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Latinoamericana de lnfectología Pediátrica.
Órgano de la Asociación Mexicana de
Infectología Pediátrica, A.C.
Órgano difusor de la Sociedad Española
de lnfectología

2020, Number 1

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Rev Latin Infect Pediatr 2020; 33 (1)

Versatile drugs: searching for magic bullets

Rosales-Hernández LA, Rivas-Larrauri FE, Yamazaki-Nakashimada MA

Language: Spanish
References: 92
Page: 32-43
PDF size: 355.74 Kb.


ABSTRACT

Autoimmunity and immunodeficiency were previously considered mutually exclusive conditions, however, with progress in understanding regulatory mechanisms and genetic analysis it has been found that the relationship is closer than predicted. A patient may present both infectious and autoimmune manifestations simultaneously. Thus, there are multifaceted drugs (called «magic bullets» by Paul Ehrlich) with immunomodulatory and antimicrobial properties. In this article, we review the anti-infective mechanisms of drugs routinely used as immunosuppressants; the immunomodulatory properties of antibiotics, antiparasitic, metabolic pathway regulators and angiogenesis inhibitors that may have clinical implications.


REFERENCES

  1. Schmidt RE, Grimbacher B, Witte T. Autoimmunity and primary immunodeficiency: two sides of the same coin? Nat Rev Rheumatol. 2018; 14 (1): 7-18. doi: 10.1038/nrrheum.2017.198.

  2. García-Sánchez JE, García E, Lucila-Merino M. Cien años de la bala mágica del Dr. Ehrlich (1909-2009). Enferm Infecc Microbiol Clin. 2010; 28 (8): 521-533. doi: 10.1016/j.eimc.2009.07.009.

  3. Juvvadi PR, Lee SC, Heitman J, Steinbach WJ. Calcineurin in fungal virulence and drug resistance: prospects for harnessing targeted inhibition of calcineurin for an antifungal therapeutic approach. Virulence. 2017; 8 (2): 186-197. doi: 10.1080/21505594.2016.1201250.

  4. Ishida Y, Matsuda H, Kida K. Effect of cyclosporin A on human bone marrow granulocyte- macrophage progenitors with anti-cancer agents. Acta Paediatr Jpn. 1995; 37: 610-613.

  5. Shinde RB, Chauhan NM, Raut JS, Karuppayil SM. Sensitization of Candida albicans biofilms to various antifungal drugs by cyclosporine A. Ann Clin Microbiol Antimicrob. 2012; 11 (1): 27. doi: 10.1186/1476-0711-11-27.

  6. Fortwendel JR, Juvvadi PR, Perfect BZ, Rogg LE, Perfect JR, Steinbach WJ. Transcriptional regulation of chitin synthases by calcineurin controls paradoxical growth of Aspergillus fumigatus in response to caspofungin. Antimicrob Agents Chemother. 2010; 54 (4): 1555-1563. doi: 10.1128/AAC.00854-09.

  7. Stevens DA, White TC, Perlin DS, Selitrennikoff CP. Studies of the paradoxical effect of caspofungin at high drug concentrations. Diagn Microbiol Infect Dis. 2005; 51 (3): 173-178. doi: 10.1016/j.diagmicrobio.2004.10.006.

  8. Cordeiro RA, Macedo RB, Teixeira CEC et al. The calcineurin inhibitor cyclosporin A exhibits synergism with antifungals against Candida parapsilosis species complex. J Med Microbiol. 2014; 63: 936-944. doi: 10.1099/jmm.0.073478-0.

  9. Lamoth F, Juvvadi PR, Gehrke C, Asfaw YG, Steinbach WJ. Transcriptional activation of heat shock protein 90 mediated via a proximal promoter region as trigger of caspofungin resistance in Aspergillus fumigatus. J Infect Dis. 2014; 209 (3): 473-481. doi: 10.1093/infdis/jit530.

  10. Zhang C, Zhang J, Yang B, Wu C. Cyclosporin A inhibits the production of IL-17 by memory Th17 cells from healthy individuals and patients with rheumatoid arthritis. Cytokine. 2008; 42 (3): 345-352. doi: 10.1016/j.cyto.2008.03.006.

