DOCSLIB.ORG

The Antifungal Antibiotic Clotrimazole Alters Calcium Homeostasis of Leukemic Lymphoblasts and Induces Apoptosis

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
The Antifungal Antibiotic Clotrimazole Alters Calcium Homeostasis of Leukemic Lymphoblasts and Induces Apoptosis Leukemia (2002) 16, 1344–1352 2002 Nature Publishing Group All rights reserved 0887-6924/02 $25.00 www.nature.com/leu The antifungal antibiotic clotrimazole alters calcium homeostasis of leukemic lymphoblasts and induces apoptosis C Ito1, C Tecchio1, E Coustan-Smith1, T Suzuki1, FG Behm2,3, SC Raimondi2,3, C-H Pui1,2,3 and D Campana1,2,3 1Department of Hematology-Oncology, St Jude Children’s Research Hospital, Memphis, TN, USA; 2Department of Pathology, St Jude Children’s Research Hospital, Memphis, TN, USA; and 3University of Tennessee College of Medicine, Memphis TN, USA Clotrimazole is an antimycotic imidazole derivative that inter- ease16,17 and the treatment of secretory diarrheas that involve 2+ feres with cellular Ca homeostasis. We investigated the chloride secretion through IK channels.18 effects of clotrimazole on acute lymphoblastic leukemia (ALL) Interest in clotrimazole as a potential antileukemic com- cells. Treatment with 10 ␮M clotrimazole (a concentration achi- evable in vivo) reduced cell recovery from cultures of all nine pound derives from the following observations. First, clotrima- ALL cell lines studied (B-lineage: OP-1, SUP-B15, RS4;11, zole suppresses the proliferation of carcinoma and melanoma NALM6, REH, and 380; T-lineage: MOLT4, CCRF-CEM, and cell lines and blocks metastasis of melanoma in immuno- CEM-C7). After 4 days of culture, median cell recovery was 10% deficient mice without evident systemic toxicity.19 Second, Ͻ (range, 1% to 37%) of cell recovery in parallel untreated cul- clotrimazole has been shown to inhibit normal lymphocyte tures. Clotrimazole also inhibited recovery of primary ALL cells proliferation,20,21 at least partially by blocking IK chan- cultured on stromal feeder layers. After leukemic cells from 16 15,22 cases of ALL were cultured for 7 days with 10 ␮M clotrimazole, nels, and it reportedly exerts beneficial effects in patients median cell recovery was Ͻ1% (range, Ͻ1% to 16%) of that in with rheumatoid arthritis.23,24 Importantly, concentrations of parallel untreated cultures. Clotrimazole was active against leu- clotrimazole and its metabolites that effectively interfere with kemic cells with genetic abnormalities associated with poor Ca2+ metabolism and block IK channels are achievable in response to therapy and against multidrug-resistant cell lines. vivo.25–27 In contrast, mature T lymphocytes and bone marrow stromal cells were not affected. Clotrimazole induced depletion of intra- We investigated the effects of clotrimazole on ALL cells and cellular Ca2+ stores in ALL cells, which was followed by found that the drug markedly suppresses the recovery of ALL apoptosis, as shown by annexin V binding and DNA fragmen- cells from culture. This effect was observed both in leukemic tation. Thus, clotrimazole is cytotoxic to ALL cells at concen- cell lines and in primary leukemic lymphoblasts sustained in trations achievable in vivo. vitro by bone marrow-derived stroma. Surprisingly, although Leukemia (2002) 16, 1344–1352. doi:10.1038/sj.leu.2402510 clotrimazole was reported to inhibit cell proliferation of vari- Keywords: clotrimazole; acute lymphoblastic leukemia; apoptosis; 15,19,21,28,29 multidrug resistance ous cell types without apparent cytotoxicity, its pri- mary mechanism of action in ALL cells was induction of apoptosis. Introduction Materials and methods Residual drug-resistant leukemic cells cause disease recur- rence in approximately 20% of children and 65% of adults Cells after intensive chemotherapy for acute lymphoblastic leuke- mia (ALL).1,2 