ACETYLSALICYLIC acid is widely seen as a modern miracle-a wonder drug of the 20th century. Curious, then, that its natural precursor was first prescribed as early as 400 BC by Hippocrates, the father of modern medicine. He gave it as an infusion of willow bark to treat headaches and labour pains. It wasn’t until 23 centuries later, in 1899, that chemists isolated and modified the active ingredient. Doctors now know that it is not just a painkiller: it also lowers fever, eases inflammation and even reduces the risk of heart disease. The drug’s popular name is aspirin.
Yet despite its undoubted benefits, aspirin and its newer synthetic cousins have a serious, sometimes deadly side effect. Long-term use causes stomach ulcers so severe that they kill about 7000 people a year in the US alone and send many more to hospital. For at least two decades, researchers worldwide have searched for a way around this fatal flaw, but only in the past few years have their efforts begun to bear fruit. Several groups using different approaches claim to have developed drugs that not only dampen down inflammation as well as or better than the originals, but they do so without causing ulcers. Amazingly, some may even heal existing ulcers.
If these drugs live up to their promise, the benefits would be huge. In 1991, doctors in the US wrote 70 million prescriptions for aspirin and related drugs, such as ibuprofen, naproxen, diclofenac and flurbiprofen, collectively known as non-steroidal anti-inflammatory drugs (NSAIDs). In addition, millions of people bought them over the counter. The worldwide market for NSAIDs is worth more than $9 billion a year.
One of the principal uses of NSAIDs is for treating rheumatoid arthritis. They not only ease the pain of swollen joints, they also dampen down the inflammation that makes them painful in the first place. But the relief comes at a price. Patients often need long-term treatment with NSAIDs, and sometimes at high doses, making them susceptible to ulcers which eat through the stomach or intestine wall, rupturing blood vessels or inflaming the abdominal cavity. Ironically, the analgesic action of NSAIDs can mask the pain of a potentially fatal ulcer and delay treatment.
Researchers still do not agree on exactly how NSAIDs wreak such havoc. Some pharmaceuticals companies have focused on the fact that NSAIDs are acidic and so irritate the lining of the stomach. To combat the problem, they have developed aspirin formulations with chemical “buffers” to neutralise the acid, and formulations that dissolve slowly, so that the drug is not released until it reaches the neutralising environment of the small intestine.
This approach can help the occasional user of aspirin to avoid minor stomach upsets, but a number of studies have shown that it does little to deter the formation of ulcers in long-term users. One other finding suggests that NSAIDs’ ability to directly irritate the stomach may not be crucial to ulcer formation: if the aspirin is injected rather than swallowed, ulcers can still form.
Today, most research is based on the assumption that the damage done by NSAIDs is a result of the same mechanism that makes them so useful. The drugs work by blocking the action of two enzymes, called cyclooxygenase 1 and 2 (COX-1 and COX-2). These catalyse the production of a host of fatty acids known as prostaglandins, which play a variety of hormone-like roles in the body, from dilating veins to inducing diuresis and muscle contraction. COX-1 looks after “housekeeping” in the body, helping to make prostaglandins that regulate normal cell activity.
By contrast, COX-2 is part of the body’s “crisis intervention system”. It is produced by many different cell types in response to trauma and catalyses production of prostaglandins such as PGE2, which helps to increase the sensitivity of pain receptors on nerve endings and dilates blood vessels. This last action brings extra blood-with its charge of immune cells-to damaged areas, and increases inflammation. While this response is helpful in the case of a bruise or cut, it can be counterproductive in a disease such as rheumatoid arthritis, which is thought to be caused by the immune system turning against the body. Most researchers in the area now think that what makes NSAIDs so useful is their ability to block production of PGE2.
