The need to bring some control in the misuse of brands in pharmaceutical industry

Multiplicity of brands in pharmaceutical industry has been a matter of concern for the regulatory authorities in the country for some time as they often lead to confusion and prescription errors amongst the medical practitioners. Although the practice of using same brand name for a particular pharmaceutical product by different companies is rather rare, pharma companies do use variants of an established brand name to confuse the practitioners and patients. Usually medium and small drug units are found to indulge in this unethical practice in small towns to take advantage of the goodwill created by an established brand over a period of time. Misbranding is another unethical practice amongst the pharma companies. 

It is a dubious way of exploiting an established brand name for a totally different product. Two cases of misbranding that occurred some years ago were that of Disprin Plus of Reckitt Benckiser and Aspro Plus of Nicholas Piramal. Disprin and Aspro were two old and well established aspirin brands in Indian pharmaceutical market belonging to these companies. 

They discontinued these products but launched Disprin Plus and Aspro Plus with paracetamol as the main ingredient to take advantage of the brand equity of Dispirin and Aspro. Such cases of misbranding can endanger lives of patients as most of them may not check the change of the ingredient in a product.

The need to bring some control in the misuse of brands in pharmaceutical industry has been long felt by the authorities but no effective action was ever taken by the health ministry or the chemicals ministry so far. The Supreme Court had issued an order around 10 years ago directing the government to develop a proper registration system for drug brands in coordination with drug regulatory authorities and the trademark office to prevent the confusion. But, nothing has been done by the concerned ministries after the order. 

Now last week, a leading financial daily reported that the government had held preliminary discussions over the issue with a few industry stakeholders. What is to be first realized is that the Indian pharmaceutical market has nearly one lakh brands although drugs approved for marketing are around 600. This is too large a number. The number of brands must be multiplying every day as the product licenses are being issued drug control authorities in 28 states with no coordination. 

The Central government has no idea about what is the actual number of brands floating in the market and their compositions. Ideally a proper audit of pharmaceutical products circulating in the market should be undertaken first and then take steps to weed out undesirable brands from the market. This may not be an easy task but needs to be done. Establishing a centralized database of brands and streamlining the issue of brands can then be done with proper coordination and support of state drug authorities.

In Mumbai has made cutting of tablet strips mandatory.

A recent circular issued by the Food and Drug Administration, Maharashtra to retail chemists in Mumbai has made cutting of tablet strips mandatory. The circular directed the chemists that strips should be cut if the customer so desires. In fact, most of the chemists in the country are indulging in this practice for several years now. 

Therefore, the rationale to issue such a circular is not very clear. What is actually required is to curb this practice in the interest of the consumers. It is possible that some poor patients may ask for strip cutting if the prescribed drug is an expensive one. But that is to be discouraged by the pharmacists at the counter in the interest of the patient safety as it could lead to under dosing and consequent in effectiveness of the drug. Incorrect and inadequate dosage of medicine by the patients is one of the main reasons for the recurrence of diseases among the poor. As such the strip cutting is not a desirable practice as that can lead to sale of expired drugs to unsuspecting and illiterate customers. At a time when some of the drug companies are colluding with retail chemists to sell expired drugs, strip cutting can actually help such unethical practices to flourish. It is obvious that when the strips are cut, the ingredient details, expiry date and batch numbers may not be there on the cut portion of the strip. This could be dangerous to patients.

Although Maharashtra FDA directed the chemists in the state in this regard, there is a lot of confusion on the issue amongst the pharmacist community including amongst regulatory officials. Indian Pharmaceutical Association, the national body of pharmacists in the country has alreadytaken objection to idea of legalising strip cutting. It has informed the DCGI that there is no

clear-cut provisions in the law whether strip cutting is allowed or not and regulatory officials have different views on the matter. 

IPA has rightfully urged the DCGI that the issue should be included in the agenda of the next meeting of the Drug Technical Advisory Body for discussion and appropriate action. Earlier pharmaceutical companies used to sell almost all drugs belonging to different therapeutic categories in strips of 10. Marketing of tablets in multiple strip sizes and different strength developed over the years as the drug companies wanted to escape price control. Today, many pharmaceutical companies including reputed ones have strip sizes of 6 to 10 and 15 to 30. 

In some cases, there are even strips of 30, 40 and 50. Such huge sizes of strips can certainly create a chaotic situation and some discipline needs to be brought in. A rationalization of strip sizes is necessary based on the therapeutic value of the drug, dosing and cost of medicine.

