Risorine- A Novel CSIR Drug Curtails TB Treatment by Dr P. Cheena Chawla

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.

A Breakthrough Project of CSIR The Birth of TKDL and Beyond by Dr P. Cheena Chawla

Open your grandmother’s medicine box and you will invariably find it full of herbs or their parts: saunf, ajwain, pepper, haldi, tulsi, Aloe, neem, and the list is endless. Strangely though, you will find that many traditional recipes, for countering a plethora of illnesses, simply work wonders. This knowledge has got passed down several generations only because the unique herbal formulations for treating the human body have given consistent results over the centuries. The ancient Indian wisdom of the usage of thousands of medicinal plants, in unique combinations and definite doses, is truly a blessing for keeping at bay the discomfort of many dreadful diseases.

The sanctity of our traditional knowledge is well established for it is codified in several classical ancient texts in the form of hundreds of thousands of Sanskrit slokas that mention scores of unique formulations of various herbs. This vedic knowledge – a handiwork of our sages and learned forefathers – is a treasure trove of information that unfortunately remained accessible to only a few experts, and long languished in the prison of ignorance of the common masses. Besides, the tribal and indigenous communities have also for long been the custodians of our country’s rich biodiversity. Nonetheless, this enormous traditional wealth, collected over millennia with some of it codified in a large number of old treatises of medicine, is a part of our rich legacy and belongs to India.

In modern times, with global resurgence of interest in herbal medicine, medicinal plants and their products are not just the source of affordable healthcare with minimal side effects, but are also important In terms of international trade and commerce. Realizing the potential of earning huge profits, many multinational pharmaceutical companies began to target the exploitation of traditional knowledge related to medicinal plants. To stop this exploitation, the need to protect the owners of traditional knowledge and provide them their rightful dues stemmed. It thus became imperative to safeguard the IPR on traditional knowledge.

       A new era dawned when a US patent granted for the wound-healing properties of turmeric was challenged successfully by CSIR. In a landmark decision, the United States Patent and Trademark Office (USPTO) revoked it after ascertaining the medicinal use of turmeric in India for centuries. This opened the floodgates for successful fights for the rights to neem and basmati rice, which firmly established the need to document our precious traditional knowledge for shielding it from the assault of wrongful grant of patents. Although these tough fights were won, a lot of time and funds were invested. Cancellation of the patent for turmeric took about two years while it took five years for revoking the patent on the anti-fungal properties of neem.

        It thus became clear that it is possible to revoke the grant of wrong patents at international level and also exposed the fact that relevant information on traditional knowledge was not available to International patent examiners in a retrievable format. The need to systematize the documentation of knowledge existing in the public domain, on various traditional systems of medicine, thus assumed great significance for preventing the misuse of this knowledge through non-original inventions.

While considering the patentability of any subject matter, the patent examiners search available resources for non-patent and patent literature. Although patent literature is available in many databases that can be easily retrieved, non-patent literature normally appeared scattered. Thus arose the challenge to create non-patent literature databases, containing information on traditional knowledge that was easily accessible. 