Recurrent ALL is particularly resistant to chemo- Bone marrow cells were collected at the time of diagnosis therapy, as is newly diagnosed ALL with BCR-ABL, MLL gene (n = 14) or relapse (n = 2) from patients with ALL, ages 1 to 17 rearrangements or near-haploidy.1,2 Thus, the cure rates for years (median, 8 years) (Table 1). Fourteen cases were B-lin- ALL cannot be significantly improved unless new drugs are + + + eage ALL (CD19 ,CD22 and HLA-DR ); four of these were developed that bypass cellular mechanisms of resistance. pre-B ALL (cytoplasmic ␮ immunoglobulin heavy chains were The imidazole derivative clotrimazole is an antimycotic + present). The remaining two cases were T-lineage ALL (CD3 , agent that modulates cellular ionic signaling pathways that are + + CD2 and CD7 ). The viability of cells was Ͼ90% in all crucial to cell survival and growth. In blood cells and other samples, as demonstrated by trypan blue dye exclusion. Per- cell types, the transduction of external signals via surface ipheral blood lymphocytes were obtained from healthy receptors triggers the production of inositol (1,4,5)-trisphosph- + donors. Mononuclear cells were separated by density gradient ate and the resultant release of Ca2 from the endoplasmic centrifugation (Lymphoprep, Nycomed, Oslo, Norway) and reticulum.3–5 Normally, this release induces the opening of + then washed three times in phosphate-buffered saline and plasma membrane Ca2 channels and activates the intermedi- + + + once in AIM-V (Gibco, Grand Island, NY, USA), a serum-free, ate-conductance Ca2 -activated K (IK) channel, allowing Ca2 cytokine-free tissue culture medium. These studies were influx from the extracellular space.3–9 Clotrimazole disrupts + + approved by the St Jude Children’s Research Hospital Insti- cellular Ca2 homeostasis by releasing Ca2 from intracellular + tutional Review Board, and informed consent was given by stores while inhibiting Ca2 influx and blocking IK chan- the patients, their parents or guardians, or both. nels.7,10–15 It is being evaluated clinically for the treatment of The B-lineage ALL cell lines RS4;11,30 380,31 REH,32 OP133 IK channel-driven erythrocyte dehydration in sickle cell dis- and NALM634 and the T-lineage ALL cell lines MOLT-435 and CCRF-CEM were available in our laboratory.36 The cell lines CEM-C737 and SUP-B1538 were obtained from Dr G Melnyco- vych (University of Kansas Medical Center, Kansas City, MO, Correspondence: D Campana, Department of Hematology-Oncology, St Jude Children’s Research Hospital, 332 North Lauderdale, Memphis USA) and Dr SD Smith (University of Chicago, Chicago, IL, TN 38105-2794, USA; Fax: 901-495 3749 USA), respectively; the drug-resistant subclones of CCRF-CEM 39,40 Received 2 November 2001; accepted 8 February 2002 (CEM-VLB100 and CEM/VM-1) were obtained from Dr WM Clotrimazole induced apoptosis of leukemic cells C Ito et al 1345 Table 1 Immunophenotypes and karyotypes of 16 cases of ALL Patient No. Age Immunophenotypec Karyotype (years) 1a 5 Early B 46,XY,t(9;22)(q34;q11.2)[19] 2 8 Early B 46,XY,t(9;22)(q34;q11.2)[23] 3a 17 Pre-B 58,XY,+X,+2,+3,+5,+6,t(9;22)(q34;q11.2),−13,+14,+17,+18,+19,+20,+21,+der(22)t(9;22),+mar [3]/46,XY[20] 4 9 Early B 47,XY,+X,t(11;19)(q23;p13.3)[22]/46,XY[4] 5b 4 Early B 47,XY,+21[3]/46,XY,del(9)(p21)[2]/47,XY[23] 6 4 Pre-B 54,XX,+X,+4,+6,+10,+14,+17,+18,+21/56,XX,+X,+4,+6,+10,+14,+17,+18,+21,+mar,+mar 7 8 Early B 29,XY,+4,+8,+18,+21,+mar[5]/57,XY,+X,+?Y,+4,+5,del(5)(p13),?del(6) (q21),+6,+8,+9,+14,+18,+21,+mar[6] 8 15 Pre-B 46,XY,del(3)(q21q26)[9]/46,XY[5] 9b 6 Pre-B 47,XX,+10,del(11)(q23),t(1;12)(p22;p13),t(4;12)(q21;p13)[7]/45,X, −X,t(4;12)(q21;p13)[2] 10 1 Early B 45,XX,−7,del(1)(q32),dic(7;12)(p11.2;p11.2)[10]/46,XX[8] 11 14 Early B 46,XX[23] 12 14 Early B 46,XX,del(11)(q23)[4]/46,XX[24] 13b 8 Early B 46,XX,t(8;9)(q12–13;p22),t(15;19)(q15;p13)[19]/46,idem,−14,+mar[1] 