Code of ethics for doctors

The Department of Pharmaceuticals seems to have abandoned its initiative to evolve a mechanism for discouraging the drug companies from bribing doctors for prescriptions. After convening some meetings last year in the wake of growing public outcry against this unethical marketing practice of pharma companies, the officials in the Department has now become virtually inactive. The DoP had last year asked the industry to evolve a common code of ethics for all pharmaceutical units as existing codes do not cover members of all the pharma industry associations. 

The OPPI was asked to take lead in this matter and compile a marketing code in consultation with all major industry associations. There were sharp differences amongst the industry associations over the proposed common marketing code. While the industry associations representing big and medium pharma companies wanted a uniform code of marketing practices but not binding on the industry, the associations representing 5000 small companies were in favour of a uniform code which should be legally binding on the companies. The stand of smaller pharma companies was based on the belief that only a legal document can ensure compliance of the code and any violation can invite punishments both in terms of money and jail term.

Subsequently, Medical Council of India, the regulatory body for the conduct of the medical profession, has been making some efforts to curb the practice amongst the doctors. It had come out with a code of ethics for doctors prohibiting them from receiving gifts, travel facilities, hospitality, monetary grants, endorsements, etc. As per this code, medical practitioners are prohibited from receiving favours from pharma or healthcare companies under any pretext. 

MCI has the powers to regulate the practice of medical professionals and take action against them. But, MCI has not been able to bring any discipline amongst the medical practitioners as yet. Now, the question is how effectively the MCI will be able to monitor the conduct of lakhs of doctors spread across the country. The practice of bribing doctors by pharmaceutical companies for generating prescriptions has been part of their marketing strategy for many years but has not been causing any serious concern. It has now grown to a major public health issue with the increased competition amongst the pharma companies to capture the market share.

 It is believed that a major part of the cost of prescription drugs is due to loading of promotional expenditure on their prices. Today, more than 80 per cent of the drugs marketed in the country are outside the purview of the DPCO as several new drugs have been allowed to be marketed in the country after the DPCO,1995. Considering this, DoP should not have given up its initiative to check this unethical practice just because there is non cooperation from some industry bodies. Such a stand from a section of the industry should be expected. Even now, DoP should take up the matter and make a serious attempt to implement the marketing code with the support of MCI.

Ban three unsafe drugs namely nimesulide, cisapride and phenylpropanolamine

DCGI finally took a decision to ban three unsafe drugs namely nimesulide, cisapride and phenylpropanolamine after several years of debate on their safety. The drugs were found to have serious side effects since early 2000 and many developed countries had already banned all of them. The Drugs Technical Advisory Board has been examining the safety profiles of the three drugs for several years and has now recommended their withdrawal from the market as their adverse effects outweigh the benefits. Among the three drugs, nimesulide was the most controversial one.

The drug was banned in US, Britain, Canada, Sweden, Denmark, Australia, New Zealand, Japan and other 168 countries but it was being freely sold in India by prominent drug companies like Dr Reddy's, Panacea Biotech and some others. Cisapride is another unsafe drug found to increase motility in the upper gastrointestinal tract of patients. The drug is also withdrawn from the markets of many countries due to its side effects. In India, the possible dangerous side effects of the drug has been brought to the notice of the Drug Controller General of India first time sometime by the Ahmedabad based Consumer Education and Research Centre in April 2000. DCGI has promptly ordered an investigation to assess the safety profile of the drug in the Indian context. The drug remained in the market almost ten years since then. PPA used in cold and cough remedies was banned in North America and western Europe some years ago. But, in India, PPA -containing cough and cold remedies such as D’Cold, Vicks Action-500, Wincold, etc are freely available in the market. Gatifloxacine, tegaserod and deanxit. are the other three drugs which are being reviewed by DTAB for their side effects. These drugs have also been banned in some of the developed countries.

Two drugs which have been banned in India last year are rosiglitazone, a high profile and widely prescribed diabetic drug and rimonabant, an anti obesity drug. Both the drugs have been withdrawn from the European markets early last year for their serious side effects. In India, the DCGI had placed rosiglitazone, under the scanner of national pharmacovigilance programme in August, 2007 in the wake of US FDA warning against the use of the drug. And it took three years for DCGI to decide whether its marketing should be allowed to be continued in the Indian market. Apart from these, quite a few drugs have been withdrawn from the markets of developed countries and India in the recent past.

