoletta, A; Mantero, F; Ziliotto, D

    1991-10-01

    Ketoconazole treatment of Cushing's syndrome has been reported in single cases and a few small groups of 5-8 patients. We report our experience in 34 patients. Clinical study, with pretreatment and post-treatment evaluations. Out of 67 patients with Cushing's syndrome admitted during the last 6 years, 34 (28 females/six males; age range 14-67 years) received ketoconazole as a palliative treatment due to severe clinical conditions or management of the disease while awaiting results of definitive therapy. Urinary cortisol, plasma cortisol and ACTH, and routine chemistry were measured every week for 4 weeks, and then once a month. Comparing the last values (mean +/- SEM) during treatment with baseline, urinary cortisol decreased from 1296 +/- 176 to 270 +/- 69 nmol/d (n = 34; P less than 0.001); plasma cortisol decreased from 672 +/- 31 to 549 +/- 35 nmol/l (n = 34; P less than 0.001). For patients with pituitary-dependent Cushing's syndrome, urinary cortisol decreased from 1073 +/- 126 to 200 +/- 21 nmol/d (n = 28; P less than 0.001) while plasma ACTH changed from 12.5 +/- 1.3 to 11.3 +/- 0.8 pmol/l (n = 26; not significant). Twelve patients were treated for more than 6 months, and those with pituitary-dependent disease all received pituitary radiation therapy, except the two who eventually escaped pharmacological control. One additional patient with adrenal carcinoma and one with ectopic ACTH syndrome showed lack of control of urinary cortisol levels. Ketoconazole was withdrawn within the first week in two patients for allergic reaction and acute liver toxicity. Other side-effects included: asymptomatic liver function abnormalities in three patients; gastrointestinal symptoms in four; worsening of gynaecomastia in one. Rapid clinical improvement was observed together with the normalization of urinary cortisol levels, with regression of symptoms such as diabetes mellitus, hypertension, hypokalaemia, and restoration of well being. These data confirm that ketoconazole

  3. Ketoconazole inhibition of testicular secretion of testosterone and displacement of steroid hormones from serum transport proteins.

    PubMed Central

    Grosso, D S; Boyden, T W; Pamenter, R W; Johnson, D G; Stevens, D A; Galgiani, J N

    1983-01-01

    In vivo perfusion of canine testes with ketoconazole inhibited the stimulation of testosterone production by human chorionic gonadotropin in a dose-dependent manner. Ketoconazole also selectively displaced steroids from serum-binding globulins. Dihydrotestosterone and estradiol binding to sex hormone-binding globulin were inhibited by ketoconazole. Cortisol binding to corticosteroid-binding globulin was unaffected. The concentrations of ketoconazole that inhibited human chorionic gonadotropin stimulation of testicular androgen production and displaced sex steroids from sex hormone-binding globulin were in the range of blood levels found in patients on higher therapeutic dosage regimens. Suppression of testicular testosterone synthesis and displacement of estrogens from sex hormone-binding globulin may decrease the androgen/estrogen ratio of the blood and contribute to the development of gynecomastia that has been reported in some ketoconazole-treated patients. PMID:6301363

  4. Orally administered ketoconazole: route of delivery to the human stratum corneum.

    PubMed Central

    Harris, R; Jones, H E; Artis, W M

    1983-01-01

    Delivery of ketoconazole to human stratum corneum was studied. Thirteen healthy volunteers, three patients with chronic fungal disease and one patient with palmar-plantar hyperhidrosis were given 400 mg of ketoconazole daily for various lengths of time. The ketoconazole content of palmar stratum corneum, eccrine sweat, sebum, and serum was measured by high-pressure liquid chromatography (sensitivity, 0.005 to 0.010 microgram/ml). Palmar stratum corneum obtained after 7 and 14 days of daily administration contained up to 14 micrograms of ketoconazole per g. Ketoconazole was not found in sebum after 7 or 14 days of daily ingestion of the antimycotic agent. Sebum from three patients with chronic fungal infection treated for greater than 9 months contained ketoconazole (means, 4.7 micrograms/g). Thermogenic whole body eccrine sweat contained a mean of 0.059 microgram/ml on day 7 and 0.084 microgram/ml on day 14 of daily administration. Ketoconazole appeared in thermogenic whole body eccrine sweat and palmar hyperhidrotic sweat within 1 h after a single oral dose. Partition studies of ketoconazole containing eccrine sweat demonstrated a 10-fold greater concentration in the sediment phase (desquamated keratinocytes) compared with the clear supernatant phase. In vitro studies with [3H]ketoconazole-supplemented supernatant sweat revealed preferential binding to stratum corneum, hair, and nails and its partitioning to lipid-rich sebum. We conclude that eccrine sweat rapidly transports ketoconazole across the blood-skin barrier, where it may bind or partition to keratinocytes and surface lipids. PMID:6318663

  5. Pharmacokinetic modulation of oral etoposide by ketoconazole in patients with advanced cancer.

    PubMed

    Yong, Wei Peng; Desai, Apurva A; Innocenti, Federico; Ramirez, Jacqueline; Shepard, Dale; Kobayashi, Ken; House, Larry; Fleming, Gini F; Vogelzang, Nicholas J; Schilsky, Richard L; Ratain, Mark J

    2007-11-01

    Etoposide is a widely used cytotoxic drug that is commercially available in both intravenous and oral formulations. High interpatient pharmacokinetic variability has been associated with oral etoposide administration. Various strategies used in the past to reduce such variability have not been successful. Hence, this study was designed to evaluate if pharmacokinetic modulation of oral etoposide with ketoconazole could lead to a favorable alteration of etoposide pharmacokinetics, and to assess the feasibility and safety of this approach. Thirty-two patients were treated with ketoconazole 200 mg daily with an escalating dose of oral etoposide starting at a dose of 50 mg every other day. Pharmacokinetic samples were obtained during the first treatment cycle after the administration of an oral etoposide and ketoconazole dose. Additional baseline pharmacokinetic studies of etoposide alone were performed 4 days prior to the first treatment cycle. Dose limiting toxicities were neutropenia and fatigue. Ketoconazole increased the area under the plasma concentration-time curve (AUC) of oral etoposide by a median of 20% (p < 0.005). Ketoconazole did not reduce the interpatient variability in etoposide pharmacokinetics. Pretreatment bilirubin levels correlated with etoposide clearance (Spearman's r = -0.48, p = 0.008). The maximum tolerated dose was etoposide administered at 50 mg daily and ketoconazole 200 mg qd for 3 of 5 weeks. Ketoconazole reduces the apparent clearance of oral etoposide, does not alter its toxicity profile and does not reduce interpatient pharmacokinetic variability. Other methods to reduce the pharmacokinetic variability of oral etoposide are needed.

  6. Effects of ketoconazole on the pharmacokinetics and pharmacodynamics of morphine in healthy Greyhounds.

    PubMed

    Kukanich, Butch; Borum, Stacy L

    2008-05-01

    To assess pharmacokinetics and pharmacodynamics of morphine and the effects of ketoconazole on the pharmacokinetics and pharmacodynamics of morphine in healthy Greyhounds. 6 healthy Greyhounds, 3 male and 3 female. Morphine sulfate (0.5 mg/kg. IV) was administered to Greyhounds prior to and after 5 days of ketoconazole (12.7 +/- 0.6 mg/kg, PO) treatment. Plasma samples were obtained from blood samples that were collected at predetermined time points for measurement of morphine and ketoconazole concentrations by mass spectrometry. Pharmacokinetics of morphine were estimated by use of computer software. Pharmacodynamic effects of morphine in Greyhounds were similar to those of other studies in dogs and were similar between treatment groups. Morphine was rapidly eliminated with a half-life of 1.28 hours and a plasma clearance of 32.55 mL/min/kg. The volume of distribution was 3.6 L/kg. No significant differences in the pharmacokinetics of morphine were found after treatment with ketoconazole. Plasma concentrations of ketoconazole were high and persisted longer than expected in Greyhounds. Ketoconazole had no significant effect on morphine pharmacokinetics, and the pharmacodynamics were similar between treatment groups. Plasma concentrations of ketoconazole were higher than expected and persisted longer than expected in Greyhounds.

  7. Biofilm formation in Malassezia pachydermatis strains isolated from dogs decreases susceptibility to ketoconazole and itraconazole.

    PubMed

    Jerzsele, Akos; Gyetvai, Béla; Csere, István; Gálfi, Péter

    2014-12-01

    Malassezia pachydermatis is a commonly isolated yeast in veterinary dermatology that can produce biofilms in vitro and in vivo, lowering its susceptibility to antimicrobial drugs. The aim of this study was to determine and compare the in vitro susceptibility of planktonic cells and biofilms of M. pachydermatis isolates to ketoconazole and itraconazole. The presence of biofilm formation was confirmed by crystal violet staining and absorbance measurement at 595 nm wavelength, and by a scanning electron microscopy method. Cell viability was determined by the Celltiter 96 Aqueous One solution assay containing a water-soluble tetrazolium compound (MTS) with absorbance measurement at 490 nm. Planktonic cell minimum inhibitory concentrations (MICs) and minimum fungicidal concentrations (MFCs) of ketoconazole and itraconazole were very low: MIC90 and MFC90 were 0.032 and 0.125 μg/ml for ketoconazole, while 0.063 and 0.25 μg/ml for itraconazole, respectively. Also, the half maximal effective concentrations (EC50) of itraconazole were higher for planktonic cells and biofilms compared to ketoconazole. The EC50 values of ketoconazole were 18-169 times higher and those of itraconazole 13-124 times higher for biofilms than for planktonic cells. Biofilm EC50 levels exceeded MICs 103-2060 times for ketoconazole and 84-1400 times for itraconazole. No significant difference was found between these values of the two substances. In conclusion, biofilms of all examined M. pachydermatis strains were much less susceptible to ketoconazole and itraconazole than their planktonic forms.

  8. Comparative Hepatotoxicity of Fluconazole, Ketoconazole, Itraconazole, Terbinafine, and Griseofulvin in Rats.

    PubMed

    Khoza, Star; Moyo, Ishmael; Ncube, Denver

    2017-01-01

    Oral ketoconazole was recently the subject of regulatory safety warnings because of its association with increased risk of inducing hepatic injury. However, the relative hepatotoxicity of antifungal agents has not been clearly established. The aim of this study was to compare the hepatotoxicity induced by five commonly prescribed oral antifungal agents. Rats were treated with therapeutic oral doses of griseofulvin, fluconazole, itraconazole, ketoconazole, and terbinafine. After 14 days, only ketoconazole had significantly higher ALT levels ( p = 0.0017) and AST levels ( p = 0.0008) than the control group. After 28 days, ALT levels were highest in the rats treated with ketoconazole followed by itraconazole, fluconazole, griseofulvin, and terbinafine, respectively. The AST levels were highest in the rats treated with ketoconazole followed by itraconazole, fluconazole, terbinafine, and griseofulvin, respectively. All drugs significantly elevated ALP levels after 14 days and 28 days of treatment ( p < 0.0001). The liver enzyme levels suggested that ketoconazole had the highest risk in causing liver injury followed by itraconazole, fluconazole, terbinafine, and griseofulvin. However, histopathological changes revealed that fluconazole was the most hepatotoxic, followed by ketoconazole, itraconazole, terbinafine, and griseofulvin, respectively. Given the poor correlation between liver enzymes and the extent of liver injury, it is important to confirm liver injury through histological examination.

  9. [Long-term treatment of Cushing's disease using ketoconazole. Possibility of therapeutic escape].

    PubMed

    Diop, S N; Warnet, A; Duet, M; Firmin, C; Mosse, A; Lubetzki, J

    Five women suffering from Cushing's disease were treated with ketoconazole 800 mg per day for 2 to 28 months (mean 12.4 months). Four of them had full clinical and biochemical regression. However, after 8 months of therapy the disease failed to respond in three of these four women. Increasing the ketoconazole dosage up to 1,200 mg per day was ineffective in two patients. Such an escape phenomenon, not described until now, will restrict the use of ketoconazole in the treatment of Cushing's disease, although the drug is easy to administer and well tolerated globally and by the liver in most cases.

  10. Ketoconazole hepatotoxicity in a patient treated for environmental illness and systemic candidiasis

    SciT

    Brusko, C.S.; Marten, J.T.

    1991-12-01

    Environmental illness, a hypothesized disease caused by exposure to substances such as combustion products, pesticides, food additives, and Candida albicans, is discussed. The case of a patient with environmental illness and systemic candidiasis for six weeks with ketoconazole, liver enzyme concentrations increased. One month after discontinuation of ketoconazole, the liver enzyme concentrations decreased; however, over the next five months, liver enzymes and bilirubin increased. The patient developed encephalopathy and eventually was transferred to a medical center for possible liver transplant. A review of the literature pertaining to ketoconazole hepatotoxicity is also presented.16 references.

  11. Ketoconazole in the treatment of dermatomycosis in cats and dogs.

    PubMed

    De Keyser, H; Van den Brande, M

    1983-07-01

    Ketoconazole (Nizoral, Janssen Pharmaceutica) a new systemic antimycotic was tested in dermatomycosis in cats and dogs. The daily dose (10 mg/kg body weight) was administered for 10 or 20 days without any other measures being taken. After the 20-day treatments new hair growth was observed in 96.7 per cent of the cats and 89.9 per cent of the dogs. Clinical cure was complete in 96.8 per cent of the cats and 90.5 per cent of the dogs. Particularly the good tolerance in the cat was appreciated. There were practically no side-effects in dogs (except vomiting in two pups) or in cats.

  12. Treatment of seborrhoeic dermatitis of the scalp with ketoconazole shampoo. A double-blind study.

    PubMed

    Faergemann, J

    1990-01-01

    Thirty-six patients with seborrhoeic dermatitis of the scalp and culture positive for Pityrosporum ovale were treated in a double-blind placebo controlled study with ketoconazole shampoo twice weekly for 4 weeks. In the ketoconazole group, 16 of 18 patients (89%) became free of lesions or improved, compared with only 8 of 18 (p less than 0.01) in the placebo group. The patients found the shampoo effective, easy to use and cosmetically attractive.

  13. Pharmacokinetics of oral neratinib during co-administration of ketoconazole in healthy subjects

    PubMed Central

    Abbas, Richat; Hug, Bruce A; Leister, Cathie; Burns, Jaime; Sonnichsen, Daryl

    2011-01-01

    AIM The primary objective was to evaluate the pharmacokinetics of a single dose of neratinib, a potent, low-molecular-weight, orally administered, irreversible pan-ErbB (ErbB-1, -2, -4) receptor tyrosine kinase inhibitor, during co-administration with ketoconazole, a potent CYP3A4 inhibitor. METHODS This was an open-label, randomized, two-period, crossover study. Fasting healthy adults received a single oral dose of neratinib 240 mg alone and with multiple oral doses of ketoconazole 400 mg. Blood samples were collected up to 72 h after each neratinib dose. Plasma concentration data were analyzed using a noncompartmental method. The least square geometric mean ratios [90% confidence interval (CI)] of Cmax(neratinib+ketoconazole) : Cmax(neratinib alone), and AUC(neratinib+ketoconazole) : AUC(neratinib alone) were assessed. RESULTS Twenty-four subjects were enrolled. Compared with neratinib administered alone, co-administration of ketoconazole increased neratinib Cmax by 3.2-fold (90% CI: 2.4, 4.3) and AUC by 4.8-fold (3.6, 6.5). Median tmax was 6.0 h with both regimens. Ketoconazole decreased mean apparent oral clearance of neratinib from 346 l h−1 to 87.1 l h−1 and increased mean elimination half-life from 11.7 h to 18.0 h. The incidence of adverse events was comparable between the two regimens (50% neratinib alone, 65% co-administration with ketoconazole). CONCLUSION Co-administration of neratinib with ketoconazole, a potent CYP3A inhibitor, increased neratinib Cmax by 3.2-fold and AUC by 4.8-fold compared with administration of neratinib alone. These results indicate that neratinib is a substrate of CYP3A and is susceptible to interaction with potent CYP3A inhibitors and, thus, dose adjustments may be needed if neratinib is administered with such compounds. PMID:21395644

  14. Effects of an acidic beverage (Coca-Cola) on absorption of ketoconazole.

    PubMed Central

    Chin, T W; Loeb, M; Fong, I W

    1995-01-01

    Absorption of ketoconazole is impaired in patients with achlorhydria. The purpose of this study was to determine the effectiveness of a palatable acidic beverage (Coca-Cola Classic, pH 2.5) in improving the absorption of ketoconazole in the presence of drug-induced achlorhydria. A prospective, randomized, three-way crossover design with a 1-week wash-out period between each treatment was employed. Nine healthy nonsmoking, nonobese volunteers between 22 and 41 years old were studied. Each subject was randomized to receive three treatments: (A) ketoconazole 200-mg tablet with water (control), (B) omeprazole (60 mg) followed by ketoconazole (200 mg) taken with water, and (C) omeprazole (60 mg) followed by ketoconazole (200 mg) taken with 240 ml of Coca-Cola Classic. The pH values of gastric aspirates were checked after omeprazole was administered to confirm attainment of a pH of > 6. Multiple serum samples were obtained for measurements of ketoconazole concentrations by high-pressure liquid chromatography. The mean area under the ketoconazole concentration-time curve from zero to infinity for the control treatment (17.9 +/- 13.1 mg.h/liter) was significantly greater than that for treatment B (3.5 +/- 5.1 mg.h/liter; 16.6% +/- 15.0% of control). The mean peak concentration was highest for the control treatment (4.1 +/- 1.9 micrograms/ml), for which the mean peak concentration showed a significant increase over that for treatment B. The absorption of ketoconazole was reduced in the presence of omeprazole-induced achlorhydria. However, drug absorption was significantly increased, to approximately 65% of the mean for the control treatment, when the drug was taken with an acidic beverage, such as Coca-Cola. PMID:7486898

  15. Putative contact ketoconazole shampoo-triggered pemphigus foliaceus in a dog

    PubMed Central

    Sung, Hyun-Jeong; Yoon, In-Hwa; Kim, Jung-Hyun

    2017-01-01

    A 10-year-old spayed female cocker spaniel dog was referred for an evaluation of acute-onset generalized pustular cutaneous lesions following application of ketoconazole shampoo. Cytologic and histopathologic examinations of the lesions revealed intra-epidermal pustules with predominantly neutrophils and acantholytic cells. This is the first description of putative contact ketoconazole shampoo-triggered pemphigus foliaceus in a dog. PMID:28878412

  16. Mechanisms underlying ketoconazole-induced Ca(2+) mobilization in Madin-Darby canine kidney cells.

    PubMed

    Jan, C; Tseng, C

    2000-04-15

    The effect of ketoconazole on Ca(2+) signaling in Madin-Darby canine kidney (MDCK) cells was investigated by using fura-2 as a Ca(2+) probe. Ketoconazole evoked increases in cytosolic free Ca(2+) concentration ([Ca(2+)](i)) concentration dependently. The response was decreased by external Ca(2+) removal. In Ca(2+)-free medium, pretreatment with ketoconazole abolished the [Ca(2+)](i) rise induced by thapsigargin, an inhibitor of the endoplasmic reticulum Ca(2+) pump. Addition of 3 mM Ca(2+) induced a significant [Ca(2+)](i) rise after preincubation with 150 microM ketoconazole in Ca(2+)-free medium. Pretreatment with aristolochic acid (40 microM) to inhibit phospholipase A(2) inhibited the 150-microM-ketoconazole-induced internal Ca(2+) release by 37%, but inhibition of phospholipase C with 1-(6-((17beta-3-methoxyestra-1,3, 5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione (U73122) (2 microM) had no effect. Collectively, we found that ketoconazole increases [Ca(2+)](i) in MDCK cells by releasing Ca(2+) from thapsigargin-sensitive pools in a manner independent of the production of inositol-1,4,5-trisphosphate, followed by Ca(2+) influx from the external space.

  17. Ketoconazole inhibits the in vitro and in vivo metabolism of all-trans-retinoic acid

    SciT

    Van Wauwe, J.P.; Coene, M.C.; Goossens, J.

    1988-05-01

    Ketoconazole, an antifungal agent and inhibitor of certain mammalian cytochrome P-450-dependent enzymes, was studied for its effects on the in vitro and in vivo metabolism of all-trans-retinoic acid (RA). In vitro, ketoconazole (Ki = 0.75 microM) inhibited, in an apparently competitive manner, the cytochrome P-450-mediated metabolism to 4-hydroxy- and 4-keto-retinoic acids by hamster liver microsomes. In vivo, ketoconazole suppressed the formation of polar RA metabolites by normal rats dosed intrajugularly with 200 ng of (/sup 3/H)RA. After p.o. treatment with ketoconazole (2.5-40 mg/kg) given 1 hr before the (/sup 3/H)RA injection, the radioactivity extracted from the liver consisted of 25more » to 50% polar metabolites (control 66 +/- 1%) and 50 to 75% undegraded RA (control 34 +/- 1%) as evidenced by reverse-phase high-performance liquid chromatography. Time course experiments showed that ketoconazole's inhibitory effects lasted for 3 hr. Our data indicate the quantitative importance of the cytochrome P-450 enzymatic pathway in the biotransformation of RA. They also suggest that ketoconazole is capable of prolonging the biological half-life of RA and of improving the tissue levels of this compound.« less

  18. Effects of high-dose ketoconazole treatment on adrenal mineralocorticoid biosynthesis in dogs and rats.

    PubMed

    De Coster, R; Coene, M C; Haelterman, C; Beerens, D; Goeminne, N

    1987-07-01

    At high doses, ketoconazole blocks both testicular and adrenal androgen biosyntheses and partially inhibits the glucocorticoid production. To investigate the effects of this imidazole derivative on the mineralocorticoid biosynthesis, 7 male mongrel dogs received a single oral dose of 15 mg/kg of ketoconazole or placebo, in a cross-over way. From 2 to 4 h after treatment, an iv infusion of angiotensin II (10 ng/kg per min) was performed. Ketoconazole treatment significantly blunted the aldosterone and cortisol increment, whereas 18-hydroxycorticosterone, corticosterone, 11-deoxycorticosterone (DOC), progesterone, and 17 alpha-hydroxyprogesterone rose to peak concentrations, respectively 2.5-, 6-, 8-, 2.5- and 1.5-fold higher than those observed after placebo administration. Plasma 11-deoxycortisol and renin activity levels remained similar in both groups. On the other hand, 2 X 2 groups of 10 male adult rats each were fed with a normal or a sodium-depleted diet. Of the two sets of groups, one was treated ip with ketoconazole (20 mg/kg twice a day), the other with vehicle solution. In animals on either diet, ketoconazole lowered 18-hydroxycorticosterone and aldosterone concentrations. Plasma DOC rose up to 25-fold in the salt-deprived animals. Serum Na+, Cl-, corticosterone and plasma renin activity remained unaffected by the treatment. These results show that high-dose ketoconazole treatment partially inhibits the biosynthesis of aldosterone by affecting the cytochrome P-45011 beta.(ABSTRACT TRUNCATED AT 250 WORDS)

  19. In vitro additive interaction between ketoconazole and antimony against intramacrophage Leishmania (Leishmania) amazonensis amastigotes.

    PubMed

    Nunes, Débora Cristina de Oliveira; Bispo-da-Silva, Luiz Borges; Napolitano, Danielle Reis; Costa, Mônica Soares; Figueira, Márcia Moura Nunes Rocha; Rodrigues, Renata Santos; Rodrigues, Veridiana de Melo; Yoneyama, Kelly Aparecida Geraldo

    2017-01-01

    Leishmaniasis is a group of diseases caused by protozoa of Leishmania genus. The currently available treatments for this disease are expensive, present high toxicity and are associated to difficulties of healing and parasite resistance. Therefore, the development of strategies for leishmaniasis treatment is indispensable and includes reposition of existing drugs, as well as drug combination therapy. The aim of this study was to assess the nature of ketoconazole and antimony association on the cytotoxic effect against Leishmania (Leishmania) amazonensis amastigotes. The calculated mean sum of fractional 50% inhibitory concentration ([Formula: see text]ΣFIC50) was 2.54 and 1.43 for free and intracellular amastigotes, respectively, values that suggest an additive interaction between ketoconazole and antimony concerning to Leishmania toxicity only in the intramacrophage parasite form. Despite the clinical efficacy of ketoconazole-antimony combination has been shown in the literature, our study is the first to describe the nature of ketoconazole-antimony interaction against L. (L.) amazonensis amastigotes. Moreover, our results point out the need for future in vivo studies to confirm the nature of ketoconazole-antimony interaction and also to determine possible effective dosage regimens related to ketoconazole administration in association with the optimal lower dose of antimony.

  20. Ketoconazole, an antifungal agent, protects against adiposity induced by a cafeteria diet.

    PubMed

    Campión, J; Martínez, J A

    2004-07-01

    Ketoconazole, an anti-glucocorticoid agent, is widely used in humans as an antifungal agent. It inhibits ergosterol synthesis and reduces cortisol levels in the treatment of Cushing's Syndrome. The aim of this work was to study the drug's preventive potential against adiposity induced by a high-fat cafeteria diet in rats. Female Wistar rats were fed on standard pelleted diet or cafeteria diet during 42 days in the presence or absence of an oral treatment with ketoconazole (24 mg/kg of body weight). The cafeteria diet increased energy intake and body weight. In addition, this high-fat diet increased body-fat weight and adipose tissue depots analyzed. Interestingly, ketoconazole was able to protect against increased total body fat and adipose depot enlargement induced after cafeteria-diet feeding. Moreover, ex vivo isoproterenol-induced lipolysis was reduced in adipocytes from cafeteria-fed animals; this decrease was reverted by treatment with ketoconazole. Thus, ketoconazole was able to protect against adiposity induced by a cafeteria diet, revealing an interaction between fat intake and glucocorticoids on adipose deposition.

  1. Effect of ketoconazole and diltiazem on the pharmacokinetics of apixaban, an oral direct factor Xa inhibitor

    PubMed Central

    Frost, Charles E; Byon, Wonkyung; Song, Yan; Wang, Jessie; Schuster, Alan E; Boyd, Rebecca A; Zhang, Donglu; Yu, Zhigang; Dias, Clapton; Shenker, Andrew; LaCreta, Frank

    2015-01-01

    Aim Apixaban is an orally active inhibitor of coagulation factor Xa and is eliminated by multiple pathways, including renal and non-renal elimination. Non-renal elimination pathways consist of metabolism by cytochrome P450 (CYP) enzymes, primarily CYP3A4, as well as direct intestinal excretion. Two single sequence studies evaluated the effect of ketoconazole (a strong dual inhibitor of CYP3A4 and P-glycoprotein [P-gp]) and diltiazem (a moderate CYP3A4 inhibitor and a P-gp inhibitor) on apixaban pharmacokinetics in healthy subjects. Method In the ketoconazole study, 18 subjects received apixaban 10 mg on days 1 and 7, and ketoconazole 400 mg once daily on days 4–9. In the diltiazem study, 18 subjects received apixaban 10 mg on days 1 and 11 and diltiazem 360 mg once daily on days 4–13. Results Apixaban maximum plasma concentration and area under the plasma concentration–time curve extrapolated to infinity increased by 62% (90% confidence interval [CI], 47, 78%) and 99% (90% CI, 81, 118%), respectively, with co-administration of ketoconazole, and by 31% (90% CI, 16, 49%) and 40% (90% CI, 23, 59%), respectively, with diltiazem. Conclusion A 2-fold and 1.4-fold increase in apixaban exposure was observed with co-administration of ketoconazole and diltiazem, respectively. PMID:25377242

  2. Ketoconazole inhibits Malassezia furfur morphogenesis in vitro under filamentation optimized conditions.

    PubMed

    Youngchim, Sirida; Nosanchuk, Joshua D; Chongkae, Siriporn; Vanittanokom, Nongnuch

    2017-01-01

    Malassezia furfur, a constituent of the normal human skin flora, is an etiological agent of pityriasis versicolor, which represents one of the most common human skin diseases. Under certain conditions, both exogenous and endogenous, the fungus can transition from a yeast form to a pathogenic mycelial form. To develop a standardized medium for reproducible production of the mycelial form of M. furfur to develop and optimize susceptibility testing for this pathogen, we examined and characterized variables, including kojic acid and glycine concentration, agar percentage, and pH, to generate a chemically defined minimal medium on which specific inoculums of M. furfur generated the most robust filamentation. Next, we examined the capacity of ketoconazole to inhibit the formation of M. furfur mycelial form. Both low and high, 0.01, 0.05 and 0.1 µg/ml concentrations of ketoconazole significantly inhibited filamentation at 11.9, 54.5 and 86.7%, respectively. Although ketoconazole can have a direct antifungal effect on both M. furfur yeast and mycelial cells, ketoconazole also has a dramatic impact on suppressing morphogenesis. Since mycelia typified the pathogenic form of Malassezia infection, the capacity of ketoconazole to block morphogenesis may represent an additional important effect of the antifungal.

  3. Lack of effect of ketoconazole on the pharmacokinetics of rosuvastatin in healthy subjects

    PubMed Central

    Cooper, Kelvin J; Martin, Paul D; Dane, Aaron L; Warwick, Mike J; Raza, Ali; Schneck, Dennis W

    2003-01-01

    Aims To examine in vivo the effect of ketoconazole on the pharmacokinetics of rosuvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor. Methods This was a randomized, double-blind, two-way crossover, placebo-controlled trial. Healthy male volunteers (n = 14) received ketoconazole 200 mg or placebo twice daily for 7 days, and rosuvastatin 80 mg was coadministered on day 4 of dosing. Plasma concentrations of rosuvastatin, and active and total HMG-CoA reductase inhibitors were measured up to 96 h postdose. Results Following coadministration with ketoconazole, rosuvastatin geometric least square mean AUC(0,t) and Cmax were unchanged compared with placebo (treatment ratios (90% confidence intervals): 1.016 (0.839, 1.230), 0.954 (0.722, 1.260), respectively). Rosuvastatin accounted for essentially all of the circulating active HMG-CoA reductase inhibitors and most (> 85%) of the total inhibitors. Ketoconazole did not affect the proportion of circulating active or total inhibitors accounted for by circulating rosuvastatin. Conclusions Ketoconazole did not produce any change in rosuvastatin pharmacokinetics in healthy subjects. The data suggest that neither cytochrome P450 3A4 nor P-gp-mediated transport contributes to the elimination of rosuvastatin. PMID:12534645

  4. The effects of ketoconazole and cimetidine on the pharmacokinetics of oral tramadol in greyhound dogs.

    PubMed

    KuKanich, B; KuKanich, K; Black, J

    2017-12-01

    Tramadol is administered to dogs for analgesia but has variability in its extent of absorption, which may hinder its efficacy. Additionally, the active opioid metabolite (M1) occurs in low concentrations. The purpose of this study was to determine if administration of oral tramadol with suspected metabolism inhibitors (ketoconazole, cimetidine) would lead to improved bioavailability of tramadol and M1. Six healthy Greyhounds were included. They were administered tramadol orally and intravenously, M1 intravenously, oral tramadol with oral ketoconazole and oral tramadol with oral cimetidine. Oral tramadol bioavailability was low (2.6%). Ketoconazole and cimetidine significantly increased tramadol bioavailability to 18.2% and 20.3%, respectively. The mean maximum plasma concentration of tramadol alone was 22.9 ng/ml, and increased to 109.9 and 143.2 μg/ml with ketoconazole and cimetidine, respectively. However, measured tramadol plasma concentrations were below the minimum concentration considered effective in humans (228 μg/ml). In all treatment groups, measured M1 concentrations (<7 μg/ml) were below concentrations associated with efficacy in humans. To conclude, tramadol and M1 concentrations were low and variable in dogs after oral dosing of tramadol, even in combination with cimetidine or ketoconazole, but effective concentrations in dogs have not been defined. © 2017 John Wiley & Sons Ltd.

  5. Cyclosporine and ketoconazole for the treatment of perianal fistulas in dogs.

    PubMed

    Patricelli, Alison J; Hardie, Robert J; McAnulty, Jonathan E

    2002-04-01

    To evaluate efficacy and cost of using cyclosporine and ketoconazole for the treatment of perianal fistulas in dogs. Clinical trial. 12 dogs with perianal fistulas. Dogs received cyclosporine and ketoconazole orally (target whole blood trough cyclosporine concentrations of 400 to 600 ng/ml). Study endpoints were resolution of clinical signs, remission, and recurrence of disease. Adverse effects and cost of medications were reported. Results were compared with those from previous studies in humans and in dogs in which single agent cyclosporine treatment for perianal fistulas was used. All dogs had resolution of clinical signs. Eight dogs went into remission; however, 5 of those 8 had recurrence of fistulas. Adverse effects of treatment were minimal and well tolerated. Cost of treatment was comparable to traditional surgical options and less than single agent cyclosporine treatment. Administration of cyclosporine with ketoconazole is an effective and cost-comparable treatment for perianal fistulas in dogs.

  6. Additive effect of ketoconazole and octreotide in the treatment of severe adrenocorticotropin-dependent hypercortisolism.

    PubMed

    Vignati, F; Loli, P

    1996-08-01

    Over the last few years ketoconazole and octreotide have been employed in the treatment of pituitary-dependent or ectopic Cushing's syndrome. In four patients (two men and two women, aged 25-64 yr) with severe ACTH-dependent hypercortisolism in whom medical treatment with ketoconazole showed limited effectiveness and/or tolerability, we tried the association with octreotide. In all patients ketoconazole (200-1000 mg) induced a marked decrease in urinary free cortisol (UFC) excretion, but normalization could not be achieved. After ketoconazole discontinuation, three patients received octreotide alone (300-1500 micrograms/day, sc). This drug caused a dramatic decrease in UFC excretion, although not normalization; in all patients, escape from treatment occurred. Combined treatment was carried out for 10-180 days. Urinary cortisol excretion normalized and remained steadily within normal limits in three of four patients in whom normal UFC excretion had never been attained with both single drug regimens; in the fourth patient, UFC excretion decreased to levels lower than those achieved with ketoconazole or octreotide alone. The association with octreotide allowed a reduction in the daily dose of ketoconazole in three patients. Consistent with the steady reduction of cortisol production, a striking clinical improvement occurred in all patients after starting combined treatment. The normalization of UFC in three of four patients treated with both agents suggests that this approach may be useful in the long term treatment of severe forms of hypercortisolism of both pituitary and ectopic origin. In contrast to the limited effectiveness of each drug taken singularly at the same or higher doses, the association of the two drugs had an additive effect in the attainment of normal urinary cortisol excretion.

  7. Inhibition of Propionibacterium acnes lipase activity by the antifungal agent ketoconazole.

    PubMed

    Unno, Mizuki; Cho, Otomi; Sugita, Takashi

    2017-01-01

    The common skin disease acne vulgaris is caused by Propionibacterium acnes. A lipase secreted by this microorganism metabolizes sebum and the resulting metabolites evoke inflammation in human skin. The antifungal drug ketoconazole inhibits P. acnes lipase activity. We previously showed that the drug also inhibits the growth of P. acnes. Thus, ketoconazole may serve as an alternative treatment for acne vulgaris, which is important because the number of antibiotic-resistant P. acnes strains has been increasing. © 2017 The Societies and John Wiley & Sons Australia, Ltd.

  8. Pharmacokinetics of oral neratinib during co-administration of ketoconazole in healthy subjects.

    PubMed

    Abbas, Richat; Hug, Bruce A; Leister, Cathie; Burns, Jaime; Sonnichsen, Daryl

    2011-04-01

    The primary objective was to evaluate the pharmacokinetics of a single dose of neratinib, a potent, low-molecular-weight, orally administered, irreversible pan-ErbB (ErbB-1, -2, -4) receptor tyrosine kinase inhibitor, during co-administration with ketoconazole, a potent CYP3A4 inhibitor. This was an open-label, randomized, two-period, crossover study. Fasting healthy adults received a single oral dose of neratinib 240 mg alone and with multiple oral doses of ketoconazole 400 mg. Blood samples were collected up to 72 h after each neratinib dose. Plasma concentration data were analyzed using a noncompartmental method. The least square geometric mean ratios [90% confidence interval (CI)] of C(max) (neratinib+ketoconazole): C(max) (neratinib alone), and AUC(neratinib+ketoconazole): AUC(neratinib alone) were assessed. Twenty-four subjects were enrolled. Compared with neratinib administered alone, co-administration of ketoconazole increased neratinib C(max) by 3.2-fold (90% CI: 2.4, 4.3) and AUC by 4.8-fold (3.6, 6.5). Median t(max) was 6.0 h with both regimens. Ketoconazole decreased mean apparent oral clearance of neratinib from 346 lh(-1) to 87.1 lh(-1) and increased mean elimination half-life from 11.7 h to 18.0 h. The incidence of adverse events was comparable between the two regimens (50% neratinib alone, 65% co-administration with ketoconazole). Co-administration of neratinib with ketoconazole, a potent CYP3A inhibitor, increased neratinib C(max) by 3.2-fold and AUC by 4.8-fold compared with administration of neratinib alone. These results indicate that neratinib is a substrate of CYP3A and is susceptible to interaction with potent CYP3A inhibitors and, thus, dose adjustments may be needed if neratinib is administered with such compounds. © 2011 The Authors. British Journal of Clinical Pharmacology © 2011 The British Pharmacological Society.

  9. Thermodynamic scaling of molecular dynamics in supercooled liquid state of pharmaceuticals: Itraconazole and ketoconazole.

    PubMed

    Tarnacka, M; Madejczyk, O; Adrjanowicz, K; Pionteck, J; Kaminska, E; Kamiński, K; Paluch, M

    2015-06-14

    Pressure-Volume-Temperature (PVT) measurements and broadband dielectric spectroscopy were carried out to investigate molecular dynamics and to test the validity of thermodynamic scaling of two homologous compounds of pharmaceutical activity: itraconazole and ketoconazole in the wide range of thermodynamic conditions. The pressure coefficients of the glass transition temperature (dT(g)/dp) for itraconazole and ketoconazole were determined to be equal to 183 and 228 K/GPa, respectively. However, for itraconazole, the additional transition to the nematic phase was observed and characterized by the pressure coefficient dT(n)/dp = 258 K/GPa. From PVT and dielectric data, we obtained that the liquid-nematic phase transition is governed by the relaxation time since it occurred at constant τ(α) = 10(-5) s. Furthermore, we plotted the obtained relaxation times as a function of T(-1)v(-γ), which has revealed that the validity of thermodynamic scaling with the γ exponent equals to 3.69 ± 0.04 and 3.64 ± 0.03 for itraconazole and ketoconazole, respectively. Further analysis of the scaling parameter in itraconazole revealed that it unexpectedly decreases with increasing relaxation time, which resulted in dramatic change of the shape of the thermodynamic scaling master curve. While in the case of ketoconazole, it remained the same within entire range of data (within experimental uncertainty). We suppose that in case of itraconazole, this peculiar behavior is related to the liquid crystals' properties of itraconazole molecule.

  10. A phase I trial of pharmacokinetic modulation of carboxyamidotriazole (CAI) with ketoconazole in patients with advanced cancer.

    PubMed

    Desai, Apurva A; Innocenti, Federico; Janisch, Linda; DeMario, Mark; Shepard, Dale; Ramirez, Jacqueline; Fleming, Gini F; Ratain, Mark J

    2004-11-01

    Carboxyamidotriazole (CAI) is a novel antineoplastic agent in clinical development with limited oral bioavailability. In vitro, ketoconazole has been demonstrated to inhibit CYP3A4-mediated metabolism of CAI. We performed this phase I trial to determine if ketoconazole-mediated CYP3A4 inhibition would lead to favorable alteration of CAI pharmacokinetics, and to evaluate the safety, toxicity and tolerability of the proposed combination. Forty-seven patients were treated using a standard three patients per cohort CAI dose-escalation scheme. In cycle 1, CAI was administered alone on day-6 followed by a single dose of ketoconazole (200 mg) on day 0. CAI and ketoconazole (200 mg/day) were subsequently coadministered on days 1 and 3-28. Plasma samples for pharmacokinetic analysis were obtained following the doses on days-6 and 1. All subsequent cycles were of 28-day duration, and consisted of daily CAI and ketoconazole coadministration. Pharmacokinetic analysis was performed on samples from 44 patients. In most patients administration of ketoconazole produced an increase in CAI AUC and Cmax with a decrease in CAI clearance. Seven patients experienced stable disease for up to 12 months. Gastrointestinal and constitutional toxicities were the most common toxicities. Coadministration of CAI with ketoconazole increased CAI exposure in most of the patients without altering the toxicity profile of CAI. The highest CAI dose administered on the trial was 300 mg/day. The clinical utility of such a modulation strategy might be explored in future clinical trials of CAI.

  11. The contribution of hepatic inactivation of testosterone to the lowering of serum testosterone levels by ketoconazole.

    PubMed

    Wilson, V S; LeBlanc, G A

    2000-03-01

    Hepatic biotransformation processes can be modulated by chemical exposure and these alterations can impact the biotransformation of endogenous substrates. Furthermore, chemically mediated alterations in the biotransformation of endogenous steroid hormones have been implicated as a mechanism by which steroid hormone homeostasis can be disrupted. The fungicide ketoconazole has been shown to lower serum testosterone levels and alter both gonadal synthesis and hepatic inactivation of testosterone. The present study examined whether the effects of ketoconazole on the hepatic biotransformation of testosterone contribute to its lowering of serum testosterone levels. Results also were used to validate further the use of the androgen-regulated hepatic testosterone 6alpha/15alpha-hydroxylase ratio as an indicator of androgen status. Male CD-1 mice were fed from 0 to 160 mg/kg ketoconazole in honey. Four h after the initial treatment, serum testosterone levels, gonadal testosterone secretion, and hepatic testosterone hydroxylase activity decreased, and the hepatic testosterone 6alpha/15alpha-hydroxylase ratio increased in a dose-dependent manner. Immunoblot analysis indicated that the transient decline in hepatic biotransformation was not due to reduced P450 protein levels. Rather, hepatic testosterone biotransformation activities were found to be differentially susceptible to direct inhibition by ketoconazole. Differential inhibition was also responsible for the increase seen in the 6alpha/15alpha-hydroxylase ratio. The changes in serum testosterone levels could be explained by decreased gonadal synthesis of testosterone and were not impacted by decreased hepatic biotransformation of testosterone. These results demonstrate that changes in the hepatic hydroxylation of testosterone by ketoconazole, and perhaps other chemicals, have little or no influence serum testosterone levels.

  12. A noninferiority clinical trial comparing fluconazole and ketoconazole in combination with cephalexin for the treatment of dogs with Malassezia dermatitis.

    PubMed

    Sickafoose, L; Hosgood, G; Snook, T; Westermeyer, R; Merchant, S

    2010-01-01

    This double-blinded noninferiority clinical trial evaluated the use of oral fluconazole for the treatment of Malassezia dermatitis in dogs by comparing it with use of an accepted therapeutic agent, ketoconazole. Dogs presenting with Malassezia dermatitis were treated with either fluconazole or ketoconazole in addition to cephalexin for concurrent bacterial dermatitis. Statistically significant improvements in cytologic yeast count, clinical signs associated with Malassezia dermatitis, and pruritus were seen with both antifungal treatments. There was no statistical difference between the treatments with regard to the magnitude of reduction in these parameters. These results suggest that fluconazole is at least as effective as ketoconazole for the treatment of dogs with Malassezia dermatitis.

  13. Transcription of Key Genes Regulating Gonadal Steroidogenesis in Control and Ketoconazole- or Vinclozolin-exposed Fathead Minnows

    EPA Science Inventory

    This paper provides the first report on the effects of two endocrine-active fungicides, ketoconazole and vinclozolin, on the expression of steroidogenesis-related genes in the testis of male fathead minnows.

  14. Severe Adverse Reactions Following Ketoconazole, Fluconazole, and Environmental Exposures: A Case Report.

    PubMed

    Lieberman, Allan; Curtis, Luke

    2018-04-18

    In this case report, we describe a 66-year-old man who developed multiple adverse reactions beginning at age 56 after exposure to several azole antifungal drugs including ketoconazole and fluconazole. He also had a history of more than 40 years exposure to chemicals including pesticides, wood preservatives, fertilizers, and welding chemicals. His reactions involved dehydration (requiring several liters of intravenous fluids in less than an hour to alleviate this condition), angioedema, nausea, tinnitus, hypotension, and difficulty breathing. His acute adverse reactions were triggered by a wide range of chemicals including gasoline, diesel fuel, pesticides, chlorine, topical isopropyl alcohol, and paper mill emissions. His acute reactions were also triggered by a wide range of foods such as bananas, apples, milk, white potatoes, and processed sweets. A number of mechanisms could be responsible for his increased sensitivity to chemicals following exposure to fluconazole/ketoconazole, including inhibition of P450 and other detoxification enzymes, acetaldehyde buildup, and neurogenic sensitization.

  15. Cyclosporin and ketoconazole interaction for treatment of perianal fistulas in the dog.

    PubMed

    Mouatt, J G

    2002-04-01

    To assess the use of concurrent ketoconazole and low dose cyclosporin administration in a group of dogs with clinical evidence of perianal fistulas, and to determine if this combination could be used to manage perianal fistulas effectively. Prospective clinical trial Sixteen dogs with clinical evidence of perianal fistulas were given ketoconazole (10 mg/kg once daily) and cyclosporin (1 mg/kg twice daily initially) for 16 weeks. Blood cyclosporin assays were performed regularly and cyclosporin doses were altered to achieve a stable blood level above 200 ng/mL. Regular examinations assessed the dogs' general health, changes in clinical behaviour, fistula size and number. A complete blood count and serum biochemical analysis was performed in all dogs before and after the treatment period, and after 8 weeks of treatment in 12 dogs. Dogs were assessed for recurrence of lesions at 1, 3 and 12 months after the trial. All dogs showed marked improvement in lesions and behaviour within 14 days of the medication. Fourteen dogs completed the trial. Two dogs were excluded due to concurrent disease. Thirteen dogs (93%) showed complete resolution of fistulas during the treatment period. Seven dogs (50%) had no recurrence after 12 months. Recurrence was seen in three dogs (21%) at 8, 10 and 12 months after treatment, and in three dogs (21%) within 1 month of treatment. The medication was well tolerated. Side effects included transient anorexia, vomiting and lethargy in some dogs, increased shedding of hair and gingival hyperplasia. Ketoconazole administration allowed a dramatic reduction in cyclosporin dose (over 90% in 12 dogs and 80% in the other two) compared to previously reported cases treated with cyclosporin alone. The use of combined ketoconazole and cyclosporin provided an effective treatment for perianal fistulas. Outcomes were similar to those seen with cyclosporin alone, but allowed a significant reduction in cyclosporin dose and, therefore, cost. The use of

  16. Prophylactic ketoconazole shampoo for tinea capitis in a high-risk pediatric population.

    PubMed

    Bookstaver, P Brandon; Watson, Holly J; Winters, Shauna D; Carlson, Adrian L; Schulz, Richard M

    2011-07-01

    Although topical agents for the treatment of tinea capitis decrease viable fungal elements and reduce shedding, their use as a prophylactic agent has not been investigated. This study evaluated the effectiveness of a prophylactic ketoconazole shampoo (Nizoral 2%) protocol to reduce the number of clinically evident tinea capitis infections in a high-risk African American, urban population. We conducted a retrospective analysis of a ketoconazole prophylaxis protocol that was implemented at an urban pediatric clinic for medically fragile children. Patients at high risk for tinea capitis received twice-weekly ketoconazole shampoo. The primary outcome of the study was a reduction in the number of documented tinea capitis infections between the 12-month preprotocol and 12-month postprotocol periods. A secondary outcome included the evaluation of predisposing risk factors for acquiring tinea infections. Ninety-seven patients, with a mean age of 8.06 years, were included. Most patients (78%) were African American. There were a total of 13 tinea capitis infections during the 12-month preprotocol period. During the 12-month postprotocol period, 41 infections were documented: 37 (90.2%) in the prophylaxis group and 4 (9.8%) in the nonprophylaxis group. The average numbers of per-patient infections in the postprotocol period were 0.79 and 0.08 in the prophylaxis and nonprophylaxis groups, respectively. Initiation of prophylaxis did not reduce tinea capitis infections (p=NS). Previous history of infection and a high level of care were significant predictors of infections (p<0.05). Improved hygiene, adherence to prescribed treatment regimens, and prevention of recurrent environmental exposure to surviving fomites should be stressed in high-risk patients and supersede the need for an antifungal (ketoconazole shampoo) prophylaxis protocol.

  17. Thermodynamic scaling of molecular dynamics in supercooled liquid state of pharmaceuticals: Itraconazole and ketoconazole

    SciT

    Tarnacka, M., E-mail: mtarnacka@us.edu.pl; Madejczyk, O.; Kamiński, K.

    2015-06-14

    Pressure-Volume-Temperature (PVT) measurements and broadband dielectric spectroscopy were carried out to investigate molecular dynamics and to test the validity of thermodynamic scaling of two homologous compounds of pharmaceutical activity: itraconazole and ketoconazole in the wide range of thermodynamic conditions. The pressure coefficients of the glass transition temperature (dT{sub g}/dp) for itraconazole and ketoconazole were determined to be equal to 183 and 228 K/GPa, respectively. However, for itraconazole, the additional transition to the nematic phase was observed and characterized by the pressure coefficient dT{sub n}/dp = 258 K/GPa. From PVT and dielectric data, we obtained that the liquid-nematic phase transition ismore » governed by the relaxation time since it occurred at constant τ {sub α} = 10{sup −5} s. Furthermore, we plotted the obtained relaxation times as a function of T{sup −1}v{sup −γ}, which has revealed that the validity of thermodynamic scaling with the γ exponent equals to 3.69 ± 0.04 and 3.64 ± 0.03 for itraconazole and ketoconazole, respectively. Further analysis of the scaling parameter in itraconazole revealed that it unexpectedly decreases with increasing relaxation time, which resulted in dramatic change of the shape of the thermodynamic scaling master curve. While in the case of ketoconazole, it remained the same within entire range of data (within experimental uncertainty). We suppose that in case of itraconazole, this peculiar behavior is related to the liquid crystals’ properties of itraconazole molecule.« less

  18. Prophylactic Ketoconazole Shampoo for Tinea Capitis in a High-Risk Pediatric Population

    PubMed Central

    Bookstaver, P. Brandon; Watson, Holly J.; Winters, Shauna D.; Carlson, Adrian L.; Schulz, Richard M.

    2011-01-01

    OBJECTIVES Although topical agents for the treatment of tinea capitis decrease viable fungal elements and reduce shedding, their use as a prophylactic agent has not been investigated. This study evaluated the effectiveness of a prophylactic ketoconazole shampoo (Nizoral 2%) protocol to reduce the number of clinically evident tinea capitis infections in a high-risk African American, urban population. METHODS We conducted a retrospective analysis of a ketoconazole prophylaxis protocol that was implemented at an urban pediatric clinic for medically fragile children. Patients at high risk for tinea capitis received twice-weekly ketoconazole shampoo. The primary outcome of the study was a reduction in the number of documented tinea capitis infections between the 12-month preprotocol and 12-month postprotocol periods. A secondary outcome included the evaluation of predisposing risk factors for acquiring tinea infections. RESULTS Ninety-seven patients, with a mean age of 8.06 years, were included. Most patients (78%) were African American. There were a total of 13 tinea capitis infections during the 12-month preprotocol period. During the 12-month postprotocol period, 41 infections were documented: 37 (90.2%) in the prophylaxis group and 4 (9.8%) in the nonprophylaxis group. The average numbers of per-patient infections in the postprotocol period were 0.79 and 0.08 in the prophylaxis and nonprophylaxis groups, respectively. Initiation of prophylaxis did not reduce tinea capitis infections (p=NS). Previous history of infection and a high level of care were significant predictors of infections (p<0.05). CONCLUSIONS Improved hygiene, adherence to prescribed treatment regimens, and prevention of recurrent environmental exposure to surviving fomites should be stressed in high-risk patients and supersede the need for an antifungal (ketoconazole shampoo) prophylaxis protocol. PMID:22479162

  19. Validating the Predicted Effect of Astemizole and Ketoconazole Using a Drosophila Model of Parkinson's Disease.

    PubMed

    Styczyńska-Soczka, Katarzyna; Zechini, Luigi; Zografos, Lysimachos

    2017-04-01

    Parkinson's disease is a growing threat to an ever-ageing population. Despite progress in our understanding of the molecular and cellular mechanisms underlying the disease, all therapeutics currently available only act to improve symptoms and do not stop the disease process. It is therefore imperative that more effective drug discovery methods and approaches are developed, validated, and used for the discovery of disease-modifying treatments for Parkinson's. Drug repurposing has been recognized as being equally as promising as de novo drug discovery in the field of neurodegeneration and Parkinson's disease specifically. In this work, we utilize a transgenic Drosophila model of Parkinson's disease, made by expressing human alpha-synuclein in the Drosophila brain, to validate two repurposed compounds: astemizole and ketoconazole. Both have been computationally predicted to have an ameliorative effect on Parkinson's disease, but neither had been tested using an in vivo model of the disease. After treating the flies in parallel, results showed that both drugs rescue the motor phenotype that is developed by the Drosophila model with age, but only ketoconazole treatment reversed the increased dopaminergic neuron death also observed in these models, which is a hallmark of Parkinson's disease. In addition to validating the predicted improvement in Parkinson's disease symptoms for both drugs and revealing the potential neuroprotective activity of ketoconazole, these results highlight the value of Drosophila models of Parkinson's disease as key tools in the context of in vivo drug discovery, drug repurposing, and prioritization of hits, especially when coupled with computational predictions.

  20. Endocrinological effects of single daily ketoconazole administration in male beagle dogs.

    PubMed

    De Coster, R; Beerens, D; Dom, J; Willemsens, G

    1984-10-01

    Some endocrinological effects of single daily oral administration of 150 mg ketoconazole for 15 days were investigated in 4 male beagle dogs. Plasma testosterone fell markedly within 3-4 h and then progressively returned to control concentrations by 10 h after drug administration. On the other hand, plasma 17 alpha-hydroxyprogesterone, progesterone and 17 alpha, 20 alpha-dihydroxyprogesterone increased within 3-10 h before returning to basal values after 24 h. Plasma LH did not rise significantly though some high individual levels were noted. Plasma cortisol and oestradiol-17 alpha levels were not significantly modified by the treatment. These results confirm that a high therapeutic dose of ketoconazole, given orally once a day, transiently inhibits in vivo the 17-20 lyase enzyme of the testis, without modifying basal cortisol and oestradiol-17 beta plasma concentrations and that enzymatic inhibition still occurs after daily treatment for up to 2 weeks but remains transient and parallels the resorption profile of the drug so that normal plasma testosterone levels are observed from 10 to 24 h after drug intake. However, permanent inhibition of androgen biosynthesis might be obtained by the administration of high doses of ketoconazole given several times a day.

  1. Adverse interaction between colchicine and ketoconazole in a Chinese shar pei.

    PubMed

    McAlister, Amber; Center, Sharon A; Bender, Hannah; McDonough, Sean P

    2014-01-01

    A Chinese shar pei with a 2 yr history of episodic fever, lethargy, and shifting lameness was presumptively diagnosed with familial shar pei fever but had never been treated for the syndrome. After being presented for a superficial pyoderma with possible dermatophyte coinfection, treatment with a cephalosporin and ketoconazole were prescribed. One wk later, colchicine was initiated for familial shar pei fever using cautious dose escalation. Nevertheless, gastrointestinal toxicity, skeletal muscle myopathy, and hepatotoxicity developed within 2 wk. Abrupt resolution of gastrointestinal toxicity and myopathy followed drug withdrawal. However, escalating liver enzyme activity and hyperbilirubinemia led to liver biopsy to rule out an antecedent hepatopathy. Biopsy characterized canalicular cholestasis and colchicine-associated metaphase arrest and ring mitoses reflecting repression of mitotic spindle formation. Signs of illness completely resolved 3 mo after drug discontinuation. Although avoidable adverse interactions between ketoconazole and drugs reliant on cytochrome oxidase biotransformation and/or drug efflux mediated by multiple drug-resistant transporters are well documented in humans, these are rarely reported in veterinary patients. This case exemplifies an important and avoidable ketoconazole/colchicine drug interaction from which the patient completely recovered. The dog tested negative for the canine MDR1 loss of function mutation that also might potentiate colchicine toxicity.

  2. The combination of amoxicillin-clavulanic acid and ketoconazole in the treatment of Madurella mycetomatis eumycetoma and Staphylococcus aureus co-infection.

    PubMed

    Mhmoud, Najwa A; Fahal, Ahmed Hassan; Mahgoub, El Sheikh; van de Sande, Wendy W J

    2014-06-01

    Eumycetoma is a chronic progressive disabling and destructive inflammatory disease which is commonly caused by the fungus Madurella mycetomatis. It is characterized by the formation of multiple discharging sinuses. It is usually treated by antifungal agents but it is assumed that the therapeutic efficiency of these agents is reduced by the co-existence of Staphylococcus aureus co-infection developing in these sinuses. This prospective study was conducted to investigate the safety, efficacy and clinical outcome of combined antibiotic and antifungal therapy in eumycetoma patients with superimposed Staphylococcus aureus infection. The study enrolled 337 patients with confirmed M. mycetomatis eumycetoma and S. aureus co-infection. Patients were allocated into three groups; 142 patients received amoxicillin-clavulanic acid and ketoconazole, 93 patients received ciprofloxacin and ketoconazole and 102 patients received ketoconazole only. The study showed that, patients who received amoxicillin-clavulanic acid and ketoconazole treatment had an overall better clinical outcome compared to those who had combined ciprofloxacin and ketoconazole or to those who received ketoconazole only. In this study, 60.6% of the combined amoxicillin-clavulanic acid/ketoconazole group showed complete or partial clinical response to treatment compared to 30.1% in the ciprofloxacin/ketoconazole group and 36.3% in the ketoconazole only group. The study also showed that 64.5% of the patients in the ciprofloxacin/ketoconazole group and 59.8% in the ketoconazole only group had progressive disease and poor outcome. This study showed that the combination of amoxicillin-clavulanic acid and ketoconazole treatment is safe and offers good clinical outcome and it is therefore recommended to treat eumycetoma patients with Staphylococcus aureus co-infection.

  3. Characterization of 1-Aminobenzotriazole and Ketoconazole as Novel Inhibitors of Monoamine Oxidase (MAO): An In Vitro Investigation.

    PubMed

    Shaik, Abdul Naveed; LeDuc, Barbara W; Khan, Ansar A

    2017-10-01

    1-Aminobenzotriazole, a known time-dependent inhibitor of cytochrome P450 (CYP) enzymes, and ketoconazole, a strong inhibitor of the human CYP3A4 isozyme, are used as standard probe inhibitors to characterize the CYP and/or non-CYP-mediated metabolism of xenobiotics. In the present investigation, 1-Aminobenzotriazole and ketoconazole are characterized as potent monoamine oxidase (MAO) inhibitors in vitro using mouse, rat and human liver microsomes and S9 fractions. Inhibition potential of 1-aminobenzotriazole and ketoconazole was studied in mice, rat and human liver microsomes, S9 fractions, MAO-A and MAO-B expressed enzymes by monitoring the formation of 4-hydroxyquinoline (4-HQ) from kynuramine, a specific substrate of MAO by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Mechanism of MAO inhibition was studied by incubating varying concentration of kynuramine with mouse, rat and human S9 fractions at varying concentration of 1-aminobenzatriazole and ketoconazole and monitoring the formation of 4-HQ. 1-aminobenzotriazole and ketoconazole inhibited both MAO isozymes (MAO-A and MAO-B) with more specificity towards MAO-B. Kynuramine substrate kinetics in mouse, rat and human S9 fractions with varying 1-aminobenzotriazole and ketoconazole concentrations showed decreased maximum rate (V max ) for 4-HQ formation without affecting the Michaelis-Menten constant (K m ). A non-competitive inhibition model was constructed and inhibition constants (K i ) for 1-aminobenzotriazole (7.87 ± 0.61, 8.61 ± 0.92, 65.2 ± 1.61 µM for mice, rat and humans, respectively) and ketoconazole (0.12 ± 0.01, 2.04 ± 0.08, 5.52 ± 0.47 µM for mice, rat and humans, respectively) were determined. 1-Aminobenzotriazole and ketoconazole are characterized as non-competitive inhibitors of mice, rat and human MAO in vitro and the extent of their MAO inhibition potential is species specific. 1-Aminobenzotriazole or ketoconazole can be used as a probe inhibitor in vitro

  4. Successful outcome of pregnancy in a patient with Cushing's disease under treatment with ketoconazole during the first trimester of gestation.

    PubMed

    Boronat, Mauro; Marrero, Dunia; López-Plasencia, Yaiza; Barber, Miguel; Schamann, Yaiza; Nóvoa, Francisco J

    2011-09-01

    Ketoconazole is the most widely used medical treatment for Cushing's syndrome, but, because of its potential to cause birth defects, it is not recommended during pregnancy. Specifically, due to its antiandrogenic effects, ketoconazole entails theoretical risks of interfering with the development of external genitalia in male fetuses. A pregnancy was diagnosed at 13 weeks of gestation in a 26-year-old woman with Cushing's disease under treatment with ketoconazole. The drug was withdrawn and the patient underwent transsphenoidal surgery at 16 weeks of pregnancy. She did not develop postsurgical adrenal insufficiency and was treated with metyrapone during the second and third trimesters of gestation. Partum was induced at 34 weeks of pregnancy. The patient delivered a healthy male infant with normal external genitalia. Treatment with ketoconazole during the critical period of organogenesis did not cause congenital birth defects to the male fetus of a woman with Cushing's disease. This report should be taken into account for future cases of unplanned pregnancies in women with Cushing's syndrome treated with ketoconazole, as well in those cases in which other therapeutic options are not feasible.

  5. Effects of ketoconazole treatment on the pharmacokinetics of safinamide and its plasma metabolites in healthy adult subjects.

    PubMed

    Krösser, Sonja; Marquet, Anne; Gallemann, Dieter; Wolna, Peter; Fauchoux, Nicolas; Hermann, Robert; Johne, Andreas

    2012-12-01

    The purpose of this mechanistic drug interaction study was to investigate the effects of ketoconazole on the pharmacokinetics of safinamide. Ketoconazole was applied as a potent prototypic inhibitor of cytochrome CYP3A4, to determine the role of CYP3A4 in the metabolic clearance of safinamide. In an open-label, randomized, two-period, two-sequence cross-over study, 14 healthy adult subjects (7 males/7 females) received two single doses of 100 mg safinamide: alone and on top of multiple doses of ketoconazole (200 mg b.i.d.) given over 6 days. Serial blood samples were collected over 240 h post dose to quantify safinamide parent drug and metabolite concentrations for pharmacokinetic evaluation. Safinamide exposure was essentially unchanged when administered with and without ketoconazole: C(max) and AUC(0-∞) point estimates (90% CIs) for the treatment comparison were 106.6 (101.0; 112.4) and 112.9 (109.8; 116.03), respectively. Similarly, ketoconazole did not influence the formation and clearance of safinamide metabolites to a clinically relevant extent. Overall, the study shows that CYP3A4 plays a minor role in the metabolism of safinamide in vivo. Therefore, safinamide can be administered together with potent CYP3A4 inhibitors without any requirement for dose adjustment. Copyright © 2012 John Wiley & Sons, Ltd.

  6. Flutrimazole shampoo 1% versus ketoconazole shampoo 2% in the treatment of pityriasis versicolor. A randomised double-blind comparative trial.

    PubMed

    Rigopoulos, D; Gregoriou, S; Kontochristopoulos, G; Ifantides, A; Katsambas, A

    2007-05-01

    Flutrimazole is an imidazole derivative that has been proven to be efficient in superficial skin fungal infections. The aim of this randomised double-blind study was to compare for the first time, the efficiency and safety of flutrimazole 1% shampoo versus ketoconazole 2% shampoo in the treatment of tinea versicolor. Study population consisted of 60 patients with pityriasis versicolor diagnosed clinically and through direct microscopy and culture. Patients were randomly assigned to two groups: one instructed to apply flutrimazole shampoo 1% and one instructed to apply ketoconazole shampoo 2% both on head and body for 14 days. Patients were re-evaluated 14 days after the end of treatment clinically and through direct microscopy and culture. Twenty-one of 26 patients (80.8%) in the ketoconazole and 22 of 29 patients (75.9%) in the flutrimazole group had both visual healing and negative mycological evaluation. Comparison of the response between the two groups with the Yates' corrected chi-square was found statistically not significant (chi(2) = 0.19, d.f. = 1, P = 0.91). None of the patients in the two groups reported any adverse effects. Fourteen (53%) patients in the ketoconazole group and 23 (79%) in the flutrimazole group assessed the shampoos as cosmetically acceptable regarding texture, smell and foam properties. Flutrimazole shampoo 1% appears to present efficacy comparable with ketoconazole 2% in the treatment of tinea versicolor.

  7. Herbal liposome for the topical delivery of ketoconazole for the effective treatment of seborrheic dermatitis

    NASA Astrophysics Data System (ADS)

    Dave, Vivek; Sharma, Swati; Yadav, Renu Bala; Agarwal, Udita

    2017-11-01

    The aim of the present study was to develop liposomal gel containing ketoconazole and neem extract for the treatment of seborrheic dermatitis in an effectual means. Azoles derivatives that are commonly used to prevent superficial fungal infections include triazole category like itraconazole. These drugs are available in the form of oral dosage that required a long period of time for treatment. Ketoconazole is available in the form of gel but is not used with any herbal extract. Neem ( Azadirachta indica) leaves show a good anti-bacterial and anti-fungal activity and have great potential as a bioactive compound. The thin film hydration method was used to design an herbal liposomal preparation. The formulation was further subjected to their characterization as particle size, zeta potential, entrapment efficiency, % cumulative drug release, and anti-fungal activity and it was also characterized by the mean of their physicochemical properties such as FTIR, SEM, DSC, TGA, and AFM. The results show that the formulation of liposomes with neem extract F12 were found to be optimum on the basis of entrapment efficiency in the range 88.9 ± 0.7%, with a desired mean particle size distribution of 141.6 nm and zeta potential - 45 mV. The anti-fungal activity of liposomal formulation F12 was carried out against Aspergillus niger and Candida tropicalis by measuring the inhibition zone 8.9 and 10.2 mm, respectively. Stability of optimized formulation was best seen at refrigerated condition. Overall, these results indicated that developed liposomal gel of ketoconazole with neem extract could have great potential for seborrheic dermatitis and showed synergetic effect for the treatment.

  8. Effects of cytochrome P450 3A modulators ketoconazole and carbamazepine on quetiapine pharmacokinetics

    PubMed Central

    Grimm, Scott W; Richtand, Neil M; Winter, Helen R; Stams, Karen R; Reele, Stots B

    2006-01-01

    Aims To explore the potential for drug interactions on quetiapine pharmacokinetics using in vitro and in vivo assessments. Methods The CYP enzymes responsible for quetiapine metabolite formation were assessed using recombinant expressed CYPs and CYP-selective inhibitors. P-glycoprotein (Pgp) transport was tested in MDCK cells expressing the human MDR1 gene. The effects of CYP3A4 inhibition were evaluated clinically in 12 healthy volunteers that received 25 mg quetiapine before and after 4 days of treatment with ketoconazole 200 mg daily. To assess CYP3A4 induction in vivo, 18 patients with psychiatric disorders were titrated to steady-state quetiapine levels (300 mg twice daily), then titrated to 600 mg daily carbamazepine for 2 weeks. Results CYP3A4 was found to be responsible for formation of quetiapine sulfoxide and N- and O-desalkylquetiapine and not a Pgp substrate. In the clinical studies, ketoconazole increased mean quetiapine plasma Cmax by 3.35-fold, from 45 to 150 ng ml−1 (mean Cmax ratio 90% CI 2.51, 4.47) and decreased its clearance (Cl/F) by 84%, from 138 to 22 l h−1 (mean ratio 90% CI 0.13, 0.20). Carbamazepine decreased quetiapine plasma Cmax by 80%, from 1042 to 205 ng ml−1 (mean Cmax ratio 90% CI 0.14, 0.28) and increased its clearance 7.5-fold, from 65 to 483 l h−1 (mean ratio 90% CI 6.04, 9.28). Conclusions Cytochrome P450 3A4 is a primary enzyme responsible for the metabolic clearance of quetiapine. Quetiapine pharmacokinetics were affected by concomitant administration of ketoconazole and carbamazepine, and therefore other drugs and ingested natural products that strongly modulate the activity or expression of CYP3A4 would be predicted to change exposure to quetiapine. PMID:16390352

  9. Efficacy of combined cyclosporine A and ketoconazole treatment of anal furunculosis.

    PubMed

    O'Neill, T; Edwards, G A; Holloway, S

    2004-05-01

    Cyclosporine A and ketoconazole were used as a combined therapy to treat 19 dogs with anal furunculosis. Complete resolution of all lesions was achieved in three to 10 weeks, but recurrences occurred in seven of the 19 dogs (36.8 per cent), with remission periods extending from one to six months for these dogs. Adverse effects of treatment included excessive hair loss, intermittent lethargy, vomiting and decreased appetite in some dogs, but none of the signs were considered serious. The results of treatment are comparable with, if not better than, the surgical alternatives. There is an approximate 70 per cent cost saving over the use of cyclosporine alone.

  10. Preparation, characterization, and scale-up of ketoconazole with enhanced dissolution and bioavailability.

    PubMed

    Elder, Edmund J; Evans, Jonathan C; Scherzer, Brian D; Hitt, James E; Kupperblatt, Gary B; Saghir, Shakil A; Markham, Dan A

    2007-07-01

    Many new molecular entities targeted for pharmaceutical applications face serious development challenges because of poor water solubility. Although particle engineering technologies such as controlled precipitation have been shown to enhance aqueous dissolution and bioavailability of poorly water soluble active pharmaceutical ingredients, the data available are the results of laboratory-scale experiments. These technologies must be evaluated at larger scale to ensure that the property enhancement is scalable and that the modified drugs can be processed on conventional equipment. In experiments using ketoconazole as the model drug, the controlled precipitation process was shown to produce kg-scale modified drug powder with enhanced dissolution comparable to that of lab-scale powder. Ketoconazole was demonstrated to be stable throughout the controlled precipitation process, with a residual methanol level below the ICH limit. The modified crystalline powder can be formulated, and then compressed using conventional high-speed tableting equipment, and the resulting tablets showed bioavailability more than double that of commercial tablets. When appropriately protected from moisture, both the modified powder and tablets prepared from the modified powder showed no change in dissolution performance for at least 6 months following storage at accelerated conditions and for at least 18 months following storage at room temperature.

  11. Laboratory and clinical assessment of ketoconazole in deep-seated mycoses.

    PubMed

    Drouhet, E; Dupont, B

    1983-01-24

    Forty-eight cases of deep mycoses were studied and treated with ketoconazole, each with in vitro evaluation of the minimum inhibitory concentrations (MIC) of the causative fungi, in vivo pharmacokinetic, clinical, and mycologic evaluations, several months to two years after the treatment was stopped. Excellent results were obtained in six cases of chronic mucocutaneous candidiasis, with restoration of immunologic disturbances; 23 cases of systemic candidiasis, including new aspects of heroin addicts with cutaneous, ocular, or osteoarticular manifestations; eight cases of histoplasmosis, five due to Histoplasma capsulatum and three to Histoplasma duboisii, with cure in seven and remission in one; one case of African blastomycosis (Blastomyces dermatitidis); three cases of mycetoma, two due to Monosporium apiospermum, one due to a dematiacious fungus; three cases of entomophthoromycosis with cure; one case of fungal arthritis, due to new hyphomycete similar to M. apiospermum, pathogenic for laboratory animals; one case of Drechslera longirostrata causing vertebral arthritis, following a fungal endocarditis and cured by combination of ketoconazole with amphotericin B, each agent alone being ineffective; and other deep mycoses.

  12. DISRUPTION OF THE SACCHAROMYCES CEREVISIAE GENE FOR NADPH-CYTOCHROME P450-REDUCTASE CAUSES INCREASED SENSITIVITY TO KETOCONAZOLE

    EPA Science Inventory

    Strains of Saccharomyces cerevisiae deleted in the NADPH-cytochrome P450 reductase gene by transplacement are 200-fold more sensitive to ketoconazole, an inhibitor of the cytochrome P450 lanosterol 14-demethylase. Resistance is restored through complementation by the plasmid-born...

  13. Ketoconazole and the modulation of multidrug resistance-mediated transport in Caco-2 and MDCKII-MDR1 drug transport models.

    PubMed

    Fan, Y; Rodriguez-Proteau, R

    2008-02-01

    The hypothesis tested was that ketoconazole can modulate P-glycoprotein, thereby altering cellular uptake and apparent permeability (P(app)) of multidrug-resistant substrates, such as cyclosporin A (CSA) and digoxin, across Caco-2, MDCKII-MDR1, and MDCKII wild-type cell transport models. (3)H-CSA/(3)H-digoxin transport experiments were performed with and without co-exposure to ketoconazole, and (3)H-ketoconzole transport experiments were performed with and without co-exposure to dietary flavonoids, epigallocatechin-3-gallate, and xanthohumol. Ketoconazole (3 microM) reduced the P(app) efflux of CSA and digoxin from 5.07 x 10(-6) to 2.91 x 10(-6) cm s(-1) and from 2.60 x 10(-6) to 1.41 x 10(-6) cm s(-1), respectively, in Caco-2 cells. In the MDCKII-MDR1 cells, ketoconazole reduced the P(app) efflux of CSA and increased the P(app) absorption of digoxin. Cellular uptake of ketoconazole in the Caco-2 cells was significantly inhibited by CSA and digoxin, whereas epigallocatechin-3-gallate and xanthohumol exhibited biphasic responses. In conclusion, ketoconazole modulates the P(app) of P-glycoprotein substrates by interacting with MDR1 protein. Epigallocatechin-3-gallate and xanthohumol modulate the transport and uptake of ketoconazole.

  14. Determination of minimum inhibitory concentrations of itraconazole, terbinafine and ketoconazole against dermatophyte species by broth microdilution method.

    PubMed

    Bhatia, V K; Sharma, P C

    2015-01-01

    Various antifungal agents both topical and systemic have been introduced into clinical practice for effectively treating dermatophytic conditions. Dermatophytosis is the infection of keratinised tissues caused by fungal species of genera Trichophyton, Epidermophyton and Microsporum, commonly known as dermatophytes affecting 20-25% of the world's population. The present study aims at determining the susceptibility patterns of dermatophyte species recovered from superficial mycoses of human patients in Himachal Pradesh to antifungal agents; itraconazole, terbinafine and ketoconazole. The study also aims at determining the minimum inhibitory concentrations (MICs) of these agents following the recommended protocol of Clinical and Laboratory Standards Institute (CLSI) (M38-A2). A total of 53 isolates of dermatophytes (T. mentagrophyte-34 in no., T. rubrum-18 and M. gypseum-1) recovered from the superficial mycoses were examined. Broth microdilution method M38-A2 approved protocol of CLSI (2008) for filamentous fungi was followed for determining the susceptibility of dermatophyte species. T. mentagrophyte isolates were found more susceptible to both itraconazole and ketoconazole as compared to terbinafine (MIC50: 0.125 µg/ml for itraconazole, 0.0625 µg/ml for ketoconazole and 0.5 µg/ml for terbinafine). Three isolates of T. mentagrophytes (VBS-5, VBSo-3 and VBSo-73) and one isolate of T. rubrum (VBPo-9) had higher MIC values of itraconazole (1 µg/ml). Similarly, the higher MIC values of ketoconazole were observed in case of only three isolates of T. mentagrophyte (VBSo-30 = 2 µg/ml; VBSo-44, VBM-2 = 1 µg/ml). The comparative analysis of the three antifungal drugs based on t-test revealed that 'itraconazole and terbinafine' and 'terbinafine and ketoconazole' were found independent based on the P < 0.005 in case of T. mentagrophyte isolates. In case of T. rubrum, the similarity existed between MIC values of 'itraconazole and ketoconazole' and 'terbinafine and

  15. Pharmacokinetic interaction between domperidone and ketoconazole leads to QT prolongation in healthy volunteers: a randomized, placebo-controlled, double-blind, crossover study

    PubMed Central

    Boyce, Malcolm J; Baisley, Kathy J; Warrington, Steven J

    2012-01-01

    AIMS To assess the steady-state pharmacokinetic and QTc effects of domperidone and ketoconazole, given alone and together. METHODS A randomized, placebo-controlled, double-blind, crossover study was carried out. Healthy subjects (14 men, 10 women; age 18–39 years; mean weight 73.5 kg, range 53.8–98.8 kg; 23 Europid, 1 Afro-Caribbean) received orally, for 7 days each, placebo, domperidone 10 mg, four doses daily, at 4 h intervals, ketoconazole 200 mg 12-hourly and domperidone and ketoconazole together. The washout period was 15 days. Pharmacokinetics and serial 12-lead ECGs were assessed on day 7, and serial ECGs on day −1 and at follow-up. Two subjects withdrew before the third treatment period, so data were available for 22–24 subjects. RESULTS Ketoconazole tripled domperidone concentrations at steady-state. Domperidone, ketoconazole and their combination significantly increased QTcF in men. Overall adjusted mean differences from placebo were 4.20 (95% CI 0.77, 7.63), 9.24 (95% CI 5.85, 12.63) and 15.90 (95% CI 12.47, 19.33) ms, respectively. In women, QTcF was not significantly different from placebo on either domperidone or ketoconazole alone, or in combination. However, QTc was positively correlated with plasma drug concentrations, in both men and women. ΔQTcF increased by about 2 ms per 10 ng ml–1 rise in domperidone concentration, and per 1 µg ml–1 rise in ketoconazole concentration. CONCLUSIONS Ketoconazole tripled the plasma concentrations of domperidone. Domperidone and ketoconazole increased QTcF in men, whether given together or separately. The effect of domperidone alone was below the level of clinical importance. The negative result in women is unexplained. PMID:21883386

  16. Pharmacokinetics of ketoconazole administered intravenously to dogs and orally as tablet and solution to humans and dogs.

    PubMed

    Baxter, J G; Brass, C; Schentag, J J; Slaughter, R L

    1986-05-01

    The single-dose pharmacokinetics and bioavailability of three ketoconazole formulations were evaluated using HPLC in five healthy human volunteers and six male mongrel dogs. The human volunteers received 400 mg po of ketoconazole as tablet (Ktab) and solution (Ksol) formulations. The dogs received 400 mg po of Ktab and Ksol, and 376 mg iv of an intravenous dose (Kiv). In humans the AUC value for Ksol (62.21 +/- 21.2 microgram X h/ml; mean +/- SD) was significantly greater than for Ktab (50.0 +/- 15.2 micrograms X h/ml; p less than 0.05). Peak serum concentrations (Cmax), time to peak serum concentrations (tmax), t1/2, and the terminal elimination rate constant (kel) did not differ between Ktab and Ksol. This suggests that the administration of Ksol may be a useful alternative to dosage increases in situations where low bioavailability of ketoconazole in tablet form is suspected. The mean systemic clearance (CLs) of Kiv in dogs was 2.74 +/- 1.10 mL/min/kg, the volume of distribution at steady state (Vdss) was 0.72 +/- 0.28 L/kg, and the half-life was 2.7 +/- 1.6 h. Considerable variability was seen in the AUC of ketoconazole, particularly with the oral preparations. The absolute bioavailability of Ktab was 0.50 +/- 0.38, which did not differ statistically from that of Ksol, 0.56 +/- 0.23. The Ksol showed less variability in AUC, Cmax, and F values than did Ktab, and two dogs with low bioavailability with Ktab (0.04 and 0.07) had substantially greater bioavailability with Ksol (F = 0.96 and 0.57, respectively). Evaluation of Kiv in dogs confirms decreased bioavailability from orally administered tablet formulations of ketoconazole.

  17. Ketoconazole Topical

    MedlinePlus

    ... infection of the skin that causes brown or light colored spots on the chest, back, arms, legs, ... not in the bathroom). Protect the medication from light and do not allow it to freeze.Unneeded ...

  18. Temporary remission of disseminated paecilomycosis in a German shepherd dog treated with ketoconazole.

    PubMed

    Booth, M J; van der Lugt, J J; van Heerden, A; Picard, J A

    2001-06-01

    Disseminated mycosis caused by Paecilomyces varioti in a female German shepherd dog presented with chronic forelimb lameness is described. Radiographs of the swollen carpal joint revealed geographic lysis of the radial epiphysis. Diagnosis was based on cytological demonstration of fungal hyphae and chlamydiospores, as well as fungal culture of fluid obtained by arthrocentesis. Temporary remission was characterised by markedly improved clinical signs and laboratory parameters, following treatment with ketoconazole. The dog was euthanased 9 months after the initial diagnosis, following the diagnosis of multifocal discospondylitis. This appears to be the longest described period of temporary remission obtained with treatment in dogs with paecilomycosis. Clinical, clinicopathological and necropsy findings of this disease in another German shepherd dog are briefly described.

  19. Presumptive Nocardia spp. infection in a dog treated with cyclosporin and ketoconazole.

    PubMed

    Paul, A E H; Mansfield, C S; Thompson, M

    2010-10-01

    A dog that had received 8 months of cyclosporin and ketoconazole therapy for treatment of atopic dermatitis subsequently developed severe neurological disease, that failed to respond to treatment with trimethoprim-sulphadiazine and clindamycin. HISTOPATHOLOGICAL FINDINGS: Histopathological examination of the pulmonary parenchyma and spinal cord revealed loose aggregates of Gram-positive, partially acid-fast, fine, beaded, filamentous bacteria, most consistent with Nocardia spp. A presumptive diagnosis was made of disseminated nocardiosis of the spinal cord and lungs. Nocardia spp. is an opportunistic actinomycete that may cause disseminated disease, particularly in immunocompromised animals. Cyclosporin is used in veterinary medicine to control immune-mediated and allergic disorders, with few reported adverse side effects. This case gives further evidence that involvement of the spinal cord in nocardiosis of the central nervous system (CNS) carries a poor prognosis, and opportunistic infection by Nocardia spp. may be a potential complication of immunosuppressive cyclosporin therapy in the dog.

  20. Hepatic safety of ketoconazole in Cushing's syndrome: results of a Compassionate Use Programme in France.

    PubMed

    Young, Jacques; Bertherat, Jérôme; Vantyghem, Marie Christine; Chabre, Olivier; Senoussi, Salima; Chadarevian, Rita; Castinetti, Frédéric

    2018-05-01

    Ketoconazole (KTZ) is one of few available treatments for Cushing's syndrome (CS). Although KTZ has been associated with severe hepatotoxicity, little information is available about hepatic safety in CS. The aim of this study was to document changes in liver function in patients with CS treated with KTZ. An observational prospective French cohort study (Compassionate Use Programme (CUP)). Enrolled patients were stratified into a KTZ-naive cohort and a cohort already treated by another formulation of ketoconazole (KTZ-switch cohort). Liver function markers (alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase, γ-glutamyltransferase and bilirubin) were monitored at regular intervals. Patients with ALT > 3 × ULN (upper limit of normal), total bilirubin > 2 × ULN or both ALP > 2 × ULN and ALT > ULN were considered to have liver injury. Overall, 108 patients were analysed (47 KTZ-naïve; 61 KTZ-switch). The median KTZ dose was 600 mg/day. Most abnormalities observed were asymptomatic mild increases of liver enzymes. Four patients in the KTZ-naïve cohort (8.5%) and two in the KTZ-switch cohort (3.3%) developed liver injury, considered related to KTZ in three cases (all KTZ-naïve in the first month of treatment). Five patients had mild liver function abnormalities at baseline and two had proven liver metastases. Two patients recovered on discontinuation of KTZ and the remaining patient died of unrelated causes. These findings highlight the need for close monitoring of liver enzymes especially during the first six months of treatment. Liver enzyme abnormalities usually occurred within four weeks were asymptomatic and could be reversed on timely discontinuation of KTZ. © 2018 European Society of Endocrinology.

