The mechanism by which the phenothiazine thioridazine contributes to cure problematic drug-resistant forms of pulmonary tuberculosis: Recent patents for "new use"

Recent Patents on Anti-Infective Drug Discovery

Volumn 8, Issue 3, 2013, Pages 206-212

  Amaral, Leonard ^a   Martins, Ana ^a,b,c   Spengler, Gabriella ^b   Hunyadi, Attila ^d   Molnar, Joseph ^b  

^a INSTITUTO DE HIGIENE E MEDICINA TROPICAL   (Portugal)

^b UNIVERSITY OF SZEGED   (Hungary)

^c Unidade de Parasitologia e Microbiologia Médica Institute of Hygiene and Tropical Medicine Universidade Nova de Lisboa ^*  (Portugal)

^d UNIVERSITY OF SZEGED   (Hungary)

Author keywords

Curing of XDR TB; Mechanism of killing; Mycobacterium tuberculosis; Thioridazine

Indexed keywords

CHLORPROMAZINE; METHYLENE BLUE; PHENOTHIAZINE; THIORIDAZINE; TUBERCULOSTATIC AGENT;

BACTERIAL GENE; DRUG RESISTANT TUBERCULOSIS; DRUG USE; HUMAN; MACROPHAGE; MINIMUM BACTERICIDAL CONCENTRATION; MINIMUM INHIBITORY CONCENTRATION; MYCOBACTERIUM TUBERCULOSIS; NONHUMAN; OXYGEN CONSUMPTION; PATENT; PRIORITY JOURNAL; RESPIRATORY CHAIN; REVIEW; DRUG EFFECTS; EXTENSIVELY DRUG-RESISTANT TUBERCULOSIS; METABOLISM; SALVAGE THERAPY; TUBERCULOSIS, MULTIDRUG-RESISTANT; TUBERCULOSIS, PULMONARY;

ANTITUBERCULAR AGENTS; EXTENSIVELY DRUG-RESISTANT TUBERCULOSIS; HUMANS; MYCOBACTERIUM TUBERCULOSIS; PATENTS AS TOPIC; SALVAGE THERAPY; THIORIDAZINE; TUBERCULOSIS, MULTIDRUG-RESISTANT; TUBERCULOSIS, PULMONARY;

EID: 84901773492     PISSN: 1574891X     EISSN: 22124071     Source Type: Journal    
DOI: 10.2174/1574891X08666131210141521     Document Type: Review

References (139)