These actions by drug authorities establish the fact that there has been a steady rise in post marketing complications of newly approved drugs especially during the last ten years. That is what is forcing regulatory authorities to pull out more and more approved drugs from the markets. This trend shows that there is something seriously wrong with the whole system of new drug approval by world's top regulatory bodies including in India. A stricter evaluation of safety and efficacy of any new drug is therefore called for before it is allowed for marketing in the country by DCGI to protect the public health. Marketing approval by US FDA or European drug regulatory authority should not be the criterion for approving a new drug in India any more.

Violations of Drug Price Control Order

A proposal to set up price monitoring cells in state drug control administrations for tracking violations of Drug Price Control Order was made by the ministry of chemicals some months ago. The proposal was made in the context of increasing number of price violations and circumvention of DPCO by a large number of pharmaceutical companies over the years.

As per the latest data compiled by ORG-IMS, the number of prima facie violations were rising steadily in the recent years. From 2007 to November 2010, 2782 samples of non-scheduled drugs were collected and prima facie violations were detected in as many as 1495 cases. Out of these, 956 samples were referred for overcharging. Similarly, out of the 309 samples collected from the market during June 2009 to March 31, 2010, in 153 cases the companies were found to have violated the norms and 139 were referred for overcharging. However, only 14 samples finally came under price fixation. During the current year up to November 2010, 348 samples were collected from the market and 125 were found to be with prima facie violations. It is extremely difficult for NPPA to detect such growing number of violations all over the country considering its current staff. NPPA put up the proposal to set up price monitoring cells in the state was in this context. It is unfortunate that the Planning Commission is yet to act on the proposal.

The chemicals ministry has been regulating prices of 74 drugs since 1995 through NPPA and later it also started monitoring prices of several non scheduled drugs as many of them remained outside the price control in the absence of finalization of a new drug policy. Formulations of over 500 drugs are being marketed in the country by 5000 companies. Now, as the Planning Commission is taking its own time to consider the NPPA’s proposal, the regulatory body feels that building its own team of officers to pick up random samples from the market would be a better option. It has, therefore, urged the Pharma Department to process the files for creating its own cells in the States.

In fact, this is one of the key suggestions made by the chemicals ministry to be incorporated in the long pending national pharmaceutical policy. Currently NPPA has very limited staff available to it but still it monitors the prices of non scheduled formulations through various methods like scrutiny of price lists submitted by manufacturers, analysis of monthly Stockists Secondary Audit Reports published by IMS-Health and complaints and references received from official and non- official sources. Considering the massive number of formulations in the domestic market and with only a small number of them coming under price fixing by way of scheduled drugs, the quantum of samples needs to be increased for better price monitoring and strengthening of NPPA with own monitoring cells would be a better option.

DCGI had then ordered an investigation to assess the safety profile of the drug in the Indian

It is after several years of debate, the Drug Controller General of India decided to ban the manufacture and sale of 4 controversial drugs namely nimesulide suspension, cisapride, PPA and human placenta extracts in the country in February last. The notification to this effect was issued on February 10 after Drug Technical Advisory Board recommended their withdrawal from the market. The DTAB has been examining the safety profiles of the drugs for some years and advised their recall from the market as their adverse effects outweigh the benefits. 

These drugs have been already banned by many developed countries over ten years ago. In India, the dangerous side effects of nimesulide was brought to the notice of the DCGI first time by the Ahmedabad based Consumer Education and Research Centre in April 2000. DCGI had then ordered an investigation to assess the safety profile of the drug in the Indian context and nothing further happened and the drug remained in the market since then. Obviously there has been pressure on the office of DCGI to not to issue the ban order as some of the drug companies stand to lose several crores of rupees of business. However due to persistent pressure from independent medical experts and consumer groups, DCGI came out with the notification.

The decision for withdrawal of four drugs by the DCGI was well received by the pharma industry associations and there has been no serious objections to the order as it is in larger public interest. Subsequently, the state drug controllers have started taking the follow up actions to enforce the order. 

In fact, Andhra Pradesh and Gujarat drug control departments have already issued stop sale orders of these four drugs in their states within a few days of the DCGI’s directive. The only demand from some of the associations representing small scale units was to postpone the ban of sale these products till the expiry of stocks in the trade channels. That is a reasonable request and state drug controllers have already agreed to consider this demand. What is disturbing the DCGI and medical experts now is the stay granted by the Madras High Court against the government ban order last week on a petition filed by a leading pharmaceutical company. 