  11. Rolain JM, Colson P, Raoult D. Recycling of chloroquine and its hydroxyl analogue to face bacterial, fungal and viral infections in the 21st century. Int J Antimicrob Agents. 2007; 30 (4): 297-308. doi: 10.1016/j.ijantimicag.2007.05.015.

  12. Piconi S, Parisotto S, Rizzardini G et al. Hydroxychloroquine drastically reduces immune activation in HIV-infected, antiretroviral therapy-treated immunologic nonresponders. Blood. 2011; 118 (12): 3263-3272. doi: 10.1182/blood-2011-01-329060.

  13. Ornstein MH, Sperber K. The antiinflammatory and antiviral effects of hydroxychloroquine in two patients with acquired immunodeficiency syndrome and active inflammatory arthritis. Arthritis Rheum. 1996; 39 (1): 157-161. doi: 10.1002/art.1780390122.

  14. Chang TH, Wang LF, Lin YS, Yang CS, Yu CY, Lin YL. Hydroxychloroquine activates host antiviral innate immunity. Cytokine. 2014; 70 (1): 33-34. doi: 10.1016/j.cyto.2014.07.032.

  15. Byrd TF, Horwitz MA. Chloroquine inhibits the intracellular multiplication of legionella pneumophila by limiting the availability of iron: a potential new mechanism for the therapeutic effect of chloroquine against intracellular pathogens. J Clin Invest. 1991; 88 (1): 351-357. doi: 10.1172/JCI115301.

  16. Mazzolla R, Barluzzi R, Brozzetti A et al. Enhanced resistance to Cryptococcus neoformans infection induced by chloroquine in a murine model of meningoencephalitis. Antimicrob Agents Chemother. 1997; 41 (4): 802-807.

  17. Tsai WP, Nara PL, Kung HF, Oroszlan S. Inhibition of human immunodeficiency virus infectivity by chloroquine. AIDS Res Hum Retroviruses. 1990; 6 (4): 481-489. doi: 10.1089/aid.1990.6.481.

  18. Chiang G, Sassaroli M, Louie M, Chen H, Stecher VJ, Sperber K. Inhibition of HIV-1 replication by hydroxychloroquine: mechanism of action and comparison with zidovudine. Clin Ther. 1996; 18 (6): 1080-1092. doi: 10.1016/S0149-2918(96)80063-4.

  19. Paton NI, Goodall RL, Dunn DT et al. Effects of hydroxychloroquine on immune activation and disease progression among HIV-infected patients not receiving antiretroviral therapy. JAMA. 2012; 308 (4): 353-361. doi: 10.1001/jama.2012.6936.

  20. Bishop NE. Examination of potential inhibitors of hepatitis A virus uncoating. Intervirology. 1998; 41 (6): 261-271. doi: 10.1159/000024948.

  21. Keshavarzi F. Fungistatic effect of hydroxychloroquine, lessons from a case. Med Mycol Case Rep. 2016; 13: 17-18. doi: 10.1016/j.mmcr.2016.09.003.

  22. Ciszek M, Mucha K, Foroncewicz B, Chmura A, Paczek L. Leflunomide as a rescue treatment in ganciclovir-resistant cytomegalovirus infection in a seronegative renal transplant recipient - a case report. Ann Transplant. 2014; 19 (1): 60-63. doi: 10.12659/AOT.884035.

  23. Lu CH, Tsai JH, Wu MZ, Yu CL, Hsieh SC. Can leflunomide play a role in cytomegalovirus disease prophylaxis besides its antirheumatic effects? Antivir Ther. 2015; 20 (1): 93-96. doi: 10.3851/IMP2796.

  24. Avery RK, Mossad SB, Poggio E et al. Utility of leflunomide in the treatment of complex cytomegalovirus syndromes. Transplantation. 2010; 90 (4): 419-426. doi: 10.1097/TP.0b013e3181e94106.

  25. Waldman WJ, Knight DA, Blinder L, Shen J, Lurain NS, Miller DM. Inhibition of cytomegalovirus in vitro and in vivo. Intervirology. 1999; 42 (5-6): 412-428.

  26. Cuellar-Rodriguez J, Stephany B, Poggio E et al. Contrasting patterns of viral load response in transplant recipients with BK polyomavirus DNAemia on leflunomide therapy. Clin Transplant. 2013; 27 (3). doi: 10.1111/ctr.12110.