In this endeavour, CSIR was on the forefront as a collaborative Project – the Traditional Knowledge Digital Library (TKDL) – was initiated between the National Institute of Science Communication & Information Resources (NISCAIR) and the Department of Indian System of the Department of Ayurveda, Yoga & Naturopathy, Unani, Siddha and Homoeopathy (AYUSH), erstwhile Department of Indian System of Medicine and Homoeopathy (ISM&H), Ministry of Health & Family Welfare. The MoU for this Project was signed on June 6, 2001.        It all, however, started in June 1999 when the need for creating Traditional Knowledge databases was realized by the Standing Committee on Information Technology (SCIT) of World Intellectual Property Organization (WIPO), under the Chairmanship of Dr. R. A. Mashelkar, the then Director General of CSIR, India. A few months later, an Approach Paper on setting up of TKDL was prepared by Mr. V. K. Gupta, the then Senior Technical Director, National Informatics Centre, the former Director, NISCAIR. This paper was submitted to SCIT, WIPO the same year.          In January 2000, an inter-disciplinary Task Force on TKDL, consisting of experts from the then Department of ISM&H, Central Council of Research in Ayurveda & Siddha (CCRAS), Banaras Hindu University (BHU), National Informatics Centre (NIC), and Controller General of Patents Designs & Trade Marks (CGPDTM) was set up under the Chairmanship of Mr. V. K. Gupta. In January 2001, the Cabinet Committee of Economic Affairs (CCEA’s) finally gave approval on the TKDL Project – a triumph for the entire TKDL team.            Implemented at CSIR, the TKDL Project comprises an inter-disciplinary team of Traditional Medicine (Ayurveda, Unani, Siddha and Yoga) experts, patent examiners, IT experts, scientists and technical officers. The focus of this Project has been to create database on the codified traditional knowledge on Indian Systems of Medicine. For example, for documenting knowledge in Ayurveda, the available information in public domain was first searched, sifted and collated. The coded information lying dormant in the Sanskrit slokas was understood and converted into structured language using the specially created Traditional Knowledge Resource Classification (TKRC) and saved in the database by experts in the field. The saved information can be read in five different languages (English, German, French, Japanese and Spanish) and is simple to comprehend. The TKDL software is special for it does smart translation, instead of mere transliteration, of Ayurvedic descriptions from traditional terminology into modern terminology.          Several thousands of herbal formulations from various Ayurvedic texts have been thus transcribed in patent application format. Similarly, traditional knowledge available in public domain, related to Unani, Siddha and Yoga, has also been converted to the user-friendly digitized format that is easily understandable. This TKDL database thus acts as a strong bridge between the traditional knowledge available in public domain and the patent examiners in various patent offices.         In yet another achievement in February 2002, about 200 subgroups on Traditional Knowledge on medicinal plants were included against the existing few besides the linking of TKRC to the international Patent Classification (IPC). Several specialized subgroups were later included as the Project advanced. A demo CD containing a sample of 500 formulations was released in October, 2003 by the then Hon’ble Union Minister of Human Resource Development, Science & Technology, and Ocean Development at NISCAIR. Three years later, in a landmark achievement, the Cabinet Committee on Economic Affairs gave its approval on the access to TKDL database to International Patent Offices.        In the year 2009 access to TKDL database was given first to the European Patent office, and then to the Indian Patent Office (CGPDTM), German Patent and Trademark Office (DPMA) and more recently to the USPTO (CSIR News, Vol. 59, 15 & 30 December 2009) under the respective TKDL Access Agreements. This allows the various patent offices access to about two lakh medicinal formulations on Ayurveda, Unani and Siddha, comprising a whopping 30 million pages!  Following this, there have been innumerable cases of withdrawal of patent applications, where the subject matter was not considered to be original work due to TKDL prior art evidence. With a cost of about 1.18 crore, the TKDL Project — a breakthrough that benefits the owners of traditional knowledge from theft of their knowledge — is a classic example of integrating the enormous capabilities of Information technology for creating mechanisms of effective access and retrieval of the rich traditional knowledge on medicinal plants collected over millennia, which in addition, has opened up new possibilities for further research.

The Tick-Tock of TeleClock by Dr P. Cheena Chawla

The weary battery of your clock may halt the tick-tock temporarily but the fact remains that time never stops. As you place a new battery, the tick-tock is once again restored but you have to adjust the clock to the exact time. Now for adjusting your clock, you perhaps set the time according to clocks that are in function. But what is the surety that the time displayed by those clocks is accurate? This challenge of non-synchronicity of the clocks in use is most evident when you miss your train or flight by a few minutes or find your bank closed for the day, which may sometimes cost you quite heavily. 

            Well, you could just dial 174 and know the exact time of the day — the Indian Standard Time (IST) — precise to the second! Maintained by the Time and Frequency Standards Laboratory at the National Physical Laboratory (NPL), CSIR, the IST is followed by the Doordarshan and the All India Radio (AIR) for the announcement of accurate time, which most of us listen to for adjusting time in our hand watches and wall clocks. Another increasingly popular means of obtaining the time is through Global Positioning System (GPS) receivers.

            Now comes the question of disseminating the IST across the nation. The most common method is to transmit the time signal via satellites or from a broadcast station. The classic example is the transmission of the Standard Time and Frequency Signal (STFS) via INSAT by the NPL, CSIR. INSAT satellite based standard time and frequency broadcast service offers IST correct up to ±10 microsecond on a continuous basis. However, there is still a considerable variance in the display of time by other customer service providers like the Indian Railways, Airlines, Banks and so on. For example, the times displayed by clocks on different platforms of a railway station are often quite different. This strongly necessitates the need for synchronizing the clocks for display in public places to one source clock. In the fast paced life of today, synchronization of time has surely assumed importance.

            In a landmark achievement, CSIR has fulfilled the requirement of one and all for easy access of IST data for updating the local clocks. The wonder product is a ‘Teleclock’, which has been developed by a team of scientists led by Dr P. Banerjee, Head of the Time and Frequency Section at NPL, CSIR, New Delhi. Dr Banerjee conceived the idea of developing a Teleclock sometime in 1994-95. Today this innovative Teleclock Service is the first of its kind in India, which is a digital time data service, facilitated through the telephone network. Simply put, the Teleclock has a unique in-built system, which auto-dials the telephone number of the Teleclock Service at the user-defined time. It has its own clock and a modem that facilitates the connection to the local telephone line.

NPL maintains the IST with the help of a bank of caesium atomic clocks, which are so accurate that it is only one second that they can lose or gain in a span of 30,000 years!  “The primary standard of time the world over is Cesium atomic clock. Cesium is preferred because of its long-term, high order stability”, says Dr Banerjee. “These atomic clocks are synchronized with the worldwide system of clocks that support the Coordinated Universal Time, through GPS network,” he further adds.

