Treating tuberculosis via lungs shows potential

Administering a repurposed drug to treat tuberculosis through the lungs instead of orally is effective at a dose estimated up to 10 times less, and can potentially reduce toxicity to the body, according to new research presented at the American Association of Pharmaceutical Scientists annual meeting.

“When it comes to TB therapy, there have not been a lot of new drugs introduced to market during the past two decades, and progress is slow despite enormous effort in new drug discovery,” Phillip G. Durham, BSc, biochemist at Research Triangle Institute (RTI) International, said in the press release. “What we’ve done in our research is to use a derivative of a drug that has been around for many years — Pyrazinoic acid — and reproduced the drug to deliver it to the lungs, with some very promising results.”

Previous research shows oral pyrazinoic acid (POA) is ineffective against disease, however delivery of POA and its hydrolysable ester, n-propyl POA (PAE) directly via the lungs can avoid oral bioavailability issues and requires less of the drug to reduce infection and transmission for TB in the lungs.

The investigators infected guinea pigs with Mycobacterium tuberculosis (H37Rv) by low dose aerosol in a whole-body exposure chamber for a multiplicity infection of 10-20 bacteria per animal. They divided the animals into four treatment groups (six per group): treatment with oral rifampicin (RIF, 50 mg/kg) alone, oral rifampicin plus oral pyrazinamide (PZA, 25 mg/kg), oral rifampicin plus POA/PAE dry powder aerosol, or no treatment.

Durham and colleagues found the aerosol outperformed the high dose oral PZA in the spleen, and was effective in the lungs and lymph nodes, indicating that local delivery of therapeutics for the treatment of TB may require less drug than administered orally. RIF plus aerosol and RIF plus PZA treatments both significantly lowered the bacterial burden in the lungs.

In guinea pigs receiving inhaled drug, researchers observed systematic effects with a 3.0 log reduction in the spleen bacterial burden compared with the RIF plus PZA (log reduction, 2.4) and the RIF-alone group (log reduction, 1.4).

“For drugs that are not orally bioavailable, the alternative is often injection,” Durham added in the release. “Given the dose required, daily therapy, and the physical health of the patients, inhaled therapy has the potential to be far less painful, does not generate biohazardous waste like HIV contaminated needles (HIV/TB coinfection is a problem), and does not need to be kept cold, which is required by many injectables.” –by Savannah Demko

Reference:

Durhan PG, et al. Abstract 23T0830. Presented at: American Association of Pharmaceutical Scientists Annual Meeting and exposition; Nov 13-17, 2016; Denver.

Disclosure: The researchers report no relevant financial disclosures.