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).

CONCLUSION:

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.

TRIAL REGISTRATION:

clinicaltrials.gov NCT01580007.

• Authors: Akhirunnesa Mily, Rokeya Sultana Rekha, S M Mostafa Kamal, Abu Saleh Mohammad Arifuzzaman, Zeaur Rahim, Lamia Khan, Md Ahsanul Haq, Khaliqu Zaman, Peter Bergman, Susanna Brighenti, Gudmundur H Gudmundsson, Birgitta Agerberth, Rubhana Raqib
• Journal: PloS one (PLoS One) Vol. 10 Issue 9 Pg. e0138340 ( 2015) ISSN: 1932-6203 [Electronic] United States
• PMID: 26394045 (Publication Type: Clinical Trial, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Antimicrobial Cationic Peptides
• Antitubercular Agents
• Phenylbutyrates
• RNA, Messenger
• Cholecalciferol
• 4-phenylbutyric acid
• C-Reactive Protein
• Calcifediol
• Calcium
• Cathelicidins

Topics

• Administration, Oral
• Adult
• Antimicrobial Cationic Peptides (genetics, metabolism)
• Antitubercular Agents (therapeutic use)
• C-Reactive Protein (analysis)
• Calcifediol (blood)
• Calcium (blood)
• Cholecalciferol (therapeutic use)
• Double-Blind Method
• Drug Therapy, Combination
• Female
• Humans
• Leukocytes, Mononuclear (metabolism)
• Logistic Models
• Macrophages (cytology, immunology, metabolism)
• Phenylbutyrates (therapeutic use)
• Placebo Effect
• RNA, Messenger (metabolism)
• Sputum (microbiology)
• Treatment Outcome
• Tuberculosis, Pulmonary (drug therapy, microbiology, pathology)
• Cathelicidins