1. Devirgiliis C, Zinno P, Perozzi G. Update on antibiotic resistance in foodborne Lactobacillus and Lactococcus species. Front Microbiol 2013; 4: 301.
2. Fournier PE, Drancourt M, Colson P, Rolain JM, La Scola B, Raoult D. Modern clinical microbiology: New challenges and solutions. Nat Rev Microbiol 2013; 11: 574-85.
3. Mathur P, Singh S. Multidrug resistance in bacteria: A serious patient safety challenge for India. J Lab Phys 2013; 5: 5-10.
4. Gatta L, Vakil N, Vaira D, Scarpignato C. Global eradication rates for Helicobacter pylori infection: Systematic review and metaanalysis of sequential therapy. BMJ 2013; 347: f4587.
5. Furuta T, Sugimoto M, Uotani T, Sahara S, Ichikawa H. [Present status and future prospects of third line rescue regimens for H. pylori infection]. Nihon Rinsho 2013; 71: 1404-12.
6. Pagès JM, Amaral L. Mechanisms of drug efflux and strategies to combat them: Challenging the efflux pump of Gram-negative bacteria. Biochim Biophys Acta 2009; 1794: 826-33.
7. Shalimar, Acharya SK. Difficult to treat spontaneous bacterial peritonitis. Trop Gastroenterol 2013; 34: 7-13.
8. Neveur M. [Multi-drug resistant bacteria in the home] Rev Infirm 2013; 192: 24-6.
9. Nair GB, Niederman MS. Nosocomial pneumonia: Lessons learned. Crit Care Clin 2013; 29: 521-46.
10. Ji Y, Lei T. Antisense RNA regulation and application in the development of novel antibiotics to combat multidrug resistant bacteria. Sci Prog 2013; 96(Pt 1): 43-60.
11. Belardinelli JM, Morbidoni HR. Recycling and refurbishing old antitubercular drugs: The encouraging case of inhibitors of mycolic acid biosynthesis. Expert Rev Anti Infect Ther 2013; 11: 429-40.
12. Boyanova L, Mitov I. Antibiotic resistance rates in causative agents of infections in diabetic patients: Rising concerns. Expert Rev Anti Infect Ther 2013; 11: 411-20.
13. Viveiros M, Martins M, Rodrigues L, Machado D, Couto I, Ainsa J, et al. Inhibitors of mycobacterial efflux pumps as potential boosters for anti-tubercular drugs. Expert Rev Anti Infect Ther 2012; 10: 983-98.
14. Llamas-González YY, Flores-Valdez MA. [Extensively drugresistant tuberculosis (XDR-TB): Successful therapies used in the clinic to the disease]. Rev Invest Clin 2013; 65: 255-62.
15. Barbier F, Andremont A, Wolff M, Bouadma L. Hospital-acquired pneumonia and ventilator-associated pneumonia: Recent advances in epidemiology and management. Curr Opin Pulm Med 2013; 19: 216-28.
16. Karaiskos I, Galani L, Baziaka F, Giamarellou H. Intraventricular and intrathecal colistin as the last therapeutic resort for the treatment of multidrug-resistant and extensively drug-resistant Acinetobacter baumannii ventriculitis and meningitis: A literature review. Int J Antimicrob Agents 2013; 41: 499-508.
17. Unemo M, Nicholas RA. Emergence of multidrug-resistant, extensively drug-resistant and untreatable gonorrhea. Future Microbiol 2012; 7: 1401-22.
18. Cattoir V, Leclercq R. Twenty-five years of shared life with vancomycin-resistant enterococci: Is it time to divorce?. J Antimicrob Chemother 2013; 68: 731-42.
19. Vila J, Pachón J. Therapeutic options for Acinetobacter baumannii infections: An update. Expert Opin Pharmacother 2012; 13: 2319-36.
20. Whiley DM, Goire N, Lahra MM, Donovan B, Limnios AE, Nissen MD, et al. The ticking time bomb: Escalating antibiotic resistance in Neisseria gonorrhoeae is a public health disaster in waiting. J Antimicrob Chemother 2012; 67: 2059-61.