  27. Ritter ML, Pirofski L. Mycophenolate mofetil: Effects on cellular immune subsets, infectious complications, and antimicrobial activity: review article. Transpl Infect Dis. 2009; 11 (4): 290-297. doi: 10.1111/j.1399-3062.2009.00407.x

  28. Fang S, Su J, Liang B et al. Suppression of autophagy by mycophenolic acid contributes to inhibition of HCV replication in human hepatoma cells. Sci Rep. 2017; 7: 1-12. doi: 10.1038/srep44039.

  29. Ye L, Li J, Zhang T et al. Mycophenolate mofetil inhibits hepatitis C virus replication in human hepatic cells. Virus Res. 2012; 168 (1-2): 33-40. doi: 10.1016/j.virusres.2012.06.009.

  30. Pan Q, de Ruiter PE, Metselaar HJ et al. Mycophenolic acid augments interferon-stimulated gene expression and inhibits hepatitis C virus infection in vitro and in vivo. Hepatology. 2012; 55 (6): 1673-1683. doi: 10.1002/hep.25562.

  31. Cho J, Yi H, Jang EY et al. Mycophenolic mofetil, an alternative antiviral and immunomodulator for the highly pathogenic avian influenza H5N1 virus infection. Biochem Biophys Res Commun. 2017; 494 (1-2): 298-304. doi: 10.1016/j.bbrc.2017.10.037.

  32. Neyts J, Andrei G, De Clercq E. The novel immunosuppressive agent mycophenolate mofetil markedly potentiates the antiherpesvirus activities of acyclovir, ganciclovir, and penciclovir in vitro and in vivo. Antimicrob Agents Chemother. 1998; 42 (2): 216-222. doi: 10.1128/aac.44.6.1667-1673.2000.

  33. Siebert A, Wysocka M, Krawczyk B, Cholewiński G, Rachoń J. Synthesis and antimicrobial activity of amino acid and peptide derivatives of mycophenolic acid. Eur J Med Chem. 2018; 143: 646-655. doi: 10.1016/j.ejmech.2017.11.094.

  34. Dang W, Yin Y, Wang Y et al. Inhibition of calcineurin or IMP dehydrogenase exerts moderate to potent antiviral activity against norovirus replication. Antimicrob Agents Chemother. 2017; 61 (11). doi: 10.1128/AAC.01095-17.

  35. Paravar T, Lee DJ. Thalidomide: Mechanisms of action. Int Rev Immunol. 2008; 27 (3): 111-135. doi: 10.1080/08830180801911339.

  36. Chaulet C, Croix C, Alagille D et al. Design, synthesis and biological evaluation of new thalidomide analogues as TNF-α and IL-6 production inhibitors. Bioorganic Med Chem Lett. 2011; 21 (3): 1019-1022. doi: 10.1016/j.bmcl.2010.12.031.

  37. Hernandez MDO, Fulco TDO, Pinheiro RO et al. Thalidomide modulates Mycobacterium leprae-induced NF-κB pathway and lower cytokine response. Eur J Pharmacol. 2011; 670 (1): 272-279. doi: 10.1016/j.ejphar.2011.08.046.

  38. Leite MR, Santos SS, Lyra AC, Mota J, Santana GO. Thalidomide induces mucosal healing in Crohn’s disease: case report. World J Gastroenterol. 2011; 17 (45): 5028-5031. doi: 10.3748/wjg.v17.i45.5028.

  39. Fu LM, Fu-Liu CS. Thalidomide and tuberculosis. Int J Tuberc Lung Dis. 2002; 6 (7): 569-572.

  40. Tramontana JM, Utaipat U, Molloy A et al. Thalidomide treatment reduces tumor necrosis factor alpha production and enhances weight gain in patients with pulmonary tuberculosis. Mol Med. 1995; 1 (4): 384-397.

  41. Viel-Thériault I, Thibeault R, Boucher FD, Drolet JP. Thalidomide in refractory tuberculomas and pseudo abscesses. Pediatr Infect Dis J. 2016; 35 (11): 1262-1264. doi: 10.1097/INF.0000000000001285.

  42. Kawai T, Watanabe N, Yokoyama M et al. Thalidomide attenuates excessive inflammation without interrupting lipopolysaccharide-driven inflammatory cytokine production in chronic granulomatous disease. Clin Immunol. 2013; 147 (2): 122-128. doi: 10.1016/j.clim.2013.03.004.