14 3 Early B 47,XY,add(19)(p13),+21[8]/46,XY[17] 15 4 T Insufficient material 16 16 T 46,XY,del(6)(q15q21)[5]/46,XY[5] aStudied at the time of relapse. bt(12;21)-positive by fluorescence in situ hybridization. cEarly B, CD19+, CD10+/−; Pre-B, same plus cytoplasmic ␮; T, CD7+, cytoplasmic or surface CD3+. Beck (University of Illinois Cancer Center, Chicago, IL, USA). ocyanate (FITC) and anti-CD3 conjugated to phycoerythrin All cell lines were maintained in RPMI-1640 (BioWhittaker, (PE); T-lineage ALL cells were incubated with anti-CD7 FITC. Walkersville, MD, USA) with 10% fetal calf serum (FCS; Normal peripheral blood lymphocytes were incubated with BioWhittaker), l-glutamine, and antibiotics. anti-CD3 FITC. All monoclonal antibodies and isotype- matched nonreactive controls were purchased from Becton Dickinson (San Jose, CA, USA) or Dako (Carpinteria, CA, Cell culture USA). The cells were washed twice in phosphate-buffered saline with 0.2% bovine serum albumin and 0.2% sodium Bone marrow stromal cells derived from healthy bone marrow azide, resuspended in 0.5% paraformaldehyde, and analyzed transplant donors were depleted of T cells by CD6- and CD8- with a FACScan flow cytometer and Cell Quest software mediated rabbit complement lysis. Stroma was prepared in (Becton Dickinson). An identical procedure was used for cell 96-well flat-bottomed plates (Costar, Cambridge, MA, USA) lines except that immunophenotyping was omitted. and fed with RPMI-1640, 10% FCS, and 10−6 m hydrocorti- We set ‘gates’ around the area of the light-scatter dot plot sone (Sigma, St Louis, MO, USA), as previously described.41–44 that included virtually all leukemic cells. These gates were To prepare cultures of primary leukemic cells, we removed used to count cells with the same light-scattering properties the media from the bone marrow stroma and washed the before and after culture with or without clotrimazole.
Load more

Recommended publications
  • Topical Corticosteroids and Fungal Keratitis: a Review of the Literature and Case Series
    Journal of Clinical Medicine Review Topical Corticosteroids and Fungal Keratitis: A Review of the Literature and Case Series Karl Anders Knutsson 1,*, Alfonso Iovieno 2,3, Stanislav Matuska 1, Luigi Fontana 2 and Paolo Rama 1 1 Cornea and Ocular Surface Unit, San Raffaele Scientific Institute, 20132 Milan, Italy; [email protected] (S.M.); [email protected] (P.R.) 2 Arcispedale Santa Maria Nuova—IRCCS, 42123 Reggio Emilia, Italy; [email protected] (A.I.); [email protected] (L.F.) 3 Department of Ophthalmology, University of British Columbia, Vancouver, BC V6T 1Z, Canada * Correspondence: [email protected] or [email protected]; Tel./Fax: +39-022-6432-648 Abstract: The management of fungal keratitis is complex since signs and symptoms are subtle and ocular inflammation is minimal in the preliminary stages of infection. Initial misdiagnosis of the condition and consequent management of inflammation with corticosteroids is a frequent occurrence. Topical steroid use is considered to be a principal factor for development of fungal keratitis. In this review, we assess the studies that have reported outcomes of fungal keratitis in patients receiving steroids prior to diagnosis. We also assess the possible rebound effect present when steroids are abruptly discontinued and the clinical characteristics of three patients in this particular clinical scenario. Previous reports and the three clinical descriptions presented suggest that in fungal keratitis, discontinuing topical steroids can induce worsening of clinical signs. In these cases, we recommend to slowly taper steroids and continue or commence appropriate antifungal therapy. Citation: Knutsson, K.A.; Iovieno, A.; Keywords: fungal keratitis; topical corticosteroids; topical steroids; rebound effect Matuska, S.; Fontana, L.; Rama, P.