21. Amaral L, Viveiros M. Why thioridazine in combination with antibiotics cures extensively drug-resistant Mycobacterium tuberculosis infections. Int J Antimicrob Agents 2012; 39: 376-80.
22. Walsh FM, Amyes SG. Microbiology and drug resistance mechanisms of fully resistant pathogens. Curr Opin Microbiol 2004; 7: 439-44.
23. Berger-Bächi B. Resistance mechanisms of gram-positive bacteria. Int J Med Microbiol 2002; 292: 27-35.
24. Leclercq R. Enterococci acquire new kinds of resistance. Clin Infect Dis 1997; 24 (Suppl 1): S80-4. Review.
25. Jensenius M, von der Lippe B, Melby K, Steinbakk M. [The end of antibiotics? Increasing bacterial resistance in global and Norwegian perspective]. Tidsskr Nor Laegeforen 1995; 115: 3382-6.
26. Amaral L, Kristiansen JE. Phenothiazines: An alternative to conventional therapy for the initial management of suspected multidrug resistant tuberculosis. A call for studies. Int J Antimicrob Agents 2000; 14: 173-6.
27. Amaral L. Thioridazine: An old neuroleptic effective against totally drug resistant tuberculosis. Acta Med Port 2012; 25: 118-21.
28. Udwadia ZF, Amale RA, Ajbani KK, Rodrigues CS. Nomenclature of drug-resistant tuberculosis. Lancet Infect Dis 2013; 13: 917.
29. Udwadia ZF. Totally drug-resistant tuberculosis in India: Who let the djinn out? Respirology 2012; 17(5): 741-2.
30. Udwadia ZF. MDR, XDR, TDR tuberculosis: Ominous progression. Thorax 2012; 67: 286-8.
31. Mégraud F. Current recommendations for Helicobacter pylori therapies in a world of evolving resistance. Gut Microbes 2013; 4(6), in press.
32. Stanton TB. A call for antibiotic alternatives research. Trends Microbiol 2013; 21: 111-3.
33. Kimang'a AN. A situational analysis of antimicrobial drug resistance in Africa: Are we losing the battle? Ethiop J Health Sci 2012; 22: 135-43.
34. Rice LB. Mechanisms of resistance and clinical relevance of resistance to β-lactams, glycopeptides, and fluoroquinolones. Mayo Clin Proc 2012; 87: 198-208.
35. Deasy J. The antibiotic challenge: Changing clinical management of infections. JAAPA 2009; 22: 22-6.
36. Kollef MH. Broad-spectrum antimicrobials and the treatment of serious bacterial infections: Getting it right up front. Clin Infect Dis 2008; 47 Suppl 1: S3-13.
37. Hayden MK. Insights into the epidemiology and control of infection with vancomycin-resistant enterococci. Clin Infect Dis 2000; 31: 1058-65.
38. Nathwani D, Wood MJ. Penicillins. A current review of their clinical pharmacology and therapeutic use. Drugs 1993; 45: 866-94.
39. Hurst JM, Bosso JA. Antimicrobial stewardship in the management of community-acquired pneumonia. Curr Opin Infect Dis 2013; 26: 184-8.
40. Baguley D, Lim E, Bevan A, Pallet A, Faust SN. Prescribing for children-taste and palatability affect adherence to antibiotics: A review. Arch Dis Child 2012; 97: 293-7.
41. Haggard M. Poor adherence to antibiotic prescribing guidelines in acute otitis media--obstacles, implications, and possible solutions. Eur J Pediatr 2011; 170: 323-32.
42. Leung CC, Rieder HL, Lange C, Yew WW. Treatment of latent infection with Mycobacterium tuberculosis: Update 2010. Eur Respir J 2011; 37(3): 690-711.
43. Bernthsen A. Zur Kenntniss des Methylenblau und verwandter Farbstoffe. Berichte der deutschen chemischen Gesellschaft 1883; 16: 2896-904.
44. Wainwright M, Amaral L. The phenothiazinium chromophore and the evolution of antimalarial drugs. Trop Med Int Health 2005; 10: 501-11.
45. Guttmann P & Ehrlich P. Über die Wirkung des Methylenblau bei Malaria. Berliner Klinische Wochenschrift 1891; 28: 953-6.
