快猫短视频

鈥淧hysiology of chemotherapy-induced emesis and antiemetic therapy鈥� by C. Veyrat-Follet and others, Drugs, vol 53, p 206 (1997)

HIS experiments are enough to make you vomit鈥攁lthough he requests that you refrain. 鈥淚 study nausea鈥攏ot vomiting, thank you very much,鈥� says Robert Stern of Pennsylvania State University in University Park. 鈥淚 tell my subjects, if you鈥檙e going to throw up, let me know and I鈥檒l turn the machine off right away.鈥�

The machine in question looks innocent enough: a comfy chair in which the subject settles down, and a large metal drum that lowers over said subject鈥檚 head, painted on the inside with a natty motif of black and white stripes. But one flick of the switch, and that nattiness soon turns nauseating as the drum turns, the stomach churns, and a disquieting signal鈥攂est articulated as 鈥淓uuuuurrgh鈥濃�攊ntrudes slowly but surely into the rider鈥檚 consciousness.

It is a reflection of the perverseness of undergraduates that they love to take a spin in Stern鈥檚 drum. Those revolving stripes give the sensation of movement, and soon the rider is every bit as queasy as if he or she were languishing below deck on a brisk day at sea. The 鈥渙ptokinetic drum鈥� or 鈥渟ick machine鈥濃�攚hatever you wish to call it鈥攊t鈥檚 the perfect piece of hardware for studying the whys and wherefores of motion sickness.

Stern is one of those researchers who get more than their fair share of ribbing if they mention their profession at a party. But the subject has its sober side, too. Nausea and vomiting are not just the lot of revellers rolling home after a night on the town, or of queasy kids decorating the back seat of their parents鈥� BMW, or even of pallid day-trippers retching over the deck rails.

It is a fact, for instance, that maybe 70 per cent of astronauts experience transient 鈥渟pace sickness鈥�, which doesn鈥檛 make for tip-top performance during pricey space missions. And throwing up after a general anaesthetic is an all too common side effect. Then there is what is know as 鈥渋diopathic鈥� nausea and vomiting鈥攗nexplained queasiness and retching that afflict some people for years. But most serious of all is the abject suffering caused by chemotherapy or radiation therapy for cancer. The ordeal can be so nasty that some patients refuse potentially life-saving treatment, and others, years later, will react by vomiting should they bump into their doctor in the supermarket.

Despite their profound effects on patient welfare, nausea and vomiting have been largely neglected by medical research. 鈥淭hey鈥檝e always been a problem for the patient and the family and the nurses,鈥� and less so for the medics, says Robert Naylor, a neuropharmacologist at Bradford University. Yet those medics have had few decent drugs to work with.

Quality of life

Things were even worse a decade ago. 鈥淚t鈥檚 not pretty to see small children who鈥檝e had chemo, desperately, desperately ill from intractable, incessant nausea and vomiting,鈥� says Naylor. But the lot of such patients improved dramatically in the 1980s with the advent of a class of chemicals called the serotonin3 receptor antagonists. 鈥淭he newer drugs have revolutionised the quality of life of cancer patients,鈥� says Paul Andrews, a physiologist at London鈥檚 St George鈥檚 Hospital Medical School. But these drugs do less for subjective feelings of nausea than for the act of vomiting and they help mostly only during the first day after chemotherapy. After that doctors are forced to try a variety of other antinausea drugs that may or may not work. The serotonin blockers do nothing at all for other types of nausea and vomiting such as motion sickness. 鈥淭hey are not,鈥� says Andrews, 鈥渢he final answer.鈥�

If they aren鈥檛, a brand-new set of drugs just might be. Known as NK1 receptor antagonists, these chemicals seem to wipe out vomiting caused by motion sickness, radiation or drugs used in chemotherapy in various animals. 快猫短视频s are excited as they wait for the drugs companies to lift the veils on several medical trials that are now coming close to fruition. Excited, but anxious, too, because an unsettling issue remains. Do the NK1 antagonists eliminate both vomiting and nausea? Or do they just stamp out the vomiting? It鈥檚 a question that can鈥檛 easily be answered in animals. 鈥淣ausea is a subjective experience鈥攁nimals will never be able to tell us if and when they feel it,鈥� says Naylor.