Unfortunately, most existing NSAIDs block the action not only of COX-2 but also COX-1, which leaves the body short on housekeeping prostaglandins, some of which help to regulate the functioning of the stomach and intestine. For example, by maintaining a layer of mucus over the cells that line the stomach, these prostaglandins protect them from digestive acid. They also regulate blood flow and immune response. So the simplest explanation for the harm caused by NSAIDs is that they reduce prostaglandin production, which in turn depletes the stomach’s mucous lining, leaving it open to attack by stomach acid.
One solution to this problem has already moved from the laboratory to the pharmacy shelves. In the late 1980s, the pharmaceuticals company Searle introduced misoprostol, an analogue of the housekeeping prostaglandin PGE 1, which simply replaces any prostaglandin lost through taking an NSAID. It can be prescribed separately or in a combined pill with an NSAID. F. D Baragar, professor of medicine at the rheumatic diseases unit at Winnipeg Health Sciences Centre believes that the combination pill is a “fairly significant advance”. But while misoprostol helps some people, its value is limited by its own side effects, including stomach cramps and diarrhoea. Potentially more serious are the drug’s association with menstrual problems and miscarriage.
More recently, there has been a great deal of interest in designing new NSAIDs using state-of-the-art molecular modelling. COX-2 was only found in 1991. Before that, researchers thought a single COX enzyme catalysed all the prostaglandins. The discovery of COX-2 opened the door to designer drugs that would block the action of just this enzyme, so reducing the pain and inflammation caused by PGE2 but leaving the housekeeping functions of COX-1 untouched. Most importantly, these ideal drugs would be stomach-friendly. A number of large drugs companies, such as Merck, Roche, Searle and Boehringer Ingelheim, have created NSAIDs that are COX-2 blockers, some of which are now undergoing human trials.
But even if these drugs live up to the companies’ high expectations, they will not solve all the problems of NSAIDs. Many patients have gastrointestinal disorders such as ulcers and colitis before they begin NSAID therapy. In such cases, PGE2 may be needed to help in healing these existing problems. Knocking out COX-2 entirely could make them worse, even if no new ulcers are created.
Lenard Lichtenberger of the University of Texas Medical School at Houston believes he may have a solution to this dilemma. His approach focuses on just one component of the mucosal lining of the stomach-waxy phospholipid molecules that allow the mucus to repel water, and hence acid. Two years ago, tests in rats by Lichtenberger found that a chemical combination of aspirin and the phospholipid lecithin greatly decreased damage to the stomach. Lichtenberger’s group began human trials earlier this year. Healthy volunteers are taking six aspirin tablets a day either with or without lecithin. At the end of the trial, tests such as endoscopic examination of the stomach surface will determine which group has suffered the most ulceration.
More surprising is that early results from animal studies, also by Lichtenberger, suggest that aspirin plus lecithin may well speed up the healing of pre-existing ulcers. All the data are not yet in, but he is cautiously optimistic. While phospholipids seem far removed from the generally accepted prostaglandin theory for ulcer formation, Lichtenberger believes there may be a connection. “Prostaglandins are likely to be involved with phospholipid synthesis and regulation in the stomach,” he says.
Another area of research into safer NSAIDs recently threw up some unexpected and exciting results. John Wallace, professor of pharmacology medicine at the University of Calgary in Alberta, Canada, working with an international team including Giuseppe Cirino of the University of Naples and Piero Del Soldato of Milan, have focused on the way prostaglandins affect blood flow through the capillaries that supply the stomach and intestines. In 1993, they found that when prostaglandin levels fall, the capillaries narrow and blood flow decreases. Also, the local immune system responds in an odd way: white blood cells begin to collect on the capillary walls in large numbers, clumping together to further choke off the blood supply.
Wallace’s team started from the assumption that these changes in the microcirculation are the cause of NSAID-induced ulcers. The precise mechanism is uncertain, but one theory is that the aggregating white cells release destructive chemicals that induce ulcers. To combat the effect, the researchers looked for a compound that would open up the capillaries and restore the blood supply. They decided to focus on nitric oxide. NO plays a number of roles in physiology and is produced in large amounts by the body itself. Its ability to dilate blood vessels is already exploited by doctors to ease the pain of angina, which is caused by a narrowing of the coronary arteries. They give angina patients nitroglycerin, which releases NO.