46. Roehl W. Foundations of chemotherapy. Deutsche Medizinische Wochenschrift 1926; 52, 2017-21.
47. Schulemann W. Synthetic anti-malarial preparations. Proc R Soc Med 1932; 25: 897-905.
48. Kristiansen JE and Amaral L. The potential management of resistant infections with non-antibiotics. J Antimicrob Chemoth 1997; 40: 319-27.
49. Bodoni M. Dellàzione sedative delblue di metilene in vaire forme di psicosi. Clinica Medica Italiana 1899; 24: 217-22.
50. López-Muñoz F, Alamo C, Cuenca E, Shen WW, Clervoy P, Rubio G. History of the discovery and clinical introduction of chlorpromazine. Ann Clin Psychiatry 2005; 17: 113-5.
51. Pleasure H. Chlorpromazine (thorazine) for mental illness in the presence of pulmonary tuberculosis. Psychiatr Q 1956; 30: 23-30.
52. Aguet F, Bossy A, Ducommun P, Favez G. [Non-specific therapeutic stimulation in evolutive pulmonary tuberculosis. I. Properties of chlorpromazine and phenylsemicarbazide]. Schweiz Med Wochenschr 1956; 86: 1239-45.
53. Marchand H, Reuter C. [Phenothiazine derivatives in treatment of pulmonary tuberculosis]. Tuberkulosearzt 1957; 11: 19-27.
54. Shubin H, Heiken CA, Glaskin A, Pennes E, Arsenian J. Chlorpromazine as an adjunct in managing tuberculous patients. Int Rec Med Gen Pract Clin 1957; 170: 369-73.
55. Hyvert M, Le Cloarec J, Carrer J. [Chlorpromazine & atypical tuberculosis in 578 chronic mental patients; Need for combined therapy]. Ann Med Psychol (Paris) 1957; 115: 296-300.
56. Zamfir D, Ionesco G. [Healing of tuberculous caverns of the lung, with persistence of the cavitary image, after treatment by antibiotics associated with chlorpromazine and phenylsemicarbazide]. Poumon Coeur 1958; 14: 1093-7.
57. Hollister LE, Eokenberry DT, Raffel S. Chlorpromazine in nonpsychotic patients with pulmonary tuberculosis. Am Rev Respir Dis 1960; 81: 562-6.
58. Raffel S, Kochan I, Poland N, Hollister LE. The action of chlorpromazine upon Mycobacterium tuberculosis. Am Rev Respir Dis 1960; 81: 555-61.
59. Viktorov IT, Galina S. [Experience with aminazin therapy of mental patients suffering from pulmonary tuberculosis]. Vopr Psikhiatr Nevropatol 1961; 7: 293-304.
60. Kamińska M. [Role of chlorpromazine in the treatment of pulmonary tuberculosis in psychiatric patients]. Folia Med Cracov 1967; 9: 115-43.
61. Molnár J, Béládi I, Földes I. Studies on antituberculotic action of some phenothiazine derivatives in vitro. Zentralbl Bakteriol Orig A 1977; 239: 521-6.
62. Kristiansen JE, Vergmann B. The antibacterial effect of selected phenothiazines and thioxanthenes on slow-growing mycobacteria. Acta Pathol Microbiol Immunol Scand B 1986; 94: 393-8.
63. Crowle AJ, Douvas GS, May MH. Chlorpromazine: A drug potentially useful for treating mycobacterial infections. Chemotherapy 1992; 38(6): 410-9.
64. Amaral L, Kristiansen JE, Viveiros M, Atouguia J. Activity of phenothiazines against antibiotic-resistant Mycobacterium tuberculosis: A review supporting further studies that may elucidate the potential use of thioridazine as anti-tuberculosis therapy. J Antimicrob Chemother 2001; 47: 505-11.
65. Amaral L, Kristiansen JE, Abebe LS, Millett W. Inhibition of the respiration of multi-drug resistant clinical isolates of Mycobacterium tuberculosis by thioridazine: Potential use for initial therapy of freshly diagnosed tuberculosis. J Antimicrob Chemother 1996; 38: 1049-53.