    [Show full text]
  • Antiprotozoal and Antitumor Activity of Natural Polycyclic Endoperoxides: Origin, Structures and Biological Activity
    molecules Review Antiprotozoal and Antitumor Activity of Natural Polycyclic Endoperoxides: Origin, Structures and Biological Activity Valery M. Dembitsky 1,2,*, Ekaterina Ermolenko 2, Nick Savidov 1, Tatyana A. Gloriozova 3 and Vladimir V. Poroikov 3 1 Centre for Applied Research, Innovation and Entrepreneurship, Lethbridge College, 3000 College Drive South, Lethbridge, AB T1K 1L6, Canada; [email protected] 2 A.V. Zhirmunsky National Scientific Center of Marine Biology, 17 Palchevsky Str., 690041 Vladivostok, Russia; [email protected] 3 Institute of Biomedical Chemistry, 10 Pogodinskaya Str., 119121 Moscow, Russia; [email protected] (T.A.G.); [email protected] (V.V.P.) * Correspondence: [email protected]; Tel.: +1-403-320-3202 (ext. 5463); Fax: +1-888-858-8517 Abstract: Polycyclic endoperoxides are rare natural metabolites found and isolated in plants, fungi, and marine invertebrates. The purpose of this review is a comparative analysis of the pharmacological potential of these natural products. According to PASS (Prediction of Activity Spectra for Substances) estimates, they are more likely to exhibit antiprotozoal and antitumor properties. Some of them are now widely used in clinical medicine. All polycyclic endoperoxides presented in this article demonstrate antiprotozoal activity and can be divided into three groups. The third group includes endoperoxides, which show weak antiprotozoal activity with a reliability of up to 70%, and this group includes only 1.1% of metabolites. The second group includes the largest number of endoperoxides, Citation: Dembitsky, V.M.; which are 65% and show average antiprotozoal activity with a confidence level of 70 to 90%. Lastly, Ermolenko, E.; Savidov, N.; the third group includes endoperoxides, which are 33.9% and show strong antiprotozoal activity with Gloriozova, T.A.; Poroikov, V.V.
    [Show full text]
  • Antiparasitic, Antibacterial, and Antifungal Activities Derived from a Terminalia Catappa Solution Against Some Tilapia (Oreochromis Niloticus) Pathogens
    Antiparasitic, Antibacterial, and Antifungal Activities Derived from a Terminalia catappa Solution against Some Tilapia (Oreochromis niloticus) Pathogens C. Chitmanat, K. Tongdonmuan, P. Khanom, P. Pachontis and W. Nunsong Department of Fisheries Technology College of Agricultural Production Maejo University, Chiang Mai, 50290 Thailand Keywords: antibacterial activity, antiparasitic activity, antifungal activity, Terminalia catappa, medicinal plant, tilapia Abstract Tilapia, Oreochromis niloticus, is one of the most economically important fishery products of Thailand with export viability. Unfortunately, disease losses cause a major problem in the production of farmed tilapia. Most farmers have been using chemicals and antibiotics to treat fish pathogens which leads to the creation of antibiotic resistant pathogens and undesired residues in the fish and in the environment. Food safety is currently a great concern worldwide and Thailand’s inspectors are now finding antibiotic residues in exported fish products. The purpose of the present research is to apply the Indian almond, Terminalia catappa, as an alternative to the use of chemicals and antibiotics in the aquaculture industry. Dried leaves of Indian almond were ground and dissolved in water. A variety of concentrations of this solution were used to determine resulting activities against tilapia pathogens. The results indicated that Trichodina, fish ectoparasites, were eradicated at 800 ppm. The growth of two strains of Aeromonas hydrophila was also inhibited at a concentration of 0.5 mg/ml Indian almond leaves upward. In addition, this solution can reduce the fungal infection in tilapia eggs. Research is underway to determine the toxicity of this solution, if any, on tilapia and the isolation of the active ingredients in the Indian almond for fish pathogen treatment.
