The numbers are staggering. Each year as many as 15% of all U.S. hospital admissions, some 100,000 deaths and $136 billion in medical costs result from harmful reactions to drugs. But relief is on the way. All too aware of the toll on the nation's health and pocketbook, medical researchers are devising a host of safer and more effective drug-delivery systems, many of them also designed to overcome the pain and inconvenience of traditional remedies. They range from such low-tech items as anal suppositories to innerspace-age microcraft reminiscent of the tiny ship that carried Raquel Welch through a patient's blood vessels in the movie Fantastic Voyage.
In their pursuit of better systems, researchers are finding ingenious ways to bypass such natural body defenses as the blood-brain barrier and the macrophages of the immune system, which can block or gobble up newly administered drugs. Another problem, says M.I.T. professor of biomedical engineering Robert Langer, is adverse effects that result even when "people take prescription drugs exactly as prescribed."
The trouble, says Langer, a leading innovator of drug-delivery systems, is that drugs do not stay at constant levels in the body. They typically start low, rise to a peak and then decline. When that happens, Langer says, "those peaks can sometimes be toxic and the valleys totally ineffective." He cites as examples insulin and sleeping pills: "Too much insulin can put you into a coma. Not getting enough insulin can be fatal. Too much sleeping pill can kill you. Too little, and you lie awake all night."
At the Battelle laboratories in Columbus, Ohio, researchers are working on those problems. They are devising painless alternatives to the hypodermic needle, fear of which causes many diabetics, for example, to delay necessary injections of insulin. One such device is the Mosquito, a small disk equipped with a tiny needle that penetrates only seven micrometers into the skin - not deep enough to impinge on nerve endings and cause pain. Attached to a patient's side, the disk allows mobility while it delivers the prescribed dose of drug evenly over a 24-hour period.
Another delivery system, the inhaler, is getting a second look. While inhalers have been used for years to treat asthma and, more recently, cystic fibrosis, only 10% of the medication actually reaches the deepest regions of the lungs. Battelle and other companies are designing inhalers that use compressed air and drug powders to push much more of the medication deep enough into the lungs to be effectively absorbed. Among the drugs that researchers hope will be administered with the new inhalers are antibiotics, insulin and interferon. Other new systems enable doctors to apply drugs through the eyes or through the mucous linings of the nose, mouth and vagina.
A substantial portion of drugs taken orally, in pill or liquid form, is lost to digestive processes and removed by the liver, and what remains can irritate the intestinal tract. Enter transdermal patches. First designed to treat motion sickness, they slowly deliver drugs through the skin from a reservoir within the patch, and are being used increasingly to treat hypertension, angina and other disorders. So far, the patches are limited to carrying small-molecule drugs that can diffuse through the skin. But several teams are experimenting with electrical or ultrasonic devices that can also push larger-molecule drugs through the skin or create temporary macropores through which these bulky molecules can pass.
Some of the new drug-delivery solutions are elegant but decidedly low tech. "For people who have a tough time swallowing pills," says Langer, "a company called Alkermes has developed a special straw that is loaded with a premeasured dose of dry medication. The patient then uses the straw to sip water, a soft drink or apple juice." And for a toddler who spits out, throws up or gags on fever-reducing medication, there are fast-acting suppositories to which parents can resort.
At the opposite end of the technology scale, Eldrid Sequeira, a Utah State University graduate student, is designing microscopic "submarines" - drug-bearing capsules that someday could be propelled through the bloodstream by bacteria to attack disease. Looking even further ahead for alternative means of driving these tiny craft, he is considering building biomotors 100 billionths of a meter wide that would use only the bacteria's hairlike, propelling flagella to move ahead.
Equally remarkable, Langer and his colleagues reported in the journal Nature that they had engineered a prototype microchip that could someday be swallowed or implanted and work as a programmable "pharmacy." It contains up to 1,000 tiny reservoirs of chemicals that are released in the proper quantity and sequence when the chip is exposed to low voltages.
Brain tumors have long presented a major challenge to drug delivery because of the especially leakproof blood-vessel walls in the brain, which make it difficult to administer conventional chemotherapy there. Drug-bearing wafers may be one answer. After the brain surgeon removes as much of the tumor as possible, small drug wafers are inserted at the tumor sites. Over time the wafers slowly release a chemical that prevents the recurrence of new tumors. The technique seems to work. A 1997 clinical trial showed that after two years, 31% of glioblastoma patients with implanted wafers were still alive, compared with only 6% in the control group.
For all the promise of the new drug systems, M.I.T.'s Langer is still looking ahead to what many researchers hold out as an ultimate goal: a magic bullet placed in the bloodstream that "goes right to where you want it and only there, and does exactly what you want it to do and only that. We are not there yet."
But apparently we're getting closer.