            As the NPL numbers are dialed by the Teleclock, the internal clock gets synchronized with the help of received time data through the telephone line. After the time updation, the Teleclock automatically gets disengaged. An additional feature provided in the Teleclock Service is to set the Real Time Clock (RTC) of a computer. All that is required is that the computer should be connected to a telephone line through a standard modem. For this, the NPL scientists have developed the necessary software for the computer's RTC. This cost-effective way of disseminating universal standard time for all users in the country was launched in February 2000. Dr P. Banerjee has to his credit a US Patent (No. 6091804, dated July 18, 2000) entitled, ‘Device Useful as Master/Slave Clock for Transmitting Standard Time Over a Telephone Network and a Telephone Network Incorporating the Device for Transmitting and Receiving Standard Time.’

            The Teleclock service through the landline network is, however, accessible to users having a landline telephone, which becomes a limiting factor for some key applications like police patrolling vans, remote locations where telephone lines are not available and personal vehicles. The NPL scientists have met this challenge by adding a new dimension to time dissemination by developing an improved version of the Teleclock.

            In a significant advancement, Dr P. Banerjee’s team has developed the Mobile Teleclock receiver that receives data through wireless mobile telephone network. The receiver has the provision of dialing the telephone number of the line dedicated for this service manually by pressing a switch or automatically at a pre programmed time. The Mobile Teleclock receiver was formally launched by Prof. Samir K. Bramachari, former Director General CSIR on July 28, 2009.  This improved Teleclock receiver is an inexpensive and advanced solution to access Standard Time of any country without any separate landline telephone connection. The basic requirement of the Teleclock receiver for mobile network is that it should have GSM SIM card with ‘Data Communication Mode Enabled’.        For this innovation, patents have been granted in India as well as in the United States Patent and Trademarks Office, besides five European countries namely, Germany, France, U.K., Italy and Sweden. A patent No.1390DEL2009 on, ‘Improved Teleclock Receiver Utilizing Mobile Telephone Network’ by P. Banerjee, P. P. Thorat and A. K. Suri was filed in 2009 in India, Japan, Korea and Europe.

            NPL has also transferred this technology to M/s Excel Technologies, based in Noida, on a non-exclusive basis. The other manufacturers to whom this technology has been transferred include M/s Bihar Communications Pvt. Ltd. in Patna and M/s Electronics Equipment Company based in Kolkata. The Mobile Teleclock is currently in use in the Parliament House, airports, railway platforms, Delhi police control rooms, besides the CSIR laboratories and some private organizations. But why this highly useful, scientifically developed product still not popular with the Indian masses? To this Dr Banerjee says,  “Manufacturers in our country are not so aggressive. As there is low profit per unit, bulk orders are few”. “The need is to give a more decorative look to the otherwise boxy appearance of the Mobile Teleclock receiver, so that people are interested to buy it. As the demand increases, manufacturers will have to produce more units and this will reduce the cost per unit”, Dr Banerjee explains. This service can be implemented in any country with very low investment like it is operational in Saudi Arabia and Nepal.

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   Atomic Clocks

All clocks basically keep track of the passage of time by counting the ‘ticks’ or oscillations of a ‘resonator’. The oscillation in an ordinary clock is between the balance wheel and the hairspring, while the oscillation in an atomic clock is between the nucleus of an atom and the surrounding electrons. Similarly, in a pendulum clock the resonator is a pendulum, which swings back and forth. The gears in the clock keep track of time by counting the resonations of the pendulum, which are usually at a frequency of one swing per second. A digital clock uses either the oscillations on the power line or the oscillations of a quartz crystal as the resonator, and counts them using digital counters. Needless to say, the accuracy of the clock is dependent on the accuracy of the resonator at the specified frequency.

Atomic clocks are the most accurate keepers of time. They are, however, not radioactive as they do not rely on atomic decay.  They use the resonance frequencies of atoms as its resonator. Cesium-133 oscillates at 9,192,631,770 cycles per second. The oscillation frequencies within the atom are determined by the mass and the gravity and electrostatic ‘spring’ between the positive charge on the nucleus and the electron cloud surrounding it. Atoms of different elements have their characteristic oscillation frequencies. 

 The accuracy of an atomic clock is completely different from the accuracy of a quartz clock. In a quartz clock, the quartz crystal is manufactured so that its oscillating frequency is close to some standard frequency, but every crystal may be slightly different, and temperature could change its frequency. Whereas a cesium atom always resonates at the same known frequency, which makes an atomic clock so precise.

             There are different types of atomic clocks, which only differ with regard to the element used and the means of detecting the changes in the energy level. The various types of atomic clocks are: Cesium atomic clocks that employ a beam of cesium atoms; Hydrogen atomic clocks that use hydrogen atoms at the required energy level and Rubidium atomic clocks that use rubidium gas. The most accurate atomic clocks use the cesium atom (Cesium 133).