    [Show full text]
  • Itraconazole Inhibits AKT/Mtor Signaling and Proliferation in Endometrial Cancer Cells
    ANTICANCER RESEARCH 37 : 515-520 (2017) doi:10.21873/anticanres.11343 Itraconazole Inhibits AKT/mTOR Signaling and Proliferation in Endometrial Cancer Cells HIROSHI TSUBAMOTO 1,2 , KAYO INOUE 1, KAZUKO SAKATA 1, TOMOKO UEDA 1, RYU TAKEYAMA 1, HIROAKI SHIBAHARA 1 and TAKASHI SONODA 2 1Department of Obstetrics and Gynecology, Hyogo College of Medicine, Nishinomiya, Japan; 2Department of Medical Oncology, Meiwa Hospital, Nishinomiya, Japan Abstract. Background: Itraconazole is a common antifungal functions by blocking ergosterol synthesis in fungal cell agent that has demonstrated anticancer activity in preclinical membrane. Itraconazole has been repositioned as an anticancer and clinical studies. This study investigated whether agent in both pre-clinical and clinical studies, and was found itraconazole exerts this effect in endometrial cancer (EC) cells. to reverse P-glycoprotein-mediated chemoresistance of cancer Materials and Methods: Cell viability was evaluated with the cells (4, 5) and inhibit angiogenesis (6) as well as Hedgehog 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (7, 8) and AKT/mammalian target of rapamycin (mTOR) (9, assay, and gene and protein expression were assessed by 10) signaling, which are associated with dysregulation of microarray analysis and immunoblotting, respectively, in five intracellular cholesterol transport (9, 11). Recent studies have EC cell lines. Results: Itraconazole-suppressed proliferation of also reported the induction of autophagy and inhibition of AN3-CA, HEC-1A and Ishikawa cells (p<0.05) but not of lymphangiogenesis by itraconazole (11, 12). HEC-50B or SNG-II cells. Itraconazole did not suppress GLI1 We have been treating patients with refractory solid or GLI2 transcription but did inhibit the expression of tumours by combination itraconazole chemotherapy since mammalian target of rapamycin (mTOR) signaling components 2008.
    [Show full text]
  • 2021 Formulary List of Covered Prescription Drugs
    2021 Formulary List of covered prescription drugs This drug list applies to all Individual HMO products and the following Small Group HMO products: Sharp Platinum 90 Performance HMO, Sharp Platinum 90 Performance HMO AI-AN, Sharp Platinum 90 Premier HMO, Sharp Platinum 90 Premier HMO AI-AN, Sharp Gold 80 Performance HMO, Sharp Gold 80 Performance HMO AI-AN, Sharp Gold 80 Premier HMO, Sharp Gold 80 Premier HMO AI-AN, Sharp Silver 70 Performance HMO, Sharp Silver 70 Performance HMO AI-AN, Sharp Silver 70 Premier HMO, Sharp Silver 70 Premier HMO AI-AN, Sharp Silver 73 Performance HMO, Sharp Silver 73 Premier HMO, Sharp Silver 87 Performance HMO, Sharp Silver 87 Premier HMO, Sharp Silver 94 Performance HMO, Sharp Silver 94 Premier HMO, Sharp Bronze 60 Performance HMO, Sharp Bronze 60 Performance HMO AI-AN, Sharp Bronze 60 Premier HDHP HMO, Sharp Bronze 60 Premier HDHP HMO AI-AN, Sharp Minimum Coverage Performance HMO, Sharp $0 Cost Share Performance HMO AI-AN, Sharp $0 Cost Share Premier HMO AI-AN, Sharp Silver 70 Off Exchange Performance HMO, Sharp Silver 70 Off Exchange Premier HMO, Sharp Performance Platinum 90 HMO 0/15 + Child Dental, Sharp Premier Platinum 90 HMO 0/20 + Child Dental, Sharp Performance Gold 80 HMO 350 /25 + Child Dental, Sharp Premier Gold 80 HMO 250/35 + Child Dental, Sharp Performance Silver 70 HMO 2250/50 + Child Dental, Sharp Premier Silver 70 HMO 2250/55 + Child Dental, Sharp Premier Silver 70 HDHP HMO 2500/20% + Child Dental, Sharp Performance Bronze 60 HMO 6300/65 + Child Dental, Sharp Premier Bronze 60 HDHP HMO
    [Show full text]
  • Verapamil Inhibits Aspergillus Biofilm, but Antagonizes Voriconazole