  1. A time-course analysis of effects of the steroidogenesis inhibitor ketoconazole on components of the hypothalamic-pituitary-gonadal axis of fathead minnows (Presentation)

    EPA Science Inventory

    The objective of this study was to evaluate temporal effects of the model steroidogenesis inhibitor ketoconazole (KTC) on aspects of reproductive endocrine function controlled by the hypothalamic-pituitary-gonadal (HPG) axis in the fathead minnow (Pimephales promelas). Ketoconazo...

  2. A Time-course Analysis of Effects of the Steroidogenesis Inhibitor Ketoconazole on Components of the Hypothalamic-pituitary-gonadal Axis of Fathead Minnows

    EPA Science Inventory

    The objective of this study was to evaluate temporal effects of the model steroidogenesis inhibitor ketoconazole (KTC) on aspects of reproductive endocrine function controlled by the hypothalamic-pituitary-gonadal (HPG) axis in the fathead minnow (Pimephales promelas). Ketoconazo...

  3. A Time-course Analysis of Effects of the Steroidogenesis Inhibitor Ketoconazole on Components of the Hypothalamic-pituitary-gonadal Axis of Fathead Minnows

    EPA Science Inventory

    The objective of this study was to evaluate temporal effects of the model steroidogenesis inhibitor ketoconazole (KTC) on aspects of reproductive endocrine function controlled by the hypothalamic-pituitary-gonadal (HPG) axis in the fathead minnow (Pimephales promelas). Ketoconaz...

  4. Comparative study of ketoconazole 2% foaming gel and betamethasone dipropionate 0.05% lotion in the treatment of seborrhoeic dermatitis in adults.

    PubMed

    Ortonne, J P; Lacour, J P; Vitetta, A; Le Fichoux, Y

    1992-01-01

    Sixty-two patients with seborrhoeic dermatitis were treated topically with a 2% ketoconazole foaming gel or with a 0.05% betamethasone dipropionate lotion in a single-blind study for 4 months. Changes in the number of Pityrosporum ovale were scored by a mycologist. The investigator rated the severity of erythema, scaling and itching of the patients' scalp, eyelashes, nasolabial folds and thorax. In addition, both the investigator and the patients evaluated the treatments globally. At the end of treatment, the response rate for ketoconazole 2% foaming gel was significantly higher than that for betamethasone dipropionate 0.05% lotion according to the global evaluation by the physician (89 vs. 62%, p less than 0.05) and the patient (89 vs. 65%, p less than 0.05). Ketoconazole was also superior to betamethasone with reference to the evolution of the symptoms, irrespective of their localization. This efficacy manifested itself by a significant reduction of the number of P. ovale on the scalp in the ketoconazole group (p less than 0.001) compared to the betamethasone group, in which the count was hardly changed during therapy. The treatment was also better tolerated in the ketoconazole group (5 vs. 16 patients with side-effects, p less than 0.001). It is concluded that ketoconazole 2% foaming gel offers an excellent alternative to local corticosteroids in the treatment of seborrhoeic dermatitis.

  5. Clinical efficacies of shampoos containing ciclopirox olamine (1.5%) and ketoconazole (2.0%) in the treatment of seborrhoeic dermatitis.

    PubMed

    Ratnavel, Ravi C; Squire, Ruth A; Boorman, Graham C

    2007-01-01

    Ciclopirox olamine (CPO) is a broad-spectrum antifungal with anti-inflammatory properties effective against the yeast implicated in seborrhoeic dermatitis, Malassezia spp. This study compared 1.5% CPO shampoo with 2.0% ketoconazole shampoo and placebo in scalp seborrhoeic dermatitis. A randomized, double-blind, 4-week treatment period was preceded by a 2-week run-in period and followed by a 2-week run-out period. A total of 350 patients (150 CPO, 150 ketoconazole, 50 placebo) were enrolled. Assessments included scalp area affected, the severity of scaling, erythema, itching and scaling, and overall signs and symptoms. Both shampoos were significantly more effective than placebo in reducing the area affected. The mean reduction from baseline to end of treatment was 48.2 cm(2) with CPO, 41.4 cm(2) with ketoconazole and 20.0 cm(2) with placebo. Patients rated the CPO shampoo as superior to placebo (p<0.001) and ketoconazole shampoo (p<0.05) on the basis of overall signs and symptoms. Assessments of itching and scaling were also significantly in favour of the CPO shampoo over placebo at the end of treatment. All three shampoos were well tolerated. CPO shampoo was superior to placebo and at least as effective as ketoconazole shampoo in treating scalp seborrhoeic dermatitis. Patients rated the overall improvement as better with CPO than with ketoconazole shampoo.

  6. A randomized, double-blind, placebo-controlled trial of ketoconazole 2% shampoo versus selenium sulfide 2.5% shampoo in the treatment of moderate to severe dandruff.

    PubMed

    Danby, F W; Maddin, W S; Margesson, L J; Rosenthal, D

    1993-12-01

    Ketoconazole is highly effective against the yeast Pityrosporum ovale, an organism believed to be involved in the pathogenesis of dandruff. Our purpose was to evaluate the safety and effectiveness of ketoconazole 2% shampoo versus selenium sulfide 2.5% shampoo and placebo shampoo in patients with moderate to severe dandruff. Features assessed included adherent and loose dandruff scores, presence or absence of irritation, itching, yeast cells, and global improvement rating by the investigator. A total of 246 patients were included. Mean total adherent dandruff score declined throughout the treatment period with both ketoconazole 2% and selenium sulfide 2.5% shampoos significantly better than placebo at all visits. Ketoconazole was statistically superior to selenium sulfide at day 8 only (p = 0.0026). Both medicated shampoos were significantly better than placebo for reducing irritation and itching. Of the nine adverse experiences reported during the treatment phase, all involved patients treated with selenium sulfide 2.5% shampoo. Both ketoconazole 2% shampoo and selenium sulfide 2.5% shampoo are effective in the treatment of moderate to severe dandruff; however, ketoconazole 2% shampoo appears to be better tolerated.

  7. Physiochemical Characterization and Release Rate Studies of SolidDispersions of Ketoconazole with Pluronic F127 and PVP K-30

    PubMed Central

    Kumar, Pankaj; Mohan, Chander; KanamSrinivasan Uma Shankar, Mara; Gulati, Monica

    2011-01-01

    In the present study solid dispersions of the antifungal drug Ketoconazole were prepared with Pluronic F-127 and PVP K-30 with an intention to improve its dissolution properties. Investigations of the properties of the dispersions were performed using release studies, Differential scanning calorimetery (DSC), X-ray powder diffraction (XRD) and Fourier transform infrared (FTIR). The results obtained showed that the rate of dissolution of Ketoconazole was considerably improved when formulated in solid dispersions with PVP K-30 and Pluronic F-127 as compared with pure drug and physical mixtures. The results from DSC and XRD studies showed the transition of crystalline nature of drug to amorphous form, while FTIR studies demonstrated the absence of drug-carriers interaction. PMID:24250403

  8. Temporal decline in filling prescriptions for terfenadine closely in time with those for either ketoconazole or erythromycin.

    PubMed

    Burkhart, G A; Sevka, M J; Temple, R; Honig, P K

    1997-01-01

    Temporal changes in the rates of filling terfenadine prescriptions within 2 days of those for either oral erythromycin or oral ketoconazole were described with use of paid pharmacy claims data from 1988 through 1994 in state Medicaid programs from Michigan and Ohio and in a large health maintenance organization. There were rapid and significant declines in the rates of filling prescriptions for either erythromycin or ketoconazole within 2 days of prescriptions for terfenadine in all three databases that coincided with 1992 publicity about the cardiovascular risk of terfenadine. These findings suggest that the use of terfenadine with contraindicated medications has declined in response to relabeling and publicity concerning the safe use of terfenadine. Further study is necessary to estimate the absolute level of concurrent use of terfenadine with contraindicated medications.

  9. Immunohistochemistry of LAMP-2 and adipophilin for phospholipidosis in liver and kidney in ketoconazole-treated mice.

    PubMed

    Asaoka, Yoshiji; Togashi, Yuko; Imura, Naoko; Sai, Takafumi; Miyoshi, Tomoya; Miyamoto, Yohei

    2013-09-01

    Drug-induced phospholipidosis is an abnormal accumulation of phospholipids in the lysosomes following repeated administration of cationic amphiphilic drugs. Phospholipidosis is detected histopathologically as cytoplasmic vacuolation; however, it is difficult to distinguish from lipid accumulation since their morphological features are similar. In this study, we investigated the usefulness of immunohistochemistry for lysosome-associated membrane protein-2 (LAMP-2) and adipophilin, a membrane protein of cytosolic non-lysosomal lipid droplets, in the liver and kidneys of mice orally administered ketoconazole, an inducer of hepatic phospholipidosis. In 7-week-old mice administered ketoconazole (300 mg/kg/day) for 7 days, cytoplasmic vacuolation was histopathologically observed in centrilobular hepatocytes and proximal tubular epithelial cells under the fasted condition. The cytoplasmic vacuolation consisted of foamy vacuoles, which were revealed to be phospholipidosis-characteristic lamellar bodies by electron microscopy. Furthermore, lipid-like vacuoles were observed in the perilobular hepatocytes, and revealed to be lipid droplets by electron microscopy. In immunohistochemistry, the foamy vacuoles and lipid-like vacuoles were positive for LAMP-2 and adipophilin, respectively. These results indicate that immunohistochemistry for LAMP-2 and adipophilin could distinguish between phospholipidosis and lipid accumulation. Additionally, it could detect ketoconazole-induced phospholipidosis in the glycogen-rich livers of non-fasted mice. In conclusion, ketoconazole induced phospholipidosis in not only the liver but also the kidneys, and immunohistochemistry for LAMP-2 and adipophilin could be useful for the pathological evaluation of drug-induced phospholipidosis in mice. Crown Copyright © 2012. Published by Elsevier GmbH. All rights reserved.

  10. Comparative efficacies of oral ketoconazole and terbinafine for reducing Malassezia population sizes on the skin of Basset Hounds.

    PubMed

    Guillot, Jacques; Bensignor, Emmanuel; Jankowski, François; Seewald, Wolfgang; Chermette, René; Steffan, Jean

    2003-06-01

    The objective of this study was to compare the efficacy of oral ketoconazole and terbinafine for reducing population sizes of Malassezia yeasts on canine skin. Twenty-one Basset Hounds were randomised in three groups of seven according to Malassezia populations. Dogs in the first group were treated by oral administration of ketoconazole (Ketofungol) 200 mg, Janssen-Cilag) at 10 mg x kg-1, every 24 h with food, for 3 weeks. Dogs in the second group were treated by oral administration of terbinafine (Lamisil) 250 mg, Novartis) at 30 mg x kg-1, every 24 h with food, for 3 weeks. The seven remaining dogs were used as controls. Malassezia population sizes were assessed by use of contact plates on four cutaneous sites at days 7, 14 and 21. Both ketoconazole and terbinafine were effective in reducing the baseline levels of Malassezia organisms with no significant difference between the two drugs. In further studies, oral terbinafine should be evaluated for the management of canine cases of Malassezia dermatitis.

  11. [Mixed vaginitis prevalence in Latin-American women, according to physician perception. Preference, effectiveness and security of clindamycin plus ketoconazole].

    PubMed

    Hernández Bueno, José Alberto; Vázquez Alanís, Alejandro; Olguín Ramírez, Claudia; Dumet Hinostroza, Pablo F; Gutiérrez Ramos, Miguel; De Zordo, Daniel

    2008-11-01

    Vaginitis is an inflammatory process in vaginal mucosa that affects millions of woman worldwide. To evaluate prevalence perception and prescription preference among Latin-American gyneco-obstetricians in mixed vaginitis, and to identify attributes of various active principles. multicentric and transversal study during January 2008. Close Up was used to poll gyneco-obstetricians prescribing clyndamicin plus ketoconazole. 1,198 gyneco-obstetricians were selected to answer a poll (scales and measuring attributes) to identify differences among various therapeutic schemes to mixed vaginitis. 34% of gyneco-obstetricians consider that 30 to 50% of them patients had mixed vaginitis, 38% consider a 50 to 70% of its prevalence, and 20% a 70% or higher figure. In a bad to excellent scale, 97% had very good to excellent results with antimycotic and antibacterial mix, 73% had a bad to good result with antimycotics alone and 79% with antibacterial alone. Clyndamicin plus ketoconazole had a meaningful difference from mean results (standard), and from the second best mix (metronidazole plus nystatin), with a rapid itch healing, efficacy, and relapse decrease. Metronidazole plus nystatin had the highest score in tolerance and treatment period. 90% of polled Latin-American obstetricians prescribe clyndamicin plus ketoconazole as the best available treatment to mixed vaginitis.

  12. Allosteric activation of midazolam CYP3A5 hydroxylase activity by icotinib - Enhancement by ketoconazole.

    PubMed

    Zhuang, XiaoMei; Zhang, TianHong; Yue, SiJia; Wang, Juan; Luo, Huan; Zhang, YunXia; Li, Zheng; Che, JinJing; Yang, HaiYing; Li, Hua; Zhu, MingShe; Lu, Chuang

    2016-12-01

    Icotinib (ICO), a novel small molecule and a tyrosine kinase inhibitor, was developed and approved recently in China for non-small cell lung cancer. During screening for CYP inhibition potential in human liver microsomes (HLM), heterotropic activation toward CYP3A5 was revealed. Activation by icotinib was observed with CYP3A-mediated midazolam hydroxylase activity in HLM (∼40% over the baseline) or recombinant human CYP3A5 (rhCYP3A5) (∼70% over the baseline), but not in the other major CYPs including rhCYP3A4. When co-incubated with selective CYP3A4 inhibitor CYP3cide or monoclonal human CYP3A4 inhibitory antibody in HLM, the activation was extended to ∼60%, suggesting CYP3A5 might be the isozyme involved. Further, the relative activation was enhanced to ∼270% in rhCYP3A5 in the presence of ketoconazole. The activation was substrate and pathway dependent and observed only in the formation of 1'-OH-midazolam, and not 4-OH-midazolam, 6β-OH-testosterone, or oxidized nifedipine. The activation requires the presence of cytochrome b5 and it is only observed in the liver microsomes of dogs, monkeys, and humans, but not in rats and mice. Kinetic analyses of 1'-OH-midazolam formation showed that ICO increased the V max values in HLM and rhCYP3A5 with no significant changes in K m values. By adding CYP3cide with ICO to the incubation, the V max values increased 2-fold over the CYP3cide control. Addition of ketoconazole with ICO alone or ICO plus CYP3cide resulted in an increase in V max values and decrease in K m values compared to their controls. This phenomenon may be attributed to a new mechanism of CYP3A5 heterotropic activation, which warrants further investigation. Copyright © 2016 Elsevier Inc. All rights reserved.

  13. Inhibitors of alprazolam metabolism in vitro: effect of serotonin-reuptake-inhibitor antidepressants, ketoconazole and quinidine.

    PubMed Central

    von Moltke, L L; Greenblatt, D J; Cotreau-Bibbo, M M; Harmatz, J S; Shader, R I

    1994-01-01

    1. The biotransformation of the triazolobenzodiazepine alprazolam (ALP) to its hydroxylated metabolites (4-OH-ALP and alpha-OH-ALP) was evaluated in human, monkey, rat, and mouse liver microsomes. 2. In all species 4-OH-ALP was the principal metabolite, accounting for 84% of clearance in human microsomes compared with 16% for alpha-OH-ALP. 3. Among the serotonin-specific reuptake inhibitors fluoxetine (FLU) and sertraline (SERT), and their respective demethylated metabolites norfluoxetine (NOR) and desmethylsertraline (DES), NOR was the most potent inhibitor (mean Ki for 4-OH-ALP formation in humans: 11 microM), FLU the weakest (Ki = 83 microM), with SERT and DES falling in between (Ki = 24 and 20 microM). 4. The in vitro data predict 29% inhibition of ALP clearance at mean FLU and NOR plasma concentrations of 77 ng ml-1 and 72 ng ml-1, respectively, after correction for liver:water partition ratios in the range of 12-14. The observed mean degree of inhibition in a previous in vivo study was 21%. 5. Ketoconazole was a potent inhibitor of ALP metabolism in vitro (Ki = 0.046 microM), suggesting that ALP hydroxylation is mediated by the cytochrome P450-3A sub-family. Quinidine was a weak inhibitor (Ki = 626 microM). PMID:7946933

  14. Effect of oral ketoconazole on first-pass effect of nifedipine after oral administration in dogs.

    PubMed

    Kuroha, Masanori; Kayaba, Hideki; Kishimoto, Shizuka; Khalil, Waleed F; Shimoda, Minoru; Kokue, Eiichi

    2002-03-01

    The long-term oral ketoconazole (KTZ) treatment extensively inhibits hepatic CYP3A activity. We investigated the effect of the KTZ treatment on hepatic and intestinal extraction of nifedipine (NIF) using beagle dogs. Four dogs were given orally KTZ for 20 days (200 mg, bid). NIF was administered either intravenously (0.5 mg/kg) or orally (20 mg) 10 and 20 days before the KTZ treatment and 10 and 20 days after start of KTZ treatment. CLtot of NIF after intravenous administration decreased to about 50% during the KTZ treatment. C(max) and AUC after oral administration increased to 2.5-fold and fourfold, respectively, by the KTZ treatment. The hepatic extraction ratio of NIF decreased to about a half by KTZ. A significant decrease in intestinal extraction ratio was not observed. In conclusion, the KTZ treatment inhibits hepatic extraction more profoundly than intestinal extraction of NIF. Therefore, inhibition of hepatic extraction of NIF by the KTZ treatment mainly results in substantial increase in systemic bioavailability in dogs. Because KTZ inhibits human CYP3A activities similar to canine CYP3A activities, the long-term oral KTZ treatment may dramatically increase bioavailability of NIF or other CYP3A substrates in humans. Copyright 2002 Wiley-Liss, Inc. and the American Pharmaceutical Association.

  15. Ketoconazole-induced testicular damage in rats reduced by Gentiana extract.

    PubMed

    Amin, Amr

    2008-04-01

    Ketoconazole (KET) is an antifungal drug with a broad spectrum of activity that also induces reproductive toxicity in humans and animals. The protective effect of Gentiana (GEN) extract (Gentiana lutea) against KET-induced testicular damage was evaluated in male Wistar rats. GEN extract was administered orally (1g/kgbwt/day) for 26 days. Three weeks after extract administration, KET was co-administered intraperitoneally at a dose of 100mg/kg once a day for 5 days. KET-induced reproductive toxicity was associated with clear reductions of the weights of testes and epididymides, sperm indices and serum testosterone levels. KET also induced severe testicular histopathological lesions such as degeneration of the seminiferous tubules and depletion of germ cells. In addition, marked oxidative damage to testicular lipids and alterations of natural antioxidants (catalase (CAT) and superoxide dismutase (SOD)) were reported in association with KET toxicity. Most of the KET-induced effects were greatly decreased with the concomitant application of GEN extract. This study suggests a protective role of GEN extract that could be attributed to its antioxidant properties.

  16. Interaction Between Domperidone and Ketoconazole: Toward Prediction of Consequent QTc Prolongation Using Purely In Vitro Information

    PubMed Central

    Mishra, H; Polak, S; Jamei, M; Rostami-Hodjegan, A

    2014-01-01

    We aimed to investigate the application of combined mechanistic pharmacokinetic (PK) and pharmacodynamic (PD) modeling and simulation in predicting the domperidone (DOM) triggered pseudo-electrocardiogram modification in the presence of a CYP3A inhibitor, ketoconazole (KETO), using in vitro–in vivo extrapolation. In vitro metabolic and inhibitory data were incorporated into physiologically based pharmacokinetic (PBPK) models within Simcyp to simulate time course of plasma DOM and KETO concentrations when administered alone or in combination with KETO (DOM+KETO). Simulated DOM concentrations in plasma were used to predict changes in gender-specific QTcF (Fridericia correction) intervals within the Cardiac Safety Simulator platform taking into consideration DOM, KETO, and DOM+KETO triggered inhibition of multiple ionic currents in population. Combination of in vitro–in vivo extrapolation, PBPK, and systems pharmacology of electric currents in the heart was able to predict the direction and magnitude of PK and PD changes under coadministration of the two drugs although some disparities were detected. PMID:25116274

  17. Optimization and validation of a high-performance liquid chromatographic method with UV detection for the determination of ketoconazole in canine plasma.

    PubMed

    Vertzoni, M V; Reppas, C; Archontaki, H A

    2006-07-24

    An isocratic high-performance liquid chromatographic method with detection at 240 nm was developed, optimized and validated for the determination of ketoconazole in canine plasma. 9-Acetylanthracene was used as internal standard. A Hypersil BDS RP-C18 column (250 mm x 4.6 mm, 5 microm particle size), was equilibrated with a mobile phase composed of methanol, water and diethylamine 74:26:0.1 (v/v/v). Its flow rate was 1 ml/min. The elution time for ketoconazole and 9-acetylanthracene was approximately 9 and 8 min, respectively. Calibration curves of ketoconazole in plasma were linear in the concentration range of 0.015-10 microg/ml. Limits of detection and quantification in plasma were 5 and 15 ng/ml, respectively. Recovery was greater than 95%. Intra- and inter-day relative standard deviation for ketoconazole in plasma was less than 3.1 and 4.7%, respectively. This method was applied to the determination of ketoconazole plasma levels after administration of a commercially available tablet to dogs.

  18. Pharmacokinetic Evaluation of the Interactions of Amenamevir (ASP2151) with Ketoconazole, Rifampicin, Midazolam, and Warfarin in Healthy Adults.

    PubMed

    Kusawake, Tomohiro; den Adel, Martin; Groenendaal-van de Meent, Dorien; Garcia-Hernandez, Alberto; Takada, Akitsugu; Kato, Kota; Ohtsu, Yoshiaki; Katashima, Masataka

    2017-11-01

    Amenamevir is a nonnucleoside antiherpes virus compound available for treating herpes zoster infections. Four studies aimed to determine any potential interactions between amenamevir and ketoconazole, rifampicin, midazolam, or warfarin in healthy male participants. Two studies were open-label studies that evaluated the effects of multiple doses of ketoconazole (400 mg) and rifampicin (600 mg) on the pharmacokinetics of a single oral dose of amenamevir. The other two studies were randomized, double-blind, parallel-group studies that evaluated the effects of multiple doses of amenamevir on the pharmacokinetics of a single dose of midazolam (7.5 mg) and warfarin (25 mg). A drug interaction was considered to occur if the 90% confidence interval (CI) of the least squares geometric mean ratio (GMR) of amenamevir to the comparator was outside the prespecified interval of 0.80-1.25. Interactions were observed between amenamevir and ketoconazole, rifampicin, and midazolam, but not between amenamevir and warfarin. After a single 400-mg dose of amenamevir, the GMRs of amenamevir plus ketoconazole or rifampicin versus amenamevir alone for C max and the area under the plasma concentration-time curve from time zero to infinity (AUC inf ) were 1.30 (90% CI 1.17-1.45) and 2.58 (90% CI 2.32-2.87), respectively, for ketoconazole and 0.42 (90% CI 0.37-0.49) and 0.17 (90% CI 0.15-0.19), respectively, for rifampicin. Following multiple doses of amenamevir (400 mg), the GMRs of midazolam plus amenamevir versus midazolam alone for AUC inf and C max were 0.53 (90% CI 0.47-0.61) and 0.63 (90% CI 0.50-0.80), respectively. After a single dose of warfarin, the (S)-warfarin and (R)-warfarin mean C max increased and mean AUC inf decreased in the presence of amenamevir; however, the 90% CIs of the GMRs for these parameters remained within the predefined limits. These findings confirm that amenamevir (as a cytochrome P450 3A4 substrate) can interact with ketoconazole or rifampicin, and (as a

  19. The effect of ketoconazole on whole blood and skin ciclosporin concentrations in dogs.

    PubMed

    Gray, Laura L; Hillier, Andrew; Cole, Lynette K; Rajala-Schultz, Päivi J

    2013-02-01

    Ciclosporin (CSA) is approved for the treatment of canine atopic dermatitis. Ciclosporin is metabolized by liver cytochrome P450 enzymes, a process inhibited by ketoconazole (KTZ). The aims of this study were to determine skin and blood CSA concentrations when CSA was administered alone at 5.0 (Treatment 1) or 2.5 mg/kg (Treatment 2) and when CSA was administered at 2.5 mg/kg concurrently with KTZ at 5 (Treatment 3) or 2.5 mg/kg (Treatment 4). We hypothesized that skin and blood CSA concentrations in Treatment 1 would not differ from those obtained with T3 or T4. In a randomized cross-over study, six healthy research dogs received each of the treatments (Treatment 1, 2, 3 and 4) once daily for 7 days. After the first, fourth and seventh dose for each treatment, a peak and trough skin punch biopsy sample and whole blood sample were collected and analysed with high-performance liquid chromatography-tandem mass spectrometry. Data were analysed using a repeated measures approach with PROC MIXED in SAS. Pairwise comparisons were performed with least squares means and Tukey-Kramer adjustment for multiple comparisons. Mean blood CSA concentrations in Treatment 1 were not different from those in Treatment 2 or 4, but were less than in Treatment 3. Mean skin CSA concentrations in Treatment 1 were greater than in Treatment 2, not different from those in Treatment 4, and less than those in Treatment 3. Administration of CSA and KTZ concurrently at 2.5 mg/kg each may be as effective as CSA alone at 5.0 mg/kg for treatment of canine atopic dermatitis. © 2013 The Authors. Veterinary Dermatology © 2013 ESVD and ACVD.

  20. Metabolism of halofantrine to its equipotent metabolite, desbutylhalofantrine, is decreased when orally administered with ketoconazole.

    PubMed

    Khoo, S M; Porter, J H; Edwards, G A; Charman, W N

    1998-12-01

    Halofantrine (Hf) is a highly lipophilic antimalarial with poor and erratic absorption. Published data indicates that the oral bioavailability of Hf was increased 3-fold in humans and 12-fold in dogs when administered postprandially; however, the proportional formation of the active desbutyl metabolite (desbutylhalofantrine, Hfm) decreased 2.4-fold in humans and 6.8-fold in dogs (Milton et al., Br. J. Clin. Pharmacol. 1989, 28, 71-77; Humberstone et al., J. Pharm. Sci. 1996, 85, 525-529). The current study was undertaken to confirm the putative involvement of CYP3A4 in the N-dealkylation of Hf to Hfm by administering Hf with and without ketoconazole (KC), a specific CYP3A4 inhibitor, and measuring the resulting plasma concentration profiles of Hf and Hfm. The plasma Hfm/Hf AUC(0-72 h) ratio after fasted oral administration of Hf without KC was 0.56, whereas the ratio after fasted oral administration with KC was less than 0.05. It is likely that both hepatic and prehepatic (enterocyte-based) CYP3A4 contributed to metabolism of Hf to Hfm after oral administration. Interestingly, the low plasma Hfm/Hf AUC ratios observed after fasted administration of Hf with KC were similar to the low values previously observed when Hf was administered postprandially (despite increased Hf absorption). The mechanism(s) by which postprandial administration of Hf led to a decrease in its metabolism are unknown, but based on the current data, could include inhibition of CYP3A4-mediated metabolism by components of the ingested meal. Other possibilities include a lipid-induced postprandial recruitment of intestinal lymphatic transport or avoidance of metabolism during transport through the enterocyte into the portal blood. Further studies are required to determine the relative contributions by which these different processes may decrease the presystemic metabolism of Hf.

  1. Electron paramagnetic resonance method for the quantitative assay of ketoconazole in pharmaceutical preparations.

    PubMed

    Morsy, Mohamed A; Sultan, Salah M; Dafalla, Hatim

    2009-08-15

    In this study, electron paramagnetic resonance (EPR) is used, for the first time, as an analytical tool for the quantitative assay of ketoconazole (KTZ) in drug formulations. The drug was successfully characterized by the prominent signals by two radical species produced as a result of its oxidation with 400 microg/mL cerium(IV) in 0.10 mol dm(-3) sulfuric acid. The EPR signal of the reaction mixture was measured in eight capillary tubes housed in a 4 mm EPR sample tube. The radical stability was investigated by obtaining multi-EPR scans of each KTZ sample solution at time intervals of 2.5 min of the reaction mixing time. The plot of the disappearance of the radical species show that the disappearance is apparently of zero order. The zero-time intercept of the EPR signal amplitude, which should be proportional to the initial radical concentration, is linear in the sample concentration in the range between 100 and 400 microg/mL, with a correlation coefficient, r, of 0.999. The detection limit was determined to be 11.7 +/- 2.5 microg/mL. The method newly adopted was fully validated following the United States Pharmacopeia (USP) monograph protocol in both the generic and the proprietary forms. The method is very accurate, such that we were able to measure the concentration at confidence levels of 99.9%. The method was also found to be suitable for the assay of KTZ in its tablet and cream pharmaceutical preparations, as no interferences were encountered from excipients of the proprietary drugs. High specificity, simplicity, and rapidity are the merits of the present method compared to the previously reported methods.

  2. Ketoconazole modulates the infectivity of Ichthyophonus sp. (Mesomycetozoa) in vivo in experimentally injected European sea bass.

    PubMed

    Hontoria, Francisco; González, Ma Angeles; Sitjà-Bobadilla, Ariadna; Palenzuela, Oswaldo; Alvarez-Pellitero, Pilar

    2013-09-03

    In vitro studies have confirmed the inhibitory effect of the azol-derivative ketoconazole (KZ) on the growth of Ichthyophonus, an important pathogen causing epizootics in wild and cultured fish. We evaluated the effect of KZ in vivo in European sea bass Dicentrarchus labrax experimentally infected with the same Ichthyophonus isolate. Liposomes were used to vehiculate different doses of KZ to increase the effect on Ichthyophonus and lower the toxicity of the drug, and KZ toxicity was assessed in cultured sea bass juveniles. We also studied the effect of liposome-vehiculated KZ included in medicated food on ichthyophoniasis. KZ causes clear toxic effects in D. labrax juveniles at doses >80 mg kg-1, apparent in the reduced survival of fish and histological alterations to livers, kidneys and spleens. Fish injected with Ichthyophonus and treated with KZ dosages of ≤80 mg kg-1 d-1 presented lower ichthyophoniasis prevalence, fewer organs infected per fish, and fewer spores in the affected organs than the untreated fish. KZ seems to delay the onset of infection, but cannot stop further progression once established. However, this behaviour is not clearly reflected in the biometric and haematological data collected from these fish. We hypothesise that KZ's delaying effect would increase, if lower infective doses (more similar to natural situations) were used. The drug administration vehicle (liposomes vs. emulsions) did not affect the results. Our data confirm the potential utility of KZ in treating ichthyophoniasis and reveal its low toxicity for sea bass. Nevertheless, the optimal dose and appropriate application protocol remain to be determined.

  3. Optimization of drug-drug interaction study design: comparison of minimal physiologically based pharmacokinetic models on prediction of CYP3A inhibition by ketoconazole.

    PubMed

    Han, Bing; Mao, Jialin; Chien, Jenny Y; Hall, Stephen D

    2013-07-01

    Ketoconazole is a potent CYP3A inhibitor used to assess the contribution of CYP3A to drug clearance and quantify the increase in drug exposure due to a strong inhibitor. Physiologically based pharmacokinetic (PBPK) models have been used to evaluate treatment regimens resulting in maximal CYP3A inhibition by ketoconazole but have reached different conclusions. We compare two PBPK models of the ketoconazole-midazolam interaction, model 1 (Chien et al., 2006) and model 2 implemented in Simcyp (version 11), to predict 16 published treatment regimens. With use of model 2, 41% of the study point estimates of area under the curve (AUC) ratio and 71% of the 90% confidence intervals were predicted within 1.5-fold of the observed, but these increased to 82 and 100%, respectively, with model 1. For midazolam, model 2 predicted a maximal midazolam AUC ratio of 8 and a hepatic fraction metabolized by CYP3A (f(m)) of 0.97, whereas model 1 predicted 17 and 0.90, respectively, which are more consistent with observed data. On the basis of model 1, ketoconazole (400 mg QD) for at least 3 days and substrate administration within 2 hours is required for maximal CYP3A inhibition. Ketoconazole treatment regimens that use 200 mg BID underestimate the systemic fraction metabolized by CYP3A (0.86 versus 0.90) for midazolam. The systematic underprediction also applies to CYP3A substrates with high bioavailability and long half-lives. The superior predictive performance of model 1 reflects the need for accumulation of ketoconazole at enzyme site and protracted inhibition. Model 2 is not recommended for inferring optimal study design and estimation of fraction metabolized by CYP3A.

  4. Improvement of bioavailability of the HIV protease inhibitor SC-52151 in the beagle dog by coadministration of the CYP3A4 inhibitor, ketoconazole.

    PubMed

    Yuan, J H; Stolzenbach, J C; Salamon, C M; Snook, S S; Schoenhard, G L

    1997-05-01

    1. SC-52151, an HIV protease inhibitor, is mainly metabolized by CYP3A4 and is poorly bioavailable after oral administration. After i.v. administration of SC-52151 to the female beagle dog (2.5 mg/kg), SC-52151 was rapidly eliminated in plasma with an elimination half-life of about 1 h, a plasma clearance of 44 ml/min/kg and an apparent steady-state volume distribution of 2.2 litre/kg. The high value of plasma clearance of SC-52151 suggests an extensive hepatic first-pass metabolism since SC-52151 is highly protein bound and does not partition itself into red blood cells. 2. The extensive hepatic first-pass metabolism was reduced by coadministration of a CYP3A4 inhibitor, ketoconazole. 3. Dogs were dosed daily with ketoconazole at dose of 100 mg ketoconazole per dog (approximately 10 mg/kg) for 5 days prior to the initiation of coadministration of SC-52151 for 15 days. The doses used for SC-52151 was 0, 60 and 120 mg SC-52151/kg/day (divided t.i.d., 8-h dosing interval). Coadministration of ketoconazole improved the bioavailability of SC-52151 from 4.1 to 9.6% and also improved the Cmax of SC-52151 from 0.41 to 0.83 microgram/ml. 4. Although the absolute bioavailability of SC-52151 was still low (approximately 10%), the Cmax and AUC achieved in this study were satisfactory for conducting chronic toxicology studies. No toxicity associated with the coadministration of ketoconazole was evident. Results from this study suggest that coadministration of ketoconazole might be a practical approach to increase the exposure of SC-52151 in both preclinical and clinical studies.

  5. Synergism between macrolide antibiotics and the azole fungicide ketoconazole in growth inhibition testing of the green alga Pseudokirchneriella subcapitata.

    PubMed

    Yamagishi, Takahiro; Horie, Yoshifumi; Tatarazako, Norihisa

    2017-05-01

    Macrolide antibiotics and azole fungicides are detected widely in the aquatic environment as a result of their increased use in humans and animal livestock disease and their incomplete removal by wastewater treatment plants. In most cases, ecotoxicological tests are performed by using individual chemical substances, but because of the coexistence of a number of chemicals in the environment, organisms are exposed to many chemicals simultaneously. Therefore, it is important to evaluate effects of chemical interactions, adding to potential hazards of individual chemical. Here, we investigated the synergetic effects of combined chemicals (the azole fungicide ketoconazole and either of two macrolide antibiotics, erythromycin and clarithromycin) in growth inhibition testing using Pseudokirchneriella subcapitata according to OECD Test guideline 201. Combination index plots, isobolograms, and curve-shift analyses revealed that the combination of macrolide antibiotic and ketoconazole at various ratios resulted in strong synergism that enhanced growth inhibition of P. subcapitata, suggesting the necessity of investigating potential hazard of combined chemicals for regulatory purposes. Copyright © 2017 Elsevier Ltd. All rights reserved.

  6. Terbinafin 1% Cream and Ketoconazole 2% Cream in the Treatment of Pityriasis Versicolor: A randomized comparative clinical trial

    PubMed Central

    Rad, Farrokh; Nik-Khoo, Bahram; Yaghmaee, Roxana; Gharibi, Fardin

    2014-01-01

    Objective: To make a comparison between terbinafine 1% cream and ketoconazole 2% cream in the treatment of pityriasis versicolor. Methods: This randomized single blind study included 110 patients with clinical diagnosis of pityriasis versicolor and positive mycological test for Malassezia furfur. The patients were randomly assigned to two groups. Group 1 used terbinafine cream and group 2 applied ketoconazole cream on the skin lesions for two weeks. Each group consisted of 55 patients. Clinical and mycological examinations were performed at baseline, at the end of the 2nd, 4th and 8th week of starting the treatment regimens. Results: At the end of the 2nd week we achieved cure rates of 72% and 64.3% for group 1 and group 2 respectively. At the end of the 4th week the respective cure rates for group 1 and group 2 were 81.2% and 69%, and at the end of the 8th week 70.8% of the patients in group 1 and 61.9% of the patients in group 2 were cured. Conclusion: The results of this study showed no significant statistical differences between the two groups in regard to cure and recurrence rates. But the numbers of cured patients were higher and recurrent cases were lower in group 1. PMID:25674122

  7. Transungual Delivery of Ketoconazole Nanoemulgel for the Effective Management of Onychomycosis.

    PubMed

    Mahtab, Asiya; Anwar, Mohammed; Mallick, Neha; Naz, Zrien; Jain, Gaurav K; Ahmad, Farhan J

    2016-12-01

    Ketoconazole (KCZ) nanoemulgel containing permeation enhancer was formulated as a vehicle for transungual drug delivery, and its efficacy to inhibit the growth of onychomycotic dermatophytes was investigated in vitro. Different components of oil-in-water nanoemulsions were moderately agitated by classical titration method and passed through a high-pressure homogenizer to formulate various nanoemulsions, which were further identified by constructing pseudo-ternary phase diagrams. Stress-stability testing was carried out for the nanoemulsions, and those that passed these tests were characterized for mean droplet size, zeta potential, morphology, pH, refractive index, viscosity and transmittance. Mean droplet size and zeta potential of the optimized nanoemulsion (NE3) were found to be 77.52 ± 0.92 nm (polydispersity index (PDI) = 0.128 ± 0.035) and -5.44 ± 0.67 mV, respectively. Optimized nanoemulsion was converted into nanoemulgel (NEG 1 ) with 1% (w/w) of gelling agent (Carbopol® Ultrez 21) and 1%-2% (v/v) thioglycolic acid as permeation enhancer, and evaluated for pH, viscosity, spreadability, extrudability, tensile strength and bio-adhesion measurement. In vitro cumulative drug released at the end of 24 h from NE3, NEG 1 and drug suspension were found to be 98.87 ± 1.29, 84.42 ± 2.78% and 54.86 ± 2.19%, respectively. Ex vivo transungual permeation values for KCZ through goat hooves from NE3, NEG 1 and drug suspension were found to be 62.49 ± 2.98, 77.54 ± 2.88% and 38.54 ± 2.54%, respectively, in 24 h. The antifungal effect of NEG 1 on Trichophyton rubrum and Candida albicans showed a significant (p < 0.05) zone of inhibition as compared to drug solution. Skin irritation and histopathology studies on rat skin showed the safe topical use and enhanced permeation of formulated nanoemulgel.

  8. Synergistic anti-candidal activity of tetrandrine on ketoconazole: an experimental study.

    PubMed

    Zhang, Hong; Wang, Kaili; Zhang, Gehua; Ho, Hon In; Gao, Aili

    2010-01-01

    With the widespread use of azoles, drug resistant Candida albicans strains are increasing. The study examined the synergism of tetrandrine (TET) on ketoconazole (KCZ) candidacidal activity. The protocol M27-A2 of the Clinical and Laboratory Standards Institute (CLSI) was adopted and the minimum inhibitory concentrations (MICs) were determined for KCZ alone and in combination with a TET level that was noncytotoxic for C. albicans strains CA-1 through CA-17, with no CA-10. Colony counting techniques were used to construct time-kill curves. CA-15 was used to build the mouse candidal vaginitis model. After randomization, drugs were administered vaginally once daily from days 3-10 (both KCZ and TET were 26 mg/kg/day and 13 mg/kg/day, respectively, administered in different combinations). Mouse vaginal lavage fluid was obtained at days 2, 6, and 11 after inoculation for fungal load analysis, and vaginal tissue was obtained for pathological examination. MICs of KCZ alone and combined with 30 microg/mL TET for the C. albicans strains were 1-32 microg/mL and 0.0038-0.2500 microg/mL, respectively ( T = 24.624, p = 0.000). Time-kill curves showed that at 48 h the viable cell counts of strains treated with KCZ + TET were at least 2 log(10) CFU/mL lower compared to strains treated with corresponding doses of KCZ (p = 0.000). At day 6, the fungal load in the KCZ 26 mg/kg/day + TET 26 mg/kg/day mice was significantly lower than the KCZ 26 mg/kg/day mice (1.17 +/- 1.17 x 10(4) CFU/mL and 9.33 +/- 3.08 x 10(4) CFU/mL, respectively, p = 0.000). Mucosal and submucosal fungal clearances were complete and vaginal mucosal edema was slight with minimal inflammatory cell infiltration. We conclude that noncytotoxic doses of TET synergistically enhance KCZ candidacidal activity in vitro and in vivo. Copyright Georg Thieme Verlag KG Stuttgart . New York.

  9. Comparison of Antimicrobial Activity of Chlorhexidine, Coconut Oil, Probiotics, and Ketoconazole on Candida albicans Isolated in Children with Early Childhood Caries: An In Vitro Study

    PubMed Central

    Ahmed Bijapur, Gufran; Kottayi, Soni; Jose, Deepak

    2016-01-01

    Background. Early childhood caries (ECC) is associated with early colonisation and high levels of cariogenic microorganisms. With C. albicans being one of those, there is a need to determine the effectiveness of various chemotherapeutic agents against it. The study is aimed at isolating Candida species in children with ECC and at studying the antifungal effect of coconut oil, probiotics, Lactobacillus, and 0.2% chlorhexidine on C. albicans in comparison with ketoconazole. Materials and Methods. Samples were collected using sterile cotton swabs, swabbed on the tooth surfaces from children with ECC of 3 to 6 yrs and streaked on Sabouraud dextrose agar (HI Media) plates and incubated in a 5% CO2 enriched atmosphere at 37°C for 24 hours. Candida was isolated and its susceptibility to probiotics, chlorhexidine, ketoconazole, and coconut oil was determined using Disc Diffusion method. Results. The mean zone of inhibition for chlorhexidine was 21.8 mm, whereas for coconut oil it was 16.8 mm, for probiotics it was 13.5 mm, and for ketoconazole it was 22.3 mm. The difference between the groups was not statistically significant (Chi-square value 7.42, P value 0.06). Conclusion. Chlorhexidine and coconut oil have shown significant antifungal activity which is comparable with ketoconazole. PMID:27051559

  10. Comparison of the clinical efficacy of oral terbinafine and ketoconazole combined with cephalexin in the treatment of Malassezia dermatitis in dogs--a pilot study.

    PubMed

    Rosales, Millie S; Marsella, Rosanna; Kunkle, Gail; Harris, Bradley L; Nicklin, Constance F; Lopez, Jennifer

    2005-06-01

    The purpose of this randomized, single blinded clinical trial was to evaluate cytologically and clinically the efficacy of oral cephalexin alone and its combination with terbinafine or ketoconazole for the treatment of Malassezia dermatitis in dogs. Twenty-two client-owned dogs with Malassezia dermatitis completed the 3-week study. All received cephalexin (generic, 250 mg or 500 mg) at 22-30 mg kg(-1) twice daily. Eight dogs received terbinafine at 30 mg kg(-1) once daily and seven dogs received ketoconazole (generic, 200 mg) at 5-10 mg kg(-1) twice daily. The remaining seven dogs received cephalexin alone. At week 0 (visit 1) and week 3 (visit 2), mean yeast counts were determined from three affected areas using tape-strip cytology, a clinical index score (CIS) was assigned to the affected areas, and owners evaluated pruritus using a visual analogue scale. All groups showed reduction in mean yeast counts, CIS and pruritus. There was an 86.8%, 80.2% and 28.8% reduction in mean yeast counts from visit 1 to visit 2 for the terbinafine, ketoconazole and cephalexin-only groups, respectively. However, within treatment group comparisons a significant reduction in mean yeast count was only evident for the terbinafine (P < 0.002) and ketoconazole (P < 0.01) groups. Pruritus reduction was only significant for the terbinafine group. These preliminary results suggest that terbinafine should be further assessed for the treatment of canine Malassezia dermatitis.

  11. The anti-Malassezia furfur activity in vitro and in experimental dermatitis of six imidazole antifungal agents: bifonazole, clotrimazole, flutrimazole, ketoconazole, miconazole and sertaconazole.

    PubMed

    Van Gerven, F; Odds, F C

    1995-01-01

    Bifonazole, clotrimazole, flutrimazole, ketoconazole, miconazole and sertaconazole were tested for their activity against 23 isolates of Malassezia furfur by agar dilution in vitro. Topical formulations of the same agents were evaluated for efficacy against M. furfur skin infections in guinea pigs in vivo. The most potent inhibitor in vitro was ketoconazole (geometric mean minimum inhibitory concentration 0.51 microgram ml-1), followed by bifonazole (8.1 micrograms ml-1), then miconazole (14 micrograms ml-1), clotrimazole (15 micrograms ml-1) and flutrimazole (16 micrograms ml-1), with sertaconazole the least active (52 micrograms ml-1). In animal experiments involving three consecutive days of topical treatments, bifonazole 1% cream, clotrimazole 1% cream, flutrimazole 1% and 2% creams, ketoconazole 2% cream and shampoo and miconazole 2% cream all reduced M. furfur dermatitis lesion severity below that of untreated control animals; however, sertaconazole 2% gel and cream showed no reduction in lesion severity below control. The results confirm that ketoconazole is a more potent inhibitor of M. furfur in vitro than other topical antifungal agents of its class and suggest that sertaconazole is the least effective of such agents among those tested.

  12. Two-way pharmacokinetic interaction studies between saxagliptin and cytochrome P450 substrates or inhibitors: simvastatin, diltiazem extended-release, and ketoconazole

    PubMed Central

    Patel, Chirag G; Li, Li; Girgis, Suzette; Kornhauser, David M; Frevert, Ernest U; Boulton, David W

    2011-01-01

    Background Many medicines, including several cholesterol-lowering agents (eg, lovastatin, simvastatin), antihypertensives (eg, diltiazem, nifedipine, verapamil), and antifungals (eg, ketoconazole) are metabolized by and/or inhibit the cytochrome P450 (CYP) 3A4 metabolic pathway. These types of medicines are commonly coprescribed to treat comorbidities in patients with type 2 diabetes mellitus (T2DM) and the potential for drug-drug interactions of these medicines with new medicines for T2DM must be carefully evaluated. Objective To investigate the effects of CYP3A4 substrates or inhibitors, simvastatin (substrate), diltiazem (moderate inhibitor), and ketoconazole (strong inhibitor) on the pharmacokinetics and safety of saxagliptin, a CYP3A4/5 substrate; and the effects of saxagliptin on these agents in three separate studies. Methods Healthy subjects were administered saxagliptin 10 mg or 100 mg. Simvastatin, diltiazem extended-release, and ketoconazole doses of 40 mg once daily, 360 mg once daily, and 200 mg twice daily, respectively, were used to determine two-way pharmacokinetic interactions. Results Coadministration of simvastatin, diltiazem extended-release, or ketoconazole increased mean area under the concentration-time curve values (AUC) of saxagliptin by 12%, 109%, and 145%, respectively, versus saxagliptin alone. Mean exposure (AUC) of the CYP3A4-generated active metabolite of saxagliptin, 5-hydroxy saxagliptin, decreased with coadministration of simvastatin, diltiazem, and ketoconazole by 2%, 34%, and 88%, respectively. All adverse events were considered mild or moderate in all three studies; there were no serious adverse events or deaths. Conclusion Saxagliptin, when coadministered with simvastatin, diltiazem extended-release, or ketoconazole, was safe and generally well tolerated in healthy subjects. Clinically meaningful interactions of saxagliptin with simvastatin and diltiazem extended-release are not expected. The dose of saxagliptin does not need

  13. Evaluation of Cytochrome P450 (CYP) 3A4-Based Interactions of Levomilnacipran with Ketoconazole, Carbamazepine or Alprazolam in Healthy Subjects.

    PubMed

    Chen, Laishun; Boinpally, Ramesh; Gad, Nayra; Greenberg, William M; Wangsa, Julie; Periclou, Antonia; Ghahramani, Parviz

    2015-10-01

    Levomilnacipran is a serotonin and norepinephrine reuptake inhibitor with balanced potency for the reuptake inhibition of norepinephrine and serotonin, approved in the USA for the treatment of major depressive disorder (MDD) in adults. We conducted studies in healthy human subjects to investigate pharmacokinetic interactions when levomilnacipran extended-release (ER) is administered in combination with an inhibitor (ketoconazole), an inducer (carbamazepine), or a substrate (alprazolam) of cytochrome P450 (CYP) 3A4. Randomised, open-label studies were conducted in healthy volunteers (n = 34 ketoconazole, n = 34 carbamazepine, n = 30 alprazolam) and pharmacokinetic parameters were determined when levomilnacipran was administered alone or together with the relevant study drug. Co-administration of ketoconazole with levomilnacipran ER increased levomilnacipran maximum concentration (C max) by 39% [90% confidence interval (CI) 31-47%] and area under the concentration-time curve (AUC) by 57% (90% CI 47-67%), whereas carbamazepine reduced the C max and AUC of levomilnacipran by 26% (90% CI 22-30%) and 29% (90% CI 26-32%), respectively. Levomilnacipran at steady state had no significant effect on the pharmacokinetics of a single 1 mg dose of alprazolam extended release (XR); neither did single-dose alprazolam XR affect the steady-state pharmacokinetics of levomilnacipran. No new safety concerns were noted in these studies. Based on these results, the levomilnacipran ER dose should not exceed 80 mg once daily when used with ketoconazole, compared to 120 mg once daily in the absence of ketoconazole. No dose adjustment for levomilnacipran is suggested when levomilnacipran ER is co-administered with carbamazepine or other CYP3A4 inducers. Co-administration with levomilnacipran of drugs metabolised by CYP3A4, such as alprazolam, requires no dose adjustment due to pharmacokinetic considerations.

  14. In Vitro Susceptibility of Malassezia pachydermatis Isolates from Canine Skin with Atopic Dermatitis to Ketoconazole and Itraconazole in East Asia

    PubMed Central

    WATANABE, Shion; KOIKE, Anna; KANO, Rui; NAGATA, Masahiko; CHEN, Charles; HWANG, Cheol-Yong; HASEGAWA, Atsuhiko; KAMATA, Hiroshi

    2013-01-01

    ABSTRACT Topical or oral azole antifungals are commonly used in canine atopic dermatitis (AD), as the lipophilic yeast Malassezia pachydermatis exacerbates canine AD. To examine whether canine AD lesions harbor azole-resistant M. pachydermatis isolates in East Asia, we investigated the in vitro susceptibility of M. pachydermatis isolates to ketoconazole (KTZ) and itraconazole (ITZ) obtained from AD lesions of canines in Japan, Korea and Taiwan. The minimum inhibitory concentrations (MICs) of KTZ and ITZ were measured by the E-test using Sabouraud dextrose agar with 0.5% Tween 40. The MICs of KTZ and ITZ for isolates from canines with AD were significantly higher than the MICs for isolates from healthy canines. Our findings suggested that the clinical isolates from canine AD skin lesions were less susceptible to azoles than those from normal canine skin in East Asia. PMID:24334863

  15. In vitro susceptibility of Malassezia pachydermatis isolates from canine skin with atopic dermatitis to ketoconazole and itraconazole in East Asia.

    PubMed

    Watanabe, Shion; Koike, Anna; Kano, Rui; Nagata, Masahiko; Chen, Charles; Hwang, Cheol-Yong; Hasegawa, Atsuhiko; Kamata, Hiroshi

    2014-04-01

    Topical or oral azole antifungals are commonly used in canine atopic dermatitis (AD), as the lipophilic yeast Malassezia pachydermatis exacerbates canine AD. To examine whether canine AD lesions harbor azole-resistant M. pachydermatis isolates in East Asia, we investigated the in vitro susceptibility of M. pachydermatis isolates to ketoconazole (KTZ) and itraconazole (ITZ) obtained from AD lesions of canines in Japan, Korea and Taiwan. The minimum inhibitory concentrations (MICs) of KTZ and ITZ were measured by the E-test using Sabouraud dextrose agar with 0.5% Tween 40. The MICs of KTZ and ITZ for isolates from canines with AD were significantly higher than the MICs for isolates from healthy canines. Our findings suggested that the clinical isolates from canine AD skin lesions were less susceptible to azoles than those from normal canine skin in East Asia.

  16. Flea (Ctenocephalides felis) control efficacy of topical indoxacarb on dogs subsequently bathed with a chlorhexidine–ketoconazole shampoo

    PubMed Central

    Liebenberg, JE; Heaney, K; Guerino, F

    2015-01-01

    Objective An evaluation of the effect of chlorhexidine/ketoconazole shampoo baths on the flea control efficacy of indoxacarb applied topically to dogs. Methods and Results We randomly allocated 18 healthy mixed‐breed dogs to 3 groups: shampoo only; indoxacarb treated and medicated shampoo; and indoxacarb treated but not shampooed. Indoxacarb was administered on day 0 and dogs were shampooed on days 9 and 23. Dogs were infested with 100 adult Ctenocephalides felis initially 2 days before treatment and then weekly from days 7 to 28. Fleas were removed and counted 48 h post‐infestation. Conclusion Medicated shampoo use did not significantly reduce indoxacarb efficacy against C. felis. PMID:26220323

  17. Flea (Ctenocephalides felis) control efficacy of topical indoxacarb on dogs subsequently bathed with a chlorhexidine-ketoconazole shampoo.

    PubMed

    Armstrong, R D; Liebenberg, J E; Heaney, K; Guerino, F

    2015-08-01

    An evaluation of the effect of chlorhexidine/ketoconazole shampoo baths on the flea control efficacy of indoxacarb applied topically to dogs. We randomly allocated 18 healthy mixed-breed dogs to 3 groups: shampoo only; indoxacarb treated and medicated shampoo; and indoxacarb treated but not shampooed. Indoxacarb was administered on day 0 and dogs were shampooed on days 9 and 23. Dogs were infested with 100 adult Ctenocephalides felis initially 2 days before treatment and then weekly from days 7 to 28. Fleas were removed and counted 48 h post-infestation. Medicated shampoo use did not significantly reduce indoxacarb efficacy against C. felis. © 2015 MSD Animal Health. Australian Veterinary Journal published by Wiley Publishing Asia Pty Ltd on behalf of Australian Veterinary Association.

  18. Enhancement of in-vitro drug dissolution of ketoconazole for its optimal in-vivo absorption using Nanoparticles and Solid Dispersion forms of the drug

    NASA Astrophysics Data System (ADS)

    Syed, Mohammed Irfan

    Ketoconazole is one of the most widely prescribed oral antifungal drugs for the systemic treatment of various fungal infections. However, due its hydrophobic nature and poor solubility profiles in the gastro-intestinal fluids, variations in its bioavailability have been documented. Therefore, to enhance its dissolution in the biological fluids, this study was initiated to develop and evaluate Nanoparticles and Solid Dispersion forms of the drug. Nanoparticles of ketoconazole were developed by Wet Bead Milling technique using PVP-10k as the stabilizing material at a weight ratio of (2:1). Solid dispersion powder was prepared by Hot Melt method using PEG-8000 at a weight ratio of (1:2). A commercial product containing 200mg of ketoconazole tablet and pure drug powder were used as the control for comparison purposes. The dissolution studies were carried out in SGF, SIF, USP; and SIF with 0.2% sodium lauryl sulfate using the USP-II method for a 2 hours period. Physical characterizations were carried out using SEM, DSC, XRD and FTIR studies. Wet Bead Milling method yielded nanoparticles in the particles size range of (100-300nm.). First all samples were evaluated for their in-vitro dissolution in SGF at pH=1.2. After 15 minutes, the amounts of drug dissolved were observed to be 27% from both the pure powder and commercial tablet (control), 29% from solid dispersion and 100% from the Nanoparticles dosage form. This supports the fact that Nanoparticles had a strong influence on the dissolution rate of the drug and exhibited much faster dissolution of ketoconazole. When the same formulations were studied in the SIF, USP medium, the control formulation gave 3%, solid dispersion 8% and Nanoparticles 8% drug dissolution after 2 hours period. This could be because the weakly basic ketoconazole drug remained un-dissociated in the alkaline medium. Since this medium was unable to clearly distinguish the dissolution profiles from different formulation of the drug, the SIF solution

  19. Effect of ketoconazole, a strong CYP3A inhibitor, on the pharmacokinetics of venetoclax, a BCL‐2 inhibitor, in patients with non‐Hodgkin lymphoma

    PubMed Central

    Agarwal, Suresh K.; Danilov, Alexey V.; Hu, Beibei; Puvvada, Soham; Gutierrez, Martin; Chien, David; Lewis, Lionel D.; Wong, Shekman L.

    2017-01-01

    Aims To examine the effect of a strong cytochrome P450 (CYP) 3A inhibitor, ketoconazole, on the pharmacokinetics, safety and tolerability of venetoclax. Methods Twelve patients with non‐Hodgkin lymphoma (NHL) were enrolled in this Phase 1, open‐label, fixed‐sequence study. Patients received a single 50 mg dose of venetoclax orally on Day 1 and Day 8, and a 400 mg once daily dose of ketoconazole on Days 5–11. Blood samples were collected predose and up to 96 h after each venetoclax dose on Day 1 and Day 8. Results Eleven patients had evaluable pharmacokinetic data and were therefore included in the statistical analyses. Compared to administration of a single 50 mg dose of venetoclax alone, ketoconazole increased the venetoclax mean maximum observed plasma concentration (C max) and area under the plasma concentration–time curve from time 0 to infinity (AUC∞) by 2.3‐fold (90% confidence interval [CI]: 2.0–2.7) and 6.4‐fold (90% CI: 4.5–9.2; range: 2‐ to 12‐fold), respectively. Conclusions Coadministration of venetoclax with multiple doses of ketoconazole resulted in a significant increase of venetoclax exposures, strongly suggesting that CYP3A plays a major role in elimination of venetoclax in patients. These results suggest the need to avoid concomitant use with strong and moderate inhibitors or inducers of CYP3A during the venetoclax ramp‐up phase in chronic lymphocytic leukaemia (CLL) patients. For patients who have completed the ramp‐up phase, a modification in venetoclax dose for use with strong and moderate inhibitors or inducers of CYP3A is recommended. PMID:27859472

  20. Effect of ketoconazole, a strong CYP3A inhibitor, on the pharmacokinetics of venetoclax, a BCL-2 inhibitor, in patients with non-Hodgkin lymphoma.

    PubMed

    Agarwal, Suresh K; Salem, Ahmed Hamed; Danilov, Alexey V; Hu, Beibei; Puvvada, Soham; Gutierrez, Martin; Chien, David; Lewis, Lionel D; Wong, Shekman L

    2017-04-01

    To examine the effect of a strong cytochrome P450 (CYP) 3A inhibitor, ketoconazole, on the pharmacokinetics, safety and tolerability of venetoclax. Twelve patients with non-Hodgkin lymphoma (NHL) were enrolled in this Phase 1, open-label, fixed-sequence study. Patients received a single 50 mg dose of venetoclax orally on Day 1 and Day 8, and a 400 mg once daily dose of ketoconazole on Days 5-11. Blood samples were collected predose and up to 96 h after each venetoclax dose on Day 1 and Day 8. Eleven patients had evaluable pharmacokinetic data and were therefore included in the statistical analyses. Compared to administration of a single 50 mg dose of venetoclax alone, ketoconazole increased the venetoclax mean maximum observed plasma concentration (C max ) and area under the plasma concentration-time curve from time 0 to infinity (AUC ∞ ) by 2.3-fold (90% confidence interval [CI]: 2.0-2.7) and 6.4-fold (90% CI: 4.5-9.2; range: 2- to 12-fold), respectively. Coadministration of venetoclax with multiple doses of ketoconazole resulted in a significant increase of venetoclax exposures, strongly suggesting that CYP3A plays a major role in elimination of venetoclax in patients. These results suggest the need to avoid concomitant use with strong and moderate inhibitors or inducers of CYP3A during the venetoclax ramp-up phase in chronic lymphocytic leukaemia (CLL) patients. For patients who have completed the ramp-up phase, a modification in venetoclax dose for use with strong and moderate inhibitors or inducers of CYP3A is recommended. © 2016 The British Pharmacological Society.

  1. Effects of ketoconazole and rifampicin on the pharmacokinetics of GLS4, a novel anti-hepatitis B virus compound, in dogs

    PubMed Central

    Zhou, Xin; Gao, Zhi-wei; Meng, Jian; Chen, Xiao-yan; Zhong, Da-fang

    2013-01-01

    Aim: To investigate the metabolism of GLS4, a heteroaryldihydropyrimidine compound with anti-hepatitis B virus activity, in dog and human liver microsomes in vitro and evaluate the effects of ketoconazole (a potent CYP3A inhibitor) or rifampicin (a potent CYP3A inducer) on GLS4 pharmacokinetics in dogs. Methods: Dog and human liver microsomes and CYP3A4 were incubated with [14C]GLS4 for 15 min and then analyzed using a HPLC-dynamic online radio flow detection method. Two groups of beagle dogs were used for in vivo studies. Group A were orally administered a single dose of GLS4 (15 mg/kg) with or without ketoconazole pretreatment (100 mg/d for 8 consecutive days). Group B were orally administered a single dose of GLS4 (15 mg/kg) with or without rifampicin pretreatment (100 mg/d for 8 consecutive days). Plasma was sampled after GLS4 dosing. GLS4 concentrations were determined by HPLC-tandem mass spectrometry. Results: The metabolic profile of [14C]GLS4 in human and dog liver microsomes and CYP3A4 was similar. The major metabolites were morpholine N-dealkylated GLS4 and morpholine N,N-di-dealkylated GLS4. Pretreatment with ketoconazole or rifampicin significantly affected the plasma concentrations of GLS4 in dogs: ketoconazole increased the area under the concentration-time curve from 0 to infinity and peak concentration of GLS4 by 4.4 and 3.3 folds, respectively, whereas rifampicin decreased these parameters by 88.5% and 83.2%, respectively. Conclusion: GLS4 is a sensitive substrate of CYP3A. CYP3A inhibitors or inducers cause considerable change of GLS4 plasma concentrations in dogs, which should be considered in clinical practice. PMID:24056704

  2. Effects of ketoconazole and rifampicin on the pharmacokinetics of GLS4, a novel anti-hepatitis B virus compound, in dogs.

    PubMed

    Zhou, Xin; Gao, Zhi-wei; Meng, Jian; Chen, Xiao-yan; Zhong, Da-fang

    2013-11-01

    To investigate the metabolism of GLS4, a heteroaryldihydropyrimidine compound with anti-hepatitis B virus activity, in dog and human liver microsomes in vitro and evaluate the effects of ketoconazole (a potent CYP3A inhibitor) or rifampicin (a potent CYP3A inducer) on GLS4 pharmacokinetics in dogs. Dog and human liver microsomes and CYP3A4 were incubated with [(14)C]GLS4 for 15 min and then analyzed using a HPLC-dynamic online radio flow detection method. Two groups of beagle dogs were used for in vivo studies. Group A were orally administered a single dose of GLS4 (15 mg/kg) with or without ketoconazole pretreatment (100 mg/d for 8 consecutive days). Group B were orally administered a single dose of GLS4 (15 mg/kg) with or without rifampicin pretreatment (100 mg/d for 8 consecutive days). Plasma was sampled after GLS4 dosing. GLS4 concentrations were determined by HPLC-tandem mass spectrometry. The metabolic profile of [(14)C]GLS4 in human and dog liver microsomes and CYP3A4 was similar. The major metabolites were morpholine N-dealkylated GLS4 and morpholine N,N-di-dealkylated GLS4. Pretreatment with ketoconazole or rifampicin significantly affected the plasma concentrations of GLS4 in dogs: ketoconazole increased the area under the concentration-time curve from 0 to infinity and peak concentration of GLS4 by 4.4 and 3.3 folds, respectively, whereas rifampicin decreased these parameters by 88.5% and 83.2%, respectively. GLS4 is a sensitive substrate of CYP3A. CYP3A inhibitors or inducers cause considerable change of GLS4 plasma concentrations in dogs, which should be considered in clinical practice.

  3. Macrocyclic lactones differ in interaction with recombinant P-glycoprotein 9 of the parasitic nematode Cylicocylus elongatus and ketoconazole in a yeast growth assay.

    PubMed

    Kaschny, Maximiliane; Demeler, Janina; Janssen, I Jana I; Kuzmina, Tetiana A; Besognet, Bruno; Kanellos, Theo; Kerboeuf, Dominique; von Samson-Himmelstjerna, Georg; Krücken, Jürgen

    2015-04-01

    Macrocyclic lactones (MLs) are widely used parasiticides against nematodes and arthropods, but resistance is frequently observed in parasitic nematodes of horses and livestock. Reports claiming resistance or decreased susceptibility in human nematodes are increasing. Since no target site directed ML resistance mechanisms have been identified, non-specific mechanisms were frequently implicated in ML resistance, including P-glycoproteins (Pgps, designated ABCB1 in vertebrates). Nematode genomes encode many different Pgps (e.g. 10 in the sheep parasite Haemonchus contortus). ML transport was shown for mammalian Pgps, Pgps on nematode egg shells, and very recently for Pgp-2 of H. contortus. Here, Pgp-9 from the equine parasite Cylicocyclus elongatus (Cyathostominae) was expressed in a Saccharomyces cerevisiae strain lacking seven endogenous efflux transporters. Pgp was detected on these yeasts by flow cytometry and chemiluminescence using the monoclonal antibody UIC2, which is specific for the active Pgp conformation. In a growth assay, Pgp-9 increased resistance to the fungicides ketoconazole, actinomycin D, valinomycin and daunorubicin, but not to the anthelmintic fungicide thiabendazole. Since no fungicidal activity has been described for MLs, their interaction with Pgp-9 was investigated in an assay involving two drugs: Yeasts were incubated with the highest ketoconazole concentration not affecting growth plus increasing concentrations of MLs to determine competition between or modulation of transport of both drugs. Already equimolar concentrations of ivermectin and eprinomectin inhibited growth, and at fourfold higher ML concentrations growth was virtually abolished. Selamectin and doramectin did not increase susceptibility to ketoconazole at all, although doramectin has been shown previously to strongly interact with human and canine Pgp. An intermediate interaction was observed for moxidectin. This was substantiated by increased binding of UIC2 antibodies in the

  4. Macrocyclic Lactones Differ in Interaction with Recombinant P-Glycoprotein 9 of the Parasitic Nematode Cylicocylus elongatus and Ketoconazole in a Yeast Growth Assay

    PubMed Central

    Kaschny, Maximiliane; Demeler, Janina; Janssen, I. Jana I.; Kuzmina, Tetiana A.; Besognet, Bruno; Kanellos, Theo; Kerboeuf, Dominique; von Samson-Himmelstjerna, Georg; Krücken, Jürgen

    2015-01-01

    Macrocyclic lactones (MLs) are widely used parasiticides against nematodes and arthropods, but resistance is frequently observed in parasitic nematodes of horses and livestock. Reports claiming resistance or decreased susceptibility in human nematodes are increasing. Since no target site directed ML resistance mechanisms have been identified, non-specific mechanisms were frequently implicated in ML resistance, including P-glycoproteins (Pgps, designated ABCB1 in vertebrates). Nematode genomes encode many different Pgps (e.g. 10 in the sheep parasite Haemonchus contortus). ML transport was shown for mammalian Pgps, Pgps on nematode egg shells, and very recently for Pgp-2 of H. contortus. Here, Pgp-9 from the equine parasite Cylicocyclus elongatus (Cyathostominae) was expressed in a Saccharomyces cerevisiae strain lacking seven endogenous efflux transporters. Pgp was detected on these yeasts by flow cytometry and chemiluminescence using the monoclonal antibody UIC2, which is specific for the active Pgp conformation. In a growth assay, Pgp-9 increased resistance to the fungicides ketoconazole, actinomycin D, valinomycin and daunorubicin, but not to the anthelmintic fungicide thiabendazole. Since no fungicidal activity has been described for MLs, their interaction with Pgp-9 was investigated in an assay involving two drugs: Yeasts were incubated with the highest ketoconazole concentration not affecting growth plus increasing concentrations of MLs to determine competition between or modulation of transport of both drugs. Already equimolar concentrations of ivermectin and eprinomectin inhibited growth, and at fourfold higher ML concentrations growth was virtually abolished. Selamectin and doramectin did not increase susceptibility to ketoconazole at all, although doramectin has been shown previously to strongly interact with human and canine Pgp. An intermediate interaction was observed for moxidectin. This was substantiated by increased binding of UIC2 antibodies in the

  5. The effect of ketoconazole on the pharmacokinetics and pharmacodynamics of ixabepilone: a first in class epothilone B analogue in late-phase clinical development.

    PubMed

    Goel, Sanjay; Cohen, Marvin; Cömezoglu, S Nilgün; Perrin, Lionel; André, François; Jayabalan, David; Iacono, Lisa; Comprelli, Adriana; Ly, Van T; Zhang, Donglu; Xu, Carrie; Humphreys, W Griffith; McDaid, Hayley; Goldberg, Gary; Horwitz, Susan B; Mani, Sridhar

    2008-05-01

    To determine if ixabepilone is a substrate for cytochrome P450 3A4 (CYP3A4) and if its metabolism by this cytochrome is clinically important, we did a clinical drug interaction study in humans using ketoconazole as an inhibitor of CYP3A4. Human microsomes were used to determine the cytochrome P450 enzyme(s) involved in the metabolism of ixabepilone. Computational docking (CYP3A4) studies were done for epothilone B and ixabepilone. A follow-up clinical study was done in patients with cancer to determine if 400 mg/d ketoconazole (inhibitor of CYP3A4) altered the pharmacokinetics, drug-target interactions, and pharmacodynamics of ixabepilone. Molecular modeling and human microsomal studies predicted ixabepilone to be a good substrate for CYP3A4. In patients, ketoconazole coadministration resulted in a maximum ixabepilone dose administration to 25 mg/m(2) when compared with single-agent therapy of 40 mg/m(2). Coadministration of ketoconazole with ixabepilone resulted in a 79% increase in AUC(0-infinity). The relationship of microtubule bundle formation in peripheral blood mononuclear cells to plasma ixabepilone concentration was well described by the Hill equation. Microtubule bundle formation in peripheral blood mononuclear cells correlated with neutropenia. Ixabepilone is a good CYP3A4 substrate in vitro; however, in humans, it is likely to be cleared by multiple mechanisms. Furthermore, our results provide evidence that there is a direct relationship between ixabepilone pharmacokinetics, neutrophil counts, and microtubule bundle formation in PBMCs. Strong inhibitors of CYP3A4 should be used cautiously in the context of ixabepilone dosing.

  6. In vitro antifungal efficacy of ciclopirox olamine alone and associated with zinc pyrithione compared to ketoconazole against Malassezia globosa and Malassezia restricta reference strains.

    PubMed

    Roques, Christine; Brousse, Sabine; Panizzutti, Cédric

    2006-12-01

    The aim of this study was to determine the in vitro fungicidal and growth inhibitory activity of ciclopirox olamine alone (1% and 1.5%) or in association with 1% zinc pyrithione compared to 2% ketoconazole, against Malassezia species particularly involved in the pathogenesis of seborrheic dermatitis. Experiments were performed on Malassezia globosa IP 2387.96 and M. restricta IP 2392.96 strains. Growth inhibitory activity of the active compounds in solution was evaluated by measuring minimal inhibitory concentrations using a broth micro-method and their fungicidal activity by a filtration method after contact times between solutions and yeasts ranging from 3-5 to 30 min. Concerning the determination of minimal inhibitory concentration of ciclopirox olamine/zinc pyrithione, it revealed the marked synergistic inhibitory effect of the association, leading to a higher efficacy compared to ketoconazole. As to the fungicidal activity of ciclopirox olamine, it significantly increased with the contact time. After 15-30 min of contact between 1.5% ciclopirox olamine and Malassezia strains, a 2-log reduction of Malassezia counts was observed. The 1.5% ciclopirox olamine/1% zinc pyrithione association was characterized by a steady fungicidal efficacy whereas the 2% ketoconazole solution did not express any fungicidal effect. In conclusion, this study demonstrates the in vitro inhibitory and fungicidal efficacy of the ciclopirox olamine/zinc pyrithione association against Malassezia species and underscores its potential interest in the treatment of seborrheic dermatitis.

  7. Role of the Strength of Drug-Polymer Interactions on the Molecular Mobility and Crystallization Inhibition in Ketoconazole Solid Dispersions.

    PubMed

    Mistry, Pinal; Mohapatra, Sarat; Gopinath, Tata; Vogt, Frederick G; Suryanarayanan, Raj

    2015-09-08

    The effects of specific drug-polymer interactions (ionic or hydrogen-bonding) on the molecular mobility of model amorphous solid dispersions (ASDs) were investigated. ASDs of ketoconazole (KTZ), a weakly basic drug, with each of poly(acrylic acid) (PAA), poly(2-hydroxyethyl methacrylate) (PHEMA), and polyvinylpyrrolidone (PVP) were prepared. Drug-polymer interactions in the ASDs were evaluated by infrared and solid-state NMR, the molecular mobility quantified by dielectric spectroscopy, and crystallization onset monitored by differential scanning calorimetry (DSC) and variable temperature X-ray diffractometry (VTXRD). KTZ likely exhibited ionic interactions with PAA, hydrogen-bonding with PHEMA, and weaker dipole-dipole interactions with PVP. On the basis of dielectric spectroscopy, the α-relaxation times of the ASDs followed the order: PAA > PHEMA > PVP. In addition, the presence of ionic interactions also translated to a dramatic and disproportionate decrease in mobility as a function of polymer concentration. On the basis of both DSC and VTXRD, an increase in strength of interaction translated to higher crystallization onset temperature and a decrease in extent of crystallization. Stronger drug-polymer interactions, by reducing the molecular mobility, can potentially delay the crystallization onset temperature as well as crystallization extent.

  8. Revisiting the Metabolism and Bioactivation of Ketoconazole in Human and Mouse Using Liquid Chromatography–Mass Spectrometry-Based Metabolomics

    PubMed Central

    Kim, Ju-Hyun; Choi, Won-Gu; Lee, Sangkyu; Lee, Hye Suk

    2017-01-01

    Although ketoconazole (KCZ) has been used worldwide for 30 years, its metabolic characteristics are poorly described. Moreover, the hepatotoxicity of KCZ limits its therapeutic use. In this study, we used liquid chromatography–mass spectrometry-based metabolomics to evaluate the metabolic profile of KCZ in mouse and human and identify the mechanisms underlying its hepatotoxicity. A total of 28 metabolites of KCZ, 11 of which were novel, were identified in this study. Newly identified metabolites were classified into three categories according to the metabolic positions of a piperazine ring, imidazole ring, and N-acetyl moiety. The metabolic characteristics of KCZ in human were comparable to those in mouse. Moreover, three cyanide adducts of KCZ were identified in mouse and human liver microsomal incubates as “flags” to trigger additional toxicity study. The oxidation of piperazine into iminium ion is suggested as a biotransformation responsible for bioactivation. In summary, the metabolic characteristics of KCZ, including reactive metabolites, were comprehensively understood using a metabolomics approach. PMID:28335386

  9. Design, synthesis, and evaluation of (2S,4R)-Ketoconazole sulfonamide analogs as potential treatments for Metabolic Syndrome.

    PubMed

    Blass, Benjamin E; Iyer, Pravin; Abou-Gharbia, Magid; Childers, Wayne E; Gordon, John C; Ramanjulu, Mercy; Morton, George; Arumugam, Premkumar; Boruwa, Joshodeep; Ellingboe, John; Mitra, Sayan; Nimmareddy, Rajashekar Reddy; Paliwal, Shalini; Rajasekhar, Jamallamudi; Shivakumar, Savithiri; Srivastava, Pratima; Tangirala, Raghuram S; Venkataramanaiah, Konda; Yanamandra, Mahesh

    2016-12-01

    Metabolic Syndrome, also referred to as 'Syndrome X' or 'Insulin Resistance Syndrome,' remains a major, unmet medical need despite over 30years of intense effort. Recent research suggests that there may be a causal link between this condition and abnormal glucocorticoid processing. Specifically, dysregulation of the hypothalamic-pituitary-adrenocortical (HPA) axis leads to increased systemic cortisol concentrations. Cushing' syndrome, a disorder that is also typified by a marked elevation in levels of cortisol, produces clinical symptomology that is similar to those observed in MetS, and they can be alleviated by decreasing circulating cortisol concentrations. As a result, it has been suggested that decreasing systemic cortisol concentration might have a positive impact on the progression of MetS. This could be accomplished through inhibition of enzymes in the cortisol synthetic pathway, 11β-hydroxylase (Cyp11B1), 17α-hydroxylase-C17,20-lyase (Cyp17), and 21-hydroxylase (Cyp21). We have identified a series of novel sulfonamide analogs of (2S,4R)-Ketoconazole that are potent inhibitors of these enzymes. In addition, selected members of this class of compounds have pharmacokinetic properties consistent with orally delivered drugs, making them well suited to further investigation as potential therapies for MetS. Copyright © 2016 Elsevier Ltd. All rights reserved.

  10. In-vitro release and permeation studies of ketoconazole from optimized dermatological vehicles using powder, nanoparticles and solid dispersion forms of drug

    NASA Astrophysics Data System (ADS)

    Mohammed, Irfan A.

    To optimize the clinical efficacy of Ketoconazole from an externally applied product, this project was undertaken to evaluate the drug release/permeation profile from various dermatological vehicles using regular powder, nanoparticles and solid dispersion forms with reduced level of drug. Nanoparticles of drug were prepared by wet media milling method using Polyvinylpyrrolidone (PVP-10K) as a stabilizer. The nanoparticles were in the size range of 250-300nm. Solid dispersion was prepared by solvent evaporation method using drug to PVP-10K at a weight ratio of (1:2). Formulations containing 1% w/w drug were developed using HPMC gel, Carbomer gel and a cationic cream as the vehicles. Penetration enhancers including propylene glycol (PG), dimethylsulfoxide (DMSO) and polyethylene glycol 400 (PEG-400) at various levels were evaluated. A commercial 2% w/w ketoconazole product was included as a control for comparison. Studies were carried out with Franz Diffusion Cells using cellulose membrane and human cadaver skin for two and six hour studies. Among the formulations evaluated, the general rank order of the drug release through the cellulose membrane was observed to be: HPMC gel base > Anionic gel base > Cationic gel base > Commercial product. The addition of penetration enhancers showed variable effects in all samples evaluated. However, the HPMC gel-based vehicle showed significant effect in enhancing the drug release in the presence of DMSO. The formulation containing 1% w/w ketoconazole and 20% w/w DMSO gave a maximum drug release of 20.21% when compared to only 1.60% from the commercial product. This represents a twelve fold increase in the release of ketoconazole from the formulation. Furthermore, when the optimum gel-based formulation containing 1% w/w ketoconazole was studied over an extended period of 6 hours, it gave 36.01% drug release from the sample formulation compared to only 2.00% from the commercial product. Finally, this formulation was selected to

  11. Improved dissolution and absorption of ketoconazole in the presence of organic acids as pH-modifiers.

    PubMed

    Adachi, Masashi; Hinatsu, Yuta; Kusamori, Kosuke; Katsumi, Hidemasa; Sakane, Toshiyasu; Nakatani, Manabu; Wada, Koichi; Yamamoto, Akira

    2015-08-30

    Formulation development of poorly water-soluble compounds can be challenging because of incomplete dissolution that causes low and variable bioavailability. Enhancing compound solubility is important and many techniques have been investigated to that end, but they require specific materials and machinery. This study investigates the incorporation of a pH-modifier as a method to increase compound solubility and uses ketoconazole (KZ), which is weakly basic (pKa: 6.5), as a model compound. Organic acids are effective pH-modifiers and are generally used in pharmaceutical industries. We successfully obtained granules containing variable organic acids (KZ/acid granule) using a high-shear mixer. Dissolution tests of the KZ/acid granule resulted in highly enhanced solubility under non-sink conditions. Adding water-soluble acids, such as citric acid (CA) and tartaric acid, resulted in more than 8-fold higher dissolution at pH 6.0 compared to that of KZ only. The granules containing citric acid (KZ/CA granule) improved the dissolution of KZ after oral administration to rats under low gastric acid conditions, where the bioavailability of the KZ/CA granules at elevated gastric pH was comparable with that of KZ only at gastric acidic pH. The incorporation of organic acids would result in effective therapeutic outcomes independent of gastric pH in patients. In addition, higher bioavailability of KZ was observed after oral administration of KZ/CA granules under gastric acidic pH conditions than that of KZ alone. Thus, CA improved the dissolution and absorption rate of KZ after oral administration. Copyright © 2015 Elsevier B.V. All rights reserved.

  12. Antioxidant activity and protective effect of Clitoria ternatea flower extract on testicular damage induced by ketoconazole in rats.