            The genesis for developing an atomic clock took root in 1945, which was based on the technique called atomic beam magnetic resonance developed by Isidor Rabi, a physics professor of the Columbia University. In 1949, the National Bureau of Standards (now the National Institute of Standards and Technology, NIST) announced the world’s first atomic clock using the ammonia molecule.  Later in 1952 it came up with the first atomic clock using cesium atoms as the source of vibrations. The National Physical Laboratory in England built the first cesium-beam clock in 1955 that was used as a calibration source.

            The keeper of Indian Standard Time (IST), NPL, CSIR has five such atomic clocks. A cesium atomic clock typically has a life span of less than a decade. They are electronic boxes with digital displays, stacked together in a sanitized chamber at an appropriate temperature and humidity.  Atomic clocks make GPS navigation possible, and help synchronizing the Internet.

CSIR Paves the Way for Equity in Healthcare Open Source Drug Discovery (OSDD)

Countless diseases afflict humankind all over the globe. What differentiates one individual from another with respect to tackling the menace of myriad illnesses is the sheer access to healthcare.

Social injustice in health arises primarily due to lack of information and financial barriers that invariably deprive the poor, in any community, from a fair opportunity to attain good health. Needless to say, for enhancing equity in healthcare, it is crucial to have effective health policies that timely bring the fruits of modern technologies to improve the health of the financially weaker individuals of society.

            

The high cost of a drug is mainly due to the huge monetary investment that has gone into developing that formulation. It is a hard fact that pharmaceutical companies go through a long, tough struggle to bring a brand new drug in the market, which may or may not become the standard treatment for a major disease. The journey of a new drug formulation from the laboratory to the market takes normally more than a decade of research involving both arduous bench work and millions of dollars, with no guarantee of success, as many a times even after years of investment of time and money, the new drug is unable to hit the market.

New drug research involves the Phase I, II and III trials followed by Clinical Trials. Only on successful completion of all these studies, which evaluate the efficacy and safety of the new drug, that the latter gets the final stamp of approval from the drug regulatory authorities of the country. It is all for this jubilant moment – akin to winning a jackpot – that pharmaceutical companies heavily invest and patiently wait for years, as the market returns from the sale of a new drug would be stupendous. However, only a few contenders in this race of new drug development succeed to reach the endpoint. No doubt then why most pharmaceutical companies prefer to just license the marketing rights of a drug from the original discoverer or they create and market generic versions of drugs developed by others.

In this light, just imagine a scenario where scientists from various research institutions worldwide, both public and private, join hands to collaboratively work to discover new drugs for a target disease. This is open source model of drug discovery that is poised to give even brilliant young researchers in colleges and universities an opportunity to contribute to the design and development of new drugs. Undoubtedly, the free flow of information amongst different sources on diverse aspects of drug discovery research would speed up the unraveling of new molecules that could become components of novel drug formulations to fight a particular disease. Sure, this model involves the coordinated activities of scientists from different areas like molecular biology, biophysics, biochemistry, chemistry and genetics to name a few.

Thanks to the Open Source Drug Discovery (OSDD) initiative of CSIR, today it is possible to establish a novel open source platform for both computational and experimental technologies to discover new drugs for infectious/neglected diseases that are affordable to the poor populations of the developing world. According to Dr Samir. K Brahmachari, former Director General CSIR and Chief Coordinator and Mentor, OSDD, not even a single new drug molecule against tuberculosis could come up despite over a decade of effort by Industry and R&D Laboratories, after the complete genome sequencing of Mycobacterium tuberculosis. This was because of lack of knowledge sharing among researchers as they worked as isolated groups.

IPR protection does not allow free knowledge sharing for drug discovery and also increases the cost of the drug. This patent-protected route of discovering new drugs, in the long run, suits only the rich who can afford those high-priced drugs. “I believe that affordable healthcare is a right for all. But, pragmatically speaking, when it comes to health, we need to have a balanced view between health as a right and health as a business,” says Dr Brahmachari. “With respect to diseases of the poor, like tuberculosis, where the market incentive is very small, it is not possible to convince the pharmaceutical companies to work on these drugs. Therefore, it is the responsibility of public-funded institutions to participate in this area in an open collaborative mode”, Dr Brahmachari further adds. In other words, for drugs that are primarily meant to be consumed by the poor, open source drug discovery is the right route.

OSDD is a CSIR-led Team India consortium with a global partnership. For popularizing the concept of OSDD, Dr Brahmachari explains through a simple analogy: “The strategy used to protect a factory is different from the strategy used to protect a paddy field. It might be worth building a wall around a factory and restricting access, but one does not build walls around paddy fields. If you do, then the cost of building and maintaining the wall will add to the price of rice, and the poor will no longer be able to buy it. Open source is for the 'paddy fields' that everyone needs, not for the luxury goods factory.”

OSDD aims to provide a global platform where the best minds can collaborate to solve the complex problems associated with discovering novel therapies for neglected tropical diseases like malaria, tuberculosis, leishmaniasis, etc. This joint endeavor promises to provide a unique opportunity for scientists, doctors, technocrats among other experts to work for a common cause.  The first phase of OSDD focused on developing drugs against M. tuberculosis including drug resistant and latent tuberculosis. The objective was to develop a web-based portal for data deposition, exchange, evaluation and tabulation for analysis. This would encourage collaborative sharing of know-how for the entire spectrum of processes in discovering new drugs for this age-old scourge that has one-third of the entire human population on Earth under its grip, particularly in the developing countries.