    Journal of Fungi Article Verapamil Inhibits Aspergillus Biofilm, but Antagonizes Voriconazole Hasan Nazik 1,2,*,†, Varun Choudhary 1 and David A. Stevens 1,2 1 California Institute for Medical Research, 2260 Clove Dr., San Jose, CA 95128, USA; [email protected] (V.C.); [email protected] (D.A.S.) 2 Division of Infectious Diseases and Geographic Medicine, Stanford University Medical School, Stanford, CA 94305, USA * Correspondence: [email protected]; Tel.: +1-408-998-4554; Fax: +1-408-998-2723 † Permanent address: Department of Medical Microbiology, Faculty of Medicine, Istanbul University, Istanbul 34452, Turkey. Received: 10 August 2017; Accepted: 18 September 2017; Published: 20 September 2017 Abstract: The paucity of effective antifungals against Aspergillus and increasing resistance, the recognition of the importance of Aspergillus biofilm in several clinical settings, and reports of verapamil—a calcium channel blocker—efficacy against Candida biofilm and hyphal growth, and synergy with an azole antifungal in vitro, led to a study of verapamil ± voriconazole against Aspergillus. Broth macrodilution methodology was utilized for MIC (minimum inhibitory concentration) and MFC (minimum fungicidal concentration) determination. The metabolic effects (assessed by XTT [2,3-bis[2-methoxy-4-nitro-5-sulfophenyl]-2H-tetrazolium-5-carboxanilide inner salt]) on biofilm formation by conidia were studied upon exposure to verapamil, verapamil plus voriconazole, or voriconazole alone. For biofilm formation, we found less inhibition from the combinations than with either drug alone, or less inhibition from the combination than that of the more potent drug alone. For preformed biofilm, we found no significant change in activity comparing voriconazole alone compared to added verapamil, and no significant alteration of activity of the more potent voriconazole, at any concentration in the range tested, by addition of a concentration of verapamil that is inhibitory alone.
    [Show full text]
  • Anatomical Classification Guidelines V2020 EPHMRA ANATOMICAL
    EPHMRA ANATOMICAL CLASSIFICATION GUIDELINES 2020 Anatomical Classification Guidelines V2020 "The Anatomical Classification of Pharmaceutical Products has been developed and maintained by the European Pharmaceutical Marketing Research Association (EphMRA) and is therefore the intellectual property of this Association. EphMRA's Classification Committee prepares the guidelines for this classification system and takes care for new entries, changes and improvements in consultation with the product's manufacturer. The contents of the Anatomical Classification of Pharmaceutical Products remain the copyright to EphMRA. Permission for use need not be sought and no fee is required. We would appreciate, however, the acknowledgement of EphMRA Copyright in publications etc. Users of this classification system should keep in mind that Pharmaceutical markets can be segmented according to numerous criteria." © EphMRA 2020 Anatomical Classification Guidelines V2020 CONTENTS PAGE INTRODUCTION A ALIMENTARY TRACT AND METABOLISM 1 B BLOOD AND BLOOD FORMING ORGANS 28 C CARDIOVASCULAR SYSTEM 35 D DERMATOLOGICALS 50 G GENITO-URINARY SYSTEM AND SEX HORMONES 57 H SYSTEMIC HORMONAL PREPARATIONS (EXCLUDING SEX HORMONES) 65 J GENERAL ANTI-INFECTIVES SYSTEMIC 69 K HOSPITAL SOLUTIONS 84 L ANTINEOPLASTIC AND IMMUNOMODULATING AGENTS 92 M MUSCULO-SKELETAL SYSTEM 102 N NERVOUS SYSTEM 107 P PARASITOLOGY 118 R RESPIRATORY SYSTEM 120 S SENSORY ORGANS 132 T DIAGNOSTIC AGENTS 139 V VARIOUS 141 Anatomical Classification Guidelines V2020 INTRODUCTION The Anatomical Classification was initiated in 1971 by EphMRA. It has been developed jointly by Intellus/PBIRG and EphMRA. It is a subjective method of grouping certain pharmaceutical products and does not represent any particular market, as would be the case with any other classification system.