66. Ordway D, Viveiros M, Leandro C, Bettencourt R, Almeida J, Martins M, et al. Clinical concentrations of thioridazine kill intracellular multidrug-resistant Mycobacterium tuberculosis. Antimicrob Agents Chemother 2003; 47: 917-22.
67. Martins M, Schelz Z, Martins A, Molnar J, Hajös G, Riedl Z, et al. In vitro and ex vivo activity of thioridazine derivatives against Mycobacterium tuberculosis. Int J Antimicrob Agents 2007; 29: 338-40.
68. Martins M, Viveiros M, Ramos J, Couto I, Molnar J, Boeree M, et al. SILA 421, an inhibitor of efflux pumps of cancer cells, enhances the killing of intracellular extensively drug-resistant tuberculosis (XDR-TB). Int J Antimicrob Agents 2009; 33: 479-82.
69. Martins M, Viveiros M, Kristiansen JE, Molnar J, Amaral L. The curative activity of thioridazine on mice infected with Mycobacterium tuberculosis. In vivo 2007; 21: 771-5
70. van Soolingen D, Hernandez-Pando R, Orozco H, Aguilar D, Magis-Escurra C, Amaral L, et al. The antipsychotic thioridazine shows promising therapeutic activity in a mouse model of multidrug-resistant tuberculosis. PLoS One 2010; 5(9), e12640.
71. Dutta NK, Pinn ML, Zhao M, Rudek MA, Karakousis PC. Thioridazine lacks bactericidal activity in an animal model of extracellular tuberculosis. J Antimicrob Chemother 2013; 68(6): 1327-30
72. Abbate E, Vescovo M, Natiello M, Cufré M, García A, Gonzalez Montaner P, et al. Successful alternative treatment of extensively drug-resistant tuberculosis in Argentina with a combination of linezolid, moxifloxacin and thioridazine. J Antimicrob Chemother 2012; 67: 473-7.
73. Sohaskey C. Latent tuberculosis: Is there a role for thioridazine?. Recent Pat Antiinfect Drug Discov 2011; 6: 139-46.
74. Alsaad N, Wilffert B, van Altena R, de Lange WCM, van der Werf TS, Kosterink JGW, et al. Potential antimicrobial agents for the treatment of MDR-TB. ERJ 2013; doi:10.1183/09031936.00113713.
75. Sarathy J, Dartois V, Dick T, Gengenbacher M. Reduced drug uptake in phenotypically resistant nutrient-starved nonreplicating Mycobacterium tuberculosis. Antimicrob Agents Chemother 2013; 57(4): 1648-53.
76. Udwadia ZF, Sen T, Pinto LM. Safety and efficacy of thioridazine as salvage therapy in Indian patients with XDR-TB. Recent Pat Antiinfect Drug Discov 2011; 6: 88-91.
77. Amaral L, Udwadia Z, Abbate E, van Soolingen D. The added effect of thioridazine in the treatment of drug-resistant tuberculosis. Int J Tuberc Lung Dis 2012; 16: 1706-2.
78. Amaral L. It is anticipated that as is usually the case, financial motivation will move TZ from its current status "potential anti-MDR/XDR agent," to one that will cure MDR and XDR TB. Foreword. Recent Pat Antiinfect Drug Discov 2011; 6: 76.
79. Boeree MJ. Global clinical trials for the treatment of TB with thioridazine. Recent Pat Antiinfect Drug Discov 2011; 6: 99-103.
80. Warman AJ, Rito TS, Fisher NE, Moss DM, Berry NG, O'Neill PM, et al. Antitubercular pharmacodynamics of phenothiazines. J Antimicrob Chemother 2013; 68: 869-80.
81. Field SK, Fisher D, Jarand JM, Cowie RL. New treatment options for multidrug-resistant tuberculosis. Ther Adv Respir Dis 2012; 6: 255-68.
82. Sharma S, Singh A. Phenothiazines as anti-tubercular agents: Mechanistic insights and clinical implications. Expert Opin Investig Drugs 2011; 20: 1665-76.
83. Gillespie SH, Singh K. XDR-TB, what is it?; how is it treated?; and why is therapeutic failure so high? Recent Pat Antiinfect Drug Discov 2011; 6: 77-83.