  43. Rosman Y, Lidiar M, Shoenfeld Y. Antibiotic therapy in autoimmune disorders. Clin Pract. 2014; 11 (1): 91-103. doi: 10.2217/cpr.13.84.

  44. Lutz A. New ether oxime derivatives a structure-activity of erythromycin a relationship study. J Antibiot. 1990; 44 (3): 313-330.

  45. Amsden GW. Anti-inflammatory effects of macrolides-An underappreciated benefit in the treatment of community-acquired respiratory tract infections and chronic inflammatory pulmonary conditions? J Antimicrob Chemother. 2005; 55 (1): 10-21. doi: 10.1093/jac/dkh519.

  46. Kipourou M, Manika K, Papavasileiou A et al. Immunomodulatory effect of macrolides: At what cost? Respir Med Case Reports. 2016; 17: 44-46. doi: 10.1016/j.rmcr.2016.01.004.

  47. Ichiyama T, Nishikawa M, Yoshitomi T et al. Clarithromycin inhibits NF-kappaB activation in human peripheral blood mononuclear cells and pulmonary epithelial cells. Antimicrob Agents Chemother. 2001; 45 (1): 44-47. doi: 10.1128/AAC.45.1.44.

  48. Araujo FG, Slifer TL, Remington JS. Inhibition of secretion of interleukin-1 alpha and tumor necrosis factor alpha by the ketolide antibiotic telithromycin. Antimicrob Agents Chemother. 2002; 46 (10): 3327-3330. doi: 10.1128/AAC.46.10.3327.

  49. Ivetić-Tkalčević V, Bošnjak B, Hrvačić B et al. Anti-inflammatory activity of azithromycin attenuates the effects of lipopolysaccharide administration in mice. Eur J Pharmacol. 2006; 539 (1-2): 131-138. doi: 10.1016/j.ejphar.2006.03.074.

  50. Ratzinger F, Haslacher H, Poeppl W et al. Azithromycin suppresses CD4(+) T-cell activation by direct modulation of mTOR activity. Sci Rep. 2014; 4: 7438. doi: 10.1038/srep07438.

  51. Čulić O, Eraković V, Parnham MJ. Anti-inflammatory effects of macrolide antibiotics. Eur J Pharmacol. 2001; 429 (1-3): 209-229. doi: 10.1016/S0014-2999 (01)01321-8.

  52. Thanou-Stavraki A, Aberle T, Aksentijevich I, Bane BL, Harley JB. Clarithromycin in adult-onset still’s disease: a potentially useful therapeutic. J Clin Rheumatol. 2011; 17 (7): 373-376. doi: 10.1097/RHU.0b013e3182320680.

  53. Saviola G, Abdi-Ali L, Rossini P et al. Clarithromycin in rheumatoid arthritis patients not responsive to disease-modifying antirheumatic drugs: an open, uncontrolled pilot study. Clin Exp Rheumatol. 2002; 20 (3): 373-378.

  54. Saviola G, Benucci M, Abdi-Ali L et al. Clarithromycin in adult-onset Still’s disease: a study of 6 cases. Rheumatol Int. 2010; 30 (4): 555-560. doi: 10.1007/s00296-009-1277-9.

  55. Ogrendik M. Effects of clarithromycin in patients with active rheumatoid arthritis. Curr Med Res Opin. 2007; 23 (3): 515-522. doi: 10.1185/030079906X167642.

  56. Nanishi E, Nishio H, Takada H et al. Clarithromycin plus intravenous immunoglobulin therapy can reduce the relapse rate of Kawasaki disease: a phase 2, open-label, randomized control study. J Am Heart Assoc. 2017; 6 (7): 1-9. doi: 10.1161/JAHA.116.005370.

  57. Täubel J, Lorch U, Rossignol JF, Ferber G, John Camm A. Analyzing the relationship of QT interval and exposure to nitazoxanide, a prospective candidate for influenza antiviral therapy-A formal TQT study. J Clin Pharmacol. 2014; 54 (9): 987-994. doi: 10.1002/jcph.300.

  58. Rossignol JF. Nitazoxanide: a first-in-class broad-spectrum antiviral agent. Antiviral Res. 2014; 110: 94-103. doi: 10.1016/j.antiviral.2014.07.014.