    [Show full text]
  • Antibacterial Antibiotic Antifungal Antiparasitic Antiviral
    All-In-One Flooring Solutions: Antibacterial Antibiotic Antifungal Antiparasitic Antiviral What are antimicrobials? The Dex-O-Cide Difference: Antimicrobials provide a much broader range Based on the active agent N-butyl-1, 2- benzisothiazo- lin-3-one (BBIT), it is specially formulated to protect of protection than antibacterials. While anti- flooring in tough and demanding environments, bacterials kill a range of bacteria, antimocro- especially those exposed to high levels of moisture, UV bials go further, acting also as an antibiotic, light, or unsanitary conditions. The silver ion producing additive is integrated throughout the floor coating matrix antifungal, antiparasitic and antiviral agent. - not just the surface, so scratches and other points of Antimicrobials kill, and prevent the growth and wear do not create a place where pathogens can create spread of, dangerous microscopic organisms a home to grow and spread. The antimicrobial does not wash or wear away, preserving the protective proper- including bacteria, viruses, yeast, fungi, proto- ties for the life of the floor. zoa and some algae. Bacterial Resistance: Dex-O-Cide Standards: How antimicrobials work: CoV (Covid19) • • ISO 22196 SARS • • ISO JIS 222801 Salmonella Typhi • Instead of using chemicals, Dex-O-Cide • FSANZ Staphylococcus Aureus • Antibacterial Flooring leverages the all- Streptococcus Pygenes • natural power of silver ions to penetrate cell MRSA • membranes of bacteria and kill the pathogen. E-coli • Listeria Welshimeri • Common bacterium have no defense against
    [Show full text]
  • Growth Inhibition of Candida Species and Aspergillus Fumigatus by Statins Ian G
    Growth inhibition of Candida species and Aspergillus fumigatus by statins Ian G. Macreadie, Georgia Johnson, Tanja Schlosser & Peter I. Macreadie CSIRO Health and Molecular and Technologies and P-Health Flagship, Parkville, Vic., Australia Correspondence: Ian G. Macreadie, CSIRO Abstract Molecular and Health Technologies, 343 Royal Parade, Parkville, Vic. 3052, Australia. Statins are a class of drugs widely used for lowering high cholesterol levels through Tel.: 1613 9662 7299; fax: 1613 9662 7266; their action on 3-hydroxy-3-methylglutaryl-CoA reductase, a key enzyme in the e-mail: [email protected] synthesis of cholesterol. We studied the effects of two major statins, simvastatin and atorvastatin, on five Candida species and Aspergillus fumigatus. The statins Received 10 March 2006; revised 16 May 2006; strongly inhibited the growth of all species, except Candida krusei. Supplementa- accepted 18 May 2006. tion of Candida albicans and A. fumigatus with ergosterol or cholesterol in aerobic First published online August 2006. culture led to substantial recovery from the inhibition by statins, suggesting specificity of statins for the mevalonate synthesis pathway. Our findings suggest DOI:10.1111/j.1574-6968.2006.00370.x that the statins could have utility as antifungal agents and that fungal colonization could be affected in those on statin therapy. Editor: Geoffrey Gadd Keywords antifungal; cholesterol; ergosterol; HMG-CoA reductase inhibition; simvastatin; atorvastatin. Introduction provided in the form of a lactone prodrug, it was hydrolysed in ethanolic NaOH [15% (v/v) ethanol and 0.25% (w/v) Statins are the main therapeutic agents used to decrease high NaOH] at 60 1C for 1 h (Lorenz & Parks, 1990).
    [Show full text]
  • Amlodipine: “The Delicate Balance Between Drug Design and Desired Effect” Poster Team: Dewaa Ali, Craig Bishop, Kelly Cobb
    Amlodipine: The Delicate Balance between Drug Design and Desired Effect Poster Team: Dewaa Ali, Craig Bishop, Kelly Cobb, Kayla Deitte, Brittany Jensen, Michelle Meunier Jmol Design Team: Katie Kotz, Jason Slaasted Faculty Educators: Dr. Borys and Dr. Sem School of Pharmacy, Concordia University Wisconsin, Mequon, WI, 53097 Professional Mentors: Chris Doede, PharmD, St. Luke’s Hospital, Milwaukee, WI; Jake Olson, PharmD, Skywalk Pharmacy, Milwaukee, WI; Jeffrey Zimmerman, PharmD, St. Luke's Hospital, Milwaukee, WI Amlodipine and 4-CPI both have covalent reactions with the heme molecule found Abstract 7, 6 Hypertension affects 1 in 3 Americans. It can be treated in a variety of ways within CYP450 2B6 , which helps orient the drug in the active site . • The 2-aminomethoxymethyl of amlodipine forms a covalent bond with the heme but most often, drug interventions are needed. Amlodipine, a calcium 7 channel antagonist; commonly used for hypertension, is a CYP450 inhibitor. iron (fig 2) When using multiple CYP450 inhibitors concurrently drug interactions need • The nitrogen on the imidazole ring of 4-CPI is covalently bound to the heme iron 6 to be monitored closely. (fig 3) Amlodipine and 4-CPI both interact with Thr302 in CYP450 2B6 Introduction • The ethoxy oxygen of amlodipine forms a hydrogen bond with the hydroxyl A patient taking amlodipine for hypertension has recently been prescribed oxygen of Thr302 (fig 2) • The second nitrogen within the imidazole ring of 4-CPI forms a hydrogen bond itraconazole for a fungal infection. After taking the first dose of itraconazole the patient became dizzy and lost consciousness. At the ER the patient was with the hydroxyl oxygen of Thr302 (fig 3) Figure 4.