84. Boshoff HI, Myers TG, Copp BR, McNeil MR, Wilson MA, Barry CE 3rd. The transcriptional responses of Mycobacterium tuberculosis to inhibitors of metabolism: Novel insights into drug mechanisms of action. J Biol Chem 2004; 279: 40174-84.
85. Ratnakar P, Rao SP, Sriramarao P, Murthy PS. Structureantitubercular activity relationship of phenothiazine-type calmodulin antagonists. Int Clin Psychopharmacol 1995; 10: 39-43.
86. Meindl W, Laske R. [Antimycobacterial properties of phenothiazine type compounds]. Arch Pharm (Weinheim) 1989; 322: 133-6.
87. Advani MJ, Siddiqui I, Sharma P, Reddy H. Activity of trifluoperazine against replicating, non-replicating and drug resistant Mycobacterium tuberculosis. PLoS One 2012; 7: e44245.
88. Kunciw DL, Liechty JJ, Mitchell MO, Wan B, Franzblau SG. Structural requirements for the antitubercular quaternized triflupromazine pharmacophore. Bioorg Med Chem Lett 2012; 22: 5679-80.
89. Koul S, Somayajulu A, Advani MJ, Reddy H. A novel calcium binding protein in Mycobacterium tuberculosis--potential target for trifluoperazine. Indian J Exp Biol 2009; 47: 480-8.
90. Gadre DV, Talwar V. In vitro susceptibility testing of Mycobacterium tuberculosis strains to trifluoperazine. J Chemother 1999; 11: 203-6.
91. Gadre DV, Talwar V, Gupta HC, Murthy PS. Effect of trifluoperazine, a potential drug for tuberculosis with psychotic disorders, on the growth of clinical isolates of drug resistant Mycobacterium tuberculosis. Int Clin Psychopharmacol 1998; 13: 129-31.
92. Reddy MV, Nadadhur G, Gangadharam PR. In-vitro and intracellular antimycobacterial activity of trifluoperazine. J Antimicrob Chemother 1996; 37: 196-7.
93. Ratnakar P, Murthy PS. Trifluoperazine inhibits the incorporation of labeled precursors into lipids, proteins and DNA of Mycobacterium tuberculosis H37Rv. FEMS Microbiol Lett 1993; 110: 291-4.
94. Ratnakar P, Murthy PS. Antitubercular activity of trifluoperazine; a calmodulin antagonist. FEMS Microbiol Lett 1992; 76: 73-6.
95. Dutta NK, Mazumdar K, DasGupta A, Dastidar SG. Activity of the phenothiazine methdilazine alone or in combination with isoniazid or streptomycin against Mycobacterium tuberculosis in mice. J Med Microbiol 2009; 58: 1667-8.
96. Chakrabarty AN, Bhattacharya CP, Dastidar SG. Antimycobacterial activity of methdilazine (Md), an antimicrobic phenothiazine. APMIS 1993; 101: 449-54.
97. Bate AB, Kalin JH, Fooksman EM, Amorose EL, Price CM, Williams HM, et al. Synthesis and antitubercular activity of quaternized promazine and promethazine derivatives. Bioorg Med Chem Lett 2007; 17: 1346-8.
98. Bettencourt MV, Bosne-David S, Amaral L. Comparative in vitro activity of phenothiazines against multidrug-resistant Mycobacterium tuberculosis. Int J Antimicrob Agents 2000; 16: 69-71.
99. Molcan J, Floreánová L, Kukucová H, Motýlová E, Polák L. Therapeutic effect of fluphenazin in various doses and forms. Act Nerv Super (Praha) 1971; 13: 182-3.
100. Henson EC, Brunson JG. Effects of epinephrine and propiomazine used alone and as a mixture on granuloma formation. J Reticuloendothel Soc 1970; 7: 109-20.
101. Grosse-Schönepauck D. [Toluidine blue--a tuberculostatic substance?]. Dtsch Med Wochenschr 1970; 95: 786-7.
102. Madrid PB, Polgar WE, Toll L, Tanga MJ. Synthesis and antitubercular activity of phenothiazines with reduced binding to dopamine and serotonin receptors. Bioorg Med Chem Lett 2007; 17: 3014-7.
103. Yano T, Li LS, Weinstein E, Teh JS, Rubin H. Steady-state kinetics and inhibitory action of antitubercular phenothiazines on Mycobacterium tuberculosis type-II NADH-menaquinone oxidoreductase (NDH-2). J Biol Chem 2006; 281: 11456-63.