In the early 1990s, research by Wallace and others found that NO, like housekeeping prostaglandins, protects the gastrointestinal tract from the harmful effects of NSAIDs. Animal studies in Poland showed that drugs such as nitroglycerin helped to heal ulcers. To exploit this effect, Wallace’s group tacked a nitroxybutyl chemical group onto aspirin and other NSAIDs via an ester bond. This ester slowly breaks down in the body to release NO-the slow delivery is critical because rapid release can produce a rush of NO and a fatal drop in blood pressure.
Results from the new approach are encouraging. Animal tests in 1994 showed that while the NO-NSAIDs reduce joint inflammation just as well as or better than the NSAIDs by themselves, they produce no stomach damage. It seems the release of NO compensates for the loss of prostaglandins, probably by boosting blood flow to the stomach and intestine. Further tests showed that blood vessels in rats given a NSAID alone started to clog with white blood cells within 30 minutes, whereas those of animals receiving the corresponding NO-NSAID actually expanded slightly.
Taking the research still further, last year the team tried out their new compounds on rats with existing ulcers. They gave a placebo or a NO-NSAID and found that the new compounds actually helped to heal the rats’ ulcers. Wallace believes NO enhances the stomach’s defence system and may promote tissue growth in the gastrointestinal lining, helping ulcers to heal.
Today, it is not only people with arthritis who are at risk from ulcers induced by NSAIDs. Doctors are increasingly prescribing aspirin to prevent heart attacks. A clutch of papers published in 1988 showed that taking a small amount of aspirin every day can reduce the risk of heart attacks. This beneficial effect stems from the fact that when aspirin knocks out COX-1, it also blocks production of a blood borne substance called thromboxane A2, which induces platelets to stick to each other and to blood vessel walls. By depressing thromboxane production, aspirin reduces the likelihood of clots forming. This in turn wards off angina and, ultimately, heart attacks.
Obviously, blocking COX-1 brings all the side effects that researchers are trying to avoid. But NO-NSAIDs may provide a route round this problem, because nitric oxide itself reduces platelet aggregation. Last year, Stephen Hanson of Emory University in Atlanta, Georgia, found that far fewer platelets stuck to artificial blood vessels after he saturated them with NO. Aspirin is the best NSAID for blocking thromboxane production, but a NO-aspirin compound should do the same job with fewer side effects.
Indeed, when Wallace’s team tested a NO-aspirin combination in animals last year they found that it reduced platelet aggregation far more than aspirin on its own, and did not damage the stomach. Curiously, however, the NO-aspirin accomplished this task without suppressing thromboxane levels. At first glance, it appears that aspirin isn’t acting like aspirin any more, but Wallace cautions against this interpretation. “This might not be the case,” he says. “It is possible that the aspirin portion does contribute to the anti-thrombotic effects, even though we can’t detect any effect.” His group is now trying to find out exactly how the new drug works.
Human trials of the NO-NSAIDs are now under way in Britain, and Wallace predicts that if all goes well they should be on the market within five years. The group has teamed up with a company in Paris, called Nicox, to oversee further testing of their drugs and to negotiate patents and licences.
The result of all this research into safer NSAIDs is that the future looks much brighter than it did just a few years ago.
Perhaps the last word should go to Dennis Morris, the president of the Canadian Arthritis Society, who knows only too well the problems that existing drugs cause. “More than half the people on arthritis medication refuse to take it, largely because of the side effects,” he says. “I think that we are starting to move to a whole new generation of anti-inflammatories. When you consider that arthritis is the single largest cause of long-term disability you can see that this breakthrough is absolutely phenomenal.”