The Telegraph
Since 1st March, 1999
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Slight modification
Pain control: Non-steroidal drugs may bring relief fast, but cause problems later

It's a painkiller widely used in treating bone and joint aches, post-surgical pain, and abdominal cramps associated with menstrual periods. And just as would any other standard nonsteroidal anti-inflammatory drug (NSAID), diclofenac, too, carries the risk of ulcers in the gastrointestinal tract.

Now, a study by two scientists at the Jamia Hamdard in New Delhi has indicated that subtle chemical tweaking of the diclofenac molecule may help make the drug safer. Prof. Mohammad Sardar Yar Khan and his student Mymoona Akhter have shown that diclofenac may be temporarily transformed into a slightly different molecule that can reduce the risk of ulceration and yet remain effective as an anti-inflammatory drug and painkiller.

'We've used a chemical trick to change the site at which the drug gets absorbed into the bloodstream,' said Akhter, a doctoral student and member of the teaching faculty at the department of pharmaceutical chemistry at Jamia Hamdard, a deemed university. A significant amount of the conventional pure diclofenac gets absorbed through the stomach, but the chemical modification that Akhter has demonstrated moves the process of absorption from the stomach into the small intestine. 'This reduces the risk of ulcers,' she said.

Doctors estimate that some 35 million people around the world take NSAIDs daily and about 30 per cent among routine users of these drugs may be suffering from gastrointestinal toxicity that requires medical attention. In India NSAIDs are among the most common drugs responsible for adverse reactions, according to a review of NSAID-induced gastrointestinal toxicity published last year in the Journal of the Indian Association of Clinical Medicine.

When consumed in the prescribed doses and for short durations, NSAIDs are safe for the vast majority of patients. However, the drugs can cause ulceration, perforation and severe bleeding in the stomach in some patients. The risk of ulceration is higher in patients with a family history of ulcers, patients on prolonged use of high doses of NSAIDs, and those who are simultaneously consuming other substances that may irritate the gastrointestinal tract, such as some drugs or excessively large amounts of coffee.

In their review paper, the doctors from the All India Institute of Medical Sciences and the Ram Manohar Lohia Hospital in New Delhi said that more than 100,000 patients are hospitalised each year because of NSAID-induced gastrointestinal problems and up to 16,500 deaths occur each year among patients with arthritis.

'The figures for all NSAID-users would be overwhelming,' the researchers said, highlighting the importance of the need to make NSAIDs 'safer and more tolerable'.

The ulcer-causing effect of diclofenac stems from what chemists call a carboxylic acid group attached to one end of the diclofenac molecule. 'But carboxylic acid is also a key component of the molecule responsible for its medical action. So we can't get rid of it either,' said Akhter.

In their study based on laboratory and animal experiments, Khan and Akhter have shown that it is possible to temporarily mask the carboxylic acid group by creating a chemically different version of the molecule.

They have created a glyceride version of diclofenac ' a structure in which two molecules of fatty acids are attached to the diclofenac molecule, masking the carboxylic acid group. 'It is a complex molecule, containing diclofenac and fatty acids. In the body, the complex structure breaks down, giving rise to fatty acids and the original diclofenac,' said Khan. Because glycerides are large molecules, the glyceride derivative does not get absorbed through the stomach.

When swallowed, the glyceride version of diclofenac would move through the stomach into the small intestine where it begins to break down, and diclofenac's carboxylic acid group is now ready to begin its action against the pain and the inflammation. The fatty acids released in the process are processed by digestive enzymes. The Jamia Hamdard researchers evaluated the ulcer-causing potential and the anti-inflammatory activity of the glyceride-diclofenac drug in rats.

Reporting their findings in the latest issue of the Indian Journal of Experimental Biology, they said the glyceride versions of the drug were 'significantly less ulcerogenic than the parent drugs.' While 80 per cent of the rats given diclofenac revealed ulcers, just 38 per cent of the animals administered the glyceride version of diclofenac had ulcers.

The studies have also shown that the glyceride version of diclofenac is more effective as an anti-inflammatory and analgesic agent than conventional diclofenac. 'The enhanced activity is also due to the change in the site of absorption,' said Akhter.

'Any substance is absorbed into the bloodstream better when the process of absorption occurs in the small intestine rather than in the stomach,' she said. The increased absorption leads to higher levels and more effective painkilling activity.

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