    PubMed

    Iamsaard, Sitthichai; Burawat, Jaturon; Kanla, Pipatpong; Arun, Supatcharee; Sukhorum, Wannisa; Sripanidkulchai, Bungorn; Uabundit, Nongnut; Wattathorn, Jintanaporn; Hipkaeo, Wiphawi; Fongmoon, Duriya; Kondo, Hisatake

    2014-06-01

    Ketoconazole (KET), an antifungal drug, has adverse effects on the male reproductive system. Pre-treatments with antioxidant plant against testicular damage induced by KET are required. The flowers of Clitoria ternatea (CT) are proven to have hepatoprotective potential. However, the protective effect on KET-induced testicular damage has not been reported. To investigate the protective effect of CT flower extracts with antioxidant activity on male reproductive parameters including sperm concentration, serum testosterone level, histopathology of the testis, and testicular tyrosine phosphorylation levels in rats induced with KET. The antioxidant activity of CT flower extracts was determined using 2,2-diphenyl-1-picrylhydrazyl (DPPH) and ferric reducing antioxidant power (FRAP) assays. Male rats were treated with CT flower extracts (10, 50, or 100 mg/kg BW) or distilled water via a gastric tube for 28 d (preventive period: Days 1-21) and induced by KET (100 mg/kg BW) via intraperitoneal injection for 7 d (induction period: Days 22-28). After the experiment, all animals were examined for the weights of the testis, epididymis plus vas deferens and seminal vesicle, serum testosterone levels, sperm concentration, histological structures and diameter of testis, and testicular tyrosine phosphorylation levels by immunoblotting. The CT flower extracts had capabilities for DPPH scavenging and high reducing power. At 100 mg/kg BW, the extract had no toxic effects on the male reproductive system. Significantly, in CT+KET groups, CT flower extracts (50 and 100 mg/kg BW) alleviated the reduction of reproductive organ weight parameters, testosterone levels, and sperm concentration. In addition, CT flower extracts gave protection from testicular damage in KET-induced rats. Moreover, in the CT100+KET group, CT flower extracts significantly enhanced the expression of a testicular 50-kDa tyrosine phosphorylated protein compared with that of other groups. C. ternatea flower extracts

  13. Effect of Ketoconazole, a Cytochrome P450 Inhibitor, on the Efficacy of Quinine and Halofantrine against Schistosoma mansoni in Mice

    PubMed Central

    Sabra, Abdel-Nasser Abdel-Aal; Hammam, Olfat Ali; El-Lakkany, Naglaa Mohamed

    2013-01-01

    The fear that schistosomes will become resistant to praziquantel (PZQ) motivates the search for alternatives to treat schistosomiasis. The antimalarials quinine (QN) and halofantrine (HF) possess moderate antischistosomal properties. The major metabolic pathway of QN and HF is through cytochrome P450 (CYP) 3A4. Accordingly, this study investigates the effects of CYP3A4 inhibitor, ketoconazole (KTZ), on the antischistosomal potential of these quinolines against Schistosoma mansoni infection by evaluating parasitological, histopathological, and biochemical parameters. Mice were classified into 7 groups: uninfected untreated (I), infected untreated (II), infected treated orally with PZQ (1,000 mg/kg) (III), QN (400 mg/kg) (IV), KTZ (10 mg/kg)+QN as group IV (V), HF (400 mg/kg) (VI), and KTZ (as group V)+HF (as group VI) (VII). KTZ plus QN or HF produced more inhibition (P<0.05) in hepatic CYP450 (85.7% and 83.8%) and CYT b5 (75.5% and 73.5%) activities, respectively, than in groups treated with QN or HF alone. This was accompanied with more reduction in female (89.0% and 79.3%), total worms (81.4% and 70.3%), and eggs burden (hepatic; 83.8%, 66.0% and intestinal; 68%, 64.5%), respectively, and encountering the granulomatous reaction to parasite eggs trapped in the liver. QN and HF significantly (P<0.05) elevated malondialdehyde levels when used alone or with KTZ. Meanwhile, KTZ plus QN or HF restored serum levels of ALT, albumin, and reduced hepatic glutathione (KTZ+HF) to their control values. KTZ enhanced the therapeutic antischistosomal potential of QN and HF over each drug alone. Moreover, the effect of KTZ+QN was more evident than KTZ+HF. PMID:23710083

  14. Multiple oral dosing of ketoconazole influences pharmacokinetics of quinidine after intravenous and oral administration in beagle dogs.

    PubMed

    Kuroha, M; Shirai, Y; Shimoda, M

    2004-10-01

    In this study, we investigated the effect of multiple oral dosing of ketoconazole (KTZ) on pharmacokinetics of quinidine (QN), a CYP3A substrate with low hepatic clearance, after i.v. and oral administration in beagle dogs. Four dogs were given p.o. KTZ for 20 days (200 mg, b.i.d.). QN was administered either i.v. (1 mg/kg) or p.o. (100 mg) 10 and 20 days before the KTZ treatment and 10 and 20 days after start of KTZ treatment. Multiple oral dosing of KTZ decreased significantly alpha and beta, whereas increased t(1/2beta), V(1), and k(a). The KTZ treatment also decreased significantly both total body clearance (Cl(tot)) and oral clearance (Cl(oral)). No significant change in bioavailability was observed in the presence of KTZ. Co-administration of KTZ increased C(max) of QN to about 1.5-fold. Mean resident time after i.v. administration (MRT(i.v.)), and after oral administration (MRT(p.o.)) of QN were prolonged to about twofold, whereas mean absorption time (MAT) was decreased to 50%. Volume of distribution at steady state (V(d(ss))) of QN was unchanged in the presence of KTZ. These alterations may be because of a decrease in metabolism of QN by inhibition of KTZ on hepatic CYP3A activity. In conclusion, multiple oral dosing of KTZ affected largely pharmacokinetics of QN after i.v. and oral administration in beagle dogs. Therefore, KTZ at a clinical dosing regimen may markedly change the pharmacokinetics of drugs primarily metabolized by CYP3A with low hepatic clearance in dogs. In clinical use, much attention should be paid to concomitant administration of KTZ with the drug when given either p.o. or i.v.

  15. In vitro characterization of the inhibitory effects of ketoconazole on metabolic activities of cytochrome P-450 in canine hepatic microsomes.

    PubMed

    Kuroha, Masanori; Kuze, Yoji; Shimoda, Minoru; Kokue, Eiichi

    2002-06-01

    To evaluate the inhibitory potency of ketoconazole (KTZ) on the metabolic activities of isozymes of cytochrome P-450 (CYP) in dogs. 4 healthy 1-year-old male Beagles. Hepatic microsomes were harvested from 4 dogs after euthanasia. To investigate the effects of KTZ on CYP metabolic activities, 7-ethoxyresorufin, tolbutamide, bufuralol, and midazolam hydrochloride were used as specific substrates for CYP1A1/2, CYP2C21, CYP2D15, and CYP3A12, respectively. The concentrations of metabolites formed by CYP were measured by high-performance liquid chromatography, except for the resorufin concentrations that were measured by a fluorometric method. The reaction velocity-substrate concentration data were analyzed to obtain kinetic variables, including maximum reaction velocity, Michaelis-Menten constant, and inhibitory constant (Ki). KTZ competitively inhibited 7-ethoxyresorufin O-deethylation and midazolam 4-hydroxylation; it noncompetitively inhibited tolbutamide methylhydroxylation. Bufuralol 1'-hydroxylation was inhibited slightly by KTZ. The mean Ki values of KTZ were 10.6+/-6.0, 170+/-2.5, and 0.180+/-0.131 microM for 7-ethoxyresorufin O-deethylation, tolbutamide methylhydroxylation, and midazolam 4-hydroxylation, respectively. In dogs, KTZ at a therapeutic dose may change the pharmacokinetics of CYP3A12 substrates as a result of inhibition of their biotransformation. Furthermore, no influence of KTZ on the pharmacokinetics of CYP1A1/2, CYP2C21, and CYP2D15 substrates are likely. In clinical practice, adverse drug effects may develop when KTZ is administered concomitantly with a drug that is primarily metabolized by CYP3A12.

  16. Effect of multiple dosing of ketoconazole on pharmacokinetics of midazolam, a cytochrome P-450 3A substrate in beagle dogs.

    PubMed

    Kuroha, Masanori; Azumano, Akinori; Kuze, Yoji; Shimoda, Minoru; Kokue, Eiichi

    2002-01-01

    To evaluate effects of multiple dosing of ketoconazole (KTZ) on hepatic CYP3A, the pharmacokinetics of intravenous midazolam (MDZ, 0.5 mg/kg) before and during multiple dosing of KTZ were investigated in beagle dogs. KTZ tablets were given orally to dogs (n = 4) for 30 days (200 mg b.i.d.). With coadministration of KTZ, t(1/2beta) of MDZ were significantly increased both on day 1 (2-fold) and on day 30 (3-fold). Total body clearance (CL(tot)) of MDZ declined gradually during the first 5 days after the start of KTZ treatment, and thereafter CL(tot) appeared to reach a plateau phase (one-fourth), depending on plasma KTZ concentrations. The effects of KTZ on the biotransformation of MDZ were also investigated using dog liver microsomes (n = 5). The K(i) values of KTZ for MDZ 1'-hydroxylation and 4-hydroxylation were 0.0237 and 0.111 microM, respectively, indicating that KTZ extensively inhibits hepatic CYP3A activity in dogs. CL(tot) values estimated from in vitro K(i) values corrected by unbound fraction of KTZ and unbound concentrations of the drug in plasma were consistent with in vivo CL(tot) of MDZ. The results in this study suggest that KTZ treatment is necessary until plasma concentrations of the drug reach a steady state to evaluate the effect of multiple dosing of the drug on hepatic CYP3A in vivo. In addition, it is suggested that K(i) values corrected by unbound fraction of KTZ and unbound concentrations of the drug in plasma enable precise in vitro-in vivo scaling.

  17. Transcription of key genes regulating gonadal steroidogenesis in control and ketoconazole- or vinclozolin-exposed fathead minnows

    SciT

    Villeneuve, Daniel L.; Blake, Lindsey S.; Brodin, Jeffrey

    2007-08-01

    This study evaluated changes in the expression of steroidogenesis-related genes in male fathead minnows exposed to ketoconazole (KTC) or vinclozolin (VZ) for 21 days. The aim was to evaluate links between molecular changes and higher level outcomes after exposure to endocrine-active chemicals (EACs) with different modes of action. To aid our analysis and interpretation of EAC-related effects, we first examined variation in the relative abundance of steroidogenesis-related gene transcripts in the gonads of male and female fathead minnows as a function of age, gonad development, and spawning status, independent of EAC exposure. Gonadal expression of several genes varied with agemore » and/or gonadal somatic index in either males or females. However, with the exception of aromatase, steroidogenesis-related gene expression did not vary with spawning status. Following the baseline experiments, expression of the selected genes in male fathead minnows exposed to KTC or VZ was evaluated in the context of effects observed at higher levels of organization. Exposure to KTC elicited changes in gene transcription that were consistent with an apparent compensatory response to the chemical's anticipated direct inhibition of steroidogenic enzyme activity. Exposure to VZ, an antiandrogen expected to indirectly impact steroidogenesis, increased pituitary expression of follicle-stimulating hormone beta-subunit as well as testis expression of 20beta-hydroxysteroid dehydrogenase and luteinizing hormone receptor transcripts. Results of this study contribute to ongoing research aimed at understanding responses of the teleost hypothalamic-pituitary-gonadal axis to different types of EACs and how changes in molecular endpoints translate into apical outcomes reflective of either adverse effect or compensation.« less

  18. Vitamin D3 May Ameliorate the Ketoconazole Induced Adrenal Injury: Histological and Immunohistochemical Studies on Albino Rats.

    PubMed

    Khalil, Mahmoud Salah

    2015-08-27

    Ketoconazole (KZ) is used widely for treating the superficial, systemic fungal activities and hyperandrogenemic states. Its uses are limited by its deleterious effect on histological structure and function of the adrenal cortex. This study investigates whether vitamin D3 supplement can ameliorate the morphological changes induced by KZ. Thirty four adult male albino rats were randomized into control group (Group I) which was subdivided into: control 1 (n=7) and control 2 (n=7): In control 1, rats were intraperitoneal (I.P) injected once with 1 ml of polyethylene glycol-400 for 15 consecutive days and control 2 rats were injected I.P with (1 μg/kg) of vitamin D3 for the same period. Group II (n=10): rats were I.P injected with KZ (10 mg/100 g of body weight) once daily for 15 days; Group III (n=10): rats were I.P concomitantly injected with KZ and vitamin D3 similar doses to animals in groups II and control 2 respectively. Blood samples were collected to determine plasma ACTH, corticosterone and aldosterone levels. The right adrenal specimens sections were stained with Haematoxylin & Eosin and Masson Trichrome for histological studies and treated with Bax, Ubiquitin and vitamin D receptors for immunohistochemical studies. KZ induced adrenal cortical morphological changes in forms of disturbed adrenocorticocyte cytological architecture, nuclear changes, and intracellular lipid accumulation. KZ also increased adrenal Bax and Ub but decreased the vitamin D receptors immunopositive staining expression, in addition to increased plasma ACTH as well as decreased corticosterone and aldosterone levels. These changes were ameliorated by supplementing with vitamin D3.

  19. Vitamin D3 May Ameliorate the Ketoconazole Induced Adrenal Injury: Histological and Immunohistochemical Studies on Albino Rats

    PubMed Central

    Khalil, Mahmoud Salah

    2015-01-01

    Ketoconazole (KZ) is used widely for treating the superficial, systemic fungal activities and hyperandrogenemic states. Its uses are limited by its deleterious effect on histological structure and function of the adrenal cortex. This study investigates whether vitamin D3 supplement can ameliorate the morphological changes induced by KZ. Thirty four adult male albino rats were randomized into control group (Group I) which was subdivided into: control 1 (n=7) and control 2 (n=7): In control 1, rats were intraperitoneal (I.P) injected once with 1 ml of polyethylene glycol-400 for 15 consecutive days and control 2 rats were injected I.P with (1 μg/kg) of vitamin D3 for the same period. Group II (n=10): rats were I.P injected with KZ (10 mg/100 g of body weight) once daily for 15 days; Group III (n=10): rats were I.P concomitantly injected with KZ and vitamin D3 similar doses to animals in groups II and control 2 respectively. Blood samples were collected to determine plasma ACTH, corticosterone and aldosterone levels. The right adrenal specimens sections were stained with Haematoxylin & Eosin and Masson Trichrome for histological studies and treated with Bax, Ubiquitin and vitamin D receptors for immunohistochemical studies. KZ induced adrenal cortical morphological changes in forms of disturbed adrenocorticocyte cytological architecture, nuclear changes, and intracellular lipid accumulation. KZ also increased adrenal Bax and Ub but decreased the vitamin D receptors immunopositive staining expression, in addition to increased plasma ACTH as well as decreased corticosterone and aldosterone levels. These changes were ameliorated by supplementing with vitamin D3. PMID:26379312

  20. Pharmacokinetic interaction between the CYP3A4 inhibitor ketoconazole and the hormone drospirenone in combination with ethinylestradiol or estradiol.

    PubMed

    Wiesinger, Herbert; Berse, Matthias; Klein, Stefan; Gschwend, Simone; Höchel, Joachim; Zollmann, Frank S; Schütt, Barbara

    2015-12-01

    The present study was conducted to investigate the influence of the strong CYP3A4 inhibitor ketoconazole (KTZ) on the pharmacokinetics of drospirenone (DRSP) administered in combination with ethinylestradiol (EE) or estradiol (E2). This was a randomized, multicentre, open label, one way crossover, fixed sequence study with two parallel treatment arms. A group sequential design allowed terminating the study for futility after first study cohort. About 50 healthy young women were randomized 1 : 1 to 'DRSP/EE' or 'DRSP/E2'. Subjects in the 'DRSP/EE' group received DRSP 3 mg/EE 0.02 mg (YAZ®, Bayer) once daily for 21 to 28 days followed by DRSP 3 mg/EE 0.02 mg once daily plus KTZ 200 mg twice daily for 10 days. Subjects in the 'DRSP/E2' group received DRSP 3 mg/E2 1.5 mg (research combination) once daily for 21 to 28 days followed by DRSP 3 mg/E2 1.5 mg once daily plus KTZ 200 mg twice daily for 10 days. Oral co-administration of DRSP/EE or DRSP/E2 and KTZ resulted in an increase in DRSP exposure (AUC(0,24 h)) in both treatment groups: DRSP/EE group: 2.68-fold DRSP increase (90% CI 2.44, 2.95); DRSP/E2 group: 2.30-fold DRSP increase (90% CI 2.08, 2.54). EE and estrone (metabolite of E2) exposures were increased ~1.4-fold whereas E2 exposure was largely unaffected by KTZ co-administration. A moderate pharmacokinetic drug-drug interaction between DRSP and KTZ was demonstrated in this study. No relevant changes of medical concern were detected in the safety data collected in this study. © 2015 The British Pharmacological Society.

  1. Multicenter, double-blind, parallel group study investigating the non-inferiority of efficacy and safety of a 2% miconazole nitrate shampoo in comparison with a 2% ketoconazole shampoo in the treatment of seborrhoeic dermatitis of the scalp.

    PubMed

    Buechner, Stanislaw A

    2014-06-01

    This study investigated the non-inferiority of efficacy and tolerance of 2% miconazole nitrate shampoo in comparison with 2% ketoconazole shampoo in the treatment of scalp seborrheic dermatitis. A randomized, double-blind, comparative, parallel group, multicenter study was done. A total of 274 patients (145 miconazole, 129 ketoconazole) were enrolled. Treatment was twice-weekly for 4 weeks. Safety and efficacy assessments were made at baseline and at weeks 2 and 4. Assessments included symptoms of erythema, itching, scaling ['Symptom Scale of Seborrhoeic Dermatitis' (SSSD)], disease severity and global change [Clinical Global Impressions (CGIs) and Patient Global Impressions (PGIs)]. Miconazole shampoo is at least as effective and safe as ketoconazole shampoo in treating scalp seborrheic dermatitis scalp.

  2. Molecular design of two sterol 14α-demethylase homology models and their interactions with the azole antifungals ketoconazole and bifonazole

    NASA Astrophysics Data System (ADS)

    Rupp, Bernd; Raub, Stephan; Marian, Christel; Höltje, Hans-Dieter

    2005-03-01

    Sterol 14α-demethylase (CYP51) is one of the known major targets for azole antifungals. Therapeutic side effects of these antifungals are based on interactions of the azoles with the human analogue enzyme. This study describes for the first time a comparison of a human CYP51 (HU-CYP51) homology model with a homology model of the fungal CYP51 of Candida albicans (CA-CYP51). Both models are constructed by using the crystal structure of Mycobacterium tuberculosis MT-CYP51 (PDB code: 1EA1). The binding mode of the azole ketoconazole is investigated in molecular dynamics simulations with the GROMACS force field. The usage of special parameters for the iron azole complex binding is necessary to obtain the correct complex geometry in the active site of the enzyme models. Based on the dynamics simulations it is possible to explain the enantioselectivity of the human enzyme and also to predict the binding mode of the isomers of ketoconazole in the active site of the fungal model.

  3. Cytochrome P450 3A4 in vivo ketoconazole competitive inhibition: determination of Ki and dangers associated with high clearance drugs in general.

    PubMed

    Boxenbaum, H

    1999-01-01

    Assuming complete hepatic substrate metabolism and system linearity, quantitative effects of in vivo competitive inhibition are investigated. Following oral administration of a substrate in the presence of a competitive inhibitor, determination of the inhibition constant (Ki) is possible when plasma concentration-time profiles of both substrate and inhibitor are available. When triazolam is the P450 3A4 substrate and ketoconazole the competitive inhibitor, Ki approximately 1.2 microg/mL in humans. The effects of competitive inhibition can be divided into two components: first-pass hepatic metabolism and systemic metabolism. For drugs with high hepatic extraction ratios, the impact of competitive inhibition on hepatic first-pass metabolism can be particularly dramatic. For example, human terfenadine hepatic extraction goes from 95% in the absence of a competitive inhibitor to 35% in the presence of one (ketoconazole, 200 mg po Q 12 h dosed to steady-state). First-pass extraction therefore goes from 5% in the absence of the inhibitor to 65% in its presence. The combined effect on first-pass and systemic metabolism produces an approximate 37 fold increase in terfenadine area under the plasma concentration-time curve. Assuming intact drug is active and/or toxic, development of metabolized drugs with extensive first-pass metabolism should be avoided if possible, since inhibition of metabolism may lead to profound increases in exposure.

  4. The impact of supersaturation level for oral absorption of BCS class IIb drugs, dipyridamole and ketoconazole, using in vivo predictive dissolution system: Gastrointestinal Simulator (GIS).

    PubMed

    Tsume, Yasuhiro; Matsui, Kazuki; Searls, Amanda L; Takeuchi, Susumu; Amidon, Gregory E; Sun, Duxin; Amidon, Gordon L

    2017-05-01

    The development of formulations and the assessment of oral drug absorption for Biopharmaceutical Classification System (BCS) class IIb drugs is often a difficult issue due to the potential for supersaturation and precipitation in the gastrointestinal (GI) tract. The physiological environment in the GI tract largely influences in vivo drug dissolution rates of those drugs. Thus, those physiological factors should be incorporated into the in vitro system to better assess in vivo performance of BCS class IIb drugs. In order to predict oral bioperformance, an in vitro dissolution system with multiple compartments incorporating physiologically relevant factors would be expected to more accurately predict in vivo phenomena than a one-compartment dissolution system like USP Apparatus 2 because, for example, the pH change occurring in the human GI tract can be better replicated in a multi-compartmental platform. The Gastrointestinal Simulator (GIS) consists of three compartments, the gastric, duodenal and jejunal chambers, and is a practical in vitro dissolution apparatus to predict in vivo dissolution for oral dosage forms. This system can demonstrate supersaturation and precipitation and, therefore, has the potential to predict in vivo bioperformance of oral dosage forms where this phenomenon may occur. In this report, in vitro studies were performed with dipyridamole and ketoconazole to evaluate the precipitation rates and the relationship between the supersaturation levels and oral absorption of BCS class II weak base drugs. To evaluate the impact of observed supersaturation levels on oral absorption, a study utilizing the GIS in combination with mouse intestinal infusion was conducted. Supersaturation levels observed in the GIS enhanced dipyridamole and ketoconazole absorption in mouse, and a good correlation between their supersaturation levels and their concentration in plasma was observed. The GIS, therefore, appears to represent in vivo dissolution phenomena and

  5. In vitro activity of an ear rinse containing tromethamine, EDTA, benzyl alcohol and 0.1% ketoconazole on Malassezia organisms from dogs with otitis externa.

    PubMed

    Cole, Lynette K; Luu, Dao H; Rajala-Schultz, Paivi J; Meadows, Cheyney; Torres, Audrey H

    2007-04-01

    The purpose of this study was to evaluate the in vitro activity of an ear rinse containing tromethamine, EDTA, benzyl alcohol and 0.1% ketoconazole in purified water on Malassezia organisms from dogs with otitis externa. Malassezia organisms were collected from ear swab samples from the external ear canal of 19 dogs with otitis externa plus one control strain of Malassezia pachydermatis. Three test solutions were evaluated: ER (EDTA, tromethamine, benzyl alcohol), ER + keto (EDTA, tromethamine, benzyl alcohol, ketoconazole), and H2O (purified water). Ten-millilitre aliquots of each test solution was transferred into 20 tubes and inoculated with one of the isolates (1 tube per isolate: 19 clinical and 1 control strain). Samples were retrieved from each tube at five time points (0, 15, 30, 45 and 60 min), transferred to Petri dishes, mixed with Sabouraud dextrose agar supplemented with 0.5% Tween 80 and incubated. Following incubation, the plates were examined for growth and colonies counted as colony-forming units per millilitre. The data were analysed using a repeated measures analysis, with pair-wise comparisons of solution-time combinations. There was a significant reduction in Malassezia growth in ER + keto at all time points (P < 0.0001) compared to time zero. Neither ER nor H2O had any effect on the growth of Malassezia. ER + keto was significantly more effective in reducing Malassezia growth (P < 0.0001) at all time points compared to both ER and H2O. ER + keto may be useful in the treatment of Malassezia otitis externa. Future studies should be performed to evaluate the in vivo efficacy of ER + keto as treatment for otic infections caused by Malassezia.

  6. A rapid MCM-41 dispersive micro-solid phase extraction coupled with LC/MS/MS for quantification of ketoconazole and voriconazole in biological fluids.

    PubMed

    Yahaya, Noorfatimah; Sanagi, Mohd Marsin; Abd Aziz, Noorizan; Wan Ibrahim, Wan Aini; Nur, Hadi; Loh, Saw Hong; Kamaruzaman, Sazlinda

    2017-02-01

    A rapid dispersive micro-solid phase extraction (D-μ-SPE) combined with LC/MS/MS method was developed and validated for the determination of ketoconazole and voriconazole in human urine and plasma samples. Synthesized mesoporous silica MCM-41 was used as sorbent in d-μ-SPE of the azole compounds from biological fluids. Important D-μ-SPE parameters, namely type desorption solvent, extraction time, sample pH, salt addition, desorption time, amount of sorbent and sample volume were optimized. Liquid chromatographic separations were carried out on a Zorbax SB-C 18 column (2.1 × 100 mm, 3.5 μm), using a mobile phase of acetonitrile-0.05% formic acid in 5 mm ammonium acetate buffer (70:30, v/v). A triple quadrupole mass spectrometer with positive ionization mode was used for the determination of target analytes. Under the optimized conditions, the calibration curves showed good linearity in the range of 0.1-10,000 μg/L with satisfactory limit of detection (≤0.06 μg/L) and limit of quantitation (≤0.3 μg/L). The proposed method also showed acceptable intra- and inter-day precisions for ketoconazole and voriconazole from urine and human plasma with RSD ≤16.5% and good relative recoveries in the range 84.3-114.8%. The MCM-41-D-μ-SPE method proved to be rapid and simple and requires a small volume of organic solvent (200 μL); thus it is advantageous for routine drug analysis. Copyright © 2016 John Wiley & Sons, Ltd.

  7. The in vitro antifungal activity of ketoconazole, zinc pyrithione, and selenium sulfide against Pityrosporum and their efficacy as a shampoo in the treatment of experimental pityrosporosis in guinea pigs.

    PubMed

    Van Cutsem, J; Van Gerven, F; Fransen, J; Schrooten, P; Janssen, P A

    1990-06-01

    The fungistatic and fungicidal activity of ketoconazole, zinc pyrithione, and selenium sulfide against Pityrosporum, a yeast thought to play a pathogenic role in seborrheic dermatitis and dandruff, was assessed in Dixon broth for Pityrosporum ovale and Sabouraud broth for Pityrosporum pachydermatis. Ketoconazole inhibited growth at concentrations ranging from 0.001 to 1 micrograms/ml. For zinc pyrithione and selenium sulfide higher concentrations were needed. In a guinea pig model the efficacy of treatment with four shampoos (Nizoral [Jansen], EDS Zinc [Schering], Zinkan [Lederle], and Selsun [Abbott]) was compared. The animals were inoculated for 7 consecutive days on intact skin. The lesions were scored for erythema, folliculitis, and hyperkeratosis 24 hours after the last inoculation and after treatment. Final evaluations were made 13 days after infection (10 days after last shampoo application). Treatment with undiluted and diluted (1:10) shampoos showed consistently superior clinical and mycologic results for Nizoral shampoo. None of the shampoos produced side effects.

  8. Selected endocrine disrupting compounds (vinclozolin, flutamide, ketoconazole and dicofol): effects on survival, occurrence of males, growth, molting and reproduction of Daphnia magna.

    PubMed

    Haeba, Maher H; Hilscherová, Klára; Mazurová, Edita; Bláha, Ludek

    2008-05-01

    Pollution-induced endocrine disruption in vertebrates and invertebrates is a worldwide environmental problem, but relatively little is known about effects of endocrine disrupting compounds (EDCs) in planktonic crustaceans (including Daphnia magna). Aims of the present study were to investigate acute 48 h toxicity and sub-chronic (4-6 days) and chronic (21 days) effects of selected EDCs in D. magna. We have investigated both traditional endpoints as well as other parameters such as sex determination, maturation, molting or embryogenesis in order to evaluate the sensitivity and possible use of these endpoints in ecological risk assessment. We have studied effects of four model EDCs (vinclozolin, flutamide, ketoconazole and dicofol) on D. magna using (i) an acute 48 h immobilization assay, (ii) a sub-chronic, 4-6 day assay evaluating development and the sex ratio of neonates, and (iii) a chronic, 21 day assay studying number of neonates, sex of neonates, molting frequency, day of maturation and the growth of maternal organisms. Acute EC50 values in the 48 h immobilization test were as follows (mg/L): dicofol 0.2, ketoconazole 1.5, flutamide 2.7, vinclozolin >3. Short-term, 4-6 day assays with sublethal concentrations showed that the sex ratio in Daphnia was modulated by vinclozolin (decreased number of neonate males at 1 mg/L) and dicofol (increase in males at 0.1 mg/L). Flutamide (up to 1 mg/L) had no effect on the sex of neonates, but inhibited embryonic development at certain stages during chronic assay, resulting in abortions. Ketoconazole had no significant effects on the studied processes up to 1 mg/L. Sex ratio modulations by some chemicals (vinclozolin and dicofol) corresponded to the known action of these compounds in vertebrates (i.e. anti-androgenicity and anti-oestrogenicity, respectively). Our study revealed that some chemicals known to affect steroid-regulated processes in vertebrates can also affect sublethal endpoints (e.g. embryonic sex determination

  9. Noncorticosteroid Combination Shampoo versus 1% Ketoconazole Shampoo for the Management of Mild-to-Moderate Seborrheic Dermatitis of the Scalp: Results from a Randomized, Investigator-Single-Blind Trial Using Clinical and Trichoscopic Evaluation

    PubMed Central

    Dall'Oglio, Federica; Lacarrubba, Francesco; Verzì, Anna Elisa; Micali, Giuseppe

    2016-01-01

    Purpose The aim of this study was to assess the efficacy and tolerability of a combination noncorticosteroid, antiinflammatory/antifungal shampoo versus 1% ketoconazole shampoo in the treatment of mild-to-moderate scalp seborrheic dermatitis (SD). Procedures Twenty patients were randomized to using the combination shampoo (group A, 10 patients) or the 1% ketoconazole shampoo (group B, 10 patients) 3 times a week every other day for 8 weeks. Efficacy was evaluated by measuring the degree of scaling and pruritus by clinical and trichoscopic examination using a 4-point scale. Additionally, a physician global assessment (PGA) was assessed at the end of the study. Results At 4 weeks, there was a significant reduction of scaling from baseline for both groups, while pruritus showed a significant reduction only for group A. After 8 weeks, there was a significant reduction of scaling and pruritus for both groups. PGA showed a complete response in 90% of the cases in both groups. Conclusions The results of our study demonstrate that the combination noncorticosteroid, antiinflammatory/antifungal shampoo represents an alternative approach to standard topical treatment for scalp SD. A noncorticosteroid shampoo may be equally safe and effective as ketoconazole shampoo for scalp SD, and trichoscopy provides accurate and reliable quantifiable data to assist in therapeutic monitoring. PMID:27171495

  10. Noncorticosteroid Combination Shampoo versus 1% Ketoconazole Shampoo for the Management of Mild-to-Moderate Seborrheic Dermatitis of the Scalp: Results from a Randomized, Investigator-Single-Blind Trial Using Clinical and Trichoscopic Evaluation.

    PubMed

    Dall'Oglio, Federica; Lacarrubba, Francesco; Verzì, Anna Elisa; Micali, Giuseppe

    2016-02-01

    The aim of this study was to assess the efficacy and tolerability of a combination noncorticosteroid, antiinflammatory/antifungal shampoo versus 1% ketoconazole shampoo in the treatment of mild-to-moderate scalp seborrheic dermatitis (SD). Twenty patients were randomized to using the combination shampoo (group A, 10 patients) or the 1% ketoconazole shampoo (group B, 10 patients) 3 times a week every other day for 8 weeks. Efficacy was evaluated by measuring the degree of scaling and pruritus by clinical and trichoscopic examination using a 4-point scale. Additionally, a physician global assessment (PGA) was assessed at the end of the study. At 4 weeks, there was a significant reduction of scaling from baseline for both groups, while pruritus showed a significant reduction only for group A. After 8 weeks, there was a significant reduction of scaling and pruritus for both groups. PGA showed a complete response in 90% of the cases in both groups. The results of our study demonstrate that the combination noncorticosteroid, antiinflammatory/antifungal shampoo represents an alternative approach to standard topical treatment for scalp SD. A noncorticosteroid shampoo may be equally safe and effective as ketoconazole shampoo for scalp SD, and trichoscopy provides accurate and reliable quantifiable data to assist in therapeutic monitoring.

  11. Lack of significant effect of bilastine administered at therapeutic and supratherapeutic doses and concomitantly with ketoconazole on ventricular repolarization: results of a thorough QT study (TQTS) with QT-concentration analysis.

    PubMed

    Tyl, Benoît; Kabbaj, Meriam; Azzam, Sara; Sologuren, Ander; Valiente, Román; Reinbolt, Elizabeth; Roupe, Kathryn; Blanco, Nathalie; Wheeler, William

    2012-06-01

    The effect of bilastine on cardiac repolarization was studied in 30 healthy participants during a multiple-dose, triple-dummy, crossover, thorough QT study that included 5 arms: placebo, active control (400 mg moxifloxacin), bilastine at therapeutic and supratherapeutic doses (20 mg and 100 mg once daily, respectively), and bilastine 20 mg administered with ketoconazole 400 mg. Time-matched, triplicate electrocardiograms (ECGs) were recorded with 13 time points extracted predose and 16 extracted over 72 hours post day 4 dosing. Four QT/RR corrections were implemented: QTcB; QTcF; a linear individual correction (QTcNi), the primary correction; and a nonlinear one (QTcNnl). Moxifloxacin was associated with a significant increase in QTcNi at all time points between 1 and 12 hours, inclusively. Bilastine administration at 20 mg and 100 mg had no clinically significant impact on QTc (maximum increase in QTcNi, 5.02 ms; upper confidence limit [UCL] of the 1-sided, 95% confidence interval, 7.87 ms). Concomitant administration of ketoconazole and bilastine 20 mg induced a clinically relevant increase in QTc (maximum increase in QTcNi, 9.3 ms; UCL, 12.16 ms). This result was most likely related to the cardiac effect of ketoconazole because for all time points, bilastine plasma concentrations were lower than those observed following the supratherapeutic dose.

  12. A Phase I, open-label, randomized, crossover study in three parallel groups to evaluate the effect of Rifampicin, Ketoconazole, and Omeprazole on the pharmacokinetics of THC/CBD oromucosal spray in healthy volunteers.

    PubMed

    Stott, Colin; White, Linda; Wright, Stephen; Wilbraham, Darren; Guy, Geoffrey

    2013-12-01

    This Phase I study aimed to assess the potential drug-drug interactions (pharmacokinetic [PK] and safety profile) of Δ9-tetrahydrocannabinol (THC)/cannabidiol (CBD) oromucosal spray (Sativex (®), nabiximols) in combination with cytochrome P450 (CYP450) inducer (rifampicin) or inhibitors (ketoconazole or omeprazole). Thirty-six healthy male subjects were divided into three groups of 12, and then randomized to one of two treatment sequences per group. Subjects received four sprays of THC/CBD (10.8/10 mg) alongside single doses of the CYP3A and 2C19 inducer rifampicin (600 mg), CYP3A inhibitor ketoconazole (400 mg) or CYP2C19 inhibitor omeprazole (40 mg). Plasma samples were analyzed for CBD, THC and its metabolite 11-hydroxy-THC (11-OH-THC). A single dose of four sprays of THC/CBD spray (10.8/10 mg) following repeated doses of rifampicin (600 mg) reduced the Cmax and AUC of all analytes. Cmax reduced from 2.94 to 1.88 ng/mL (-36%), 1.03 to 0.50 ng/mL (-52%) and 3.38 to 0.45 ng/mL (-87%) for THC, CBD and 11-OH-THC, respectively compared to single dose administration of THC/CBD spray alone. Ketoconazole co-administration with THC/CBD spray had the opposite effect, increasing the Cmax of the respective analytes from 2.65 to 3.36 ng/mL (+27%), 0.66 to 1.25 ng/mL (+89%) and 3.59 to 10.92 ng/mL (+204%). No significant deviations in Cmax or AUC for any analyte were observed when THC/CBD spray was co-administered with omeprazole. THC/CBD spray was well tolerated by the study subjects both alone and in combination with rifampicin, ketoconazole and omeprazole. Evaluation of the PKs of THC/CBD spray alone and in combination with CYP450 inhibitors/inducers suggests that all analytes are substrates for the isoenzyme CYP3A4, but not CYP2C19. On the basis of our findings, there is likely to be little impact on other drugs metabolized by CYP enzymes on the PK parameters of THC/CBD spray, but potential effects should be taken into consideration when co-administering THC/CBD spray

  13. Evaluation of selected Indian medicinal plants for antagonistic potential against Malassezia spp. and the synergistic effect of embelin in combination with ketoconazole.

    PubMed

    Sivasankar, Chandran; Gayathri, Subramanian; Bhaskar, James Prabhanand; Krishnan, Venkat; Pandian, Shunmugiah Karutha

    2017-09-01

    The genus Malassezia comprises of extremely lipophilic yeasts secreting lipases as a vital factor for survival. They are emerging as opportunistic pathogens in medical microbiology and dermatology by causing recurring and recalcitrant infection. Combinatorial therapy is a constructive way to combat infectious diseases. In that prospect, totally 16 Indian medicinal plants were screened, among which a maximum degree of antimicrobial activity was ascertained in Embelia ribes. Subsequently embelin was identified as the bioactive principle with antagonistic potential by comparative antimicrobial assay and FTIR analysis. The MIC of embelin was determined as 400 μg/ml exhibiting ∼75% of growth inhibition. Further, a fungistatic activity based on anti-lipase potential (65-89%) of embelin has been clearly substantiated by XTT and lipase assay. In addition, embelin exhibited a synergistic effect with the antifungal drug ketoconazole (KTZ) against four different Malassezia spp. with FIC index of 0.5. Therefore, the combinations of embelin and KTZ may represent a promising therapeutic regimen to treat Malassezia infections with subjugated clinical and environmental toxicity. To the best of our knowledge, this is the first report delineating the anti-lipase activity of embelin and in vitro synergistic interaction between embelin and KTZ against Malassezia spp. Copyright © 2017 Elsevier Ltd. All rights reserved.

  14. Development of ketoconazole nanovesicular system using 1,2-hexanediol and 1,4-cyclohexanediol for dermal targeting delivery: physicochemical characterization and in vitro/in vivo evaluation

    NASA Astrophysics Data System (ADS)

    Wang, Jinping; Guo, Fang; Ma, Man; Li, Nan; Tan, Fengping

    2014-07-01

    The present study was aimed at the encapsulation of ketoconazole (KCZ) in the novel modified nanovesicles for dermal targeting delivery. To this purpose, innovative modified vesicles were prepared with soy phospholipid and aqueous solutions containing different concentrations of two targeting modifiers, 1,2-hexanediol and 1,4-cyclohexanediol. Conventional liposomes, with soy phospholipid and cholesterol, were used as control. The prepared formulations were characterized in terms of entrapment efficiency, size distribution, morphology, and stability. Dermal KCZ targeting delivery from modified vesicles was investigated in vitro and in vivo through newborn pig and rat skin, respectively. All vesicles showed a mean size ranging from 58 to 147 nm with fairly narrow size distribution and drug entrapment efficiency between 20 and 75 %. Results of in vitro and in vivo studies indicated that modified vesicles provided an improved KCZ targeting delivery into skin layers. Images of the confocal laser scanning microscopy analyses supported the conclusion that modified vesicles could enhance the drug deposition into the skin strata and reduce the drug permeation into the blood, due to a synergic effect of phospholipid and modifiers. Finally, histological evaluation showed that KCZ-loaded modified vesicles caused no irritation to the skin. The results obtained encouraged the use of the KCZ-loaded modified vesicles as the formulation for the potential topical treatment of fungal infections.

  15. Investigating the effect of moisture protection on solid-state stability and dissolution of fenofibrate and ketoconazole solid dispersions using PXRD, HSDSC and Raman microscopy.

    PubMed

    Kanaujia, Parijat; Lau, Grace; Ng, Wai Kiong; Widjaja, Effendi; Schreyer, Martin; Hanefeld, Andrea; Fischbach, Matthias; Saal, Christoph; Maio, Mario; Tan, Reginald B H

    2011-09-01

    Enhanced dissolution of poorly soluble active pharmaceutical ingredients (APIs) in amorphous solid dispersions often diminishes during storage due to moisture-induced re-crystallization. This study aims to investigate the influence of moisture protection on solid-state stability and dissolution profiles of melt-extruded fenofibrate (FF) and ketoconazole (KC) solid dispersions. Samples were kept in open, closed and Activ-vials(®) to control the moisture uptake under accelerated conditions. During 13-week storage, changes in API crystallinity were quantified using powder X-ray diffraction (PXRD) (Rietveld analysis) and high sensitivity differential scanning calorimetry (HSDSC) and compared with any change in dissolution profiles. Trace crystallinity was observed by Raman microscopy, which otherwise was undetected by PXRD and HSDSC. Results showed that while moisture protection was ineffective in preventing the re-crystallization of amorphous FF, KC remained X-ray amorphous despite 5% moisture uptake. Regardless of the degree of crystallinity increase in FF, the enhanced dissolution properties were similarly diminished. Moisture uptake above 10% in KC samples also led to re-crystallization and significant decrease in dissolution rates. In conclusion, eliminating moisture sorption may not be sufficient in ensuring the stability of solid dispersions. Analytical quantification of API crystallinity is crucial in detecting subtle increase in crystallinity that can diminish the enhanced dissolution properties of solid dispersions.

  16. Evaluation of the Effects of Ketoconazole and Voriconazole on the Pharmacokinetics of Oxcarbazepine and Its Main Metabolite MHD in Rats by UPLC-MS-MS.

    PubMed

    Chen, Xinxin; Gu, Ermin; Wang, Shuanghu; Zheng, Xiang; Chen, Mengchun; Wang, Li; Hu, Guoxin; Cai, Jian-ping; Zhou, Hongyu

    2016-03-01

    Oxcarbazepine (OXC), a second-generation antiepileptic drug, undergoes rapid reduction with formation of the active metabolite 10,11-dihydro-10-hydroxy-carbazepine (MHD) in vivo. In this study, a method for simultaneous determination of OXC and MHD in rat plasma using ultra-performance liquid chromatography with tandem mass spectrometry (UPLC-MS-MS) was developed and validated. Under given chromatographic conditions, OXC, MHD and internal standard diazepam were separated well and quantified by electrospray positive ionization mass spectrometry in the multiple reaction monitoring transitions mode. The method validation demonstrated good linearity over the range of 10-2,000 ng/mL for OXC and 5-1,000 ng/mL for MHD. The lower limit of quantification was 5 ng/mL for OXC and 2.5 ng/mL for MHD, respectively. The method was successfully applied to the evaluation of the pharmacokinetics of OXC and MHD in rats, with or without pretreatment by ketoconazole (KET) and voriconazole (VOR). Statistics indicated that KET and VOR significantly affected the disposition of OXC and MHD in vivo, whereas VOR predominantly interfered with the disposition of MHD. This method is suitable for pharmacokinetic study in small animals. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  17. Effects of Manufacturing Methods on Dissolution and Absorption of Ketoconazole in the Presence of Organic Acid as a pH Modifier.

    PubMed

    Adachi, Masashi; Hinatsu, Yuta; Kusamori, Kosuke; Katsumi, Hidemasa; Sakane, Toshiyasu; Nakatani, Manabu; Wada, Koichi; Yamamoto, Akira

    2017-05-01

    Poorly water-soluble compounds have a potential risk of low and variable bioavailability caused by incomplete dissolution. Incorporation of organic acids as pH modifiers is effective method for solubility enhancement of basic compounds and requires no special technique and equipment. The purpose of this study was to evaluate the effect of manufacturing method on the extent of drug solubility enhancement. We successfully prepared the granules and tablets containing ketoconazole (KZ), which is weakly basic, as a model compound and citric acid as a pH modifier using conventional wet and dry granulations. KZ solubility under non-sink condition was enhanced with supersaturation using both wet and dry granulations. High-shear granulation was the most effective method in terms of KZ dissolution enhancement, because both an intimate contact and strong bonding between KZ and incorporated acid were achieved. KZ dissolved amount from the granules prepared by high-shear granulation was about eight times higher than that from the granules without the acid. The granulation involved to suppress a diffusion of acid dissolved, leading to the effectively maintained supersaturation state. The bioavailability of KZ after oral administration to rats was improved by applying high-shear granulation with citric acid independent of gastrointestinal pH. The granules prepared by high-shear granulation showed the bioavailability about 1.7-fold higher than that of the physical mixture in rats with and without neutralization of stomach. As a result, both the dissolution and absorption rates of KZ after oral administration were enhanced using conventional manufacturing technology.

  18. Efficacious and safe management of moderate to severe scalp seborrhoeic dermatitis using clobetasol propionate shampoo 0·05% combined with ketoconazole shampoo 2%: a randomized, controlled study.

    PubMed

    Ortonne, J-P; Nikkels, A F; Reich, K; Ponce Olivera, R M; Lee, J H; Kerrouche, N; Sidou, F; Faergemann, J

    2011-07-01

    Topical antifungals and corticosteroids are the mainstay of treatment for seborrhoeic dermatitis. The short-contact clobetasol propionate 0·05% shampoo (CP) is an efficacious and safe once-daily treatment for scalp psoriasis. To evaluate the efficacy and safety of CP alone and combined with ketoconazole shampoo 2% (KC) in the treatment of moderate to severe scalp seborrhoeic dermatitis. This randomized and investigator-blinded study consisted of three phases, each lasting 4 weeks. During the treatment phase, subjects were randomized to receive KC twice weekly (K2), CP twice weekly (C2), CP twice weekly alternating with KC twice weekly (C2 + K2) or CP four times weekly alternating with KC twice weekly (C4+K2). All subjects received KC once weekly during the maintenance phase and were untreated during the follow-up phase. At the end of the treatment phase, all three CP-containing regimens were significantly more efficacious than K2 in decreasing the overall disease severity (P < 0·05). Both combination regimens were also significantly more efficacious than K2 in decreasing each individual sign of the disease (P < 0·05). While the C2 and C4 + K2 groups experienced slight worsening during the maintenance phase, the efficacy of C2 + K2 was sustained and remained the highest among all groups. All regimens were well tolerated without inducing any skin atrophy. Similarly low incidences of telangiectasia, burning and adverse events were observed among the four groups. The combination therapy of twice-weekly CP alternating with twice-weekly KC provided significantly greater efficacy than KC alone and a sustained effect in the treatment of moderate to severe scalp seborrhoeic dermatitis. © 2011 The Authors. BJD © 2011 British Association of Dermatologists 2011.

  19. Biliary excretion of technetium-99m-sestamibi in wild-type dogs and in dogs with intrinsic (ABCB1-1Delta mutation) and extrinsic (ketoconazole treated) P-glycoprotein deficiency.

    PubMed

    Coelho, J C; Tucker, R; Mattoon, J; Roberts, G; Waiting, D K; Mealey, K L

    2009-10-01

    P-glycoprotein (P-gp), the product of ABCB1 gene, is thought to play a role in the biliary excretion of a variety of drugs, but specific studies in dogs have not been performed. Because a number of endogenous (ABCB1 polymorphisms) and exogenous (pharmacological P-gp inhibition) factors can interfere with normal P-gp function, a better understanding of P-gp's role in biliary drug excretion is crucial in preventing adverse drug reactions and drug-drug interactions in dogs. The objectives of this study were to compare biliary excretion of technetium-99m-sestamibi ((99m)Tc-MIBI), a radio-labelled P-gp substrate, in wild-type dogs (ABCB1 wild/wild), and dogs with intrinsic and extrinsic deficiencies in P-gp function. Dogs with intrinsic P-gp deficiency included ABCB1 mut/mut dogs, and dogs with presumed intermediate P-gp phenotype (ABCB1 mut/wild). Dogs with extrinsic P-gp deficiency were considered to be ABCB1 wild/wild dogs treated with the P-gp inhibitor ketoconazole (5 mg/kg PO q12h x 9 doses). Results from this study indicate that ABCB1 mut/mut dogs have significantly decreased biliary excretion of (99m)Tc-MIBI compared with ABCB1 wild/wild dogs. Treatment with ketoconazole significantly decreased biliary excretion of (99m)Tc-MIBI in ABCB1 wild/wild dogs. P-gp appears to play an important role in the biliary excretion of (99m)Tc-MIBI in dogs. It is likely that concurrent administration of a P-gp inhibitor such as ketoconazole will decrease P-gp-mediated biliary excretion of other substrate drugs as well.

  20. Randomized, open-labeled, non-inferiority study between ciclopiroxolamine 1% cream and ketoconazole 2% foaming gel in mild to moderate facial seborrheic dermatitis.

    PubMed

    Chosidow, O; Maurette, C; Dupuy, P

    2003-01-01

    Topical ketoconazole (KC) is considered a standard treatment for seborrheic dermatitis. In a placebo-controlled, double-blind clinical study, we demonstrated that antifungal ciclopiroxolamine (CIC) 1% cream was effective in mild to moderate facial seborrheic dermatitis. We report here the results of a randomized, open-labeled clinical study comparing CIC 1% cream and KC 2% foaming gel in patients with mild to moderate facial seborrheic dermatitis, using a non-inferiority trial design. Three hundred and three patients were enrolled, 154 patients in the CIC group and 149 patients in the KC group, and comprised the study population for intent-to-treat (ITT) analysis. The per protocol (PP) population comprised a total of 282 patients, 147 in the CIC group and 135 in the KC group. Patients were randomly allocated to apply either the CIC 1% cream twice a day for 28 days maximum (initial phase), followed by once a day for another 28 days (maintenance phase); or the KC 2% foaming gel twice a week at the initial phase, followed by once a week during the maintenance phase. Test lesions were defined as lesions localized to the nasolabial folds, alae nasi, and/or the eyebrows. The main efficacy parameter (endpoint) was the proportion of patients who presented a complete disappearance of both erythema and scaling on test lesions and pruritus on all lesions at the end of the initial phase (28 days or less). At baseline, both treatment groups were comparable in terms of demographic data and lesional status. At the end of the initial phase, responders were found to be non-inferior with CIC treatment compared with KC treatment in both study populations (ITT population: 37% CIC responders and 34% KC responders; in the PP population: 39 and 36% responders, respectively). The 95% confidence interval limit for differences were -7.99-13.56 in the ITT population, and -8.06-14.5 in the PP population. At the end of the maintenance phase, treatment response to CIC was greater than to KC in

  1. Stability of Allopurinol, Amitriptyline Hydrochloride, Carbamazepine, Domperidone, Isoniazid, Ketoconazole, Lisinopril, Naproxen, Paracetamol (Acetaminophen), and Sertraline Hydrochloride in SyrSpend SF PH4 Oral Suspensions.

    PubMed

    Polonini, Hudson C; Loures, Sharlene; de Araujo, Edson Peter; Brandão, Marcos Antônio F; Ferreira, Anderson O

    2016-01-01

    Oral liquids are safe alternatives to solid dosage forms, notably for elderly and pediatric patients that present dysphagia. The use of ready-to-use suspending vehicles such as SyrSpend SF PH4 is a suitable resource for pharmacists as they constitute a safe and timesaving option that has been studied often. The objective of this study was to evaluate the stability of 10 commonly used active pharmaceutical ingredients (allopurinol 20 mg/mL; amitriptyline hydrochloride 10 mg/mL; carbamazepine 25 mg/mL; domperidone 5 mg/mL; isoniazid 10 mg/mL; ketoconazole 20 mg/mL; lisinopril 1 mg/mL; naproxen 25 mg/mL; paracetamol [acetaminophen] 50 mg/mL; and sertraline hydrochloride 10 mg/mL) compounded in oral suspensions using SyrSpend SF PH4 as the vehicle throughout the study period and stored both at controlled refrigerated (2°C to 8°C) and room temperature (20°C to 25°C). Stability was assessed by means of measuring the percent recovery at varying time points throughout a 90-day period. The quantification of the active pharmaceutical ingredients was performed by high-performance liquid chromatography through a stability-indicating method. Methods were adequately validated. Forced-degradation studies showed that at least one parameter influenced the stability of the active pharmaceutical ingredients. All suspensions were assayed and showed active pharmaceutical ingredient contents between 90% and 110% during the 90-day study period. Although the forced-degradation experiments led to visible fluctuations in the chromatographic responses, the final preparations were stable in the storage conditions. The beyond-use dates of the preparations were found to be at least 90 days for all suspensions, both for controlled refrigerated temperature and room temperature. This confirms that SyrSpend SF PH4 is a stable suspending vehicle for compounding with a broad range of different active pharmaceutical ingredients for different medical usages. Copyright© by International Journal of

  2. Model-Based Analysis of Biopharmaceutic Experiments To Improve Mechanistic Oral Absorption Modeling: An Integrated in Vitro in Vivo Extrapolation Perspective Using Ketoconazole as a Model Drug.

    PubMed

    Pathak, Shriram M; Ruff, Aaron; Kostewicz, Edmund S; Patel, Nikunjkumar; Turner, David B; Jamei, Masoud

    2017-12-04

    Mechanistic modeling of in vitro data generated from metabolic enzyme systems (viz., liver microsomes, hepatocytes, rCYP enzymes, etc.) facilitates in vitro-in vivo extrapolation (IVIV_E) of metabolic clearance which plays a key role in the successful prediction of clearance in vivo within physiologically-based pharmacokinetic (PBPK) modeling. A similar concept can be applied to solubility and dissolution experiments whereby mechanistic modeling can be used to estimate intrinsic parameters required for mechanistic oral absorption simulation in vivo. However, this approach has not widely been applied within an integrated workflow. We present a stepwise modeling approach where relevant biopharmaceutics parameters for ketoconazole (KTZ) are determined and/or confirmed from the modeling of in vitro experiments before being directly used within a PBPK model. Modeling was applied to various in vitro experiments, namely: (a) aqueous solubility profiles to determine intrinsic solubility, salt limiting solubility factors and to verify pK a ; (b) biorelevant solubility measurements to estimate bile-micelle partition coefficients; (c) fasted state simulated gastric fluid (FaSSGF) dissolution for formulation disintegration profiling; and (d) transfer experiments to estimate supersaturation and precipitation parameters. These parameters were then used within a PBPK model to predict the dissolved and total (i.e., including the precipitated fraction) concentrations of KTZ in the duodenum of a virtual population and compared against observed clinical data. The developed model well characterized the intraluminal dissolution, supersaturation, and precipitation behavior of KTZ. The mean simulated AUC 0-t of the total and dissolved concentrations of KTZ were comparable to (within 2-fold of) the corresponding observed profile. Moreover, the developed PBPK model of KTZ successfully described the impact of supersaturation and precipitation on the systemic plasma concentration profiles of

  3. Metabolism of a 5HT6 antagonist, 2-methyl-1-(phenylsulfonyl)-4-(piperazin-1-yl)-1H-benzo[d]imidazole (SAM-760): impact of sulfonamide metabolism on diminution of a ketoconazole mediated clinical drug-drug interaction.

    PubMed

    Sawant-Basak, Aarti; Obach, R Scott; Doran, Angela C; Lockwood, Peter; Schildknegt, Klaas; Gao, Hongying; Mancuso, Jessica; Tse, Susanna; Comery, Tom

    2018-04-25

    SAM-760, (2-methyl-1-(phenylsulfonyl)-4-(piperazin-1-yl)-1H-benzo[d]imidazole), a 5HT 6 antagonist, was investigated in humans for the treatment of Alzheimer's dementia. In liver microsomes and recombinant CYP450 isozymes, SAM-760 was predominantly metabolized by CYP3A (~85%). Based on these observations and an expectation of 5-fold magnitude of interaction with moderate to strong CYP3A inhibitors, a clinical DDI study was performed. In presence of ketoconazole, mean C max and AUC 0-inf of SAM-760 showed only a modest increase by 30% and 38%, respectively. In vitro investigation of this unexpectedly low interaction was undertaken using [ 14 C]SAM-760. Radiometric profiling in human hepatocytes, confirmed all oxidative metabolites observed previously with unlabeled SAM-760; however the pre-dominant radiometric peak was an unexpected polar metabolite which was insensitive to pan-CYP inhibitor, 1-aminobenzotriazole. In human hepatocytes, radiometric integration attributed 43% of total metabolism of SAM-760 to this non-CYP pathway. Using an authentic standard, this predominant metabolite was confirmed as benzenesulfinic acid. Additional investigation revealed that the benzenesulfinic acid metabolite may be a novel, non-enzymatic, thiol mediated reductive cleavage of aryl sulfonamide group of SAM-760. We also determined the relative contribution of P450 to metabolism of SAM-760 in human hepatocytes, by following the rate of formation of oxidative metabolites in presence and absence of P450 isoform specific inhibitors. P450 mediated oxidative metabolism of SAM-760 was still primarily attributed to CYP3A (33%), with minor contributions from CYP isoforms 2C19 and 2D6. Thus, disposition of [ 14 C]SAM-760 in human hepatocytes via novel sulfonamide metabolism and CYP3A verified the lower than expected clinical DDI when SAM-760 was co-administered with ketoconazole. The American Society for Pharmacology and Experimental Therapeutics.

  4. Commentary on "Comparison of abiraterone acetate versus ketoconazole in patients with metastatic castration resistant prostate cancer refractory to docetaxel." Peer A, Gottfried M, Sinibaldi V, Carducci MA, Eisenberger MA, Sella A, Leibowitz-Amit R, Berger R, Keizman D, Department of Oncology, Rambam Medical Center, Haifa, Israel.: Prostate 2014 Apr;74(4):433-40; doi:10.1002/pros.22765. [Epub 2013 Dec 11].

    PubMed

    Trump, Donald

    2016-05-01

    Abiraterone, a potent CYP 17 inhibitor, is standard treatment in docetaxel refractory, metastatic castrate resistant prostate cancer (mCRPC). However, in countries where abiraterone has not been approved yet, or for patients who cannot afford it, ketoconazole is used as an alternative CYP 17 inhibitor. Although preclinical data suggests that ketoconazole is a less potent inhibitor of CYP 17, there are limited clinical data comparing both agents. We aimed to compare the clinical effectiveness of abiraterone versus ketoconazole in docetaxel refractory mCRPC. Records from mCRPC patients treated with ketoconazole (international multicenter database, n = 162) were reviewed retrospectively. Twenty-six patients treated post docetaxel were individually matched by clinicopathologic factors to patients treated with abiraterone (national multicenter database, n = 140). We compared the PSA response, biochemical and radiological progression free survival (PFS), and overall survival (OS) between the groups. PFS and OS were determined by Cox regression. The groups were matched by Gleason score, pre-treatment disease extent, ECOG PS, pre-treatment risk category (Keizman, Oncologist 2012). Furthermore, they were balanced regarding other known confounding risk factors. In the groups of abiraterone versus ketoconazole, PSA response was 46% versus 19% (OR 4.3, P = 0.04), median biochemical PFS 7 versus 2 months (HR 1.54, P = 0.02), median radiological PFS 8 versus 2.5 months (HR 1.8, P = 0.043), median OS 19 versus 11 months (HR 0.53, P = 0.79), and treatment interruption d/t severe adverse events 8% (n = 2) versus 31% (n = 8) (OR 0.6, P = 0.023). In docetaxel refractory mCRPC, the outcome of abiraterone treatment may be superior to ketoconazole. Copyright © 2016 Elsevier Inc. All rights reserved.

  5. Study to Evaluate the Effect of Rifampicin, Ketoconazole, and Omeprazole on the Pharmacokinetics of Sativex

    ClinicalTrials.gov

    2017-02-22

    Evaluation of Pharmacokinetics of Sativex in the Absence and Presence of a Known Inducer of CYP3A4; Evaluation of Pharmacokinetics of Sativex in the Absence and Presence of a Potent Inhibitor of CYP3A4; Evaluation of Pharmacokinetics of Sativex in the Absence and Presence of a CYP2C19 Inhibitor

  6. Perturbation of Gene Expression and Steroidogenesis with In vitro Exposure of Fathead Minnow Ovaries to Ketoconazole

    EPA Science Inventory

    Various chemicals in the environment can disrupt normal endocrine function, including steroid hormone synthesis, causing deleterious effects. Because these compounds can act at different levels of the hypothalamus-pituitary-gonadal (HPG) axis, their effects can lead to a mixture...

  7. Effects of Fadrozole, Ketoconazole, and 17β-trenbolone on Ex Vivo Steroidogenesis in the Fathead Minnow

    EPA Science Inventory

    A variety of endocrine-disrupting chemicals have the ability to disrupt steroidogenesis through interaction with the hypothalamic-pituitary-gonadal (HPG) axis. We examined the effects of the competitive aromatase inhibitor fadrozole (0, 3, and 30 g/L), the cytochrome P450 enzyme...

  8. Tinea Versicolor

    MedlinePlus

    ... distress or self-consciousness. Antifungal creams, lotions or shampoos can help treat tinea versicolor. But even after ... Selenium sulfide (Selsun) 2.5 percent lotion or shampoo Ketoconazole (Ketoconazole, Nizoral, others) cream, gel or shampoo ...

  9. Cushing’s Syndrome with Concurrent Diabetes Mellitus in a Rhesus Monkey

    DTIC Science & Technology

    1999-05-01

    adverse effects ( 10). Feldman et al. evaluated ketoconazole in over 50 dogs with spontaneous hyperadrenocorticism due to Cushing’s disease and...choice to control the hypercortisolism. The monkey bas shown remarkable improvement with the dual therapies of insulin and ketoconazole . Approximately 2...months after the initiation of ketoconazole therapy, the animal wu returned to an experimental protocol under the conditions of twi~ treatment and

  10. ADMINISTRATION OF POTENTIALLY ANTIANDROGENIC PESTICIDES (PROCYMIDONE, LINURON, IPRODIONE, CHLOZOLINATE, P,P'-DDE AND KETOCONAZOLE) AND TOXIC SUBSTANCES (DIBUTYL-AND DIETHYLHEXYL PHTHALATE, PCB 169, AND ETHANE DIMETHANE SULPHONATE) DURING SEXUAL DIFFERENTIATION PRODUCES DIVERSE PROFILES OF REPRODUCTIVE MALFORMATIONS IN THE MALE RAT

    EPA Science Inventory

    Antiandrogenic chemicals alter sexual differentiation by a variety of mechanisms, and as a consequence, they induce different profiles of effects. For example, in utero treatment with the androgen receptor (AR) antagonist, flutamide, produces ventral prostate agenesis and testicu...

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

    PubMed

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

    1996-01-01

    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.

  12. Ciclesonide Oral Inhalation

    MedlinePlus

    ... you were taking an oral steroid such as dexamethasone, methylprednisolone (Medrol), or prednisone (Rayos), your doctor may ... the following: ketoconazole (Nizoral); oral steroids such as dexamethasone, methylprednisolone (Medrol), and prednisone (Rayos); and medications for ...

  13. Disseminated histoplasmosis presenting with ileal perforation in a renal transplant recipient.

    PubMed

    Zainudin, B M; Kassim, F; Annuar, N M; Lim, C S; Ghazali, A K; Murad, Z

    1992-08-01

    A renal transplant patient presented with ileal perforation due to histoplasmosis 3 years after transplantation. Mesenteric lymph nodes and lungs were also affected by the disease. She was successfully treated with amphotericin B followed by ketoconazole.

  14. Bexarotene

    MedlinePlus

    ... gets on your skin, wash the area with soap and water immediately and call your doctor.Your ... the following: amiodarone (Cordarone); certain antifungals such as ketoconazole (Nizoral) and itraconazole (Sporanox); cimetidine (Tagamet); clarithromycin (Biaxin); ...

  15. Sertaconazole Topical

    MedlinePlus

    ... cream into the skin. Wash your hands with soap and water after applying sertaconazole cream. Do not ... any other antifungal medications such as clotrimazole (Lotrimin), ketoconazole (Nizoral), or miconazole (Desenex, Lotrimin AF); any of ...

  16. Sodium Bicarbonate

    MedlinePlus

    ... conditions.This medication is sometimes prescribed for other uses; ask your doctor or pharmacist for more information. ... like medicines, benzodiazepines, flecainide (Tambocor), iron, ketoconazole (Nizoral), lithium (Eskalith, Lithobid), methenamine (Hiprex, Urex), methotrexate, quinidine, sulfa- ...

  17. Effect of 2-(4-aminophenylmethyl)-6-hydroxy-3, 4-dihydronaphthalen-1(2H)-one on all-trans and 13-cis-retinoic acid levels in plasma quantified by high perfomance liquid chromatography coupled to tandem mass spectrometry.

    PubMed

    Angotti, Marc; Hartmann, Rolf W; Kirby, Andrew J; Simons, Claire; Nicholls, Paul J; Sewell, Robert D E; Smith, H John

    2005-06-01

    The effect of the titled tetralone as a retinoic acid metabolism blocking agent (RAMBA) in vivo in comparison with ketoconazole, a well known cytochrome P450 inhibitor, was studied. Development of a HPLC/MS/MS method for the quantification of retinoic acid levels extracted from rat plasma was used to demonstrate that ketoconazole and the tetralone (100 mg/kg) enhanced the endogenous plasma concentration of retinoic acid. Levels of retinoid were raised from a control value of 0.11 to 0.15 and 0.17 ng/mL after treatment with tetralone and ketoconazole respectively showing that the tetralone and ketoconazole lead to comparable effects, indicating an inhibitory activity of the tetralone on retinoic acid metabolism.

  18. Cushing's Support and Research Foundation

    MedlinePlus

    ... available. LEARN MORE > Cushing's Patient Day Summaries and Videos Available On March 1, 2014, the CSRF hosted ... issued new warnings for ketoconazole. READ MORE > News Video on Cushing's! ABC 7 Eyewitness News in Southern ...

  19. Dandruff (For Teens)

    MedlinePlus

    ... you have any questions: selenium sulfide 1% shampoo sulfur shampoo tar-based shampoo zinc pyrithione shampoo ketoconazole ... After treatment, some people notice that areas of skin that had severe seborrhea may be lighter than ...

  20. Effect of a Hypocretin/Orexin Antagonist on Neurocognitive Performance

    DTIC Science & Technology

    2012-09-01

    NEY-1413 FINAL Version 8.05JAN2012 Page 5 of 45 ABBREVIATIONS AE Adverse Event AASM American Academy of Sleep Medicine BzRAs...Current use of statins, ketoconazole, prescription or over- the-counter medications or herbal supplements containing psychoactive properties or...Current use of statins, ketoconazole, prescription or over-the-counter medications or herbal supplements containing psychoactive properties or

  1. Effect of a Hypocretin/Orexin Antagonist on Neurocognitive Performance

    DTIC Science & Technology

    2014-09-01

    46 NEY-1413 FINAL Version 10.30 JANUARY 2014 ABBREVIATIONS AE Adverse Event AASM American Academy of Sleep Medicine BzRAs Benzodiazepine...ketoconazole, prescription or over- the-counter medications or herbal supplements containing psychoactive properties or stimulants in the judgment of the...medical conditions; 12.) Current use of statins, ketoconazole, prescription or over-the-counter medications or herbal supplements containing

  2. Adrenal response to corticotropin during therapy with itraconazole.

    PubMed Central

    Phillips, P; Graybill, J R; Fetchick, R; Dunn, J F

    1987-01-01

    Itraconazole is a triazole with a mechanism of action similar to that of ketoconazole. Endocrine side effects of ketoconazole, including impaired cortisol synthesis, have been well documented (A. Pont, J. R. Graybill, P. C. Craven, J. N. Galgiani, W. E. Dismukes, R. E. Reitz, and D. A. Stevens, Arch. Intern. Med. 144:2150-2153, 1984). We examined the adrenal response to corticotropin in 10 patients being treated with itraconazole. No impairment of cortisol synthesis could be demonstrated. PMID:3038002

  3. The influence of modulation of P-glycoprotein and /or cytochrome P450 3A on the pharmacokinetics and pharmacodynamics of orally administered morphine in dogs.

    PubMed

    Gadeyne, C; Van der Heyden, S; Gasthuys, F; Croubels, S; Schauvliege, S; Polis, I

    2011-10-01

    The influence of pretreatment with ketoconazole [cytochrome P450 3A (CYP3A) + P-glycoprotein (P-gp) inhibitor], elacridar (selective P-gp inhibitor) and rifampicin (CYP3A + P-gp inducer) on oral morphine pharmacokinetics and pharmacodynamics was investigated in experimental dogs. Seven beagles were used in a four-way crossover design. Morphine hydrochloride was administered orally (2.5 mg/kg) alone (control group CON) or after pretreatment with ketoconazole (group KETO), elacridar (group ELA) or rifampicin (group RIF). Morphine plasma concentrations were analysed by liquid chromatography-tandem mass spectrometry. Sedation scores (none, mild, moderate or severe) were evaluated subjectively. Dogs were significantly (P < 0.05) more sedated after ketoconazole pretreatment. There were no significant differences between group CON and the other pretreatment groups in pharmacokinetic parameters taking both sexes into account. Sex differences were apparent in some pharmacokinetic parameters of morphine. The area under the plasma concentration time curve (AUC(0-∞) ) was significantly higher, and the total body clearance was significantly lower in male compared to female dogs in all treatment groups. Ketoconazole, rifampicin and elacridar pretreatment had no significant effects on morphine pharmacokinetics, although dogs in the ketoconazole group showed higher sedation scores. © 2011 Blackwell Publishing Ltd.

  4. Zolpidem metabolism in vitro: responsible cytochromes, chemical inhibitors, and in vivo correlations.

    PubMed

    Von Moltke, L L; Greenblatt, D J; Granda, B W; Duan, S X; Grassi, J M; Venkatakrishnan, K; Harmatz, J S; Shader, R I

    1999-07-01

    To determine the human cytochromes mediating biotransformation of the imidazopyridine hypnotic, zolpidem, and the clinical correlates of the findings. Kinetic properties of zolpidem biotransformation to its three hydroxylated metabolites were studied in vitro using human liver microsomes and heterologously expressed individual human cytochromes. 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. The incomplete dependence of zolpidem clearance on CYP3A activity has clinical implications for susceptibility to metabolic inhibition.

  5. Synergistic effects of tacrolimus and azole antifungal compounds in fluconazole-susceptible and fluconazole-resistant Candida glabrata isolates.

    PubMed

    Denardi, Laura Bedin; Mario, Débora Alves Nunes; Loreto, Érico Silva; Santurio, Janio Morais; Alves, Sydney Hartz

    2015-03-01

    In vitro interaction between tacrolimus (FK506) and four azoles (fluconazole, ketoconazole, itraconazole and voriconazole) against thirty clinical isolates of both fluconazole susceptible and -resistant Candida glabrata were evaluated by the checkerboard microdilution method. Synergistic, indifferent or antagonism interactions were found for combinations of the antifungal agents and FK506. A larger synergistic effect was observed for the combinations of FK506 with itraconazole and voriconazole (43%), followed by that of the combination with ketoconazole (37%), against fluconazole-susceptible isolates. For fluconazole-resistant C. glabrata , a higher synergistic effect was obtained from FK506 combined with ketoconazole (77%), itraconazole (73%), voriconazole (63%) and fluconazole (60%). The synergisms that we observed in vitro , notably against fluconazole-resistant C. glabrata isolates, are promising and warrant further analysis of their applications in experimental in vivo studies.

  6. [In vitro assessment of the sensitivity of Candida albicans strains isolated from the vagina on basis antimycotics].

    PubMed

    Lisiak, M; Kłyszejko, C; Marcinkowski, Z; Gwieździński, Z

    2000-09-01

    The purpose of the study was to analyses the sensitivity of 73 randomly selected Candida albicans strains isolated from the vagina of pregnant and delivering women against seven basic antimycotics. The microtest FUNGITEST (Sanofi Diagnostics Pasteur) was applied in assessing the sensitivity of 5-fluorocytosin, amphotericin B, ketoconazol, fluconazol, itraconazol and miconazol and the disk-diffusion method with the use of a Casitone base for nystatin. Variations in the sensitivity against drugs have been noted between individual strains of Candida albicans species. The largest number of strains was resistant against ketoconazol--56.16%, and only 10.96% was resistant against nystatin.

  7. Testing Experimental Compounds against American Cutaneous and Mucocutaneous Leishmaniasis

    DTIC Science & Technology

    1982-06-01

    synthesize large amounts of plasma membrane ergosterol in serum-free media (26). Ketoconazole and miconazole actively disrupt ergosterol synthesis in a...walls cross- * react with L. donovani (40), it was thought that immunostimula- tion of a htst with BCG prior to infection with L. mexicana ama- zonensis

  8. Effects of beta-thujaplicin on anti-Malassezia pachydermatis remedy for canine otitis externa.

    PubMed

    Nakano, Yasuyuki; Wada, Makoto; Tani, Hiroyuki; Sasai, Kazumi; Baba, Eiichiroh

    2005-12-01

    The antifungal activity of beta-thujaplicin was evaluated against 51 Malassezia pachydermatis strains isolated from canine ear canals with or without otitis externa. For comparison, sensitivity tests were performed on M. pachydermatis isolates for nystatin, ketoconazole, and terbinafine HCl, all clinically available antifungal agents. The minimal inhibition concentrations over 50% of the tested isolates (MIC50) were 3.13 microg/ml for beta-thujaplicin and nystatin, 0.016 microg/ml for ketoconazole, and 1.56 microg/ml for terbinafine HCl. The antifungal effect for M. pachydermatis of beta-thujaplicin compared favorably with commercial antifungal agents. None of the 51 M. pachydermatis isolates showed resistance against any of the tested antibiotics investigated in this study. Ten representative isolates of M. pachydermatis were subcultured for 30 generations at concentrations close to the MIC levels of beta-thujaplicin, nystatin, ketoconazole, and terbinafine HCl, and examined to determine whether they had acquired resistance to each drug. As a result, M. pachydermatis was found to achieve resistance more easily for ketoconazole and terbinafine HCl than for beta-thujaplicin or nystatin. The MIC50 of beta-thujaplicin did not change during the course of subculture, and it is thought that the potential development of a resistant strain is low, even with continuous infusion for otitis externa therapy. beta-Thujaplicin is an inexpensive and safe treatment with anti-inflammatory and deodorant effects that can be recommended as an effective remedy for canine otitis externa.

  9. Leishmaniasis

    DTIC Science & Technology

    1993-01-01

    disease are animals such as desert rats, sloths, horses, rodents, foxes and dogs . 14. SUMrCT TERMS IS. NUMBER OF PAGES Leishmaniasis, sandflies... Ketoconazole and Allopurinol)................................... 311 E. Topical Agents (Paromomycin) ...................... 313 F. Liposomes...panamensis), horses (L. braziliensis), rodents (L. mexicana); and foxes and dogs (L. donovani). In India, inadequately treated visceral infection may

  10. The Effect of the Protease Inhibitors Ritonavir on the Rate of Metabolism of Midazolam

    DTIC Science & Technology

    1999-10-01

    demonstrated that the antifungal drug ketoconazole decreased the rate at which saquinavir metabolites were formed, thus slowing metabolism and...Kempf, D. J., Thomas, S. B. & Surber, B. W. (1997). Metabolism and disposition of the HIV-1 protease inhibitor ritonavir (AB-538) in rats, dogs , and

  11. Clinical Evaluation of a New-Formula Shampoo for Scalp Seborrheic Dermatitis Containing Extract of Rosa centifolia Petals and Epigallocatechin Gallate: A Randomized, Double-Blind, Controlled Study.

    PubMed

    Kim, Yu Ri; Kim, Jeong-Hwan; Shin, Hong-Ju; Choe, Yong Beom; Ahn, Kyu Joong; Lee, Yang Won

    2014-12-01

    Scalp seborrheic dermatitis is a chronic type of inflammatory dermatosis that is associated with sebum secretion and proliferation of Malassezia species. Ketoconazole or zinc-pyrithione shampoos are common treatments for scalp seborrheic dermatitis. However, shampoos comprising different compounds are required to provide patients with a wider range of treatment options. This study was designed to evaluate a new-formula shampoo that contains natural ingredients-including extract of Rosa centifolia petals and epigallocatechin gallate (EGCG)-that exert antioxidative, anti-inflammatory, and sebum secretion inhibitory effects, and antifungal agents for the treatment of scalp seborrheic dermatitis. Seventy-five patients were randomized into three treatment groups; new-formula shampoo, 2% ketoconazole shampoo, and 1% zinc- pyrithione shampoo. The clinical severity scores and sebum levels were assessed by the same dermatologists at baseline (week 0), and at 2 and 4 weeks after using the shampoo. User satisfaction and irritation were also assessed with the aid of a questionnaire. The efficacy of the new-formula shampoo was comparable to that of both the 1% zinc-pyrithione shampoo and the 2% ketoconazole shampoo. Furthermore, it was found to provide a more rapid response than the 1% zinc-pyrithione shampoo for mild erythema lesions and was associated with greater user satisfaction compared with the 2% ketoconazole shampoo. However, the new-formula shampoo did not exhibit the previously reported sebum inhibitory effect. Extract of R. centifolia petals or EGCG could be useful ingredients in the treatment of scalp seborrheic dermatitis.

  12. ISOLATION OF A CYTOCHROME P-450 STRUCTURAL GENE FROM SACCHAROMYCES CEREVISIAE

    EPA Science Inventory

    We have transformed a Saccharomyces cerevisiae host with an S. cerevisiae genomic library contained in the shuttle vector YEp24 and screened the resultant transformants for resistance to ketoconazole (Kc), an inhibitor of the cytochrome P-450 (P-450) enzyme lanosterol 14-demethyl...

  13. [Self-administration of an oil solution in the penis].

    PubMed

    Rebassa Llull, M J; Muñoz Vélez, D; Ferrutxe Frau, J; Gutiérrez Sanz-Gadea, C; Mus Malleu, A; Torrens Darder, I; Ozonas Moragues, M

    2000-09-01

    We report the case of a patient who has autoinjected himself the penis and the scrotum with a solution constituted by petroleum, vaseline, oxygenated water and ketoconazol gel. Treatment consists in the excision of the injected deposit of lipid material and antibiotic therapy with good result at 4 months. We review the existing literature related with this exceptional pathology.

  14. Antifungal Susceptibilities of Cryptococcus neoformans

    PubMed Central

    Tuohy, Marion J.; Wilson, Deborah A.; Nwanyanwu, Okey; Kazembe, Peter N.; Tansuphasawadikul, Somsit; Eampokalap, Boonchuay; Chaovavanich, Achara; Reller, L.Barth; Jarvis, William R.; Hall, Gerri S.; Procop, Gary W.

    2004-01-01

    Susceptibility profiles of medically important fungi in less-developed countries remain uncharacterized. We measured the MICs of amphotericin B, 5-flucytosine, fluconazole, itraconazole, and ketoconazole for Cryptococcus neoformans clinical isolates from Thailand, Malawi, and the United States and found no evidence of resistance or MIC profile differences among the countries. PMID:15078612

  15. Antifungal susceptibilities of Cryptococcus neoformans.

    PubMed

    Archibald, Lennox K; Tuohy, Marion J; Wilson, Deborah A; Nwanyanwu, Okey; Kazembe, Peter N; Tansuphasawadikul, Somsit; Eampokalap, Boonchuay; Chaovavanich, Achara; Reller, L Barth; Jarvis, William R; Hall, Gerri S; Procop, Gary W

    2004-01-01

    Susceptibility profiles of medically important fungi in less-developed countries remain uncharacterized. We measured the MICs of amphotericin B, 5-flucytosine, fluconazole, itraconazole, and ketoconazole for Cryptococcus neoformans clinical isolates from Thailand, Malawi, and the United States and found no evidence of resistance or MIC profile differences among the countries.

  16. The involvement of flavin-containing monooxygenase but not CYP3A4 in metabolism of itopride hydrochloride, a gastroprokinetic agent: comparison with cisapride and mosapride citrate.

    PubMed

    Mushiroda, T; Douya, R; Takahara, E; Nagata, O

    2000-10-01

    The goals of the present study were to identify the enzyme responsible for metabolism of itopride hydrochloride (itopride) and to evaluate the likelihood of drug interaction involving itopride. In human liver microsomes, the involvement of flavin-containing monooxygenase in N-oxygenation, the major metabolic pathway of itopride, was indicated by the following results: inhibition by methimazole and thiourea, heat inactivation, and protection against heat inactivation by NADPH. When the effects of ketoconazole on the metabolism of itopride, cisapride, and mosapride citrate (mosapride) were examined using human liver microsomes, ketoconazole strongly inhibited the formation of the primary metabolites of cisapride and mosapride, but not itopride. Other cytochrome P450 (CYP) 3A4 inhibitors, cimetidine, erythromycin, and clarithromycin, also inhibited the metabolism of cisapride and mosapride. In an in vivo study, itopride (30 mg/kg), cisapride (1.5 mg/kg), or mosapride (3 mg/kg) was orally administered to male rats with or without oral pretreatment with ketoconazole (120 mg/kg) twice daily for 2 days. The ketoconazole pretreatment significantly increased the area under the serum concentration curve and the maximum serum concentration of cisapride and mosapride but had no significant effect on the pharmacokinetics of itopride. In addition, itopride did not inhibit five specific CYP-mediated reactions of human liver microsomes. These results suggest that itopride is unlikely to alter the pharmacokinetics of other concomitantly administered drugs.

  17. Treatment of Signs and Symptoms (Pruritus) of Interdigital Tinea Pedis With Econazole Nitrate Foam, 1.

    PubMed

    Hoffman, Lauren K; Raymond, Isabelle; Kircik, Leon

    2018-02-01

    Tinea pedis is the most common dermatophyte infection. Treatment is critical to alleviate pruritic symptoms, to reduce the risk for secondary bacterial infection, and to limit the spread of infection to other body sites or other individuals. The objective of this study was to compare the abilities of econazole nitrate topical foam, 1% and ketoconazole cream (2%) to reduce pruritus, thus improving quality of life, and to determine patient preference for the foam product versus the cream product in patients with interdigital tinea pedis. A single-center, investigator-blinded, observational pilot study was conducted to compare econazole nitrate topical foam (1%) to ketoconazole cream (2%). In this split-body study, 20 subjects received both econazole nitrate topical foam and ketoconazole cream and applied the medications daily to either the right or left foot for 14 days. Improvements in patient quality of life (pruritus) and patient preference were measured using the pruritus visual analog scale (VAS), Skindex-16, and patient preference questionnaires. Nineteen subjects completed the study and one subject was lost to follow-up. Reductions in VAS scores of econazole nitrate topical foam were significantly greater than those of ketoconazole cream, indicating the superiority of the econazole nitrate foam in reducing pruritus. Skindex-16 data showed significant reductions in total scores and individual domains, including patient symptom, emotional, and functional domains, by the final visit. Since each subject received both medications the questionnaire was not medication-specific. Responses to patient preference questionnaires showed that econazole nitrate topical foam,1% was rated as "good" or "excellent" in all measures assessed. One adverse event was noted. In patients with interdigital tinea pedis, application of econazole nitrate topical foam 1% twice daily for two weeks was clinically effective and significantly superior to ketoconazole cream 2% in reducing

  18. Zolpidem metabolism in vitro: responsible cytochromes, chemical inhibitors, and in vivo correlations

    PubMed Central

    von Moltke, Lisa L; Greenblatt, David J; Granda, Brian W; Duan, Su Xiang; Grassi, Jeffrey M; Venkatakrishnan, Karthik; Harmatz, Jerold S; Shader, Richard I

    1999-01-01

    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 μm vs formation of the M-3 metabolite of zolpidem in vitro; in a clinical study, ketoconazole coadministration reduced zolpidem oral clearance by ≈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. PMID:10383565

  19. Rectal Metyrapone for Treatment of Hypercortisolism in an Infant with McCune-Albright Syndrome

    PubMed Central

    Hadjiyannakis, Stasia; Cameron, Melody; McDonald, Jaime

    2017-01-01

    Infantile Cushing syndrome is an infrequent yet potentially fatal manifestation of McCune-Albright syndrome, for which there are few safe treatments available. Ketoconazole is limited by potential hepatotoxicity in this population. Metyrapone may be an effective treatment, but it may not be tolerated when given orally. An infant with McCune-Albright syndrome presented with severe Cushing syndrome. Oral metyrapone resulted in feeding refusal, and ketoconazole caused an increase in liver enzymes; however, she was successfully treated with metyrapone given rectally. The patient avoided a feeding tube, and her serum cortisol concentration was lowered to a safe level. Metyrapone given per rectum may be a safe and effective alternative to oral metyrapone in treating young children with Cushing syndrome. PMID:28638307

  20. Ocular blastomycosis in dogs: 73 cases, 108 eyes (1985-1993).

    PubMed

    Bloom, J D; Hamor, R E; Gerding, P A

    1996-10-01

    To evaluate clinical signs of ocular blastomycosis in dogs, to determine response of blastomycosis-infected eyes to treatment with systemically administered amphotericin B and ketoconazole, and to identify prognostic indicators of successful antifungal treatment. Retrospective study. 73 dogs. Medical records were reviewed for all dogs with confirmed blastomycosis and ocular disease seen at our hospital between 1985 and 1993. 6 eyes had anterior segment disease, 24 had posterior segment disease, and 78 had endophthalmitis. 40 eyes were treated with a combination of amphotericin B and ketoconazole, and 16 of the 40 responded favorably. However, 16 of the 24 eyes that were not severely affected responded favorably, but none of the 16 eyes that were severely affected did. Dogs with blastomycosis had posterior segment disease, without complete retinal separation, had a good prognosis for retaining vision. Results of histologic examination suggested that secondary glaucoma was a manifestation of endophthalmitis and was indicative of a grave prognosis for response to antifungal and antiglaucoma treatment.