104. Musuka S, Srivastava S, Dona CWS, Meek C, Leff R, Pasipanody J, et al. Thioridazine pharmacokinetic-Pharmacodynamic parameters "Wobble" during treatment of Tuberculosis: A theoretical basis for shorter-duration curative monotherapy with congeners. Antimicrob Agents Chemother 2013; 57(12): 5870-7.
105. Bruno, C., Philippe, G. Anticancer compsns.-consists of a cytotoxic agent with a agent to prevent multi: Drug resistance, e.g. in liposome(s). CH681780 (1993)
106. Mickie, B., Eleftherios, S. Combination therapy for the treatment of cancer. WO2013143000 (2013)
107. Moitra, K., Lou, H., Dean, M. Multidrug efflux pumps and cancer stem cells: Insights into multidrug resistance and therapeutic development. Clin Pharmacol Ther 2011; 89: 491-502.
108. Christensen, J.B., Hendricks, O., Kristiansen, J. Thioridazine and derivatives thereof for reversing anti-microbial drug resistance. US20070287702 (2007)
109. Machado D, Couto I, Perdigão J, Rodrigues L, Portugal I, Baptista P, et al. Contribution of efflux to the emergence of isoniazid and multidrug resistance in Mycobacterium tuberculosis. PLoS One 2012; 7(4): e34538.
110. Martins A, Hunyadi A, Amaral L. Mechanisms of resistance in bacteria: An evolutionary approach. Open Microbiol J 2013; 7: 53-8.
111. Varga ZG, Armada A, Cerca P, Amaral L, Mior Ahmad Subki MA, Savka MA, et al. Inhibition of quorum sensing and efflux pump system by trifluoromethyl ketone proton pump inhibitors. In vivo 2012; 26: 277-85.
112. Martins A, Amaral L. Screening for efflux pump systems of bacteria by the new acridine orange agar method. In vivo 2012; 26(2): 203-6.
113. Martins A, Machado L, Costa S, Cerca P, Spengler G, Viveiros M, et al. Role of calcium in the efflux system of Escherichia coli. Int J Antimicrob Agents 2011; 37: 410-4.
114. Viveiros M, Rodrigues L, Martins M, Couto I, Spengler G, Martins A, et al. Evaluation of efflux activity of bacteria by a semiautomated fluorometric system. Methods Mol Biol 2010; 642: 159-72.
115. Paixão L, Rodrigues L, Couto I, Martins M, Fernandes P, de Carvalho CC, et al. Fluorometric determination of ethidium bromide efflux kinetics in Escherichia coli. J Biol Eng 2009; 3: 18. doi: 10.1186/1754-1611-3-18.
116. Spengler G, Rodrigues L, Martins A, Martins M, McCusker M, Cerca P, et al. Genetic response of Salmonella enterica serotype Enteritidis to thioridazine rendering the organism resistant to the agent. Int J Antimicrob Agents 2012; 39: 16-21.
117. Lawler AJ, Ricci V, Busby SJ, Piddock LJ. Genetic inactivation of acrAB or inhibition of efflux induces expression of ramA. J Antimicrob Chemother 2013; 68: 1551-7.
118. Spengler G, Martins A, Schelz Z, Rodrigues L, Aagaard L, Martins M, et al. Characterization of intrinsic efflux activity of Enterococcus faecalis ATCC29212 by a semi-automated ethidium bromide method. In vivo 2009; 23: 81-7.
119. Klitgaard JK, Skov MN, Kallipolitis BH, Kolmos HJ. Reversal of methicillin resistance in Staphylococcus aureus by thioridazine. J Antimicrob Chemother 2008; 62: 1215-21.
120. Spengler G, Molnar J, Viveiros M, Amaral L. Thioridazine induces apoptosis of multidrug-resistant mouse lymphoma cells transfected with the human ABCB1 and inhibits the expression of Pglycoprotein. Anticancer Res 2011; 31: 4201-5.