Developing drugs is where there is most money for nausea and vomiting research (though nowhere does it flow freely), and most vomit researchers do some studies that are funded by drugs companies. But there are also some basic mysteries under investigation. True, researchers have neglected so far to answer comedian Billy Connolly鈥檚 number one emesis question: why vomit always contains diced carrot, regardless of whether diced carrot has been eaten. But they have made good headway in answering others. How, for example, does the body decide when to spew? What then makes it happen? Where does that unique sensation called 鈥渘ausea鈥� reside in the brain? To what extent are the brain systems that cause nausea and vomiting intertwined? And what, anyway, is the use鈥攅volutionarily speaking鈥攐f feeling sick and throwing up?

It doesn鈥檛 take a PhD in emesis science to come up with the notion that vomiting has evolved to protect our bodies from poisons鈥攖hough that certainly isn鈥檛 the only strategy available. Rats, mice and rabbits never throw up. Instead, they usually manage to sidestep poisoning via 鈥渂ait shyness鈥�: they鈥檒l just take the tiniest nip of any new food, and if it makes them feel off-colour they鈥檒l never go near it again. Since they never get much poison in their bellies, they don鈥檛 need a forcible ejection mechanism.

We, the vomiters, are different. We toss caution to the wind when something new and appealing finds its way onto our plate or into our doggy bowl. We wolf it down. If something nasty lies therein, the brain may decide to trigger a vomit. The stomach relaxes and muscles of the oesophagus pull it into a straight tube. The small intestine squeezes its contents back into the stomach and, finally, the muscles of the abdomen and chest鈥攖he same ones we use for breathing and sit-ups鈥攕tart a pattern of contractions that force food out of the stomach, up the oesophagus and out of the mouth. All the while the subject assumes the classic 鈥渧omit posture鈥濃�攈ead forward, back straight鈥攖o aid in the food鈥檚 easy exit.

For a person to reach this sorry state, a signal鈥攕uch as 鈥渂ad shrimp鈥� or 鈥渢oxin鈥濃�攎ust first wend its way to the brain. Let鈥檚 suppose your charming host unwittingly serves you some tainted salmon mousse. The bacterium it harbours releases a toxin that enters the blood. The toxin damages cells as it travels through the body, and those cells respond by releasing chemicals, such as dopamine. Sooner or later either the poison or the dopamine arrives at the brain.

I鈥檝e been poisoned

As a rule, the brain is buffered from chemicals in the blood by the 鈥渂lood-brain barrier鈥�. But there are some leaky spots, including one that lies right next to the area postrema, a tiny region in the primitive brain stem. The nerves of the area postrema are loaded with receptors to which poisons or other signalling chemicals like dopamine can bind. 鈥淓www,鈥� say these signals. 鈥淚鈥檝e been poisoned.鈥� The area postrema then sends messages to a nearby brain region, called the nucleus tractus solitarius, or NTS, tripping the whole vomiting-nausea cascade. Inject drugs that block dopamine direct into the area postrema and the vomiting stops.

But today scientists are re-evaluating the significance of the area postrema, because there is another, quicker way for the gut to tell the brain it鈥檚 not feeling well: nervous signals. Perhaps you鈥檝e swallowed a poison, or perhaps you are in hospital and you鈥檝e just received a dose of radiation therapy or chemotherapy to kill the rapidly dividing cells of your tumour. All three will cause the cells of your gut to release serotonin, another nerve-signalling chemical.

The serotonin from the gut binds to a set of neurons in the vagus nerve, the bundle of nerve cells controlling our organs. It sends a high-speed 鈥減oison-alert鈥� signal up to the NTS. 鈥淩ight now we don鈥檛 really know the relative importance of the area postrema and vagus nerve,鈥� says Naylor. 鈥淧robably they鈥檙e both important.鈥�

The vagus and area postrema are unlikely to be the only ways that poison signals get to the NTS. But what is known so far does explain how the serotonin drugs鈥攇ranisetron, ondansetron and tropisetron鈥攄o their job. All three bind to the serotonin3 receptor, which is present in the vagus nerve, blocking the serotonin signal from the gut cells鈥攁nd hence the vomiting cascade.