  1. Azole-synergistic anti-candidal activity of altenusin, a biphenyl metabolite of the endophytic fungus Alternaria alternata isolated from Terminalia chebula Retz.

    PubMed

    Phaopongthai, Jatuporn; Wiyakrutta, Suthep; Meksuriyen, Duangdeun; Sriubolmas, Nongluksna; Suwanborirux, Khanit

    2013-12-01

    In this study, a tropical endophytic fungus, Alternaria alternata Tche-153 was isolated from a Thai medicinal plant Terminalia chebula Rezt. The ethyl acetate extract prepared from the fermentation broth exhibited significant ketoconazole-synergistic activity against Candida albicans. Bioassay-directed fractionation of the ethyl acetate extract led to the isolation of altenusin (1), isoochracinic acid (2), and altenuic acid (3) together with 2,5-dimethyl-7-hydroxychromone (4). Using the disc diffusion method and the microdilution chequerboard technique, only altenusin (1) in combination with each of three azole drugs, ketoconazole, fluconazole or itraconazole at their low sub-inhibitory concentrations exhibited potent synergistic activity against C. albicans with the fractional inhibitory concentration index range of 0.078 to 0.188. This first discovery of altenusin (1) as a new azole-synergistic prototype possessing a biphenyl structure is of significance for further development of new azole-synergists to treat invasive candidiasis.

  2. 1-[(3-Aryloxy-3-aryl)propyl]-1H-imidazoles, new imidazoles with potent activity against Candida albicans and dermatophytes. Synthesis, structure-activity relationship, and molecular modeling studies.

    PubMed

    La Regina, Giuseppe; D'Auria, Felicia Diodata; Tafi, Andrea; Piscitelli, Francesco; Olla, Stefania; Caporuscio, Fabiana; Nencioni, Lucia; Cirilli, Roberto; La Torre, Francesco; De Melo, Nadja Rodrigues; Kelly, Steven L; Lamb, David C; Artico, Marino; Botta, Maurizio; Palamara, Anna Teresa; Silvestri, Romano

    2008-07-10

    New 1-[(3-aryloxy-3-aryl)propyl]-1 H-imidazoles were synthesized and evaluated against Candida albicans and dermatophytes in order to develop structure-activity relationships (SARs). Against C. albicans the new imidazoles showed minimal inhibitory concentrations (MICs) comparable to those of ketoconazole, miconazole, and econazole, and were more potent than fluconazole. Several derivatives ( 10, 12, 14, 18- 20, 24, 28, 29, 30, and 34) turned out to be potent inhibitors of C. albicans strains resistant to fluconazole, with MIC values less than 10 microg/mL. Against dermatophytes strains, compounds 20, 25, and 33 (MIC ketoconazole, econazole, and miconazole. SARs of imidazoles 10- 44 were rationalized with reasonable accuracy by a previously developed quantitative pharmacophore for antifungal agents.

  3. Slime production and proteinase activity of Candida species isolated from blood samples and the comparison of these activities with minimum inhibitory concentration values of antifungal agents.

    PubMed

    Ozkan, Semiha; Kaynak, Fatma; Kalkanci, Ayse; Abbasoglu, Ufuk; Kustimur, Semra

    2005-05-01

    Slime and proteinase activity of 54 strains consisting of 19 Candida parapsilosis and 35 C. albicans strains isolated from blood samples were investigated in this study. Ketoconazole, amphothericin B, and fluconazole susceptibility of Candida species were compared with slime production and proteinase activity of these species. For both Candida species, no correlation was detected between the slime activity and minimum inhibitory concentration (MIC) values of the three antifungal agents. For both Candida species no correlation was detected between the proteinase activity and the MIC values of amphothericin B, and fluconazole however, statistically significant difference, was determined between the proteinase activity and MIC values of ketoconazole (p = 0.007). Slime production was determined by using modified Christensen macrotube method and proteinase activity was measured by the method of Staib. Antifungal susceptibility was determined through the guidelines of National Committee for Laboratory Standards (NCCLS M27-A).

  4. In Vitro Comparison of Activities of Terbinafine and Itraconazole against Paracoccidioides brasiliensis

    PubMed Central

    Hahn, R. C.; Fontes, C. J. F.; Batista, R. D.; Hamdan, J. S.

    2002-01-01

    In vitro, terbinafine is highly active against a broad spectrum of pathogenic fungi. We evaluated the activities of terbinafine and itraconazole against 31 isolates of Paracoccidioides brasiliensis. The tests were conducted by using a broth macrodilution procedure. MICs, in micrograms per milliliter, were as follows: terbinafine, 0.015 to 1.0 (geometric mean, 0.1188); itraconazole, 0.007 to 0.5 (geometric mean, 0.03165). The usual therapy for paracoccidioidomycosis is sulfonamides, amphotericin B, and azole derivatives (ketoconazole, itraconazole, and fluconazole). In comparison to amphotericin B, azole derivatives allow shorter treatment courses, can be administered orally, and are equally effective. Itraconazole has as high efficacy as ketoconazole, but with superior tolerance. It is the current drug of choice for treatment of paracoccidioidomycosis. The data obtained in this study indicate that terbinafine is active against P. brasiliensis in vitro and suggest that this allylamine can be considered a new option as drug therapy for paracoccidioidomycosis. PMID:12149337

  5. In Vitro Activities of Four Novel Triazoles against Scedosporium spp.

    PubMed Central

    Carrillo, A. J.; Guarro, J.

    2001-01-01

    In order to develop new approaches to the treatment of the severe and usually fatal infections caused by Scedosporium spp., the in vitro antifungal activities of four novel triazoles (posaconazole, ravuconazole, voriconazole, and UR-9825) and some current antifungals (amphotericin B, ketoconazole, itraconazole, and nystatin) were determined. The latter group was clearly ineffective against the two species tested. The four new antifungals showed activity against Scedosporium apiospermum, and UR-9825 and voriconazole were active against S. prolificans. PMID:11408242

  6. Effect of a Hypocretin/Orexin Antagonist on Neurocognitive Performance

    DTIC Science & Technology

    2013-12-18

    9.28MARCH2013 AE Adverse Event AASM American Academv of Sleep Medicine BzRAs B enzo diazepine Receptor A goni sts CRC Clinical Research Center CCRC University...medical conditions; 12.) Current use of statins, ketoconazole, prescription or over- the-counter medications or herbal supplements containing...medications or herbal supplements containing psychoactive properties or stimulants in the judgment of the Investigator-Sponsor or Medical Monitor; 13

  7. In Vitro Susceptibilities of Malassezia Species to a New Triazole, Albaconazole (UR-9825), and Other Antifungal Compounds

    PubMed Central

    Garau, Margarita; Pereiro, Jr., Manolo; del Palacio, Amalia

    2003-01-01

    The in vitro activity of the new triazole albaconazole (UR-9825) in comparison with those of flucytosine, fluconazole, ketoconazole, itraconazole, and voriconazole against 70 strains of Malassezia spp. was determined by a microdilution method using a colorimetric indicator for metabolic activity. Albaconazole showed an in vitro profile similar to those of the different antifungals tested (MIC ≤ 0.06 μg/ml for all the strains). PMID:12821494

  8. [Canine lymphadenitis caused by Cryptococcus neoformans. First case in Chile].

    PubMed

    Thomson, Pamela; Miranda, Gabriel; Silva, Víctor

    2006-12-01

    We report the first case of canine lymphoadenomegalia caused by Cryptococcus neoformans in Chile. Physical examination of a Rottweiler dog patient showed a generalized lymphoadenomegalia that affected the submandibular, superficial cervical and popliteus lymphatic nodules. Cryptococcus neoformans was isolated and identified from biopsies of the right submandibular nodule. After antifungal susceptibility, oral ketoconazole treatment was established for a period of six months showing clinical improvement. Two years post-treatment the patient showed no signs of the infection.

  9. Fenretinide metabolism in humans and mice: utilizing pharmacological modulation of its metabolic pathway to increase systemic exposure

    PubMed Central

    Cooper, Jason P; Hwang, Kyunghwa; Singh, Hardeep; Wang, Dong; Reynolds, C Patrick; Curley, Robert W; Williams, Simon C; Maurer, Barry J; Kang, Min H

    2011-01-01

    BACKGROUND AND PURPOSE High plasma levels of fenretinide [N-(4-hydroxyphenyl)retinamide (4-HPR)] were associated with improved outcome in a phase II clinical trial. Low bioavailability of 4-HPR has been limiting its therapeutic applications. This study characterized metabolism of 4-HPR in humans and mice, and to explore the effects of ketoconazole, an inhibitor of CYP3A4, as a modulator to increase 4-HPR plasma levels in mice and to increase the low bioavailability of 4-HPR. EXPERIMENTAL APPROACH 4-HPR metabolites were identified by mass spectrometric analysis and levels of 4-HPR and its metabolites [N-(4-methoxyphenyl)retinamide (4-MPR) and 4-oxo-N-(4-hydroxyphenyl)retinamide (4-oxo-4-HPR)] were quantified by high-performance liquid chromatography (HPLC). Kinetic analysis of enzyme activities and the effects of enzyme inhibitors were performed in pooled human and pooled mouse liver microsomes, and in human cytochrome P450 (CYP) 3A4 isoenzyme microsomes. In vivo metabolism of 4-HPR was inhibited in mice. KEY RESULTS Six 4-HPR metabolites were identified in the plasma of patients and mice. 4-HPR was oxidized to 4-oxo-4-HPR, at least in part via human CYP3A4. The CYP3A4 inhibitor ketoconazole significantly reduced 4-oxo-4-HPR formation in both human and mouse liver microsomes. In two strains of mice, co-administration of ketoconazole with 4-HPR in vivo significantly increased 4-HPR plasma concentrations by > twofold over 4-HPR alone and also increased 4-oxo-4-HPR levels. CONCLUSIONS AND IMPLICATIONS Mice may serve as an in vivo model of human 4-HPR pharmacokinetics. In vivo data suggest that the co-administration of ketoconazole at normal clinical doses with 4-HPR may increase systemic exposure to 4-HPR in humans. PMID:21391977

  10. Drug-drug interaction and doping: Effect of non-prohibited drugs on the urinary excretion profile of methandienone.

    PubMed

    Mazzarino, Monica; Khevenhüller-Metsch, Franziska L; Fiacco, Ilaria; Parr, Maria Kristina; de la Torre, Xavier; Botrè, Francesco

    2018-05-15

    The potential consequences of drug-drug interactions on the excretion profile of the anabolic androgenic steroid methandienone (17β-hydroxy-17α-methylandrosta-1,4-dien-3-one) are discussed here. More specifically, we have evaluated by in vitro and in vivo experiments the effects of seven non-prohibited drugs (fluconazole, ketoconazole, itraconazole, miconazole, fluoxetine, paroxetine and nefazodone) on the main metabolic pathways of methandienone. These are selected among those most commonly used by the athletes. The in vitro assays were based on the use of human liver microsomes, specific recombinant enzyme isoforms of cytochrome P450 and uridine 5'-diphospho-glucuronosyl-transferase. The in vivo study was performed by analyzing urines collected after the oral administration of methandienone with and without the co-administration of ketoconazole. Methandienone and its metabolites were determined by liquid chromatography-mass spectrometry-based techniques after sample pre-treatment including an enzymatic hydrolysis step (performed only for the investigation on phase II metabolism) and liquid/liquid extraction with t-butyl methyl-ether. The results from the in vitro experiments showed that the formation of the hydroxylated and dehydrogenated metabolites was significantly reduced in the presence of itraconazole, ketoconazole, miconazole and nefazodone, whereas the production of the 18-nor-hydroxylated metabolites and glucuronidation reactions was reduced significantly only in the presence of ketoconazole and miconazole. The analysis of the post-administration samples confirmed the in vitro observations, validating the hypothesis that drug-drug interaction may cause significant alterations in the metabolic profile of banned drugs, making their detection during doping control tests more challenging. This article is protected by copyright. All rights reserved.

  11. Oral paracoccidioidomycosis or squamous cell carcinoma?

    PubMed

    Kaminagakura, Estela; Graner, Edgard; de Almeida, Oslei Paes; Di Hipolito Júnior, Osvaldo; Lopes, Marcio Ajudarte

    2004-01-01

    Paracoccidioidomycosis is a deep, systemic, and progressive mycosis caused by Paracoccidioides brasiliensis. Oral lesions normally are multiples with a mulberry-like appearance. This article reviews an unusual case involving a chronic, solitary, and ulcerated lesion whose clinical aspects were similar to squamous cell carcinoma. Viewed microscopically, the lesion showed pseudoepitheliomatous hyperplasia and non-necrotizing granulomas. The patient was treated with systemic ketoconazole. Over the next 11 years, follow-up examinations were performed but no recurrence was observed.

  12. Sucrose ester stabilized solid lipid nanoparticles and nanostructured lipid carriers. II. Evaluation of the imidazole antifungal drug-loaded nanoparticle dispersions and their gel formulations.

    PubMed

    Das, Surajit; Ng, Wai Kiong; Tan, Reginald B H

    2014-03-14

    This study focused on: (i) feasibility of the previously developed sucrose ester stabilized SLNs and NLCs to encapsulate different imidazole antifungal drugs and (ii) preparation and evaluation of topical gel formulations of those SLNs and NLCs. Three imidazole antifungal drugs; clotrimazole, ketoconazole and climbazole were selected for this study. The results suggested that size, size distribution and drug encapsulation efficiency depend on the drug molecule and type of nanoparticles (SLN/NLC). The drug release experiment always showed faster drug release from NLCs than SLNs when the same drug molecule was loaded in both nanoparticles. However, drug release rate from both SLNs and NLCs followed the order of climbazole > ketoconazole > clotrimazole. NLCs demonstrated better physicochemical stability than SLNs in the case of all drugs. The drug release rate from ketoconazole- and clotrimazole-loaded SLNs became faster after three months than a fresh formulation. There was no significant change in drug release rate from climbazole-loaded SLNs and all drug-loaded NLCs. Gel formulations of SLNs and NLCs were prepared using polycarbophil polymer. Continuous flow measurements demonstrated non-Newtonian flow with shear-thinning behavior and thixotropy. Oscillation measurements depicted viscoelasticity of the gel formulations. Similar to nanoparticle dispersion, drug release rate from SLN- and NLC-gel was in the order of climbazole > ketoconazole > clotrimazole. However, significantly slower drug release was noticed from all gel formulations than their nanoparticle counterparts. Unlike nanoparticle dispersions, no significant difference in drug release from gel formulations containing SLNs and NLCs was observed for each drug. This study concludes that gel formulation of imidazole drug-loaded SLNs and NLCs can be used for sustained/prolonged topical delivery of the drugs.

  13. Clinical Evaluation of a New-Formula Shampoo for Scalp Seborrheic Dermatitis Containing Extract of Rosa centifolia Petals and Epigallocatechin Gallate: A Randomized, Double-Blind, Controlled Study

    PubMed Central

    Kim, Yu Ri; Kim, Jeong-Hwan; Shin, Hong-Ju; Choe, Yong Beom; Ahn, Kyu Joong

    2014-01-01

    Background Scalp seborrheic dermatitis is a chronic type of inflammatory dermatosis that is associated with sebum secretion and proliferation of Malassezia species. Ketoconazole or zinc-pyrithione shampoos are common treatments for scalp seborrheic dermatitis. However, shampoos comprising different compounds are required to provide patients with a wider range of treatment options. Objective This study was designed to evaluate a new-formula shampoo that contains natural ingredients-including extract of Rosa centifolia petals and epigallocatechin gallate (EGCG)-that exert antioxidative, anti-inflammatory, and sebum secretion inhibitory effects, and antifungal agents for the treatment of scalp seborrheic dermatitis. Methods Seventy-five patients were randomized into three treatment groups; new-formula shampoo, 2% ketoconazole shampoo, and 1% zinc- pyrithione shampoo. The clinical severity scores and sebum levels were assessed by the same dermatologists at baseline (week 0), and at 2 and 4 weeks after using the shampoo. User satisfaction and irritation were also assessed with the aid of a questionnaire. Results The efficacy of the new-formula shampoo was comparable to that of both the 1% zinc-pyrithione shampoo and the 2% ketoconazole shampoo. Furthermore, it was found to provide a more rapid response than the 1% zinc-pyrithione shampoo for mild erythema lesions and was associated with greater user satisfaction compared with the 2% ketoconazole shampoo. However, the new-formula shampoo did not exhibit the previously reported sebum inhibitory effect. Conclusion Extract of R. centifolia petals or EGCG could be useful ingredients in the treatment of scalp seborrheic dermatitis. PMID:25473226

  14. A single-dose, crossover, placebo- and moxifloxacin-controlled study to assess the effects of neratinib (HKI-272) on cardiac repolarization in healthy adult subjects.

    PubMed

    Hug, Bruce; Abbas, Richat; Leister, Cathie; Burns, Jaime; Sonnichsen, Daryl

    2010-08-01

    Neratinib is an orally administered, small-molecule, irreversible pan-ErbB inhibitor in development for the treatment of ErbB2-positive breast cancer. This study assessed the effects of therapeutic and supratherapeutic neratinib concentrations on cardiac repolarization, in accordance with current regulatory guidance. This was a two-part study in healthy subjects. In part 1, subjects were randomized to receive placebo, 400 mg moxifloxacin, or 240 mg neratinib (therapeutic dose) following a high-fat meal. In part 2, after a washout period, subjects received placebo plus 400 mg ketoconazole or 240 mg neratinib plus ketoconazole (supratherapeutic dose). ANOVA was used to compare the baseline-adjusted QTc interval for neratinib with that of placebo (reference), and for neratinib plus ketoconazole with that of placebo plus ketoconazole (reference). Pharmacokinetic/pharmacodynamic analyses and categorical summaries of interval data were done. Assay sensitivity was evaluated by the effect of moxifloxacin on QTc compared with placebo. Sixty healthy subjects were enrolled in this study. The upper bounds of the 90% confidence interval for baseline-adjusted QTcN (population-specific corrected QT) were 450 milliseconds or change from baseline >30 milliseconds. Moxifloxacin produced a significant increase in QTcN compared with placebo (P < 0.05). Therapeutic and supratherapeutic plasma concentrations of neratinib do not prolong the QTc interval in healthy subjects. (c) 2010 AACR.

  15. In Vitro Antifungal Susceptibility Profiles of 12 Antifungal Drugs against 55 Trichophyton schoenleinii Isolates from Tinea Capitis Favosa Patients in Iran, Turkey, and China

    PubMed Central

    Deng, Shuwen; Ansari, Saham; Rafati, Haleh; Taghizadeh-Armaki, Mojtaba; Nasrollahi-Omran, Ayatollah; Tolooe, Ali; Zhan, Ping; Liao, Wanqing; van der Lee, Henrich A.; Verweij, Paul E.

    2016-01-01

    ABSTRACT Trichophyton schoenleinii is an anthropophilic dermatophyte mainly causing tinea favosa of the scalp in certain regions of the world, especially Africa and Asia. We investigated the in vitro susceptibilities of 55 T. schoenleinii isolates collected over the last 30 years from Iran, Turkey, and China to 12 antifungals using the CLSI broth microdilution method. Our results revealed that terbinafine and ketoconazole were the most potent antifungal agents among those tested, independently of the geographic regions where strains were isolated. PMID:27956429

  16. Voriconazole for the treatment of refractory Aspergillus fumigatus keratitis

    PubMed Central

    Mehta, Hitendra B; Garg, Prashant; Kodial, Harish

    2008-01-01

    We report a case of Aspergillus fumigatus keratitis in a 53-year-old, well-controlled diabetic female who did not respond to standard antifungal treatment. She was started on topical natamycin eye drops, but the infiltrate continued to progress. Topical amphotericin B and systemic ketoconazole was added, however, there was no response and the infiltrate increased further. She was then switched to topical and systemic voriconazole. Steady resolution of the infiltrate was noted within 2 weeks of therapy. PMID:18417831

  17. Pityrosporum folliculitis in an immunocompetent patient: clinical case description.

    PubMed

    Viana de Andrade, Ana Carolina Dias; Pithon, Matheus Melo; Oiticica, Olga Maria

    2013-08-15

    The present report concerns Malassezia-related pityrosporum folliculitis in a patient without any predisposing factor. Once the diagnosis had been confirmed by histopathologic exam, the patient was treated with oral ketoconazole and selenium sulfide shampoo; complete remission of the clinical condition was obtained. Thus it could be concluded that in spite of being routinely associated with immunosuppression, this condition may be present in an immunocompetent patient.

  18. Drug-induced gynecomastia.

    PubMed

    Thompson, D F; Carter, J R

    1993-01-01

    Gynecomastia is a relatively common physical finding in men. A wide variety of drugs have been implicated in its cause. Sufficient evidence in the literature suggests that calcium-channel blockers, cancer chemotherapeutic agents, and histamine2-receptor blockers may play a role in the disorder. Evidence for digitalis glycosides and neuroleptic agents is insufficient. Ketoconazole and spironolactone can also produce gynecomastia, and data for marijuana are contradictory. Large numbers of drugs have only case reports of temporal association with the disorder.

  19. Effect of Antimicrobial Compounds on Balamuthia mandrillaris Encystment and Human Brain Microvascular Endothelial Cell Cytopathogenicity▿

    PubMed Central

    Siddiqui, Ruqaiyyah; Matin, Abdul; Warhurst, David; Stins, Monique; Khan, Naveed Ahmed

    2007-01-01

    Cycloheximide, ketoconazole, or preexposure of organisms to cytochalasin D prevented Balamuthia mandrillaris-associated cytopathogenicity in human brain microvascular endothelial cells, which constitute the blood-brain barrier. In an assay for inhibition of cyst production, these three agents prevented the production of cysts, suggesting that the biosynthesis of proteins and ergosterol and the polymerization of actin are important in cytopathogenicity and encystment. PMID:17875991

  20. A Randomized Phase 2 Trial of 177Lu Radiolabeled Anti-PSMA Biochemically Monoclonal Antibody J591 in Patients with High-Risk Castrate, Biochemically Relapsed Prostate Cancer

    DTIC Science & Technology

    2010-09-01

    relapsed prostate cancer (PC) after local therapy. J Clin Oncol 28: 15s, 2010 (suppl; Abstr TPS248) Presentation: Poster presentation, 2010 ASCO...Annual Meeting V. Conclusions Biochemical relapse is common after local therapy for prostate cancer. Based on the physical properties of 177Lu...ketoconazole in patients (pts) with high-risk castrate biochemically relapsed prostate cancer (PC) after local therapy. S. T. Tagawa, J. Osborne, P. J

  1. Microsporum canis infection in three familial cases with tinea capitis and tinea corporis.

    PubMed

    Yin, Bin; Xiao, Yuling; Ran, Yuping; Kang, Daoxian; Dai, Yaling; Lama, Jebina

    2013-10-01

    We report a familial infection caused by Microsporum canis. The first two patients were a 30-year-old female and her son, a 5-year-old boy, who came in contact with a pet dog at a farm house. The boy then suffered from hair loss for 3 months. There were circular and patchy alopecia with diffuse scaling on his scalp. Meanwhile, his mother also developed patchy erythema and scaling on her face. Several weeks later, the boy's sister, a 4-year-old girl, was noted to have inconspicuous scaly plaques in the center of her scalp. The development of tinea capitis in the two children and tinea corporis in their mother were diagnosed based on the positive KOH examination. Morphologic characteristics and sequencing of the internal transcribed spacers 1 and 2, amplified from primary culture isolates, confirmed that their infections were caused by the zoophilic M. canis. Repetitive sequence-based molecular typing using the DiversiLab system secreted enzymatic activity analysis, and antifungal susceptibility indicated that these isolates might share the same source. The boy and girl were cured by the treatment with oral itraconazole and topical naftifine-ketoconazole cream after washing the hair with 2 % ketoconazole shampoo, and their mother was successfully treated by terbinafine orally in combination with topical application of naftifine-ketoconazole cream.

  2. Ciclosporin use in multi-drug therapy for meningoencephalomyelitis of unknown aetiology in dogs.

    PubMed

    Adamo, P F; Rylander, H; Adams, W M

    2007-09-01

    To evaluate the efficacy and safety of ciclosporin therapy alone or in combination with corticosteroids and/or ketoconazole in dogs with diagnosis of meningoencephalomyelitis of unknown aetiology. Medical records of 10 dogs diagnosed with meningoencephalomyelitis of unknown aetiology and treated with ciclosporin therapy alone or in combination with corticosteroids and/or ketoconazole were reviewed at the Veterinary Medical Teaching Hospital, University of Wisconsin-Madison. Laboratory abnormalities, side effects, clinical and cerebrospinal fluid responses to treatment and association between blood ciclosporin level and response to treatment were evaluated. Histopathological diagnosis was available in three patients. No significant abnormalities were detected on serial complete blood count and serum chemistry panel in any of the dogs. Side effects of ciclosporin therapy included excessive shedding, gingival hyperplasia and hypertrichosis. Overall median survival time for all dogs in the study was 930 days (range, 60 to more than 1290 days). In all dogs, serial cerebrospinal fluid analysis showed a marked improvement in the inflammation. Results suggest that ciclosporin either alone or in combination with ketoconazole may be a safe and effective treatment for meningoencephalomyelitis of unknown aetiology in dogs.

  3. Ciclosporin therapy for canine generalized discoid lupus erythematosus refractory to doxycycline and niacinamide.

    PubMed

    Banovic, Frane; Olivry, Thierry; Linder, Keith E

    2014-10-01

    Generalized discoid lupus erythematosus (DLE) is an autoimmune skin disease variant rarely reported in dogs. The antimalarial immunomodulator hydroxychloroquine has been suggested as maintenance therapy for generalized DLE in one dog, but several recurrences were noted in the 1 year follow-up of that patient. To describe the effective treatment of generalized DLE with ciclosporin in one dog. A 6-year-old, castrated male crossbred dog was presented with pruritic, well-demarcated annular to polycyclic, hyperpigmented plaques with marginal erythema on the dorsal head, neck, trunk and medial extremities; these had been nonresponsive to treatment with doxycycline and niacinamide. Investigation included complete blood count, serum chemistry profile, urinalysis, serum antinuclear antibody test, histopathological examination and direct immunofluorescence testing of skin biopsies. The presence of lymphocyte-rich interface dermatitis on histology, together with generalized chronic recurrent hyperpigmented plaques, was consistent with the diagnosis of a generalized variant of DLE. The absence of systemic signs and unremarkable laboratory tests excluded concurrent systemic lupus erythematosus. Treatment was initiated with oral dexamethasone and ciclosporin. After 1 month, dexamethasone was discontinued and oral ketoconazole was added to the therapeutic regimen. Four months later, pruritus and erythema resolved, with most skin lesions becoming impalpable. Over the last 6 months, the patient's DLE was maintained in remission with oral ciclosporin and ketoconazole in combination every 3 days. The combination of ciclosporin and ketoconazole appeared effective to induce and maintain lesion remission in this dog with generalized DLE. © 2014 ESVD and ACVD.

  4. Pityriasis versicolor--epidemiological and therapeutical study.

    PubMed

    Selim, M M; Kubec, K

    1989-02-01

    Seventy-six patients with extensive pityriasis versicolor were divided into 3 groups and treated orally with ketoconazole, 200 mg daily, for 10, 20 or 30 days respectively. 50 patients out of this number completed the study. After 6 months, 46 patients were checked up. Eight of them developed relapses effectively treated with ketoconazole for another 15 days. Six out of these 8 patients belonged to the first group using ketoconazole for 20 days only. On the basis of this observation, we do not consider a 10 days' treatment to be sufficient and recommend that the patient should be treated for at least 20 days. As a preventive measure we recommend a daily bath with salicylic acid and sulphur soap. The frequency of the infection was higher in males (71.4%) than in females (28.6%). The youngest of the male patients was 4 months of age and the oldest 70 years. The youngest female was 4 months old and the oldest 50 years. Pityriasis versicolor was found to be predominant in the age group of 21--30 years. The sites most commonly involved were back, chest and the upper extremities.

  5. Clinical efficacy of a new ciclopiroxolamine/zinc pyrithione shampoo in scalp seborrheic dermatitis treatment.

    PubMed

    Lorette, Gérard; Ermosilla, Valérie

    2006-01-01

    Ciclopiroxolamine (CPO) and Zinc Pirythione (ZP) antifungals are efficient at treating scalp seborrheic dermatitis. This multicentre, single-blind, clinical study was conducted to evaluate the efficacy of a shampoo containing the 1.5% CPO/1% ZP association compared to the vehicle shampoo and to 2% ketoconazole foaming gel in the treatment of seborrheic dermatitis. In 189 patients randomised to apply 1 of the 3 products twice a week for 28 days, the global lesional score, erythema, pruritus, global efficacy, quality of life (SF12 and DLQI questionnaires) and tolerance were measured at 0, 7, 14 and 28 days. The 3 products reduced lesional score, erythema and pruritus from day 7 (p < 0.0001). The 2 antifungal treatments were significantly more efficient than the vehicle in reducing lesional score, erythema and pruritus at day 14 (p < 0.0001). At day 7, the CPO/ZP shampoo was more efficient in reducing pruritus than ketoconazole gel and vehicle (p = 0.032 and p < 0.001, respectively). The global efficacy of the 2 antifungal treatments assessed at day 28 by both investigator and patient was significantly better than that of the vehicle. Only the CPO/ZP shampoo improved all DLQI questionnaire dimensions. The CPO/ZP shampoo was as rapid and efficient as ketoconazole gel in SD treatment.

  6. Silver nanoparticles from Pilimelia columellifera subsp. pallida SL19 strain demonstrated antifungal activity against fungi causing superficial mycoses.

    PubMed

    Wypij, Magdalena; Czarnecka, Joanna; Dahm, Hanna; Rai, Mahendra; Golinska, Patrycja

    2017-09-01

    In this study, we present the in vitro antifungal activity of silver nanoparticles (AgNPs) synthesized from acidophilic actinobacterium Pilimelia columellifera subsp. pallida SL19 strain, alone and in combination with antibiotics viz., amphotericin B, fluconazole, and ketoconazole against pathogenic fungi, namely Candida albicans, Malassezia furfur, and Trichophyton erinacei. The minimum inhibitory concentration (MIC) and minimum biocidal concentration (MBC) of AgNPs against test fungi were evaluated. The fractional inhibitory concentration (FIC) index was determined to estimate antifungal activity of AgNPs combined with antibiotics. Antifungal activity of AgNPs varied among the tested fungal strains. M. furfur was found to be most sensitive to biogenic silver nanoparticles, followed by C. albicans and T. erinacei. The lowest MIC of AgNPs was noticed against M. furfur (16 μg ml -1 ). Synergistic effect was observed on C. albicans when AgNP were combined with amphotericin B and ketoconazole and on M. furfur with fluconazole and ketoconazole (FIC index of 0.5). Cytotoxic effect of AgNPs on HeLa and 3T3 cell lines was evaluated. The IC 50 values were found to be 55 and 25 μg ml -1 , respectively. The present study indicates that silver nanoparticles from P. columellifera subsp. pallida SL19 strain have antifungal activity, both alone and in combination with antibiotics, and offer a valuable contribution to nanomedicine. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  7. Strategies to Circumvent Testosterone Surge and Disease Flare in Advanced Prostate Cancer: Emerging Treatment Paradigms.

    PubMed

    Pokuri, Venkata K; Nourkeyhani, Houman; Betsy, Bodie; Herbst, Laurie; Sikorski, Marcus; Spangenthal, Edward; Fabiano, Andrew; George, Saby

    2015-07-01

    The testosterone surge and disease flare is a feared complication from initiation of gonadotropin-releasing hormone (GnRH) agonist treatment in advanced prostate adenocarcinoma. It is a common practice to start an average 7-day pretreatment regimen with an antiandrogen agent before initiating GnRH agonist therapy, to circumvent disease flare from testosterone surge. However, this might not be the best strategy and can be harmful, especially in patients at high risk of imminent organ damage from minimal testosterone surge. Surgical castration is a simple and cost-effective method that should be considered in these scenarios. But most patients refuse this procedure because of the permanent and psychologic impact of surgery. Novel GnRH antagonists, such as degarelix, and cytochrome P450 17 (CYP17) enzyme inhibitors, such as ketoconazole, achieve castrate-equivalent serum testosterone levels much faster than traditional GnRH agonists without the need for coadministration of antiandrogens. This article reports on 3 cases of impending oncologic emergencies in advanced prostate adenocarcinoma treated promptly with degarelix and ketoconazole without any disease flare related to testosterone surge. In the setting of symptomatic hormone-naïve metastatic prostate cancer, the authors suggest clinical trials using abiraterone, orteronel, and other newer agents that target the CYP17 axis (eg, ketoconazole) for fine-tuning the emergent medical castration methods and avoiding the dangers from the flare phenomenon. Copyright © 2015 by the National Comprehensive Cancer Network.

  8. An in vitro methodology for forecasting luminal concentrations and precipitation of highly permeable lipophilic weak bases in the fasted upper small intestine.

    PubMed

    Psachoulias, Dimitrios; Vertzoni, Maria; Butler, James; Busby, David; Symillides, Moira; Dressman, Jennifer; Reppas, Christos

    2012-12-01

    To develop an in vitro methodology for prediction of concentrations and potential precipitation of highly permeable, lipophilic weak bases in fasted upper small intestine based on ketoconazole and dipyridamole luminal data. Evaluate usefulness of methodology in predicting luminal precipitation of AZD0865 and SB705498 based on plasma data. A three-compartment in vitro setup was used. Depending on the dosage form administered in in vivo studies, a solution or a suspension was placed in the gastric compartment. A medium simulating the luminal environment (FaSSIF-V2plus) was initially placed in the duodenal compartment. Concentrated FaSSIF-V2plus was placed in the reservoir compartment. In vitro ketoconazole and dipyridamole concentrations and precipitated fractions adequately reflected luminal data. Unlike luminal precipitates, in vitro ketoconazole precipitates were crystalline. In vitro AZD0865 data confirmed previously published human pharmacokinetic data suggesting that absorption rates are not affected by luminal precipitation. In vitro SB705498 data predicted that significant luminal precipitation occurs after a 100 mg or 400 mg but not after a 10 mg dose, consistent with human pharmacokinetic data. An in vitro methodology for predicting concentrations and potential precipitation in fasted upper small intestine, after administration of highly permeable, lipophilic weak bases in fasted upper small intestine was developed and evaluated for its predictability in regard to luminal precipitation.

  9. 7α-Hydroxypregnenolone regulates diurnal changes in sexual behavior of male quail.

    PubMed

    Ogura, Yuki; Haraguchi, Shogo; Nagino, Koki; Ishikawa, Kei; Fukahori, Yoko; Tsutsui, Kazuyoshi

    2016-02-01

    In the Japanese quail, 7α-hydroxypregnenolone, a previously undescribed avian neurosteroid, is actively produced in the brain. 7α-Hydroxypregnenolone acts as a novel neuronal activator to stimulate locomotor activity of quail. Therefore, in this study, we determined whether 7α-hydroxypregnenolone changes the expression of sexual behavior in Japanese quail. We first measured diurnal changes in sexual behavior of male quail exposed to a long-day photoperiod. We found that sexual behavior of male quail was high in the morning when endogenous 7α-hydroxypregnenolone level is high. Subsequently, we centrally administered 7α-hydroxypregnenolone in the evening when endogenous 7α-hydroxypregnenolone level is low. In the 30 min after intracerebroventricular (ICV) injection, 7α-hydroxypregnenolone dose dependently increased the frequency of sexual behavior of male quail. However, 7β-hydroxypregnenolone, a stereoisomer of 7α-hydroxypregnenolone, did not effect on the frequency of sexual behavior of male quail. In addition, to confirm the action of 7α-hydroxypregnenolone on sexual behavior, male birds received an ICV injection of ketoconazole, an inhibitor of cytochrome P450s, and behavioral experiments were performed in the morning. Ketoconazole significantly decreased the frequency of sexual behavior of male quail, whereas administration of 7α-hydroxypregnenolone to ketoconazole-treated males increased the frequency of their sexual behavior. These results indicate that 7α-hydroxypregnenolone regulates diurnal changes in sexual behavior of male quail. Copyright © 2015 Elsevier Inc. All rights reserved.

  10. Strength of Drug–Polymer Interactions: Implications for Crystallization in Dispersions

    SciT

    Mistry, Pinal; Suryanarayanan, Raj

    We investigated the influence of the strength of drug–polymer interactions on the crystallization behavior of a model drug in amorphous solid dispersions (ASDs). Ketoconazole ASDs were prepared with each poly(acrylic acid), poly(2-hydroxyethyl methacrylate), and polyvinylpyrrolidone. Over a wide temperature range in the supercooled region, the α-relaxation time was obtained, which provided a measure of molecular mobility. Isothermal crystallization studies were performed in the same temperature interval using either a synchrotron (for low levels of crystallinity) or a laboratory X-ray (for crystallization kinetics) source. The stronger the drug–polymer interaction, the longer was the delay in crystallization onset time, indicating an increasemore » in physical stability. Stronger drug–polymer interactions also translated to a decrease in the magnitude of the crystallization rate constant. In amorphous ketoconazole as well as in the dispersions, the coupling coefficient, a measure of the extent of coupling between relaxation and crystallization times was ~0.5. This value was unaffected by the strength of drug–polymer interactions. On the basis of these results, the crystallization times in ASDs were predicted at temperatures very close to Tg, using the coupling coefficient experimentally determined for amorphous ketoconazole. The predicted and experimental crystallization times were in good agreement, indicating the usefulness of the model.« less

  11. In vitro sensitivity of medically significant Fusarium species to various antimycotics.

    PubMed

    Sekhon, A S; Padhye, A A; Garg, A K; Ahmad, H; Moledina, N

    1994-01-01

    Sixteen isolates belonging to Fusarium chlamydosporum (n = 4), Fusarium equiseti (n = 1), Fusarium moniliforme (n = 2), Fusarium oxysporum (n = 3), Fusarium proliferatum (n = 1), and Fusarium solani (n = 5) were tested against amphotericin B, 5-fluorocytosine, fluconazole, itraconazole, ketoconazole, JAI-amphotericin B (water-soluble compound), hamycin and amphotericin B combined with 5-fluorocytosine, using antibiotic medium M3, high-resolution broth (pH 7.1), Sabouraud's dextrose, and yeast-nitrogen broth media (1 ml/tube). The minimal inhibitory and minimal fungicidal concentrations of 5-fluorocytosine and fluconazole for all species were > 100 micrograms/ml. All Fusarium isolates, except F. equiseti (3.125 micrograms), gave minimal inhibitory concentrations of 12.5-100 micrograms/ml for hamycin. The values for amphotericin B, itraconazole, ketoconazole, JAI-amphotericin B, and amphotericin B combined with 5-fluorocytosine were 1.56-100, 0.78-50, 3.125-100,50-100, and 1.56 to > 100 micrograms/ml, respectively. Although a wide range of minimal inhibitory concentrations was recorded for most of the isolates studied, it appears that some--F. solani, F. oxysporum, F. chlamydosporum, F. equiseti, and F. moliniforme--were more susceptible to amphotericin B, itraconazole, ketoconazole, hamycin, and amphotericin B in the presence of 5-fluorocytosine. All isolates showed resistance to 5-fluorocytosine and fluconazole. The minimal fungicidal concentrations were either the same or several times higher than the minimal inhibitory concentrations.

  12. Relative contributions of the major human CYP450 to the metabolism of icotinib and its implication in prediction of drug-drug interaction between icotinib and CYP3A4 inhibitors/inducers using physiologically based pharmacokinetic modeling.

    PubMed

    Chen, Jia; Liu, Dongyang; Zheng, Xin; Zhao, Qian; Jiang, Ji; Hu, Pei

    2015-06-01

    Icotinib is an anticancer drug, but relative contributions of CYP450 have not been identified. This study was carried out to identify the contribution percentage of CYP450 to icotinib and use the results to develop a physiologically based pharmacokinetic (PBPK) model, which can help to predict drug-drug interaction (DDI). Human liver microsome (HLM) and supersome using relative activity factor (RAF) were employed to determine the relative contributions of the major human P450 to the net hepatic metabolism of icotinib. These values were introduced to develop a PBPK model using SimCYP. The model was validated by the observed data in a Phase I clinical trial in Chinese healthy subjects. Finally, the model was used to simulate the DDI with ketoconazole or rifampin. Final contribution of CYP450 isoforms determined by HLM showed that CYP3A4 provided major contributions to the metabolism of icotinib. The percentage contributions of the P450 to the net hepatic metabolism of icotinib were determined by HLM inhibition assay and RAF. The AUC ratio under concomitant use of ketoconazole and rifampin was 3.22 and 0.55, respectively. Percentage of contribution of CYP450 to icotinib metabolism was calculated by RAF. The model has been proven to fit the observed data and is used in predicting icotinib-ketoconazole/rifampin interaction.

  13. Clobetasol propionate shampoo 0.05% in the treatment of seborrheic dermatitis of the scalp: results of a pilot study.

    PubMed

    Reygagne, Pascal; Poncet, Michel; Sidou, Farzaneh; Soto, Pascale

    2007-05-01

    Seborrheic dermatitis (SD), a common dermatosis associating hyperseborrhea, erythema, itching, and dandruff, has frequent scalp involvement. Malassezia furfur infection seems to play an important role in the condition's etiopathology. Treatment of SD usually consists of corticosteroids or antifungals, such as ketoconazole. The aim of this multicenter, randomized, investigator-blinded, parallel-group pilot study was to evaluate the efficacy and safety of clobetasol propionate shampoo 0.05% after different short-contact application times compared with its vehicle and ketoconazole foaming gel 2% in the treatment of SD of the scalp. For 4 weeks, 55 subjects received one of the following treatments twice weekly: clobetasol propionate shampoo for 2.5, 5, or 10 minutes; clobetasol propionate vehicle for 10 minutes; or ketoconazole foaming gel for 5 minutes before rinsing off. Efficacy criteria included total severity score (TSS) and individual scores of signs such as itching and global improvement. Safety included reporting of burning, overall tolerance, and adverse events. Results showed that an application of clobetasol propionate for 5 and 10 minutes provided a similar mean percentage decrease of TSS, and the mean percentage decrease of TSS for all active groups was significantly superior to that of the vehicle (P < .01). Overall and local safety were good for all treatment groups. The present pilot study demonstrated that a short-contact application of clobetasol propionate shampoo is effective and safe in the treatment of SD of the scalp.

  14. Successful treatment of dandruff with 1.5% ciclopirox olamine shampoo in Korea.

    PubMed

    Lee, J H; Lee, H S; Eun, H C; Cho, K H

    2003-12-01

    Dandruff is a chronic scalp condition characterized by scaling. The common causative agent is now accepted to be the lipophilic yeast Malassezia furfur. Ketoconazole, a highly effective antifungal agent against M. furfur has been used for the treatment of dandruff. To determine whether a 1.5% ciclopirox olamine shampoo is as effective as a 2% ketoconazole shampoo for the treatment of mild to moderate dandruff. A total of 64 patients, with mild to moderate dandruff, participated in the study. The study consisted of three consecutive phases: a 2-week washout period, a 4-week treatment period and a 2-week post-treatment period. Patients were randomized equally to either the 1.5% ciclopirox olamine shampoo or 2% ketoconazole shampoo. An overall dandruff score was calculated using an area of dandruff involvement score and a severity score. Patients evaluated the presence of pruritus and also reported a global evaluation of efficacy. In all, 57 patients successfully completed all three phases. The overall dandruff score declined progressively throughout the treatment period for both shampoos. A slight increase in pruritus was observed in the ciclopirox olamine treatment group during the post-treatment phase. Regarding global self-assessment of efficacy, both treatment groups were pleased with their scalp condition following treatment. Ciclopirox olamine shampoo appears to offer an effective, safe and easy to use treatment for mild to moderate dandruff.

  15. Fluconazole in the treatment of Cushing's disease

    PubMed Central

    Christie-David, Darshika; Gunton, Jenny E

    2016-01-01

    Summary Ketoconazole was a first-line agent for suppressing steroidogenesis in Cushing's disease. It now has limited availability. Fluconazole, another azole antifungal, is an alternative, although its in vivo efficacy is unclear. A 61-year-old female presented with weight gain, abdominal striae and worsening depression. HbA1c increased to 76 mmol/mol despite increasing insulin. Investigations confirmed cortisol excess; afternoon serum cortisol was 552 nmol/l with an inappropriate ACTH of 9.3 pmol/l. In total, 24-h urinary free cortisol (UFC):creatinine ratio was 150 nmol/mmol with failure to suppress after 48 h of low-dose dexamethasone. Pituitary MRI revealed a 4-mm microadenoma. Inferior petrosal sinus sampling confirmed Cushing's disease. Transsphenoidal resection was performed and symptoms improved. However, disease recurred 6 months later with elevated 24-h UFC >2200 nmol/day. Metyrapone was commenced at 750 mg tds. Ketoconazole was later added at 400 mg daily, with dose reduction in metyrapone. When ketoconazole became unavailable, fluconazole 200 mg daily was substituted. Urine cortisol:creatinine ratio rose, and the dose was increased to 400 mg daily with normalisation of urine hormone levels. Serum cortisol and urine cortisol:creatinine ratios remain normal on this regimen at 6 months. In conclusion, to our knowledge, this is the first case demonstrating prolonged in vivo efficacy of fluconazole in combination with low-dose metyrapone for the treatment of Cushing's disease. Fluconazole has a more favourable toxicity profile, and we suggest that it is a potential alternative for medical management of Cushing's disease. Learning points Surgery remains first line for the management of Cushing's disease with pharmacotherapy used where surgery is unsuccessful or there is persistence of cortisol excess.Ketoconazole has previously been used to treat cortisol excess through inhibition of CYP450 enzymes 11-β-hydroxylase and 17-

  16. Topical antifungals for seborrhoeic dermatitis

    PubMed Central

    Okokon, Enembe O; Verbeek, Jos H; Ruotsalainen, Jani H; Ojo, Olumuyiwa A; Bakhoya, Victor Nyange

    2015-01-01

    Background Seborrhoeic dermatitis is a chronic inflammatory skin condition that is distributed worldwide. It commonly affects the scalp, face and flexures of the body. Treatment options include antifungal drugs, steroids, calcineurin inhibitors, keratolytic agents and phototherapy. Objectives To assess the effects of antifungal agents for seborrhoeic dermatitis of the face and scalp in adolescents and adults. A secondary objective is to assess whether the same interventions are effective in the management of seborrhoeic dermatitis in patients with HIV/AIDS. Search methods We searched the following databases up to December 2014: the Cochrane Skin Group Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL) (2014, Issue 11), MEDLINE (from 1946), EMBASE (from 1974) and Latin American Caribbean Health Sciences Literature (LILACS) (from 1982). We also searched trials registries and checked the bibliographies of published studies for further trials. Selection criteria Randomised controlled trials of topical antifungals used for treatment of seborrhoeic dermatitis in adolescents and adults, with primary outcome measures of complete clearance of symptoms and improved quality of life. Data collection and analysis Review author pairs independently assessed eligibility for inclusion, extracted study data and assessed risk of bias of included studies. We performed fixed-effect meta-analysis for studies with low statistical heterogeneity and used a random-effects model when heterogeneity was high. Main results We included 51 studies with 9052 participants. Of these, 45 trials assessed treatment outcomes at five weeks or less after commencement of treatment, and six trials assessed outcomes over a longer time frame. We believe that 24 trials had some form of conflict of interest, such as funding by pharmaceutical companies. Among the included studies were 12 ketoconazole trials (N = 3253), 11 ciclopirox trials (N = 3029), two lithium trials (N = 141

  17. Novel Yeast-based Strategy Unveils Antagonist Binding Regions on the Nuclear Xenobiotic Receptor PXR*

    PubMed Central

    Li, Hao; Redinbo, Matthew R.; Venkatesh, Madhukumar; Ekins, Sean; Chaudhry, Anik; Bloch, Nicolin; Negassa, Abdissa; Mukherjee, Paromita; Kalpana, Ganjam; Mani, Sridhar

    2013-01-01

    The pregnane X receptor (PXR) is a master regulator of xenobiotic metabolism, and its activity is critical toward understanding the pathophysiology of several diseases, including inflammation, cancer, and steatosis. Previous studies have demonstrated that ketoconazole binds to ligand-activated PXR and antagonizes receptor control of gene expression. Structure-function as well as computational docking analysis suggested a putative binding region containing critical charge clamp residues Gln-272, and Phe-264 on the AF-2 surface of PXR. To define the antagonist binding surface(s) of PXR, we developed a novel assay to identify key amino acid residues on PXR based on a yeast two-hybrid screen that examined mutant forms of PXR. This screen identified multiple “gain-of-function” mutants that were “resistant” to the PXR antagonist effects of ketoconazole. We then compared our screen results identifying key PXR residues to those predicted by computational methods. Of 15 potential or putative binding residues based on docking, we identified three residues in the yeast screen that were then systematically verified to functionally interact with ketoconazole using mammalian assays. Among the residues confirmed by our study was Ser-208, which is on the opposite side of the protein from the AF-2 region critical for receptor regulation. The identification of new locations for antagonist binding on the surface or buried in PXR indicates novel aspects to the mechanism of receptor antagonism. These results significantly expand our understanding of antagonist binding sites on the surface of PXR and suggest new avenues to regulate this receptor for clinical applications. PMID:23525103

  18. The effects of inhibiting cytochrome P450 3A, p-glycoprotein, and gastric acid secretion on the oral bioavailability of methadone in dogs.

    PubMed

    Kukanich, B; Lascelles, B D X; Aman, A M; Mealey, K L; Papich, M G

    2005-10-01

    Methadone is an opioid, which has a high oral bioavailability (>70%) and a long elimination half-life (>20 h) in human beings. The purpose of this study was to evaluate the effects of ketoconazole [a CYP3A and p-glycoprotein (p-gp) inhibitor] and omeprazole (an H+,K(+)-ATPase proton-pump inhibitor) on oral methadone bioavailability in dogs. Six healthy dogs were used in a crossover design. Methadone was administered i.v. (1 mg/kg), orally (2 mg/kg), again orally following oral ketoconazole (10 mg/kg q12 h for two doses), and following omeprazole (1 mg/kg p.o. q12 h for five doses). Plasma concentrations of methadone were analyzed by high-pressure liquid chromatography or fluorescence polarization immunoassay. The mean +/- SD for the elimination half-life, volume of distribution, and clearance were 1.75 +/- 0.25 h, 3.46 +/- 1.09 L/kg, and 25.14 +/- 9.79 mL/min.kg, respectively following i.v. administration. Methadone was not detected in any sample following oral administration alone or following oral administration with omeprazole. Following administration with ketoconazole, detectable concentrations of methadone were present in one dog with a 29% bioavailability. MDR-1 genotyping, encoding p-gp, was normal in all dogs. In contrast to its pharmacokinetics humans, methadone has a short elimination half-life, rapid clearance, and low oral bioavailability in dogs and the extent of absorption is not affected by inhibition of CYP3A, p-gp, and gastric acid secretion.

  19. CYP3A4 activity in four different animal species liver microsomes using 7-benzyloxyquinoline and HPLC/spectrofluorometric determination.

    PubMed

    Baririan, Narine; Desager, Jean-Pierre; Petit, Martine; Horsmans, Yves

    2006-01-23

    Some microplate-based direct assays with different fluorometric substrates have been developed, among which 7-benzyloxyquinoline (BOQ) has demonstrated the highest degree of selectivity for CYP3A subfamily. In our study, we firstly developed and validated an efficient, fast and cheap HPLC/spectrofluorometric analytical method to quantify 7-hydroxyquinoline (BOQ metabolite). Secondly, BOQ oxidation rate (1.95 +/- 0.24 microM/mg protein/min) was compared to that of midazolam (MDZ) (1.4 +/- 0.21 microM/mg protein/min), an other specific CYP3A probe. However, the difference did not reach statistically significance (test of Sign; p = 0.125, two tailed). Thirdly, the potential use of BOQ in other species than the rat (mouse, dog and monkey) was studied. The highest BOQ activity was observed in rat microsomes (3.75 micromol/mg protein/min) with lower P450 content (0.3 nmol/mg protein) compared to other species. Finally, the effect of CYP3A enzymes-selective inhibitor ketoconazole on the dealkylation of BOQ in control and dexamethasone (DM)-treated rat microsomes was studied. Ketoconazole inhibition potency was greater in control (IC(50) approximately 21.6 microM) compared to DM induced (IC(50) approximately 32.3 microM) microsomes. At concentrations greater than that considered to be enzyme-selective (e.g., 10-30 microM), ketoconazole inhibitory activity did not rise significantly, and at the maximal concentration tested (1,000 microM) a nearly similar inhibition (76%) was observed than that at 50 microM concentration (68.2%).

  20. Comparison of two in vitro antifungal sensitivity tests and monitoring during therapy of Sporothrix schenckii sensu stricto in Malaysian cats.

    PubMed

    Han, Hock Siew; Kano, Rui; Chen, Charles; Noli, Chiara

    2017-02-01

    Feline sporotrichosis is common in Malaysia. Thermosensitivity and effects of azole treatment on fungal susceptibility are unknown. To evaluate thermotolerance and antifungal susceptibility of feline Malaysian Sporothrix isolates, compare microdilution (MD) and E-test results, and investigate changes in susceptibility during azole therapy. Sporothrix schenckii sensu stricto was isolated from 44 cats. Thermotolerance was determined via culture at 37°C for 7 days. Susceptibility to itraconazole (ITZ), ketoconazole (KTZ) and terbinafine (TRB) was assessed in 40 isolates by MD; to amphotericin B (AMB), KTZ, ITZ, fluconazole (FLC) and posaconazole (POS) by E-test. Results were statistically compared by Pearson's Product Moment. In eight ketoconazole treated cats, susceptibility testing to itraconazole and ketoconazole was repeated every two months for six months. Thermotolerance was observed in 36 of 44 (82%) isolates. Assuming that isolates growing at antifungal concentrations ≥4 mg/mL were resistant, all were resistant on E-test to FLC and AMB, 11 (28%) to POS, 6 (15%) to ITZ and 1 (3%) to KTZ. On MD, 27 of 40 (68%) were resistant to TRB, 2 (5%) to ITZ and 3 (8%) to KTZ. There was no correlation between E-test and MD results (KTZ r = 0.10, P = 0.54, and ITZ r = 0.11, P = 0.48). MD values for ITZ and KTZ did not exceed 4 mg/L during KTZ therapy. The majority of feline isolates in Malaysia are thermosensitive. Lack of correlation between E-test and MD suggests that the E-test is unreliable to test antifungal susceptibility for Sporothrix spp. compared to MD. KTZ was the antifungal drug with the lowest MIC. Prolonged KTZ administration may not induce changes in antifungal susceptibility. © 2017 ESVD and ACVD.

  1. In vitro metabolism of testosterone in the horse liver and involvement of equine CYPs 3A89, 3A94 and 3A95.

    PubMed

    Schmitz, A; Zielinski, J; Dick, B; Mevissen, M

    2014-08-01

    Testosterone (TES) 6-β-hydroxylation is a significant metabolic step in the biotransformation of TES in human liver microsomes and reflects cytochrome P450 (CYP) 3A4/5 specific metabolic activity. Several CYP3A enzymes have been annotated in the horse genome, but functional characterization is missing. This descriptive study investigates TES metabolism in the horse liver in vitro and the qualitative contribution of three CYP3A isoforms of the horse. Metabolism of TES was investigated by using equine hepatocyte primary cultures and liver microsomes. Chemical inhibitors were used to determine the CYPs involved in TES biotransformation in equine microsomes. Single CYPs 3A89, 3A94, and 3A95, recombinantly expressed in V79 hamster lung fibroblasts, were incubated with TES and the fluorescent metabolite 7-benzyloxy-4-trifluoromethylcoumarin (BFC). The effect of ketoconazole and troleandomycin was evaluated on single CYPs. Testosterone metabolites were analyzed by HPLC and confirmed by GC/MS. In hepatocyte primary cultures, the most abundant metabolite was androstenedione (AS), whereas in liver microsomes, 6-β-hydroxytestosterone showed the largest peak. Formation of 6-β-hydroxytestosterone and 11-β-hydroxytestosterone in liver microsomes was inhibited by ketoconazole, troleandomycin, and quercetin. Equine recombinant CYP3A95 catalyzed 11-β-hydroxylation of testosterone (TES). Metabolism of BFC was significantly inhibited by ketoconazole in CYP3A95, whereas troleandomycin affected the activities of CYP3A94 and CYP3A95. Both inhibitors had no significant effect on CYP3A89. Metabolic reactions and effects of inhibitors differed between the equine CYP3A isoforms investigated. This has to be considered in future in vitro studies. © 2014 John Wiley & Sons Ltd.

  2. Treatment of pityriasis versicolor with topical application of essential oil of Cymbopogon citratus (DC) Stapf - therapeutic pilot study*

    PubMed Central

    Carmo, Egberto Santos; Pereira, Fillipe de Oliveira; Cavalcante, Neuza Maria; Gayoso, Carla Wanderley; Lima, Edeltrudes de Oliveira

    2013-01-01

    BACKGROUND Pityriasis versicolor is a fungal infection caused by Malassezia spp. that has frequent relapses. OBJECTIVES The main objective of this research was to perform phase I and II clinical studies, using formulations containing essential oil of Cymbopogon citratus in patients with pityriasis versicolor. METHODS Phase I study included twenty volunteers to ascertain the safety of the formulations. In phase II, 47 volunteers randomly received essential oil formulations at 1.25 μL/mL concentration, for forty days. The shampoo should be applied three times a week and the cream twice a day. A control group in phase II, consisting of 29 volunteers, received the same formulations but with 2% ketoconazole as the active ingredient. RESULTS No significant adverse events were observed in volunteers during Phase I. In Phase II, 30 (63.83%) volunteers using essential oil and 18 (62.07%) using ketoconazole remained until the end of the study. We observed a predominance of lesions in disseminated form, with M. sympodialis detected as the predominant agent identified in cultures. After 40 days of treatment, the rate of mycological cure was 60% (p <0.05) for the group treated with essential oil of C. citratus and over 80% (p <0.05) for the group treated with ketoconazole formulations. CONCLUSIONS Notwithstanding the safety and antifungal effects observed in this study after application of formulations containing the essential oil of C. citratus, further studies with larger populations should be performed to confirm the actual potential of these formulations in the treatment of patients with Pityriasis versicolor. PMID:23793205

  3. Phase 1 Studies of Sirolimus Alone or in Combination with Pharmacokinetic Modulators in Advanced Cancer Patients

    PubMed Central

    Cohen, Ezra EW; Wu, Kehua; Hartford, Christine; Kocherginsky, Masha; Eaton, Kimberly Napoli; Zha, Yuanyuan; Nallari, Anitha; Maitland, Michael L; Fox-Kay, Kammi; Moshier, Kristin; House, Larry; Ramirez, Jacqueline; Undevia, Samir D; Fleming, Gini F; Gajewski, Thomas F; Ratain, Mark J

    2014-01-01

    Purpose Sirolimus is the eponymous inhibitor of the mammalian target of rapamycin (mTOR); however, only its analogues have been approved as cancer therapies. Nevertheless, sirolimus is readily available, has been well-studied in organ transplant patients, and demonstrates efficacy in several preclinical cancer models. Experimental Design Three simultaneously conducted phase I studies in advanced cancer patients utilized an adaptive escalation design to find the dose of oral, weekly sirolimus alone or in combination with either ketoconazole or grapefruit juice that achieves similar blood concentrations as its intravenously administered and approved prodrug, temsirolimus. Additionally, the effect of sirolimus on inhibition of p70S6 kinase phosphorylation in peripheral T cells was determined. Results Collectively, the three studies enrolled 138 subjects. The most commonly observed toxicities were hyperglycemia, hyperlipidemia, and lymphopenia in 52%, 43%, and 41% of subjects, respectively. The target sirolimus area under the concentration curve (AUC) of 3810 ng-hr/ml was achieved at sirolimus doses of 90 mg, 16 mg, and 25 mg in the sirolimus alone, sirolimus plus ketoconazole, and sirolimus plus grapefruit juice studies, respectively. Ketoconazole and grapefruit juice increased sirolimus AUC approximately 500% and 350%, respectively. Inhibition of p70 S6 kinase phosphorylation was observed at all doses of sirolimus and correlated with blood concentrations. One partial response was observed in a patient with epithelioid hemangioendothelioma. Conclusion Sirolimus can be feasibly administered orally, once weekly with a similar toxicity and pharmacokinetic profile compared to other mTOR inhibitors and warrants further evaluation in studies of its comparative effectiveness relative to recently approved sirolimus analogues. PMID:22872575

  4. Embryotoxic and pharmacologic potency ranking of six azoles in the rat whole embryo culture by morphological and transcriptomic analysis

    SciT

    Dimopoulou, Myrto, E-mail: myrto.dimopoulou@wur.nl

    Differential gene expression analysis in the rat whole embryo culture (WEC) assay provides mechanistic insight into the embryotoxicity of test compounds. In our study, we hypothesized that comparative analysis of the transcriptomes of rat embryos exposed to six azoles (flusilazole, triadimefon, ketoconazole, miconazole, difenoconazole and prothioconazole) could lead to a better mechanism-based understanding of their embryotoxicity and pharmacological action. For evaluating embryotoxicity, we applied the total morphological scoring system (TMS) in embryos exposed for 48 h. The compounds tested showed embryotoxicity in a dose-response fashion. Functional analysis of differential gene expression after 4 h exposure at the ID{sub 10} (effectivemore » dose for 10% decreased TMS), revealed the sterol biosynthesis pathway and embryonic development genes, dominated by genes in the retinoic acid (RA) pathway, albeit in a differential way. Flusilazole, ketoconazole and triadimefon were the most potent compounds affecting the RA pathway, while in terms of regulation of sterol function, difenoconazole and ketoconazole showed the most pronounced effects. Dose-dependent analysis of the effects of flusilazole revealed that the RA pathway related genes were already differentially expressed at low dose levels while the sterol pathway showed strong regulation at higher embryotoxic doses, suggesting that this pathway is less predictive for the observed embryotoxicity. A similar analysis at the 24-hour time point indicated an additional time-dependent difference in the aforementioned pathways regulated by flusilazole. In summary, the rat WEC assay in combination with transcriptomics could add a mechanistic insight into the embryotoxic potency ranking and pharmacological mode of action of the tested compounds. - Highlights: • Embryonic exposure to azoles revealed concentration-dependent malformations. • Transcriptomics could enhance the mechanistic knowledge of embryotoxicants.

  5. Two cases of scalp white piedra caused by Trichosporon ovoides.

    PubMed

    Tambe, Swagata A; Dhurat, S Rachita; Kumar, Chaya A; Thakare, Preeti; Lade, Nitin; Jerajani, Hemangi; Mathur, Meenakshi

    2009-01-01

    White piedra is a superficial fungal infection of the hair shaft, caused by Trichosporon beigelii . We report two cases of white piedra presenting as brown palpable nodules along the hair shaft with a fragility of scalp hairs. T. beigelii was demonstrated in hair culture of both the patients and T. ovoides as a species was confirmed on carbohydrate assimilation test. The first patient responded to oral itraconazole and topical ketoconazole, with a decrease in the palpability of nodules and fragility of scalp hairs at the end of two months.

  6. Aspergillus epidural abscess in a patient with obstructive airway disease.

    PubMed Central

    Chee, Y. C.; Poh, S. C.

    1983-01-01

    A 54-year-old Chinese man with episodic bronchial asthma since 25 years of age was treated for pulmonary tuberculosis in 1976 because of left upper lobe lesions on chest radiograph. In 1981 he presented with an extradural mass compressing the thoracic spinal cord, thought to be tuberculosis but which on biopsy was found to be aspergillosis. Sputum culture, type on skin-prick reactivity and serum precipitating antibodies were positive for Aspergillus. Amphotericin B intravenously, then ketoconazole orally did not substantially improve his clinical course. He died about four months post-laminectomy. PMID:6866873

  7. Possible drug-drug interaction in dogs and cats resulted from alteration in drug metabolism: A mini review.

    PubMed

    Sasaki, Kazuaki; Shimoda, Minoru

    2015-05-01

    Pharmacokinetic drug-drug interactions (in particular at metabolism) may result in fatal adverse effects in some cases. This basic information, therefore, is needed for drug therapy even in veterinary medicine, as multidrug therapy is not rare in canines and felines. The aim of this review was focused on possible drug-drug interactions in dogs and cats. The interaction includes enzyme induction by phenobarbital, enzyme inhibition by ketoconazole and fluoroquinolones, and down-regulation of enzymes by dexamethasone. A final conclusion based upon the available literatures and author's experience is given at the end of the review.

  8. Definition of the Cellular Mechanisms Which Distinguish Between Estrogen Receptor Agonists and Antagonists

    DTIC Science & Technology

    2002-07-01

    and T877A intermediary products in the biosynthesis of aldosterone (27). The mutant AR’ production of DOG is up-regulated in a number of disease states...therapy 0O- DOG and as an antiemetic in patients undergoing chemotherapy and/or0.05 ’ -6- Dex o 0.04 -X-OH-F radiation therapy. Our results show that Dex...nonandrogenic activa- therapy; (b) the use of high-dose ketoconazole as second-line hormo- tors of the AR/T877A mutant, an AR mutant frequently found to

  9. Possible drug–drug interaction in dogs and cats resulted from alteration in drug metabolism: A mini review

    PubMed Central

    Sasaki, Kazuaki; Shimoda, Minoru

    2015-01-01

    Pharmacokinetic drug–drug interactions (in particular at metabolism) may result in fatal adverse effects in some cases. This basic information, therefore, is needed for drug therapy even in veterinary medicine, as multidrug therapy is not rare in canines and felines. The aim of this review was focused on possible drug–drug interactions in dogs and cats. The interaction includes enzyme induction by phenobarbital, enzyme inhibition by ketoconazole and fluoroquinolones, and down-regulation of enzymes by dexamethasone. A final conclusion based upon the available literatures and author’s experience is given at the end of the review. PMID:26257936

  10. Thromboxane A2 moderates permeability after limb ischemia.

    PubMed Central

    Lelcuk, S; Alexander, F; Valeri, C R; Shepro, D; Hechtman, H B

    1985-01-01

    Reperfusion after limb ischemia results in muscle edema as well as excess secretion of thromboxane A2 (TxA2), an agent associated with permeability increase in other settings. This study tests whether TxA2 moderates the permeability following limb ischemia. A tourniquet inflated to 300 mmHg was applied for 2 hours around the hind limb of four groups of dogs. In untreated animals (N = 25), 2 hours following tourniquet release, plasma TxB2 values rose from 320 pg/ml to 2416 pg/ml (p less than 0.001), and popliteal lymph values rose from 378 pg/ml to 1046 pg/ml (p less than 0.001). Platelet TxB2 was unaltered and plasma 6-keto-PGF1 alpha levels did not vary. Following ischemia, lymph flow (QL) increased from 0.07 to 0.37 ml/h (p less than 0.05), while the lymph/plasma (L/P) protein ratio was unchanged at 0.41. These measurements indicate increased permeability since increase in hydrostatic pressure in a second group by tourniquet inflation to 50 mmHg (N = 7) led to a rise in QL from 0.07 to 0.22 ml/h, but a fall in the L/P ratio to 0.32, a value lower than the ischemic group (p less than 0.05). Pretreatment with the imidazole derivative ketoconazole (N = 11) reduced platelet Tx synthesis from 42 ng to 2 ng/10(9) platelets, but lymph TxB2 levels rose to 1703 pg/ml after ischemia, indicating an extravascular or vessel wall site of synthesis not inhibited by ketoconazole. Pretreatment with a lower molecular weight imidazole derivative OKY 046 (N = 9) inhibited all Tx synthesis after ischemia. Prior to tourniquet inflation, both OKY 046 and ketoconazole lowered plasma TxB2 levels as well as the L/P ratio (p less than 0.05). After ischemia, OKY 046, but not ketoconazole, maintained the L/P ratio at 0.33, a value below that of untreated animals (p less than 0.05). These results indicate that nonplatelet-derived TxA2 modulates both baseline and ischemia-induced increases in microvascular permeability in the dog hind limb. PMID:3840349

  11. Paracoccidioidomycosis: report of 2 cases mimicking squamous cell carcinoma.

    PubMed

    Meneses-García, Abelardo; Mosqueda-Taylor, Adalberto; Morales-de la Luz, Rosario; Rivera, Luz María Ruíz-Godoy

    2002-11-01

    Paracoccidioidomycosis is an endemic fungal infection in Latin America. This mucocutaneous disease often involves the oral mucosa and may clinically resemble other infectious and neoplastic processes. Paracoccidioidomycosis that clinically suggested squamous cell carcinoma was diagnosed in 2 patients with a history of heavy alcohol and tobacco use. Antifungal therapy with ketoconazole and itraconazole resulted in resolution of the oral lesions. Interestingly, 1 patient had a pulmonary lesion that persisted after antifungal therapy, and biopsy proved this to be a squamous cell carcinoma of the lung.

  12. New options for the medical treatment of Cushing's syndrome

    PubMed Central

    Trainer, Peter J.

    2013-01-01

    A number of drugs have been advocated for the medical management of Cushing's syndrome but few have gained widespread acceptance. The most reliably effective agents are metyrapone and ketoconazole as monotherapy, or in combination. Cabergoline may be of value in a minority of patients but pasireotide is a more reliable and effective agent that lowers cortisol secretion in the great majority of patients, although only normalises UFC in a minority. The potential for combination of an agent that blocks adrenal steroidogenesis with inhibition of ACTH secretion by pasireotide needs to be explored. PMID:23776896

  13. In vitro susceptibility of Candida albicans clinical isolates to eight antifungal agents in Ouagadougou (Burkina Faso).

    PubMed

    Zida, A; Yacouba, A; Bamba, S; Sangare, I; Sawadogo, M; Guiguemde, T; Kone, S; Traore, L K; Ouedraogo-Traore, R; Guiguemde, R T

    2017-12-01

    In recent years, the infection Candida albicans infection worldwide has risen, and the incidence of resistance to traditional antifungal therapies is also increasing. The aim of this study was to evaluate in vitro susceptibility of C. albicans clinical isolates to eight antifungal agents in Ouagadougou. A cross-sectional study was conducted from January 2013 to December 2015 at Yalgado Ouédraogo University Teaching Hospital. Two hundred seven strains have been isolated from 347 symptomatic patients received in different clinical services. Samples were cultured on Sabouraud Dextrose Agar supplemented with Cloramphenicol. Isolates were diagnosed as C. albicans using germ tube test, chlamydospore formation on Corn Meal Agar, and Api-Candida test (Biomérieux). Antifungal susceptibility testing was performed by disk diffusion method and isolates classified as susceptible, susceptible dose-dependent and resistant. Three hundred forty-seven (347) patients are included in this study. Two hundred and six (206) out of 347 collected samples (59.36%) were found positive for C. albicans. The strains were mostly isolated from vulvovaginal (49%) and oral infections (40.3%). The highest resistance rates of azoles were obtained with fluconazole (66.5%), itraconazole (52.3%) and ketoconazole (22.9%) when all clinical isolates were included. The resistance rates of fluconazole, itraconazole and ketoconazole remain highest for vulvovaginal and oral isolates. The rate of resistance to the polyene amphotericin B was 32.0% for all clinical isolates and was 56.4% for vulvovaginal strains. Resistance rate to nystatin was 6.3% for all clinical isolates. Cross-resistance analysis with data of all clinical strains revealed that the incidence of resistance to ketoconazole and itraconazole in fluconazole-resistant isolates was significantly higher than recorded for fluconazole-susceptible isolates. In vitro C. albicans antifungal susceptibility test in this study showed relatively high

  14. Weakness and pain in arms and legs · dark urine · history of vertebral osteomyelitis · Dx?

    PubMed

    Charokopos, Antonios; Muhammad, Tariq; Surbhi, Sidana; Brateanu, Andrei

    2017-03-01

    Rhabdomyolysis is a serious complication of statin treatment. Both higher statin doses and pharmacokinetic factors can raise statin levels, leading to this serious usclerelated syndrome. Co-administration of statins with drugs that are strong inhibitors of cytochrome P450 (CYP) 3A4 (the main cytochrome P450 isoform that metabolizes most statins) can increase statin levels several fold. The trigger for our patient's statin-induced rhabdomyolysis was fluconazole, a known moderate inhibitor of CYP3A4, which is comparatively weaker than certain potent azoles like itraconazole or ketoconazole.

  15. In Vitro Antifungal Susceptibility Profiles of 12 Antifungal Drugs against 55 Trichophyton schoenleinii Isolates from Tinea Capitis Favosa Patients in Iran, Turkey, and China.

    PubMed

    Deng, Shuwen; Ansari, Saham; Ilkit, Macit; Rafati, Haleh; Hedayati, Mohammad T; Taghizadeh-Armaki, Mojtaba; Nasrollahi-Omran, Ayatollah; Tolooe, Ali; Zhan, Ping; Liao, Wanqing; van der Lee, Henrich A; Verweij, Paul E; Seyedmousavi, Seyedmojtaba

    2017-02-01

    Trichophyton schoenleinii is an anthropophilic dermatophyte mainly causing tinea favosa of the scalp in certain regions of the world, especially Africa and Asia. We investigated the in vitro susceptibilities of 55 T. schoenleinii isolates collected over the last 30 years from Iran, Turkey, and China to 12 antifungals using the CLSI broth microdilution method. Our results revealed that terbinafine and ketoconazole were the most potent antifungal agents among those tested, independently of the geographic regions where strains were isolated. Copyright © 2017 American Society for Microbiology.

  16. Rapid susceptibility testing of fungi by flow cytometry using vital staining.

    PubMed Central

    Wenisch, C; Linnau, K F; Parschalk, B; Zedtwitz-Liebenstein, K; Georgopoulos, A

    1997-01-01

    A 1-h assay for antifungal susceptibility testing measuring the impairment of fungal metabolic activity was developed. Yeast viability was analyzed by flow cytometry with a novel fluorescent probe, FUN-1, which emits a red fluorescence when the yeast is metabolically active. For nine Candida albicans strains tested, this method yielded results comparable to those obtained by the standard M27 procedure for amphotericin B, flucytosine, fluconazole, and ketoconazole. Whether the flow cytometry antifungal susceptibility test results correlate with the in vivo activities of the drugs remains to determined. PMID:8968873

  17. Anti-trypanosomal activity of pentacyclic triterpenes isolated from Austroplenckia populnea (Celastraceae).

    PubMed

    Duarte, Lucienir Pains; Vieira Filho, Sidney Augusto; Silva, Grácia Divina de Fátima; de Sousa, José Rego; Pinto, Artur da Silveira

    2002-01-01

    Four pentacyclic triterpenes isolated from Austroplenckia populnea and four compounds of known anti T. cruzi or anti-malarial activity were tested. Of those triterpenes tested 20alpha-hydroxy-tingenone showed high activity, epikatonic acid was less active, while populnilic and populninic acids were inactive against the trypanosome of the subgenus Schizotrypanum tested. Benzonidazole, nifurtimox, ketoconazole and primaquine presented a remarkable dose-dependent inhibitory effect reaching practically to a total growth inhibition of the parasite at the end of incubation time. The trypanosome tested appear to be a suitable model for preliminary screen for anti T. (S.) cruzi compounds.

  18. Fungicidal activity of tioconazole in relation to growth phase of Candida albicans and Candida parapsilosis.

    PubMed Central

    Beggs, W H

    1984-01-01

    It was shown that tioconazole possesses an important property not shared by ketoconazole and miconazole, its well-known relatives in the imidazole group of antifungal drugs. At a concentration of 3.8 X 10(-5) M, tioconazole, like miconazole, caused rapid 2- to 3-log reductions in CFU per milliliter when added to late-logarithmic-phase Candida albicans or Candida parapsilosis cells. Only tioconazole, however, exerted similar reductions when added to diluted stationary-phase cultures. This growth-phase-independent lethal action has important clinical implications and may explain the superior performance of tioconazole, which was observed in earlier comparative drug studies. PMID:6097174

  19. Candidaemia and antifungal susceptibility testing in a teaching hospital.

    PubMed

    Tzar, M N; Shamim, A S

    2009-03-01

    We reviewed cases of candidaemia at Universiti Kebangsaan Malaysia Medical Centre from 1st January 2005 to 30th June 2006. All blood cultures positive for Candida species or its teleomorphs within the study period were identified and antifungal susceptibility testing was performed. Out of 50 blood isolates, 20 (40%) were identified as Candida albicans, 16 (32%) C. tropicalis, five (10%) C. parapsilosis, three (6%) C. famata, two (4%) C. glabrata, two (4%) Pichia ohmeri, one (2%) C. krusei and one (2%) P. etchell/carsonii. Susceptibility to amphotericin B was 100%, fluconazole 90%, itraconazole 40%, ketoconazole 88%, 5-flucytosine 98% and voriconazole 98%.

  20. Androgen Metabolism in Progression to Androgen-Independent Prostate Cancer

    DTIC Science & Technology

    2009-06-01

    transcripts (TMPRSS2 exon 2-ERG exon 4) in 11 of 29 cases. Affymetrix oligonucleotide microarray data on these tumors versus a group of 27...medium were treated with DHT and immunoblotted. B, RT-PCR for ERG ( exon 9/10), TMPRSS2 ( exon 5/6), and PSA mRNA after DHT stimulation. C, cells in...therapeutic index CYP3A4 substrates were excluded. The treatment was ketoconazole 400 mg po TID, hydrocortisone (30 mg in AM and 10 mg in PM) and

  1. Chemical characterization of Lippia alba essential oil: an alternative to control green molds

    PubMed Central

    Glamočlija, Jasmina; Soković, Marina; Tešević, Vele; Linde, Giani Andrea; Colauto, Nelson Barros

    2011-01-01

    The essential oil of Lippia alba is reported as an antifungal against human pathogenic microorganisms but few articles report its use as an alternative to synthetic fungicides on green mould control. The objective of this study was to determine chemical characteristics of L. alba essential oil and its antifungal activity against green molds as an alternative to synthetic fungicides. Essential oil was extracted by Clevenger hydrodistillation, characterized by GC-MS analysis, and the structure of the main compounds confirmed by 1H and 13C-NMR spectroscopy. Microdilution assays evaluated the essential oil minimum inhibitory concentration (MIC) and minimum fungicidal concentration (MFC). Commercial fungicides Ketoconazole and Bifonazole were used as control. Essential oil yield is of 0.15% and the major components are neral (33.32%) and geranial (50.94%). The L. alba essential oil has MIC of 0.300–1.250 mg/mL and MFC of 0.600–1.250 mg/mL. Ketoconazole and Bifonazole show MIC ranging from 0.025–0.500 to 0.100–0.200 mg/mL, and MFC ranging from 0.250–0.100 to 0.200–0.250 mg/mL, respectively. L. alba essential oil is classified as citral type and the results indicate that it is a potential alternative to synthetic fungicides. PMID:24031788

  2. Structural interpretation in composite systems using powder X-ray diffraction: applications of error propagation to the pair distribution function.

    PubMed

    Moore, Michael D; Shi, Zhenqi; Wildfong, Peter L D

    2010-12-01

    To develop a method for drawing statistical inferences from differences between multiple experimental pair distribution function (PDF) transforms of powder X-ray diffraction (PXRD) data. The appropriate treatment of initial PXRD error estimates using traditional error propagation algorithms was tested using Monte Carlo simulations on amorphous ketoconazole. An amorphous felodipine:polyvinyl pyrrolidone:vinyl acetate (PVPva) physical mixture was prepared to define an error threshold. Co-solidified products of felodipine:PVPva and terfenadine:PVPva were prepared using a melt-quench method and subsequently analyzed using PXRD and PDF. Differential scanning calorimetry (DSC) was used as an additional characterization method. The appropriate manipulation of initial PXRD error estimates through the PDF transform were confirmed using the Monte Carlo simulations for amorphous ketoconazole. The felodipine:PVPva physical mixture PDF analysis determined ±3σ to be an appropriate error threshold. Using the PDF and error propagation principles, the felodipine:PVPva co-solidified product was determined to be completely miscible, and the terfenadine:PVPva co-solidified product, although having appearances of an amorphous molecular solid dispersion by DSC, was determined to be phase-separated. Statistically based inferences were successfully drawn from PDF transforms of PXRD patterns obtained from composite systems. The principles applied herein may be universally adapted to many different systems and provide a fundamentally sound basis for drawing structural conclusions from PDF studies.

  3. Assessing liver injury associated with antimycotics: Concise literature review and clues from data mining of the FAERS database

    PubMed Central

    Raschi, Emanuel; Poluzzi, Elisabetta; Koci, Ariola; Caraceni, Paolo; Ponti, Fabrizio De

    2014-01-01

    AIM: To inform clinicians on the level of hepatotoxic risk among antimycotics in the post-marketing setting, following the marketing suspension of oral ketoconazole for drug-induced liver injury (DILI). METHODS: The publicly available international FAERS database (2004-2011) was used to extract DILI cases (including acute liver failure events), where antimycotics with systemic use or potential systemic absorption were reported as suspect or interacting agents. The reporting pattern was analyzed by calculating the reporting odds ratio and corresponding 95%CI, a measure of disproportionality, with time-trend analysis where appropriate. RESULTS: From 1687284 reports submitted over the 8-year period, 68115 regarded liver injury. Of these, 2.9% are related to antimycotics (1964 cases, of which 112 of acute liver failure). Eleven systemic antimycotics (including ketoconazole and the newer triazole derivatives voriconazole and posaconazole) and terbinafine (used systemically to treat onychomicosis) generated a significant disproportionality, indicating a post-marketing signal of risk. CONCLUSION: Virtually all antimycotics with systemic action or absorption are commonly reported in clinically significant cases of DILI. Clinicians must be aware of this aspect and monitor patients in case switch is considered, especially in critical poly-treated patients under chronic treatment. PMID:25232453

  4. Effect of several compounds on biliary excretion of paclitaxel and its metabolites in guinea-pigs.

    PubMed

    Bun, Sok-Siya; Giacometti, Sarah; Fanciullino, Raphaëlle; Ciccolini, Joseph; Bun, Hot; Aubert, Claude

    2005-07-01

    The objective of this study was to evaluate the in vivo metabolic profile of paclitaxel and to examine the effect of potential co-administered drugs on the biliary secretion of paclitaxel and its metabolites in guinea-pigs. We first investigated in vitro paclitaxel metabolism using liver microsomes obtained from various species to identify the most suitable animal model with a similar metabolism to humans. Then, in vivo paclitaxel metabolism was investigated in male guinea-pigs. The levels of paclitaxel and its metabolites were measured by high-performance liquid chromatography in bile samples from guinea-pigs after paclitaxel i.v. injection (6 mg/kg). We further evaluated the effects of various drugs (quercetin, ketoconazole, dexamethasone, cotrimoxazole) on the biliary secretion of paclitaxel and its metabolites in guinea-pigs. This work demonstrated significant in vitro interspecies differences in paclitaxel metabolism. Our findings showed both in vitro and in vivo similarities between human and guinea-pig biotransformation of paclitaxel. 6alpha-Hydroxypaclitaxel, the main human metabolite of paclitaxel, was found in guinea-pig bile. After paclitaxel combination with ketoconazole or quercetin in guinea-pigs, the cumulative biliary excretion of paclitaxel and its metabolites up to 6 h was significantly decreased by 62 and 76%, respectively. The co-administration of cotrimoxazole or pretreatment with dexamethasone did not alter significantly cumulative biliary excretion. The guinea-pig is a suitable model to study metabolism and biliary excretion of paclitaxel, and to investigate in vivo drug interactions.