OSDD functions by breaking a large complex problem into simpler, smaller set of activities that have a clearer scope. Called ‘work packages’, the smaller sets of activities clearly specify the task to be carried out during the implementation of the Project. The timelines for the execution of such tasks is also well defined. Affordable drug development would thus be possible by concerted efforts on various work packages by all the contributing partners. For contributing to OSDD one simply needs a login followed by acceptance of ‘terms and conditions’, and depending upon one’s expertise, he/she could contribute to any of the work packages.

In this endeavor, an idea, a software, an article or molecule(s), etc., that help in expediting the process of drug discovery are treated as a contribution. The various challenges in drug discovery research are posted on the website, for anyone to take up and find relevant solutions, which are peer-reviewed. Appropriate rewards are given to select contributors in the form of credit points, for solving a defined problem. Based on the points accrued by the contributors they are awarded four levels of Membership cards (Blue, Silver, Gold and Platinum), providing the contributors of each card certain rights, privileges and responsibilities.

Explaining the essence of OSDD, Dr Samir K Brahmachari says that, "Most of the drug discoveries are made in a closed door environment, where highest degree of secrecy is maintained resulting in the lack of open participation of the entire academic world. The Open Source Drug Discovery Program aims to establish a novel web-enabled open source platform ― both computational and experimental ― to make drug discovery cost-effective and affordable by utilizing the creative potential of college and university students along with senior scientists, a collective approach to drug development.” As the mastermind behind the OSDD Project, Dr Brahmachari has also contributed to establishing an International Collaborative Center for Affordable Health (ICCAH), which operates with Government, International and Philanthropic funding.

A Towering Success of CSIR, Terafil for the Thirsty by Dr P. Cheena Chawla

Water — the elixir of life — is abundant on our planet but alas, access to safe drinking water is a major challenge faced by most developing countries including India. About 800 million people that represent the face of rural India are severely prone to water-borne diseases, primarily diarrhea in children. Sure, it is the lack of adequate drinking water — the basic requirement for survival — that poses a major health burden on our people.

It is a heartening fact that today CSIR stands strong with an ingenuously developed technology, which amply suits the needs of people in rural areas who use water from both surface and ground water sources like dug wells, ponds, tube wells and rivers for drinking purpose.  One simply needs to ‘see’ to ‘believe’ it, for how such a low cost device by the name Terafil magically cleans impure, turbid water into sparkling drinking water. This filter has astounding ability to remove sediments, suspended particles, iron and harmful microorganisms from contaminated water. 

The credit to this achievement goes to the painstaking research efforts of the team of scientists at the Institute of Minerals and Materials Technology (IMMT), (formerly known as Regional Research Laboratory), Bhubaneswar. With its filtration discs being prepared under license and training from IMMT, Terafil is gaining widespread popularity, and is already being used by thousands of households in the States of Orissa, Karnataka and Meghalaya.

Technically, Terafil disc is formed from a mixture of red clay (silt clay/terracotta), river sand and wood saw dust without using any chemicals. The dough of the mixture, in specific proportion, is sintered at high temperature in a low cost coal/wood fired furnace to make the disc structure porous. During sintering process, the wood particles are burnt and clay particles are sintered around the sand particles leaving large elliptical/circular pores in between.

If Terafil is over sintered, then the size of the pores is reduced. Thus, proper sintering of Terafil is important for obtaining the required thickness of membrane as well as the shape of pores, which defines the strength of the filter. These pores are not connected with each other, unlike that in white ceramic filter candles, but are separated by semi-permeable, thin clay walls of 50-100 micron thickness. These clay walls contain several ultra-fine capillary openings. The average diameter of the capillary openings is sub-micron in size.

During the filtration process, water flows from one pore to another pore through the capillary openings due to pressure of water over the Terafil disc. The pores inside the Terafil disc, therefore, work like micro-reservoirs of filtered water. The opening of the capillaries are, however, too small for the impurities to enter into the capillaries, which is why such impurities, comprising suspended particles and microbes, get deposited on the top of Terafil disc as water is filtered through it. It is for this reason that the core of Terafil disc is never clogged unlike the ceramic candle filters that are in vogue in most currently available filters.

The water filtered through Terafil is thus free from turbidity, colour, bad odour while the process also effectively removes microorganisms, soluble iron and heavy metals from raw water. Terafil also removes fluoride, chromium, nickel, cobalt, lead, and chloride from raw water. All these impurities get precipitated on the top surface of Terafil, which can be periodically removed by cleaning the filter disc. Thus regular cleaning of the top surface of Terafil is important as over a period of time the collected impurities may clog the outer surface of Terafil, thereby reducing the flow rate of filtered water. Besides, the rate of filtration is also dependant upon the turbidity and pressure of raw water as well as the diameter of Terafil disc inside the filter.