121. Amaral L, Spengler G, Martins A, Armada A, Handzlik J, Kiec-Kononowicz K, et al. Inhibitors of bacterial efflux pumps that also inhibit efflux pumps of cancer cells. Anticancer Res 2012; 32: 2947-57.
122. Dutta NK, Mazumdar K, Dastidar SG, Karakousis PC, Amaral L. New patentable use of an old neuroleptic compound thioridazine to combat tuberculosis: A gene regulation perspective. Recent Pat Antiinfect Drug Discov 2011; 6: 128-38.
123. Mehra S, Dutta NK, Mollenkopf HJ, Kaushal D. Mycobacterium tuberculosis MT2816 encodes a key stress-response regulator. J Infect Dis 2010; 202: 943-53.
124. Dutta NK, Mehra S, Kaushal D. A Mycobacterium tuberculosis sigma factor network responds to cell-envelope damage by the promising anti-mycobacterial thioridazine. PLoS One 2010; 5: e10069.
125. Mayur YC, Jagadeesh S, Thimmaiah KN. Targeting calmodulin in reversing multi-drug resistance in cancer cells. Mini Rev Med Chem 2006; 6: 1383-9.
126. Sheaves RM. Calmodulin: A multifunctional protein for the control of cellular activity and homeostasis. A review of its physicochemical properties and pharmacological manipulation. Braz J Med Biol Res 1982; 15: 1-9.
127. + transport enhance intracellular killing of M. tuberculosis by non-killing macrophages. In vivo 2008; 22: 69-75.
128. + channel, IK, can be blocked by the tricyclic antihistamine promethazine. Neuropharmacology 2006; 50: 458-67.
129. +: Modulation by sulfated polysaccharides and trifluoperazine. J Neurochem 1996; 66: 772-8.
130. Reddy PT, Prasad CR, Reddy PH, Reeder D, McKenney K, Jaffe H, et al. Cloning and expression of the gene for a novel protein from Mycobacterium smegmatis with functional similarity to eukaryotic calmodulin. J Bacteriol 2003; 185: 5263-8.
131. + channel is essential for innate immunity. Nature 2004; 427(6977): 853-8. Retraction in: Nature. 2010; 468: 122.
132. + transport to enhance the killing of intracellular multi-drug resistant Mycobacterium tuberculosis (MDR-TB)--a novel, patentable approach to limit the emergence of XDR-TB. Recent Pat Antiinfect Drug Discov 2011; 6: 110-7.
133. Martins M, Viveiros M, Couto I, Amaral L. Targeting human macrophages for enhanced killing of intracellular XDR-TB and MDR-TB. Int J Tuberc Lung Dis 2009; 13: 569-73.
134. Wójcikowski J, Daniel WA. Thioridazine-fluoxetine interaction at the level of the distribution process in vivo. Pol J Pharmacol 2002; 54: 647-54.
135. Daniel WA. Mechanisms of cellular distribution of psychotropic drugs. Significance for drug action and interactions. Prog Neuropsychopharmacol Biol Psychiatry 2003; 27: 65-73.
136. Martins M, Bleiss W, Marko A, Ordway D, Viveiros M, Leandro C, et al. Clinical concentrations of thioridazine enhance the killing of intracellular methicillin-resistant Staphylococcus aureus: An in vivo, ex vivo and electron microscopy study. In vivo 2004; 18: 787-94.
137. Ordway D, Viveiros M, Leandro C, Arroz MJ, Molnar J, Kristiansen JE, et al. Chlorpromazine has intracellular killing activity against phagocytosed Staphylococcus aureus at clinical concentrations. J Infect Chemother 2002; 8: 227-31.
138. Ordway D, Viveiros M, Leandro C, Arroz MJ, Amaral L. Intracellular activity of clinical concentrations of phenothiazines including thioridiazine against phagocytosed Staphylococcus aureus. Int J Antimicrob Agents 2002; 20: 34-43.
139. Weinstein EA, Yano T, Li LS, Avarbock D, Avarbock A, Helm D, et al. Inhibitors of type II NADH: Menaquinone oxidoreductase represent a class of antitubercular drugs. Proc Natl Acad Sci U S A 2005; 102(12): 4548-53.