  5. Alopecia universalis in a dog with testicular neoplasia.

    PubMed

    Outerbridge, Catherine A; White, Stephen D; Affolter, Verena K

    2016-12-01

    To describe a case of testicular neoplasia and alopecia universalis in a dog, and successful treatment of the latter with ciclosporin. Twelve-year-old intact male wirehaired fox terrier. Castration, skin biopsy for histopathology, lymphocyte immunophenotyping and clonality analysis of the canine T-cell receptor gamma locus (TCRγ) rearrangement. The dog presented with symmetrical generalized alopecia. Testicular enlargement was noted which on castration was determined to be caused by bilateral interstitial cell tumours, Sertoli cell tumours and a unilateral seminoma. During the four months after castration the alopecia became more severe and widespread. Histopathology of the skin showed moderate, multifocal, mural folliculitis, peribulbar mucinosis and lymphocytic bulbitis, and targeting of anagen hair follicles. Immunophenotyping of the infiltrate showed a population of well-differentiated, small CD3-positive T lymphocytes, some expressing CD4 and others CD8. Molecular analysis revealed a polyclonal lymphocytic infiltrate, substantiating the diagnosis of alopecia areata rather than lymphoma. Treatment with ciclosporin (4.6 mg/kg) and ketoconazole (4.6 mg/kg) resulted in complete hair regrowth. Ciclosporin treatment, in combination with ketoconazole, can be effective for treatment of alopecia universalis in the dog. Alopecia universalis may present with clinically noninflammatory, symmetrical, generalized alopecia, mimicking an endocrine alopecia, and skin biopsies are needed to confirm the diagnosis. © 2016 ESVD and ACVD.

  6. Nasal Granuloma Caused by Scedosporium apiospermum in a Dog

    PubMed Central

    Cabañes, F. J.; Roura, X.; García, F.; Domingo, M.; Abarca, M. L.; Pastor, J.

    1998-01-01

    A 10-month-old male American Staffordshire terrier was presented to the Autonomous University of Barcelona Veterinary Teaching Hospital because of a 6-month history of a mucopurulent bilateral nasal discharge. The dog had not responded to antibiotics. A follow-up X ray revealed a mixed pattern of osteolysis and increased radiodensity confined to the nasal cavity. Histologic sections of the biopsy specimens revealed the presence of granules containing numerous septate hyphae that were hyaline to pale brown and smooth, one-celled, subspherical-to-elongate conidia that were hyaline to brownish green, and bacteria. Cultures yielded numerous colonies belonging to Scedosporium apiospermum. Susceptibility tests were performed on the isolated strain. The isolate was sensitive to ketoconazole, intermediate to clotrimazole, and resistant to amphotericin B, 5-fluorocytosine, fluconazole, and itraconazole. The dog was treated with oral ketoconazole. During the treatment a general improvement in the lesions was observed. To our knowledge, S. apiospermum has not been implicated previously as an etiologic agent of nasal disease in dogs. This report provides its first description as such. PMID:9705431

  7. Structural Basis of Human CYP51 Inhibition by Antifungal Azoles

    SciT

    Strushkevich, Natallia; Usanov, Sergey A.; Park, Hee-Won

    2010-09-22

    The obligatory step in sterol biosynthesis in eukaryotes is demethylation of sterol precursors at the C14-position, which is catalyzed by CYP51 (sterol 14-alpha demethylase) in three sequential reactions. In mammals, the final product of the pathway is cholesterol, while important intermediates, meiosis-activating sterols, are produced by CYP51. Three crystal structures of human CYP51, ligand-free and complexed with antifungal drugs ketoconazole and econazole, were determined, allowing analysis of the molecular basis for functional conservation within the CYP51 family. Azole binding occurs mostly through hydrophobic interactions with conservative residues of the active site. The substantial conformational changes in the B{prime} helix andmore » F-G loop regions are induced upon ligand binding, consistent with the membrane nature of the protein and its substrate. The access channel is typical for mammalian sterol-metabolizing P450 enzymes, but is different from that observed in Mycobacterium tuberculosis CYP51. Comparison of the azole-bound structures provides insight into the relative binding affinities of human and bacterial P450 enzymes to ketoconazole and fluconazole, which can be useful for the rational design of antifungal compounds and specific modulators of human CYP51.« less

  8. The anatomical distribution and antimicrobial susceptibility of yeast species isolated from healthy dogs.

    PubMed

    Brito, Erika H S; Fontenelle, Raquel O S; Brilhante, Raimunda S N; Cordeiro, Rossana A; Monteiro, André J; Sidrim, José J C; Rocha, Marcos F G

    2009-11-01

    The aim of this work was to identify the predominant yeast species present at different anatomical sites in healthy dogs and to determine their in vitro antimicrobial susceptibility using a broth microdilution assay. Samples were collected from the preputial, vaginal, oral and perianal mucosae and the isolates cultured were identified according to their morphological characteristics and biochemical profile. Malassezia pachydermatis was the most commonly isolated yeast, followed by Candida parapsilosis, Candida tropicalis, Candida albicans, Saccharomyces cerevisiae and Rhodotorula spp. Minimum inhibitory concentrations of the azole derivatives ketoconazole, itraconazole and fluconazole against Candida spp. were 0.03-16 microg/mL, 0.06 to >16 microg/mL and 0.5-64 microg/mL, respectively and Candida isolates were sensitive to caspofungin and amphotericin B. Although all isolates of M. pachydermatis were sensitive to itraconazole, fluconazole, ketoconazole and amphotericin B, they were found to be resistant to caspofungin. The study has highlighted that Candida spp., M. pachydermatis, S. cerevisiae and Rhodotorula spp. are part of the normal canine surface microbiota and some of these organisms exhibit in vitro resistance to commonly used antimicrobials.

  9. Primary culture system of adrenocortical cells from dogs to evaluate direct effects of chemicals on steroidogenesis.

    PubMed

    Morishita, K; Okumura, H; Ito, N; Takahashi, N

    2001-08-28

    The present study was conducted to confirm the usefulness of a primary culture system of adrenocortical cells from dogs for detecting the direct effects of the chemicals on adrenal cortex. Corticosteroid levels in the culture supernatant were measured using high-performance liquid chromatography (HPLC) following 24-h incubation with the chemicals. Ketoconazole, miconazole, metyrapone, aminoglutethimide, and 1-(o-chlorophenyl)-1-(p-chlorophenyl)-2,2-dichloroethane (o,p-DDD), which were known to inhibit cortisol production were evaluated in this system. Both viable cells and corticosteroid levels were decreased by o,p-DDD treatment. Other chemicals showed various inhibition patterns of corticosteroid levels as follows without affecting cell viability. Ketoconazole decreased total corticosteroids level by mainly due to the decreases in cortisol and 11-deoxycortisol levels. Miconazole decreased cortisol and 11-deoxycortisol levels, however, slightly increased corticosterone level. Metyrapone decreased cortisol and corticosterone levels as 11-deoxycortisol and 11-deoxycorticosterone levels were increased. Aminoglutethimide decreased total corticosteroids level by mainly decreasing cortisol, corticosterone and 11-deoxycortisol levels. These results suggested that determination of the pattern of corticosteroid levels by HPLC in this system well reflected the mode of their action on steroidogenesis. Thus, we conclude this simple system was useful to determine the direct effects of chemicals on steroidogenesis in the adrenal cortex.

  10. Blastomycosis in dogs: 115 cases (1980-1995).

    PubMed

    Arceneaux, K A; Taboada, J; Hosgood, G

    1998-09-01

    To characterize diagnostic results, treatment, and outcome of dogs with blastomycosis during a 15-year period in Louisiana. Retrospective case series. 115 dogs with blastomycosis. Medical records were reviewed for dogs with blastomycosis examined between 1980 and 1995. Additional data were collected from the state veterinary diagnostic laboratory, via telephone interviews of owners, and by use of a random survey of the hospital population. Blastomycosis was detected mainly in young, large-breed dogs. Proximity to a body of water was a significant risk factor for affected dogs. Most dogs were affected in January and August through October. Clinical signs and results of physical examination reflected the multisystemic nature of the disease. Commonly affected systems included the respiratory tract and lymphatic, ocular, and cutaneous systems. Nodular interstitial and interstitial patterns were common findings on thoracic radiographs. Cytologic examination was successful in identifying organisms in samples from vitreous, skin, and lymph nodes. Similar results were achieved for dogs treated with a combination of amphotericin B and ketoconazole, compared with dogs treated with itraconazole. Results of this study should assist veterinarians with the recognition and management of blastomycosis in dogs. Blastomycosis should be considered as a differential diagnosis for large-breed dogs that live close to a body of water in areas in which the disease is endemic or in dogs with a history of being transported to endemic areas that subsequently develop signs of pulmonary, ocular, lymphatic, or cutaneous disease. Treatment with itraconazole was as effective as treatment with a combination of amphotericin B and ketoconazole.

  11. The anti-candidal activity of Satureja khuzistanica ethanol extract against clinical isolates of C. albicans.

    PubMed

    Mahboubi, M; Kazempour, N

    2016-03-01

    Candida albicans is the common cause of some infectious diseases such as vaginal candidiasis or candidemia. Due to the emergence of drug resistant isolates of C. albicans, finding a new anti-Candida agent is a new strategy for current treatments. This study evaluated the anti-candidal activity of Satureja khuzistanica ethanol extract against clinical isolates of C. albicans. S. khuzistanica ethanol extract from aerial parts of plant at full flowering stage was evaluated against 30 clinical isolates and two ATCC reference strains of C. albicans by disc diffusion and micro-broth dilution assay. Also, in this study we evaluated the synergistic effects of amphotericin B, clotrimazole and ketoconazole with S. khuzistanica ethanol extract. The means of MIC and MFC of S. khuzistanica ethanol extract against clinical isolates were 299.4 and 722.6 (μg/mL), respectively. S. khuzistanica ethanol extract increased the anti-candidal effect of amphotericin B and ketoconazole, while it had no synergistic effect on clotrimazole against clinical isolates of C. albicans. Therefore, S. khuzistanica ethanol extract can be introduced as a new source of anti-candidal agent against clinical isolates of C. albicans. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

  12. [Cutaneous Malassezia infections and Malassezia associated dermatoses: An update].

    PubMed

    Nenoff, P; Krüger, C; Mayser, P

    2015-06-01

    The lipophilic yeast fungus Malassezia (M.) spp. is the only fungal genus or species which is part of the physiological human microbiome. Today, at least 14 different Malassezia species are known; most of them can only be identified using molecular biological techniques. As a facultative pathogenic microorganism, Malassezia represents the causative agent both of superficial cutaneous infections and of blood stream infections. Pityriasis versicolor is the probably most frequent infection caused by Malassezia. Less common, Malassezia folliculitis occurs. There is only an episodic report on Malassezia-induced onychomycosis. Seborrhoeic dermatitis represents a Malassezia-associated inflammatory dermatosis. In addition, Malassezia allergenes should be considered as the trigger of "Head-Neck"-type atopic dermatitis. Ketoconazole possesses the strongest in vitro activity against Malassezia, and represents the treatment of choice for topical therapy of pityriasis versicolor. Alternatives include other azole antifungals but also the allylamine terbinafine and the hydroxypyridone antifungal agent ciclopirox olamine. "Antiseborrhoeic" agents, e.g. zinc pyrithione, selenium disulfide, and salicylic acid, are also effective in pityriasis versicolor. The drug of choice for oral treatment of pityriasis versicolor is itraconazole; an effective alternative represents fluconazole. Seborrhoeic dermatitis is best treated with topical medication, including topical corticosteroids and antifungal agents like ketoconazole or sertaconazole. Calcineurin inhibitors, e.g. pimecrolimus and tacrolimus, are reliable in seborrhoeic dermatitis, however are used off-label.

  13. Seborrheic dermatitis flare in a Dutch male due to commensal Malassezia furfur overgrowth.

    PubMed

    Ran, Yuping; He, Xiaodan; Zhang, Hao; Dai, Yaling; Li, Lina; Bulmer, G S

    2008-09-01

    This is a case of seborrheic dermatitis (SD) barbae from which Malassezia furfur (M. furfur) was isolated. The patient was a 57-year-old Dutch male, who was hospitalized for fever and weakness of extremities. He presented with symmetrical erythema with an abundance of greasy chaffy scales on his beard area. No reasons were detected for his fever following a routine search. M. furfur was identified through mycological examination, including direct microscopic examination, culture, Tween test, esculine splitting test and DNA sequencing, of samples from the skin lesions. The patient was treated with oral itraconazole capsules (200 mg, b.i.d. for 8 days, then 200 mg o.d. for 13 days), washing his scalp and face with 2% ketoconazole shampoo (once a day) and topical application of a cream containing 1% naftifine hydrochloride and 0.25% ketoconazole (b.i.d.). After treatment the fever subsided and the SD lesion gradually healed. M. furfur was not isolated again from skin scrapings and 7 days later therapy was terminated and no recurrence was noted after one week follow-up since the cessation of treatment.

  14. [Malassezia species in patients with seborrheic dermatitis and atopic dermatitis].

    PubMed

    Tajima, Mami

    2005-01-01

    Malassezia species, organisms normally colonizing the skin surface, are thought to play a role as either the cause or an exacerbating factor in a number of skin conditions, including pityriasis versicolor, Malassezia folliculitis, seborrheic dermatitis (SD) and atopic dermatitis (AD). Using a non-cultural PCR method, we analyzed Malassezia spp. extracted from the skin surface of SD and AD patients. The species most commonly detected in both patient groups were M. globosa and M. restricta, and the number of Malassezia spp. In these patients was higher than in healthy subjects. After a topical application of 2% ketoconazole cream, changes in the population of Malassezia spp. in 20 intractable cases of AD were recorded. The addition of the 2% ketoconazole cream to the standard topical treatments was found to have reduced the Malassezia spp. population by 90%, and showed a clinical efficacy rate of 70%. Furthermore, a combination of azole agents and tacrolimus produced a synergistic anti-fungal effect against Malassezia spp. in vitro. A clinical trial using this drug combination conducted on the face and neck of patients with intractable AD showed a 66.6% efficacy rate in both the reduction of the flora and in clinical improvement. From these results it was evident that Malassezia is one of the factors exacerbating AD, and that removal of the organism results in an improvement in the clinical condition of the patient.

  15. A combination turbidity and supernatant microplate assay to rank-order the supersaturation limits of early drug candidates.

    PubMed

    Morrison, John S; Nophsker, Michelle J; Haskell, Roy J

    2014-10-01

    A unique opportunity exists at the drug discovery stage to overcome inherently poor solubility by selecting drug candidates with superior supersaturation propensity. Existing supersaturation assays compare either precipitation-resistant or precipitation-inhibiting excipients, or higher-energy polymorphic forms, but not multiple compounds or multiple concentrations. Furthermore, these assays lack sufficient throughput and compound conservation necessary for implementation in the discovery environment. A microplate-based combination turbidity and supernatant concentration assay was therefore developed to determine the extent to which different compounds remain in solution as a function of applied concentration in biorelevant media over a specific period of time. Dimethyl sulfoxide stock solutions at multiple concentrations of four poorly soluble, weak base compounds (Dipyridamole, Ketoconazole, Albendazole, and Cinnarizine) were diluted with pH 6.5 buffer as well as FaSSIF. All samples were monitored for precipitation by turbidity at 600 nm over 1 h and the final supernatant concentrations were measured. The maximum supersaturation ratio was calculated from the supersaturation limit and the equilibrium solubility in each media. Compounds were rank-ordered by supersaturation ratio: Ketoconazole > Dipyridamole > Cinnarizine ∼ Albendazole. These in vitro results correlated well with oral AUC ratios from published in vivo pH effect studies, thereby confirming the validity of this approach. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association.

  16. Ethnoveterinary study for antidermatophytic activity of Piper betle, Alpinia galanga and Allium ascalonicum extracts in vitro.

    PubMed

    Trakranrungsie, N; Chatchawanchonteera, A; Khunkitti, W

    2008-02-01

    Crude ethanolic extracts of Piper betle leaves (Piperaceae), Alpinia galanga rhizomes (Zingiberaceae) and Allium ascalonicum bulbs (Liliaceae) were tested against selected zoonotic dermatophytes (Microsporum canis, Microsporum gypseum and Trichophyton mentagrophyte) and the yeast-like Candida albicans. A broth dilution method was employed to determine the inhibitory effect of the extracts and compared to those of ketoconazole and griseofulvin. All extracts suppressed the growth of the fungi in a concentration-dependent manner. Among the extracts tested, P. betle exhibited more effective antifungal properties with average IC(50) values ranging from 110.44 to 119.00 microg/ml. Subsequently, 10% Piper betle (Pb) cream was formulated, subjected to physical and microbial limit test and evaluated for antifungal effect. The disc diffusion assay revealed comparable zones of inhibition between discs of Pb cream containing 80 microg P. betle extract and 80 microg ketoconazole against tested fungi at 96 h after incubation. Thereafter, the inhibitory effect of Pb cream markedly decreased and completely lost effectiveness by day 7. In summary, the results supported the traditional wisdom of herbal remedy use and suggested a potential value-addition to agricultural products. It was suggested that the Pb cream has potential therapeutic value for treatment of dermatophytosis. However, clinical testing as well as improving the Pb cream formulation with greater efficacy and duration of action would be of interest and awaits further investigation.

  17. [In vitro antifungal resistance in Candida albicans from HIV-infected patients with and without oral candidosis.].

    PubMed

    Ceballos Salobreña, A; Gaitán Cepeda, L A; Orihuela Cañada, F; Olea Barrionuevo, D; Ceballos García, L; Quindós, G

    1999-12-01

    The main purpose of this study has been to determine the in vitro antifungal susceptibility of clinical isolates from HIV-infected or AIDS patients, depending on the presence of oral candidosis. The oral cavity of 307 HIV-infected or AIDS patients was examined and an oral swab was cultured on Sabouraud glucose agar and studied by conventional mycological methods. In vitro antifungal susceptibility to amphotericin B, nystatin, fluconazole, itraconazole and ketoconazole was tested by disk diffusion with Neo-Sensitabs tablets (Rosco Diagnostica, Dinamarca). One hundred and thirty five Candida albicans isolates (91 serotype A, 38 serotype B, three C. albicans variety stellatoidea and three untyped isolates), three Candida krusei and two Candida glabrata were obtained. All the isolates were susceptible to nystatin and amphotericin B. However, 7.9% isolates were resistant to fluconazole and 2.9% isolates were resistant to ketoconazole or itraconazole. Nearly all C. krusei and C. glabrata isolates, 31% patients with candidosis and 20% Candida-colonized patients showed decreased susceptibility to azoles. This study shows that polyenes had a great in vitro efficacy against clinical isolates from HIV-infected patients and that in vitro resistance to azoles is not as high as observed in other countries.

  18. Evaluation of Organogel Nanoparticles as Drug Delivery System for Lipophilic Compounds.

    PubMed

    Martin, Baptiste; Brouillet, Fabien; Franceschi, Sophie; Perez, Emile

    2017-05-01

    The purpose of the study was to evaluate organogel nanoparticles as a drug delivery system by investigating their stability, according to the formulation strategy, and their release profile. The gelled nanoparticles were prepared by hot emulsification (above the gelation temperature) of an organogel in water, and cooling at room temperature. In the first step, we used DLS and DSC to select the most suitable formulations by optimizing the proportion of ingredients (HSA, PVA, castor oil) to obtain particles of the smallest size and greatest stability. Then, two lipophilic drug models, indomethacin and ketoconazole were entrapped in the nanoparticles made of castor oil gelled by 12-hydroxystearic acid. Thermal studies (DSC) confirmed that there was no significant alteration of gelling due to the entrapped drugs, even at 3% w/w. Very stable dispersions were obtained (>3 months), with gelled oil nanoparticles presenting a mean diameter between 250 and 300 nm. High encapsulation efficiency (>98%) was measured for indomethacin and ketoconazole. The release profile determined by in vitro dialysis showed an immediate release of the drug from the organogel nanoparticles, due to rapid diffusion. The study demonstrates the interest of these gelled oil nanoparticles for the encapsulation and the delivery of lipophilic active compounds.

  19. Seventeen years of subcutaneous infection by Aspergillus flavus; eumycetoma confirmed by immunohistochemistry.

    PubMed

    Ahmed, Sarah A; Abbas, Manal A; Jouvion, Gregory; Al-Hatmi, Abdullah M S; de Hoog, G Sybren; Kolecka, Anna; Mahgoub, El Sheikh

    2015-12-01

    Chronic subcutaneous infections caused by Aspergillus species are considered to be extremely rare. Because these fungi are among the most common laboratory contaminants, their role as eumycetoma causative agents is difficult to ascertain. Here, we report the first case of A. flavus eumycetoma confirmed by isolation, molecular identification and immunohistochemical analysis. Patient was a 55-year-old male from Sudan suffering from eumycetoma on his left foot for a period of 17 years. He developed swelling, sinuses and white grain discharge was observed. He has been operated nine times and was treated with several regimens of ketoconazole and itraconazole without improvement. Initial diagnosis based on histology and radiology was Scedosporium eumycetoma. However, examination of the biopsy revealed A. flavus, which was identified by molecular analysis and MALDI-TOF MS. Immunohistochemistry using antibody directed against Aspergillus species was positive. Because of the earlier treatment failures with ketoconazole and itraconazole, therapy with voriconazole was initiated. However, in vitro susceptibility testing yielded a lower Minimum Inhibitory Concentration (MIC) value for itraconazole (0.25 μg ml(-1) ) than for voriconazole (1 μg ml(-1) ). Based on the presented results, A. flavus can be considered as one of the agents of white-grain eumycetoma. © 2015 Blackwell Verlag GmbH.

  20. Evaluation of 1,3-benzoxathiol-2-one Derivatives as Potential Antifungal Agents.

    PubMed

    Terra, Luciana; de L Chazin, Eliza; de S Sanches, Paola; Saito, Max; de Souza, Marcus V N; Gomes, Claudia R B; Wardell, James L; Wardell, Solange M S V; Sathler, Plinio C; Silva, Gabriela C C; Lione, Viviane O; Kalil, Marcos; Joffily, Ana; Castro, Helena C; Vasconcelos, Thatyana R A

    2018-01-01

    Over the last few years, fungal infections have emerged as a worrisome global public health problem. Candidiasis is a disease caused by Candida species and has been a problem worldwide mainly for immunosuppressed patients. Lately, the resistant strains and side effects have been reported as important issues for treating Candidiasis, which have to be solved by identifying new drugs. The goal of this work was to synthesize a series of 1,3-benzoxathiol-2-one derivatives, XYbenzo[ d][1,3]oxathiol-2-ones, and evaluate their antifungal activity against five Candida species. In vitro antifungal screening test and minimum inhibitory concentration determination were performed according to CLSI protocols using ketoconazole as the reference drug. The cytotoxicity of the most active compounds was evaluated by hemolysis and MTT (Vero cells) assays. Compounds 2 (XY = 6-hydroxy-5-nitro, MIC = 4-32 µg/mL) and 7 (XY = 6-acetoxy-5-nitro, MIC =16-64 µg/mL) showed good results when compared with current antifungals in CLSI values (MIC = 0.04-250 µg/mL). These compounds exhibited a safer cytotoxicity as well as a lower hemolytic profile than ketoconazole. Overall, the in vitro results pointed to the potential of compounds 2 and 7 as new antifungal prototypes to be further explored. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  1. Dermatophytosis of children in Kuwait: a prospective survey.

    PubMed

    al-Fouzan, A S; Nanda, A; Kubec, K

    1993-11-01

    Tinea capitis in children is widely reported, whereas there have been only isolated reports on involvement of sites other than the scalp. The purpose of this study was to examine the epidemiological features and treatment responses of dermatophytosis of children in Kuwait. Epidemiological features and the treatment responses of 202 consecutive children with dermatophytosis were studied. The 202 children constituted 44% of the total dermatophytic infections seen during a period of 1 year. Tinea capitis was the most commonly encountered infection (78%), followed by tinea corporis, tinea faciei, tinea cruris and manus, respectively. Microsporum canis was the most prevalent species (96%) in this region. A history of pets at home could be elicited in 52% of the cases. A familial occurrence of similar infections was seen in 56% of the patients. In patients with tinea capitis, addition of topical clotrimazole or ketoconazole to oral griseofulvin produced better therapeutic results compared to griseofulvin alone or in combination with selenium sulfide shampoo. Tinea capitis is the most common dermatophytic infection in children. Thirty percent of the children may have dermatophytosis at sites other than the scalp. A combination of topical clotrimazole or ketoconazole with oral griseofulvin is superior to griseofulvin alone or in combination with selenium sulfide shampoo in the treatment of tinea capitis.

  2. [In vitro susceptibility of isolates of Paracoccidioides spp complex to systemic antifungals using the microdilution method].

    PubMed

    Cermehol, Julman R; Alvarado, Primavera; Mendoza, Mireya; Herndndez, Isabel; Cuestal, De

    2015-09-01

    Broth microdilution, the reference method recommended by the Clinical Laboratory Standards Institute (CLSI), is not available for use with dimorphic fungi, such as those of the Paracoccidioides genus. In this work, in vitro susceptibility of the Paracoccidioides complex (n=19) to systemic antifungals: amphotericin B, 5-flucytosine, ketoconazole, itraconazole, fluconazole, voriconazole and caspofungin, was evaluated using the microdilution method (Document M27-A3, M27-S3), with some modifications such as: culture time in Sabouraud dextrose agar (7-10 days), RPMI 1640 medium supplemented with 2% glucose and the incubation time (7, 8 and 18 days). The sensitivity in vitro was variable; the majority of Paracoccidioides isolates was susceptible to ketoconazol (73.7%), followed by voriconazole (68.4%), itraconazole (63.1%), amphotericin B (52.6%), fluconazole (47.4%), 5-flucytosine (42.1%) and caspofungin (5%). The overall resistance was mainly to caspofungin (94.7%), followed by 5-flucytosine (52.6%) and amphotericin B (47.4%). Fifty-three percent of the isolates were susceptible-dose dependent to fluconazole followed by itraconazole (15.7%) and 5-fluorocytosine (5.3%). Amphotericin B, itraconazole and voriconazole were the most potent antifungal drugs against Paracoccidioides spp (CMI: 0.03-1 microg/mL). Based on these results, we tentatively propose a microdilution assay protocol for susceptibility testing of Paracoccidioides spp to antifungal drugs. This method may be clinically useful to predict resistance, even though further studies are needed.

  3. Prediction of Drug-Target Interactions and Drug Repositioning via Network-Based Inference

    PubMed Central

    Jiang, Jing; Lu, Weiqiang; Li, Weihua; Liu, Guixia; Zhou, Weixing; Huang, Jin; Tang, Yun

    2012-01-01

    Drug-target interaction (DTI) is the basis of drug discovery and design. It is time consuming and costly to determine DTI experimentally. Hence, it is necessary to develop computational methods for the prediction of potential DTI. Based on complex network theory, three supervised inference methods were developed here to predict DTI and used for drug repositioning, namely drug-based similarity inference (DBSI), target-based similarity inference (TBSI) and network-based inference (NBI). Among them, NBI performed best on four benchmark data sets. Then a drug-target network was created with NBI based on 12,483 FDA-approved and experimental drug-target binary links, and some new DTIs were further predicted. In vitro assays confirmed that five old drugs, namely montelukast, diclofenac, simvastatin, ketoconazole, and itraconazole, showed polypharmacological features on estrogen receptors or dipeptidyl peptidase-IV with half maximal inhibitory or effective concentration ranged from 0.2 to 10 µM. Moreover, simvastatin and ketoconazole showed potent antiproliferative activities on human MDA-MB-231 breast cancer cell line in MTT assays. The results indicated that these methods could be powerful tools in prediction of DTIs and drug repositioning. PMID:22589709

  4. Physiologically-Based Pharmacokinetic Modeling of Macitentan: Prediction of Drug-Drug Interactions.

    PubMed

    de Kanter, Ruben; Sidharta, Patricia N; Delahaye, Stéphane; Gnerre, Carmela; Segrestaa, Jerome; Buchmann, Stephan; Kohl, Christopher; Treiber, Alexander

    2016-03-01

    Macitentan is a novel dual endothelin receptor antagonist for the treatment of pulmonary arterial hypertension (PAH). It is metabolized by cytochrome P450 (CYP) enzymes, mainly CYP3A4, to its active metabolite ACT-132577. A physiological-based pharmacokinetic (PBPK) model was developed by combining observations from clinical studies and physicochemical parameters as well as absorption, distribution, metabolism and excretion parameters determined in vitro. The model predicted the observed pharmacokinetics of macitentan and its active metabolite ACT-132577 after single and multiple dosing. It performed well in recovering the observed effect of the CYP3A4 inhibitors ketoconazole and cyclosporine, and the CYP3A4 inducer rifampicin, as well as in predicting interactions with S-warfarin and sildenafil. The model was robust enough to allow prospective predictions of macitentan-drug combinations not studied, including an alternative dosing regimen of ketoconazole and nine other CYP3A4-interacting drugs. Among these were the HIV drugs ritonavir and saquinavir, which were included because HIV infection is a known risk factor for the development of PAH. This example of the application of PBPK modeling to predict drug-drug interactions was used to support the labeling of macitentan (Opsumit).

  5. Comparison study of broth macrodilution and microdilution antifungal susceptibility tests for the filamentous fungi.

    PubMed

    Pujol, I; Guarro, J; Llop, C; Soler, L; Fernández-Ballart, J

    1996-09-01

    An evaluation of broth dilution antifungal susceptibility tests was performed by determining both the micro- and macrodilution MICs of amphotericin B, fluconazole, ketoconazole, 5-fluorocytosine, miconazole, and itraconazole against representative species of opportunistic hyphomycetes (Fusarium spp. and Cladosporium [Cladophialophora] spp.) and ascomycetes (Chaetomium spp.). A total of 78 strains were tested, the majority of them twice and some three times on different days. Both methods were performed according to the recommendations of the National Committee for Clinical Laboratory Standards (Document M27-P), with the exception of the temperature of incubation, which was 25 degrees C in our case. A spectrophotometric method for inoculum preparation, RPMI 1640 medium buffered with morpholinepropanesulfonic acid (pH 7.0), and an additive drug dilution procedure were used. The MICs obtained by the two methods were read after 48, 72, and 96 h of incubation for Fusarium spp. and after 72, 96, and 120 h for the remaining isolates. The kappa test was used to calculate the degree of agreement. Considering the three fungal groups together, a good agreement between the results of both tests was observed with almost all the drugs at the different incubation times. There were no cases of poor agreement. The highest level (kappa index = 1) was observed with ketoconazole at the second-day reading. These results support the further evaluation of the broth microdilution test as an alternative to the reference broth macrodilution susceptibility test.

  6. Comparison study of broth macrodilution and microdilution antifungal susceptibility tests for the filamentous fungi.

    PubMed Central

    Pujol, I; Guarro, J; Llop, C; Soler, L; Fernández-Ballart, J

    1996-01-01

    An evaluation of broth dilution antifungal susceptibility tests was performed by determining both the micro- and macrodilution MICs of amphotericin B, fluconazole, ketoconazole, 5-fluorocytosine, miconazole, and itraconazole against representative species of opportunistic hyphomycetes (Fusarium spp. and Cladosporium [Cladophialophora] spp.) and ascomycetes (Chaetomium spp.). A total of 78 strains were tested, the majority of them twice and some three times on different days. Both methods were performed according to the recommendations of the National Committee for Clinical Laboratory Standards (Document M27-P), with the exception of the temperature of incubation, which was 25 degrees C in our case. A spectrophotometric method for inoculum preparation, RPMI 1640 medium buffered with morpholinepropanesulfonic acid (pH 7.0), and an additive drug dilution procedure were used. The MICs obtained by the two methods were read after 48, 72, and 96 h of incubation for Fusarium spp. and after 72, 96, and 120 h for the remaining isolates. The kappa test was used to calculate the degree of agreement. Considering the three fungal groups together, a good agreement between the results of both tests was observed with almost all the drugs at the different incubation times. There were no cases of poor agreement. The highest level (kappa index = 1) was observed with ketoconazole at the second-day reading. These results support the further evaluation of the broth microdilution test as an alternative to the reference broth macrodilution susceptibility test. PMID:8878589

  7. Ibrutinib Dosing Strategies Based on Interaction Potential of CYP3A4 Perpetrators Using Physiologically Based Pharmacokinetic Modeling.

    PubMed

    de Zwart, L; Snoeys, J; De Jong, J; Sukbuntherng, J; Mannaert, E; Monshouwer, M

    2016-11-01

    Based on ibrutinib pharmacokinetics and potential sensitivity towards CYP3A4-mediated drug-drug interactions (DDIs), a physiologically based pharmacokinetic approach was developed to mechanistically describe DDI with various CYP3A4 perpetrators in healthy men under fasting conditions. These models were verified using clinical data for ketoconazole (strong CYP3A4 inhibitor) and used to prospectively predict and confirm the inducing effect of rifampin (strong CYP3A4 inducer); DDIs with mild (fluvoxamine, azithromycin) and moderate inhibitors (diltiazem, voriconazole, clarithromycin, itraconazole, erythromycin), and moderate (efavirenz) and strong CYP3A4 inducers (carbamazepine), were also predicted. Ketoconazole increased ibrutinib area under the curve (AUC) by 24-fold, while rifampin decreased ibrutinib AUC by 10-fold; coadministration of ibrutinib with strong inhibitors or inducers should be avoided. The ibrutinib dose should be reduced to 140 mg (quarter of maximal prescribed dose) when coadministered with moderate CYP3A4 inhibitors so that exposures remain within observed ranges at therapeutic doses. Thus, dose recommendations for CYP3A4 perpetrator use during ibrutinib treatment were developed and approved for labeling. © 2016 American Society for Clinical Pharmacology and Therapeutics.

  8. Effect of CYP3A perpetrators on ibrutinib exposure in healthy participants.

    PubMed

    de Jong, Jan; Skee, Donna; Murphy, Joe; Sukbuntherng, Juthamas; Hellemans, Peter; Smit, Johan; de Vries, Ronald; Jiao, Juhui James; Snoeys, Jan; Mannaert, Erik

    2015-08-01

    Ibrutinib (PCI-32765), a potent covalent inhibitor of Bruton's tyrosine kinase, has shown efficacy against a variety of B-cell malignancies. Given the prominent role of CYP3A in ibrutinib metabolism, effect of coadministration of CYP3A perpetrators with ibrutinib was evaluated in healthy adults. Ibrutinib (120 mg [Study 1, fasted], 560 mg [studies 2 (fasted), and 3 (nonfasted)]) was given alone and with ketoconazole [Study 1; 400 mg q.d.], rifampin [Study 2; 600 mg q.d.], and grapefruit juice [GFJ, Study 3]. Lower doses of ibrutinib were used together with CYP3A inhibitors [Study 1: 40 mg; Study 3: 140 mg], as safety precaution. Under fasted condition, ketoconazole increased ibrutinib dose-normalized (DN) exposure [DN-AUClast: 24-fold; DN-C max: 29-fold], rifampin decreased ibrutinib exposure [C max: 13-fold; AUClast: 10-fold]. Under nonfasted condition, GFJ caused a moderate increase [DN-C max: 3.5-fold; DN-AUC: 2.2-fold], most likely through inhibition of intestinal CYP3A. Half-life was not affected by CYP perpetrators indicating the interaction was mainly on first-pass extraction. All treatments were well-tolerated.

  9. Transport Inhibition of Digoxin Using Several Common P-gp Expressing Cell Lines Is Not Necessarily Reporting Only on Inhibitor Binding to P-gp

    PubMed Central

    Lumen, Annie Albin; Li, Libin; Li, Jiben; Ahmed, Zeba; Meng, Zhou; Owen, Albert; Ellens, Harma; Hidalgo, Ismael J.; Bentz, Joe

    2013-01-01

    We have reported that the P-gp substrate digoxin required basolateral and apical uptake transport in excess of that allowed by digoxin passive permeability (as measured in the presence of GF120918) to achieve the observed efflux kinetics across MDCK-MDR1-NKI (The Netherlands Cancer Institute) confluent cell monolayers. That is, GF120918 inhibitable uptake transport was kinetically required. Therefore, IC50 measurements using digoxin as a probe substrate in this cell line could be due to inhibition of P-gp, of digoxin uptake transport, or both. This kinetic analysis is now extended to include three additional cell lines: MDCK-MDR1-NIH (National Institute of Health), Caco-2 and CPT-B2 (Caco-2 cells with BCRP knockdown). These cells similarly exhibit GF120918 inhibitable uptake transport of digoxin. We demonstrate that inhibition of digoxin transport across these cell lines by GF120918, cyclosporine, ketoconazole and verapamil is greater than can be explained by inhibition of P-gp alone. We examined three hypotheses for this non-P-gp inhibition. The inhibitors can: (1) bind to a basolateral digoxin uptake transporter, thereby inhibiting digoxin's cellular uptake; (2) partition into the basolateral membrane and directly reduce membrane permeability; (3) aggregate with digoxin in the donor chamber, thereby reducing the free concentration of digoxin, with concomitant reduction in digoxin uptake. Data and simulations show that hypothesis 1 was found to be uniformly acceptable. Hypothesis 2 was found to be uniformly unlikely. Hypothesis 3 was unlikely for GF120918 and cyclosporine, but further studies are needed to completely adjudicate whether hetero-dimerization contributes to the non-P-gp inhibition for ketoconazole and verapamil. We also find that P-gp substrates with relatively low passive permeability such as digoxin, loperamide and vinblastine kinetically require basolateral uptake transport over that allowed by +GF120918 passive permeability, while highly permeable

  10. Investigating the binding interactions of the anti-Alzheimer's drug donepezil with CYP3A4 and P-glycoprotein.

    PubMed

    McEneny-King, Alanna; Edginton, Andrea N; Rao, Praveen P N

    2015-01-15

    The anti-Alzheimer's agent donepezil is known to bind to the hepatic enzyme CYP3A4, but its relationship with the efflux transporter P-glycoprotein (P-gp) is not as well elucidated. We conducted in vitro inhibition studies of donepezil using human recombinant CYP3A4 and P-gp. These studies show that donepezil is a weak inhibitor of CYP3A4 (IC50=54.68±1.00μM) whereas the reference agent ketoconazole exhibited potent inhibition (CYP3A4 IC50=0.20±0.01μM). P-gp inhibition studies indicate that donepezil exhibits better inhibition relative to CYP3A4 (P-gp EC50=34.85±4.63μM) although it was less potent compared to ketoconazole (P-gp EC50=9.74±1.23μM). At higher concentrations, donepezil exhibited significant inhibition of CYP3A4 (69%, 84% and 87% inhibition at 100, 250 and 500μM, respectively). This indicates its potential to cause drug-drug interactions with other CYP3A4 substrates upon co-administration; however, this scenario is unlikely in vivo due to the low therapeutic concentrations of donepezil. Similarly, donepezil co-administration with P-gp substrates or inhibitors is unlikely to result in beneficial or adverse drug interactions. The molecular docking studies show that the 5,6-dimethoxyindan-1-one moiety of donepezil was oriented closer to the heme center in CYP3A4 whereas in the P-gp binding site, the protonated benzylpiperidine pharmacophore of donepezil played a major role in its binding ability. Energy parameters indicate that donepezil complex with both CYP3A4 and P-gp was less stable (CDOCKER energies=-15.05 and -4.91kcal/mol, respectively) compared to the ketoconazole-CYP3A4 and P-gp complex (CDOCKER energies=-41.89 and -20.03kcal/mol, respectively). Copyright © 2014 Elsevier Ltd. All rights reserved.

  11. Transport inhibition of digoxin using several common P-gp expressing cell lines is not necessarily reporting only on inhibitor binding to P-gp.

    PubMed

    Lumen, Annie Albin; Li, Libin; Li, Jiben; Ahmed, Zeba; Meng, Zhou; Owen, Albert; Ellens, Harma; Hidalgo, Ismael J; Bentz, Joe

    2013-01-01

    We have reported that the P-gp substrate digoxin required basolateral and apical uptake transport in excess of that allowed by digoxin passive permeability (as measured in the presence of GF120918) to achieve the observed efflux kinetics across MDCK-MDR1-NKI (The Netherlands Cancer Institute) confluent cell monolayers. That is, GF120918 inhibitable uptake transport was kinetically required. Therefore, IC50 measurements using digoxin as a probe substrate in this cell line could be due to inhibition of P-gp, of digoxin uptake transport, or both. This kinetic analysis is now extended to include three additional cell lines: MDCK-MDR1-NIH (National Institute of Health), Caco-2 and CPT-B2 (Caco-2 cells with BCRP knockdown). These cells similarly exhibit GF120918 inhibitable uptake transport of digoxin. We demonstrate that inhibition of digoxin transport across these cell lines by GF120918, cyclosporine, ketoconazole and verapamil is greater than can be explained by inhibition of P-gp alone. We examined three hypotheses for this non-P-gp inhibition. The inhibitors can: (1) bind to a basolateral digoxin uptake transporter, thereby inhibiting digoxin's cellular uptake; (2) partition into the basolateral membrane and directly reduce membrane permeability; (3) aggregate with digoxin in the donor chamber, thereby reducing the free concentration of digoxin, with concomitant reduction in digoxin uptake. Data and simulations show that hypothesis 1 was found to be uniformly acceptable. Hypothesis 2 was found to be uniformly unlikely. Hypothesis 3 was unlikely for GF120918 and cyclosporine, but further studies are needed to completely adjudicate whether hetero-dimerization contributes to the non-P-gp inhibition for ketoconazole and verapamil. We also find that P-gp substrates with relatively low passive permeability such as digoxin, loperamide and vinblastine kinetically require basolateral uptake transport over that allowed by +GF120918 passive permeability, while highly permeable

  12. A-Ring modified steroidal azoles retaining similar potent and slowly reversible CYP17A1 inhibition as abiraterone

    PubMed Central

    Yoshimoto, Francis K.; Upadhyay, Sunil K.; Bratoeff, Eugene; Auchus, Richard J.

    2014-01-01

    Abiraterone acetate is a potent inhibitor of human cytochrome P450c17 (CYP17A1, 17α-hydroxylase/17,20-lyase) and is clinically used in combination with prednisone for the treatment of castration-resistant prostate cancer. Although many studies have documented the potency of abiraterone (Abi) in a variety of in vitro and in vivo systems for several species, the exact potency of Abi for human CYP17A1 enzyme has not yet been determined, and the structural requirements for high-potency steroidal azole inhibitors are not established. We synthesized 4 Abi analogs differing in the A-B ring substitution patterns: 3α-hydroxy-Δ4-Abi (13), 3-keto-Δ4-Abi (11), 3-keto-5α-Abi (6), and 3α-hydroxy-5α-Abi (5). We measured the spectral binding constants (Ks) using purified and modified human CYP17A1 along with the determination constants (Ki) applying a native human CYP17A1 enzyme in yeast microsomes for these compounds as well as for ketoconazole. For Abi, 3-keto-Δ4-Abi, 3-keto-5α-Abi, and 3α-hydroxy-5α-Abi, the type 2 spectral changes gave the best fit for a quadratic equation, since in these experiments Ks values were 0.1-2.6 nM, much lower than that for ketoconazole and 3α-hydroxy-Δ4-Abi (Ks values were 140 and 1660 nM, respectively). Inhibition experiments showed mixed inhibition patterns with Ki values of 7-80 nM. Abi dissociation from the CYP17A1-Abi complex was incomplete and slow; the t1/2 for dissociation was 1.8 hour, with 55% of complex remaining after 5 hours. We conclude that Abi and the 3 related steroidal azoles (3-keto-Δ4-Abi, 3-keto-5α-Abi, and 3α-hydroxy-5α-Abi), which also mimic natural substrates, are extraordinarily potent inhibitors of human CYP17A1, whereas the 3α-hydroxy-Δ4-Abi is moderately potent and comparable to ketoconazole. PMID:24508512

  13. Symptomatic Cushing's syndrome and hyperandrogenemia in a steroid cell ovarian neoplasm: a case report.

    PubMed

    Sedhom, Ramy; Hu, Sophia; Ohri, Anupam; Infantino, Dorian; Lubitz, Sara

    2016-10-12

    Malignant steroid cell tumors of the ovary are rare and frequently associated with hormonal abnormalities. There are no guidelines on how to treat rapidly progressive Cushing's syndrome, a medical emergency. A 67-year-old white woman presented to our hospital with rapidly developing signs and symptoms of Cushing's syndrome secondary to a steroid-secreting tumor. Her physical and biochemical manifestations of Cushing's syndrome progressed, and she was not amenable to undergoing conventional chemotherapy secondary to the debilitating effects of high cortisol. Her rapidly progressive Cushing's syndrome ultimately led to her death, despite aggressive medical management with spironolactone, ketoconazole, mitotane, and mifepristone. We report an unusual and rare case of Cushing's syndrome secondary to a malignant steroid cell tumor of the ovary. The case is highlighted to discuss the complications of rapidly progressive Cushing's syndrome, an underreported and often unrecognized endocrine emergency, and the best available evidence for treatment.

  14. An Unusual Case of White Piedra Due to Trichosporon inkin Mimicking Trichobacteriosis.

    PubMed

    Zhuang, Kaiwen; Ran, Xin; Dai, Yaling; Tang, Jiaoqing; Yang, Qin; Pradhan, Sushmita; Ran, Yuping

    2016-12-01

    White piedra is a superficial mycosis characterized by soft, white-to-tan, irregular nodules attached to the hair shafts. A 36-year-old man presented with small lumps in his pubic hair, without any other symptoms. The clinical features were suggestive of trichobacteriosis. Pathology analysis of the infected hair revealed that the concretions surrounding the hair shaft were full of fungal elements, parts of which had invaded into the cuticle. Culture on Sabouraud dextrose agar grew creamy, yellow-white colonies identified as Trichosporon inkin by the sequence of the nuclear ribosomal intergenic spacer region. The condition was treated by shaving the pubic hair and administering antifungal therapy (oral itraconazole and topical ketoconazole).

  15. Long-term pubic dermatitis diagnosed as white piedra.

    PubMed

    Landero, James

    2017-12-01

    The case of a 58-year-old man with a pruritic rash involving the pubic area that had been undiagnosed for 30 years is presented. At least 15 different primary care physicians and dermatologists evaluated the patient during this time period. Multiple treatments were unsuccessful and a definitive diagnosis was not rendered. Wood lamp evaluation of the pubic area revealed hair shaft concretions that were confirmed on histologic evaluation to be white piedra (WP). The patient was successfully treated with topical ketoconazole and the eruption completely resolved. Our case raises awareness of the use of Wood lamp and dermoscopy to evaluate for parasitic infections of the pubic hair shafts when nonspecific dermatitis presents in this area.

  16. Antibacterial, antifungal, and antiviral activities of the lipophylic extracts of Pistacia vera.

    PubMed

    Ozçelik, Berrin; Aslan, Mustafa; Orhan, Ilkay; Karaoglu, Taner

    2005-01-01

    In the present study, antibacterial, antifungal, and antiviral properties of 15 lipohylic extracts obtained from different parts (leaf, branch, stem, kernel, shell skins, seeds) of Pistacia vera were screened against both standard and the isolated strains of Escherichia coli, Pseudomonas aeruginosa, Enterococcus faecalis, Staphylococcus aureus, Candida albicans and C. parapsilosis by microdilution method. Both Herpes simplex (DNA) and Parainfluenza viruses (RNA) were used for the determination of antiviral activity of the P. vera extracts by using Vero cell line. Ampicilline, ofloxocine, ketoconazole, fluconazole, acyclovir and oseltamivir were used as the control agents. The extracts showed little antibacterial activity between the range of 128-256 microg/ml concentrations whereas they had noticeable antifungal activity at the same concentrations. Kernel and seed extracts showed significant antiviral activity compared to the rest of the extracts as well as the controls.

  17. Direct comparison of the pharmacodynamics of four antifungal drugs in a mouse model of disseminated candidiasis using microbiological assays of serum drug concentrations.

    PubMed

    Maki, Katsuyuki; Holmes, Ann R; Watabe, Etsuko; Iguchi, Yumi; Matsumoto, Satoru; Ikeda, Fumiaki; Tawara, Shuichi; Mutoh, Seitaro

    2007-01-01

    The aim of this study was to compare the pharmacodynamics of the azole antifungal drugs fluconazole, itraconazole and ketoconazole, and the polyene antifungal amphotericin B, in a mouse model of disseminated Candida albicans infection. In order to directly compare effective serum concentrations of these antifungals, drug concentrations were assayed microbiologically by measuring inhibition of C. albicans mycelial growth (mMIC) in a mouse serum-based assay (serum antifungal titer). Efficacy in the mouse infection model was determined using an organ-based (kidney burden) endpoint. For all four drugs, the serum antifungal titers, 8 hr after administration of single doses of drugs at a range of drug concentrations, correlated closely with C. albicans kidney fungal burden in the mouse model. The results showed that determining serum antifungal titer may be used to accurately represent kidney fungal burden in a mouse model of disseminated candidiasis and allowed direct comparison of the pharmacodynamics of differing classes of antifungal drugs.

  18. Efficacy of azole therapy for tegumentary leishmaniasis: A systematic review and meta-analysis.

    PubMed

    Galvão, Endi Lanza; Rabello, Ana; Cota, Gláucia Fernandes

    2017-01-01

    Several controlled and uncontrolled studies addressing azole antifungal drugs for cutaneous and mucosal leishmaniasis have been published with inconclusive results. We conducted a systematic literature review of studies evaluating the efficacy and toxicity associated with azole therapy for tegumentary leishmaniasis. PRISMA guidelines for systematic reviews and the Cochrane manual were followed, and the review methodology was registered (PROSPERO; CRD42016048668). Sources included the EMBASE, Web of Science, MEDLINE, LILACS, and IBECS databases along with a manual search of references from evaluated studies. Additional resources such as Google Scholar and clinicaltrials.gov were also searched. We included all studies reporting cure rate after cutaneous or mucosal leishmaniasis treatment with systemic azole drugs, regardless of their design. R software was used to estimate global rates of success and adverse events with each drug. The main outcome of interest was clinical cure, defined as complete re-epithelialization of all lesions. A total of 37 studies involving 1259 patients that reported outcomes after fluconazole (9), ketoconazole (14) and itraconazole (15) treatments were included. Only 14 (38%) were randomized controlled trials (RCT). The pooled azole final efficacy rate was 64% (CI95%: 57-70%) for all studies and 60% (CI95%: 50-70%) (p = 0.41) if only RCTs studies were considered. Twenty-four studies were conducted in the Old World and 13 studies in the Americas. The final efficacy rate according to New and Old World were 62% (CI95%: 43-77%) and 66% (CI95%: 58-73%), respectively. The final efficacy rate of azoles according to species were 89% (CI95%: 50-98%) for L. mexicana; 88% for L. infantum (CI95%: 27-99%); 80% for L. donovani; 53% (CI95%: 29-76%) for L. major; 49% for L. braziliensis (CI95%: 21-78%); and 15% (CI95%: 1-84%) for L. tropica. The cure rates were similar among the fluconazole, ketoconazole and itraconazole group arms (p = 0.89), specifically

  19. Tinea pedis presenting as asymmetric purpuric papules on the sole of the foot: a case report.

    PubMed

    Chen, Jennifer Yan Fei; Stroz, Marianne J; Adam, David N

    2015-01-01

    In this report we describe a unique case of tinea pedis. A 29-year-old man presented with a 3-day history of asymptomatic purpuric papules predominantly on his left foot. Potassium hydroxide preparation demonstrated fungal hyphae and culture yielded Trichophyton mentagrophytes. This patient presented unusually with purpuric papules, unlike the three commonly described types of tinea pedis. Given the morphology, positive potassium hydroxide slide preparation, T. mentagrophytes on fungal culture and clinical response to ketoconazole cream, we conclude that this represents a unique variant of tinea pedis. We recognize that even common dermatological diagnoses can have unique presentations, and it is important for clinicians to maintain a broad differential for new dermatologic cases.

  20. Tinea Pedis Presenting as Asymmetric Purpuric Papules on the Sole of the Foot: A Case Report

    PubMed Central

    Chen, Jennifer Yan Fei; Stroz, Marianne J.; Adam, David N.

    2015-01-01

    In this report we describe a unique case of tinea pedis. A 29-year-old man presented with a 3-day history of asymptomatic purpuric papules predominantly on his left foot. Potassium hydroxide preparation demonstrated fungal hyphae and culture yielded Trichophyton mentagrophytes. This patient presented unusually with purpuric papules, unlike the three commonly described types of tinea pedis. Given the morphology, positive potassium hydroxide slide preparation, T. mentagrophytes on fungal culture and clinical response to ketoconazole cream, we conclude that this represents a unique variant of tinea pedis. We recognize that even common dermatological diagnoses can have unique presentations, and it is important for clinicians to maintain a broad differential for new dermatologic cases. PMID:25873874

  1. Multifocal Aspergillus terreus discospondylitis in two German shepherd dogs.

    PubMed

    Berry, W L; Leisewitz, A L

    1996-12-01

    Multifocal fungal (Aspergillus terreus) discospondylitis was diagnosed in 2 German shepherd dogs. In one dog, the aetiology was established by means of fluoroscopic-guided disc aspiration, cytology and culture of disc material and urine. Disseminated aspergillosis was confirmed at necropsy and A. terreus cultured from numerous organs in this dog. The aetiology in the other dog was not established until therapeutic failure forced surgical curettage of disc material from which the fungus was cultured. Ketoconazole therapy failed to effect an improvement, and at necropsy, disease was localised to the spinal column, with A. terreus cultured from the affected discs and associated vertebrae. Immunodeficiency was suspected in both cases. In the case of disseminated disease a reduced lymphocyte blastogenic response was demonstrated. Reduced IgA was shown in both cases. The German shepherd breed seems to be predisposed to Aspergillus infections and IgA deficiency.

  2. [New drugs for small animals in 2014].

    PubMed

    Emmerich, I U

    2015-01-01

    In 2014, six active pharmaceutical ingredients were released on the German market for small animals. Those are the ektoparasiticide of the isoxazoline group afoxolaner (NexGard®) and fluralaner (Bravecto®) and the neonicotinoid dinotefuran (Vectra 3D, Vectra Felis), the antidiabetic protamine zinc insulin of human origin (ProZinc®), the antifungal agent ketoconazole (Fugazid®) as well as the cytostatic drug oclacitinib (Apoquel®). Two substances were authorized for an additional species. The antiparasiticide eprinomectin and the antibiotic clindamycin were also authorized for use in cats. In addition, two active pharmaceutical ingredients, which were approved 2014 for use in human medicine and are of potential interest to veterinary medicine, are discussed. These are the antihypertensive drug riociguat and the urological substance mirabegron.

  3. Activity of terbinafine in experimental fungal infections of laboratory animals.

    PubMed Central

    Petranyi, G; Meingassner, J G; Mieth, H

    1987-01-01

    The allylamine derivative terbinafine is the first antifungal agent with primary fungicidal properties against dermatophytes which acts systemically after oral application as well as locally after topical application. Comparative oral studies carried out with griseofulvin and ketoconazole in model infections such as guinea pig trichophytosis and microsporosis revealed terbinafine to be superior to the reference compounds both clinically and mycologically. An excellent antimycotic activity of terbinafine was also demonstrable after topical treatment of guinea pig dermatophytoses caused by Trichophyton mentagrophytes or Microsporum canis. Results of comparative chemotherapeutic studies carried out with econazole and tolnaftate demonstrated superior efficacy of terbinafine in the treatment of both trichophytosis and microsporosis. Skin infections of guinea pigs caused by Candida albicans and vaginal candidiasis in rats proved to be responsive to a topical application of terbinafine also. However, the reference compounds, clotrimazole and miconazole, exhibited activity superior to that of terbinafine in both models. PMID:3435103

  4. Effects of antifungal agents alone and in combination against Candida glabrata strains susceptible or resistant to fluconazole.

    PubMed

    Alves, Izabel Almeida; Bandeira, Laíssa Arévalo; Mario, Débora Alves Nunes; Denardi, Laura Bedin; Neves, Louise Vignoles; Santurio, Janio Morais; Alves, Sydney Hartz

    2012-09-01

    The rise of Candida spp. resistant to classic triazole antifungal agents has led to a search for new therapeutic options. Here, we evaluated combinations of antifungals in a checkerboard assay against two groups of Candida glabrata strains: one containing fluconazole-susceptible clinical isolates (FS) and another containing fluconazole-resistant laboratory derivative (FR). The most synergistic combination observed was amphotericin B + flucytosine (synergistic for 61.77 % of FS strains and 76.47 % of FR strains). The most antagonistic combination observed was ketoconazole + flucytosine (FS 61.77 % and FR 55.88 %). Surprisingly, most combinations evidenced indifferent interactions, and the best synergism appeared when amphotericin B and flucytosine were combined against both groups of isolates.

  5. Promising therapies for treating and/or preventing androgenic alopecia.

    PubMed

    McElwee, K J; Shapiro, J S

    2012-06-01

    Androgenetic alopecia (AGA) may affect up to 70% of men and 40% of women at some point in their lifetime. While men typically present with a distinctive alopecia pattern involving hairline recession and vertex balding, women normally exhibit a diffuse hair thinning over the top of their scalps. The treatment standard in dermatology clinics continues to be minoxidil and finasteride with hair transplantation as a surgical option. Here we briefly review current therapeutic options and treatments under active investigation. Dutasteride and ketoconazole are also employed for AGA, while prostaglandin analogues latanoprost and bimatoprost are being investigated for their hair growth promoting potential. Laser treatment products available for home use and from cosmetic clinics are becoming popular. In the future, new cell mediated treatment approaches may be available for AGA. While there are a number of potential treatment options, good clinical trial data proving hair growth efficacy is limited.

  6. Tinea nigra by Hortaea werneckii, a report of 22 cases from Mexico

    PubMed Central

    Bonifaz, A.; Badali, H.; de Hoog, G.S.; Cruz, M.; Araiza, J.; Cruz, M.A.; Fierro, L.; Ponce, R.M.

    2008-01-01

    Tinea nigra is a superficial mycosis caused by Hortaea werneckii. It is an infrequent asymptomatic infection that affects human palms and soles, and is mostly observed in tropical countries. We evaluate retrospectively twenty-two confirmed cases of tinea nigra from a total of eleven yr (1997–2007) and discuss the epidemiology, clinical features and treatment of this disease. In twelve cases, adults were involved, in 10, children. In nineteen cases the disorder was located on palms of hands and in three on soles of feet. In all cases, the obtained isolates were morphologically identified as Hortaea werneckii and the identification of ten isolates was retrospectively confirmed with the help of sequences of the internal transcribed spacer regions of the ribosomal DNA. The patients received topical treatment with Whitfield ointment, ketoconazole, bifonazole, or terbinafine. Treatment with keratolytic agents and topical antifungals was effective. PMID:19287529

  7. Tinea nigra by Hortaea werneckii, a report of 22 cases from Mexico.

    PubMed

    Bonifaz, A; Badali, H; de Hoog, G S; Cruz, M; Araiza, J; Cruz, M A; Fierro, L; Ponce, R M

    2008-01-01

    Tinea nigra is a superficial mycosis caused by Hortaea werneckii. It is an infrequent asymptomatic infection that affects human palms and soles, and is mostly observed in tropical countries. We evaluate retrospectively twenty-two confirmed cases of tinea nigra from a total of eleven yr (1997-2007) and discuss the epidemiology, clinical features and treatment of this disease. In twelve cases, adults were involved, in 10, children. In nineteen cases the disorder was located on palms of hands and in three on soles of feet. In all cases, the obtained isolates were morphologically identified as Hortaea werneckii and the identification of ten isolates was retrospectively confirmed with the help of sequences of the internal transcribed spacer regions of the ribosomal DNA. The patients received topical treatment with Whitfield ointment, ketoconazole, bifonazole, or terbinafine. Treatment with keratolytic agents and topical antifungals was effective.

  8. Oral manifestations of paracoccidioidomycosis (South American blastomycosis).

    PubMed

    de Almeida, O P; Jorge, J; Scully, C; Bozzo, L

    1991-10-01

    Paracoccidioidomycosis (South American blastomycosis) is an uncommon, progressive systemic mycosis, potentially fatal if untreated. It is virtually restricted to persons spending time in Latin America. Reports of oral lesions are extremely rare in the English-language literature. Three adults with oral lesions as the first sign of paracoccidioidomycosis are described; this appears to be the largest series in the dental literature. The oral lesions had a characteristic appearance with a granular purpuric surface. The upper gingiva was a typical site, but lesions were also seen in the palate, tongue, and buccal mucosa. Two of the patients proved to have detectable pulmonary involvement. Long-term systemic ketoconazole therapy produced resolution of oral lesions in all cases.

  9. Candida albicans gastrointestinal colonization and invasion in the mouse: effect of antibacterial dosing, antifungal therapy and immunosuppression.

    PubMed

    Kinsman, O S; Pitblado, K

    1989-12-01

    Infant mice infected with Candida albicans by the oral-intragastric route became colonized in the gut and were persistently colonized into adulthood. Faecal levels of Candida were correlated with total gastrointestinal Candida and provided a useful means of detecting yeast overgrowth or elimination. Antibacterial agents promoting Candida overgrowth when given by the oral or parenteral route included ceftriaxone, augmentin and cefoperazone. Ceftizoxime had less effect. Ceftazidime and latamoxef produced raised levels only by the oral route. Gentamicin, vancomycin and metronidazole did not affect the Candida levels. Dosing with some antibacterials promoted an increase in gastrointestinal Candida and invasion to a greater extent than immunosuppression. Antifungal therapy to reduce gastrointestinal colonization was investigated using amphotericin B, nystatin, ketoconazole, intraconazole and fluconazole. Fluconazole was most effective at reducing faecal Candida.

  10. Tinea nigra showing a parallel ridge pattern on dermoscopy.

    PubMed

    Noguchi, Hiromitsu; Hiruma, Masataro; Inoue, Yuji; Miyata, Keishi; Tanaka, Masaru; Ihn, Hironobu

    2015-05-01

    An 18-year-old healthy female student noticed a brown macule measuring 21 mm in diameter on the left palm and visited our clinic concerned about a cancerous mole. Dermoscopic examination revealed a brown, fine-dotted and granule-like structure overlapping an amorphous light brown macule. However, unlike previous cases, analysis of the high dynamic range-converted image revealed the parallel ridge pattern frequently observed in malignant melanomas. Brown mycelia were detected on direct microscopic examination; black colonies were isolated on fungal culture and the fungus was identified as Hortaea werneckii. The lesion was treated with topical ketoconazole cream, and it diminished 1 month later. © 2015 Japanese Dermatological Association.

  11. Evaluation of drug-induced tissue injury by measuring alanine aminotransferase (ALT) activity in silkworm hemolymph

    PubMed Central

    2012-01-01

    Background Our previous studies suggest silkworms can be used as model animals instead of mammals in pharmacologic studies to develop novel therapeutic medicines. We examined the usefulness of the silkworm larvae Bombyx mori as an animal model for evaluating tissue injury induced by various cytotoxic drugs. Drugs that induce hepatotoxic effects in mammals were injected into the silkworm hemocoel, and alanine aminotransferase (ALT) activity was measured in the hemolymph 1 day later. Results Injection of CCl4 into the hemocoel led to an increase in ALT activity. The increase in ALT activity was attenuated by pretreatment with N-acetyl-L-cysteine. Injection of benzoic acid derivatives, ferric sulfate, sodium valproate, tetracycline, amiodarone hydrochloride, methyldopa, ketoconazole, pemoline (Betanamin), N-nitroso-fenfluramine, and D-galactosamine also increased ALT activity. Conclusions These findings indicate that silkworms are useful for evaluating the effects of chemicals that induce tissue injury in mammals. PMID:23137391

  12. Tinea capitis caused by Trichophyton tonsurans presenting as an obscure patchy hair loss due to daily antifungal shampoo use.

    PubMed

    Sombatmaithai, Alita; Pattanaprichakul, Penvadee; Tuchinda, Papapit; Surawan, Theetat; Muanprasart, Chanai; Matthapan, Lalita; Bunyaratavej, Sumanas

    2015-04-01

    Tinea capitis is unusual and often misdiagnosed in healthy adults. We report a case of a healthy woman with a several-year history of asymptomatic, bizarre-shaped, non-scarring alopecia. She had used over-the-counter ketoconazole shampoo regularly for a long time. An initial potassium hydroxide preparation showed negative result for fungal organism. The scalp biopsy revealed endothrix infection, and dermoscopic examination demonstrated the comma hair and corkscrew hair signs. The fungal culture showed Trichophyton tonsurans. The daily use of antifungal shampoo could be the important factor to conceal clinical and laboratory findings for diagnosis of T. tonsurans tinea capitis in our case, which required high clinical suspicion and histopathology and dermoscopic examinations.

  13. Tinea capitis caused by Trichophyton tonsurans presenting as an obscure patchy hair loss due to daily antifungal shampoo use

    PubMed Central

    Sombatmaithai, Alita; Pattanaprichakul, Penvadee; Tuchinda, Papapit; Surawan, Theetat; Muanprasart, Chanai; Matthapan, Lalita; Bunyaratavej, Sumanas

    2015-01-01

    Tinea capitis is unusual and often misdiagnosed in healthy adults. We report a case of a healthy woman with a several-year history of asymptomatic, bizarre-shaped, non-scarring alopecia. She had used over-the-counter ketoconazole shampoo regularly for a long time. An initial potassium hydroxide preparation showed negative result for fungal organism. The scalp biopsy revealed endothrix infection, and dermoscopic examination demonstrated the comma hair and corkscrew hair signs. The fungal culture showed Trichophyton tonsurans. The daily use of antifungal shampoo could be the important factor to conceal clinical and laboratory findings for diagnosis of T. tonsurans tinea capitis in our case, which required high clinical suspicion and histopathology and dermoscopic examinations. PMID:26114071

  14. Functionalized Derivatives of Benzo-Crown Ethers. Part 4. Antifungal Macrocyclic Supramolecular Complexes of Transition Metal Ions Acting as Lanosterol-14-α-Demethylase Ihibitors

    PubMed Central

    Barboiu, Mihai; Scozzafava, Andrea; Guran, Cornelia; Diaconescu, Paula; Bojin, Mihaela; Iluc, Vlad; Cot, Louis

    1999-01-01

    Poly- and mononuclear metal complexes of 2,3,11,12-bis[4-(10-aminodecylcarbonyl)]benzo-18- crown-6 (L) and Cu(II); Ni(II); Co(II) and Cr(III) have been synthesized and characterized by standard physico-chemical procedures. In the newly prepared complexes the crown moiety oxygen atoms of the macrocyclic host did not generally interact with metal ions, whereas the two amino groups of the ligand always did. Several of the newly synthesized compounds act as effective antifungal agents against Aspergillus and Candida spp., some of them showing activities comparable to ketoconazole, with minimum inhibitory concentrations in the range of 0.3−0.5 μg/mL. The mechanism of antifungal action of these coordination compounds is probably connected to an inhibition of lanosterol-14-α-demethylase, a metallo-enzyme playing a key role in sterol biosynthesis in fungi, bacteria and eukariotes. PMID:18475888

  15. Antileishmanial activities of dihydrochalcones from piper elongatum and synthetic related compounds. Structural requirements for activity.

    PubMed

    Hermoso, Alicia; Jiménez, Ignacio A; Mamani, Zulma A; Bazzocchi, Isabel L; Piñero, José E; Ravelo, Angel G; Valladares, Basilio

    2003-09-01

    Two dihydrochalcones (1 and 2) were isolated from Piper elongatum Vahl by activity-guided fractionation against extracellular promastigotes of Leishmania braziliensis in vitro. Their structures were elucidated by spectral analysis, including homonuclear and heteronuclear correlation NMR experiments. Derivatives 3-7 and 20 synthetic related compounds (8-27) were also assayed to establish the structural requirements for antileishmanial activity. Compounds 1-11 that proved to be more active that ketoconazol, used as positive control, were further assayed against promastigotes of Leishmania tropica and Leishmania infantum. Compounds 7 and 11, with a C(6)-C(3)-C(6) system, proved to be the most promising compounds, with IC(50) values of 2.98 and 3.65 microg/mL, respectively, and exhibited no toxic effect on macrophages (around 90% viability). Correlation between the molecular structures and antileishmanial activity is discussed in detail.

  16. Clinical, microbiological, and experimental animal studies of Candida lipolytica.

    PubMed Central

    Walsh, T J; Salkin, I F; Dixon, D M; Hurd, N J

    1989-01-01

    Candida lipolytica was recovered from six patients in three different clinical centers. The index isolate caused a persistent fungemia with catheter-associated Candida thrombophlebitis, the second isolate was from a polymicrobial sinusitis, and the remaining four isolates were involved in tissue colonization. These and 20 other isolates were consistent in their morphological and physiological characteristics. All formed true hyphae and blastoconidia on cornmeal-Tween 80 agar and all assimilated glucose, glycerol, and erythritol. In a murine model of disseminated candidiasis, the index isolate that caused clinical fungemia caused no mortality and produced only two lesions on a kidney, as determined at necropsy. The nine isolates selected for in vitro antifungal susceptibility studies had intermediate susceptibilities to amphotericin B but were susceptible to ketoconazole. We conclude that C. lipolytica is a weakly virulent pathogen which may require an intravascular foreign body to cause fungemia. Images PMID:2745702

  17. Dermatomycosis in a pet inland bearded dragon (Pogona vitticeps) caused by a Chrysosporium species related to Nannizziopsis vriesii.

    PubMed

    Abarca, M L; Martorell, J; Castellá, G; Ramis, A; Cabañes, F J

    2009-08-01

    A Chrysosporium sp. related to Nannizziopsis vriesii was isolated in pure culture from squames and biopsies of facial lesions in a pet inland bearded dragon (Pogona vitticeps) in Spain. The presence in histological sections of morphologically consistent fungal elements strongly incriminates this fungus as the aetiological agent of infection. Lesions regressed following treatment with oral ketoconazole and topical chlorhexidine and terbinafine until the lizard was lost to follow up 1 month later. The ITS-5.8S rRNA gene of the isolate was sequenced and a search on the GenBank database revealed a high match with the sequences of two Chrysosporium sp. strains recently isolated from green iguanas (Iguana iguana) with dermatomycosis, also in Spain. Phylogenetic analysis of the sequences revealed that all these strains are related to N. vriesii. This is the first report of dermatomycoses caused by a Chrysosporium species related to N. vriesii in a bearded dragon outside North America.

  18. Human protothecosis.

    PubMed

    Lass-Flörl, Cornelia; Mayr, Astrid

    2007-04-01

    Human protothecosis is a rare infection caused by members of the genus Prototheca. Prototheca species are generally considered to be achlorophyllic algae and are ubiquitous in nature. The occurrence of protothecosis can be local or disseminated and acute or chronic, with the latter being more common. Diseases have been classified as (i) cutaneous lesions, (ii) olecranon bursitis, or (iii) disseminated or systemic manifestations. Infections can occur in both immunocompetent and immunosuppressed patients, although more severe and disseminated infections tend to occur in immunocompromised individuals. Prototheca wickerhamii and Prototheca zopfii have been associated with human disease. Usually, treatment involves medical and surgical approaches; treatment failure is not uncommon. Antifungals such as ketoconazole, itraconazole, fluconazole, and amphotericin B are the most commonly used drugs to date. Among them, amphotericin B displays the best activity against Prototheca spp. Diagnosis is largely made upon detection of characteristic structures observed on histopathologic examination of tissue.

  19. Human Protothecosis

    PubMed Central

    Lass-Flörl, Cornelia; Mayr, Astrid

    2007-01-01

    Human protothecosis is a rare infection caused by members of the genus Prototheca. Prototheca species are generally considered to be achlorophyllic algae and are ubiquitous in nature. The occurrence of protothecosis can be local or disseminated and acute or chronic, with the latter being more common. Diseases have been classified as (i) cutaneous lesions, (ii) olecranon bursitis, or (iii) disseminated or systemic manifestations. Infections can occur in both immunocompetent and immunosuppressed patients, although more severe and disseminated infections tend to occur in immunocompromised individuals. Prototheca wickerhamii and Prototheca zopfii have been associated with human disease. Usually, treatment involves medical and surgical approaches; treatment failure is not uncommon. Antifungals such as ketoconazole, itraconazole, fluconazole, and amphotericin B are the most commonly used drugs to date. Among them, amphotericin B displays the best activity against Prototheca spp. Diagnosis is largely made upon detection of characteristic structures observed on histopathologic examination of tissue. PMID:17428884

  20. Protothecosis.

    PubMed

    Mayorga, Jorge; Barba-Gómez, José Fernando; Verduzco-Martínez, Ana Paula; Muñoz-Estrada, Víctor Fernando; Welsh, Oliverio

    2012-01-01

    Protothecosis is a rare infection caused by achlorophyllic algae that are members of the genus Prototheca. They are ubiquitous in nature in organic material. The clinical manifestations can be acute or chronic and local or disseminated. The disease is classified as cutaneous, causing bursitis or disseminated/systemic, affecting both immunocompetent and immunosuppressed patients, with more severe and disseminated infections occurring in immunocompromised individuals. Prototheca wickerhamii and Prototheca zopfii are the most frequent organisms reported in humans. Diagnosis is made by observing asexual sporangia (thecas) on histopathological examination of tissue. Medical and surgical treatment should be considered. Ketoconazole, itraconazole, fluconazole, voriconazole, posaconazole, and amphotericin B are the most commonly used antifungals. Voriconazole and amphotericin B are highly effective against Prototheca spp. Treatment failure is not uncommon because of the comorbidities that limit the therapeutic outcome. Copyright © 2012. Published by Elsevier Inc.

  1. In vitro combination of antifungal agents against Malassezia pachydermatis.

    PubMed

    Schlemmer, Karine B; de Jesus, Francielli P K; Loreto, Erico S; Farias, Julia B; Alves, Sydney H; Ferreiro, Laerte; Santurio, Janio M

    2018-06-19

    The yeast Malassezia pachydermatis is a common commensal and occasional opportunistic pathogen of theskin microbiota of animals and humans. In this study, the susceptibility of M. pachydermatis isolates to fluconazole (FLC), itraconazole (ITZ), ketoconazole (KTZ), clotrimazole (CLZ), and miconazole (MCZ) alone and in combination with terbinafine (TRB), nystatin (NYS), and caspofungin (CSP) was evaluated in vitro based on the M27-A3 technique and the checkerboard microdilution method using Sabouraud dextrose broth with 1% tween 80 (SDB). Based on the mean FICI values, the main synergies observed were combinations of ITZ+CSP and CLZ+CSP (55.17%). The most significant combinations deserve in vivo evaluations because might provide effective alternative treatments against M. pachydermatis due to their synergistic interactions.

  2. Deoxysarpagine hydroxylase--a novel enzyme closing a short side pathway of alkaloid biosynthesis in Rauvolfia.

    PubMed

    Yu, Bingwu; Ruppert, Martin; Stöckigt, Joachim

    2002-08-01

    Microsomal preparations from cell suspension cultures of the Indian plant Rauvolfia serpentina catalyze the hydroxylation of deoxysarpagine under formation of sarpagine. The newly discovered enzyme is dependent on NADPH and oxygen. It can be inhibited by typical cytochrome P450 inhibitors such as cytochrome c, ketoconazole, metyrapone, tetcyclacis and carbon monoxide. The CO-effect is reversible with light (450 nm). The data indicate that deoxysarpagine hydroxylase is a novel cytochrome P450-dependent monooxygenase. A pH optimum of 8.0 and a temperature optimum of 35 degrees C were determined. K(m) values were 25 microM for NADPH and 7.4 microM for deoxysarpagine. Deoxysarpagine hydroxylase activity was stable in presence of 20% sucrose at -25 degrees C for >3 months. The analysis of presence of the hydroxylase in nine cell cultures of seven different families indicates a very limited taxonomic distribution of this enzyme.

  3. Malassezia folliculitis in an infant

    PubMed Central

    Anane, S.; Chtourou, O.; Bodemer, C.; Kharfi, M.

    2013-01-01

    Malassezia folliculitis commonly affects the adolescents and the young adults. We describe an unusual case of Malassezia folliculitis which is particular in age of patient and scare evolution of lesions. The patient was a three-month-old immuno-competent boy. On clinical examination, 1- to 2-mm superficial follicular pustules were observed on his face, neck and upper trunk. Direct microscopy of pustule scrapings and hair follicles showed numerous Malassezia yeast cells. Based on the clinical and mycological data, the diagnosis of Malassezia folliculitis was made. The possible predisposing factors in our patient were heat and sweating, caused by the excessive heat of the summer season in Tunisia. Treatment with topical ketoconazole promoted cure with depressed varioliform scars. PMID:24432221

  4. Fluconazole resistance in Candida glabrata.

    PubMed Central

    Hitchcock, C A; Pye, G W; Troke, P F; Johnson, E M; Warnock, D W

    1993-01-01

    We report a case of infection with Candida glabrata in which the organism became resistant to fluconazole and in which pre- and posttreatment isolates were available for comparison. The organism was cross-resistant to ketoconazole and itraconazole, in common with other azole-resistant yeasts. Fluconazole was a potent inhibitor of cytochrome P-450-dependent 14 alpha-sterol demethylase (P-450DM) in lysates of cells from both susceptible and resistant cultures (50% inhibitory concentration, 0.2 microM), indicating that resistance was unrelated to changes in P-450DM. Instead, it appeared to arise from a permeability barrier to fluconazole, since resistant cells were unable to take up radiolabelled drug. PMID:8239613

  5. Leishmanicidal and reversal multidrug resistance constituents from Aeonium lindleyi.

    PubMed

    Kennedy, María L; Cortés, Fernando; Piñero, José E; Castanys, Santiago; López-Arencibia, Atteneri; Gamarro, Francisco; Bazzocchi, Isabel L; Jiménez, Ignacio A

    2011-01-01

    A new bicyclic diterpene with a labdane skeleton, 7-oxo-labd-8-en-15-ol ( 1), along with two known diterpenes and ten flavonoids were isolated from the leaves of Aeonium lindleyi (Crassulaceae). Their structures were elucidated on the basis of spectroscopic data, including 1D and 2D NMR experiments, and comparison with spectroscopic data reported in the literature. Labdan-8 α,15-diol (2) and labd-8(17)-en-3 β,15-diol (3) showed leishmanicidal activity against Leishmania tropica (IC (50) = 77.0 µM) and Leishmania braziliensis (IC (50) = 68.0 µM) similar to ketoconazole used as positive control. 5,3'-Dihydroxy-3,7,4',5'-tetramethoxyflavone (8) and combretol (9) showed moderate activity (growth inhibition 87.3 and 73.0 %, respectively, at 50 µM) against a multidrug-resistant L. tropica line. © Georg Thieme Verlag KG Stuttgart · New York.

  6. Evaluation of intestinal metabolism and absorption using the Ussing chamber system equipped with intestinal tissue from rats and dogs.

    PubMed

    Miyake, Masateru; Kondo, Satoshi; Koga, Toshihisa; Yoda, Noriaki; Nakazato, Satoru; Emoto, Chie; Mukai, Tadashi; Toguchi, Hajime

    2018-01-01

    The purpose of this study was to evaluate the intestinal metabolism and absorption in a mini-Ussing chamber equipped with animal intestinal tissues, based on the transport index (TI). TI value was defined as the sum of drug amounts transported to the basal-side component (X corr ) and drug amounts accumulated in the tissue (T corr ), which are normalized by AUC of a drug in the apical compartment, as an index for drug absorption. Midazolam was used as a test compound for the evaluation of intestinal metabolism and absorption. The metabolite formulation of midazolam was observed in both rats and dogs. Ketoconazole inhibited the intestinal metabolism of midazolam in rats and improved its intestinal absorption to a statistically significant extent. Therefore, the mini-Ussing chamber, equipped with animal intestinal tissues, showed potential to use the evaluation of the intestinal metabolism and absorption, including the assessment of species differences. Copyright © 2017. Published by Elsevier B.V.

  7. Tinea barbae (tinea sycosis): experience with nine cases.

    PubMed

    Bonifaz, Alexandro; Ramírez-Tamayo, Teresa; Saúl, Amado

    2003-12-01

    Tinea barbae is a rare dermatophytosis that affects the hair and hair follicles of the beard and mustache. This paper presents 9 cases of tinea barbae observed over an 18-year period of time and classified as follows: 1 was superficial and 8 were deep (6 folliculitis-like and 2 kerion-like). Most of the cases (4) were associated with topical steroid therapy, others with pet contact (3 cases) and one with diabetes. The causal agents isolated were: Trichophyton rubrum in 3; Microsporum canis in 3; Trichophyton mentagrophytes in 2; and Trichophyton tonsurans in one. The involvement of the hair was observed and classified in all cases. The trichophytin skin reaction was positive in all 9 patients. All the patients were treated with systemic antimycotics, 3 cases with griseofulvin, 1 with ketoconazole, 3 with itraconazole, and 2 with terbinafine. Clinical and mycologic cures were achieved at 6 to 8 weeks of treatment at the usual doses.

  8. Formation and antimicrobial activity of complexes of beta-cyclodextrin and some antimycotic imidazole derivatives.

    PubMed

    Van Doorne, H; Bosch, E H; Lerk, C F

    1988-04-22

    Complex formation between beta-cyclodextrin and six antimycotic imidazole derivatives has been studied. The solubility of all drugs was increased in the presence of beta-cyclodextrin. The smallest increase (approx. 5-fold) was observed for miconazol, and the largest increase (approx. 160-fold) was observed for bifonazol. Apparent 1:1-complex constants were measured and found to decrease in the order: bifonazol greater than ketoconazol greater than tioconazol greater than miconazol greater than itraconazol greater than clotrimazol. The complexes appeared to possess a low, if any, antimicrobial activity. Measurement of inhibition zone sizes, with four test organisms was used to study the release of the antimycotic drugs from topical preparations. The antimycotic drugs were more readily released from topical preparations containing beta-cyclodextrin than from the same vehicles without beta-cyclodextrin. The rationale of beta-cyclodextrin addition to antimycotic topical preparations is discussed.