The Court should have duly considered the entire background behind such a government order before stalling it. Any continuation of marketing drugs with major ADRs could be highly dangerous to the millions of patients who are taking them. And when the country’s most authoritative body recommends a ban on the basis of technical findings, no pharmaceutical company has the moral authority to move court against such a step. Now having issued the order and state governments started acting on it, the DCGI has to uphold the order in the public interest. DCGI’s decision to move the Supreme Court for vacating the stay is thus just humanitarian and fully justified.

Some 700 million Indians in the villages and non-urban areas don’t have access to healthcare

With multiple issues blocking access to healthcare in India, more than a million people die every year due to lack of healthcare access, most of them being women and children, according to a white paper by Pricewaterhouse Coopers and India Health Progress.

“Some 700 million Indians in the villages and non-urban areas don’t have access to healthcare facilities because around 80 per cent of the specialists and medical facilities are located in urban areas. Around 350 million Indians live Below the Poverty Line (BPL) and survive on less than Rs.100/- per day, putting nearly all medicines out of their reach. Even when the medicines are available free, the poor lack the meagre resources to travel to the nearest government-supported Primary Health Centre (PHC) located kilometers away from their village. Finally, these PHCs are often under-equipped and under-staffed,” said the white paper, mainly prepared on 'health insurance.'

Health insurance has historically played a pivotal role in improving access to healthcare around the world. Unfortunately, less than 15 per cent of the Indian population is covered under some form of health insurance, including government-supported schemes. Only around 2.2 per cent of the population is covered under private health insurance, of which rural health insurance penetration is less than 10 per cent, said the paper which has recommended insurance as a key pillar to increase access to healthcare.

“India’s diverse population has limited purchasing power. Penetrating this market therefore requires innovative insurance products at multiple price points. But innovation in the current Indian health insurance market needs to evolve considerably, with health insurers stacking their portfolios with multi-level, differentiated long-term products. Public and private sector players have already shown the way by introducing innovative insurance products with premiums as low as Re. 1 per day and Rs.10 per month, catering to community as well as individual insurance needs. Such low-priced products can play a big role in ensuring higher healthcare access and better health for all sections of Indian society,” it said.

Dr Reddy’s Laboratories has purchased the oral penicillin laboratory of GlaxoSmithKline based in USA

In a major buyout at the global pharmaceutical scenario, Dr Reddy’s Laboratories has purchased the oral penicillin laboratory of GlaxoSmithKline based in USA.

The transaction amount is not yet disclosed by Dr Reddy’s, a pharma major.

“This acquisition allows us to enter the US penicillin-containing antibacterial market segment and serve the needs of our customers. This is in line with our strategy to significantly scale up our generics business in North America, while providing an opportunity to explore additional synergy with our other businesses,” said, Abhijit Mukherjee, President (Global Generics Business), Dr Reddy’s Laboratory.

Drug Controller General of India (DCGI) has advised small units to adopt bar coding for their product

In an effort to improve efficiency of small pharma units, the Drug Controller General of India (DCGI) has advised these units to adopt bar coding for their product.

The advisory from the drug controller comes in the wake of Union Health Ministry’s proposal to make bar coding of drug formulations mandatory. The small pharma are asked to make full use of the subsidy granted by the government for the same.

“Bar codes can be very effectively used to track distribution of drugs in the marketplace and recall them if necessary. It also assists in effectively monitoring stock and consumption in hospitals. We will be happy to request all the federation members to impress upon their manufacturing units who have not so far adopted bar coding, to do so at the earliest, because this will be in their interest and in the interest of the industry as a whole,” said, T. S. Jaishankar, Chairman, Confederation of Indian Pharmaceutical Industry (CIPI).

Gujarat State FDCA in collaboration with CII is organising a one-day seminar on November 27

With a view to sensitise the pharma industry on 'Vibrant Gujarat 2011' starting on January 12, the Gujarat State Food and Drug Control Administration (FDCA) in collaboration with CII is organising a one-day seminar on November 27. The seminar is a part of Vibrant Gujarat global investors summit 2011 aimed to attract investors of pharma and boitech industry to the state.

The main aim of the seminar is to sensitise and create awareness about the investment opportunities that Gujarat holds for future investors. According to Hemant Koshia, commissioner, FDCA, "Gujarat has a lot of untapped potential and we plan to bring these into focus so as to provide lots of investment opportunities for companies. With this seminar, we want to inform our potential investors about the opportunity that Gujarat can provide them."

It would be an ideal ground to meet the potential investors who would be interested in entering into memorandum of understanding (MoU) with the Gujarat government. He adds that through this seminar the government plans to sustain and enhance the image of Gujarat as a hub of pharma industry by pro actively informing the industry about the benefits of investment in Gujarat.