The outer surface of Terafil, therefore, needs to be scrubbed, once a week or as and when required, with a soft nylon brush or coir to remove the sedimented impurities to open new pores for facilitating the filtration process. Although the thickness of Terafil may slightly reduce by scrubbing its top surface, the quality of water filtered by it does not change for about five years. As the pH of filtered water is also improved, Terafil water filter is well suitable for treatment of both surface and ground water with affordable cost and without significant maintenance for a long period.

The circular, disc shape of Terafil filter is more preferable due to its high strength, long operational life and for easy maintenance, besides being simple to produce and fix with the container. The Terafil discs in both domestic or community filters are easy to dismantle/reassemble. Generally Terafil discs of 50 mm thickness and 100 & 220 mm diameter are produced to obtain maximum benefits.

Domestic Terafil water filter is available in 20 and 30 liter sizes with 1 to 4 litre/hr rate of filtration. The cost comes to just Rs.2/- per ton of filtered water. Domestic Terafil water filters are normally made with chambers made from food grade plastic. For installing community Terafil water filters, space required is 1 to 300 square meters for filters of 1,000 to 1, 00,000 litres/day capacities. The chambers of Terafil filters, for community use, are usually cemented structures where filtration and collection of filtered water occurs. Besides, electricity is not required for operation of the Terafil water filters. On-line pressure Terafil filter with capacity of 60 to 10,000 litres/day have also been developed.

IMMT, Bhubaneswar had distributed 1000 sets of Terafil water filters to the victims of cyclone in affected areas of Orissa during November 1999 to March 2000 for evaluation of the performance of these filters. Different Govt. departments, NGOs, International organizations like UNICEF and OXFAM have distributed about 30,000 sets of water filter in rural areas of Orissa. These filters are being installed in schools, community centers and villages in Orissa by Rural Development (RD) Department, Govt. of Orissa. Such efforts are being replicated in other States as well, under Central Govt. Schemes like Bharat Nirman Yojana and Jalmani (a Ministry of Rural Development scheme for Installation of Stand Alone Drinking Water Purification Systems in Rural India).  

Meanwhile, CSIR scientists are working to develop more advanced versions of Terafil discs that have nano-silver impregnated into them for complete removal of microorganisms from raw water. Sure then, there is a bright ray of hope that as Terafil filter goes places touching the lives of common masses, it could emerge as the most promising solution to providing sustainable drinking water to our people.

SOLECKSHAW - CSIR’s Solar Solution to Street Steering by Dr P. Cheena Chawla

Unquestionably, the plight of poor rickshaw-pullers who pedal all day long, all for a meager income that barely sustains their families, is pathetic. But not any longer, thanks to CSIR’s path-breaking work in designing solar powered, non-polluting modern rickshaw that is poised to erase forever the poverty and drudgery so deeply linked to this occupation. Christened as ‘Soleckshaw’ — the new avatar of the old rickshaw — this unique vehicle is a product of the research efforts of CSIR scientists working at the Central Mechanical Engineering Research Institute (CMERI), Durgapur. The credit goes to the scientific team of this project at CMERI, comprising the Principal Investigator, Mr. A. J. Banerjee, and other key players, namely Mr. Palash

Maji, Mr. P. S. Banerjee and Mr. Sankar Karmakar.

Prior to cycle rickshaws of the present day, runner-pulled rickshaws were in vogue that personified helplessness and sheer submission to such unhealthy practice. In fact, the word ‘rickshaw’ has originated from the Japanese word jinrikisha which means ‘human-powered vehicle’.  Soleckshaw has come to the rescue of millions of rickshaw-pullers in the country, for it promises to reduce the human effort in steering the vehicle while being a faster means of transport than the traditional rickshaw and is also environment-friendly.

Soleckshaw is one of the classic examples that testifies CSIR‘s commitment to translate its meaningful technologies into relevant products and services for the common man through the CSIR 800 initiative — a pragmatic approach of reaching out to 800 million economically weak, less privileged people of the country. Soleckshaw is a promising product of CSIR that has born out of this vision.

Solekshaw has been so designed that mere manual ‘pedal pushing’ of rickshaw would get transformed to ‘driving’ a rickshaw as the latter is equipped with a solar-powered electric motor that assists the pedal drive.  Having a battery panel and a specially designed 240-350 W, 36-volt solar battery-powered electric motor, weighing about 5 kg, this new rickshaw effectively harnesses solar energy that actually brings movement to the vehicle's chain drive. The rear wheels of soleckshaw are manually driven while the front wheel is driven by the motor, which is mounted on the wheel. The specifically designed brush less direct-current (BLDC) motor has been developed for the first time in India by the Crompton Greaves based on the specifications provided by CMERI. The motor is having a proper braking system. Plying in Durgapur, Delhi-NCR,  Chandigarh, Jaipur, Ranchi, Kolkata and Ahmedabad, Soleckshaw is slowly making its presence felt in different parts of the country.

