Nanoparticles of curcumin (principal bioactive component of Turmeric) have the potential to reduce liver toxicity induced by anti-tuberculosis drugs and prevent reinfection of tuberculosis (TB), says a study published in the journal Frontiers in Immunology.
The study was initiated by Santosh K. Kar, Professor, School of Biotechnology and his team at Kalinga Institute of Industrial Technology (KIIT). So far, curcumin’s potential as a drug was hindered due to its low bioavailability — it was poorly absorbed by the intestinal lining, followed by its rapid metabolism and quick elimination from the body.
Kar and his team synthesised curcumin nanoparticles measuring ~200nm in size. “Nanoparticles of size smaller than this will enter cells, interfere with their metabolism, and may result in toxicity. We used a surfactant to prevent aggregation of the nanoparticles. Our nano-formulated curcumin shows five times greater bioavailability and enhanced half-life than normal curcumin, when injected intra-peritoneally into mice. Enhanced stability and non-toxicity make it possible to administer curcumin in large doses (upto 8g/day) to humans,” says Kar.
Further work on nano curcumin to demonstrate that it can be used as an adjunct drug along with isoniazid (INH) for TB therapy was conducted by Gobardhan Das, Professor, Special Centre for Molecular Medicine, Jawaharlal Nehru University (JNU) and his team then at International Centre for Genetic Engineering and Biotechnology (ICGEB), New Delhi.
INH is one of the first line drugs used for TB therapy. Curcumin is a known anti-inflammatory and antioxidant chemical. In this study, when mice infected with TB were treated with INH coupled with nano curcumin, they showed increased clearance of Mycobacterium tuberculosis (M. tb) infection, as compared to mice treated with INH or nano-curcumin alone. This means that curcumin provides greater immunity, which in turn means reduced duration of therapy. The study team also found that animals previously treated with nano curcumin were resistant to M. tb infection, whereas animals treated with only INH were frequently prone to reinfection by M. tb.
Animals that received both INH and curcumin showed increased levels of T helper type 1 cells (Th1) than those that received only INH, indicating increased host immune response. Prolonged therapy with INH is shown to induce apoptosis in Th1 cells. Curcumin seems to prevent this, both in vitro and in vivo, and restores antigen-specific T-cell proliferation.
India is struggling to control TB through the Directly Observed Treatment – Short course (DOTS) program mainly because a large number of patients abruptly discontinue therapy. The most common reason for this is the liver toxicity induced by the first line therapeutic drugs- INH, rifampicin and pyrazinamide. Curcumin’s antioxidant properties endow it with hepatoprotective function, as seen in a previous study. The current study found that curcumin reversed liver toxicity induced by INH in mice, observed through both macroscopic analyses and liver function tests.
TB as a disease, challenges the body through two routes: microbial infection and inflammation. Curcumin, having both anti-microbial and anti-inflammatory functions, has proven itself as an ideal choice for therapy. This may well be the elusive cure for multi-drug and extensively-drug resistant of TB. Kar is also confident of curcumin’s ability to treat other diseases, “many studies using animal models have shown curcumin to be effective against some kinds of cancer. We would like to use it in patients suffering from arthritis, neurodegenerative diseases like Alzheimer’s and Parkinson’s, as well as in cerebral malaria where no effective drug exists.”
However, there has been great opposition to curcumin being hailed as a wonder drug. The most recent instance was earlier this year, when a new report by Kathryn M. Nelson and her team from University of Minnesota caught everyone’s attention as it rubbished claims of curcumin’s therapeutic potential. The report declared that no double-blinded, placebo controlled clinical trial of curcumin had been successful. Nelson’s team also went on to add that curcumin is chemically unstable under physiological conditions of pH 7.4 and 37°C, hence falling short of the primary requirement of most therapeutic molecules. Curcumin’s pharmacokinetic parameters also came under the scanner as the team quoted instances where curcumin remains undetected in the serum of test subjects, despite dosing at ~12g/day. Nelson has highlighted the fact that while curcumin is considered as a dietary supplement by most, the FDA does not support its use as a therapeutic.
Unfazed by criticism, Kar is hopeful about curcumin’s potential. He says,“curcumin has been used in our traditional system of medicine for a long time and therefore cannot be written off without proper investigation. We have published a study showing how curcumin bound to chitosan nano particles can cure malaria in mice. Govindrajan Padmanabhan, former director, Indian Institute of Science (IISc) has been trying to develop an Artether-Curcumin combination therapy for Malaria treatment. We have also shown how nanocurcumin can prevent heart atrophy under hypoxia conditions.”
Referring to Nelson’s report, Padmanabhan lists down possible reasons for the severe opposition, “Although more than 100 clinical trials have been carried out, including 70% of them being against cancer, detailed large-scale double-blind studies have not been carried out. Preparations of curcumin used the world over are not 100% pure. Detailed studies on each of turmeric’s components are not available. In addition to all these, there is an inherent bias against traditional molecules, although FDA has opened up for the use of such therapies with adequate proof.”
Padmanabhan in his forum article hypothesizes that curcumin may offer protection through immunomodulation of the host response, rather than killing a particular pathogen. To clear the doubts raised against curcumin’s beneficial effects, he suggests conducting clinical trials with select infectious diseases where curcumin can be used as an adjunct drug to standard therapy. He further adds, “The results of such trials can be seen clearly in a short time, unlike cancer where there are complex changes for extended periods of time, providing a definite conclusion on curcumin’s efficacy. For example, malaria therapy is only for 3 or 5 days.”
Padmanabhan welcomes the results of Kar and Das’s study, “I believe that the M. tb antigens generated by INH-mediated killing, in presence of curcumin (even if it is present transiently), can create immune memory leading to long-term protection. Further studies will help understand this better.”
The researchers have their future task cut out. “After efficacy studies in mice, we have to get approval for testing curcumin as a food supplement in humans. Following that, we can get clinicians to prescribe it to a few TB patients with informed consent. If results are positive, the trial can be expanded to a larger number of patients.” says Kar.