Significant Effects of Oral Phenylbutyrate and Vitamin D3 Adjunctive Therapy in Pulmonary Tuberculosis: A Randomized Controlled Trial

Abstract

BackgroundDevelopment 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.ObjectiveTo 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.MethodsAdult 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.ResultsAt 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).ConclusionAdjunct 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 Registrationclinicaltrials.gov NCT01580007

Beneficial Effects of Sodium Phenylbutyrate Administration during Infection with Salmonella enterica Serovar Typhimurium

“…To determine the effect of PBA administration, groups of mice were orally gavaged daily with 1,000 mg/kg (of body weight) of PBA (4-phenylbutyric acid sodium salt; Scandinavian Formulas, Inc.) in 0.1 ml of phosphate-buffered saline (PBS) solution for 7 days and, if applicable, throughout S. Typhimurium infection. This dose was used in previous studies, and it is comparable to the dose used in humans (17,18). Groups of mice were orally gavaged with 0.1 ml of a 200-mg/ml streptomycin-sterile water solution 1 day prior to oral infection with 1 ϫ 10 9 CFU of S. Typhimurium in 0.1 ml LB broth.…”

“…In a subsequent study, the authors demonstrated that administration of PBA in combination with vitamin D 3 induced cathelicidin (called LL-37 in humans) in macrophages and lymphocytes, leading to effective intracellular killing of Mycobacterium tuberculosis by macrophages (17). As a result of these reports, PBA administration is now being tested in a clinical trial of adults with active pulmonary tuberculosis (17,18). Although these studies suggest that the beneficial effect of PBA during infection is indirect, as it is dependent on the increased expression of an antimicrobial protein, a recent study by Lo et al indicates that PBA could also have direct antimicrobial activity (19).…”

Sharpening nature's tools for efficient tuberculosis control: A review of the potential role and development of host-directed therapies and strategies for targeted respiratory delivery

“…With lower levels of vitamin D associated with higher mortality [71] and an increase in human cathelicidin following treatment with vitamin D3 [72] there is convincing evidence of the role of vitamin D in tuberculosis control. Nonetheless, clinical studies involving the supplementation of vitamin D have failed to meet expectations [73,74] with few showing any benefit [75].…”

Early diagnosis and effective treatment regimens are the keys to tackle antimicrobial resistance in tuberculosis (TB): A report from Euroscicon's international TB Summit 2016

“…Therefore, vitD3 and PBA can counteract downregulation of LL-37 during infection which can have positive impact on reducing antibiotic requirements for cure. [145][146][147] Dr Bhakta and his research group reported the common, over-the-counter non-steroidal anti-inflammatory drugs (NSAIDs), ibuprofen and carprofen to be antitubercular specific. 131,148,149 They were found to be active against drug resistant strains and stationary phase mycobacteria.…”