In 2009, the Gujarat government had signed 26 MoU's with pharma companies which resulted in about Rs. 27,000 crore to be invested in the state. Koshia informed that out of the 26 MoUs the government has already completed its work on eight plants which are functioning at present, where as for the others work is under progress. "The government is having high expectation from the upcoming event and is hopeful to cross the target of 26 MoUs that was achieved in Vibrant Gujarat 09," he said.

The main hubs of pharma based activities in Gujarat is clustered in and around Ankleshwar, Ahmedabad, Vadodara and the Bharuch-Vapi-Valsad belt and are home to many domestic and international pharma and biotech companies. At present there are 2322 pharma manufacturing units and 115 units manufacturing medical devises that are operational in Gujarat. National share of Gujarat's pharma industry is approximately 42 per cent, I.V. set/BT set manufacturing is approximately 80 per cent, orthopaedic implants is approximately 50 per cent, intraocular lenses is approximately 35 per cent and cardiac stent is approximately 30 per cent. The state also has five AC-GET projects coming up exclusively for pharma industry which is attracting a lot of inquiries from other parts of India for setting up units in Gujarat.

Maharashtra FDA will have 95 new inspectors in the next three months

MUMBAI: The Food and Drug Administration in Maharashtra will have 95 new inspectors in the next three months.

Last 10 years has seen no newdrug inspectors in the state. The latest recruitment drive is to make the department more efficient. Out of 161 posts of drug inspectors, 95 are still vacant. The new recruitment drive is initiated by Seema Vyas, the first women FDA commissioner of the state.

Maharashtra accounts for 40 percent of exported drugs from India. Furthermore nearly 50 percent of India’s drugs are manufactured in the state.

Temporarily banned the use of paracetamol injections - Latest Pharmaceutical News,

The state government has "temporarily banned the use of paracetamol injections in all government hospitals across the State till further orders" following the death of two people in Suntikoppa, Kodagu district after they were administered paracetamol injections in the primary health centre, said commissioner, health & family welfare, D.N. Nayak.

Two people - Susheela, 57, from Kedakkal near Suntikoppa, and Moidu 66, from Pumphouse in Suntikoppa town died soon after they were administered paracetamol injections in the PHC, Suntikoppa on Saturday morning.

The third victim, Sarita, 25, from Kushalnagar, died after she was administered dextrose IV fluid and Ranitidine - an antihistamine, said the commissioner.

He added that in the case of paracetamol the victims were given muscular injections. Mr Nayak said that though the post-mortem reports of the deceased are expected to arrive on Tuesday; the decision to temporarily ban the paracetamol injections in government hospitals has been taken as a precautionary measure. According to him deaths could possibly be due to "drug reaction and shock".

Meanwhile the drug controller Dr B.R. Jagashetty has seized the samples of the 'killer' drugs - the paracetamol vials, the dextrose IV fluid and Ranitidine and sent them to the Drug Testing Laboratory, Bengaluru. "The tests will take at least a fortnight," said Dr. Jagashetty.

"The drugs will be put through chemical and later abnormal toxicity and sterility tests on animals to rule out contamination," said Mr Nayak.

The paracetamol injections were acquired by the government from two pharmaceutical firms - SPM Drugs, Bhawani, Tamil Nadu and Nagarjuna Sagar, Hyderabad, the Commissioner said.

A new approach to drug discovery that may eventually yield drugs with fewer side effects.

Researchers at the Stanford University School of Medicine have taken an early step toward identifying a new approach to drug discovery that may eventually yield drugs with fewer side effects.

In a study to be published online Jan. 7 in Nature, investigators led by senior author Brian Kobilka, MD, professor and chair of molecular and cellular physiology, found that largely neglected regions on key cell-surface proteins undergo minute changes in shape in response to drugs and thus could prove useful in drug design. The study's first author is Michael Bokoch, an MD/PhD student in Kobilka's laboratory.

The class of proteins known as G-protein-coupled receptors, or GPCRs, is already immensely important in drug research, accounting for some 40 percent of all currently marketed drugs, said Kobilka. His laboratory focuses on a particular type of GPCR called adrenergic receptors, which are activated by adrenaline and its close cousin noradrenaline. Secreted by the adrenal glands and certain nerve cells, these two "molecules on a mission" regulate key physiological actions in the central nervous system, heart and musculature. They are acclaimed for tripping off the "fight or flight" response, which steels middle-aged mortals' melting muscles for high-stakes activities like fending off saber-tooth tigers or running to catch a bus.