  9. DIAGNOSIS AND SUCCESSFUL TREATMENT OF A POTENTIALLY ZOONOTIC DERMATOPHYTOSIS CAUSED BY MICROSPORUM GYPSEUM IN A ZOO-HOUSED NORTH AMERICAN PORCUPINE (ERETHIZON DORSATUM).

    PubMed

    Hackworth, Christine E; Eshar, David; Nau, Melissa; Bagladi-Swanson, Mary; Andrews, Gordon A; Carpenter, James W

    2017-06-01

    A female North American porcupine ( Erethizon dorsatum ) was evaluated for a unilateral pedal crusting and alopecic dermatopathy. Fungal culture and histopathology testing revealed Microsporum gypseum dermatophytosis. Treatment with topical miconazole was initiated and then discontinued after 9 days and changed to oral terbinafine. Twenty-eight days after initial examination, clinical signs were improving, and fungal cultures of the front foot, muzzle, and noninfected area along the dorsum were negative for M. gypseum. Visual exams were conducted on a regular basis. Eighty-three days after initial evaluation, clinical signs had completely resolved and repeat fungal cultures were negative. One of the animal's keepers was suspected to have acquired a dermal fungal infection 3 days after contact with this porcupine, and lesions had resolved after treatment with topical ketoconazole. To the authors' knowledge, this is the first report of M. gypseum diagnosed and treated in a captive North American porcupine. Veterinary staff and zookeepers should be aware of this potentially zoonotic infection.

  10. Quaternary ammonium salt N-(dodecyloxycarboxymethyl)-N,N,N-trimethyl ammonium chloride induced alterations in Saccharomyces cerevisiae physiology.

    PubMed

    Oblak, Ewa; Piecuch, Agata; Maciaszczyk-Dziubinska, Ewa; Wawrzycka, Donata

    2016-12-01

    We investigated the influence of the quaternary ammonium salt (QAS) called IM (N-(dodecyloxycarboxymethyl)- N,N,N-trimethyl ammonium chloride) on yeast cells of the parental strain and the IM-resistant mutant (EO25 IMR) growth. The phenotype of this mutant was pleiotropic. The IMR mutant exhibited resistance to ethanol, osmotic shock and oxidative stress, as well as increased sensitivity to UV. Moreover, it was noted that mutant EO25 appears to have an increased resistance to clotrimazole, ketoconazole, fluconazole, nystatin and cycloheximide. It also tolerated growth in the presence of crystal violet, DTT and metals (selenium, tin, arsenic). It was shown that the presence of IM decreased ergosterol level in mutant plasma membrane and increased its unsaturation. These results indicate changes in the cell lipid composition. Western blot analysis showed the induction of Pma1 level by IM. RT-PCR revealed an increased PMA1 expression after IM treatment.

  11. N-Hydroxylation of dapsone by multiple enzymes of cytochrome P450: implications for inhibition of haemotoxicity.

    PubMed Central

    Gill, H J; Tingle, M D; Park, B K

    1995-01-01

    1. The adverse reactions associated with the administration of dapsone are believed to be caused by metabolism to its hydroxylamine. Previous reports suggest that CYP3A4 is responsible for this biotransformation [1]. 2. Data presented in this paper illustrate the involvement of more than one cytochrome P450 enzyme in dapsone hydroxylamine formation using human liver microsomes. Eadie-Hofstee plots demonstrated bi-phasic kinetics in several livers. No correlation could be established between hydroxylamine formation and CYP3A concentrations in six human livers (r = -0.47; P = 0.34). 3. Studies with low molecular weight inhibitors illustrate the importance of CYP2C9 and CYP3A in dapsone N-hydroxylation. 4. Differential sensitivity of dapsone N-hydroxylation to selective CYP inhibitors indicated that the contribution of individual CYP enzymes varies between livers. Selective inhibition ranged from 6.8 to 44.1% by 5 microM ketoconazole, and from 24.0 to 68.4% by 100 microM sulphaphenazole. The extent of inhibition, by either ketoconazole or sulphaphenazole was dependent on the CYP3A content of the liver. 5. The levels of expression of these cytochrome P450 enzymes may be an important determinant of individual susceptibility to the toxic effects of dapsone, and may influence the ability of an enzyme inhibitor to block dapsone toxicity in vivo. Because of the inability to produce complete inhibition, selective CYP inhibitors are unlikely to offer any clinical advantage over cimetidine in decreasing dapsone hydroxylamine formation in vivo. PMID:8703658

  12. Sporotrichosis: The Story of an Endemic Region in Peru over 28 Years (1985 to 2012).

    PubMed

    Ramírez Soto, Max Carlos

    2015-01-01

    Abancay province is a long-standing geographical focus of sporotrichosis in the south central highlands of Peru. Therefore, we examined the features of 36 newly identified cases of sporotrichosis from two hospital centers in Abancay province. We also performed a literature review of studies conducted in this endemic geographical focus over a period of 28 years (1998 to 2012), and analyzed the demographic, clinical and epidemiological features of sporotrichosis in the cases reported in these studies. We examined the features of 36 new cases of sporotrichosis identified from two hospital centers in Abancay. Furthermore, we searched for relevant studies of cases of sporotrichosis in the endemic region using healthcare databases and literature sources. We analyzed a detailed subset of data on cases collected in Abancay, neighboring provinces, and other regions of Peru. A total of nine studies were identified, with 1467 cases included in the final analysis. We also analyzed 36 new cases found in the two hospital centers. Therefore, the combined total of cases analyzed was 1503. Of this total, 58% were male, and approximately 62% were aged ≤14 years. As expected, most cases were from Abancay province (88%), although 12% were from neighboring provinces and other regions of Peru. The lymphocutaneous form (939 cases) was the commonest. The face was the most commonly affected region (647 cases). A total of 1224 patients (81.4%) received treatment: 95.8% received potassium iodide, 2.6% ketoconazole and 1.6% itraconazole. The overall success rates were 60.7% with potassium iodide, 32.2% with ketoconazole and 85% with itraconazole. The epidemic of sporotrichosis has been occurring for three decades in the province of Abancay in Peru. This mycosis affects primarily the pediatric population, with predominantly the lymphocutaneous form in the facial region. Although treatment with potassium iodide is safe and effective, response and adherence to treatment are influenced by its

  13. Application of Physiologically Based Pharmacokinetic Modeling in Understanding Bosutinib Drug-Drug Interactions: Importance of Intestinal P-Glycoprotein.

    PubMed

    Yamazaki, Shinji; Loi, Cho-Ming; Kimoto, Emi; Costales, Chester; Varma, Manthena V

    2018-05-08

    Bosutinib is an orally available Src/Abl tyrosine kinase inhibitor indicated for the treatment of patients with Ph+ chronic myelogenous leukemia at a clinically recommended dose of 500 mg once daily. Clinical results indicated that increases in bosutinib oral exposures were supra-proportional at the lower doses (50 to 200 mg) and approximately dose-proportional at the higher doses (200 to 600 mg). Bosutinib is a substrate of CYP3A4 and P-glycoprotein and exhibits pH-dependent solubility with moderate intestinal permeability. These findings led us to investigate the factors influencing the underlying pharmacokinetic mechanisms of bosutinib with physiologically-based pharmacokinetic (PBPK) models. Our primary objectives were to: 1) refine the previously developed bosutinib PBPK model based on the latest oral bioavailability data and 2) verify the refined PBPK model with P-glycoprotein kinetics based on the bosutinib drug-drug interaction (DDI) results with ketoconazole and rifampin. Additionally, the verified PBPK model was applied to predict bosutinib DDIs with dual CYP3A/P-glycoprotein inhibitors. The results indicated that 1) the refined PBPK model adequately described the observed plasma concentration-time profiles of bosutinib and 2) the verified PBPK model reasonably predicted the effects of ketoconazole and rifampin on bosutinib exposures by accounting for intestinal P-gp inhibition/induction. These results suggested that bosutinib DDI mechanism could involve not only CYP3A4-mediated metabolism but also P-glycoprotein-mediated efflux on absorption. In summary, P-glycoprotein kinetics could constitute a critical element in the PBPK models to understand the pharmacokinetic mechanism of dual CYP3A/P-glycoprotein substrates such as bosutinib exhibiting nonlinear pharmacokinetics due largely to a saturation of intestinal P-glycoprotein-mediated efflux. The American Society for Pharmacology and Experimental Therapeutics.

  14. CYP3A4 and CYP3A5 catalyse the conversion of the N-methyl-D-aspartate (NMDA) antagonist CJ-036878 to two novel dimers.

    PubMed

    Emoto, C; Nishida, H; Hirai, H; Iwasaki, K

    2007-12-01

    CJ-036878, N-(3-phenethoxybenzyl)-4-hydroxybenzamide, was developed as an antagonist of the N-methyl-D-aspartate receptor NR2B subunit. Two dimeric metabolites, CJ-047710 and CJ-047713, were identified from the incubation mixture with CJ-036878 in human liver microsomes (HLM). The identification of the enzymes involved in the formation of these dimeric metabolites was investigated in the current study. Inhibition of the formation of CJ-047710 and CJ-047713 in pooled HLM by 1-aminobenztriazole, SKF-525A, and ketoconazole were observed. Ketoconazole played a significant role in inhibiting formation of these two metabolites in a concentration-dependent manner. Recombinant CYP3A4 and CYP3A5 exhibited a markedly high activity toward the formation of CJ-047710 and CJ-047713 from CJ-036878, but the contribution of other CYP enzymes to these formations was at a very low level or negligible. The formation of CJ-047710 and CJ-047713 in pooled HLM, CYP3A4, and CYP3A5 showed sigmoid characteristics. S50 values for CJ-047710 and CJ-047713 formation in HLM were almost equivalent with those for CYP3A4 and CYP3A5. For the CYP3A enzymes, maximal clearance due to auto-activation values for CJ-047710 and CJ-047713 formation catalysed by CYP3A5 were 3.6- and 3.1-fold higher than those catalysed by CYP3A4. This is the first report that shows both CYP3A4 and CYP3A5 simultaneously contribute to dimerization through oxidative C-C and C-O coupling reactions.

  15. The DHEA-sulfate depot following P450c17 inhibition supports the case for AKR1C3 inhibition in high risk localized and advanced castration resistant prostate cancer.

    PubMed

    Tamae, Daniel; Mostaghel, Elahe; Montgomery, Bruce; Nelson, Peter S; Balk, Steven P; Kantoff, Philip W; Taplin, Mary-Ellen; Penning, Trevor M

    2015-06-05

    Prostate cancer is the second leading cause of cancer death in the United States. Treatment of localized high-risk disease and de novo metastatic disease frequently leads to relapse. These metastatic castration resistant prostate cancers (mCRPC) claim a high mortality rate, despite the extended survival afforded by the growing armamentarium of androgen deprivation, radiation and immunotherapies. Here, we review two studies of neoadjuvant treatment of high-risk localized prostate cancer prior to prostatectomy, the total androgen pathway suppression (TAPS) trial and the neoadjuvant abiraterone acetate (AA) trial. These two trials assessed the efficacy of the non-specific P450c17 inhibitor, ketoconazole and the specific P450c17 inhibitor, AA, to inhibit tissue and serum androgen levels. Furthermore, a novel and validated stable isotope dilution liquid chromatography electrospray ionization selected reaction monitoring mass spectrometry assay was used to accurately quantify adrenal and gonadal androgens in circulation during the course of these trials. The adrenal androgens, Δ(4)-androstene-3,17-dione, dehydroepiandrosterone and dehydroepiandrosterone sulfate were significantly reduced in the patients receiving ketoconazole or AA compared to those who did not. However, in both trials, a significant amount of DHEA-S (∼20 μg/dL) persists and thus may serve as a depot for intratumoral conversion to the potent androgen receptor ligands, testosterone (T) and 5α-dihydrotestosterone (DHT). The final step in conversion of Δ(4)-androstene-3,17-dione and 5α-androstanedione to T and DHT, respectively, is catalyzed by AKR1C3. We therefore present the case that in the context of the DHEA-S depot, P450c17 and AKR1C3 inhibition may be an effective combinatorial treatment strategy. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  16. Detection of dermatophytes in healthy companion dogs and cats in eastern India.

    PubMed

    Debnath, C; Mitra, T; Kumar, A; Samanta, I

    2016-01-01

    In recent times increasing occurrence of dermatophytosis, especially among the school children in eastern India was evidenced along with increased tendency of keeping companion animals such as dogs and cats. This study was undertaken to detect the occurrence of dermatophytes with antifungal susceptibility among the companion animals. A total of 1501 healthy companion animals comprising 1209 dogs and 292 cats belonged to individual owners in and around Kolkata (West Bengal, India) were examined for the evidence of dermatophytosis during 2011-2013. The collected samples were subjected to direct examination by standard KOH mount technique. The samples were inoculated into both Sabouraud dextrose agar (SDA) with 0.05% chloramphenicol and 0.5% cycloheximide and dermatophyte test medium (DTM). Each of the fungal isolate was identified based upon its colony characteristics and hyphal and conidial cells it produced. Antifungal susceptibility of the isolates was tested by broth micro dilution assay using fluconazole, ketoconazole, itraconazole, miconazole, griseofulvin and amphotericin-B antifungals. Among the 1209 samples from dogs and 292 samples from cats, 253 (20.93%) and 109 (37.33%) samples were positive for dermatophytes by direct examination. Three identified species of dermatophytes with predominant occurrence were Microsporum canis, Microsporum gypseum and Trichophyton mentagrophytes. Ketoconazole (0.06-0.5 µgm/ml), itraconazole (0.03-0.5 µgm/ml) and amphotericin-B (0.03-0.5 µgm/ml) showed lowest MIC values against M. canis, T. mentagrophytes and M. gypseum, respectively. This is the first systemic report of dermatophytes in healthy companion animals with large numbers of samples in India.

  17. Influence of P-glycoprotein modulation on plasma concentrations and pharmacokinetics of orally administered prednisolone in dogs.

    PubMed

    Van der Heyden, Sara; Croubels, Siska; Gadeyne, Caroline; Ducatelle, Richard; Daminet, Sylvie; Murua Escobar, Hugo; Sterenczak, Katharina; Polis, Ingeborgh; Schauvliege, Stijn; Hesta, Myriam; Chiers, Koen

    2012-06-01

    To evaluate the impact of modulation of the membrane-bound efflux pump P-glycoprotein (P-gp) on plasma concentrations of orally administered prednisolone in dogs. 7 healthy adult Beagles. Each dog received 3 treatments (control [no treatment], rifampicin [100 mg/d, PO, for 21 days, as an inducer of P-gp], and ketoconazole [100 mg/d, PO, for 21 days, as an inhibitor of P-gp]). A single dose of prednisolone (1 mg/kg, PO) was administered on day 8 of each treatment period. There was a 7-day washout period between subsequent treatments. Plasma concentrations of prednisolone were determined by use of a validated liquid chromatography-tandem mass spectrometry method. Duodenum and colon biopsy specimens were obtained endoscopically from anesthetized dogs and assessed for P-gp protein labeling via immunohistochemical analysis and mRNA quantification via real-time PCR assay. Total fecal collection was performed for evaluation of effects of P-gp modulation on digestion of nutrients. Rifampicin treatment upregulated duodenal P-gp in dogs and significantly reduced the area under the plasma concentration-time curve of prednisolone. Ketoconazole typically downregulated expression of duodenal P-gp, with a subsequent increase in the area under the plasma concentration-time curve of prednisolone. There was a noticeable interindividual difference in response. Digestion of nutrients was not affected. Modulation of P-gp expression influenced plasma concentrations of prednisolone after oral administration in dogs. Thus, treatment response to prednisolone may be influenced by coadministration of P-gp-modulating medications or feed ingredients.

  18. Cutaneous reactive histiocytosis in dogs: a retrospective evaluation of 32 cases.

    PubMed

    Palmeiro, Brian S; Morris, Daniel O; Goldschmidt, Michael H; Mauldin, Elizabeth A

    2007-10-01

    Thirty-two cases of canine cutaneous histiocytosis were retrospectively evaluated. Median age at onset was 4 years. Lesions included nodules and plaques affecting the head/face, trunk and limbs, and erythema, swelling and depigmentation of the nasal planum/nares. Systemic involvement was not ruled out in all cases. All dogs had complete resolution of dermatological lesions after initial treatment (median 45 days). Initial treatment included prednisone +/- antibiotics (12 of 32 dogs), prednisone and tetracycline/niacinamide (four of 32), prednisone and azathioprine (three of 32), tetracycline/niacinamide +/- vitamin E/essential fatty acids (six of 32), antibiotics +/- antihistamines (three of 32), cyclosporine and ketoconazole (one of 32), topical therapy (two of 32), and no treatment (one of 32). Seventeen dogs received maintenance therapy which consisted of tetracycline/niacinamide +/- vitamin E/essential fatty acids (12 of 17), cyclosporine/ketoconazole (two to three times a week) (two of 17), azathioprine daily (one of 17), prednisone/azathioprine (two times a week) (one of 17), and prednisone daily (one of 17). Median follow up was 25 months. Nine dogs had a recurrence of cutaneous histiocytosis (median days to recurrence 130 days), with seven of nine having more than one recurrence. At study completion, six dogs were deceased (no lesions at the time of death) and 26 of 32 were alive with no lesions. Ten of 26 dogs were on maintenance treatment (eight tetracycline/niacinamide, one azathioprine, one vitamin E). Previous dermatological disease and season had no detectable influence on recurrence. Recurrence was significantly more likely in dogs with nasal planum/nares lesions than dogs without these lesions. Tetracycline/niacinamide was an effective treatment option for dogs in this study population.

  19. Frequency of urinary tract infection in dogs with inflammatory skin disorders treated with ciclosporin alone or in combination with glucocorticoid therapy: a retrospective study.

    PubMed

    Peterson, Andrea L; Torres, Sheila M F; Rendahl, Aaron; Koch, Sandra N

    2012-06-01

    Few studies have investigated the frequency of urinary tract infection (UTI) in dogs receiving long-term ciclosporin therapy. The goal of the study was to investigate the frequency of UTI in dogs receiving ciclosporin with or without glucocorticoids. A secondary goal was to determine whether bacteriuria, pyuria and urine specific gravity were good predictors of UTI, and if ciclosporin dose, concurrent ketoconazole therapy, sex or duration of therapy affected the frequency of UTI. Animals -  Eighty-seven dogs with various inflammatory skin disorders and 59 control dogs with inflammatory skin conditions that had not received glucocorticoids or ciclosporin for 6 months were enrolled. This study was retrospective. The first urine culture from dogs receiving ciclosporin was compared with control dogs using Fisher's exact test. A logistic mixed model was used to test for association between a positive bacterial culture and duration of treatment, dose of ciclosporin, concurrent ketoconazole therapy and sex. The sensitivities and specificities for bacteriuria, pyuria and urine specific gravity were determined. Twenty-six of 87 (30%) ciclosporin-treated dogs had at least one positive culture. Compared with 3% positive control samples, 15% were positive in treated dogs (P=0.027). The sensitivity and specificity were, respectively, 64.1 and 98.1% for bacteriuria, 74.4 and 70.9% for pyuria, and 56.4 and 65.3% for urine specific gravity. All other analysed parameters were not significantly different. The results suggest that routine urine cultures and assessment of bacteriuria by cystocentesis should be part of the monitoring for dogs on long-term ciclosporin with and without glucocorticoids. © 2012 The Authors. Veterinary Dermatology. © 2012 ESVD and ACVD.

  20. Physiologically Based Pharmacokinetic Model of All-trans-Retinoic Acid with Application to Cancer Populations and Drug Interactions

    PubMed Central

    Jing, Jing; Nelson, Cara; Paik, Jisun; Shirasaka, Yoshiyuki; Amory, John K.

    2017-01-01

    All-trans retinoic acid (atRA) is a front-line treatment of acute promyelocytic leukemia (APL). Due to its activity in regulating the cell cycle, it has also been evaluated for the treatment of other cancers. However, the efficacy of atRA has been limited by atRA inducing its own metabolism during therapy, resulting in a decrease of atRA exposure during continuous dosing. Frequent relapse occurs in patients receiving atRA monotherapy. In an attempt to combat therapy resistance, inhibitors of atRA metabolism have been developed. Of these, ketoconazole and liarozole have shown some benefits, but their usage is limited by side effects and low potency toward the cytochrome P450 26A1 isoform (CYP26A1), the main atRA hydroxylase. We determined the pharmacokinetic basis of therapy resistance to atRA and tested whether the complex disposition kinetics of atRA could be predicted in healthy subjects and in cancer patients in the presence and absence of inhibitors of atRA metabolism using physiologically based pharmacokinetic (PBPK) modeling. A PBPK model of atRA disposition was developed and verified in healthy individuals and in cancer patients. The population-based PBPK model of atRA disposition incorporated saturable metabolic clearance of atRA, induction of CYP26A1 by atRA, and the absorption and distribution kinetics of atRA. It accurately predicted the changes in atRA exposure after continuous dosing and when coadministered with ketoconazole and liarozole. The developed model will be useful in interpretation of atRA disposition and efficacy, design of novel dosing strategies, and development of next-generation atRA metabolism inhibitors. PMID:28275201

  1. Oral treatments for fungal infections of the skin of the foot.

    PubMed

    Bell-Syer, S E; Hart, R; Crawford, F; Torgerson, D J; Tyrrell, W; Russell, I

    2002-01-01

    About 15% of the population have fungal infections of the feet (tinea pedis or athlete's foot). Whilst there are many clinical presentations of tinea pedis the most common are between the toes (interdigital) and on the soles, heels and sides of the foot (plantar) which is known as moccasin foot. Once acquired the infection can spread to other sites including the nails, which can be a source of reinfection. Oral therapy is usually used for chronic conditions or when topical treatment has failed. To assess the effects and costs of oral treatments for fungal infections of the skin of the foot (tinea pedis). Randomised controlled trials were identified from MEDLINE, EMBASE and CINAHL from the beginning of these databases to January 2000. We also searched the Cochrane Controlled trials Register (Cochrane Library issue 1, 2000) the Science Citation Index, BIOSIS, CAB-Health, Health star and Economic databases. Bibliographies were searched, podiatry journals hand searched and the pharmaceutical industry and schools of podiatry contacted. Randomised controlled trials including participants who have a clinically diagnosed tinea pedis, confirmed by microscopy and growth of dermatophytes in culture. Study selection was done by two independent reviewers. Methodological quality assessment and data collection was also assessed by two independent reviewers. Twelve trials, involving 700 participants, were included. The two trials comparing terbinafine and griseofulvin produced a pooled risk difference of 52% (95% confidence intervals 33% to 71%) in favour of terbinafine's ability to cure infection. No significant difference was detected between terbinafine and itraconazole; fluconazole and either itraconazole and ketoconazole; or between griseofulvin and ketoconazole, although the trials were generally small. Two trials showed that terbinafine and itraconazole were effective compared with placebo. Adverse effects were reported for all drugs, with gastrointestinal effects most

  2. Synergistic activity of lysozyme and antifungal agents against Candida albicans biofilms on denture acrylic surfaces.

    PubMed

    Samaranayake, Y H; Cheung, B P K; Parahitiyawa, N; Seneviratne, C J; Yau, J Y Y; Yeung, K W S; Samaranayake, L P

    2009-02-01

    Denture related oral candidiasis is a recalcitrant fungal infection not easily resolved by topical antifungals. The antimycotic protein lysozyme, in saliva is an important host defense mechanism although its activity against Candida biofilms on denture acrylic has not been evaluated. (i) To establish a clinically relevant denture acrylic assay model to develop standardized Candida albicans biofilms, and (ii) assess the inhibitory effects of lysozyme alone and, the latter combined with antifungals (nystatin, amphotericin B, ketoconazole and 5-fluorocytosine) on sessile Candida cells and, finally (iii) to visualize the accompanying ultrastructural changes. The rotating-disc biofilm reactor was used to develop standardized 48 h Candida biofilms on acrylic discs in YNB/100 mM glucose medium and the biofilm metabolic activity was monitored using a tetrazolium reduction assay. The biofilm metabolic activity was similar in 18 identical denture acrylic discs (p<0.05) thus validating the rotating-disc biofilm model. Very low concentrations of lysozyme (6.25 microg/ml) significantly (p<0.01) inhibited Candida biofilm formation indicating that lysozyme may likely regulate intra-oral Candida biofilm development. Although 100 microg/ml lysozyme killed 45% of sessile Candida cells, further increasing its concentration (up to 240 microg/ml) had no such effect. Nystatin, amphotericin B, and ketoconazole in association with 100 microg/ml lysozyme exhibited effective synergistic killing of biofilm Candida in comparison to drug-free controls. Scanning electron and confocal scanning laser microscopy analysis confirmed the latter trends. Our results indicate that agents found in biological fluids such as lysozyme could be a safe adjunct to antifungals in future treatment strategies for recalcitrant candidal infections.

  3. Species distribution and antifungal susceptibility of Candida spp. isolated from superficial candidiasis in outpatients in Iran.

    PubMed

    Razzaghi-Abyaneh, M; Sadeghi, G; Zeinali, E; Alirezaee, M; Shams-Ghahfarokhi, M; Amani, A; Mirahmadi, R; Tolouei, R

    2014-06-01

    Candidiasis is the most prevalent fungal infection affecting human and animals all over the world. This study represents the epidemiological aspects of superficial candidiasis in outpatients and in vitro antifungal susceptibility of etiologic Candida species. Clinical samples were taken from 173 patients including skin and nail scrapings (107; 61.8%), vaginal discharge (28; 16.2%), sputum (20; 11.6%), oral swabs (7; 4.0%), bronchoalveolar lavage (6; 3.5%) and 1 specimen (0.6%) of each eye tumor, gastric juice, urine, biopsy and urinary catheter and confirmed as candidiasis by direct microscopy, culture and histopathology. Susceptibility patterns of the isolated Candida species were determined using the disk diffusion and broth microdilution methods. Among 173 Candida isolates, C. albicans (72.3%) was the most prevalent species followed by C. parapsilosis (11.5%). Other identified species were C. glabrata, C. krusei, C. tropicalis, C. guilliermondii, C. intermedia and C. sake. Majority of the Candida isolates were susceptible to fluconazole (95.4%) followed by 5-flucytosine (89.6%), voriconazole (78.6%) itraconazole (48.0%) and ketoconazole (42.8%). Caspofungin was the most potent antifungal drug against C. albicans (MICs; 0.062-1 μg/mL), ketoconazole for C. parapsilosis and C. tropicalis (MICs; 0.031-0.25 μg/mL) and itraconazole for C. krusei, C. glabrata and C. guilliermondii (MICs; 0.031-1 μg/mL). This study reinforces the significance of superficial candidiasis as an important fungal infection with multiple clinical presentations. Our results further indicate that susceptibility testing to commonly used antifungals is crucial in order to select the appropriate therapeutic strategies which minimize complications while improving patients' life. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

  4. Antimycotics suppress the Malassezia extract-induced production of CXC chemokine ligand 10 in human keratinocytes.

    PubMed

    Hau, Carren S; Kanda, Naoko; Makimura, Koichi; Watanabe, Shinichi

    2014-02-01

    Malassezia, a lipophilic yeast, exacerbates atopic dermatitis. Malassezia products can penetrate the disintegrated stratum corneum and encounter subcorneal keratinocytes in the skin of atopic dermatitis patients. Type 1 helper T (Th1) cells infiltrate chronic lesions with atopic dermatitis, and antimycotic agents improve its symptoms. We aimed to identify Malassezia-induced chemokines in keratinocytes and examine whether antimycotics suppressed this induction. Normal human keratinocytes were incubated with a Malassezia restricta extract and antimycotics. Chemokine expression was analyzed by enzyme-linked immunosorbent assays and real-time polymerase chain reaction. Signal transducer and activator of transcription (STAT)1 activity was examined by luciferase assays. The tyrosine-phosphorylation of STAT1 was analyzed by western blotting. The M. restricta extract increased the mRNA and protein expression of Th1-attracting CXC chemokine ligand (CXCL)10 and STAT1 activity and phosphorylation in keratinocytes, which was suppressed by a Janus kinase inhibitor. The antimycotics itraconazole, ketoconazole, luliconazole, terbinafine, butenafine and amorolfine suppressed M. restricta extract-induced CXCL10 mRNA and protein expression and STAT1 activity and phosphorylation. These effects were similarly induced by 15-deoxy-Δ-(12,14) -prostaglandin J2 (15d-PGJ2 ), a prostaglandin D2 metabolite. Antimycotics increased the release of 15d-PGJ2 from keratinocytes. The antimycotic-induced suppression of CXCL10 production and STAT1 activity was counteracted by a lipocalin-type prostaglandin D synthase inhibitor. The antimycotics itraconazole, ketoconazole, luliconazole, terbinafine, butenafine and amorolfine may suppress the M. restricta-induced production of CXCL10 by inhibiting STAT1 through an increase in 15d-PGJ2 production in keratinocytes. These antimycotics may block the Th1-mediated inflammation triggered by Malassezia in the chronic phase of atopic dermatitis. © 2014

  5. Phase I metabolism of 3-methylindole, an environmental pollutant, by hepatic microsomes from carp (Cyprinus carpio) and rainbow trout (Oncorhynchus mykiss).

    PubMed

    Zlabek, Vladimir; Burkina, Viktoriia; Borrisser-Pairó, Francesc; Sakalli, Sidika; Zamaratskaia, Galia

    2016-05-01

    We studied the in vitro metabolism of 3-methylindole (3MI) in hepatic microsomes from fish. Hepatic microsomes from juvenile and adult carp (Cyprinus carpio) and rainbow trout (Oncorhynchus mykiss) were included in the study. Incubation of 3MI with hepatic microsomes revealed the time-dependent formation of two major metabolites, 3-methyloxindole (3MOI) and indole-3-carbinol (I3C). The rate of 3MOI production was similar in both species at both ages. No differences in kinetic parameters were observed (p = 0.799 for Vmax, and p = 0.809 for Km). Production of I3C was detected only in the microsomes from rainbow trout. Km values were similar in juvenile and adult fish (p = 0.957); Vmax was higher in juvenile rainbow trout compared with adults (p = 0.044). In rainbow trout and carp, ellipticine reduced formation of 3MOI up to 53.2% and 81.9% and ketoconazole up to 65.8% and 91.3%, respectively. The formation of I3C was reduced by 53.7% and 51.5% in the presence of the inhibitors ellipticine and ketoconazole, respectively. These findings suggest that the CYP450 isoforms CYP1A and CYP3A are at least partly responsible for 3MI metabolism. In summary, 3MI is metabolised in fish liver to 3MOI and I3C by CYP450, and formation of these metabolites might be species-dependent. Copyright © 2016 Elsevier Ltd. All rights reserved.

  6. Sporotrichosis: The Story of an Endemic Region in Peru over 28 Years (1985 to 2012)

    PubMed Central

    Ramírez Soto, Max Carlos

    2015-01-01

    Background Abancay province is a long-standing geographical focus of sporotrichosis in the south central highlands of Peru. Therefore, we examined the features of 36 newly identified cases of sporotrichosis from two hospital centers in Abancay province. We also performed a literature review of studies conducted in this endemic geographical focus over a period of 28 years (1998 to 2012), and analyzed the demographic, clinical and epidemiological features of sporotrichosis in the cases reported in these studies. Methodology We examined the features of 36 new cases of sporotrichosis identified from two hospital centers in Abancay. Furthermore, we searched for relevant studies of cases of sporotrichosis in the endemic region using healthcare databases and literature sources. We analyzed a detailed subset of data on cases collected in Abancay, neighboring provinces, and other regions of Peru. Results A total of nine studies were identified, with 1467 cases included in the final analysis. We also analyzed 36 new cases found in the two hospital centers. Therefore, the combined total of cases analyzed was 1503. Of this total, 58% were male, and approximately 62% were aged ≤14 years. As expected, most cases were from Abancay province (88%), although 12% were from neighboring provinces and other regions of Peru. The lymphocutaneous form (939 cases) was the commonest. The face was the most commonly affected region (647 cases). A total of 1224 patients (81.4%) received treatment: 95.8% received potassium iodide, 2.6% ketoconazole and 1.6% itraconazole. The overall success rates were 60.7% with potassium iodide, 32.2% with ketoconazole and 85% with itraconazole. Conclusions The epidemic of sporotrichosis has been occurring for three decades in the province of Abancay in Peru. This mycosis affects primarily the pediatric population, with predominantly the lymphocutaneous form in the facial region. Although treatment with potassium iodide is safe and effective, response and

  7. LONG-TERM OUTCOME OF THE DIFFERENT TREATMENT ALTERNATIVES FOR RECURRENT AND PERSISTENT CUSHING DISEASE.

    PubMed

    Espinosa-de-Los-Monteros, Ana Laura; Sosa-Eroza, Ernesto; Espinosa, Etual; Mendoza, Victoria; Arreola, Rocio; Mercado, Moises

    2017-07-01

    Treatment alternatives for persistent and recurrent Cushing disease (CD) include pituitary surgical re-intervention, radiation therapy (RT), pharmacotherapy, and bilateral adrenalectomy (BA). The decision of which of these alternatives is better suited for the individual patient rests on clinical judgment and the availability of resources. This retrospective cohort study was performed at a referral center to evaluate the long-term efficacy of different secondary interventions for persistent and recurrent CD. We evaluated the hospital charts of 84 patients (77 female, median age 34 years, median follow up 6.3 years) with CD diagnosed, treated, and followed at our multidisciplinary clinic according to a pre-established protocol. Of the 81 patients who were initially treated with transsphenoidal surgery (TSS), 61.7% had a long-lasting remission, 16% had persistent disease, and 22% achieved remission but relapsed during follow-up. The most frequently used secondary treatment was pituitary re-intervention, followed by ketoconazole, RT, and BA. Early remissions were observed in 66.6% of the re-operated and in 58.3% of the radiated patients; long-lasting remission was achieved in 33.3% and 41.6% of these patients, respectively. Nelson syndrome developed in 41.6% of the patients who underwent BA. Upon last follow-up, 88% of all the patients are in remission, and 9.5% are biochemically controlled with ketoconazole. The efficacy of treatment alternatives for recurrent or persistent CD varies considerably among patients and multiple interventions are often required to achieve long-lasting remission. ACTH = adrenocorticotrophic hormone; BA = bilateral adrenalectomy; CBG = cabergoline; CD = Cushing disease; CV = coefficient of variation; DXM = dexamethasone; IQR = interquartile range; RT = radiation therapy; SRS = stereotactic radiosurgery; TSS = transsphenoidal surgery; UFC = urinary free cortisol; ULN = upper limit of normal.

  8. Current cytochrome P450 phenotyping methods applied to metabolic drug-drug interaction prediction in dogs.

    PubMed

    Mills, Beth Miskimins; Zaya, Matthew J; Walters, Rodney R; Feenstra, Kenneth L; White, Julie A; Gagne, Jason; Locuson, Charles W

    2010-03-01

    Recombinant cytochrome P450 (P450) phenotyping, different approaches for estimating fraction metabolized (f(m)), and multiple measures of in vivo inhibitor exposure were tested for their ability to predict drug interaction magnitude in dogs. In previous reports, midazolam-ketoconazole interaction studies in dogs have been attributed to inhibition of CYP3A pathways. However, in vitro phenotyping studies demonstrated higher apparent intrinsic clearances (CL(int,app)) of midazolam with canine CYP2B11 and CYP2C21. Application of activity correction factors and isoform hepatic abundance to liver microsome CL(int,app) values further implicated CYP2B11 (f(m) >or= 0.89) as the dog enzyme responsible for midazolam- and temazepam-ketoconazole interactions in vivo. Mean area under the curve (AUC) in the presence of the inhibitor/AUC ratios from intravenous and oral midazolam interaction studies were predicted well with unbound K(i) and estimates of unbound hepatic inlet inhibitor concentrations and intestinal metabolism using the AUC-competitive inhibitor relationship. No interactions were observed in vivo with bufuralol, although significant interactions with bufuralol were predicted with fluoxetine via CYP2D and CYP2C pathways (>2.45-fold) but not with clomipramine (<2-fold). The minor caffeine-fluvoxamine interaction (1.78-fold) was slightly higher than predicted values based on determination of a moderate f(m) value for CYP1A1, although CYP1A2 may also be involved in caffeine metabolism. The findings suggest promise for in vitro approaches to drug interaction assessment in dogs, but they also highlight the need to identify improved substrate and inhibitor probes for canine P450s.

  9. In vitro susceptibility of filamentous fungi from mycotic keratitis to azole drugs.

    PubMed

    Shobana, C S; Mythili, A; Homa, M; Galgóczy, L; Priya, R; Babu Singh, Y R; Panneerselvam, K; Vágvölgyi, C; Kredics, L; Narendran, V; Manikandan, P

    2015-03-01

    The in vitro antifungal activities of azole drugs viz., itraconazole, voriconazole, ketoconazole, econazole and clotrimazole were investigated in order to evaluate their efficacy against filamentous fungi isolated from mycotic keratitis. The specimen collection was carried out from fungal keratitis patients attending Aravind eye hospital and Post-graduate institute of ophthalmology, Coimbatore, India and was subsequently processed for the isolation of fungi. The dilutions of antifungal drugs were prepared in RPMI 1640 medium. Minimum inhibitory concentrations (MICs) were determined and MIC50 and MIC90 were calculated for each drug tested. A total of 60 fungal isolates were identified as Fusarium spp. (n=30), non-sporulating moulds (n=9), Aspergillus flavus (n=6), Bipolaris spp. (n=6), Exserohilum spp. (n=4), Curvularia spp. (n=3), Alternaria spp. (n=1) and Exophiala spp. (n=1). The MICs of ketoconazole, clotrimazole, voriconazole, econazole and itraconazole for all the fungal isolates ranged between 16 μg/mL and 0.03 μg/mL, 4 μg/mL and 0.015 μg/mL, 8 μg/mL and 0.015 μg/mL, 8 μg/mL and 0.015 μg/mL and 32 μg/mL and 0.06 μg/mL respectively. From the MIC50 and MIC90 values, it could be deciphered that in the present study, clotrimazole was more active against the test isolates at lower concentrations (0.12-5 μg/mL) when compared to other drugs tested. The results suggest that amongst the tested azole drugs, clotrimazole followed by voriconazole and econazole had lower MICs against moulds isolated from mycotic keratitis. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

  10. [Fungi isolated from the vagina and their susceptibility to antifungals].

    PubMed

    Macura, Anna B; Skóra, Magdalena

    2012-06-01

    Because of the presence of various fungi and changes in their spectrum in the mycosis of vagina it is necessary to perform periodic overviews including testing their susceptibility to antifungal agents. The objective of the study was to evaluate susceptibility of the fungi isolated from vaginas to antifungal drugs and to analyse the fungi responsible for vaginal mycosis in patients referred during a 7-year study The study was carried out in a group of patients suspected of vaginal mycosis between January 1, 2005 and December 31, 2011. An analysis of the fungi isolated from their vaginas was performed. The susceptibility of the fungi to six antifungals (5-fluorocytosine, amphotericin B, miconazole, ketoconazole, itraconazole and fluconazole) was evaluated using a semiquantitative Fungitest. A total of 4775 mycological test results were evaluated. Fungi were present in 30.6% of the material. C. albicans was the most frequently isolated fungal species (80.2%), followed by C. glabrata (5.8%), and S. cerevisiae (5.5%). Itraconazole turned out to be the least effective drug. C. krusei. was the species most resistant to antifungals, including fluconazole. 1. C. albicans is the species most frequently isolated from a vagina. It is highly susceptible to azoles, the antimycotics generally used in the treatment of vaginal mycosis. 2. Out of the azoles under study ketoconazole was the most active against fungi in vitro while itraconazole was the least active. 3. The Candida non-albicans species, and particularly C. krusei, are less susceptible to antimycotics. 4. Amphotericin B and 5-fluorocytosine are most effective against Candida strains and S. cerevisiae, however they are not used in the treatment of vaginal mycosis because of their high toxicity

  11. Multicenter, International Study of MIC/MEC Distributions for Definition of Epidemiological Cutoff Values for Sporothrix Species Identified by Molecular Methods

    PubMed Central

    Abreu, D. P. B.; Almeida-Paes, R.; Brilhante, R. S. N.; Chakrabarti, A.; Córdoba, S.; Gonzalez, G. M.; Guarro, J.; Johnson, E. M.; Kidd, S. E.; Pereira, S. A.; Rozental, S.; Szeszs, M. W.; Ballesté Alaniz, R.; Bonifaz, A.; Bonfietti, L. X.; Borba-Santos, L. P.; Capilla, J.; Colombo, A. L.; Dolande, M.; Isla, M. G.; Melhem, M. S. C.; Mesa-Arango, A. C.; Oliveira, M. M. E.; Panizo, M. M.; Pires de Camargo, Z.; Zancope-Oliveira, R. M.; Turnidge, J.

    2017-01-01

    ABSTRACT Clinical and Laboratory Standards Institute (CLSI) conditions for testing the susceptibilities of pathogenic Sporothrix species to antifungal agents are based on a collaborative study that evaluated five clinically relevant isolates of Sporothrix schenckii sensu lato and some antifungal agents. With the advent of molecular identification, there are two basic needs: to confirm the suitability of these testing conditions for all agents and Sporothrix species and to establish species-specific epidemiologic cutoff values (ECVs) or breakpoints (BPs) for the species. We collected available CLSI MICs/minimal effective concentrations (MECs) of amphotericin B, five triazoles, terbinafine, flucytosine, and caspofungin for 301 Sporothrix schenckii sensu stricto, 486 S. brasiliensis, 75 S. globosa, and 13 S. mexicana molecularly identified isolates. Data were obtained in 17 independent laboratories (Australia, Europe, India, South Africa, and South and North America) using conidial inoculum suspensions and 48 to 72 h of incubation at 35°C. Sufficient and suitable data (modal MICs within 2-fold concentrations) allowed the proposal of the following ECVs for S. schenckii and S. brasiliensis, respectively: amphotericin B, 4 and 4 μg/ml; itraconazole, 2 and 2 μg/ml; posaconazole, 2 and 2 μg/ml; and voriconazole, 64 and 32 μg/ml. Ketoconazole and terbinafine ECVs for S. brasiliensis were 2 and 0.12 μg/ml, respectively. Insufficient or unsuitable data precluded the calculation of ketoconazole and terbinafine (or any other antifungal agent) ECVs for S. schenckii, as well as ECVs for S. globosa and S. mexicana. These ECVs could aid the clinician in identifying potentially resistant isolates (non-wild type) less likely to respond to therapy. PMID:28739796

  12. In vitro susceptibility of antifungal drugs against Sporothrix brasiliensis recovered from cats with sporotrichosis in Brazil.

    PubMed

    Brilhante, Raimunda Sâmia Nogueira; Rodrigues, Anderson Messias; Sidrim, José Júlio Costa; Rocha, Marcos Fábio Gadelha; Pereira, Sandro Antonio; Gremião, Isabella Dib Ferreira; Schubach, Tânia Maria Pacheco; de Camargo, Zoilo Pires

    2016-03-01

    Sporotrichosis is an important subcutaneous mycosis of humans and animals. Classically, the disease is acquired upon traumatic inoculation of Sporothrix propagules from contaminated soil and plant debris. In addition, the direct horizontal transmission of Sporothrix among animals and the resulting zoonotic infection in humans highlight an alternative and efficient rout of transmission through biting and scratching. Sporothrix brasiliensis is the most virulent species of the Sporothrix schenckii complex and is responsible for the long-lasting outbreak of feline sporotrichosis in Brazil. However, antifungal susceptibility data of animal-borne isolates is scarce. Therefore, this study evaluated the in vitro activity of amphotericin B, caspofungin, itraconazole, voriconazole, fluconazole, and ketoconazole against animal-borne isolates of S. brasiliensis. The susceptibility tests were performed through broth microdilution (M38-A2). The results show the relevant activity of itraconazole, amphotericin B, and ketoconazole against S. brasiliensis, with the following MIC ranges: 0.125-2, 0.125-4 and 0.0312-2 μg/ml, respectively. Caspofungin was moderately effective, displaying higher variation in MIC values (0.25-64 μg/ml). Voriconazole (2-64 μg/ml) and fluconazole (62.5-500 μg/ml) showed low activity against S. brasiliensis strains. This study contributed to the characterization of the in vitro antifungal susceptibility of strains of S. brasiliensis recovered from cats with sporotrichosis, which have recently been considered the main source of human infections. © The Author 2015. Published by Oxford University Press on behalf of The International Society for Human and Animal Mycology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  13. Development of a phosphorylated Momordica charantia protein system for inhibiting susceptible dose-dependent C. albicans to available antimycotics: An allosteric regulation of protein.

    PubMed

    Qiao, Yuanbiao; Song, Li; Zhu, Chenchen; Wang, Qian; Guo, Tianyan; Yan, Yanhua; Li, Qingshan

    2017-11-15

    A regulatory Momordica charantia protein system was constructed allosterically by in vitro protein phosphorylation, in an attempt to evaluate antimycological pluripotency against dose-dependent susceptibilities in C. albicans. Fungal strain lineages susceptible to ketoconazole, econazole, miconazole, 5-flucytosine, nystatin and amphotericin B were prepared in laboratory, followed by identification via antifungal susceptibility testing. Protein phosphorylation was carried out in reactions with 5'-adenylic, guanidylic, cytidylic and uridylic acids and cyclic adenosine triphosphate, through catalysis of cyclin-dependent kinase 1, protein kinase A and protein kinase C respectively. Biochemical analysis of enzymatic reactions indicated the apparent Michaelis-Menten constants and maximal velocity values of 16.57-91.97mM and 55.56-208.33μM·min -1 , together with an approximate 1:1 reactant stoichiometric ratio. Three major protein phosphorylation sites were theoretically predicted at Thr255, Thr102 and Thr24 by a KinasePhos tool. Additionally, circular dichroism spectroscopy demonstrated that upon phosphorylation, protein folding structures were decreased in random coil, β6-sheet and α1-helix partial regions. McFarland equivalence standard testing yielded the concentration-dependent inhibition patterns, while fungus was grown in Sabouraud's dextrose agar. The minimal inhibitory concentrations of 0.16-0.51μM (at 50% response) were obtained for free protein and phosphorylated counterparts. With respect to the 3-cycling susceptibility testing regimen, individuals of total protein forms were administrated in-turn at 0.14μM/cycle. Relative inhibition ratios were retained to 66.13-81.04% of initial ones regarding the ketoconazole-susceptible C. albicans growth. An inhibitory protein system, with an advantage of decreasing antifungal susceptibilities to diverse antimycotics, was proposed because of regulatory pluripotency whereas little contribution to susceptibility in

  14. Chloramphenicol significantly affects the pharmacokinetics of oral methadone in Greyhound dogs.

    PubMed

    KuKanich, Butch; KuKanich, Kate

    2015-11-01

    To assess the effects of cytochrome P450 (CYP) inhibitors (ketoconazole, chloramphenicol, trimethoprim, fluoxetine, cimetidine and medetomidine) in various combinations on the pharmacokinetics of oral methadone in Greyhound dogs to determine the specific effects of the different inhibitors and if a clinically relevant interaction occurs. Non-randomized, sequential design. Six healthy Greyhound dogs (three male, three female). Canine CYP inhibitors (ketoconazole, chloramphenicol, trimethoprim, fluoxetine, cimetidine and medetomidine) were administered in varying combinations prior to the administration of oral methadone. Plasma was obtained from each dog to enable the determination of methadone and CYP inhibitor drug concentrations using liquid chromatography with either mass spectrometry or ultraviolet detection. Significant increases in the area under the curve (AUC) and maximum plasma concentrations (CMAX ) of methadone occurred in all groups administered chloramphenicol. The AUC (6 hours ng mL(-1)) and CMAX (6 ng mL(-1)) of methadone significantly increased to 541 hours ng mL(-1) and 47.8 ng mL(-1), respectively, when methadone was administered with chloramphenicol as a sole inhibitor. There were no significant effects of CYP inhibitors other than chloramphenicol on methadone pharmacokinetics, which suggests that chloramphenicol was primarily responsible for the pharmacokinetic interaction. This study demonstrated significant effects of chloramphenicol on the pharmacokinetics of oral methadone. Further studies should investigate the effects of chloramphenicol on methadone pharmacokinetics in multiple dog breeds and examine whether oral methadone would be an effective analgesic in dogs. In addition, the safety of chloramphenicol and its effects on the pharmacokinetics of parenteral methadone warrant assessment. © 2015 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia.

  15. Evaluation of Candida species and antifungal susceptibilities among children with invasive candidiasis

    PubMed Central

    Sütçü, Murat; Acar, Manolya; Genç, Gonca Erköse; Kökçü, İlknur; Aktürk, Hacer; Atay, Gürkan; Törun, Selda Hançerli; Salman, Nuran; Erturan, Zayre; Somer, Ayper

    2017-01-01

    Aim Non-albicans Candida species and resistant microorganisms have been more commonly isolated in invasive candidiasis in recent years. The aim of this study was to evaluate the distrubution of Candida spp and antifungal resistance in our clinic. Material and Methods Fifty-four Candida isolates and antifungal susceptibility results obtained from patients diagnosed as having invasive candidiasis between December 2012 and June 2016 were included. Clinical and laboratory data were retrospectively analyzed. E-test method was used in order to determine antifungal susceptibilities of Candida spp for amphotericin B, fluconazole, voriconazole, ketoconazole, itraconazole, anidulafungin, caspofungin, and flucytosine. Results The clinical diagnoses of the patients were candidemia (n=27, 50%), catheter-related blood stream infection (n=1, 1.8%), urinary tract infection (n=13, 24%), surgical site infection (n=4, 7.4%), intraabdominal infection (n=3, 5.5%), empyema (n=2, 3.7%), and pneumonia (n=4, 7.4%). The most common isolated agent was C. albicans (n=27, 50%) and the others were C. parapsilosis (n=13, 24%), C. tropicalis (n=6, 11.1%), C. glabrata (n=3, 5.6%), C. lusitaniae (n=2, 3.7%), and unspecified Candida spp. (n=3, 5.6%). Fluconazole resistance was 7.4% among all isolates. Resistance against itraconazole, ketoconazole, anidulafungin, voriconazole and caspofungin were 33.3%, 12.5%, 11.1%, 5%, and 2.5%, respectively. Isolates presented intermediate resistance against itraconazole (41.7%), voriconazole (5.6%), and amphotericin B (3.7%) to varying extents. All of the isolates were susceptible to flucytosine. Conclusions In our clinic, C. albicans and non-albicans Candida species were equally distributed and antifungal susceptibilities against major antifungal agents such as fluconazole, amphotericin B, and caspofungin were found considerably high. PMID:29062248

  16. The chemical composition, nutritional value and antimicrobial properties of Abelmoschus esculentus seeds.

    PubMed

    Petropoulos, Spyridon; Fernandes, Ângela; Barros, Lillian; Ciric, Ana; Sokovic, Marina; Ferreira, Isabel C F R

    2017-12-13

    Okra is a vegetable crop usually used for its immature pods. The harvest stage (fruit size) depends on consumers' preferences and the fruit that does not meet market requirements is being disposed of. Considering the short time interval from the setting of the fruit to the harvest stage, the present study evaluates the nutritional value, chemical composition, and antioxidant and antimicrobial properties of okra seeds from genotypes cultivated under Mediterranean conditions, as an alternative end-use product. For this purpose, seeds from four okra cultivars and local landraces commonly cultivated in the Mediterranean basin, as well as seeds from four commercial cultivars from North America were collected at the maturity stage. A significant variation between the studied okra genotypes was observed for all the evaluated parameters. Okra seeds of cv. "Silver Queen" are a significant source of proteins and minerals, such as Ca, K, Fe and Zn. Seeds of all the genotypes contained significant amounts of gamma-tocopherols, liposoluble pigments, and linoleic and palmitic acid. The total phenol content differed between the studied genotypes and correlated with the EC 50 values of the Reducing Power assay. Seed extracts exhibited significant antibacterial properties, especially against Listeria monocytogenes, Salmonella enteritidis and S. typhimurium, while fungistatic and fungicidal properties were better than ketoconazole in a genotype dependent manner. The antifungal properties of seeds were noticed towards all tested fungi, where Aspergillus versicolor and Caldosporium cladosporioides were the most sensitive species. Moreover, two of the tested genotypes ("Boyati" and "Clemson Spineless") exhibited higher fungistatic and fungicidal properties than ketoconazole. In conclusion, okra seeds could be considered as innovative okra products and could be proposed for alternative end-uses in the food and pharmaceutical industries, especially for functional foods with antimicrobial

  17. Rifaximin, a non-absorbable antibiotic, inhibits the release of pro-angiogenic mediators in colon cancer cells through a pregnane X receptor-dependent pathway.

    PubMed

    Esposito, Giuseppe; Gigli, Stefano; Seguella, Luisa; Nobile, Nicola; D'Alessandro, Alessandra; Pesce, Marcella; Capoccia, Elena; Steardo, Luca; Cirillo, Carla; Cuomo, Rosario; Sarnelli, Giovanni

    2016-08-01

    Activation of intestinal human pregnane X receptor (PXR) has recently been proposed as a promising strategy for the chemoprevention of inflammation-induced colon cancer. The present study was aimed at evaluating the effect of rifaximin, a non-absorbable antibiotic, in inhibiting angiogenesis in a model of human colorectal epithelium and investigating the role of PXR in its mechanism of action. Caco-2 cells were treated with rifaximin (0.1, 1.0 and 10.0 µM) in the presence or absence of ketoconazole (10 µM) and assessed for cell proliferation, migration and expression of proliferating cell nuclear antigen (PCNA). The release of vascular endothelial growth factor (VEGF) and nitric oxide (NO), expression of Akt, mechanistic target of rapamycin (mTOR), p38 mitogen activated protein kinases (MAPK), nuclear factor κB (NF-κB) and metalloproteinase-2 and -9 (MMP-2 and -9) were also evaluated. Treatment with rifaximin 0.1, 1.0 and 10.0 µM caused significant and concentration-dependent reduction of cell proliferation, cell migration and PCNA expression in the Caco-2 cells vs. untreated cells. Treatment downregulated VEGF secretion, NO release, VEGFR-2 expression, MMP-2 and MMP-9 expression vs. untreated cells. Rifaximin treatment also resulted in a concentration-dependent decrease in the phosphorylation of Akt, mTOR, p38MAPK and inhibition of hypoxia-inducible factor 1-α (HIF-1α), p70S6K and NF-κB. Ketoconazole (PXR antagonist) treatment inhibited these effects. These findings demonstrated that rifaximin causes PXR-mediated inhibition of angiogenic factors in Caco-2 cell line and may be a promising anticancer tool.

  18. Effect of Incorporation of Antifungal Agents on the Ultimate Tensile Strength of Temporary Soft Denture Liners.

    PubMed

    Neppelenbroek, Karin Hermana; Lima, Jozely Francisca Mello; Hotta, Juliana; Galitesi, Lucas Lulo; Almeida, Ana Lucia Pompéia Fraga; Urban, Vanessa Migliorini

    2018-02-01

    To investigate the ultimate tensile strength of temporary soft denture liners modified by minimum inhibitory concentrations (MICs) of antifungal agents for Candida albicans biofilm (SC5314) determined in previous microbiological research. Dumbbell-shaped specimens (n = 7) with a central cross-sectional area of 6 × 3 × 33 mm were produced by Softone and Trusoft, without (control) or with incorporation of drugs in powder form at MICs for C. albicans biofilm (per g of material powder): nystatin (0.032 g), chlorhexidine diacetate (0.064 g), ketoconazole (0.128 g), miconazole (0.256 g), and itraconazole (0.256 g). After plasticization, specimens were immersed in distilled water at 37°C for 24 hours, 7 or 14 days, and then tested in tension in a universal testing machine at 40 mm/min. Data of tensile strength (MPa) and elongation percentage (%) were submitted to 3-way ANOVA and Tukey's test (α = 0.05). At the end of 14 days, the tensile strength for both materials was significantly lower in the groups modified by miconazole and itraconazole compared to the other groups (p < 0.0001), which showed no significant difference between them (p > 0.05). After 7 and 14 days in water, miconazole and itraconazole added into both materials resulted in significantly lower elongation percentages compared to the other antifungal agents and control (p < 0.0001), which were similar to each other (p > 0.05). The addition of the nystatin, chlorhexidine, and ketoconazole at MICs for C. albicans biofilm resulted in no harmful effects on the tensile strength and elongation percentage of the temporary soft denture liner materials up to 14 days. © 2017 by the American College of Prosthodontists.

  19. CYP-dependent metabolism of PF9601N, a new monoamine oxidase-B inhibitor, by C57BL/6 mouse and human liver microsomes.

    PubMed

    Dragoni, Stefania; Materozzi, Giada; Pessina, Federica; Frosini, Maria; Marco, José Luis; Unzeta, Mercedes; Sgaragli, Giampietro; Valoti, Massimo

    2007-01-01

    The selective monoamine oxidase-B (MAO-B) inhibitor, l-deprenyl, is still used for treating Parkinson's patients, however, a disadvantage of its use lies in the formation of l-amphetamine and l-methamphetamine. Subsequently, this has promoted the design of a novel, more potent, MAO-B inhibitor PF9601N, which also has neuroprotective and antioxidant properties. The aim of this work was to investigate the effect of treatment with PF9601N on its own phase I hepatic metabolism. Kinetic parameters of PF9601N CYP-dependent N-dealkylation reaction was also studied and compared with those of l-deprenyl. C57BL/6 mice were treated with PF9601N for 4 days. After CYP content and related monooxygenase activities were assayed in liver microsomes of control and treated animals. CYP activities, cytochrome b5 content, NADPH-cytochrome P450 reductase and various monooxygenase activities were unaffected by in vivo PF9601N treatment. With microsomes from both control and treated mice, the PF9601N-dealkylation product, FA72, was the only detected metabolite with its formation rate following an hyperbolic, Michaelis-Menten curve. Among various inhibitors, only ketoconazole inhibited the FA72 formation rate, indicating a major involvement for CYP3A. Apparent Km and Vmax values generated by human liver microsomes were similar to those found with mouse microsomes. Ketoconazole inhibition indicates that CYP3A is one of the major enzymes involved in PF9601N metabolism also by human liver microsomes. In mouse liver microsomes, the intrinsic clearance of PF9601N was significantly lower than that of l-deprenyl suggestive of an improved bioavailability for the former. The observed favourable metabolic profile may suggest suitability of PF9601N for clinical use.

  20. Novel CYP17 inhibitors: synthesis, biological evaluation, structure-activity relationships and modelling of methoxy- and hydroxy-substituted methyleneimidazolyl biphenyls.

    PubMed

    Hille, Ulrike E; Hu, Qingzhong; Vock, Carsten; Negri, Matthias; Bartels, Marc; Müller-Vieira, Ursula; Lauterbach, Thomas; Hartmann, Rolf W

    2009-07-01

    Recently, the steroidal CYP17 inhibitor Abiraterone entered phase II clinical trial for the treatment of androgen-dependent prostate cancer. As 17alpha-hydroxylase-17,20-lyase (CYP17) catalyzes the last step in androgen biosynthesis, inhibition of this target should affect not only testicular but also adrenal androgen formation. Therefore CYP17 inhibitors should be advantageous over existing therapies, for example with GnRH analogues. However, steroidal drugs are known for side effects which are due to affinities for steroid receptors. Therefore we decided to synthesize non-steroidal compounds mimicking the natural CYP17 substrates pregnenolone and progesterone. The synthesis and biological evaluation of a series of 15 novel and highly active non-steroidal CYP17 inhibitors are reported. The compounds were prepared via Suzuki-cross-coupling, Grignard reaction and CDI-assisted S(N)t-reaction with imidazole and their inhibitory activity was examined with recombinant human CYP17 expressed in Escherichia coli. Promising compounds were further tested for their selectivity against the hepatic enzyme CYP3A4 and the glucocorticoid-forming enzyme CYP11B1. All compounds turned out to be potent CYP17 inhibitors. The most active compounds 7 and 8 were much more active than Ketoconazole showing activity comparable to Abiraterone (IC(50) values of 90 and 52nM vs. 72nM). Most compounds also showed higher selectivities than Ketoconazole, but turned out to be less selective than Abiraterone. Docking studies using our CYP17 protein model were performed with selected compounds to study the interactions between the inhibitors and the amino acid residues of the active site.

  1. CYP1A1 induction and CYP3A4 inhibition by the fungicide imazalil in the human intestinal Caco-2 cells-comparison with other conazole pesticides.

    PubMed

    Sergent, Thérèse; Dupont, Isabelle; Jassogne, Coralie; Ribonnet, Laurence; van der Heiden, Edwige; Scippo, Marie-Louise; Muller, Marc; McAlister, Dan; Pussemier, Luc; Larondelle, Yvan; Schneider, Yves-Jacques

    2009-02-10

    Imazalil (IMA) is a widely used imidazole-antifungal pesticide and, therefore, a food contaminant. This compound is also used as a drug (enilconazole). As intestine is the first site of exposure to ingested drugs and pollutants, we have investigated the effects of IMA, at realistic intestinal concentrations, on xenobiotic-metabolizing enzymes and efflux pumps by using Caco-2 cells, as a validated in vitro model of the human intestinal absorptive epithelium. For comparison, other conazole fungicides, i.e. ketoconazole, propiconazole and tebuconazole, were also studied. IMA induced cytochrome P450 (CYP) 1A1 activity to the same extent as benzo(a)pyrene (B(a)P) or 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), in a dose- and time-dependent manner. Cell-free aryl hydrocarbon receptor (AhR) binding assay and reporter gene assay suggested that IMA is not an AhR-ligand, implying that IMA-mediated induction should involve an AhR-independent pathway. Moreover, IMA strongly inhibited the CYP3A4 activity in 1,25-vitamin D(3)-induced Caco-2 cells. The other fungicides had weak or nil effects on CYP activities. Study of the apical efflux pump activities revealed that ketoconazole inhibited both P-glycoprotein (Pgp) and multidrug resistance-associated protein 2 (MRP-2) or breast cancer resistance protein (BCRP), whereas IMA and other fungicides did not. Our results imply that coingestion of IMA-contaminated food and CYP3A4- or CYP1A1-metabolizable drugs or chemicals could lead to drug bioavailability modulation or toxicological interactions, with possible adverse effects for human health.

  2. Human variation in CYP-specific chlorpyrifos metabolism.

    PubMed

    Croom, Edward L; Wallace, Andrew D; Hodgson, Ernest

    2010-10-29

    Chlorpyrifos, an organophophorothioate insecticide, is bioactivated to the neurotoxic metabolite, chlorpyrifos-oxon (CPO) by cytochromes P450 (CYPs). To determine the variability in chlorpyrifos bioactivation, CPO production by human liver microsomes from 17 individual donors was compared relative to phenotype and genotype. CPO production varied over 14-fold between individuals in incubations utilizing 20 μM chlorpyrifos as substrate, while CPO production varied 57-fold in incubations with 100 μM chlorpyrifos. For all but two samples, the formation of the less toxic metabolite, 3,5,6-trichloro-2-pyridinol (TCP), was greater than CPO production. TCP production varied 9-fold in incubations utilizing 20 μM chlorpyrifos as substrate and 19-fold using 100 μM chlorpyrifos. Chlorpyrifos metabolism by individual human liver microsomes was significantly correlated with CYP2B6, CYP2C19 and CYP3A4 related activity. CPO formation was best correlated with CYP2B6 related activity at low (20 μM) chlorpyrifos concentrations while CYP3A4 related activity was best correlated with CPO formation at high concentrations (100 μM) of chlorpyrifos. TCP production was best correlated with CYP3A4 activity at all substrate concentrations of chlorpyrifos. The production of both CPO and TCP was significantly lower at a concentration of 20 μM chlorpyrifos as compared to 100 μM chlorpyrifos. Calculations of percent total normalized rates (% TNR) and the chemical inhibitors ketoconazole and ticlopidine were used to confirm the importance of CYP2B6, CYP2C19, and CYP3A4 for the metabolism of chlorpyrifos. The combination of ketoconazole and ticlopidine inhibited the majority of TCP and CPO formation. CPO formation did not differ by CYP2B6 genotype. Individual variations in CPO production may need to be considered in determining the risk of chlorpyrifos poisoning. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

  3. Detecting signals of drug-drug interactions in a spontaneous reports database.

    PubMed

    Thakrar, Bharat T; Grundschober, Sabine Borel; Doessegger, Lucette

    2007-10-01

    The spontaneous reports database is widely used for detecting signals of ADRs. We have extended the methodology to include the detection of signals of ADRs that are associated with drug-drug interactions (DDI). In particular, we have investigated two different statistical assumptions for detecting signals of DDI. Using the FDA's spontaneous reports database, we investigated two models, a multiplicative and an additive model, to detect signals of DDI. We applied the models to four known DDIs (methotrexate-diclofenac and bone marrow depression, simvastatin-ciclosporin and myopathy, ketoconazole-terfenadine and torsades de pointes, and cisapride-erythromycin and torsades de pointes) and to four drug-event combinations where there is currently no evidence of a DDI (fexofenadine-ketoconazole and torsades de pointes, methotrexade-rofecoxib and bone marrow depression, fluvastatin-ciclosporin and myopathy, and cisapride-azithromycine and torsade de pointes) and estimated the measure of interaction on the two scales. The additive model correctly identified all four known DDIs by giving a statistically significant (P < 0.05) positive measure of interaction. The multiplicative model identified the first two of the known DDIs as having a statistically significant or borderline significant (P < 0.1) positive measure of interaction term, gave a nonsignificant positive trend for the third interaction (P = 0.27), and a negative trend for the last interaction. Both models correctly identified the four known non interactions by estimating a negative measure of interaction. The spontaneous reports database is a valuable resource for detecting signals of DDIs. In particular, the additive model is more sensitive in detecting such signals. The multiplicative model may further help qualify the strength of the signal detected by the additive model.

  4. Detecting signals of drug–drug interactions in a spontaneous reports database

    PubMed Central

    Thakrar, Bharat T; Grundschober, Sabine Borel; Doessegger, Lucette

    2007-01-01

    Aims The spontaneous reports database is widely used for detecting signals of ADRs. We have extended the methodology to include the detection of signals of ADRs that are associated with drug–drug interactions (DDI). In particular, we have investigated two different statistical assumptions for detecting signals of DDI. Methods Using the FDA's spontaneous reports database, we investigated two models, a multiplicative and an additive model, to detect signals of DDI. We applied the models to four known DDIs (methotrexate-diclofenac and bone marrow depression, simvastatin-ciclosporin and myopathy, ketoconazole-terfenadine and torsades de pointes, and cisapride-erythromycin and torsades de pointes) and to four drug-event combinations where there is currently no evidence of a DDI (fexofenadine-ketoconazole and torsades de pointes, methotrexade-rofecoxib and bone marrow depression, fluvastatin-ciclosporin and myopathy, and cisapride-azithromycine and torsade de pointes) and estimated the measure of interaction on the two scales. Results The additive model correctly identified all four known DDIs by giving a statistically significant (P< 0.05) positive measure of interaction. The multiplicative model identified the first two of the known DDIs as having a statistically significant or borderline significant (P< 0.1) positive measure of interaction term, gave a nonsignificant positive trend for the third interaction (P= 0.27), and a negative trend for the last interaction. Both models correctly identified the four known non interactions by estimating a negative measure of interaction. Conclusions The spontaneous reports database is a valuable resource for detecting signals of DDIs. In particular, the additive model is more sensitive in detecting such signals. The multiplicative model may further help qualify the strength of the signal detected by the additive model. PMID:17506784

  5. Prediction of Drug-Drug Interactions with Crizotinib as the CYP3A Substrate Using a Physiologically Based Pharmacokinetic Model.

    PubMed

    Yamazaki, Shinji; Johnson, Theodore R; Smith, Bill J

    2015-10-01

    An orally available multiple tyrosine kinase inhibitor, crizotinib (Xalkori), is a CYP3A substrate, moderate time-dependent inhibitor, and weak inducer. The main objectives of the present study were to: 1) develop and refine a physiologically based pharmacokinetic (PBPK) model of crizotinib on the basis of clinical single- and multiple-dose results, 2) verify the crizotinib PBPK model from crizotinib single-dose drug-drug interaction (DDI) results with multiple-dose coadministration of ketoconazole or rifampin, and 3) apply the crizotinib PBPK model to predict crizotinib multiple-dose DDI outcomes. We also focused on gaining insights into the underlying mechanisms mediating crizotinib DDIs using a dynamic PBPK model, the Simcyp population-based simulator. First, PBPK model-predicted crizotinib exposures adequately matched clinically observed results in the single- and multiple-dose studies. Second, the model-predicted crizotinib exposures sufficiently matched clinically observed results in the crizotinib single-dose DDI studies with ketoconazole or rifampin, resulting in the reasonably predicted fold-increases in crizotinib exposures. Finally, the predicted fold-increases in crizotinib exposures in the multiple-dose DDI studies were roughly comparable to those in the single-dose DDI studies, suggesting that the effects of crizotinib CYP3A time-dependent inhibition (net inhibition) on the multiple-dose DDI outcomes would be negligible. Therefore, crizotinib dose-adjustment in the multiple-dose DDI studies could be made on the basis of currently available single-dose results. Overall, we believe that the crizotinib PBPK model developed, refined, and verified in the present study would adequately predict crizotinib oral exposures in other clinical studies, such as DDIs with weak/moderate CYP3A inhibitors/inducers and drug-disease interactions in patients with hepatic or renal impairment. Copyright © 2015 by The American Society for Pharmacology and Experimental

  6. Antileishmanial Activity of Ezetimibe: Inhibition of Sterol Biosynthesis, In Vitro Synergy with Azoles, and Efficacy in Experimental Cutaneous Leishmaniasis

    PubMed Central

    Andrade-Neto, Valter Viana; Cunha-Júnior, Edézio Ferreira; do Canto-Cavalheiro, Marilene Marcuzzo; Atella, Geórgia Correa; Fernandes, Talita de Almeida; Costa, Paulo Roberto Ribeiro

    2016-01-01

    Leishmaniasis affects mainly low-income populations in tropical regions. Radical innovation in drug discovery is time-consuming and expensive, imposing severe restrictions on the ability to launch new chemical entities for the treatment of neglected diseases. Drug repositioning is an attractive strategy for addressing a specific demand more easily. In this project, we have evaluated the antileishmanial activities of 30 drugs currently in clinical use for various morbidities. Ezetimibe, clinically used to reduce intestinal cholesterol absorption in dyslipidemic patients, killed Leishmania amazonensis promastigotes with a 50% inhibitory concentration (IC50) of 30 μM. Morphological analysis revealed that ezetimibe caused the parasites to become rounded, with multiple nuclei and flagella. Analysis by gas chromatography (GC)-mass spectrometry (MS) showed that promastigotes treated with ezetimibe had smaller amounts of C-14-demethylated sterols, and accumulated more cholesterol and lanosterol, than untreated promastigotes. We then evaluated the combination of ezetimibe with well-known antileishmanial azoles. The fractional inhibitory concentration index (FICI) indicated synergy when ezetimibe was combined with ketoconazole or miconazole. The activity of ezetimibe against intracellular amastigotes was confirmed, with an IC50 of 20 μM, and ezetimibe reduced the IC90s of ketoconazole and miconazole from 11.3 and 11.5 μM to 4.14 and 8.25 μM, respectively. Subsequently, we confirmed the activity of ezetimibe in vivo, showing that it decreased lesion development and parasite loads in murine cutaneous leishmaniasis. We concluded that ezetimibe has promising antileishmanial activity and should be considered in combination with azoles in further preclinical and clinical studies. PMID:27600041

  7. Antileishmanial Activity of Ezetimibe: Inhibition of Sterol Biosynthesis, In Vitro Synergy with Azoles, and Efficacy in Experimental Cutaneous Leishmaniasis.

    PubMed

    Andrade-Neto, Valter Viana; Cunha-Júnior, Edézio Ferreira; Canto-Cavalheiro, Marilene Marcuzzo do; Atella, Geórgia Correa; Fernandes, Talita de Almeida; Costa, Paulo Roberto Ribeiro; Torres-Santos, Eduardo Caio

    2016-11-01

    Leishmaniasis affects mainly low-income populations in tropical regions. Radical innovation in drug discovery is time-consuming and expensive, imposing severe restrictions on the ability to launch new chemical entities for the treatment of neglected diseases. Drug repositioning is an attractive strategy for addressing a specific demand more easily. In this project, we have evaluated the antileishmanial activities of 30 drugs currently in clinical use for various morbidities. Ezetimibe, clinically used to reduce intestinal cholesterol absorption in dyslipidemic patients, killed Leishmania amazonensis promastigotes with a 50% inhibitory concentration (IC 50 ) of 30 μM. Morphological analysis revealed that ezetimibe caused the parasites to become rounded, with multiple nuclei and flagella. Analysis by gas chromatography (GC)-mass spectrometry (MS) showed that promastigotes treated with ezetimibe had smaller amounts of C-14-demethylated sterols, and accumulated more cholesterol and lanosterol, than untreated promastigotes. We then evaluated the combination of ezetimibe with well-known antileishmanial azoles. The fractional inhibitory concentration index (FICI) indicated synergy when ezetimibe was combined with ketoconazole or miconazole. The activity of ezetimibe against intracellular amastigotes was confirmed, with an IC 50 of 20 μM, and ezetimibe reduced the IC 90 s of ketoconazole and miconazole from 11.3 and 11.5 μM to 4.14 and 8.25 μM, respectively. Subsequently, we confirmed the activity of ezetimibe in vivo, showing that it decreased lesion development and parasite loads in murine cutaneous leishmaniasis. We concluded that ezetimibe has promising antileishmanial activity and should be considered in combination with azoles in further preclinical and clinical studies. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

  8. Beauveria keratitis and biopesticides: case histories and a random amplification of polymorphic DNA comparison.

    PubMed

    Pariseau, Brett; Nehls, Sarah; Ogawa, Gregory S H; Sutton, Deanna A; Wickes, Brian L; Romanelli, Anna M

    2010-02-01

    The purposes of this study were to describe 2 contact lens-associated Beauveria keratitis cases and to compare the isolates of 3 contact lens-associated Beauveria keratitis cases with Beauveria-based biopesticides using random amplification of polymorphic DNA (RAPD). A 55-year-old diabetic woman from New Mexico and a 31-year-old healthy woman from southern Wisconsin developed soft contact lens-related corneal ulcers unresponsive to topical moxifloxacin and prednisolone acetate drops. Their corneal cultures grew B. bassiana. These isolates, an isolate from a third soft contact lens-related Beauveria keratitis case, and Beauveria-based biopesticides sold in the United States were analyzed using morphological features, DNA sequencing, and RAPD. A PubMed, Cochrane Library, OVID, UpToDate, and Google search using the term "Beauveria" found only 9 reported Beauveria keratitis infections. Patient 1 responded to topical natamycin, ketoconazole, and 200 mg oral ketoconazole twice daily before developing a secondary bacterial infection requiring penetrating keratoplasty. After subsequent cataract surgery, the best-corrected visual acuity was 20/20. Patient 2 was treated with topical natamycin, topical amphotericin, and 200 mg oral voriconazole twice daily for 1 month with residual scarring and a best-corrected visual acuity of 20/25. RAPD showed that all isolates were unrelated. Although earlier reported Beauveria keratitis cases occurred after corneal injury in patients who did not wear contact lenses, 3 recent patients wore soft contact lenses and denied trauma, mirroring a changing trend in microbial keratitis. RAPD analysis showed that the Beauveria isolates were unrelated to one another and to Beauveria-based biopesticides. In Patient 2, oral voriconazole worked well.

  9. Antimicrobial activity and chemical composition of Brunfelsia uniflora flower oleoresin extracted by supercritical carbon dioxide.

    PubMed

    Thiesen, L C T; Sugauara, E Y Y; Tešević, V; Glamočlija, J; Soković, M; Gonçalves, J E; Gazim, Z C; Linde, G A; Colauto, N B

    2017-04-13

    Brunfelsia genus is traditionally utilized in popular medicine due to its antibacterial and antifungal properties to name but a few. However, studies on the antimicrobial activity of Brunfelsia uniflora flower oleoresin have not been found yet. This study aimed to evaluate the chemical composition and antimicrobial activity of B. uniflora flower oleoresin obtained by supercritical carbon dioxide. Oleoresin from the plant dried flowers was obtained by carbon dioxide, and the chemical composition was analyzed by gas chromatographic-mass spectrometry. The minimum inhibitory concentration (MIC), minimum bactericidal concentration (MBC), and minimum fungicidal concentration (MFC) of this oleoresin for seven bacteria and eight fungi were determined using 96-well microtiter plates. The oleoresin MBC for Bacillus cereus, Enterobacter cloacae, Escherichia coli, Listeria monocytogenes, Pseudomonas aeruginosa, Salmonella enterica, and Staphylococcus aureus ranged from 0.01 to 0.08 mg/mL, whereas the controls streptomycin and ampicillin varied from 0.1 and 0.5 mg/mL. The oleoresin MFC for Aspergillus fumigatus, Aspergillus niger, Aspergillus ochraceus, Aspergillus versicolor, Penicillium funiculosum, Penicillium ochrochloron, Penicillium verrucosum var. cyclopium, and Trichoderma viride varied from 0.01 to 0.08 mg/mL, whereas the controls bifonazole and ketoconazole ranged from 0.2 to 3.5 mg/mL. The oleoresin obtained by supercritical carbon dioxide presented bacteriostatic, bactericidal, fungistatic, and fungicidal activities that were higher than the positive controls streptomycin, ampicillin, bifonazole, and ketoconazole. The high antimicrobial activity was related to the high content of (E, E)-geranyllinalool that composes 21.0% of the oleoresin and a possible synergic action with fatty acid esters that made up 50.5% of the oleoresin. The oleoresin antimicrobial activity against common multiresistant bacteria in severe infectious processes as P. aeruginosa or against toxin

  10. Comparative CYP-dependent binding of the adrenocortical toxicants 3-methylsulfonyl-DDE and o,p'-DDD in Y-1 adrenal cells.

    PubMed

    Hermansson, Veronica; Asp, Vendela; Bergman, Ake; Bergström, Ulrika; Brandt, Ingvar

    2007-11-01

    The environmental pollutant 3-MeSO(2)-DDE [2-(3-methylsulfonyl-4-chlorophenyl)-2-(4-chlorophenyl)-1,1-dichloroethene] is an adrenocortical toxicant in mice, specifically in the glucocorticoid-producing zona fasciculata, due to a cytochrome P450 11B1 (CYP11B1)-catalysed bioactivation and formation of covalently bound protein adducts. o,p'-DDD [2-(2-chlorophenyl)-2-(4-chlorophenyl)-1,1-dichloroethane] is toxic and inhibits steroidogenesis in the human adrenal cortex after bioactivation by unidentified CYPs, but does not exert any toxic effects on the mouse adrenal. As a step towards determining in vitro/in vivo relationships for the CYP-catalysed binding and toxicity of 3-MeSO(2)-DDE and o,p'-DDD, we have investigated the irreversible protein binding of these two toxicants in the murine adrenocortical cell line Y-1. The irreversible binding of 3-MeSO(2)-DDE previously demonstrated in vivo was successfully reproduced and could be inhibited by the CYP-inhibitors etomidate, ketoconazole and metyrapone. Surprisingly, o,p'-DDD reached similar levels of binding as 3-MeSO(2)-DDE. The binding of o,p'-DDD was sensitive to etomidate and ketoconazole, but not to metyrapone. Moreover, GSH depletion increased the binding of 3-MeSO(2)-DDE, but not of o,p'-DDD, indicating an important role of GSH conjugation in the detoxification of the 3-MeSO(2)-DDE-derived reactive metabolite. In addition, the specificity of CYP11B1 in activating 3-MeSO(2)-DDE was investigated using structurally analogous compounds. None of the analogues produced histopathological lesions in the mouse adrenal in vivo following a single i.p. injection of 100 mg/kg body weight, but two of the compounds were able to decrease the irreversible binding of 3-MeSO(2)-DDE to Y-1 cells. These results indicate that the bioactivation of 3-MeSO(2)-DDE by CYP11B1 is highly structure-dependent. In conclusion, both 3-MeSO(2)-DDE and o,p'-DDD bind irreversibly to Y-1 cells despite differences in binding and adrenotoxicity in mice

  11. Covalent modification of proteins by ligands of steroid hormone receptors.

    PubMed Central

    Takahashi, N; Breitman, T R

    1992-01-01

    Retinoylation, acylation with retinoic acid (RA), is a covalent modification of proteins occurring in a variety of eukaryotic cell lines. In this study, we found that proteins in HL-60 cells were labeled by 17 beta-[3H]estradiol (E2), [3H]progesterone (Pg), 1 alpha,25-dihydroxy[3H]vitamin D3 [1,25(OH)2D3], [125I]triiodothyronine (T3), [125I]thyroxine (T4), and [3H]prostaglandin E2 (PGE2). All of these hormones, except PGE2, are ligands of the steroid hormone receptor family. Addition to the growth medium of 5 microM ketoconazole, an inhibitor of cytochrome P450-dependent enzymes, increased about 2-fold the labeling of proteins by T3, T4, 1,25(OH)2D3, and PGE2. In contrast, ketoconazole did not change markedly the extent of labeling by RA, E2, or Pg. Alkaline methanolysis, which cleaves ester bonds, released variable percentages of the radioactive ligands bound to protein. These values were about 80% for RA and PGE2; 50% for T3, T4, and Pg; and 20% for E2 and 1,25(OH)2D3. Treatment with thioether-cleavage reagents, iodomethane or Raney nickel catalyst, released < 2% of the covalently bound ligands. Two-dimensional polyacrylamide gel electrophoresis patterns of labeled proteins were unique for each ligand. Proteins of M(r) 47,000 and 51,000 were labeled by RA, E2, T3, and T4. These proteins had the same mobilities as RI and RII, the cAMP-binding regulatory subunits of type I and type II cAMP-dependent protein kinases. 1,25(OH)2D3 also bound to proteins of M(r) 47,000 and 51,000. However, these proteins had pI values different from those of RI or RII. These results suggest that some activities of ligands of the steroid hormone receptor family and of PGE2 may be mediated by their covalent modification of proteins. Images PMID:1438281

  12. Covalent modification of proteins by ligands of steroid hormone receptors.

    PubMed

    Takahashi, N; Breitman, T R

    1992-11-15

    Retinoylation, acylation with retinoic acid (RA), is a covalent modification of proteins occurring in a variety of eukaryotic cell lines. In this study, we found that proteins in HL-60 cells were labeled by 17 beta-[3H]estradiol (E2), [3H]progesterone (Pg), 1 alpha,25-dihydroxy[3H]vitamin D3 [1,25(OH)2D3], [125I]triiodothyronine (T3), [125I]thyroxine (T4), and [3H]prostaglandin E2 (PGE2). All of these hormones, except PGE2, are ligands of the steroid hormone receptor family. Addition to the growth medium of 5 microM ketoconazole, an inhibitor of cytochrome P450-dependent enzymes, increased about 2-fold the labeling of proteins by T3, T4, 1,25(OH)2D3, and PGE2. In contrast, ketoconazole did not change markedly the extent of labeling by RA, E2, or Pg. Alkaline methanolysis, which cleaves ester bonds, released variable percentages of the radioactive ligands bound to protein. These values were about 80% for RA and PGE2; 50% for T3, T4, and Pg; and 20% for E2 and 1,25(OH)2D3. Treatment with thioether-cleavage reagents, iodomethane or Raney nickel catalyst, released < 2% of the covalently bound ligands. Two-dimensional polyacrylamide gel electrophoresis patterns of labeled proteins were unique for each ligand. Proteins of M(r) 47,000 and 51,000 were labeled by RA, E2, T3, and T4. These proteins had the same mobilities as RI and RII, the cAMP-binding regulatory subunits of type I and type II cAMP-dependent protein kinases. 1,25(OH)2D3 also bound to proteins of M(r) 47,000 and 51,000. However, these proteins had pI values different from those of RI or RII. These results suggest that some activities of ligands of the steroid hormone receptor family and of PGE2 may be mediated by their covalent modification of proteins.

