Our battle against the disease-causing
bugs is endless. Since antiquity scores of infectious diseases caused by
bacteria, viruses and fungi have affected millions of people worldwide. Fighting
these formidable foes has not been easy as these tiny life forms that cause
life threatening diseases in human beings are clever enough to thwart all our
attempts made to pin them down. Take, for example, a wide range of antibiotics
– the potent tools to kill many harmful bacteria – that are turning ineffective
in the wake of development of resistance in microorganisms to these drugs.
Moreover, due to the indiscriminate use of antibiotics there is an increasing
microbial resistance to many new antibiotics as well.
To
make matters worse, most antibiotics have their well known side effects on the
human body. This is particularly a matter of great concern for diseases like
tuberculosis for which patients have to take long-term treatment with drugs namely,
rifampicin and isoniazid that have many adverse reactions on different organs
of the body. In this light, the development of special molecules called
‘bio-enhancers’ is a scientific breakthrough, as bio-enhancers have no drug
activity of their own but are uniquely endowed with properties for promoting
the biological activity or simply the uptake of other drugs.
The
bountiful Nature is replete with natural products, mainly contained in plant
sources, which have played an important role in the development of drugs.
Synergism – increase in the action of one biomolecule by another unrelated
chemical – is the hallmark of herbal drugs. For example, ‘berberine’ is an
anti-microbial alkaloid isolated from Berberis fremontii that has very weak anti-microbial activity in
solution. However, in combination with a compound called 5-Methoxy hydnocarpin
(5-MHC) the anti-microbial activity of berberine is increased by 200 folds
against the bacterium, Staphylococcus aureus. Similarly, such
bioenhancer activity of cow-urine distillate in a composition containing
antibiotics and anti-cancer agents is also well known. Undoubtedly, bioavailability enhancement
helps to lower dosage levels and shorten the treatment course.
In
a significant development, Indian Institute of Integrative Medicine (IIIM),
Jammu in public private partnership with
Cadila Pharmaceutical Ltd, Ahmedabad has released a new drug formulation
against tuberculosis called ‘risorine’ that contains reduced dose (200
mg) of rifampicin + isoniazid (300 mg) + piperine (10 mg) found to be
bioequivalent to standard rifampicin regimen. Launched in November 2009, this indigenously developed drug
formulation could drastically cut short the duration of TB treatment. Risorine has
been approved for marketing by Drug Controller General of India after
successful completion of all the phased clinical trials.
The R&D work on developing this
formulation was started in the erstwhile Regional Research Laboratory, Jammu
now renamed as Indian Institute of Integrative Medicine by Dr. C. K. Atal, former Director, in early 1980s. On scrutinizing a
large number of ancient Indian Ayurvedic formulations used in the treatment of
a wide range of diseases, it was observed that in a
majority of formulations ‘Trikatu’ was used as one of the ingredients. Trikatu
is a combination of three herbal products namely Piper nigrum (black pepper) and Piper
longum (long pepper) and ginger.
Concerted research
efforts resulted in the isolation of an active alkaloidal molecule called
‘piperine’ from piper species, which was shown to increase the bioavailability
of specific drugs. On combining
piperine with many common drugs, a reduction of dose of that drug was observed
for the same pharmacological effects, without any activity of piperine itself. This is due to enhanced uptake of the
drug by body cells, and also because the drug remains available in blood for
long durations.
Popularly known as bioenhancers’,
such compounds simply enhance the bioavailability and bio-efficacy of other
drugs with which they are combined, without any pharmacological activity of
their own at the same dose level. Scientists
at IIIM, Jammu tested the bioenhancing activity of piperine on various drugs,
which ultimately resulted in designing the risorine formulation useful for the
treatment of tuberculosis. The work, now patented, has been documented in
various national and international journals particularly in India, Europe and
USA.
The
bacterium, Mycobacterium tuberculosis, infects one in three people
worldwide and kills about 3 million victims every year on a global scale. Nearly 9 million new TB cases add to the TB burden
of our planet annually. TB
is a major public health problem in our country as India accounts for one-fifth
of the global TB incident cases. Besides this
huge burden of TB patients, the cases with multi-drug resistant tuberculosis
(MDR-TB) are on the rise as many patients discontinue with the TB drugs,
primarily rifampicin and isoniazid, due to long treatment and unpleasant
side effects of the drugs.
Rifampicin has been a first line anti-tubercular drug for a
long time. It has been used for treating tuberculosis since 1960s and is known
for causing many side effects. Also, the levels of rifampicin in blood decrease
over a period of time due to the auto-induction of drug metabolizing enzymes by
rifampicin. In fact, cells of the human body contain on their surface membranes
certain proteins called ‘transporter’ proteins that ‘pump’ specific substances
out of cells, for being taken away by the blood. Undoubtedly, these proteins can protect cells from toxic
overloads of many substances, but at the same time they can also spoil the
efficacy of otherwise beneficial drugs, like rifampicin, by pumping them out of
the cells before they can act. One of the most important such ‘pump’ proteins
is p-glycoprotein, which is found in the membranes of cells in the
intestines, brain, liver, pancreas, kidneys, and other tissues.
At the
molecular level, p
iperine acts
by suppressing p-glycoprotein and cytohrome P450 enzymes, which
counteract the
metabolism of rifampicin via these
proteins, thus enhancing the oral bioavailability of rifampicin. Piperine also decreases the intestinal
production of glucuronic acid, thus allowing more substances to enter the body
in active form. This wonder compound thus allows many drugs to enter and remain
within their target cells for longer durations.
Management of TB with risorine is
poised to have remarkable benefits as the use of bioavailability enhancers, in
general, not only increase the bioavailability for a drug, but also help
reducing the cost of treatment and incidents of drug resistance while
minimizing adverse drug reactions. In this new formulation, the rifampicin dose
has been reduced from 450 mg to 200 mg along with isoniazid and piperine, with
the same pharmacological activity as used earlier. Risorine could even replace the currently
used rifampicin used in the 'Directly Observed Treatment Short-course' (DOTS)
therapy, run by the Central government in association with different States.
According to the team of scientists
at IIIM, risorine is very safe, effective and
economical for the management of tuberculosis. In other words, with use of risorine TB patients would get
cured in a shorter span of treatment. Interestingly, in a multi-centric
clinical trial conducted across India in patients with radiologically confirmed
diagnosis of pulmonary tuberculosis, more than 90% of the patients treated with
risorine were cured of tuberculosis with lesser side effects. This
formulation for tackling TB is poised to capture foreign markets like China,
Russia and African countries and expects to multiply several times its turnover
from this segment.
A marvel of the plant world and a sure gift to
humankind, the black pepper has both culinary and medicinal values. Among its
myriad medicinal properties, the one that makes its compound piperine a
bioenhancer holds immense promise for making ‘dose economy’ drugs that
particularly suit the health needs of people in the developing countries.
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