Like all GPCRs, an adrenergic receptor consists of three portions. One is anchored within a cell's outer membrane. The second juts from the cell's outer membrane surface and is exposed to the external environment. And the third extends into the cell's fluid interior, or cytoplasm.

Cell-surface receptors are akin to customized doorbells that ring only if pressed by molecular fingers with precisely the right shape. For an adrenergic receptor, the fingers with the magic touch are adrenaline and noradrenaline. When a molecule of one of these structurally similar substances happens upon an adrenergic receptor, it is drawn to a site on the receptor called a binding pocket with just the right shape and charge for a snug fit. (An adrenergic receptor's binding pocket sits within the portion of the receptor that is anchored in the cell's outer membrane.) The binding event alters the shape (or "conformation") of the receptor's cytoplasm-facing domain, setting off a massive redirection of activity inside the cell.

Other molecules besides adrenaline and noradrenaline can slip into adrenergic receptors' binding pockets. That's the basis for many effective drugs. Cell-surface receptors are great targets for the small molecules that drug developers discover and deliver into our bodies to stimulate or shut down a physiological process. Various drugs can affect the same receptor quite differently. "Agonists" lock their targeted receptor into an active or even hyperactive mode. "Antagonists" force the receptor into a sluggish or inactive posture so that it stalls out, or they simply get in the way of the naturally occurring molecules the receptor was meant to match.

Adrenergic receptors come in nine different varieties, or subtypes, all responsive to adrenaline and noradrenaline but playing different roles in regulating bodily functions. For instance, Kobilka said, the beta-2 adrenergic receptor is the chief regulator of smooth muscle, especially in relaxing air passages such as the lungs (a fight-or-flight necessity). This makes beta-2 agonists, which open airways, good for combating an asthma attack.

It is primarily the beta-1 receptor that accelerates the heartbeat and stimulates the heart to pump more blood per beat. That's also great for a fight-or-flight response. But too much beta-1 stimulation over an extended period can lead to medical problems like heart failure. Thus, beta-1 antagonists (also known as beta-blockers) are often prescribed for patients with coronary artery disease, heart failure or arrhythmias.

The trouble is, drugs that fit in one subtype's binding pocket can often climb into the other's. "The beta-1 and beta-2 receptors largely respond to drugs in the same way. That's one reason we get side effects," said Kobilka. "Say you have a patient with both heart disease and asthma. You want to treat that patient's lung problem with beta-2 agonists. But those may stimulate beta-1 receptors in the heart, potentially causing arrhythmias. So you can't use beta-2 agonists in that patient. Similarly, you may not be able to use a beta-1 antagonist for this patient's heart problem, because it may exacerbate the asthma."

While the binding pockets of various adrenergic-receptor subtypes have to be nearly identical so they can all attract and bind adrenaline and noradrenaline, certain portions of these receptors' exposed outer domains have been freer to diverge over eons of evolution. The extracellular portions of the beta-1 and beta-2 adrenergic receptors, for instance, are quite different. A drug that bound selectively to an extracellular section of one receptor subtype - but not of the second subtype - in a way that altered the receptor's cytoplasmic conformation just as do drugs that target the receptor's binding pocket might be more selective, minimizing side effects.

Kobilka and his colleagues used a sensitive technique called nuclear magnetic resonance spectroscopy to zero in on one specific part of the beta-2 adrenergic receptor's extracellular domain to see if they could detect subtle changes in that area when they applied three different drugs: a beta-2 adrenergic-receptor agonist, an antagonist and a third one with a neutral effect on the receptor's activation status. Even though the drug molecules themselves landed smack-dab in their binding pockets as expected, each drug coaxed this part of the receptor's extracellular domain into a different conformation. This suggests, said Kobilka, that the conformational shifts of this region were coupled to those triggered by the drugs' interactions with the receptor's binding pocket.

If this coupling works in reverse, molecules that bind to the extracellular domain could conceivably modulate receptor function. Thus, the diversity of different receptors' extracellular domains could be exploited to modulate receptor activity, with high subtype selectivity.

Even if the tail-wags-the-dog effect were only slight, Kobilka said, drugs targeting GPCRs' extracellular surfaces would still let natural molecules fit into their binding pockets. "So, instead of simply switching receptor activity on or off they could instead fine-tune that activity, like rheostats. For therapy, it would be nice to control the receptor's activity in this way."