  13. Potato Dextrose Agar Antifungal Susceptibility Testing for Yeasts and Molds: Evaluation of Phosphate Effect on Antifungal Activity of CMT-3

    PubMed Central

    Liu, Yu; Tortora, George; Ryan, Maria E.; Lee, Hsi-Ming; Golub, Lorne M.

    2002-01-01

    The broth macrodilution method (BMM) for antifungal susceptibility testing, approved by the National Committee for Clinical Laboratory Standards (NCCLS), was found to have deficiencies in testing of the antifungal activity of a new type of antifungal agent, a nonantibacterial chemically modified tetracycline (CMT-3). The high content of phosphate in the medium was found to greatly increase the MICs of CMT-3. To avoid the interference of phosphate in the test, a new method using potato dextrose agar (PDA) as a culture medium was developed. Eight strains of fungi, including five American Type Culture Collection strains and three clinical isolates, were used to determine the MICs of amphotericin B and itraconazole with both the BMM and the PDA methods. The MICs of the two antifungal agents determined with the PDA method showed 99% agreement with those determined with the BMM method within 1 log2 dilution. Similarly, the overall reproducibility of the MICs with the PDA method was above 97%. Three other antifungal agents, fluconazole, ketoconazole, and CMT-3, were also tested in parallel against yeasts and molds with both the BMM and the PDA methods. The MICs of fluconazole and ketoconazole determined with the PDA method showed 100% agreement within 1 log2 dilution of those obtained with the BMM method. However, the MICs of CMT-3 determined with the BMM method were as high as 128 times those determined with the PDA method. The effect of phosphate on the antifungal activity of CMT-3 was evaluated by adding Na2HPO4 to PDA in the new method. It was found that the MIC of CMT-3 against a Penicillium sp. increased from 0.5 μg/ml (control) to 2.0 μg/ml when the added phosphate was used at a concentration of 0.8 mg/ml, indicating a strong interference of Na2HPO4 with the antifungal activity of CMT-3. Except for fluconazole, all the other antifungal agents demonstrated clear end points among the yeasts and molds tested. Nevertheless, with its high reproducibility, good

  14. Canine intestinal contents vs. simulated media for the assessment of solubility of two weak bases in the human small intestinal contents.

    PubMed

    Kalantzi, Lida; Persson, Eva; Polentarutti, Britta; Abrahamsson, Bertil; Goumas, Konstantinos; Dressman, Jennifer B; Reppas, Christos

    2006-06-01

    This study was conducted to assess the relative usefulness of canine intestinal contents and simulated media in the prediction of solubility of two weak bases (dipyridamole and ketoconazole) in fasted and fed human intestinal aspirates that were collected under conditions simulating those in bioavailability/bioequivalence studies. After administration of 250 mL of water or 500 mL of Ensure plus [both containing 10 mg/mL polyethylene glycol (PEG) 4000 as nonabsorbable marker], intestinal aspirates were collected from the fourth part of the duodenum of 12 healthy adults and from the mid-jejunum of four Labradors. Pooled samples were analyzed for PEG, pH, buffer capacity, osmolality, surface tension, pepsin, total carbohydrates, total protein content, bile salts, phospholipids, and neutral lipids. The shake-flask method was used to measure the solubility of dipyridamole and ketoconazole in pooled human and canine intestinal contents and in fasted-state-simulating intestinal fluid (FaSSIF) and fed-state-simulating intestinal fluid (FeSSIF) containing various bile salts and pH-buffering agents. For both compounds, solubility in canine contents may be predictive of human intralumenal solubility in the fasting state but not in the fed state. The poor agreement of results in canine and human aspirates can be attributed to the higher bile salt content in canine bile. Solubility in FaSSIF containing a mixture of bile salts from crude bile predicted satisfactorily the intralumenal solubility of both drugs in the fasted state in humans. Solubility in FeSSIF, regardless of the identity of bile salts or of the buffering species, deviated from intralumenal values in the fed human aspirates by up to 40%. This was attributed to the lack of lipolytic products in FeSSIF, the higher bile salt content of FeSSIF, and the lower pH of FeSSIF. FaSSIF containing a mixture of bile salts from crude bile, and FeSSIF containing lipolytic products and, perhaps, having lower bile salt content but

  15. Ursodeoxycholic acid increases low-density lipoprotein binding, uptake and degradation in isolated hamster hepatocytes.

    PubMed Central

    Bouscarel, B; Fromm, H; Ceryak, S; Cassidy, M M

    1991-01-01

    Ursodeoxycholic acid (UDCA), in contrast to both chenodeoxycholic acid (CDCA), its 7 alpha-epimer, and lithocholic acid, enhanced receptor-dependent low-density lipoprotein (LDL) uptake and degradation in isolated hamster hepatocytes. The increase in cell-associated LDL was time- and concentration-dependent, with a maximum effect observed at approx. 60 min with 1 mM-UDCA. This increase was not associated with a detergent effect of UDCA, as no significant modifications were observed either in the cellular release of lactate dehydrogenase or in Trypan Blue exclusion. The effect of UDCA was not due to a modification of the LDL particle, but rather was receptor-related. UDCA (1 mM) maximally increased the number of 125I-LDL-binding sites (Bmax.) by 35%, from 176 to 240 ng/mg of protein, without a significant modification of the binding affinity. Furthermore, following proteolytic degradation of the LDL receptor with Pronase, specific LDL binding decreased to the level of non-specific binding, and the effect of UDCA was abolished. Conversely, the trihydroxy 7 beta-hydroxy bile acid ursocholic acid and its 7 alpha-epimer, cholic acid, induced a significant decrease in LDL binding by approx. 15%. The C23 analogue of UDCA (nor-UDCA) and CDCA did not affect LDL binding. On the other hand, UDCA conjugated with either glycine (GUDCA) or taurine (TUDCA), increased LDL binding to the same extent as did the free bile acid. The half maximum time (t1/2) to reach the full effect was 1-2 min for UDCA and TUDCA, while GUDCA had a much slower t1/2 of 8.3 min. Ketoconazole (50 microM), an antifungal agent, increased LDL binding, but this effect was not additive when tested in the presence of 0.7 mM-UDCA. The results of the studies indicate that, in isolated hamster hepatocytes, the UDCA-induced increase in receptor-dependent LDL binding and uptake represents a direct effect of this bile acid. The action of the bile acid is closely related to its specific structural conformation, since

  16. Efficacy of Neem Extract and Three Antimicrobial Agents Incorporated into Tissue Conditioner in Inhibiting the Growth of C. Albicans and S. Mutans

    PubMed Central

    Barua, Dikshita Ray; Varghese, Rana Kalappattil

    2017-01-01

    Introduction Denture stomatitis is an inflammatory condition which compromises the mucosal surface beneath dentures. The aetiology of denture stomatitis is usually multifactorial which varies from trauma from ill fitting denture to poor immune system. There are evidences that denture stomatitis is an outcome of multispecies biofilms that include Candida albicans and Streptococcus mutans. Tissue conditioners are found to be more susceptible to colonisation by micro-organisms. Aim The purpose of this study was to compare the efficacy of neem leaf extract and three other antimicrobial agents incorporated in a tissue conditioner against both Candida albicans and Streptococcus mutans. Materials and Methods Standard strain of Candida albicans and Streptococcus mutans were inoculated into Sabouraud Dextrose broth and Mitis-Salivarius-Bacitracin broth respectively incubated at 37°C. Tissue conditioner (Viscogel) mixed with two different concentrations of ketoconazole, nystatin and chlorhexidine diacetate (5%, 10% w/w) and neem leaf extract (7.5% w/w and 15% w/w) and control group (plain tissue conditioner) were placed into punch hole (6 mm diameter) agar plate inoculated with Candida albicans and Streptococcus mutans. A total of 216 samples were prepared for both Candida albicans and Streptococcus mutans. Mean Inhibition Diameter (MID) across each punch holes were measured in millimetres at 24 hours and seven days and data were statistically analysed using Kruskal Wallis test followed by Mann-Whitney U test. Results Both ketoconazole and nystatin (10% w/w) showed maximum inhibition of 32 mm and mean of 31.75 followed by 15% w/w neem leaf extract with an inhibition of 21 mm and mean of 20.67 after 24 hours against Candida albicans whereas chlorhexidine diacetate (10% w/w) showed mean of 25.67 followed by chlorhexidine diacetate (5% w/w) and neem extract (15% w/w) which showed mean of 24.17 and 23.67 respectively against Streptococcus mutans. Conclusion Neem leaf extract

  17. Synergistic antifungal activity of statin-azole associations as witnessed by Saccharomyces cerevisiae- and Candida utilis-bioassays and ergosterol quantification.

    PubMed

    Cabral, María Eugenia; Figueroa, Lucía I C; Fariña, Julia I

    2013-01-03

    Frequent opportunist fungal infections and the resistance to available antifungal drugs promoted the development of new alternatives for treatment, like antifungal drug combinations. This work aimed to detect the antifungal synergism between statins and azoles by means of an agar-well diffusion bioassay with Saccharomyces cerevisiae ATCC 32051 and Candida utilis Pr(1-2) as test strains. Synergistic antifungal effects were tested by simultaneously adding a sub inhibitory concentration (SIC) of statin (atorvastatin, lovastatin, pravastatin, rosuvastatin or simvastatin) plus a minimal inhibitory concentration (MIC) of azole (clotrimazole, fluconazole, itraconazole, ketoconazole or miconazole) to yeast-embedded YNB agar plates, and a positive result corresponded to a yeast growth inhibition halo higher than that produced by the MIC of the azole alone. Yeast cell ergosterol quantification by RP-HPLC was used to confirm statin-azole synergism, and ergosterol rescue bioassays were performed for evaluating statin-induced ergosterol synthesis blockage. Growth inhibition was significantly increased when clotrimazole, fluconazole, itraconazole, ketoconazole and miconazole were combined with atorvastatin, lovastatin, rosuvastatin and simvastatin. Highest growth inhibition increments were observed on S. cerevisiae (77.5%) and C. utilis (43.2%) with a SIC of simvastatin plus a MIC of miconazole, i.e. 4 + 2.4 μg/ml or 20 + 4.8 μg/ml, respectively. Pravastatin showed almost no significant effects (0-7.6% inhibition increase). Highest interaction ratios between antifungal agents corresponded to simvastatin-miconazole combinations and were indicative of synergism. Synergism was also confirmed by the increased reduction in cellular ergosterol levels (S. cerevisiae, 40% and C. utilis, 22%). Statin-induced ergosterol synthesis blockage was corroborated by means of ergosterol rescue bioassays, pravastatin being the most easily abolished inhibition whilst rosuvastatin being the most

  18. Evaluation of various dissolution media for predicting in vivo performance of class I and II drugs.

    PubMed

    Galia, E; Nicolaides, E; Hörter, D; Löbenberg, R; Reppas, C; Dressman, J B

    1998-05-01

    In this paper we seek to verify the differences in dissolution behavior between class I and class II drugs and to evaluate the suitability of two new physiologically based media, of Simulated Gastric Fluid (SGF) and of milk for their ability to forecast trends in the in vivo performance of class II compounds and their formulations. Dissolution behavior of two class I drugs, i.e. acetaminophen and metoprolol, and of three class II drugs, i.e. danazol, mefenamic acid and ketoconazole, was studied with USP Apparatus 2 in water, SGF, milk, Simulated Intestinal Fluid without pancreatin (SIFsp) and in two media simulating the small intestinal contents in the fed (FeSSIF) and fasted (FaSSIF) states, respectively. Class I powders dissolved rapidly in all media tested. Acetaminophen dissolution in milk was slow from one tablet formulation, in all other cases dissolution was more than 85% complete in 15 minutes. The dissolution rate of metoprolol was shown to be dependent on formulation and manufacturing method, and one of the three tablet formulations did not meet compendial specifications (80%/30 minutes). Dissolution behavior of class II drugs was greatly affected by choice of medium. Dissolution from a capsule formulation of danazol proved to be dependent on the concentration of solubilizing agents, with a the 30-fold increase in percentage dissolved within 90 minutes upon changing from aqueous media without surfactants to FaSSIF. Use of FeSSIF or milk as the dissolution medium resulted in an even greater increase in percentage dissolved, 100 and 180-fold respectively. Dissolution of the weak acid mefenamic acid from a capsule formulation is dependent on both pH and bile salt concentration, which leads to an offset between increased bile salt concentration and lower pH in the fed state compared to the fasted state medium. The weak base ketoconazole showed complete dissolution from a tablet formulation in Simulated Gastric Fluid without pepsin (SGFsp) within 30 minutes

  19. Metabolism of endosulfan-alpha by human liver microsomes and its utility as a simultaneous in vitro probe for CYP2B6 and CYP3A4.

    PubMed

    Casabar, Richard C T; Wallace, Andrew D; Hodgson, Ernest; Rose, Randy L

    2006-10-01

    Endosulfan-alpha is metabolized to a single metabolite, endosulfan sulfate, in pooled human liver microsomes (Km = 9.8 microM, Vmax = 178.5 pmol/mg/min). With the use of recombinant cytochrome P450 (P450) isoforms, we identified CYP2B6 (Km = 16.2 microM, Vmax = 11.4 nmol/nmol P450/min) and CYP3A4 (Km = 14.4 microM, Vmax = 1.3 nmol/nmol P450/min) as the primary enzymes catalyzing the metabolism of endosulfan-alpha, although CYP2B6 had an 8-fold higher intrinsic clearance rate (CL(int) = 0.70 microl/min/pmol P450) than CYP3A4 (CL(int) = 0.09 microl/min/pmol P450). Using 16 individual human liver microsomes (HLMs), a strong correlation was observed with endosulfan sulfate formation and S-mephenytoin N-demethylase activity of CYP2B6 (r(2) = 0.79), whereas a moderate correlation with testosterone 6 beta-hydroxylase activity of CYP3A4 (r(2) = 0.54) was observed. Ticlopidine (5 microM), a potent CYP2B6 inhibitor, and ketoconazole (10 microM), a selective CYP3A4 inhibitor, together inhibited approximately 90% of endosulfan-alpha metabolism in HLMs. Using six HLM samples, the percentage total normalized rate (% TNR) was calculated to estimate the contribution of each P450 in the total metabolism of endosulfan-alpha. In five of the six HLMs used, the percentage inhibition with ticlopidine and ketoconazole in the same incubation correlated with the combined % TNRs for CYP2B6 and CYP3A4. This study shows that endosulfan-alpha is metabolized by HLMs to a single metabolite, endosulfan sulfate, and that it has potential use, in combination with inhibitors, as an in vitro probe for CYP2B6 and 3A4 catalytic activities.

  20. Vitamin and mineral supplements: friend or foe when combined with medications?

    PubMed

    Donaldson, Mark; Touger-Decker, Riva

    2014-11-01

    Given the prevalence of vitamin and mineral supplement use among consumers and the potential for vitamin- and mineral-drug interactions, as well as oral and systemic adverse effects of excess consumption, oral health care providers (OHCPs) should ask all patients about their use. The challenges for OHCPs are how to recognize oral and systemic manifestations of these interactions and how to safely manage the care of these patients while avoiding potential interactions. The authors reviewed the literature regarding interactions between popular vitamin and mineral supplements and medications used commonly in dentistry. They used clinical databases and decision support tools to classify interactions according to their level of patient risk. They address interactions of greatest clinical concern with a high-quality evidence-based foundation in either randomized controlled clinical trials or meta-analyses. Most medications used commonly in dentistry can be prescribed safely without regard to vitamin- and mineral-drug interactions. However, patients taking anticoagulants or cytochrome P450 3A4 substrates (such as clarithromycin, erythromycin, ketoconazole, itraconazole, midazolam and triazolam) in addition to specific vitamin or mineral supplements (vitamins D, E, K, calcium, fluoride, iron, magnesium, selenium or zinc) may face additional challenges. OHCPs need to recognize these potential interactions and know how to manage the care of patients who may be receiving treatment with these combination therapies. Recognition and avoidance of potential vitamin- and mineral-drug interactions will help clinicians optimize patient treatment while emphasizing patient safety.

  1. Antifungal Monoterpene Derivatives from the Plant Endophytic Fungus Pestalotiopsis foedan.

    PubMed

    Xu, Dan; Zhang, Bing-Yang; Yang, Xiao-Long

    2016-10-01

    A new monoterpene lactone, (1R,4R,5R,8S)-8-hydroxy-4,8-dimethyl-2-oxabicyclo[3.3.1]nonan-3-one (1), along with one related known compound, (2R)-2-[(1R)-4-methylcyclohex-3-en-1-yl]propanoic acid (2), were isolated from the liquid culture of the plant endophytic fungus Pestalotiopsis foedan obtained from the branch of Bruguiera sexangula. The structure and absolute configuration of 1 were determined on the basis of extensive analysis of NMR spectra combined with computational methods via calculation of the optical rotation (OR) and 13 C-NMR. Both compounds exhibited strong antifungal activities against Botrytis cinerea and Phytophthora nicotianae with MIC values of 3.1 and 6.3 μg/ml, respectively, which are comparable to those of the known antifungal drug ketoconazole. Compound 2 also showed modest antifungal activity against Candida albicans with a MIC value of 50 μg/ml. © 2016 Wiley-VHCA AG, Zürich.

  2. Alginate Immobilization of Metabolic Enzymes (AIME) for High ...

    EPA Pesticide Factsheets

    Alginate Immobilization of Metabolic Enzymes (AIME) for High-Throughput Screening Assays DE DeGroot, RS Thomas, and SO SimmonsNational Center for Computational Toxicology, US EPA, Research Triangle Park, NC USAThe EPA’s ToxCast program utilizes a wide variety of high-throughput screening (HTS) assays to assess chemical perturbations of molecular and cellular endpoints. A key criticism of using HTS assays for toxicity assessment is the lack of xenobiotic metabolism (XM) which precludes both metabolic detoxification as well as bioactivation of chemicals tested in vitro thereby mischaracterizing the potential risk posed by these chemicals. To address this deficiency, we have developed an extracellular platform to retrofit existing HTS assays with XM activity. This platform utilizes the S9 fraction of liver homogenate encapsulated in an alginate gel network which reduces the cytotoxicity caused by direct addition of S9 to cells in culture. Alginate microspheres containing encapsulated human liver S9 were cross-linked to solid supports extending from a 96-well plate lid and were assayed using a pro-luciferin substrate specific for CYP3A4 (IPA). We demonstrate that S9 was successfully encapsulated and remained enzymatically active post-encapsulation with 5-10X the CYP3A4 activity as compared to 1 µg solubilized human liver S9. Ketoconazole, a known inhibitor of human CYP3A4, inhibited CYP3A4 activity in a concentration-dependent manner (IC50: 0.27 µM) and inhibiti

  3. Eumycetoma and actinomycetoma--an update on causative agents, epidemiology, pathogenesis, diagnostics and therapy.

    PubMed

    Nenoff, P; van de Sande, W W J; Fahal, A H; Reinel, D; Schöfer, H

    2015-10-01

    Mycetoma is a chronic putrid infection of the cutaneous and subcutaneous tissue concerning predominantly the feet, and more rarely other body parts. Mycetoma can be caused by both fungi (eumycetoma) and bacteria (actinomycetoma). Mode of infection is an inoculation of the causative microorganism via small injuries of the skin. The clinical correlate of both forms of mycetoma is tumescence with abscesses, painless nodules, sinuses and discharge. The latter is commonly serous-purulent and contains grains (filamentous granules) which can be expressed for diagnostic purposes. Distinctive for both eumycetoma and actinomycetoma, are the formation of grains. Grains represent microcolonies of the microorganism in vivo in the vital tissue. The most successful treatment option for eumycetomas offers itraconazole in a dosage of 200 mg twice daily. This triazole antifungal is considered as 'gold standard' for eumycetomas. Alternatively, the cheaper ketoconazole was widely used, however, it was currently stopped by the FDA. Actinomycetomas should be treated by the combination of trimethoprim-sulphamethoxazole (co-trimoxazole 80/400 to 160/800 mg per day) and amikacin 15 mg/kg body weight per day. Mycetomas are neglected infections of the poor. They are more than a medical challenge. In rural areas of Africa, Asia and South America mycetomas lead to socio-economic consequences involving the affected patients, their families and the society in general. © 2015 European Academy of Dermatology and Venereology.

  4. Management Strategies for Aggressive Cushing's Syndrome: From Macroadenomas to Ectopics

    PubMed Central

    Pozza, Carlotta; Graziadio, Chiara; Giannetta, Elisa; Lenzi, Andrea; Isidori, Andrea M.

    2012-01-01

    Cushing's syndrome (CS) is a rare but severe clinical condition represented by an excessive endogenous cortisol secretion and hence excess circulating free cortisol, characterized by loss of the normal feedback regulation and circadian rhythm of the hypothalamic-pituitary axis due to inappropriate secretion of ACTH from a pituitary tumor (Cushing's disease, CD) or an ectopic source (ectopic ACTH secretion, EAS). The remaining causes (20%) are ACTH independent. As soon as the diagnosis is established, the therapeutic goal is the removal of the tumor. Whenever surgery is not curative, management of patients with CS requires a major effort to control hypercortisolemia and associated symptoms. A multidisciplinary approach that includes endocrinologists, neurosurgeons, oncologists, and radiotherapists should be adopted. This paper will focus on traditional and novel medical therapy for aggressive ACTH-dependent CS. Several drugs are able to reduce cortisol levels. Their mechanism of action involves blocking adrenal steroidogenesis (ketoconazole, metyrapone, aminoglutethimide, mitotane, etomidate) or inhibiting the peripheral action of cortisol through blocking its receptors (mifepristone “RU-486”). Other drugs include centrally acting agents (dopamine agonists, somatostatin receptor agonists, retinoic acid, peroxisome proliferator-activated receptor γ “PPAR-γ” ligands) and novel chemotherapeutic agents (temozolomide and tyrosine kinase inhibitors) which have a significant activity against aggressive pituitary or ectopic tumors. PMID:22934113

  5. Cushing's syndrome in infancy due to ectopic ACTH secretion by a sacro-coccygeal teratoma.

    PubMed

    Rydzewska, Marta; Krawczuk-Rybak, Maryna; Zajkowska, Adrianna; Jurczuk, Natalia; Polnik, Dariusz; Szalecki, Mieczysław; Moszczyńska, Elżbieta; Savage, Martin O; Bossowski, Artur

    2017-04-01

    Adenocorticotropic hormone (ACTH)-dependent Cushing's syndrome in infancy is extremely rare. We describe the case of a sacro-coccygeal ectopic ACTH-secreting immature teratoma in an infant who also presented the triad of defects characteristic of Currarino syndrome. A girl was born with a large immature teratoma in the sacro-coccygeal region associated with anal atresia. At the age of 7 days, the concentration of α-fetoprotein (AFP) was above the age-specific normal range. Two non-radical surgical excisions of the tumour were performed. At the age of 7 months, she developed polyphagia, acne, hirsutism, hypertension and hypokalemia with elevated ACTH and absence of serum cortisol circadian rhythm. Immunostaining of tumour tissue showed ACTH-immunoreactive cells. Due to unsuccessful therapy with ketoconazole and resistance to antihypertensive medications [blood pressure (BP) 210/160 mmHg], metyrapone was administered, which controlled her ACTH and cortisol levels in the normal range. Following further removal of tumour bulk after three operations during the first year of life, there was a decrease of BP to normal values. A rare case of ectopic ACTH syndrome causing Cushing's syndrome in infancy in the context of Currarino syndrome is reported. Radical surgery has resulted in excision of the tumour and current control of Cushing's syndrome.

  6. In Vitro Biotransformation of Two Human CYP3A Probe Substrates and Their Inhibition during Early Zebrafish Development.

    PubMed

    Verbueken, Evy; Alsop, Derek; Saad, Moayad A; Pype, Casper; Van Peer, Els M; Casteleyn, Christophe R; Van Ginneken, Chris J; Wilson, Joanna; Van Cruchten, Steven J

    2017-01-22

    At present, the zebrafish embryo is increasingly used as an alternative animal model to screen for developmental toxicity after exposure to xenobiotics. Since zebrafish embryos depend on their own drug-metabolizing capacity, knowledge of their intrinsic biotransformation is pivotal in order to correctly interpret the outcome of teratogenicity assays. Therefore, the aim of this in vitro study was to assess the activity of cytochrome P450 (CYP)-a group of drug-metabolizing enzymes-in microsomes from whole zebrafish embryos (ZEM) of 5, 24, 48, 72, 96 and 120 h post-fertilization (hpf) by means of a mammalian CYP substrate, i.e., benzyloxy-methyl-resorufin (BOMR). The same CYP activity assays were performed in adult zebrafish liver microsomes (ZLM) to serve as a reference for the embryos. In addition, activity assays with the human CYP3A4-specific Luciferin isopropyl acetal (Luciferin-IPA) as well as inhibition studies with ketoconazole and CYP3cide were carried out to identify CYP activity in ZLM. In the present study, biotransformation of BOMR was detected at 72 and 96 hpf; however, metabolite formation was low compared with ZLM. Furthermore, Luciferin-IPA was not metabolized by the zebrafish. In conclusion, the capacity of intrinsic biotransformation in zebrafish embryos appears to be lacking during a major part of organogenesis.

  7. Synthesis, characterization, antimicrobial screening and computational studies of 4-[3-(4-methoxy-phenyl)-allylideneamino]-1,5-dimethyl-2-phenyl-1,2-dihydro-pyrazol-3-one

    NASA Astrophysics Data System (ADS)

    Obasi, L. N.; Kaior, G. U.; Rhyman, L.; Alswaidan, Ibrahim A.; Fun, Hoong-Kun; Ramasami, P.

    2016-09-01

    The Schiff base, 4-[3-(4-methoxy-phenyl)-allylideneamino]-1,5-dimethyl-2-phenyl-1,2-dihydro-pyrazol-3-one (TPMC/AAP) was synthesized by the condensation of 4-aminoantipyrine (4-amino-1,5-dimethyl-2-phenylpyrazole-3-one) and trans-para-methoxycinnamaldehyde (trans-3,4-methoxyphenyl-2-propenal) in dry methanol at 75 °C. The compound was characterized using elemental microanalysis, IR, NMR, UV spectroscopies and single-crystal X-ray crystallography. The X-ray structure determination shows that the Schiff base, (TPMC/AAP) is orthorhombic with the Pbca space group. The anti-microbial screening of the compound was carried out with Escherichia coli, Bacillus subtillis, Staphylococcus aureus, Pseudemonas aeruginosa, Candida albicans and Aspergillus niger using agar well diffusion method. The Schiff base possesses significant antimicrobial activity. The minimum inhibitory concentration (MIC) of the compound was also determined and the activity was compared with that of conventional drugs ciprofloxacin and ketoconazole. The compound (TPMC/AAP) showed varying activity against the cultured bacteria and fungi used. To complement the experimental data, density functional theory (DFT) was used to have deeper understanding into the molecular parameters and infrared spectra of the compound.

  8. Recent Advances in Electrochemical Biosensors Based on Enzyme Inhibition for Clinical and Pharmaceutical Applications

    PubMed Central

    El Harrad, Loubna; Bourais, Ilhame; Mohammadi, Hasna; Amine, Aziz

    2018-01-01

    A large number of enzyme inhibitors are used as drugs to treat several diseases such as gout, diabetes, AIDS, depression, Parkinson’s and Alzheimer’s diseases. Electrochemical biosensors based on enzyme inhibition are useful devices for an easy, fast and environment friendly monitoring of inhibitors like drugs. In the last decades, electrochemical biosensors have shown great potentials in the detection of different drugs like neostigmine, ketoconazole, donepezil, allopurinol and many others. They attracted increasing attention due to the advantage of being high sensitive and accurate analytical tools, able to reach low detection limits and the possibility to be performed on real samples. This review will spotlight the research conducted in the past 10 years (2007–2017) on inhibition based enzymatic electrochemical biosensors for the analysis of different drugs. New assays based on novel bio-devices will be debated. Moreover, the exploration of the recent graphical approach in diagnosis of reversible and irreversible inhibition mechanism will be discussed. The accurate and the fast diagnosis of inhibition type will help researchers in further drug design improvements and the identification of new molecules that will serve as new enzyme targets. PMID:29315246

  9. In vivo measurement of human skin absorption of topically applied substances by a photoacoustic technique.

    PubMed

    Gutiérrez-Juárez, G; Vargas-Luna, M; Córdova, T; Varela, J B; Bernal-Alvarado, J J; Sosa, M

    2002-08-01

    A photoacoustic technique is used for studying topically applied substance absorption in human skin. The proposed method utilizes a double-chamber PA cell. The absorption determination was obtained through the measurement of the thermal effusivity of the binary system substance-skin. The theoretical model assumes that the effective thermal effusivity of the binary system corresponds to that of a two-phase system. Experimental applications of the method employed different substances of topical application in different parts of the body of a volunteer. The method is demonstrated to be an easily used non-invasive technique for dermatology research. The relative concentrations as a function of time of substances such as ketoconazol and sunscreen were determined by fitting a sigmoidal function to the data, while an exponential function corresponds to the best fit for the set of data for nitrofurazona, vaseline and vaporub. The time constants associated with the rates of absorption, were found to vary in the range between 10 and 58 min, depending on the substance and the part of the body.

  10. A conceptually new treatment approach for relapsed glioblastoma: Coordinated undermining of survival paths with nine repurposed drugs (CUSP9) by the International Initiative for Accelerated Improvement of Glioblastoma Care

    PubMed Central

    Kast, Richard E.; Boockvar, John A.; Brüning, Ansgar; Cappello, Francesco; Chang, Wen-Wei; Cvek, Boris; Dou, Q. Ping; Duenas-Gonzalez, Alfonso; Efferth, Thomas; Focosi, Daniele; Ghaffari, Seyed H.; Karpel-Massler, Georg; Ketola, Kirsi; Khoshnevisan, Alireza; Keizman, Daniel; Magné, Nicolas; Marosi, Christine; McDonald, Kerrie; Muñoz, Miguel; Paranjpe, Ameya; Pourgholami, Mohammad H.; Sardi, Iacopo; Sella, Avishay; Srivenugopal, Kalkunte S.; Tuccori, Marco; Wang, Weiguang; Wirtz, Christian R.; Halatsch, Marc-Eric

    2013-01-01

    To improve prognosis in recurrent glioblastoma we developed a treatment protocol based on a combination of drugs not traditionally thought of as cytotoxic chemotherapy agents but that have a robust history of being well-tolerated and are already marketed and used for other non-cancer indications. Focus was on adding drugs which met these criteria: a) were pharmacologically well characterized, b) had low likelihood of adding to patient side effect burden, c) had evidence for interfering with a recognized, well-characterized growth promoting element of glioblastoma, and d) were coordinated, as an ensemble had reasonable likelihood of concerted activity against key biological features of glioblastoma growth. We found nine drugs meeting these criteria and propose adding them to continuous low dose temozolomide, a currently accepted treatment for relapsed glioblastoma, in patients with recurrent disease after primary treatment with the Stupp Protocol. The nine adjuvant drug regimen, Coordinated Undermining of Survival Paths, CUSP9, then are aprepitant, artesunate, auranofin, captopril, copper gluconate, disulfiram, ketoconazole, nelfinavir, sertraline, to be added to continuous low dose temozolomide. We discuss each drug in turn and the specific rationale for use- how each drug is expected to retard glioblastoma growth and undermine glioblastoma's compensatory mechanisms engaged during temozolomide treatment. The risks of pharmacological interactions and why we believe this drug mix will increase both quality of life and overall survival are reviewed. PMID:23594434

  11. Currently used and investigational drugs for Cushing´s disease.

    PubMed

    Ciato, Denis; Mumbach, Aizhar G; Paez-Pereda, Marcelo; Stalla, Günter K

    2017-01-01

    Cushing's disease (CD) is caused by a corticotroph adenoma of the pituitary gland that secretes excess adrenocorticotropic hormone (ACTH) causing increased morbidity and mortality. Surgery is the treatment of choice, but is not always successful. Alternatives include radiotherapy, adrenal surgery, and pharmaceutical therapy. The latter is increasingly gaining momentum due to the recent development of compounds that reduce hypercortisolaemia or its symptoms, acting through different mechanisms. Areas covered: In this article, the authors provide a complete overview of the treatment options for Cushing´s disease, including adrenal-directed, tumor-targeted, and peripheral therapies that are currently used or in development, and discuss their potential advantages and limitations. Expert opinion: Considering the lack of long-term remission in up to half of the patients after surgery, and the delayed response to radiotherapy along with potential side effects, there is a strong need for an effective pharmaceutical treatment. Pasireotide, mifepristone, ketoconazole and metyrapone have been approved by regulatory authorities but their use remains limited due to considerable costs and side effects. Research in this field has focused recently on the improvement of pre-existing drugs and the development of safe new ones. However, few approaches aim at targeting the source of the disease, the ACTH-secreting adenoma.

  12. In Vitro Antifungal Susceptibility of Neoscytalidium dimidiatum Clinical Isolates from Malaysia.

    PubMed

    James, Jasper Elvin; Santhanam, Jacinta; Lee, Mei Chen; Wong, Choon Xian; Sabaratnam, Parameswari; Yusoff, Hamidah; Tzar, Mohd Nizam; Razak, Mohd Fuat Abdul

    2017-04-01

    Neoscytalidium dimidiatum is an opportunistic fungus causing cutaneous infections mostly, which are difficult to treat due to antifungal resistance. In Malaysia, N. dimidiatum is associated with skin and nail infections, especially in the elderly. These infections may be mistaken for dermatophyte infections due to similar clinical appearance. In this study, Neoscytalidium isolates from cutaneous specimens, identified using morphological and molecular methods (28 Neoscytalidium dimidiatum and 1 Neoscytalidium sp.), were evaluated for susceptibility towards antifungal agents using the CLSI broth microdilution (M38-A2) and Etest methods. Amphotericin B, voriconazole, miconazole and clotrimazole showed high in vitro activity against all isolates with MIC ranging from 0.0313 to 1 µg/mL. Susceptibility towards fluconazole and itraconazole was noted in up to 10% of isolates, while ketoconazole was inactive against all isolates. Clinical breakpoints for antifungal drugs are not yet available for most filamentous fungi, including Neoscytalidium species. However, the results indicate that clinical isolates of N. dimidiatum in Malaysia were sensitive towards miconazole, clotrimazole, voriconazole and amphotericin B, in vitro.

  13. Bioprospection of actinobacteria derived from freshwater sediments for their potential to produce antimicrobial compounds.

    PubMed

    Zothanpuia; Passari, Ajit Kumar; Leo, Vincent Vineeth; Chandra, Preeti; Kumar, Brijesh; Nayak, Chandra; Hashem, Abeer; Abd Allah, Elsayed Fathi; Alqarawi, Abdulaziz A; Singh, Bhim Pratap

    2018-05-05

    Actinobacteria from freshwater habitats have been explored less than from other habitats in the search for compounds of pharmaceutical value. This study highlighted the abundance of actinobacteria from freshwater sediments of two rivers and one lake, and the isolates were studied for their ability to produce antimicrobial bioactive compounds. 16S rRNA gene sequencing led to the identification of 84 actinobacterial isolates separated into a common genus (Streptomyces) and eight rare genera (Nocardiopsis, Saccharopolyspora, Rhodococcus, Prauserella, Amycolatopsis, Promicromonospora, Kocuria and Micrococcus). All strains that showed significant inhibition potentials were found against Gram-positive, Gram-negative and yeast pathogens. Further, three biosynthetic genes, polyketide synthases type II (PKS II), nonribosomal peptide synthetases (NRPS) and aminodeoxyisochorismate synthase (phzE), were detected in 38, 71 and 29% of the strains, respectively. Six isolates based on their antimicrobial potentials were selected for the detection and quantification of standard antibiotics using ultra performance liquid chromatography (UPLC-ESI-MS/MS) and volatile organic compounds (VOCs) using gas chromatography mass spectrometry (GC/MS). Four antibiotics (fluconazole, trimethoprim, ketoconazole and rifampicin) and 35 VOCs were quantified and determined from the methanolic crude extract of six selected Streptomyces strains. Infectious diseases still remain one of the leading causes of death globally and bacterial infections caused millions of deaths annually. Culturable actinobacteria associated with freshwater lake and river sediments has the prospects for the production of bioactive secondary metabolites.

  14. Co-isolation of Trichosporon inkin and Candida parapsilosis from a scalp white piedra case.

    PubMed

    Taj-Aldeen, Saad J; Al-Ansari, Hamda I; Boekhout, Teun; Theelen, Bart

    2004-02-01

    White piedra is a rare fungal infection of the hair shaft characterized by small, firm, irregular white-brown nodules. The infection is caused by basidiomycetous yeasts in the genus Trichosporon. We report a case of a 28-year-old female patient who acquired the infection in Qatar. In this case, the scalp was the only site affected, but infection at that site was extensive. The hair had a Saccharomyces-like yeast odor and appeared to be beaded, with light-brown nodules of varying sizes up to 2 mm long. Trichosporon sp. accompanied by Candida parapsilosis grew out along hair shafts planted in primary isolation media. Molecular identification of the Trichosporon carried out by analyzing the 26S ribosomal gene gave a 100% match with Trichosporon inkin, a major cause of pubic white piedra. The patient was treated with daily applications of ketoconazole shampoo followed by econazole shampoo and cream, and was considered clinically and mycologically cured after 2 months. Novel findings in the present case are the first identification of T. inkin as an agent of scalp white piedra, and the heavy outgrowth of C. parapsilosis from the concretions, although in the latter case it is not clear if the co-occurring yeast was etiologically contributory to the pathogenesis of the white piedra.

  15. Cytochrome P-450 isoforms involved in carboxylic acid ester cleavage of Hantzsch pyridine ester of pranidipine.

    PubMed

    Kudo, S; Okumura, H; Miyamoto, G; Ishizaki, T

    1999-02-01

    Cytochrome P-450 (CYP) isoforms responsible for the cleavage of Hantzsch pyridine ester at the 3-position of pranidipine were studied in vitro using cDNA-expressed human CYP enzymes. CYP1A1, 1A2, 2D6, and 3A4 cleaved the ester with a catalytic activity of 5.5, 0. 93, 13.1, and 22.4 nmol/30 min/nmol P-450, respectively. CYP2A6, 2B6, 2C8, 2C9, 2C19, and 2E1 were not involved in the de-esterification. The Km and Vmax values for the de-esterification were 11.8 microM and 0.47 nmol/min/nmol P-450 in the CYP2D6-catalyzed reaction and 8. 7 microM and 0.84 nmol/min/nmol P-450 in the CYP3A4-catalyzed reaction. The intrinsic clearance (Vmax/Km) of the de-esterification by CYP3A4 was 2-fold greater than that by CYP2D6. Quinidine almost completely inhibited the CYP2D6-mediated de-esterification at the concentration of 1 x 10(-6) M. Ketoconazole and troleandomycin inhibited the CYP3A4-mediated reaction in a dose-related manner. The results indicate that although the multiple CYP isoforms can catalyze the de-esterification, CYP3A4 and 2D6 are the major isoforms.

  16. In vitro metabolism and interaction of cilostazol with human hepatic cytochrome P450 isoforms.

    PubMed

    Abbas, R; Chow, C P; Browder, N J; Thacker, D; Bramer, S L; Fu, C J; Forbes, W; Odomi, M; Flockhart, D A

    2000-03-01

    1. Cilostazol (OPC-13013) undergoes extensive hepatic metabolism. The hydroxylation of the quinone moiety of cilostazol to OPC-13326 was the predominant route in all the liver preparations studies. The hydroxylation of the hexane moiety to OPC-13217 was the second most predominant route in vitro. 2. Ketoconazole (1 microM) was the most potent inhibitor of both quinone and hexane hydroxylation. Both the CYP2D6 inhibitor quinidine (0.1 microM) and the CYP2C19 inhibitor omeprazole (10 microM) failed to consistently inhibit metabolism of cilostazol via either of these two predominant routes. 3. Data obtained from a bank of pre-characterized human liver microsomes demonstrated a stronger correlation (r2=0.68, P < 0.01) between metabolism of cilostazol to OPC-13326 and metabolism of felodipine, a CYP3A probe, that with probes for any other isoform. Cimetidine demonstrated concentration-dependent competitive inhibition of the metabolism of cilostazol by both routes. 4. Kinetic data demonstrated a Km value of 101 microM for cilostazol, suggesting a relatively low affinity of cilostazol for CYP3A. While recombinant CYP1A2, CYP2D6 and CYP2C19 were also able to catalyze formation of specific cilostazol metabolites, they did not appear to contribute significantly to cilostazol metabolism in whole human liver microsomes.

  17. [Morphological characteristics and physiological properties of aflatoxin B1 producing and non-producing Aspergillus flavus strains].

    PubMed

    Kogbo, W; Lemarinier, S; Boutibonnes, P

    1985-09-01

    Comparison between about 80 strains of Aspergillus flavus, belonging to the series flavus and oryzae, obtained from international collections but also isolated from French or African substrates revealed the following observations: 1. Cultural and morphological characteristics of toxicogenic and atoxicogenic strains of A. flavus are similar. However, the former produce a diffusible yellow pigment in 83% of isolates. 2. The two groups of conidiospores have the same resistance to UV irradiation (254 nm, 5 and 10 min). All the strains are equally sensitive to 4 antifungal antibiotics: nystatine, ketoconazole, clotrimazole and amphotericine. 3. A difference was seen in the capacity to produce enzymes as alpha-galactosidase, beta-galactosidase and beta-glucosidase, implicated in the glucid metabolism. The specific hydrolytic activity has been confirmed by the characterization of a large amount of beta-galactosidase and by a diauxic growth on glucose medium supplemented by lactose. Possible relationship between these characters and aflatoxin B1 production by A. flavus strains is discussed.

  18. PCOS.

    PubMed

    Cahill, David

    2009-01-15

    Polycystic ovary syndrome (PCOS) is diagnosed in up to 10% of women attending gynaecology clinics, but the prevalence in the population as a whole is unclear. PCOS has been associated with hirsutism, infertility, acne, weight gain, type 2 diabetes, cardiovascular disease (CVD), and endometrial hyperplasia. We conducted a systematic review and aimed to answer the following clinical question: What are the effects of treatments? We searched: Medline, Embase, The Cochrane Library, and other important databases up to December 2007 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). We found 24 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. In this systematic review we present information relating to the effectiveness and safety of the following interventions: finasteride, flutamide, metformin, spironolactone, cyproterone acetate-ethinylestradiol (co-cyprindiol), interventions to achieve weight loss, ketoconazole, and mechanical hair removal.

  19. Quantitative determination of some pharmaceutical piperazine derivatives through complexation with iron(III) chloride.

    PubMed

    Abou-Attia, F M; Issa, Y M; Abdel-Gawad, F M; Abdel-Hamid, S M

    2003-08-01

    A simple, accurate and sensitive spectrophotometric method has been developed for the determination of three pharmaceutical piperazine derivatives, namely ketoconazole (KC), trimetazidine hydrochloride (TMH) and piribedil (PD). This method is based on the formation of yellow orange complexes between iron(III) chloride and the investigated drugs. The optimum reaction conditions, spectral characteristics, conditional stability constants and composition of the water soluble complexes have been established. The method permits the determination of KC, TMH and PD over a concentration range 1-15, 1-12 and 1-12 microg ml(-1), respectively. Sandell sensitivity is found to be 0.016, 0.013 and 0.013 microg cm(-2) for KC, TMH and PD, respectively. The method was sensitive, simple, reproducible and accurate within +/-1.5%. The method is applicable to the assay of the three drugs under investigation in different dosage forms and the results are in good agreement with those obtained by the official methods (USP and JP).

  20. Yeast Colonization and Drug Susceptibility Pattern in the Pediatric Patients With Neutropenia

    PubMed Central

    Haddadi, Pedram; Zareifar, Soheila; Badiee, Parisa; Alborzi, Abdolvahab; Mokhtari, Maral; Zomorodian, Kamiar; Pakshir, Keyvan; Jafarian, Hadis

    2014-01-01

    Background: Pediatric patients with neutropenia are vulnerable to invasive Candida infections. Candida is the primary cause of fungal infections, particularly in immunosuppressed patients. Candida albicans has been the most common etiologic agent of these infections, affecting 48% of patients Objectives: The aim of this study was to identify Candida spp. isolated from children with neutropenia and determine the antifungal susceptibility pattern of the isolated yeasts. Patients and Methods: In this study 188 children with neutropenia were recruited, fungal surveillance cultures were carried out on nose, oropharynx, stool, and urine samples. Identification of Candida strains was performed using germ tube and chlamydospore production tests on an API 20 C AUX system. Susceptibility testing on seven antifungal agents was performed using the agar-based E-test method. Results: A total of 229 yeasts were isolated. Among those, C. albicans was the most common species followed by C. krusei, C. parapsilosis, C. glabrata, C. tropicalis, C. famata, C. dubliniensis, C. kefyr, and other Candida species. C. glabrata was the most resistant isolated yeasts, which was 70% resistant to fluconazole and 50% to itraconazole, 7.5% to amphotericin B and 14% to ketoconazole. All the tested species were mostly sensitive to caspofungin. Conclusions: Knowledge about the susceptibility patterns of colonized Candida spp. can be helpful for clinicians to manage pediatric patients with neutropenia. In this study, caspofungin was the most effective antifungal agent against the colonized Candida spp. followed by conventional amphotericin B. PMID:25485060

  1. A human intermediate conductance calcium-activated potassium channel.

    PubMed

    Ishii, T M; Silvia, C; Hirschberg, B; Bond, C T; Adelman, J P; Maylie, J

    1997-10-14

    An intermediate conductance calcium-activated potassium channel, hIK1, was cloned from human pancreas. The predicted amino acid sequence is related to, but distinct from, the small conductance calcium-activated potassium channel subfamily, which is approximately 50% conserved. hIK1 mRNA was detected in peripheral tissues but not in brain. Expression of hIK1 in Xenopus oocytes gave rise to inwardly rectifying potassium currents, which were activated by submicromolar concentrations of intracellular calcium (K0.5 = 0.3 microM). Although the K0.5 for calcium was similar to that of small conductance calcium-activated potassium channels, the slope factor derived from the Hill equation was significantly reduced (1.7 vs. 3. 5). Single-channel current amplitudes reflected the macroscopic inward rectification and revealed a conductance level of 39 pS in the inward direction. hIK1 currents were reversibly blocked by charybdotoxin (Ki = 2.5 nM) and clotrimazole (Ki = 24.8 nM) but were minimally affected by apamin (100 nM), iberiotoxin (50 nM), or ketoconazole (10 microM). These biophysical and pharmacological properties are consistent with native intermediate conductance calcium-activated potassium channels, including the erythrocyte Gardos channel.

  2. A human intermediate conductance calcium-activated potassium channel

    PubMed Central

    Ishii, Takahiro M.; Silvia, Christopher; Hirschberg, Birgit; Bond, Chris T.; Adelman, John P.; Maylie, James

    1997-01-01

    An intermediate conductance calcium-activated potassium channel, hIK1, was cloned from human pancreas. The predicted amino acid sequence is related to, but distinct from, the small conductance calcium-activated potassium channel subfamily, which is ≈50% conserved. hIK1 mRNA was detected in peripheral tissues but not in brain. Expression of hIK1 in Xenopus oocytes gave rise to inwardly rectifying potassium currents, which were activated by submicromolar concentrations of intracellular calcium (K0.5 = 0.3 μM). Although the K0.5 for calcium was similar to that of small conductance calcium-activated potassium channels, the slope factor derived from the Hill equation was significantly reduced (1.7 vs. 3.5). Single-channel current amplitudes reflected the macroscopic inward rectification and revealed a conductance level of 39 pS in the inward direction. hIK1 currents were reversibly blocked by charybdotoxin (Ki = 2.5 nM) and clotrimazole (Ki = 24.8 nM) but were minimally affected by apamin (100 nM), iberiotoxin (50 nM), or ketoconazole (10 μM). These biophysical and pharmacological properties are consistent with native intermediate conductance calcium-activated potassium channels, including the erythrocyte Gardos channel. PMID:9326665

  3. Regioselective hydroxylation of isoflavones by Streptomyces avermitilis MA-4680.

    PubMed

    Roh, Changhyun; Seo, Su-Hyun; Choi, Kwon-Young; Cha, Minho; Pandey, Bishnu Prasad; Kim, June-Hyung; Park, Jun-Seong; Kim, Duck Hee; Chang, Ih Seop; Kim, Byung-Gee

    2009-07-01

    Screening of bacterial whole cells was performed for regioselective hydroxylation of daidzein and genistein. Among the strains examined, Streptomyces avermitilis MA-4680 showed high ortho-dihydroxylation activity to produce 3',4',7-trihydroxyisoflavone and 3',4',5,7-tetrahydroxyisoflavone from daidzein (4',7-dihydroxyisoflavone) and genistein (4',5,7-trihydroxyisoflavone), respectively. Using 100 mg cells (wet wt.) and 1% (v/v) Triton X100 in 1 ml of total reaction volume, where 100 microl of the substrate solution (0.5 mM in 10% (v/v) mixed solvent of DMSO:MeOH = 3:7) was added to 900 microl of potassium phosphate buffer (100 mM, pH 7.2), a 16% molar conversion yield of 3',4',7-trihydroxyisoflavone was obtained from 0.5 mM daidzein after 24 h of reaction time at 28 degrees C and 200 rpm. Ketoconazole significantly (ca. 90%) inhibited the ortho-hydroxylation activity of daidzein, suggesting that cytochrome P450 enzymes putatively play roles in regiospecific daidzein hydroxylation. The analysis of the reaction products was determined by gas chromatography/mass spectrometry (GC/MS) and (1)H NMR.

  4. Purification, Reconstitution, and Inhibition of Cytochrome P-450 Sterol Δ22-Desaturase from the Pathogenic Fungus Candida glabrata

    PubMed Central

    Lamb, David C.; Maspahy, Segula; Kelly, Diane E.; Manning, Nigel J.; Geber, Antonia; Bennett, John E.; Kelly, Steven L.

    1999-01-01

    Sterol Δ22-desaturase has been purified from a strain of Candida glabrata with a disruption in the gene encoding sterol 14α-demethylase (cytochrome P-45051; CYP51). The purified cytochrome P-450 exhibited sterol Δ22-desaturase activity in a reconstituted system with NADPH–cytochrome P-450 reductase in dilaurylphosphatidylcholine, with the enzyme kinetic studies revealing a Km for ergosta-5,7-dienol of 12.5 μM and a Vmax of 0.59 nmol of this substrate metabolized/min/nmol of P-450. This enzyme is encoded by CYP61 (ERG5) in Saccharomyces cerevisiae, and homologues have been shown in the Candida albicans and Schizosaccharomyces pombe genome projects. Ketoconazole, itraconazole, and fluconazole formed low-spin complexes with the ferric cytochrome and exhibited type II spectra, which are indicative of an interaction between the azole moiety and the cytochrome heme. The azole antifungal compounds inhibited reconstituted sterol Δ22-desaturase activity by binding to the cytochrome with a one-to-one stoichiometry, with total inhibition of enzyme activity occurring when equimolar amounts of azole and cytochrome P-450 were added. These results reveal the potential for sterol Δ22-desaturase to be an antifungal target and to contribute to the binding of drugs within the fungal cell. PMID:10390230

  5. Topical Treatment of Facial Seborrheic Dermatitis: A Systematic Review.

    PubMed

    Gupta, Aditya K; Versteeg, Sarah G

    2017-04-01

    Facial seborrheic dermatitis (SD), a chronic inflammatory skin condition, can impact quality of life, and relapses can be frequent. Three broad categories of agents are used to treat SD: antifungal agents, keratolytics, and corticosteroids. Topical therapies are the first line of defense in treating this condition. Our objective was to critically review the published literature on topical treatments for facial SD. We searched PubMed, Scopus, Clinicaltrials.gov, MEDLINE, Embase, and Cochrane library databases for original clinical studies evaluating topical treatments for SD. We then conducted both a critical analysis of the selected studies by grading the evidence and a qualitative comparison of results among and within studies. A total of 32 studies were eligible for inclusion, encompassing 18 topical treatments for facial SD. Pimecrolimus, the focus of seven of the 32 eligible studies, was the most commonly studied topical treatment. Promiseb ® , desonide, mometasone furoate, and pimecrolimus were found to be effective topical treatments for facial SD, as they had the lowest recurrence rate, highest clearance rate, and the lowest severity scores (e.g., erythema, scaling, and pruritus), respectively. Ciclopirox olamine, ketoconazole, lithium (gluconate and succinate), and tacrolimus are also strongly recommended (level A recommendations) topical treatments for facial SD, as they are consistently effective across high-quality trials (randomized controlled trials).

  6. Mechanistic Physiologically Based Pharmacokinetic Modeling of the Dissolution and Food Effect of a Biopharmaceutics Classification System IV Compound-The Venetoclax Story.

    PubMed

    Emami Riedmaier, Arian; Lindley, David J; Hall, Jeffrey A; Castleberry, Steven; Slade, Russell T; Stuart, Patricia; Carr, Robert A; Borchardt, Thomas B; Bow, Daniel A J; Nijsen, Marjoleen

    2018-01-01

    Venetoclax, a selective B-cell lymphoma-2 inhibitor, is a biopharmaceutics classification system class IV compound. The aim of this study was to develop a physiologically based pharmacokinetic (PBPK) model to mechanistically describe absorption and disposition of an amorphous solid dispersion formulation of venetoclax in humans. A mechanistic PBPK model was developed incorporating measured amorphous solubility, dissolution, metabolism, and plasma protein binding. A middle-out approach was used to define permeability. Model predictions of oral venetoclax pharmacokinetics were verified against clinical studies of fed and fasted healthy volunteers, and clinical drug interaction studies with strong CYP3A inhibitor (ketoconazole) and inducer (rifampicin). Model verification demonstrated accurate prediction of the observed food effect following a low-fat diet. Ratios of predicted versus observed C max and area under the curve of venetoclax were within 0.8- to 1.25-fold of observed ratios for strong CYP3A inhibitor and inducer interactions, indicating that the venetoclax elimination pathway was correctly specified. The verified venetoclax PBPK model is one of the first examples mechanistically capturing absorption, food effect, and exposure of an amorphous solid dispersion formulated compound. This model allows evaluation of untested drug-drug interactions, especially those primarily occurring in the intestine, and paves the way for future modeling of biopharmaceutics classification system IV compounds. Copyright © 2018 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

  7. Characterisation of the cytochrome P450 enzymes involved in the in vitro metabolism of granisetron.

    PubMed Central

    Bloomer, J C; Baldwin, S J; Smith, G J; Ayrton, A D; Clarke, S E; Chenery, R J

    1994-01-01

    1. The metabolism of granisetron was investigated in human liver microsomes to identify the specific forms of cytochrome P450 responsible. 2. 7-hydroxy and 9'-desmethyl granisetron were identified as the major products of metabolism following incubation of granisetron with human liver microsomes. At low, clinically relevant, concentrations of granisetron the 7-hydroxy metabolite predominated. Rates of granisetron 7-hydroxylation varied over 100-fold in the human livers investigated. 3. Enzyme kinetics demonstrated the involvement of at least two enzymes contributing to the 7-hydroxylation of granisetron, one of which was a high affinity component with a Km of 4 microM. A single, low affinity, enzyme was responsible for the 9'-desmethylation of granisetron. 4. Granisetron caused no inhibition of any of the cytochrome P450 activities investigated (CYP1A2, CYP2A6, CYP2B6, CYP2C9/8, CYP2C19, CYP2D6, CYP2E1 and CYP3A), at concentrations up to 250 microM. 5. Studies using chemical inhibitors selective for individual P450 enzymes indicated the involvement of cytochrome P450 3A (CYP3A), both pathways of granisetron metabolism being very sensitive to ketoconazole inhibition. Correlation data were consistent with the role of CYP3A3/4 in granisetron 9'-desmethylation but indicated that a different enzyme was involved in the 7-hydroxylation. PMID:7888294

  8. Evaluation of virulence factors and antifungal susceptibility patterns of different Candida species isolated from the female camel (Camelus dromedarius) genital tract.

    PubMed

    Sharifzadeh, Aghil; Soltani, Minoo; Shokri, Hojjatollah

    2015-08-01

    The purposes of this study were to investigate the enzymatic activity of different Candida species and their antifungal susceptibility patterns. The study involved a total of 83 isolates of Candida from the genital tract of the female Camelus dromedarius. After species identification, the isolates were analysed for the production/activity of phospholipase, proteinase and haemolysin. In addition, the agar disc diffusion method was performed on the basis of CLSI guidelines M44-A2 protocol for antifungal susceptibility testing. All the isolates were able to produce phospholipase, proteinase and haemolysin. A total of 35.48%, 87.09% and 64.51% of C. albicans isolates exhibited very high phospholipase, proteinase and haemolytic activities, respectively, whereas very high phospholipase, proteinase and haemolytic activities were determined in 5.76%, 23.07% and 45.16% of non-C. albicans isolates respectively. Overall, 61 (73.5%) of Candida isolates were susceptible to fluconazole, 70 (84.3%) susceptible to clotrimazole, 82 (98.8%) susceptible to voriconazole, 76 (91.6%) susceptible to itraconazole, 75 (90.4%) susceptible to ketoconazole, 83 (100%) susceptible to amphotericin B, 81 (97.6%) susceptible to nystatin and 36 (43.4%) susceptible to flucytosine. Candida isolates showed higher haemolytic activity than that of other secreted hydrolases among vaginal Candida species. In addition, amphotericin B was the most in vitro effective antifungal drug and flucytosine had the poorest activity under such conditions. © 2015 Blackwell Verlag GmbH.

  9. Aromatase inhibitory activity of 1,4-naphthoquinone derivatives and QSAR study

    PubMed Central

    Prachayasittikul, Veda; Pingaew, Ratchanok; Worachartcheewan, Apilak; Sitthimonchai, Somkid; Nantasenamat, Chanin; Prachayasittikul, Supaluk; Ruchirawat, Somsak; Prachayasittikul, Virapong

    2017-01-01

    A series of 2-amino(chloro)-3-chloro-1,4-naphthoquinone derivatives (1-11) were investigated for their aromatase inhibitory activities. 1,4-Naphthoquinones 1 and 4 were found to be the most potent compounds affording IC50 values 5.2 times lower than the reference drug, ketoconazole. A quantitative structure-activity relationship (QSAR) model provided good predictive performance (R2CV = 0.9783 and RMSECV = 0.0748) and indicated mass (Mor04m and H8m), electronegativity (Mor08e), van der Waals volume (G1v) and structural information content index (SIC2) descriptors as key descriptors governing the activity. To investigate the effects of structural modifications on aromatase inhibitory activity, the model was employed to predict the activities of an additional set of 39 structurally modified compounds constructed in silico. The prediction suggested that the 2,3-disubstitution of 1,4-naphthoquinone ring with halogen atoms (i.e., Br, I and F) is the most effective modification for potent activity (1a, 1b and 1c). Importantly, compound 1b was predicted to be more potent than its parent compound 1 (11.90-fold) and the reference drug, letrozole (1.03-fold). The study suggests the 1,4-naphthoquinone derivatives as promising compounds to be further developed as a novel class of aromatase inhibitors. PMID:28827987

  10. Therapeutic effectiveness of Ageratina pichinchensis on the treatment of chronic interdigital tinea pedis: a randomized, double-blind clinical trial.

    PubMed

    Romero-Cerecero, Ofelia; Zamilpa, Alejandro; Jiménez-Ferrer, Enrique; Tortoriello, Jaime

    2012-06-01

    Interdigital tinea pedis is the most frequent presentation, as well as the most severe clinical form of tinea pedis, constituting a therapeutic challenge. The aim of the study was to evaluate the effectiveness and tolerability of two concentrations of Ageratina pichinchensis extract (encecalin content, 0.76 and 1.52%, respectively) on patients with clinical and mycological diagnosis of chronic interdigital tinea pedis. By means of a randomized, double-blind clinical trial, three groups of patients were treated topically for 4 weeks with a cream containing the following: Group I-the lower concentration of A. pichinchensis extract, group II-the higher concentration, group III-2% ketoconazole. One hundred and sixty (160) ambulatory patients of either sex between the ages of 18 and 65 years were enrolled. The primary outcome variables were: clinical effectiveness, mycological effectiveness, therapeutic cure, tolerability, and treatment compliance. The secondary outcome variable was therapeutic success. At the end of treatment, therapeutic cure was achieved by 34.1, 41.8, and 39.53% of Groups I, II, and III, respectively. No statistical difference between the groups was observed. Both treatments were effective for the treatment of interdigital-type tinea pedis, while better results were observed on patients that received the higher concentration of the extract.

  11. Clinical, Morphological, and Molecular Characterization of Penicillium canis sp. nov., Isolated from a Dog with Osteomyelitis

    PubMed Central

    Sutton, Deanna A.; Swenson, Cheryl L.; Bailey, Chris J.; Wiederhold, Nathan P.; Nelson, Nathan C.; Thompson, Elizabeth H.; Wickes, Brian L.; French, Stephanie; Fu, Jianmin; Vilar-Saavedra, Paulo

    2014-01-01

    Infections caused by Penicillium species are rare in dogs, and the prognosis in these cases is poor. An unknown species of Penicillium was isolated from a bone lesion in a young dog with osteomyelitis of the right ilium. Extensive diagnostic evaluation did not reveal evidence of dissemination. Resolution of lameness and clinical stability of disease were achieved with intravenous phospholipid-complexed amphotericin B initially, followed by long-term combination therapy with terbinafine and ketoconazole. A detailed morphological and molecular characterization of the mold was undertaken. Sequence analysis of the internal transcribed spacer revealed the isolate to be closely related to Penicillium menonorum and Penicillium pimiteouiense. Additional sequence analysis of β-tubulin, calmodulin, minichromosome maintenance factor, DNA-dependent RNA polymerase, and pre-rRNA processing protein revealed the isolate to be a novel species; the name Penicillium canis sp. nov. is proposed. Morphologically, smooth, ovoid conidia, a greenish gray colony color, slow growth on all media, and a failure to form ascomata distinguish this species from closely related Penicillium species. PMID:24789186

  12. Clinical, morphological, and molecular characterization of Penicillium canis sp. nov., isolated from a dog with osteomyelitis.

    PubMed

    Langlois, Daniel K; Sutton, Deanna A; Swenson, Cheryl L; Bailey, Chris J; Wiederhold, Nathan P; Nelson, Nathan C; Thompson, Elizabeth H; Wickes, Brian L; French, Stephanie; Fu, Jianmin; Vilar-Saavedra, Paulo; Peterson, Stephen W

    2014-07-01

    Infections caused by Penicillium species are rare in dogs, and the prognosis in these cases is poor. An unknown species of Penicillium was isolated from a bone lesion in a young dog with osteomyelitis of the right ilium. Extensive diagnostic evaluation did not reveal evidence of dissemination. Resolution of lameness and clinical stability of disease were achieved with intravenous phospholipid-complexed amphotericin B initially, followed by long-term combination therapy with terbinafine and ketoconazole. A detailed morphological and molecular characterization of the mold was undertaken. Sequence analysis of the internal transcribed spacer revealed the isolate to be closely related to Penicillium menonorum and Penicillium pimiteouiense. Additional sequence analysis of β-tubulin, calmodulin, minichromosome maintenance factor, DNA-dependent RNA polymerase, and pre-rRNA processing protein revealed the isolate to be a novel species; the name Penicillium canis sp. nov. is proposed. Morphologically, smooth, ovoid conidia, a greenish gray colony color, slow growth on all media, and a failure to form ascomata distinguish this species from closely related Penicillium species. Copyright © 2014, American Society for Microbiology. All Rights Reserved.

  13. Nocardia transvalensis keratitis: an emerging pathology among travelers returning from Asia.

    PubMed

    Trichet, Elodie; Cohen-Bacrie, Stéphan; Conrath, John; Drancourt, Michel; Hoffart, Louis

    2011-10-31

    The incidence rate of Nocardia keratitis is increasing, with new species identified thanks to molecular methods. We herein report a case of Nocardia transvalensis keratitis, illustrating this emerging pathology among travellers returning from Asia. A 23-year-old man presented with a 10-week history of ocular pain, redness, and blurred vision in his right eye following a projectile foreign body impacting the cornea while motor biking in Thaïland. At presentation, a central epithelial defect with a central whitish stromal infiltrate associated with pinhead satellite infiltrates was observed. Identification with 16S rRNA PCR sequencing and microbiological culture of corneal scraping and revealed N. transvalensis as the causative organism. Treatment was initiated with intensive topical amikacin, oral ketoconazole and oral doxycycline. After a four-week treatment period, the corneal infiltrate decreased so that only a faint subepithelial opacity remained. Nocardia organisms should be suspected as the causative agent of any case of keratitis in travelers returning from Asia. With appropriate therapy, Nocardia keratitis resolves, resulting in good visual outcome.

  14. Cushing's disease in dogs: cabergoline treatment.

    PubMed

    Castillo, V A; Gómez, N V; Lalia, J C; Cabrera Blatter, M F; García, J D

    2008-08-01

    The treatment of pituitary-dependent hyperadrenocorticism (PDH) in dogs has for a long time been focused on inhibiting the adrenal gland using drugs such as o-p'-DDD, Ketoconazole and Trilostane, without attacking the primary cause: the corticotrophinoma. Corticotroph cells can express the D2 dopaminergic receptor; therefore cabergoline (Cbg) could be effective as a treatment. Follow-up over 4 years was carried out in 40 dogs with PDH that were treated with Cbg (0.07 mg/kg/week. Out of the 40 dogs, 17 responded to Cbg (42.5%). A year after the treatment, there was a significant decrease in ACTH (p<0.0001), alpha-MSH (p<0.01), urinary cortisol/creatinine ratio (p<0.001), and of the tumor size (p<0.0001) evaluated by nuclear magnetic resonance. Dogs responding to Cbg lived significantly longer (p<0.001) than those in the control group. To conclude, Cbg is useful in 42.5% of dogs with PDH, justifying its use as a treatment.

  15. Retinoic acid as a novel medical therapy for Cushing's disease in dogs.

    PubMed

    Castillo, Victor; Giacomini, Damiana; Páez-Pereda, Marcelo; Stalla, Johanna; Labeur, Marta; Theodoropoulou, Marily; Holsboer, Florian; Grossman, Ashley B; Stalla, Günter K; Arzt, Eduardo

    2006-09-01

    Cushing's disease is almost always caused by an ACTH-secreting pituitary tumor, but effective medical therapy is currently limited. Because retinoic acid has been shown to be potentially useful in decreasing corticotroph secretion and proliferation in rodent models, we have studied its action in dogs with Cushing's disease. A randomized treatment with retinoic acid (n = 22) vs. ketoconazole (n = 20) in dogs with Cushing's disease was assigned for a period of 180 d. Clinical signs, plasma ACTH and alpha-MSH, the cortisol/creatinine urine ratio, and pituitary magnetic resonance imaging were assessed and compared at different time points. We recorded a significant reduction in plasma ACTH and alpha-MSH, and also in the cortisol/creatinine urine ratio, of the dogs treated with retinoic acid. Pituitary adenoma size was also significantly reduced at the end of retinoic acid treatment. Survival time and all the clinical signs evaluated showed an improvement in the retinoic-acid-treated dogs. No adverse events or signs of hepatotoxicity were observed, suggesting that the drug is not only effective but also safe. Retinoic acid treatment controls ACTH and cortisol hyperactivity and tumor size in dogs with ACTH-secreting tumors, leading to resolution of the clinical phenotype. This study highlights the possibility of using retinoic acid as a novel therapy in the treatment of ACTH-secreting tumors in humans with Cushing's disease.

  16. Species differences in metabolism of EPZ015666, an oxetane-containing protein arginine methyltransferase-5 (PRMT5) inhibitor.

    PubMed

    Rioux, Nathalie; Duncan, Kenneth W; Lantz, Ronald J; Miao, Xiusheng; Chan-Penebre, Elayne; Moyer, Mikel P; Munchhof, Michael J; Copeland, Robert A; Chesworth, Richard; Waters, Nigel J

    2016-01-01

    1. Metabolite profiling and identification studies were conducted to understand the cross-species differences in the metabolic clearance of EPZ015666, a first-in-class protein arginine methyltransferase-5 (PRMT5) inhibitor, with anti-proliferative effects in preclinical models of Mantle Cell Lymphoma. EPZ015666 exhibited low clearance in human, mouse and rat liver microsomes, in part by introduction of a 3-substituted oxetane ring on the molecule. In contrast, a higher clearance was observed in dog liver microsomes (DLM) that translated to a higher in vivo clearance in dog compared with rodent. 2. Structure elucidation via high resolution, accurate mass LC-MS(n) revealed that the prominent metabolites of EPZ015666 were present in hepatocytes from all species, with the highest turnover rate in dogs. M1 and M2 resulted from oxidative oxetane ring scission, whereas M3 resulted from loss of the oxetane ring via an N-dealkylation reaction. 3. The formation of M1 and M2 in DLM was significantly abrogated in the presence of the specific CYP2D inhibitor, quinidine, and to a lesser extent by the CYP3A inhibitor, ketoconazole, corroborating data from human recombinant isozymes. 4. Our data indicate a marked species difference in the metabolism of the PRMT5 inhibitor EPZ015666, with oxetane ring scission the predominant metabolic pathway in dog mediated largely by CYP2D.

  17. Development of an in vitro test battery for assessing chemical effects on bovine germ cells under the ReProTect umbrella

    SciT

    Lazzari, Giovanna; Tessaro, Irene; Crotti, Gabriella

    2008-12-15

    Current European legislation for the registration and authorisation of chemicals (REACH) will require a dramatic increase in the use of animals for reproductive toxicity testing. Since one objective of REACH is to use vertebrates only as last resort, the development and validation of alternative methods is urgently needed. For this purpose ReProTect, an integrated research project funded by the European Union, joining together 33 partners with complementary expertise in reproductive toxicology, was designed. The study presented here describes a battery of two tests developed within ReProTect. The objective of these tests is the detection of chemical effects during the processesmore » of oocyte maturation and fertilisation in a bovine model. The corresponding toxicological endpoints are the reaching of metaphase II and the formation of the pronuclei respectively. Fifteen chemicals have been tested (Benzo[a]pyrene, Busulfan, Butylparaben, Cadmium Chloride, Carbendazim, Cycloheximide, Diethylstilbestrol, Genistein, Ionomycin, Ketoconazole, Lindane, Methylacetoacetate, Mifepristone, Nocodazole and DMSO as solvent) demonstrating high intra-laboratory reproducibility of the tests. Furthermore, the responses obtained in both tests, for several substances, had a good correlation with the available in vivo and in vitro data. These tests therefore, could predictably become part of an integrated testing strategy that combines the bovine models with additional in vitro tests, in order to predict chemical hazards on mammalian fertility.« less

  18. Stereoselective metabolism of tetrahydropalmatine enantiomers in rat liver microsomes.

    PubMed

    Zhao, Ming; Li, Li-Ping; Sun, Dong-Li; Sun, Si-Yuan; Huang, Shan-Ding; Zeng, Su; Jiang, Hui-Di

    2012-05-01

    Tetrahydropalmatine (THP), with one chiral center, is an active alkaloid ingredient in Rhizoma Corydalis. The aim of the present paper is to study whether THP enantiomers are metabolized stereoselectively in rat, mouse, dog, and monkey liver microsomes, and then, to elucidate which Cytochrome P450 (CYP) isoforms are predominately responsible for the stereoselective metabolism of THP enantiomers in rat liver microsomes (RLM). The results demonstrated that (+)-THP was preferentially metabolized by liver microsomes from rats, mice, dogs, and monkeys, and the intrinsic clearance (Cl(int)) ratios of (+)-THP to (-)-THP were 2.66, 2.85, 4.24, and 1.67, respectively. Compared with the metabolism in untreated RLM, the metabolism of (-)-THP and (+)-THP was significantly increased in dexamethasone (Dex)-induced and β-naphthoflavone (β-NF)-induced RLM; meanwhile, the Cl(int) ratios of (+)-THP to (-)-THP in Dex-induced and β-NF-induced RLM were 5.74 and 0.81, respectively. Ketoconazole had stronger inhibitory effect on (+)-THP than (-)-THP, whereas fluvoxamine had stronger effect on (-)-THP in untreated and Dex-induced or β-NF-induced RLM. The results suggested that THP enantiomers were predominately metabolized by CYP3A1/2 and CYP1A2 in RLM, and CYP3A1/2 preferred to metabolize (+)-THP, whereas CYP1A2 preferred (-)-THP. Copyright © 2012 Wiley Periodicals, Inc.

  19. ARACHIDONIC ACID PRODUCTS IN AIRWAY NOCICEPTOR ACTIVATION DURING ACUTE LUNG INJURY

    PubMed Central

    Lin, Shuxin; Li, Huafeng; Xu, Ling; Moldoveanu, Bogdan; Guardiola, Juan; Yu, Jerry

    2011-01-01

    We have reported that airway nociceptors [C fiber receptors (CFRs) and high threshold A-delta fiber receptors (HTARs)] are activated during oleic acid (OA) induced acute lung injury. In the current studies, we tested the hypothesis that this nociceptor activation is mediated by arachidonic acid products. In anesthetized, open chest, and mechanically ventilated rabbits, we examined the response of the nociceptors to intravenous injection of OA before and after blocking the cyclo-oxygenase pathways by indomethacin. Pre-treatment with indomethacin (20 mg/kg) decreased the background activities of both CFRs (from 0.48±0.12 to 0.25±0.08, n=7, p<0.05) and HTARs (from 0.54±0.14 to 0.23±0.08, n=10, p<0.01). It also blocked the nociceptors’ response to OA. Similarly, pre-treatment with thromboxane synthase inhibitor (ketoconazole) also blocked the nociceptor response to OA. In addition, local microinjection or intravenous injection of a thromboxane mimetic stimulated CFRs and HTARs. The current results clearly indicate that arachidonic acid metabolites mediate airway nociceptor activation during OA-induced acute lung injury and suggest that thromboxane may be a key mediator. PMID:21622966

  20. Lecythophora hoffmannii isolated from a case of canine osteomyelitis in Japan.

    PubMed

    Sakaeyama, Shin-Ichi; Sano, Ayako; Murata, Yoshiteru; Kamei, Katsuhiko; Nishimura, Kazuko; Hatai, Kishio

    2007-05-01

    A 2-year-old spayed female mongrel dog showed claudication with abnormal ossification containing fungal cells detected by biopsy. The dog was treated with ketoconazole and itraconazole perorally for 5 months; however, the osteomyelitis became aggravated, and an amputation from the scapula was performed. The right superficial cervical lymph node became swollen 5 months after the operation. The lymph node contained PAS positive fungal elements and a portion of tissue produced mycelial fungal growth on potato dextrose agar supplemented with chloramphenicol. The culture was identified as Lecythophora hoffmannii based on morphology, physiology and 100% identity in the sequence of the D1/D2 domain of the large subunit ribosomal RNA gene of the fungal species in the GenBank database (accession number AB100627). In addition, the sequence from the present isolate was submitted as AB189164. The isolate showed resistance to antifungal agents, i.e., amphotericin B, 5-FC, fluconazole, itraconazole, miconazole and micafungin. The dog developed cachexia 2 months after the onset of lymphadenopathy, and was euthanized on the 459th day after onset of clinical symptoms. This was the first disseminated case of L. hoffmannii infection in Japan.

  1. Hypocortisolemic clamp unmasks jointly feedforward- and feedback-dependent control of overnight ACTH secretion

    PubMed Central

    Iranmanesh, Ali; Veldhuis, Johannes D

    2009-01-01

    Background ACTH secretion is under hypothalamic stimulatory (feedforward) and adrenal inhibitory (feedback) control. Hypothesis Assessment of overnight ACTH secretion during a hypocortisolemic clamp will permit the estimation of changing feedforward and feedback. Subjects Seven healthy men. Interventions An oral dose of placebo (PLAC), metyrapone (METY, 3 g), or ketoconazole (KTCZ, 1.2 g) was given at midnight (MN) to block glucocorticoid synthesis. Plasma ACTH was sampled every 10 min (MN to 0800 h). Analysis Variable-waveform deconvolution analysis of ACTH secretion and approximate entropy (ApEn) analysis of pattern regularity. Results Compared with PLAC, administration of METY and KTCZ reduced morning cortisol concentrations by ≥77 and 54% respectively (P<0.001). Hypocortisolemia elevated pulsatile ACTH secretion by 8.2- (METY) and 5.3-fold (KTCZ; both P<0.001). Basal ACTH secretion rose by 3.4-fold under METY-induced cortisol depletion (P = 0.020). ACTH secretory-burst shape and half-life were stable. ApEn of ACTH release declined overnight (P = 0.021) and with the drug (P = 0.001), denoting enhanced feedforward coordination. Conclusion The combined data predict overnight amplification and coordination of hypothalamic feedforward drive onto ACTH release. Therefore, disruption of either mechanism might contribute to clinical pathophysiology, such as late-day elevations of cortisol output in fasting, alcoholism, depression, or aging. PMID:18713842

  2. Use of basal serum or plasma cortisol concentrations to rule out a diagnosis of hypoadrenocorticism in dogs: 123 cases (2000-2005).

    PubMed

    Lennon, Elizabeth M; Boyle, Tonya E; Hutchins, Rae Grace; Friedenthal, Arit; Correa, Maria T; Bissett, Sally A; Moses, Lorra S; Papich, Mark G; Birkenheuer, Adam J

    2007-08-01

    To determine whether basal serum or plasma cortisol concentration can be used as a screening test to rule out hypoadrenocorticism in dogs. Retrospective case-control study. 110 dogs with nonadrenal gland illnesses and 13 dogs with hypoadrenocorticism. Sensitivity and specificity of basal serum or plasma cortisol concentrations of either 2 microg/dL that are not receiving corticosteroids, mitotane, or ketoconazole are highly unlikely to have hypoadrenocorticism. However, if the basal cortisol concentration is

  3. Use of capecitabine after renal allograft transplantation in dog erythrocyte antigen-matched dogs.

    PubMed

    Schmiedt, Chad; Penzo, Chiara; Schwab, Michelle; Dubielzig, Richard; McAnulty, Jonathan

    2006-02-01

    To investigate the use of a capecitabine (CAP)-based regimen after renal transplantation in dogs. Prospective, pilot study. Healthy, unrelated, dog erythrocyte antigen (DEA)-matched, adult beagles. Standard heterotopic renal transplantation with native nephrectomy was performed in 7 dogs. Dogs received oral, twice daily, CAP (250 mg/m2), cyclosporine-A (CsA) (4 mg/kg), ketoconazole (5 mg/kg), and prednisolone (0.25 mg/kg). After 90 days the surviving dogs were euthanatized and complete necropsy was performed. Seven transplants were performed. All dogs survived surgery. Six dogs had acute neurotoxicity, which resulted in death or euthanasia of 2 dogs within 2 days of surgery. In the remaining dogs, toxicity resolved rapidly with cessation of drug administration. Thereafter, modification of the regimen minimized toxicity. The 5 remaining dogs survived to study end; 4 dogs had no evidence of graft rejection. Necropsy examination was mostly unremarkable in all dogs. There were no major changes in CBC or biochemical values, except for a significant increase in serum calcium. CAP appeared well tolerated in most dogs. Toxicity occurred but abated with modification of the drug regimen. Efficacy for postoperative immunosuppression cannot be determined by this study, although results are promising. CAP-CsA-prednisolone is an effective, oral immunosuppressive regimen for prevention of acute allograft rejection in DEA-matched beagles. Further studies on dose, toxicity, and efficacy compared with current immunosuppressive regimens are needed before use in clinical practice.

  4. Preoperative immunosuppressive therapy and surgery as a treatment for anal furunculosis.

    PubMed

    Klein, Arnaud; Deneuche, Aymeric; Fayolle, Pascal; Hidalgo, Antoine; Scotti, Stefano; Zylberstein, Luca; Desbois, Christophe; Tessier, Dominique; Moissonnier, Pierre; Viateau, Véronique

    2006-12-01

    To evaluate the efficacy of combining preoperative immunosuppressive therapy with surgical excision for treatment of anal furunculosis (AF) in dogs. Retrospective study. Dogs (n=25) with stages 1-4 AF. Preoperative immunosuppressive therapy was either cyclosporine A (CyA) alone or in combination with ketoconazole (Group 1; n=18), or azathioprine combined with prednisolone (Group 2; n=7). Surgical excision of residual draining tracts, cryptectomy, and anal sacculectomy were performed. Only dogs with postoperative clinical follow-up exceeding 9 months were retained for the study. Both immunosuppressive protocols were effective in reducing progression of AF. Subsequent draining tracts excision, cryptectomy, and anal sacculectomy were bilateral (12 dogs) or unilateral (13 dogs of which 4 had bilateral anal sacculectomy). Postoperative recovery was uneventful, except for 2 dogs that had wound breakdown. Recurrence was not observed in any of the dogs that had bilateral surgical excision and or in 9 dogs that had unilateral excision. Preoperative immunosuppressive therapy, combined with bilateral surgical resection of affected tissue consistently, resulted in resolution of AF. Four dogs that had recurrence had unilateral excision despite initial bilateral involvement, suggesting that all diseased tissue should be excised. These preliminary results suggest that immunosuppressive therapy before surgical excision for AF yields minimizes recurrence in dogs.

  5. Plasma pharmacokinetics and CYP3A12-dependent metabolism of c-kit inhibitor imatinib in dogs.

    PubMed

    Ishizuka, M; Nagai, S; Sakamoto, K Q; Fujita, S

    2007-05-01

    Imatinib is a highly selective tyrosine kinase inhibitor, and is used for the treatment of chronic myeloid leukaemia (CML) and gastrointestinal stromal tumours (GISTs) in humans. The aim of this study is to determine the in vitro and in vivo pharmacokinetics of imatinib in dogs and which cytochrome P450 (CYPs) contribute to its metabolism. Imatinib was administered orally or intravenously to dogs and the time of the peak concentration (T(max)) of imatinib was 4-9 h. The mean half-life was 622 +/- 368 min, and the AUC was 1256 +/- 809 microM * min after oral administration. The range of C0 of intravenously injected dogs was 12-24 microM. The half-life and AUC after intravenous injection were 206 +/- 112 min and 1026 +/- 371 microM * min, respectively. Recombinant system of dog CYP3A12 and CYP2C21 showed that CYP3A12 contributed to the metabolism of imatinib. The inhibition of CYP3A-dependent activity using a rat anti-CYP3A antibody or ketoconazole revealed that CYP3A12 plays a major role in the metabolism of imatinib in dog liver microsomes.