Not all vomiting, though. And certainly not all nausea. When the drugs were first developed, scientists noticed that ferrets treated with the anticancer drug cisplatin stopped vomiting when given serotonin blockers. They even looked pretty cheerful: they refrained from backing up in their cages, and from burying their heads in the sawdust, implying that the nausea, too, might have been eradicated by the drugs.

But in those early trials, the scientists couldn鈥檛 follow the animals鈥� progress past day one. Soon, from the cancer clinics, another story emerged. In chemotherapy and radiation treatment, there are two phases of vomiting and nausea. The acute phase is well controlled by the serotonin drugs. The delayed phase, which lingers for days after treatment, is not. Obviously, the delayed nausea and vomiting has a different root cause, one that doesn鈥檛 involve serotonin3 receptors.

Of course, not all nausea and vomiting emanates from the gut. The brain alone can make people want to vomit too鈥攚hich explains the phenomenon of 鈥渁nticipatory鈥� nausea and vomiting that afflicts one in four cancer patients even before the drug enters their system.

鈥淧atients typically get sick the night before when they鈥檙e thinking of coming in, they get sick that morning when they鈥檙e eating breakfast, more sick when they鈥檙e in the car driving to the clinic, sicker still seeing the parking lot to the hospital, and then going into the lobby, going into the clinic, seeing the clinic nurse, the treatment room, the needle,鈥� says Gary Morrow, a psychologist at the University of Rochester Cancer Center in New York.

Most likely this is a simple case of 鈥渃lassical conditioning鈥�. A neutral stimulus (seeing the hospital lobby) when paired with a noxious stimulus (a nausea-inducing drug) is eventually enough to cause the effect all on its own. You don鈥檛 have to be going through anything as serious as treatment for cancer to get a first-hand experience of conditioning like this. 鈥淭he last time I got the flu I鈥檇 just eaten in a Mexican restaurant and I still can鈥檛 look at a taco,鈥� recalls James Lucot, a pharmacologist at Wright State University in Dayton, Ohio. If vomiting is nature鈥檚 way of getting toxic substances out of the system, nausea is how it teaches you to avoid them next time round.

And once the association is learnt, the serotonin drugs will do nothing for you. The best treatment, says Morrow, is good old-fashioned behaviour modification. Show the patient the doctor鈥檚 face again and again when the patient is relaxed, and sooner or later the link 鈥渙ncologist鈥檚 face means I鈥檓 going to feel deathly ill soon鈥� will be broken.

Seasick

Nor are the serotonin blockers effective against the type of nausea that Stern elicits in his dastardly rotating drum: motion sickness. We鈥檝e all experienced it. But how does it happen? The prevailing thought is that motion sickness arises when our eyes and ears, and perhaps other position sensors in the muscles, tell us different things about the movement of our body.

We sit in the back seat of the car, say, eagerly thumbing through the National Enquirer for the latest update on Dolly the clone. As far as our eyes are concerned, we are not moving. Our bodies, though, are jigging around, and our balance organs鈥攖he semicircular canals and gravity sensors of our inner ear鈥攖ell us so. Somewhere in the brain, information from all the different sources comes together鈥攁nd if different parts don鈥檛 match up as usual, then that doesn鈥檛 agree with us.

It makes sense, then, that people with damage in a part of the brain that processes information from the balance organs never get motion sick, and removing the balance organs from a dog鈥檚 ear makes for a dog with sea legs. But none of this explains why our brains should be designed to react to motion by making us chuck up.