  59. Wang YM, Lu JW, Lin CC et al. Antiviral activities of niclosamide and nitazoxanide against chikungunya virus entry and transmission. Antiviral Res. 2016; 135: 81-90. doi: 10.1016/j.antiviral.2016.10.003.

  60. Cao RY, Xu Y fen, Zhang TH et al. Pediatric drug nitazoxanide: a potential choice for control of Zika. Open Forum Infect Dis. 2017; 4 (1): 2-6. doi: 10.1093/OFID/OFX009.

  61. Nikolova K, Gluud C, Grevstad B, Jakobsen-Janus C. Nitazoxanide for chronic hepatitis C. Cochrane Database Syst Rev. 2014; (4). doi: 10.1002/14651858.CD009182.pub2.

  62. Kaufmann SHE, Dorhoi A, Hotchkiss RS, Bartenschlager R. Host-directed therapies for bacterial and viral infections. Nat Rev Drug Discov. 2018; 17 (1): 35-56. doi: 10.1038/nrd.2017.162.

  63. Di Santo N, Ehrisman J. A functional perspective of nitazoxanide as a potential anticancer drug. Mutat Res. 2014; 768: 16-21. doi: 10.1016/j.mrfmmm.2014.05.005.

  64. Di Santo N, Ehrisman J. Research perspective: potential role of nitazoxanide in ovarian cancer treatment. old drug, new purpose? Cancers (Basel). 2013; 5 (3): 1163-1176. doi: 10.3390/cancers5031163.

  65. Rozin A, Schapira D, Braun-Moscovici Y, Nahir AM. Cotrimoxazole treatment for rheumatoid arthritis. Semin Arthritis Rheum. 2001; 31 (2): 133-141. doi: 10.1053/sarh.2001.27734.

  66. Stegeman CA, Tervaert JW, de Jong PE, Kallenberg CG. Trimethoprim-sulfamethoxazole (co-trimoxazole) for the prevention of relapses of Wegener’s granulomatosis. Dutch Co-Trimoxazole Wegener Study Group. N Engl J Med. 1996; 335 (1): 16-20.

  67. Tervaert JWC. Trimethoprim-sulfamethoxazole and antineutrophil cytoplasmic antibodies-associated vasculitis. Curr Opin Rheumatol. 2018; 30 (4): 388-394. doi: 10.1097/BOR.0000000000000508.

  68. Garrido-Mesa N, Zarzuelo A, Gálvez J. Minocycline: far beyond an antibiotic. Br J Pharmacol. 2013; 169: 337-352.

  69. Szeto GL, Pomerantz JL, Graham DR, Clements JE. Minocycline suppresses activation of nuclear factor of activated T cells 1 (NFAT1) in human CD4+ T cells. J Biol Chem. 2011; 286 (13): 11275-11282.

  70. Metz LM, Zhang Y, Yeung M, Patry DG, Bell RB, Stoian CA et al. Minocycline reduces gadolinium-enhancing magnetic resonance imaging lesions in multiple sclerosis. Ann Neurol. 2004; 55 (5): 756.

  71. Metz LM, Li DKB, Traboulsee AL, Duquette P, Eliasziw M, Cerchiaro G et al. Trial of minocycline in a clinically isolated syndrome of multiple sclerosis. N Engl J Med. 2017; 376 (22): 2122-2133.

  72. Gelfand EW. Intravenous immune globulin in autoimmune and inflammatory diseases. N Engl J Med. 2012; 367 (21): 2015-2025. doi: 10.1056/NEJMra1009433.

  73. Berger M. Subcutaneous IgG in neurologic diseases. Immunotherapy. 2014; 6 (1): 71-83. doi: 10.2217/imt.13.146.

  74. Bruton O. Agammaglobulinemia. Pediatrics. 1952; 9 (6): 722-728.

  75. Imbach P, Barandun S, D’Apuzzo V et al. High-dose intravenous gammaglobulin for idiopathic thrombocytopenic purpura in childhood. Lancet. 1981; 317 (8232): 1228-1231. doi: 10.1016/S0140-6736 (81)92400-4.

  76. Wahn V. From immune substitution to immunomodulation. Semin Hematol. 2016; 53: S7-S9. doi: 10.1053/j.seminhematol.2016.04.003.