Reducing the effort made by its driver to minimum, Soleckshaw can carry a load of as much as 200 kg that is about two or three passengers. It also has a sturdier frame and is equipped with FM radio, while having power-sockets for charging mobile phones during the ride. The solar battery, weighing around 15 kg, is placed under the passenger’s seat. Interestingly, the ‘pedicab’ has additional features like head-light, a tail lamp and indicators. It also has a low footboard that is user-friendly especially helpful for children, senior citizens and the disabled.  With a top speed of 15 Km per hour, a fully charged solar battery of Soleckshaw can ferry passengers for up to 50-70 Kms that is quite impressive. 

However, this design of rickshaw does not have a solar charging mechanism integrated into it, which is why replenishing/charging stations, which house the solar panels, are needed for the purpose of recharging the batteries. A battery takes about 5-6 hours for charging. According to Dr Gautam Biswas, former Director, CMERI, setting up of solar charging stations is quite costly. The Central Electronics Limited, (CEL), a Govt. of India undertaking is authorized to set up such stations in India. The Kolkata-based INSILICA is also ready for setting up solar charging stations, where a used battery could be replaced with a charged one. On the other hand, solar panels can be added while manufacturing the Soleckshaws, but understandably, this would raise the cost of each rickshaw. Usually a 1 m x 1.5 m panel is capable of producing 300 W that is needed to power a Soleckshaw.

Apart from the chassis, the sub-assemblies that need to be manufactured include the differential drive, the special hub motor and the light weight solar panel. CSIR has so far transferred the license for manufacture of soleckshaws to many companies that include Modular Machines, Faridabad, Dean Systems, Kolkata; HBL Power Systems Ltd, Hyderabad and Stilam Automobiles Pvt Ltd., Gurgaon.

The main body structure of the scientifically-designed Soleckshaw has been customized in different models that suit different terrains and purposes. Unlike the existing rickshaws, Soleckshaw can be driven easily both on the plains as well as uphill, without any risk of imbalance. Moreover, different materials have been tested for optimising the most suitable design, thanks to the team of CMERI scientists working on this project tirelessly. The Mark I version of soleckshaw, designed and developed by CMERI was the one that was launched in Delhi in October 2008 by the then Hon. Chief Minister of Delhi, Mrs Sheila Dikshit and Mr Kapil Sibal, who was the then Minister of Science and Technology and Earth Sciences.

With focus on designing slimmer and lighter versions of soleckshaw, CMERI scientists have also developed the Mark II soleckshaw with one of its model having a solar panel on top. It is faster than Mark 1 model, as it can reach a speed of up to 30 Km per hour. A still advanced version, Mark III soleckshaw, is poised to be more spacious family vehicle having reclined seats and aerodynamic body. Besides reducing the physical stress of present-day rickshaw pullers and providing them a decent employment with higher economic returns, soleckshaw would help mitigate global warming as well, as this public transport vehicle is free from carbon dioxide emission and its large-scale use is poised to reduce our dependence on polluting vehicles like auto-rickshaws that use fossil fuels. 

CSIR’s Novel Contraceptive Drug – A Woman’s True Saheli by Dr P. Cheena Chawla

Having a baby is no joke, for it brings tremendous responsibility on the part of both parents right from the day of conception, through the next nine months and endlessly thereafter. While treading on the path of parenthood, one faces the music of bringing up a completely helpless newborn to an adult. Surely then, a couple must be mentally prepared to take up the challenge of parenting, and therefore, must avoid unplanned pregnancy.

The trauma of an unplanned pregnancy is sometimes so unbearable that the woman takes the extreme step of getting the baby aborted. Shockingly, according to an estimate of the World Health Organisation, the annual abortion rate worldwide is 46 million, a majority of which occurs in developing countries. This reflects an unmet need of millions of couples for a family planning measure that does not take away the pleasure of the nuptial knot.

Coming to the rescue of hundreds of thousands of couples, CSIR developed the world’s first non-steroidal, once-a-week oral contraceptive drug that gave women the freedom to decide when to get pregnant.  Rightly named, Saheli, this drug is indeed a true friend as it helps to avoid pregnancy without any side effects.  A product of over two decades of research at the Central Drugs Research Institute (CDRI), Lucknow, Saheli comprises a novel non-steroidal biochemical namely, ‘centchroman’. This drug is not only unique due to its composition and mode of action but it is also very convenient to take. The recommended dose is taken twice a week for the first three months, followed by once a week schedule. This drug reached the general public in India in the year 1991 and was included in the National Family Welfare Programme in 1995.  

Hormonal contraception was pioneered by Ludwig Haberlandt, an Austrian scientist who in 1921, showed that rabbits could be rendered infertile by transplanting in them ovaries from a pregnant animal that contained high levels of progesterone. By the 1930s, it was well known that high doses of sex hormones, namely estrogen and progesterone could inhibit the release of eggs. In 1957 the first oral contraceptive pill, containing both these steroid hormones, was marketed in the United States under the brand name Envoid. It was first approved for the treatment of menstrual disorders and later marketed as a contraceptive pill.  As Envoid contained a high level of hormones, there were serious side effects of this drug.