  6. An azole-resistant isolate of Malassezia pachydermatis.

    PubMed

    Nijima, Misako; Kano, Rui; Nagata, Masahiko; Hasegawa, Atsuhiko; Kamata, Hiroshi

    2011-04-21

    Canine Malassezia dermatitis (MD) is frequently treated with systemic ketoconazole (KTZ) and itaconazole (ITZ). However, the antifungal susceptibility of clinical isolates of M. pachydermatis from dogs and cats to the azoles has not been well investigated. In the present study, the in vitro susceptibility of the standard strain (CBS1879: the neotype strain of M. pachydermatis) and 29 clinical isolates of M. pachydermatis to the azoles was measured by a modified CLSI M27-A2 test using modified Dixon medium as well as by the E-test. The minimum inhibitory concentrations (MICs) of the 30 isolates of M. pachydermatis (including the neotype strain) against KTZ and ITZ were <0.03 μg/ml by the two methods. The MICs of 1 clinical isolate (ASC-11) were 1 and 2 μg/ml against KTZ, and 2 and 8 μg/ml against ITZ, by the modified CLSI M27-A2 test and the E-test, respectively. Thus, isolate ASC-11 may be resistant to these azoles, making this the first report of a resistant isolate of M. pachydermatis to KTZ and ITZ. Copyright © 2010 Elsevier B.V. All rights reserved.

  7. In vitro antifungal susceptibility of Malassezia pachydermatis from dogs with and without skin lesions.

    PubMed

    Cafarchia, Claudia; Figueredo, Luciana A; Iatta, Roberta; Montagna, Maria Teresa; Otranto, Domenico

    2012-03-23

    Canine Malassezia dermatitis is frequently treated with systemic ketoconazole (KTZ) and itraconazole (ITZ). However, no information is available on the antifungal susceptibility to azoles and allilamine of Malassezia pachydermatis isolates from dogs with or without skin lesions. The present study was designed to evaluate the in vitro antifungal susceptibility of M. pachydermatis strains from dogs with or without skin lesions to KTZ, ITZ, miconazole (MICO), fluconazole (FLZ), posaconazole (POS), voriconazole (VOR) and terbinafine (TER) using the Clinical and Laboratory Standards Institute reference Broth Microdilution Method (CLSI M27-A2). The association between the susceptibility to antifungal compounds and the origin of M. pachydermatis, from skin with or without lesions has been also assessed. A total of 62 M. pachydermatis strains from healthy dogs (i.e., Group A=30) or with skin lesions (i.e., Group B=32) were tested. ITZ, KTZ and POS showed the highest activity against M. pachydermatis strains, whereas MICO TER and FLZ the lowest. A higher number of Malassezia resistant strains were registered among isolates from Group B than those from Group A. This study indicates that M. pachydermatis strains were susceptible to ITZ, KTZ, and POS. However, dogs with lesions may harbour strains with low susceptibility to antifungal agents and displaying cross-resistance phenomena to azole. The antifungal therapy in Malassezia infections requires careful appraisal of choice of drugs especially in cases of unresponsiveness to antifungal treatment or recurrent infections. Copyright © 2011 Elsevier B.V. All rights reserved.

  8. Systemic mycosis in three dogs from nonendemic regions.

    PubMed

    Pratt, Carmela L; Sellon, Rance K; Spencer, Erick S; Johnson, Ty W; Righter, Daniel J

    2012-01-01

    Three dogs were examined for clinical signs ultimately attributed to systemic fungal infections. One dog was evaluated for chronic, ulcerated dermal lesions and lymphadenomegaly; one dog was examined for acute onset of unilateral blepharospasm; and one dog had diarrhea and hematochezia. Two of the dogs were diagnosed with blastomycosis (one with disseminated disease and the other with the disease localized to the left eye). The third dog was diagnosed with disseminated histoplasmosis. None of the dogs originated from, or had traveled to, typical regions endemic for these fungal diseases. All diagnoses were established from histopathology and either polymerase chain reaction (PCR) or cytology and culture. The two dogs diagnosed with blastomycosis were treated with either itraconazole or ketoconazole with apparent resolution of the infections. The dog with ocular involvement had an enucleation prior to beginning therapy. The dog diagnosed with histoplasmosis was euthanized without treatment. In patients with characteristic clinical features, systemic fungal infections should still be considered as differential diagnoses regardless of their travel history.

  9. Cutaneous nocardiosis in two dogs receiving ciclosporin therapy for the management of canine atopic dermatitis.

    PubMed

    Siak, Meng K; Burrows, Amanda K

    2013-08-01

    Ciclosporin is a calcineurin inhibitor that is currently registered for the treatment of canine atopic dermatitis. The most common adverse effects include mild, transient gastrointestinal disturbances. Single case reports of opportunistic infections due to Nocardia spp., Neospora spp. and papillomaviruses have also been reported. Clinicians should be aware of the potential risk of systemic immunosuppression and subsequent infection with Nocardia spp. in dogs receiving ciclosporin. Cutaneous nocardiosis in two dogs receiving ciclosporin therapy for management of canine atopic dermatitis. Histopathology, PCR for Nocardia spp. and computed tomography. One dog developed disseminated nocardiosis due to Nocardia brasiliensis and a second dog developed localized cutaneous nocardiosis due to a novel Nocardia species subsequent to ciclosporin administration at the recommended dose rate for the management of canine atopic dermatitis. The second case was receiving a combination of ciclosporin and ketoconazole, and serum trough ciclosporin levels were elevated. Clinicians should be aware of the potential risk of systemic immunosuppression and subsequent infection with Nocardia spp. in dogs receiving ciclosporin. Measurement of serum ciclosporin levels may be useful in identifying those individuals which are at risk of opportunistic infections. © 2013 ESVD and ACVD.

  10. [Metabolic kinetics of MN9202 in Beagle dog liver microsomes].

    PubMed

    Yang, Zhi-fu; Zhou, Si-yuan; Mei, Qi-bing; Yang, Tie-hong; Liu, Zhen-guo

    2005-11-01

    To study the metabolic kinetics of MN9202 in Beagle dog liver microsome. Beagle dog liver microsomes were prepared by using ultracentrifuge method. After incubating 0.4 micromol x L(-1) MN9202 with 1 g x L(-1) microsomes for 30 min at 37 degrees C, the reaction was terminated by adding 0.5 mL alkalization. The RP-HPLC was used to determine the drug in the incubation mixture. The Michaelis-Menten parameters Km, and Vmax in Beagle dog liver microsomes were initially estimated by analyzing Lineweave-Brurk plot. Various selective CYP inhibitors were used to investigate their inhibitory effect on the metabolism of MN9202. The Km, Vmax and CLint of MN9202 were (22.6 +/- 8.0) micromol x L(-1), (0.54 +/- 0.17) micromol x g(-1) x min(-1) and (0.0242 +/- 0.0009) L x g(-1) x min(-1), respectively. The metabolism of MN9202 was significantly inhibited by ketoconazole (Ket) and troleandomycin (Tro) in Beagle dog liver microsomes. Tranylcypromine (Tra) could inhibit the metabolism of drug as well. While other inhibitors showed little inhibitory effect on the metabolism of MN9202. It was shown that CYP3A and CYP2C19 were involved in MN9202 metabolism. The inhibitors of human CYP3A and CYP2C19 may have potential interaction with MN9202, and this can reduce the metabolism rate and increase the toxicity of MN9202.

  11. Clinicopathologic features of an unusual outbreak of cryptococcosis in dogs, cats, ferrets, and a bird: 38 cases (January to July 2003).

    PubMed

    Lester, Sally J; Kowalewich, Natalie J; Bartlett, Karen H; Krockenberger, Mark B; Fairfax, Theyne M; Malik, Richard

    2004-12-01

    To determine clinical and pathologic findings associated with an outbreak of cryptococcosis in an unusual geographic location (British Columbia, Canada). Retrospective study. 1 pink-fronted cockatoo, 2 ferrets, 20 cats, and 15 dogs. A presumptive diagnosis of cryptococcosis was made on the basis of serologic, histopathologic, or cytologic findings, and a definitive diagnosis was made on the basis of culture or immunohistochemical staining. No breed or sex predilections were detected in affected dogs or cats. Eleven cats had neurologic signs, 7 had skin lesions, and 5 had respiratory tract signs. None of 17 cats tested serologically for FeLV yielded positive results; 1 of 17 cats yielded positive results for FIV (western blot). Nine of 15 dogs had neurologic signs, 2 had periorbital swellings, and only 3 had respiratory tract signs initially. Microbiologic culture in 15 cases yielded 2 isolates of Cryptococcus neoformans var grubii (serotype A) and 13 isolates of C. neoformans var gattii (serotype B); all organisms were susceptible to amphotericin B and ketoconazole. Serologic testing had sensitivity of 92% and specificity of 98%. Serologic titers were beneficial in identifying infection in animals with nonspecific signs, but routine serum biochemical or hematologic parameters were of little value in diagnosis. Most animals had nonspecific CNS signs and represented a diagnostic challenge. Animals that travel to or live in this region and have nonspecific malaise or unusual neurologic signs should be evaluated for cryptococcosis.

  12. Candida glabrata species complex prevalence and antifungal susceptibility testing in a culture collection: First description of Candida nivariensis in Argentina.

    PubMed

    Morales-López, Soraya Eugenia; Taverna, Constanza G; Bosco-Borgeat, María Eugenia; Maldonado, Ivana; Vivot, Walter; Szusz, Wanda; Garcia-Effron, Guillermo; Córdoba, Susana B

    2016-12-01

    The presence of the cryptic species belonging to the Candida glabrata complex has not been studied in Argentina. We analyzed a collection of 117 clinical isolates of C. glabrata complex belonging to a National Culture Collection of Instituto Nacional de Microbiología "Dr. Carlos G. Malbrán" from Argentina (40 isolates from blood samples, 18 from other normally sterile sites, 20 from vagina, 14 from urine, 7 from oral cavity, 3 from catheter, 1 from a stool sample and 14 isolates whose clinical origin was not recorded). The aims of this work were to determine the prevalence of the cryptic species Candida nivariensis and Candida bracarensis and to evaluate the susceptibility profile of isolates against nine antifungal drugs. Identification was carried out by using classical phenotypic tests, CHROMagar™ Candida, PCR and MALDI-TOF. The minimal inhibitory concentrations of amphotericin B, 5-fluorocytosine, fluconazole, itraconazole, voriconazole, ketoconazole, posaconazole, caspofungin and anidulafungin were determined according to the EDef 7.3 (EUCAST) reference document. Of the 117 isolates, 114 were identified as C. glabrata and three as C. nivariensis by using PCR and MALDI-TOF. There were no major differences between C. nivariensis and C. glabrata susceptibility profiles. No resistant strains were found to echinocandins. We have found that the percentage of C. nivariensis in our culture collection was 2.56. This is the first description of C. nivariensis in Argentina, and data obtained could contribute to the knowledge of the epidemiology of this cryptic species.

  13. CYP17 inhibitors for prostate cancer therapy

    PubMed Central

    Vasaitis, Tadas S.; Bruno, Robert D.; Njar, Vincent C. O.

    2010-01-01

    Prostate cancer (PC) is now the second most prevalent cause of death in men in the USA and Europe. At present, the major treatment options include surgical or medical castration. These strategies cause ablation of the production of testosterone (T), dihydrotestosterone (DHT) and related androgens by the testes. However, because these procedures do not affect adrenal, prostate and other tissues androgen production, they are often combined with androgen receptor antagonists to block their action. Indeed, recent studies have unequivocally established that in castration-resistant prostate cancer (CRPC) many androgen-regulated genes become re-expressed and tissue androgen levels increase despite low serum levels. Clearly, inhibition of the key enzyme which catalyzes the biosynthesis of androgens from pregnane precursors, 17α-hydroxy/17,20-lyase (hereafter referred to as CYP17) could prevent androgen production from all sources. Thus, total ablation of androgen production by potent CYP17 inhibitors may provide effective treatment of prostate cancer patients. This review highlights the role of androgen biosynthesis in the progression of prostate cancer and the impact of CYP17 inhibitors, such as ketoconazole, abiraterone acetate, VN/124-1 (TOK-001) and TAK-700 in the clinic and in clinical development. PMID:21092758

  14. In vitro susceptibility of 137 Candida sp. isolates from HIV positive patients to several antifungal drugs.

    PubMed

    Magaldi, S; Mata, S; Hartung, C; Verde, G; Deibis, L; Roldán, Y; Marcano, C

    2001-01-01

    Oropharyngeal candidiasis caused by various species of Candida is one of the most common infections in HIV seropositive or AIDS patients. Drug resistance among these yeasts is an increasing problem. We studied the frequency of resistance profile to fluconazole, itraconazole, ketoconazole, amphotericin B and terbinafine of 137 isolates of Candida sp. From HIV positive or AIDS patients with oropharyngeal candidiasis at Instituto de Inmunología, U.C.V. and the Hospital "Jose Ignacio Baldó", Caracas Venezuela, using the well diffusion susceptibility test (Magaldi et al.). We found that nearly 10% of C. albicans isolates were primarily fluconazole resistant, 45% of C. albicans isolates from patients with previous treatment were resistant to fluconazole, of which 93% showed cross-resistance to itraconazole, and even about 30% of C. tropicalis (n = 13) were resistant to fluconazole and/or itraconazole. To this respect, several recent reports have been described antifungal cross-resistance among azoles. Therefore, we consider that C. tropicalis should be added to the growing list of yeast in which antifungal drug resistance is common. This report could be useful for therapeutic aspect in AIDS patients with oral candidiasis.

  15. Synthesis, SAR and molecular docking studies of benzo[d]thiazole-hydrazones as potential antibacterial and antifungal agents.

    PubMed

    Zha, Gao-Feng; Leng, Jing; Darshini, N; Shubhavathi, T; Vivek, H K; Asiri, Abdullah M; Marwani, Hadi M; Rakesh, K P; Mallesha, N; Qin, Hua-Li

    2017-07-15

    A series of new benzo[d]thiazole-hydrazones analogues were synthesized and screened for their in vitro antibacterial and antifungal activities. The results revealed that compounds 13, 14, 15, 19, 20, 28 and 30 exhibited superior antibacterial potency compared to the reference drug chloramphenicol and rifampicin. Compounds 5, 9, 10, 11, 12, 28 and 30 were found to be good antifungal activity compared to the standard drug ketoconazole. A preliminary study of the structure-activity relationship (SAR) revealed that the antimicrobial activity depended on the effect of different substituents on the phenyl ring. The electron donating (OH and OCH 3 ) groups presented in the analogues, increase the antibacterial activity (except compound 12), interestingly, while the electron withdrawing (Cl, NO 2 , F and Br) groups increase the antifungal activity (except compound 19 and 20). In addition, analogues containing thiophene (28) and indole (30) showed good antimicrobial activities. Whereas, aliphatic analogues (24-26) shown no activities in both bacterial and fungal stains even in high concentrations (100µg/mL). Molecular docking studies were performed for all the synthesized compounds of which compounds 11, 19 and 20 showed the highest glide G-score. Copyright © 2017 Elsevier Ltd. All rights reserved.

  16. [Prevalence of vaginal candidiasis in pregnant women. Identification of yeasts and susceptibility to antifungal agents].

    PubMed

    García Heredia, M; García, S D; Copolillo, E F; Cora Eliseth, M; Barata, A D; Vay, C A; de Torres, R A; Tiraboschi, N; Famiglietti, A M R

    2006-01-01

    Pregnant women are more susceptible to both vaginal colonization and infection by yeast. Our objectives were to determine the prevalence in pregnant women of yeasts isolated from vaginal exudates and their susceptibility to current antifungal drugs. A total of 493 patients was studied between December 1998 and February 2000. The prevalence of Candida spp. was 28% (Candida albicans 90.4%; Candida glabrata 6.3%; Candida parapsilosis 1.1%, Candida kefyr 1.1 %; unidentified species 1.1 %). The diffusion test in Shadomy agar was employed to determine the susceptibility to fluconazole, ketoconazole, itraconazole and nistatine. All C. albicans, C. kefyr and C. parapsilosis isolates were susceptible in vitro to the antifungal agents tested, while 1 in 6 C. glabrata isolates showed resistance to azole drugs; all strains were susceptible to nistatine. In pregnant women, C. albicans was the yeast most frequently isolated from vaginal exudates; it continues to be highly susceptible to antifungal drugs. Azole resistance was detected only among C. glabrata isolates. Identification to the species level is recommended, specially in cases of treatment failure and recurrent or chronic infection.

  17. The effect of polymeric excipients on the physical properties and performance of amorphous dispersions: Part I, free volume and glass transition.

    PubMed

    Li, Jinjiang; Zhao, Junshu; Tao, Li; Wang, Jennifer; Waknis, Vrushali; Pan, Duohai; Hubert, Mario; Raghavan, Krishnaswamy; Patel, Jatin

    2015-02-01

    To investigate the structural effect of polymeric excipients on the behavior of free volume of drug-polymer dispersions in relation to glass transition. Two drugs (indomethacin and ketoconazole) were selected to prepare amorphous dispersions with PVP, PVPVA, HPC, and HPMCAS through spray drying. The physical attributes of the dispersions were characterized using SEM and PXRD. The free volume (hole-size) of the dispersions along with drugs and polymers was measured using positron annihilation lifetime spectroscopy (PALS). Their glass transition temperatures (Tgs) were determined using DSC and DMA. FTIR spectra were recorded to identify hydrogen bonding in the dispersions. The chain structural difference-flexible (PVP and PVPVA) vs. inflexible (HPC and HPMCAS)-significantly impacts the free volume and Tgs of the dispersions as well as their deviation from ideality. Relative to Tg, free volume seems to be a better measure of hydrogen bonding interaction for the dispersions of PVP, HPC, and HPMCAS. The free volume of polymers and their dispersions in general appears to be related to their conformations in solution. Both the backbone chain rigidity of polymers as well as drug-polymer interaction can impact the free volume and glass transition behaviors of the dispersions.

  18. Polar Quassinoids in Standardized Eurycoma longifolia Extract Formulated into a Lipid-Based Solid Dispersion to Improve Rat Sperm Count.

    PubMed

    Ma, Hai-Qiu; Ebrahimi, Forough; Low, Bin-Seng; Khan, Nurzalina Abdul Karim; Chan, Kit-Lam

    2017-12-01

    Eurycoma longifolia Jack is popularly sought in Southeast Asian countries for traditional remedies to improve sexual performance and fertility. 13α(21)-Epoxyeurycomanone and eurycomanone, two major quassinoids in a root extract (TAF2) were reported to improve rat spermatogenesis and fertility. Unfortunately, these quassinoids possess low bioavailability because of high aqueous solubility and low lipid membrane permeability. Often, other possible barriers may be P-glycoprotein (P-gp) efflux in the gut and presystemic hepatic metabolism. The present study attempted to solve these problems by formulating a lipid-based solid dispersion (TAF2-SD) of optimized mixture of TAF2 and emulsifiers, which was then orally administered to rats prior to sperm count analysis. The TAF2-SD-treated rats showed significantly twofold (p < 0.001) and fourfold (p < 0.001) higher sperm count than did TAF2-treated and vehicle-treated (control) rats, respectively. The study also demonstrated no significant in vitro ileal absorption changes of the quassinoids by P-gp efflux inhibitors and concentration change or secondary metabolite formation upon in vitro incubation with rat liver homogenates, suggesting that P-gp-mediated efflux and presystemic metabolism were not limiting their bioavailability. Further study on orally TAF2-treated rats confirmed that the area under the curve and bioavailability curve of each quassinoid in the absence and presence of ketoconazole were unchanged. Copyright © 2017 John Wiley & Sons, Ltd. Copyright © 2017 John Wiley & Sons, Ltd.

  19. Green synthesized zinc oxide nanoparticles as a therapeutic tool to combat candidiasis

    NASA Astrophysics Data System (ADS)

    Rathod, Tejas; Padalia, Hemali; Chanda, Sumitra

    2017-05-01

    Advancement of modern medicine, the increasing ratio of immunocompromised and immunosuppressive individuals is increased in hospitalized with serious underlying disease. This has resulted in a rise in the incidence of fungal infections, especially those due to Candida species. For many years the conventional antibiotic therapy has been critical in the fight against Candidiasis. Candidiasis is a fungal infection due to various types of Candida (yeast) species. In this study, zinc oxide nanoparticles (ZnONPs) were synthesized using the Cinnamomum verum bark plus Cassia auriculata leaf powder extracts. The characterization of synthesized ZnONPs was done by UV-Vis spectrophotometer and SEM analysis. The average size of nanoparticles was 77 nm. Synergistic anticandidal activity of ZnONPs (ZnONPs plus antibiotics) was determined by disc diffusion method against 16 multidrug resistant clinical pathogens of Candida species. Antibiotic Ketoconazole plus ZnONPs showed best synergistic anticandidal activity against all the 16 isolates. Green synthesized ZnONPs appears to be a new promising approach to fight against Candidiasis.

  20. Oral Candida in Patients with Fixed Orthodontic Appliance: In Vitro Combination Therapy.

    PubMed

    Alhamadi, Wisam; Al-Saigh, Rafal J; Al-Dabagh, Nebras N; Al-Humadi, Hussam W

    2017-01-01

    Fixed orthodontic appliance (FOA) increases the cariogenic microorganisms of mouth including candida. The aim was to evaluate the pharmacodynamic effects of some antibacterial drugs in combination with most applicable antifungal agents on candida isolated from patients with FOA. Three antifungal agents (amphotericin B (AMB), ketoconazole (KET), and itraconazole (ITZ)) and three antibacterial drugs (ciprofloxacin (CIP), doxycycline (DOX), and metronidazole (MET)) with serial concentrations have been used and microdilution broth method has been done for single and combination therapy, then fungal growth was assessed spectrophotometrically, and the combinations were evaluated by bliss independent analysis. According to bliss independent interaction, the synergistic interactions depended on Δ E values that showed the best for CIP was with AMB (Δ E = 55.14) followed with KET (Δ E = 41.23) and lastly ITR (Δ E = 39.67) at CIP = 150 mg/L. DOX was optimal with KET (Δ E = 42.11) followed with AMB (Δ E = 40.77) and the lowest with ITR (Δ E = 9.12) at DOX = 75 mg/L. MET is the best with AMB (Δ E = 40.95) and then with ITR (Δ E = 35.45) and finally KET (Δ E = 15.15) at MET 200 mg/L. Moreover, usage of higher concentrations of antibacterial agents revealed inhibitory effects. This study uncovers the optimum antibiotic combination therapy against cariogenic candida with FOA by usage of low therapeutic concentrations.

  1. Synergistic anticandidal activity of pure polyphenol curcumin I in combination with azoles and polyenes generates reactive oxygen species leading to apoptosis.

    PubMed

    Sharma, Monika; Manoharlal, Raman; Negi, Arvind Singh; Prasad, Rajendra

    2010-08-01

    We have shown previously that pure polyphenol curcumin I (CUR-I) shows antifungal activity against Candida species. By employing the chequerboard method, filter disc and time-kill assays, in the present study we demonstrate that CUR-I at non-antifungal concentration interacts synergistically with azoles and polyenes. For this, pure polyphenol CUR-I was tested for synergy with five azole and two polyene drugs - fluconazole (FLC), miconazole, ketoconazole (KTC), itraconazole (ITR), voriconazole (VRC), nystatin (NYS) and amphotericin B (AMB) - against 21 clinical isolates of Candida albicans with reduced antifungal sensitivity, as well as a drug-sensitive laboratory strain. Notably, there was a 10-35-fold drop in the MIC(80) values of the drugs when CUR-I was used in combination with azoles and polyenes, with fractional inhibitory concentration index (FICI) values ranging between 0.09 and 0.5. Interestingly, the synergistic effect of CUR-I with FLC and AMB was associated with the accumulation of reactive oxygen species, which could be reversed by the addition of an antioxidant such as ascorbic acid. Furthermore, the combination of CUR-I and FLC/AMB triggered apoptosis that could also be reversed by ascorbic acid. We provide the first evidence that pure CUR-I in combination with azoles and polyenes represents a novel therapeutic strategy to improve the activity of common antifungals.

  2. In vitro investigation of antifungal activity of allicin alone and in combination with azoles against Candida species.

    PubMed

    Khodavandi, Alireza; Alizadeh, Fahimeh; Aala, Farzad; Sekawi, Zamberi; Chong, Pei Pei

    2010-04-01

    Candidiasis is a term describing infections by yeasts from the genus Candida, and the type of infection encompassed by candidiasis ranges from superficial to systemic. Treatment of such infections often requires antifungals such as the azoles, but increased use of these drugs has led to selection of yeasts with increased resistance to these drugs. In this study, we used allicin, an allyl sulfur derivative of garlic, to demonstrate both its intrinsic antifungal activity and its synergy with the azoles, in the treatment of these yeasts in vitro. In this study, the MIC(50) and MIC(90) of allicin alone against six Candida spp. ranged from 0.05 to 25 microg/ml. However, when allicin was used in combination with fluconazole or ketoconazole, the MICs were decreased in some isolates. Our results demonstrated the existing synergistic effect between allicin and azoles in some of the Candida spp. such as C. albicans, C. glabrata and C. tropicalis, but synergy was not demonstrated in the majority of Candida spp. tested. Nonetheless, In vivo testing needs to be performed to support these findings.

  3. Female pattern alopecia: current perspectives

    PubMed Central

    Levy, Lauren L; Emer, Jason J

    2013-01-01

    Hair loss is a commonly encountered problem in clinical practice, with men presenting with a distinctive pattern involving hairline recession and vertex balding (Norwood-Hamilton classification) and women exhibiting diffuse hair thinning over the crown (increased part width) and sparing of the frontal hairline (Ludwig classification). Female pattern hair loss has a strikingly overwhelming psychological effect; thus, successful treatments are necessary. Difficulty lies in successful treatment interventions, as only two medications – minoxidil and finasteride – are approved for the treatment of androgenetic alopecia, and these medications offer mediocre results, lack of a permanent cure, and potential complications. Hair transplantation is the only current successful permanent option, and it requires surgical procedures. Several other medical options, such as antiandrogens (eg, spironolactone, oral contraceptives, cyproterone, flutamide, dutasteride), prostaglandin analogs (eg, bimatoprost, latanoprost), and ketoconazole are reported to be beneficial. Laser and light therapies have also become popular despite the lack of a profound benefit. Management of expectations is crucial, and the aim of therapy, given the current therapeutic options, is to slow or stop disease progression with contentment despite patient expectations of permanent hair regrowth. This article reviews current perspectives on therapeutic options for female pattern hair loss. PMID:24039457

  4. Age related changes in fractional elimination pathways for drugs: assessing the impact of variable ontogeny on metabolic drug-drug interactions.

    PubMed

    Salem, Farzaneh; Johnson, Trevor N; Barter, Zoe E; Leeder, J Steven; Rostami-Hodjegan, Amin

    2013-08-01

    The magnitude of any metabolic drug-drug interactions (DDIs) depends on fractional importance of inhibited pathway which may not necessarily be the same in young children when compared to adults. The ontogeny pattern of cytochrome P450 (CYP) enzymes (CYPs 1A2, 2B6, 2C8, 2C9, 2C18/19, 2D6, 2E1, 3A4) and renal function were analyzed systematically. Bootstrap methodology was used to account for variability, and to define the age range over which statistical differences existed between each pair of specific pathways. A number of DDIs were simulated (Simcyp Pediatric v12) for virtual compounds to highlight effects of age on fractional elimination and consequent magnitude of DDI. For a theoretical drug metabolized 50% by each of CYP2D6 and CYP3A4 pathways at birth, co-administration of ketoconazole (3 mg/kg) resulted in a 1.65-fold difference between inhibited versus uninhibited AUC compared to 2.4-fold in 1 year olds and 3.2-fold in adults. Conversely, neonates could be more sensitive to DDI than adults in certain scenarios. Thus, extrapolation from adult data may not be applicable across all pediatric age groups. The use of pediatric physiologically based pharmacokinetic (p-PBPK) models may offer an interim solution to uncovering potential periods of vulnerability to DDI where there are no existing clinical data derived from children. © The Author(s) 2013.

  5. The interaction of representative members from two classes of antimycotics--the azoles and the allylamines--with cytochromes P-450 in steroidogenic tissues and liver.

    PubMed

    Schuster, I

    1985-06-01

    Spectrophotometric studies with ketoconazole, clotrimazole and miconazole show strong type-II interactions with several cytochromes P-450, particularly (Ks greater than 10(7)M-1; pH7.4; 25 degrees C) with the 11 beta-hydroxylase of adrenal mitochondria, with the 17 alpha/20 lyase of testis microsomes and with some forms of cytochromes P-450 of liver. A tight binding of the azoles also occurs to the reduced cytochromes, giving rise to an impeded CO binding to the haem iron. The binding of the azoles to 11 beta-hydroxylase and 17 alpha/20 lyase is much tighter than the binding of endogenous substrates, and consequently inhibition of steroidogenesis will occur at these sites. The metabolism of xenobiotic substrates by the cytochromes P-450 of liver will also be severely impeded. In contrast, the allylamines naftifine and SF 86-327 are type-I substrates for a small portion of cytochromes P-450 of liver microsomes only and there is no spectral evidence for binding to the cytochromes P-450 involved in steroid biosynthesis.

  6. Hollow polycaprolactone composite fibers for controlled magnetic responsive antifungal drug release.

    PubMed

    Wang, Baolin; Zheng, Hongxia; Chang, Ming-Wei; Ahmad, Zeeshan; Li, Jing-Song

    2016-09-01

    Hollow magnetic fibers for trigger based drug release were synthesized using one-step co-axial electrospinning (COX-ES). This was achieved by encapsulating the antifungal active 'ketoconazole' (KCZ) and iron oxide (Fe3O4) nanoparticles (NPs) in composite form within the core shell polymeric matrix material (polycaprolactone, PCL) during the COX-ES process. Dimethyl silicone oil was used as the inner core (liquid) of co-flowing solutions, which subsequently perfused out of the two-phase electrospun microstructures to form hollow fibers. Resulting drug-loaded magnetic hollow fibers were characterized using optical microscopy, scanning electron microscopy and Fourier Transform Infra-Red. The tensile strength and magnetization properties of composite fibers were also assessed. KCZ drug concentration in electrospinning solutions strongly influenced resulting fiber morphology, drug loading efficiency and release. Expedited drug release during a slow-sustained phase was demonstrated through the application of an auxiliary magnetic field. Variations in tensile strength (∼1.3-6.3MPa) were due to composite fiber components compromising polymer chain integrity. In-vitro cell studies (using human cervical carcinoma cell lines) demonstrated fiber biocompatibility. The present study demonstrates the potential application of magnetic hollow fibers for controlled treatment of fungal infections and antimicrobial indications. Copyright © 2016 Elsevier B.V. All rights reserved.

  7. In vitro antifungal activity of topical and systemic antifungal drugs against Malassezia species.

    PubMed

    Carrillo-Muñoz, Alfonso Javier; Rojas, Florencia; Tur-Tur, Cristina; de Los Ángeles Sosa, María; Diez, Gustavo Ortiz; Espada, Carmen Martín; Payá, María Jesús; Giusiano, Gustavo

    2013-09-01

    The strict nutritional requirements of Malassezia species make it difficult to test the antifungal susceptibility. Treatments of the chronic and recurrent infections associated with Malassezia spp. are usually ineffective. The objective of this study was to obtain in vitro susceptibility profile of 76 clinical isolates of Malassezia species against 16 antifungal drugs used for topical or systemic treatment. Isolates were identified by restriction fragment length polymorphism. Minimal inhibitory concentrations (MIC) were obtained by a modified microdilution method based on the Clinical Laboratory Standards Institute reference document M27-A3. The modifications allowed a good growth of all tested species. High in vitro antifungal activity of most tested drugs was observed, especially triazole derivatives, except for fluconazole which presented the highest MICs and widest range of concentrations. Ketoconazole and itraconazole demonstrated a great activity. Higher MICs values were obtained with Malassezia furfur indicating a low susceptibility to most of the antifungal agents tested. Malassezia sympodialis and Malassezia pachydermatis were found to be more-susceptible species than M. furfur, Malassezia globosa, Malassezia slooffiae and Malassezia restricta. Topical substances were also active but provide higher MICs than the compounds for systemic use. The differences observed in the antifungals activity and interspecies variability demonstrated the importance to studying the susceptibility profile of each species to obtain reliable information for defining an effective treatment regimen. © 2013 Blackwell Verlag GmbH.

  8. Biofilm production and antifungal susceptibility of co-cultured Malassezia pachydermatis and Candida parapsilosis isolated from canine seborrheic dermatitis.

    PubMed

    Bumroongthai, K; Chetanachan, P; Niyomtham, W; Yurayart, C; Prapasarakul, N

    2016-07-01

    The yeasts Malassezia (M.) pachydermatis and Candida (C.) parapsilosis are often co-isolated in case of canine seborrhea dermatitis (SD) and also are emerging as opportunistic pathogens of immunocompromised human beings. Increased information about how their relationship results in biofilm production and an antifungal response would be useful to inform treatment and control. This study was designed to investigate biofilm production derived from co-culture of M. pachydermatis and C. parapsilosis from dog skin and to determine their in vitro antifungal susceptibility. We demonstrated that regardless of yeast strain or origin all single and dual cultures produced biofilms within 24 hours, and the greatest amount was present after 72 hours. Biofilm production from mixed cultures was greater than for single strains (P < .05). All sessile forms of the single and dual cultures were resistant to the tested antifungals itraconazole and ketoconazole, whereas planktonic forms were susceptible. The study suggests that dual cultures produce stronger biofilms that are likely to enhance persistence in skin lesions in dogs and result in greater resistance to antifungal treatment. © The Author 2016. Published by Oxford University Press on behalf of The International Society for Human and Animal Mycology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  9. [In vitro antifungal activity of azoles and amphotericin B against Malassezia furfur by the CLSI M27-A3 microdilution and Etest® methods].

    PubMed

    Galvis-Marín, Juan Camilo; Rodríguez-Bocanegra, María Ximena; Pulido-Villamarín, Adriana Del Pilar; Castañeda-Salazar, Rubiela; Celis-Ramírez, Adriana Marcela; Linares-Linares, Melva Yomary

    Malassezia furfur is a human skin commensal yeast that can cause skin and opportunistic systemic infections. Given its lipid dependant status, the reference methods established by the Clinical and Laboratory Standards Institute (CLSI) to evaluate antifungal susceptibility in yeasts are not applicable. To evaluate the in vitro susceptibility of M. furfur isolates from infections in humans to antifungals of clinical use. The susceptibility profile to amphotericin B, itraconazole, ketoconazole and voriconazole of 20 isolates of M. furfur, using the broth microdilution method (CLSI M27-A3) and Etest ® , was evaluated. Itraconazole and voriconazole had the highest antifungal activity against the isolates tested. The essential agreement between the two methods for azoles antifungal activity was in the region of 60-85% and the categorical agreement was around 70-80%, while the essential and categorical agreement for amphotericin B was 10%. The azoles were the compounds that showed the highest antifungal activity against M. furfur, as determined by the two techniques used; however more studies need to be performed to support that Etest ® is a reliable method before its implementation as a routine clinical laboratory test. Copyright © 2016 Asociación Española de Micología. Publicado por Elsevier España, S.L.U. All rights reserved.

  10. Antifungal susceptibility of Malassezia furfur, Malassezia sympodialis, and Malassezia globosa to azole drugs and amphotericin B evaluated using a broth microdilution method.

    PubMed

    Rojas, Florencia D; Sosa, María de los A; Fernández, Mariana S; Cattana, María E; Córdoba, Susana B; Giusiano, Gustavo E

    2014-08-01

    We studied the in vitro activity of fluconazole (FCZ), ketoconazole (KTZ), miconazole (MCZ), voriconazole (VCZ), itraconazole (ITZ) and amphotericin B (AMB) against the three major pathogenic Malassezia species, M. globosa, M. sympodialis, and M. furfur. Antifungal susceptibilities were determined using the broth microdilution method in accordance with Clinical and Laboratory Standards Institute reference document M27-A3. To support lipid-dependent yeast development, glucose, peptone, ox bile, malt extract, glycerol, and Tween supplements were added to Roswell Park Memorial Institute RPMI 1640 medium. The supplemented medium allowed good growth of all three species studied. The minimal inhibitory concentrations (MICs) were recorded after 72 h of incubation at 32ºC. The three species showed different susceptibility profiles for the drugs tested. Malassezia sympodialis was the most susceptible and M. furfur the least susceptible species. KTZ, ITZ, and VCZ were the most active drugs, showing low variability among isolates of the same species. FCZ, MCZ, and AMB showed high MICs and wide MIC ranges. Differences observed emphasize the need to accurately identify and evaluate antifungal susceptibility of Malassezia species. Further investigations and collaborative studies are essential for correlating in vitro results with clinical outcomes since the existing limited data do not allow definitive conclusions. © The Author 2014. Published by Oxford University Press on behalf of The International Society for Human and Animal Mycology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  11. Functional expression and characterization of CYP51 from dandruff-causing Malassezia globosa.

    PubMed

    Kim, Donghak; Lim, Young-Ran; Ohk, Seul Ong; Kim, Beom Joon; Chun, Young-Jin

    2011-02-01

    Malassezia globosa is one of the most common yeasts to cause various human skin diseases including dandruff and seborrheic dermatitis. Genomic analysis of M. globosa revealed four putative cytochrome P450 (CYP) enzymes. Here, we report the purification and characterization of recombinant CYP51, a putative lanosterol 14α-demethylase, from M. globosa. The M. globosa CYP51 was expressed heterologously in Escherichia coli, followed by purification. Purified CYP51 showed a typical reduced CO-difference spectrum of P450, with a maximum absorption at 447 nm. Purified CYP51 exhibited tight binding to azole antifungal agents such as ketoconazole, econazole, fluconazole, or itraconazole, with K(d) values around 0.26-0.84 μM, which suggests that CYP51 is an orthologous target for antifungal agents in the M. globosa. In addition, three mutations (Y127F, A169S, and K176N) in the amino acid sequence of M. globosa CYP51 were identified in one of the azole-resistant strains. Homology modeling of M. globosa CYP51 suggested that the Y127F mutation may influence the resistance to azoles by blocking substrate access channels. Taken together, functional expression and characterization of the CYP51 enzyme can provide a fundamental basis for a specific antifungal drug design for dandruff caused by M. globosa. © 2010 Federation of European Microbiological Societies. Published by Blackwell Publishing Ltd. All rights reserved.

  12. Synthesis, Molecular Docking, and Antimycotic Evaluation of Some 3-Acyl Imidazo[1,2-a]pyrimidines.

    PubMed

    Gómez-García, Omar; Andrade-Pavón, Dulce; Campos-Aldrete, Elena; Ballinas-Indilí, Ricardo; Méndez-Tenorio, Alfonso; Villa-Tanaca, Lourdes; Álvarez-Toledano, Cecilio

    2018-03-07

    A series of 3-benzoyl imidazo[1,2- a ]pyrimidines, obtained from N -heteroarylformamidines in good yields, was tested in silico and in vitro for binding and inhibition of seven Candida species ( Candida albicans (ATCC 10231), Candida dubliniensis (CD36), Candida glabrata (CBS138), Candida guilliermondii (ATCC 6260), Candida kefyr , Candida krusei (ATCC 6358) and Candida tropicalis (MYA-3404)). To predict binding mode and energy, each compound was docked in the active site of the lanosterol 14α-demethylase enzyme (CYP51), essential for fungal growth of Candida species. Antimycotic activity was evaluated as the 50% minimum inhibitory concentration (MIC50) for the test compounds and two reference drugs, ketoconazole and fluconazole. All test compounds had a better binding energy (range: -6.11 to -9.43 kcal/mol) than that found for the reference drugs (range: 48.93 to -6.16 kcal/mol). In general, the test compounds showed greater inhibitory activity of yeast growth than the reference drugs. Compounds 4j and 4f were the most active, indicating an important role in biological activity for the benzene ring with electron-withdrawing substituents. These compounds show the best MIC50 against C. guilliermondii and C. glabrata, respectively. The current findings suggest that the 3-benzoyl imidazo[1,2- a ]pyrimidine derivatives, herein synthesized by an accessible methodology, are potential antifungal drugs.

  13. Potential prostate cancer drug target: bioactivation of androstanediol by conversion to dihydrotestosterone.

    PubMed

    Mohler, James L; Titus, Mark A; Wilson, Elizabeth M

    2011-09-15

    High-affinity binding of dihydrotestosterone (DHT) to the androgen receptor (AR) initiates androgen-dependent gene activation, required for normal male sex development in utero, and contributes to prostate cancer development and progression in men. Under normal physiologic conditions, DHT is synthesized predominantly by 5α-reduction of testosterone, the major circulating androgen produced by the testis. During androgen deprivation therapy, intratumoral androgen production is sufficient for AR activation and prostate cancer growth, even though circulating testicular androgen levels are low. Recent studies indicate that the metabolism of 5α-androstane-3α, 17β-diol by 17β-hydroxysteroid dehydrogenase 6 in benign prostate and prostate cancer cells is a major biosynthetic pathway for intratumoral synthesis of DHT, which binds AR and initiates transactivation to promote prostate cancer growth during androgen deprivation therapy. Drugs that target the so-called backdoor pathway of DHT synthesis provide an opportunity to enhance clinical response to luteinizing-hormone-releasing hormone (LHRH) agonists or antagonists, AR antagonists, and inhibitors of 5α-reductase enzymes (finasteride or dutasteride), and other steroid metabolism enzyme inhibitors (ketoconazole or the recently available abiraterone acetate). ©2011 AACR.

  14. Determination and production of antimicrobial compounds by Aspergillus clavatonanicus strain MJ31, an endophytic fungus from Mirabilis jalapa L. using UPLC-ESI-MS/MS and TD-GC-MS analysis

    PubMed Central

    Mishra, Vineet Kumar; Passari, Ajit Kumar; Chandra, Preeti; Leo, Vincent Vineeth; Kumar, Brijesh; Uthandi, Sivakumar; Thankappan, Sugitha; Gupta, Vijai Kumar

    2017-01-01

    Endophytic fungi associated with medicinal plants are reported as potent producers of diverse classes of secondary metabolites. In the present study, an endophytic fungi, Aspergillus clavatonanicus strain MJ31, exhibiting significant antimicrobial activity was isolated from roots of Mirabilis jalapa L., was identified by sequencing three nuclear genes i.e. internal transcribed spacers ribosomal RNA (ITS rRNA), 28S ribosomal RNA (28S rRNA) and translation elongation factor 1- alpha (EF 1α). Ethyl acetate extract of strain MJ31displayed significant antimicrobial potential against Bacillus subtilis, followed by Micrococccus luteus and Staphylococcus aureus with minimum inhibitory concentrations (MIC) of 0.078, 0.156 and 0.312 mg/ml respectively. In addition, the strain was evaluated for its ability to synthesize bioactive compounds by the amplification of polyketide synthase (PKS) and non ribosomal peptide synthetase (NRPS) genes. Further, seven antibiotics (miconazole, ketoconazole, fluconazole, ampicillin, streptomycin, chloramphenicol, and rifampicin) were detected and quantified using UPLC-ESI-MS/MS. Additionally, thermal desorption-gas chromatography mass spectrometry (TD-GC-MS) analysis of strain MJ31 showed the presence of 28 volatile compounds. This is the first report on A. clavatonanicus as an endophyte obtained from M. jalapa. We conclude that A. clavatonanicus strain MJ31 has prolific antimicrobial potential against both plant and human pathogens and can be exploited for the discovery of new antimicrobial compounds and could be an alternate source for the production of secondary metabolites. PMID:29049321

  15. Determination and production of antimicrobial compounds by Aspergillus clavatonanicus strain MJ31, an endophytic fungus from Mirabilis jalapa L. using UPLC-ESI-MS/MS and TD-GC-MS analysis.

    PubMed

    Mishra, Vineet Kumar; Passari, Ajit Kumar; Chandra, Preeti; Leo, Vincent Vineeth; Kumar, Brijesh; Uthandi, Sivakumar; Thankappan, Sugitha; Gupta, Vijai Kumar; Singh, Bhim Pratap

    2017-01-01

    Endophytic fungi associated with medicinal plants are reported as potent producers of diverse classes of secondary metabolites. In the present study, an endophytic fungi, Aspergillus clavatonanicus strain MJ31, exhibiting significant antimicrobial activity was isolated from roots of Mirabilis jalapa L., was identified by sequencing three nuclear genes i.e. internal transcribed spacers ribosomal RNA (ITS rRNA), 28S ribosomal RNA (28S rRNA) and translation elongation factor 1- alpha (EF 1α). Ethyl acetate extract of strain MJ31displayed significant antimicrobial potential against Bacillus subtilis, followed by Micrococccus luteus and Staphylococcus aureus with minimum inhibitory concentrations (MIC) of 0.078, 0.156 and 0.312 mg/ml respectively. In addition, the strain was evaluated for its ability to synthesize bioactive compounds by the amplification of polyketide synthase (PKS) and non ribosomal peptide synthetase (NRPS) genes. Further, seven antibiotics (miconazole, ketoconazole, fluconazole, ampicillin, streptomycin, chloramphenicol, and rifampicin) were detected and quantified using UPLC-ESI-MS/MS. Additionally, thermal desorption-gas chromatography mass spectrometry (TD-GC-MS) analysis of strain MJ31 showed the presence of 28 volatile compounds. This is the first report on A. clavatonanicus as an endophyte obtained from M. jalapa. We conclude that A. clavatonanicus strain MJ31 has prolific antimicrobial potential against both plant and human pathogens and can be exploited for the discovery of new antimicrobial compounds and could be an alternate source for the production of secondary metabolites.

  16. Fusarium species causing eumycetoma: Report of two cases and comprehensive review of the literature.

    PubMed

    Al-Hatmi, Abdullah M S; Bonifaz, Alexandro; Tirado-Sánchez, Andrés; Meis, Jacques F; de Hoog, G Sybren; Ahmed, Sarah A

    2017-03-01

    Recently, mycetoma was added to the World Health Organization's list of neglected tropical disease priorities. Fusarium as a genus has been reported to cause eumycetoma, but little is known about the species involved in this infection and their identification. In this study, molecular tools were applied to identify Fusarium agents from human eumycetoma cases. The partial translation elongation factor 1-alpha (TEF-1α) gene was used as diagnostic parameter. Two additional cases of eumycetoma, due to F. keratoplasticum and F. pseudensiforme, respectively, are presented. A systematic literature review was performed to assess general features, identification, treatment and outcome of eumycetoma infections due to Fusarium species. Of the 20 reviewed patients, the majority (75%) were male. Most agents belonged to the F. solani species complex, ie F. keratoplasticum, F. pseudensiforme, and an undescribed lineage of F. solani. In addition, F. thapsinum, a member of Fusarium fujikuroi species complex was encountered. The main antifungal drugs used were itraconazole, ketoconazole and amphotericin B, but cure rates were low (15%). Partial response or relapse was observed in some cases, and a case ended in amputation. Clinical management of eumycetoma due to Fusarium is complex and combination therapy might be required to increase cure rates. © 2016 Blackwell Verlag GmbH.

  17. Antifungal and antioxidant activities of Coleonema album and C. pulchellum against skin diseases.

    PubMed

    Fajinmi, Olufunke O; Grúz, Jiří; Tarkowski, Petr; Kulkarni, Manoj G; Finnie, Jeffrey F; Van Staden, Johannes

    2017-12-01

    Coleonema album (Thunb) Bart. & H. L. Wendl (Rutaceae) has been used in the formulation of skincare products, and the Khoisan people rub it on their skin to add luster. Coleonema pulchellum I. Williams has received less attention in the South African traditional medicine. This study investigates the antifungal and antioxidant activities of C. album and C. pulchellum essential oil (EO) and leaf extracts; and analyzes the chemical components of their EOs. Antifungal activity of leaf extracts was determined using the microdilution method with griseofulvin and ketoconazole as controls. Antifungal capacity of EO was investigated using the 'Volatile release plate method'. Trichophyton rubrum (ATCC 28188) and T. mentagrophytes (ATCC 9533) mycelia (0.3 cm diameter) were placed on fresh yeast malt agar in Petri dishes with filter paper (impregnated with 20 μL of EO) on the lid for direct exposure to EO volatiles while plates without EO were used as controls. The incubation time was seven days. Antioxidant activities of the leaf extracts were determined. Methanol leaf extract of C. pulchellum inhibited the growth of three fungi tested with MIC values of 195, 391 and 49 μg/mL for Trichophyton rubrum, Trichophyton mentagrophytes and Microsporum gypseum, respectively. Terpenes formed the major components of the EO. The EO from both plants inhibited the growth of T. rubrum in vitro. This study revealed the therapeutic value of C. pulchellum. Coleonema album and C. pulchellum should be considered as potential plants for skin ointment from natural origin.

  18. The Candida albicans Ddr48 protein is essential for filamentation, stress response, and confers partial antifungal drug resistance.

    PubMed

    Dib, Leila; Hayek, Peter; Sadek, Helen; Beyrouthy, Berna; Khalaf, Roy A

    2008-06-01

    Candida albicans is a dimorphic pathogenic fungus that causes mucosal and systemic infections. C. albicans pathogenicity is attributed to its ability to exist in different morphologic states and to respond to stress by up regulating several key genes. DDR48 is a stress-associated gene involved in DNA repair and in response to antifungal drug exposure. One allele of DDR48 was knocked out by homologous recombination that inserted a marker cassette in its position. Furthermore, reintroducing DDR48 on a plasmid created a revertant strain. Strains were grown on filamentation inducing and noninducing media, subjected to an oxidative stress challenge, injected into mice to assess virulence, and assayed for antifungal susceptibility by the E-test method. DDR48 was found to be haploid insufficient and possibly essential, since only a heterozygote, but not a homozygous, null mutant was generated. The mutant was filamentation defective on all hyphal media tested including serum and corn meal agar. Discrepancies in drug resistance profiles also were present: compared with the parental strain, DDR48/ddr48 heterozygote strain was susceptible in a dose-dependent manner to itraconazole and fluconazole and susceptible to ketoconazole. The mutant also appeared to be hypersensitive to a potentially lethal hydrogen peroxide challenge. However, no reduction in virulence of the mutant was observed. The present findings provide evidence that DDR48 is essential for filamentation, stress response, and possibly viability of C. albicans, making it a prime target for antifungal drug design.

  19. SciT

    Hirode, Mitsuhiro; Ono, Atsushi; Miyagishima, Toshikazu

    We have constructed a large-scale transcriptome database of rat liver treated with various drugs. In an effort to identify a biomarker for diagnosis of hepatic phospholipidosis, we extracted 78 probe sets of rat hepatic genes from data of 5 drugs, amiodarone, amitriptyline, clomipramine, imipramine, and ketoconazole, which actually induced this phenotype. Principal component analysis (PCA) using these probes clearly separated dose- and time-dependent clusters of treated groups from their controls. Moreover, 6 drugs (chloramphenicol, chlorpromazine, gentamicin, perhexiline, promethazine, and tamoxifen), which were reported to cause phospholipidosis but judged as negative by histopathological examination, were designated as positive by PCA usingmore » these probe sets. Eight drugs (carbon tetrachloride, coumarin, tetracycline, metformin, hydroxyzine, diltiazem, 2-bromoethylamine, and ethionamide), which showed phospholipidosis-like vacuolar formation in the histopathology, could be distinguished from the typical drugs causing phospholipidosis. Moreover, the possible induction of phospholipidosis was predictable by the expression of these genes 24 h after single administration in some of the drugs. We conclude that these identified 78 probe sets could be useful for diagnosis of phospholipidosis, and that toxicogenomics would be a promising approach for prediction of this type of toxicity.« less

  20. The peculiar behavior of the glass transition temperature of amorphous drug-polymer films coated on inert sugar spheres.

    PubMed

    Dereymaker, Aswin; Van Den Mooter, Guy

    2015-05-01

    Fluid bed coating has been proposed in the past as an alternative technology for manufacturing of drug-polymer amorphous solid dispersions, or so-called glass solutions. It has the advantage of being a one-step process, and thus omitting separate drying steps, addition of excipients, or manipulation of the dosage form. In search of an adequate sample preparation method for modulated differential scanning calorimetry analysis of beads coated with glass solutions, glass transition broadening and decrease of the glass transition temperature (Tg ) were observed with increasing particle size of crushed coated beads and crushed isolated films of indomethacin (INDO) and polyvinylpyrrolidone (PVP). Substituting INDO with naproxen gave comparable results. When ketoconazole was probed or the solvent in INDO-PVP films was switched to dichloromethane (DCM) or a methanol-DCM mixture, two distinct Tg regions were observed. Small particle sizes had a glass transition in the high Tg region, and large particle sizes had a glass transition in the low Tg region. This particle size-dependent glass transition was ascribed to different residual solvent amounts in the bulk and at the surface of the particles. A correlation was observed between the deviation of the Tg from that calculated from the Gordon-Taylor equation and the amount of residual solvent at the Tg of particles with different sizes. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association.

  1. Onychomycosis: Pathogenesis, Diagnosis, and Management

    PubMed Central

    Elewski, Boni E.

    1998-01-01

    Although not life-threatening, onychomycosis (a fungal infection of the nail, usually caused by a dermatophyte) constitutes an important public health problem because of its high prevalence (about 10% of the U.S. population) and associated morbidity. The disease can have certain negative consequences for patients, such as pain, and can potentially undermine work and social lives. This review discusses the etiology, classification, diagnosis, and treatment of onychomycosis. Four types of onychomycosis are recognized based on the site and pattern of fungal invasion. Dermatophyte fungi are the predominant pathogens, but yeasts (especially Candida albicans) and nondermatophyte molds may also be implicated. Accurate diagnosis requires direct microscopy and fungal culture. The differential diagnosis includes psoriasis, lichen planus, onychogryphosis, and nail trauma. Onychomycosis is more difficult to treat than most dermatophytoses because of the inherent slow growth of the nail. Older antifungal agents (ketoconazole and griseofulvin) are unsuitable for onychomycosis because of their relatively poor efficacy and potential adverse effects. Three recently developed antimycotic agents (fluconazole, itraconazole, and terbinafine) offer high cure rates and good safety profiles. In addition, the short treatment times (<3 months) and intermittent dosing schedules are likely to enhance compliance and reduce the costs of therapy. PMID:9665975

  2. Molecular identification and antifungal susceptibility profile of Candida species isolated from patients with vulvovaginitis in Tehran, Iran.

    PubMed

    Sharifynia, Somayeh; Falahati, Mehraban; Akhlaghi, Lame; Foroumadi, Alireza; Fateh, Roohollah

    2017-01-01

    Rapid and accurate identification and evaluation of antifungal susceptibility pattern of Candida isolates are crucial to determine suitable antifungal drugs for the treatment of patients with vulvovaginitis candidiasis. Vaginal samples were collected from 150 women with suspicious vaginal candidiasis, and then cultured on Sabouraoud's Dextrose Agar with chloramphenicol to isolate Candida species. After identification of Candida isolates using polymerase chain reaction-restriction fragment length polymorphism technique, antifungal susceptibility testing of four azolic antifungal drugs was carried out using broth microdilution method according to the CLSI M27-A3. Candida species were isolated from eighty suspected patients (61.79%). The most common pathogen was Candida albicans (63.75%). Resistance to fluconazole and ketoconazole was observed in 27.5% and 23.75% of Candida isolates, respectively, and only 2% of Candida isolates were resistant to miconazole. Interestingly, resistance to fluconazole in C. albicans was more than other Candida species. The results indicated that therapy should be selected according to the antifungal susceptibility tests for the prevention of treatment failure and miconazole therapy can be considered as the best therapeutic choice in the management of vulvovaginitis.

  3. Susceptibility and molecular characterization of Candida species from patients with vulvovaginitis.

    PubMed

    Fornari, Gheniffer; Vicente, Vania Aparecida; Gomes, Renata Rodrigues; Muro, Marisol Dominguez; Pinheiro, Rosangela Lameira; Ferrari, Carolina; Herkert, Patricia Fernanda; Takimura, Marcos; Carvalho, Newton Sérgio de; Queiroz-Telles, Flavio

    2016-01-01

    Vulvovaginal candidiasis affects women of reproductive age, which represents approximately 15-25% of vaginitis cases. The present study aimed to isolate and characterize yeast from the patients irrespective of the presentation of clinical symptoms. The isolates were subjected to in vitro susceptibility profile and characterization by molecular markers, which intended to assess the distribution of species. A total of 40 isolates were obtained and identified through the CHROMagar, API20aux and by ITS and D1/D2 regions sequencing of DNAr gene. Candida albicans strains were genotyped by the ABC system and the isolates were divided into two genotypic groups. The identity of the C. albicans, C. glabrata, C. guilliermondii, C. kefyr and Saccharomyces cerevisiae isolates was confirmed by the multilocus analysis. The strains of Candida, isolated from patients with complications, were found to be resistant to nystatin but sensitive to fluconazole, amphotericin B and ketoconazole, as observed by in vitro sensitivity profile. The isolates from asymptomatic patients, i.e., the colonized group, showed a dose-dependent sensitivity to the anti-fungal agents, fluconazole and amphotericin B. However, the isolates of C. albicans that belong to distinct genotypic groups showed the same in vitro susceptibility profile. Copyright © 2016. Published by Elsevier Editora Ltda.

  4. A history of adjunctive glucocorticoid treatment for pediatric sepsis: moving beyond steroid pulp fiction toward evidence-based medicine.

    PubMed

    Zimmerman, Jerry J

    2007-11-01

    To review the history of clinical use of corticosteroids with particular reference to adjunctive therapy for severe pediatric sepsis and, in this context, to provide an overview of what is known, what is not known, and what research questions are particularly relevant at this time. Literature review using PubMed, cross-referenced article citations, and the Internet. The history of corticosteroid use in clinical medicine has been colorful, noisy, and always controversial. Therapeutic corticosteroid indications that initially seemed rational have frequently been refuted on closer, rigorous clinical trial inspection. Although it may be prudent to provide stress-dose steroids to children with septic shock who are clinically at risk for adrenal insufficiency (chronic or recent steroid use, purpura fulminans, etomidate or ketoconazole administration, hypothalamic, pituitary, adrenal disease), the safety and efficacy of stress-dose steroids as general adjunctive therapy for pediatric septic shock have not been established. Glucocorticoid administration does add potential risk to critically ill children. In particular, although adjunctive corticosteroids may hasten resolution of unstable hemodynamics in septic shock, this may occur at the metabolic cost of hyperglycemia. Clinical practice that fosters innovative therapy (off-label use) over research probably represents bad medical and social policy. Accordingly, pediatric critical care researchers have a responsibility to generate pediatric-specific evidence-based medicine for adjunctive corticosteroid therapy for severe sepsis in children.

  5. Effects of Inula racemosa root and Gymnema sylvestre leaf extracts in the regulation of corticosteroid induced diabetes mellitus: involvement of thyroid hormones.

    PubMed

    Gholap, S; Kar, A

    2003-06-01

    The efficacy of Inula racemosa (root) and Gymnema sylvestre (leaf) extracts either alone or in combination was evaluated in the amelioration of corticosteroid-induced hyperglycaemia in mice. Simultaneously thyroid hormone levels were estimated by radio-immunoassay (RIA) in order to ascertain whether the effects are mediated through thyroid hormones or not. While the corticosteroid (dexamethasone) administration increased the serum glucose concentration, it decreased serum concentrations of the thyroid hormones, thyroxine (T4) and triiodothyronine (T3). Administration of the two plant extracts either alone or in combination decreased the serum glucose concentration in dexamethasone induced hyperglycaemic animals. However, the administration of Inula racemosa and Gymnema sylvestre extracts in combination proved to be more effective than the individual extracts. These effects were comparable to a standard corticosteroid-inhibiting drug, ketoconazole. As no marked changes in thyroid hormone concentrations were observed by the administration of any of the plant extracts in dexamethasone treated animals, it is further suggested that these plant extracts may not prove to be effective in thyroid hormone mediated type II diabetes, but for steroid induced diabetes.

  6. Antimicrobial Susceptibility of Tinea Capitis in Children from Egypt

    PubMed Central

    Doss, Reham William; El-Rifaie, Abdel-Aziz; Radi, Nagla; El-Sherif, Aya Yehia

    2018-01-01

    Background: Dermatophytic fungi of genera Trichophyton and Microsporum are the most important fungal species causing tinea capitis. Choice of treatment for tinea capitis is determined by the species of fungus. Aim: The aim of the study was to investigate the most prevalent fungal species causing tinea capitis in children from Egypt and the most useful antifungal agent for treatment. Patients and Methods: A total of 100 patients diagnosed clinically with tinea capitis were included in the study. Samples were collected and sent to the microbiology and immunology laboratory for sample processing and fungal identification by routine laboratory techniques. A study of antifungal susceptibility to chosen antifungal medications (fluconazole, ketoconazole, clotrimazole, miconazole, amphotericin, caspofungin, itraconazole, terbinafine, and griseofulvin) was done by minimum inhibitory concentration technique. Results: Our analysis revealed that Microsporum canis is the most commonly isolated strain. Amphotericin was the most effective antifungal agent followed by terbinafine. The most sensitive strain to fluconazole and griseofulvin is Microsporum gypseum, while Microsporum audouinii was mostly responsive to terbinafine. Conclusion: Identification and evaluation of the antifungal susceptibility of the pathogenic species in a certain geographic region is important to achieve a good clinical response. PMID:29692458

  7. Tinea capitis favosa misdiagnosed as tinea amiantacea

    PubMed Central

    Anane, Sonia; Chtourou, Olfa

    2012-01-01

    Introduction Favus of the scalp or tinea capitis favosa is a chronic dermatophyte infection of the scalp. In almost cases, favus is caused by Trichophyton schoenleinii, anthropophilic dermatophyte. It is characterized by the presence of scutula and severe alopecia. Besides the classic clinical type of tinea capitis favosa, there are many variant of clinical form which may persist undiagnosed for many years. In this work, we report an atypical form of favus to Trichophyton schoenleinii which was misdiagnosed as tinea amiantacea. Case-report An 11-year old girl came to the outpatient department of dermatology (day 0) with history of tinea amiantacea treated unsuccessfully with keratolytic shampoo (day – 730). She presented a diffuse scaling of the scalp with thick scaly patches and without scutula or alopecia. A diagnosis of tinea favosa by T. schoenleinii was made by mycological examination. She was treated with griseofulvin and ketoconazole in the form of foaming gel for twelve weeks. Despite treatment, clinical evolution was marked by appearance of permanent alopecia patches. The follow-up mycological examination was negative. Conclusion Because of ultimate evolution of favus into alopecia, we emphasize the importance of mycological examination in case of diffuse scaling. PMID:24432210

  8. Antimicrobial Susceptibility of Tinea Capitis in Children from Egypt.

    PubMed

    Doss, Reham William; El-Rifaie, Abdel-Aziz; Radi, Nagla; El-Sherif, Aya Yehia

    2018-01-01

    Dermatophytic fungi of genera Trichophyton and Microsporum are the most important fungal species causing tinea capitis. Choice of treatment for tinea capitis is determined by the species of fungus. The aim of the study was to investigate the most prevalent fungal species causing tinea capitis in children from Egypt and the most useful antifungal agent for treatment. A total of 100 patients diagnosed clinically with tinea capitis were included in the study. Samples were collected and sent to the microbiology and immunology laboratory for sample processing and fungal identification by routine laboratory techniques. A study of antifungal susceptibility to chosen antifungal medications (fluconazole, ketoconazole, clotrimazole, miconazole, amphotericin, caspofungin, itraconazole, terbinafine, and griseofulvin) was done by minimum inhibitory concentration technique. Our analysis revealed that Microsporum canis is the most commonly isolated strain. Amphotericin was the most effective antifungal agent followed by terbinafine. The most sensitive strain to fluconazole and griseofulvin is Microsporum gypseum , while Microsporum audouinii was mostly responsive to terbinafine. Identification and evaluation of the antifungal susceptibility of the pathogenic species in a certain geographic region is important to achieve a good clinical response.

  9. Biotransformation of 2,2',5,5'-tetrachlorobiphenyl (PCB 52) and 3,3',4,4'-tetrachlorobiphenyl (PCB 77) by liver microsomes from four species of sea turtles.

    PubMed

    Richardson, Kristine L; Schlenk, Daniel

    2011-05-16

    The rates of oxidative metabolism of two tetrachlorobiphenyl congeners were determined in hepatic microsomes from four species of sea turtles, green (Chelonia mydas), olive ridley (Lepidochelys olivacea), loggerhead (Caretta caretta), and hawksbill (Eretmochelys imbricata). Hydroxylation of 3,3',4,4'-tetrachlorobiphenyl (PCB 77), an ortho-meta unsubstituted rodent cytochrome P450 (P450) 1A substrate PCB, was not observed in sea turtle microsomes. Sea turtle microsomes hydroxylated 2,2',5,5'-tetrachlorobiphenyl (PCB 52), a meta-para unsubstituted rodent P450 family 2 substrate PCB, at rates ranging from less than 0.5 to 53 pmol/min/mg protein. The P450 inhibitor ketoconazole inhibited hydroxylation of PCB 52, supporting the role of P450 catalysis. Sea turtle PCB 52 hydroxlyation rates strongly correlated with immunodetected P450 family 2-like and less so with P450 family 3-like hepatic proteins. Testosterone 6β-, 16α-, 16β-hydroxylase activities were also significantly correlated with the expression of these enzymes, indicating that P450 family 2 or P450 family 3 proteins are responsible for PCB hydroxylation in sea turtles. This study indicated species-specific PCB biotransformation in sea turtles and preferential elimination of meta-para unsubstituted PCB congeners over ortho-meta unsubstituted PCB congeners consistent with PCB accumulation patterns observed in tissues of sea turtles.

  10. Molecular identification and antifungal susceptibility profile of Candida species isolated from patients with vulvovaginitis in Tehran, Iran

    PubMed Central

    Sharifynia, Somayeh; Falahati, Mehraban; Akhlaghi, Lame; Foroumadi, Alireza; Fateh, Roohollah

    2017-01-01

    Background: Rapid and accurate identification and evaluation of antifungal susceptibility pattern of Candida isolates are crucial to determine suitable antifungal drugs for the treatment of patients with vulvovaginitis candidiasis. Materials and Methods: Vaginal samples were collected from 150 women with suspicious vaginal candidiasis, and then cultured on Sabouraoud's Dextrose Agar with chloramphenicol to isolate Candida species. After identification of Candida isolates using polymerase chain reaction-restriction fragment length polymorphism technique, antifungal susceptibility testing of four azolic antifungal drugs was carried out using broth microdilution method according to the CLSI M27-A3. Results: Candida species were isolated from eighty suspected patients (61.79%). The most common pathogen was Candida albicans (63.75%). Resistance to fluconazole and ketoconazole was observed in 27.5% and 23.75% of Candida isolates, respectively, and only 2% of Candida isolates were resistant to miconazole. Interestingly, resistance to fluconazole in C. albicans was more than other Candida species. Conclusion: The results indicated that therapy should be selected according to the antifungal susceptibility tests for the prevention of treatment failure and miconazole therapy can be considered as the best therapeutic choice in the management of vulvovaginitis. PMID:29387119

  11. New Thiazolyl-triazole Schiff Bases: Synthesis and Evaluation of the Anti-Candida Potential.

    PubMed

    Stana, Anca; Enache, Alexandra; Vodnar, Dan Cristian; Nastasă, Cristina; Benedec, Daniela; Ionuț, Ioana; Login, Cezar; Marc, Gabriel; Oniga, Ovidiu; Tiperciuc, Brîndușa

    2016-11-22

    In the context of the dangerous phenomenon of fungal resistance to the available therapies, we present here the chemical synthesis of a new series of thiazolyl-triazole Schiff bases B1 - B15 , which were in vitro assessed for their anti- Candida potential. Compound B10 was found to be more potent against Candida spp. when compared with the reference drugs Fluconazole and Ketoconazole. A docking study of the newly synthesized Schiff bases was performed, and results showed good binding affinity in the active site of co-crystallized Itraconazole-lanosterol 14α-demethylase isolated from Saccharomyces cerevisiae . An in silico ADMET (absorption, distribution, metabolism, excretion, toxicity) study was done in order to predict some pharmacokinetic and pharmacotoxicological properties. The Schiff bases showed good drug-like properties. The results of in vitro anti- Candida activity, a docking study and ADMET prediction revealed that the newly synthesized compounds have potential anti- Candida activity and evidenced the most active derivative, B10 , which can be further optimized as a lead compound.

  12. Species Distribution and Susceptibility to Azoles of Vaginal Yeasts Isolated Prostitutes

    PubMed Central

    Gross, Norma T.; Arias, M. L.; Moraga, M.; Baddasarow, Y.; Jarstrand, C.

    2007-01-01

    Objective. We investigated the use of miconazole among female prostitutes in Costa Rica as well as the distribution of vaginal yeasts and the susceptibility pattern to azoles of strains obtained from this population. Our intention was to relate a frequent use of miconazole to occurrence of vaginal yeasts resistant to azoles. Methods. Vaginal samples were taken from 277 patients that have previously used azoles. Vaginal swabs were obtained for direct microscopy and culture. Yeast isolates were identified by germ tube test and assimilation pattern. Susceptibility testing was determined using a tablet diffusion method. Results. The number of clinical Candida isolates (one from each patient) was 57 (20.6%). C. albicans was the predominant species (70%), followed by C. parapsilosis (12%), C. tropicalis (5.3%), C. glabrata and C. famata (3.5% each), C. krusei, C. inconspicua and C. guilliermondii (1.7% each). The majority of vaginal Candida isolates were susceptible to ketoconazole (91%), fluconazole (96.5%), and itraconazole (98%). A lower susceptibility of some isolates to miconazole (63%) was observed as compared to the other azoles tested. Moreover, the strains, nonsusceptible to miconazole, were more often obtained from patients that have used this antifungal at least four times within the last year before taking the samples as compared to those with three or less treatments (P<.01). Conclusion. An indiscriminate use of miconazole, such as that observed among female prostitutes in Costa Rica, results in a reduced susceptibility of vaginal yeasts to miconazole but not to other azoles. PMID:18273407

  13. Comparative study of the complex forming ability and enantioselectivity of cyclodextrin polymers by CE and 1H NMR.

    PubMed

    Danel, Cécile; Azaroual, Nathalie; Chavaria, Cédric; Odou, Pascal; Martel, Bernard; Vaccher, Claude

    2013-02-15

    The interactions between nine drugs (baclofen, bupivacaine, chlorpheniramine, ketoconazole, paliperidone, promethazine, propranolol, risperidone and verapamil) and six cyclodextrins (α-CD, β-CD, γ-CD, HP-β-CD, HP-γ-CD and Me-β-CD) or six polymers of cyclodextrins (polyα-CD, polyβ-CD, polyγ-CD, polyHP-β-CD, polyHP-γ-CD and polyMe-β-CD) were studied by affinity capillary electrophoresis and/or (1)H NMR at pH 2.5. An exhaustive qualitative study was performed through the determination of the retardation factor. Then, four compounds and both β-CD and polyβ-CD were selected for the quantitative study of the interactions at pH 2.5 and 7.0. By comparing the results obtained with the β-CD and polyβ-CD, it appears that the apparent binding constants are up to five times higher with the polymer. The 2D-NMR results seem to indicate that the structure of the polymeric network favours the inclusion of the guest in the hydrophobic cavity of the CD units. Moreover, the poly-CDs have shown very high enantioselective abilities at both pH. Copyright © 2012 Elsevier Ltd. All rights reserved.

  14. Melanins Protect Sporothrix brasiliensis and Sporothrix schenckii from the Antifungal Effects of Terbinafine

    PubMed Central

    Almeida-Paes, Rodrigo; Figueiredo-Carvalho, Maria Helena Galdino; Brito-Santos, Fábio; Almeida-Silva, Fernando; Oliveira, Manoel Marques Evangelista; Zancopé-Oliveira, Rosely Maria

    2016-01-01

    Terbinafine is a recommended therapeutic alternative for patients with sporotrichosis who cannot use itraconazole due to drug interactions or side effects. Melanins are involved in resistance to antifungal drugs and Sporothrix species produce three different types of melanin. Therefore, in this study we evaluated whether Sporothrix melanins impact the efficacy of antifungal drugs. Minimal inhibitory concentrations (MIC) and minimal fungicidal concentrations (MFC) of two Sporothrix brasiliensis and four Sporothrix schenckii strains grown in the presence of the melanin precursors L-DOPA and L-tyrosine were similar to the MIC determined by the CLSI standard protocol for S. schenckii susceptibility to amphotericin B, ketoconazole, itraconazole or terbinafine. When MICs were determined in the presence of inhibitors to three pathways of melanin synthesis, we observed, in four strains, an increase in terbinafine susceptibility in the presence of tricyclazole, a DHN-melanin inhibitor. In addition, one S. schenckii strain grown in the presence of L-DOPA had a higher MFC value when compared to the control. Growth curves in presence of 2×MIC concentrations of terbinafine showed that pyomelanin and, to a lesser extent, eumelanin were able to protect the fungi against the fungicidal effect of this antifungal drug. Our results suggest that melanin protects the major pathogenic species of the Sporothrix complex from the effects of terbinafine and that the development of new antifungal drugs targeting melanin synthesis may improve sporotrichosis therapies. PMID:27031728

  15. Abiraterone treatment in castration-resistant prostate cancer selects for progesterone responsive mutant androgen receptors.

    PubMed

    Chen, Eddy J; Sowalsky, Adam G; Gao, Shuai; Cai, Changmeng; Voznesensky, Olga; Schaefer, Rachel; Loda, Massimo; True, Lawrence D; Ye, Huihui; Troncoso, Patricia; Lis, Rosina L; Kantoff, Philip W; Montgomery, Robert B; Nelson, Peter S; Bubley, Glenn J; Balk, Steven P; Taplin, Mary-Ellen

    2015-03-15

    The CYP17A1 inhibitor abiraterone markedly reduces androgen precursors and is thereby effective in castration-resistant prostate cancer (CRPC). However, abiraterone increases progesterone, which can activate certain mutant androgen receptors (AR) identified previously in flutamide-resistant tumors. Therefore, we sought to determine if CYP17A1 inhibitor treatment selects for progesterone-activated mutant ARs. AR was examined by targeted sequencing in metastatic tumor biopsies from 18 patients with CRPC who were progressing on a CYP17A1 inhibitor (17 on abiraterone, 1 on ketoconazole), alone or in combination with dutasteride, and by whole-exome sequencing in residual tumor in one patient treated with neoadjuvant leuprolide plus abiraterone. The progesterone-activated T878A-mutant AR was present at high allele frequency in 3 of the 18 CRPC cases. It was also present in one focus of resistant tumor in the neoadjuvant-treated patient, but not in a second clonally related resistant focus that instead had lost one copy of PTEN and both copies of CHD1. The T878A mutation appeared to be less common in the subset of patients with CRPC treated with abiraterone plus dutasteride, and transfection studies showed that dutasteride was a more potent direct antagonist of the T878A versus the wild-type AR. These findings indicate that selection for tumor cells expressing progesterone-activated mutant ARs is a mechanism of resistance to CYP17A1 inhibition. ©2014 American Association for Cancer Research.

  16. Antifungal and antibacterial activities of Petroselinum crispum essential oil.

    PubMed

    Linde, G A; Gazim, Z C; Cardoso, B K; Jorge, L F; Tešević, V; Glamoćlija, J; Soković, M; Colauto, N B

    2016-07-29

    Parsley [Petroselinum crispum (Mill.) Fuss] is regarded as an aromatic, culinary, and medicinal plant and is used in the cosmetic, food, and pharmaceutical industries. However, few studies with conflicting results have been conducted on the antimicrobial activity of parsley essential oil. In addition, there have been no reports of essential oil obtained from parsley aerial parts, except seeds, as an alternative natural antimicrobial agent. Also, microorganism resistance is still a challenge for health and food production. Based on the demand for natural products to control microorganisms, and the re-evaluation of potential medicinal plants for controlling diseases, the objective of this study was to determine the chemical composition and antibacterial and antifungal activities of parsley essential oil against foodborne diseases and opportunistic pathogens. Seven bacteria and eight fungi were tested. The essential oil major compounds were apiol, myristicin, and b-phellandrene. Parsley essential oil had bacteriostatic activity against all tested bacteria, mainly Staphylococcus aureus, Listeria monocytogenes, and Salmonella enterica, at similar or lower concentrations than at least one of the controls, and bactericidal activity against all tested bacteria, mainly S. aureus, at similar or lower concentrations than at least one of the controls. This essential oil also had fungistatic activity against all tested fungi, mainly, Penicillium ochrochloron and Trichoderma viride, at lower concentrations than the ketoconazole control and fungicidal activity against all tested fungi at higher concentrations than the controls. Parsley is used in cooking and medicine, and its essential oil is an effective antimicrobial agent.

  17. High-throughput synergy screening identifies microbial metabolites as combination agents for the treatment of fungal infections

    PubMed Central

    Zhang, Lixin; Yan, Kezhi; Zhang, Yu; Huang, Ren; Bian, Jiang; Zheng, Chuansen; Sun, Haixiang; Chen, Zhihui; Sun, Nuo; An, Rong; Min, Fangui; Zhao, Weibo; Zhuo, Ying; You, Jianlan; Song, Yongjie; Yu, Zhenyan; Liu, Zhiheng; Yang, Keqian; Gao, Hong; Dai, Huanqin; Zhang, Xiaoli; Wang, Jian; Fu, Chengzhang; Pei, Gang; Liu, Jintao; Zhang, Si; Goodfellow, Michael; Jiang, Yuanying; Kuai, Jun; Zhou, Guochun; Chen, Xiaoping

    2007-01-01

    The high mortality rate of immunocompromised patients with fungal infections and the limited availability of highly efficacious and safe agents demand the development of new antifungal therapeutics. To rapidly discover such agents, we developed a high-throughput synergy screening (HTSS) strategy for novel microbial natural products. Specifically, a microbial natural product library was screened for hits that synergize the effect of a low dosage of ketoconazole (KTC) that alone shows little detectable fungicidal activity. Through screening of ≈20,000 microbial extracts, 12 hits were identified with broad-spectrum antifungal activity. Seven of them showed little cytotoxicity against human hepatoma cells. Fractionation of the active extracts revealed beauvericin (BEA) as the most potent component, because it dramatically synergized KTC activity against diverse fungal pathogens by a checkerboard assay. Significantly, in our immunocompromised mouse model, combinations of BEA (0.5 mg/kg) and KTC (0.5 mg/kg) prolonged survival of the host infected with Candida parapsilosis and reduced fungal colony counts in animal organs including kidneys, lungs, and brains. Such an effect was not achieved even with the high dose of 50 mg/kg KTC. These data support synergism between BEA and KTC and thereby a prospective strategy for antifungal therapy. PMID:17360571

  18. Mechanisms of fenthion activation in rainbow trout (Oncorhynchus mykiss) acclimated to hypersaline environments

    SciT

    Lavado, Ramon; Rimoldi, John M.; Schlenk, Daniel

    2009-03-01

    Previous studies in rainbow trout have shown that acclimation to hypersaline environments enhances the toxicity to thioether organophosphate and carbamate pesticides. In order to determine the role of biotransformation in this process, the metabolism of the thioether organophosphate biocide, fenthion was evaluated in microsomes from gills, liver and olfactory tissues in rainbow trout (Oncorhynchus mykiss) acclimated to freshwater and 17 per mille salinity. Hypersalinity acclimation increased the formation of fenoxon and fenoxon sulfoxide from fenthion in liver microsomes from rainbow trout, but not in gills or in olfactory tissues. NADPH-dependent and independent hydrolysis was observed in all tissues, but onlymore » NADPH-dependent fenthion cleavage was differentially modulated by hypersalinity in liver (inhibited) and gills (induced). Enantiomers of fenthion sulfoxide (65% and 35% R- and S-fenthion sulfoxide, respectively) were formed in liver and gills. The predominant pathway of fenthion activation in freshwater appears to be initiated through initial formation of fenoxon which may be subsequently converted to the most toxic metabolite fenoxon R-sulfoxide. However, in hypersaline conditions both fenoxon and fenthion sulfoxide formation may precede fenoxon sulfoxide formation. Stereochemical evaluation of sulfoxide formation, cytochrome P450 inhibition studies with ketoconazole and immunoblots indicated that CYP3A27 was primarily involved in the enhancement of fenthion activation in hypersaline-acclimated fish with limited contribution of FMO to initial sulfoxidation.« less

  19. Simulation and Prediction of the Drug-Drug Interaction Potential of Naloxegol by Physiologically Based Pharmacokinetic Modeling.

    PubMed

    Zhou, D; Bui, K; Sostek, M; Al-Huniti, N

    2016-05-01

    Naloxegol, a peripherally acting μ-opioid receptor antagonist for the treatment of opioid-induced constipation, is a substrate for cytochrome P450 (CYP) 3A4/3A5 and the P-glycoprotein (P-gp) transporter. By integrating in silico, preclinical, and clinical pharmacokinetic (PK) findings, minimal and full physiologically based pharmacokinetic (PBPK) models were developed to predict the drug-drug interaction (DDI) potential for naloxegol. The models reasonably predicted the observed changes in naloxegol exposure with ketoconazole (increase of 13.1-fold predicted vs. 12.9-fold observed), diltiazem (increase of 2.8-fold predicted vs. 3.4-fold observed), rifampin (reduction of 76% predicted vs. 89% observed), and quinidine (increase of 1.2-fold predicted vs. 1.4-fold observed). The moderate CYP3A4 inducer efavirenz was predicted to reduce naloxegol exposure by ∼50%, whereas weak CYP3A inhibitors were predicted to minimally affect exposure. In summary, the PBPK models reasonably estimated interactions with various CYP3A modulators and can be used to guide dosing in clinical practice when naloxegol is coadministered with such agents. © 2016 The Authors CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.

  20. The in vitro efficacy of SunSmile® Fruit & Vegetable Rinse against pathogenic strains of Prototheca algae that cause mastitis in cows.

    PubMed

    Grzesiak, B; Krukowski, H; Głowacka, A

    2018-04-16

    The research concerns algae of the genus Prototheca. They are found in the natural environment and they can cause a disease in animals and humans called protothecosis. The aim of the study was to evaluate the in vitro activity of the fruit and vegetable rinse agent SunSmile ® Fruit & Vegetable Rinse (Sunrider International) against P. zopfii isolates. The materials consisted of ten P. zopfii strains isolated from the milk of cows with mastitis. The following antifungal chemotherapeutic agents were also used in the study for comparison: nystatin, ketoconazole, amphothericin B, miconazole, clotrimazole, econazole, fluconazole, and flucytosine. The tube dilution method were used to evaluate the effect of a fruit and vegetable rinse agent and the disc-diffusion method to evaluate the effect of antifungal chemotherapeutic agents on P. zopfii strains. All tested strains of P. zopfii were susceptible to the action of the SunSmile ® agent. The MMC was in the range of 0.0024-0.0190%. The SunSmile ® Fruit & Vegetable Rinse can be used in prevention of mastitis in cows and in human protothecosis due to its safe, natural composition and efficacy. Copyright © 2018 Elsevier Masson SAS. All rights reserved.