  77. Bozzo J, Jorquera JI. Use of human immunoglobulins as an anti-infective treatment: the experience so far and their possible re-emerging role. Expert Rev Anti Infect Ther. 2017; 15 (6): 585-604. doi: 10.1080/14787210.2017.1328278.

  78. Rena G, Pearson ER, Sakamoto K. Molecular mechanism of action of metformin: old or new insights? Diabetologia. 2013; 56 (9): 1898-1906. doi: 10.1007/s00125-013-2991-0.

  79. Pollak M. The effects of metformin on gut microbiota and the immune system as research frontiers. Diabetologia. 2017; 60 (9): 1662-1667. doi: 10.1007/s00125-017-4352-x.

  80. Lee SY, Moon SJ, Kim EK et al. Metformin suppresses systemic autoimmunity in roquin san/san mice through inhibiting B cell differentiation into plasma cells via regulation of AMPK/mTOR/STAT3. J Immunol. 2017; 1403088. doi: 10.4049/jimmunol.1403088.

  81. Restrepo BI. Metformin: candidate host-directed therapy for tuberculosis in diabetes and non-diabetes patients. Tuberculosis. 2016; 101: S69-S72. doi: 10.1016/j.tube.2016.09.008.

  82. Singhal A, Jie L, Kumar P et al. Metformin as adjunct antituberculosis therapy. Sci Transl Med. 2014; 6 (263). doi: 10.1126/scitranslmed.3009885.

  83. Lee YJ, Han SK, Park JH et al. The effect of metformin on culture conversion in tuberculosis patients with diabetes mellitus. Korean J Intern Med. 2018; 33 (5): 933-940.

  84. Marupuru S, Senapati P, Pathadka S, Miraj SS, Unnikrishnan MK, Manu MK. Protective effect of metformin against tuberculosis infections in diabetic patients: an observational study of south Indian tertiary healthcare facility. Brazilian J Infect Dis. 2017; 21 (3): 312-316. doi: 10.1016/j.bjid.2017.01.001.

  85. Abeles AM, Pillinger MH. Statins as antiinflammatory and immunomodulatory agents: a future in rheumatologic therapy? Arthritis Rheum. 2006; 54 (2): 393-407. doi: 10.1002/art.21521.

  86. Lobato LS, Rosa PS, Da Silva Ferreira J et al. Statins increase rifampin mycobactericidal effect. Antimicrob Agents Chemother. 2014; 58 (10): 5766-5774. doi: 10.1128/AAC.01826-13.

  87. Mehrbod P, Omar AR, Hair-Bejo M, Haghani A, Ideris A. Mechanisms of action and efficacy of statins against influenza. Biomed Res Int. 2014; 2014: 11-14. doi: 10.1155/2014/872370.

  88. Yamazaki H, Suzuki M, Aoki T et al. Influence of 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibitors on ubiquinone levels in rat skeletal muscle and heart: relationship to cytotoxicity and inhibitory activity for cholesterol synthesis in human skeletal muscle cells. J Atheroscler Thromb. 2006; 13 (6): 295-307. doi: 10.5551/jat.13.295.

  89. Masadeh M, Mhaidat N, Alzoubi K, Al-Azzam S, Alnasser Z. Antibacterial activity of statins: a comparative study of atorvastatin, simvastatin, and rosuvastatin. Ann Clin Microbiol Antimicrob. 2012; 11: 1-5. doi: 10.1186/1476-0711-11-13.

  90. Tapia-Pérez JH, Kirches E, Mawrin C, Firsching R, Schneider T. Cytotoxic effect of different statins and thiazolidinediones on malignant glioma cells. Cancer Chemother Pharmacol. 2011; 67 (5): 1193-1201. doi: 10.1007/s00280-010-1535-2.

  91. Schramm R, Menger MD, Harder Y et al. Statins inhibit lymphocyte homing to peripheral lymph nodes. Immunology. 2007; 120 (3): 315-324. doi: 10.1111/j.1365-2567.2006.02505.x

  92. Fernandez-Boyanapalli RF, Frasch SC, Thomas SM et al. Pioglitazone restores phagocyte mitochondrial oxidants and bactericidal capacity in chronic granulomatous disease. J Allergy Clin Immunol. 2015; 135 (2): 517-527. doi: 10.1016/j.jaci.2014.10.034.




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