Newer generation of combined contraceptive pills that came in vogue later contained reduced levels of the steroid hormones, estrogen and progesterone, in different proportions. For example, a low dose combination pill like Mala-D was found to be safer than the high dose combination pills. Another type of contraceptive pill, that is popular today, contains only progesterone. It prevents pregnancy by increasing the cervical mucus that slows down the motility of the sperm, and also does not allow the uterine lining to develop properly.

Next in line were injectible contraceptives like Depo-Provera (Depot Medroxyprogesterone Acetate) that contain only progesterone. This high-dose progestin injection was introduced in 1969. Although a very effective contraceptive, the many side effects of Depo-Provera outweight the benefits. Several other types of progestogen-only contraceptives were later developed like Progestasert, the first hormonal intrauterine device and Norplant, the first contraceptive implant.

High dose or prolonged use of hormonal contraceptives is known to have many side effects such as menstrual disturbances, cardiovascular diseases, and body weight changes among others. Nonetheless, millions of women around the world are today using hormone-based contraceptives. The focus of CSIR scientists was, therefore, on designing a novel contraceptive drug, which had the properties of fertility regulation minus the side effects of existing steroidal contraceptive pills.

The role of estrogen-progesterone balance in the development of fertilized ovum is well known. The understanding of the subtle biochemical events that play a role in priming of the uterus for implantation of the fertilized ovum have helped in zeroing down on molecules that interfere with the process of implantation without disturbing the normal levels of estrogen and progesterone. Concerted research efforts of CSIR scientists have shown that centchroman is bestowed with dual properties of being mildly estrogenic while being a potent anti-estrogenic agent. With this unique blend of natural properties, centchroman is equipped to inhibit the fertilized ovum from implantation without disturbing the other effects of estrogen, which means that this drug does not disturb the normal hormonal balance. Thanks to CSIR scientists, centchroman is the only anti-implantation agent approved for clinical use in the world. Judicious use of this safe and effective anti-fertility drug is even poised to check population growth.

Centchroman comprises ormeloxifene, which is a selective estrogen receptor modulator (SERM). These substances are characterized by their different actions in different body tissues. In other words, SERMs selectively inhibit or stimulate estrogen-like action in various tissues. At molecular level, estrogen acts by linking itself to receptor molecules that are present on tissues that respond to this hormone.  As SERMs have a tissue selective activity, they behave like estrogen in some tissues and at the same time, block its action in other tissues.

Estrogen is, in fact, the wonder hormone that is crucial for programming a woman’s body for child birth. It prepares the womb for nourishing the fetus and promotes the glands in breast to produce milk. It also regulates the production of cholesterol by the liver, and thus safeguards the heart, protecting women from cardiovascular diseases. Estrogen even preserves bones by maintaining their required density. However, high levels of estrogen may promote breast cancer and also the cancer in the inner lining of uterus (endometrial cancer).

Exhaustive studies, in thousands of women, evaluating the use of centchroman as a contraceptive have shown that this drug is quite safe. Unlike steroidal contraceptives, centchroman does not cause nausea, vomiting or dizziness and has no adverse effects on the woman’s lipid profile and platelet function. Moreover, the contraceptive effect of centchroman is reversible and a woman can experience normal pregnancy on stopping the drug. Besides its use as a contraceptive, this drug works as an effective treatment for dysfunctional uterine bleeding. To top it all, centchroman is bestowed with a unique property of being effective against breast cancer. Multi-centric trials have shown the efficacy of centchroman in treating breast cancer patients.

Centchroman has been licensed to two companies in India. It was first manufactured by Torrent Pharmaceuticals Ltd, Ahmedabad, and marketed as birth control under the trade name Centron that was later discontinued. Torrent Pharmaceuticals now manufactures ormeloxifene under the trade name Sevista, as a treatment for dysfunctional uterine bleeding.  HLL Lifecare Limited (HLL), formerly Hindustan Latex Limited, Trivandrum, is marketing this drug under the trade name, Saheli. In October 2008, HLL launched this once-a-week oral contraceptive pill, containing the drug centchroman, in Peru under the brand name ‘Ivyfemme’, which in Spanish means ‘friendship flower’.

In yet another achievement, CDRI has developed a contraceptive cream named CONSAP from the saponins obtained from soap nuts (Reetha) of the plant, Sapindus mukorosii. Approved by the Drugs Controller General of India for its marketing and use, this local spermicidal cream is found to be quite safe on prolonged use, and can thus come handy to women to avoid pregnancy. Moreover, in one study CDRI scientists have also shown the activity of soap nuts against a protozoan parasite, Trichomonas vaginalis that causes a common sexually transmitted disease, Trichomoniasis. This endows CONSAP with both contraceptive and microbicidal properties. CONSAP has been already licensed to the Hindustan Latex Limited for its large-scale production and marketing.