    [Show full text]
  • Health Antifungal and Anti-Biofilm Effect of the Calcium Channel Blocker Verapamil on Non-Albicans Candida Species
    An Acad Bras Cienc (2020) 92(4): e20200703 DOI 10.1590/0001-3765202020200703 Anais da Academia Brasileira de Ciências | Annals of the Brazilian Academy of Sciences Printed ISSN 0001-3765 I Online ISSN 1678-2690 www.scielo.br/aabc | www.fb.com/aabcjournal HEALTH SCIENCES Antifungal and anti-biofilm effect of Running title: Verapamil effect on the calcium channel blocker verapamil Candida non-albicans species on non-albicans Candida species Academy Section: Health LILIANA SCORZONI, RAQUEL T. DE MENEZES, THAIS CRISTINE PEREIRA, PRISCILA Sciences S. OLIVEIRA, FELIPE DE CAMARGO RIBEIRO, EVELYN LUZIA DE SOUZA SANTOS, LUCIANA R.O. FUGISAKI, LUCIANE D. DE OLIVEIRA & JOSÉ BENEDITO O. AMORIM e20200703 Abstract: Candida is a human fungal pathogen that causes a wide range of diseases. Candida albicans is the main etiologic agent in these diseases; however, infections can be caused by non-albicans Candida species. Virulence factors such as biofilm production, 92 which protect the fungus from host immunity and anti-fungal drugs, are important for the (4) 92(4) infection. Therefore, available antifungal drugs for candidiasis treatment are limited and the investigation of new and effective drugs is needed. Verapamil is a calcium channel blocker with an inhibitory effect on hyphae development, adhesion, and colonization of C. albicans. In this study, we investigated the effect of verapamil on cell viability and its antifungal and anti-biofilm activity in non-albicans Candida species. Verapamil was not toxic to keratinocyte cells; moreover, C. krusei, C. parapsilosis, and C. glabrata were susceptible to verapamil with a minimal inhibitory concentration (MIC) of 1250 μM; in addition, this drug displayed fungistatic effect at the evaluated concentrations.
    [Show full text]
  • Azasterol As Possible Antifungal and Antiparasitic Drugs
    Journal of Analytical & Pharmaceutical Research Azasterol as Possible Antifungal and Antiparasitic Drugs Abstract Mini Review The aim of this mini review is to bring together the azasterols of synthetic origin Volume 7 Issue 1 - 2018 with antifungal and antiparasitic activity. Particular emphasis on those ones have shown to be sterol biosynthesis inhibitors (SBIs). Instituto Nacional de Metrologia, Brazil Keywords: Azasterols; Antiparasitic; Antifungal; Sterols; Eukaryotic microorganisms *Corresponding author: Gonzalo Visbal, Instituto Nacional de Metrologia, Qualidade e Tecnologia (INMETRO), Diretoria de Metrologia Aplicada à Ciências da Vida, Rio de Janeiro, Brazil, Email: 24 Abbreviations: SMT: ∆ Sterol Methyl Transferase; SBIs: Sterol Received: January 30, 2018 | Published: February 06, 2018 Biosynthesis Inhibitors Introduction Sterols are constituents of the cellular membranes that intermediates (carbocation) generated at C-25 during the are essential for their normal structure and function [1-3]. methylation reaction and consequently, bind tightly to the SMT In mammalian cells, cholesterol is the main sterol found in [6,8]. the various membranes [1-3]. However, other sterols (e.g. Although many side chain azasterols have been synthesized, ergosterol) predominate in eukaryotic microorganisms such as few have been successful in the inhibition of the SMT or possess fungi and protozoa [4]. Ergosterol biosynthesis is an extremely any antifungal or antiparasitic activity [9]. Indeed, in the 90’s important area of biochemical difference between eukaryotic microorganisms and their human host that is currently exploited a SMT inhibitor, an synthetic analogue of solacongestidina a in chemotherapy and in the development of new antifungal agents was reported by the first time the 22,26-azasterol or AZA-1 as [5].
    [Show full text]