Kenneth Money, a Toronto-based business consultant, who until recently studied vomit physiology, is a champion of the idea that motion sickness is a side effect of a strategy that evolved to detect poisoning. Poisons enter our brain, he argues, and damage the nerve cells that process position information. As a result, such information no longer makes sense, and poisoning, the brain decides, could be why. A hearty vomit is called for. 鈥淚t鈥檚 similar when we get into airplanes or ships. Our receptors report information that can鈥檛 be reconciled,鈥� says Money. 鈥淪o our brain says: 鈥楩alse information, eh? I鈥檝e been poisoned!'鈥�

Not all scientists buy this poisoning theory, however. What good, asks Charles Oman, a self-described barf scientist at the Massachusetts Institute of Technology, is a system that waits until brain cells are seriously damaged, maybe dying, before eliciting a vomit? His speculation is that sensory mismatch causes nausea and vomiting only accidentally, because the brain regions dealing with mismatch and chucking up both lie within the NTS.

Something鈥檚 up

Studies on ferrets and other animals make it look likely that the NTS is the brain鈥檚 main centre for vomiting, and perhaps nausea, too. Messages of things gone amiss converge on the NTS鈥攆rom the area postrema, the 鈥渢hinking鈥� centres in the brain鈥檚 cortex, and so on, and trigger exactly the same vomiting process.

A drug that could block such a central program should stop vomiting and nausea whatever their cause. It鈥檚 a drug that medics would love to have in their tool-kit. Acute, delayed and anticipatory nausea and vomiting in cancer patients would be blocked by one simple pill. Space sickness and motion sickness would be things of the past. Idiopathic nausea and vomiting would vanish.

This utopia may be close at hand, if the NK1 antagonists hold true to their early promise. Under study at drugs companies such as Pfizer, Glaxo Wellcome and Merck, their beauty is that they appear to work directly on the NTS by blocking another nerve-signalling chemical, known as substance P. The results of the first clinical trials are expected by the end of this year, although for business reasons they may not be made public.

In ferrets, cats, dogs, and a tiny Japanese shrew called Suncus murinus that vomits an impressive four times a second, the NK1 antagonists stop vomiting triggered by radiation, motion sickness, cisplatin and sundry other noxious chemicals. 鈥淭he drugs really look very good,鈥� says Andrews, who has worked on both the NK1 drugs and the earlier serotonin drugs with various companies.

Whether they will eradicate nausea in humans we don鈥檛 yet know, however. After all, one can throw up without first feeling queasy, and vice versa. And no one is certain whether the same, overlapping, or entirely separate brain systems trigger the phenomena. The problem is that nausea is still not properly understood.

Alan Miller, a neuroscientist at New York鈥檚 Rockefeller University, knows from brain imaging studies that a region of the brain鈥檚 cortex is activated when people feel queasy. This could be where we consciously experience nausea, but the trigger for the nasty sensation must lie elsewhere, probably in the NTS.

Stomach contractions

From placing electrodes on people鈥檚 bellies to measure the activity of their stomach muscles, Stern knows that nausea is associated with a total cessation of the stomach鈥檚 regular, rhythmic contractions. He has used this measure to test the nausea-quashing potential of everything from drugs and small non-greasy meals to a motion-sickness remedy called Sailor鈥檚 Delight. But this is about as much as anyone knows.

The reason, of course, is that nausea is extremely difficult to study in animals. The creatures give hints: prior to vomiting, ferrets do their backing-up, head-burying routine. And cats drool before they retch. But are these strange behaviours due to nausea? And do they go away when animals get NK1 antagonists? Most of the scientists aren鈥檛 yet talking, although Lucot has found that cats still salivate after rides on a cat-sized Ferris wheel when given NK1 drugs, suggesting that even if they no longer vomit they aren鈥檛 feeling good.

In the end, though, 鈥渋t doesn鈥檛 matter what happens in the ferret鈥攖he bottom line is what happens in man鈥�, says Naylor. And so as the end of the NK1 antagonist clinical trials draw near, the feeling in the nausea and vomiting community remains one of nervous anticipation. 鈥淚f we had a drug that completely took out vomiting, it would be a nice advance,鈥� says Andrews. 鈥淏ut if it took out nausea too鈥攚ell, it would be the answer. We could all pack up and go home.鈥