title: Significant Effects of Oral Phenylbutyrate and Vitamin D3 Adjunctive Therapy in Pulmonary Tuberculosis: A Randomized Controlled Trial.
abstract: BACKGROUND
  Development of new tuberculosis (TB) drugs and alternative treatment strategies are urgently required to control the global spread of TB. Previous results have shown that vitamin D3 (vitD3) and 4-phenyl butyrate (PBA) are potent inducers of the host defense peptide LL-37 that possess anti-mycobacterial effects.
  
  
  OBJECTIVE
  To examine if oral adjunctive therapy with 5,000IU vitD3 or 2x500 mg PBA or PBA+vitD3 to standard chemotherapy would lead to enhanced recovery in sputum smear-positive pulmonary TB patients.
  
  
  METHODS
  Adult TB patients (n = 288) were enrolled in a randomized, double-blind, placebo-controlled trial conducted in Bangladesh. Primary endpoints included proportions of patients with a negative sputum culture at week 4 and reduction in clinical symptoms at week 8. Clinical assessments and sputum smear microscopy were performed weekly up to week 4, fortnightly up to week 12 and at week 24; TB culture was performed at week 0, 4 and 8; concentrations of LL-37 in cells, 25-hydroxyvitamin D3 (25(OH)D3) in plasma and ex vivo bactericidal function of monocyte-derived macrophages (MDM) were determined at week 0, 4, 8, 12 and additionally at week 24 for plasma 25(OH)D3.
  
  
  RESULTS
  At week 4, 71% (46/65) of the patients in the PBA+vitD3-group (p = 0.001) and 61.3% (38/62) in the vitD3-group (p = 0.032) were culture negative compared to 42.2% (27/64) in the placebo-group. The odds of sputum culture being negative at week 4 was 3.42 times higher in the PBA+vitD3-group (p = 0.001) and 2.2 times higher in vitD3-group (p = 0.032) compared to placebo. The concentration of LL-37 in MDM was significantly higher in the PBA-group compared to placebo at week 12 (p = 0.034). Decline in intracellular Mtb growth in MDM was earlier in the PBA-group compared to placebo (log rank 11.38, p = 0.01).
  
  
  CONCLUSIONS
  Adjunct therapy with PBA+vitD3 or vitD3 or PBA to standard short-course therapy demonstrated beneficial effects towards clinical recovery and holds potential for host-directed-therapy in the treatment of TB.
  
  
  BACKGROUND
  clinicaltrials.gov NCT01580007.
authors.affiliation: International Centre for Diarrheal Disease Research, Bangladesh (icddr,b), Mohakhali, Dhaka-1212 Bangladesh.
authors.forename: Akhirunnesa
authors.initials: A
authors.lastname: Mily
authors.affiliation: International Centre for Diarrheal Disease Research, Bangladesh (icddr,b), Mohakhali, Dhaka-1212 Bangladesh; Department of Laboratory Medicine, Clinical Microbiology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Rokeya Sultana
authors.initials: RS
authors.lastname: Rekha
authors.affiliation: National Institute of the Diseases of the Chest and Hospital, Mohakhali, Dhaka, Bangladesh.
authors.forename: S M Mostafa
authors.initials: SM
authors.lastname: Kamal
authors.affiliation: International Centre for Diarrheal Disease Research, Bangladesh (icddr,b), Mohakhali, Dhaka-1212 Bangladesh.
authors.forename: Abu Saleh Mohammad
authors.initials: AS
authors.lastname: Arifuzzaman
authors.affiliation: International Centre for Diarrheal Disease Research, Bangladesh (icddr,b), Mohakhali, Dhaka-1212 Bangladesh.
authors.forename: Zeaur
authors.initials: Z
authors.lastname: Rahim
authors.affiliation: International Centre for Diarrheal Disease Research, Bangladesh (icddr,b), Mohakhali, Dhaka-1212 Bangladesh.
authors.forename: Lamia
authors.initials: L
authors.lastname: Khan
authors.affiliation: International Centre for Diarrheal Disease Research, Bangladesh (icddr,b), Mohakhali, Dhaka-1212 Bangladesh.
authors.forename: Md Ahsanul
authors.initials: MA
authors.lastname: Haq
authors.affiliation: International Centre for Diarrheal Disease Research, Bangladesh (icddr,b), Mohakhali, Dhaka-1212 Bangladesh.
authors.forename: Khaliqu
authors.initials: K
authors.lastname: Zaman
authors.affiliation: Department of Laboratory Medicine, Clinical Microbiology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Peter
authors.initials: P
authors.lastname: Bergman
authors.affiliation: Center for Infectious Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Susanna
authors.initials: S
authors.lastname: Brighenti
authors.affiliation: Biomedical Center, University of Iceland, 101 Reykjavik, Iceland.
authors.forename: Gudmundur H
authors.initials: GH
authors.lastname: Gudmundsson
authors.affiliation: Department of Laboratory Medicine, Clinical Microbiology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Birgitta
authors.initials: B
authors.lastname: Agerberth
authors.affiliation: International Centre for Diarrheal Disease Research, Bangladesh (icddr,b), Mohakhali, Dhaka-1212 Bangladesh.
authors.forename: Rubhana
authors.initials: R
authors.lastname: Raqib
mesh_terms: D000284:Administration, Oral; D000328:Adult; D023181:Antimicrobial Cationic Peptides / Q000235:genetics / Q000378:metabolism; D000995:Antitubercular Agents / Q000627:therapeutic use; D002097:C-Reactive Protein / Q000032:analysis; D002112:Calcifediol / Q000097:blood; D002118:Calcium / Q000097:blood; D002762:Cholecalciferol / Q000627:therapeutic use*; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D016015:Logistic Models; D008264:Macrophages / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D010654:Phenylbutyrates / Q000627:therapeutic use*; D015990:Placebo Effect; D012333:RNA, Messenger / Q000378:metabolism; D013183:Sputum / Q000382:microbiology; D016896:Treatment Outcome; D014397:Tuberculosis, Pulmonary / Q000188:drug therapy* / Q000382:microbiology / Q000473:pathology; D054804:Cathelicidins
chemical_list: D023181:Antimicrobial Cationic Peptides; D000995:Antitubercular Agents; D010654:Phenylbutyrates; D012333:RNA, Messenger; D002762:Cholecalciferol; C075773:4-phenylbutyric acid; D002097:C-Reactive Protein; D002112:Calcifediol; D002118:Calcium; D054804:Cathelicidins