News & Views Newletter
edited by Jack Nicholas, cornishpro@aol.co

PSORIATIC ARTHRITIS NEWS AND VIEWS
VOL. 3 ISSUE 1 January 15, 2003
PSORIATIC ARTHRITIS MEDICAL NEWS

You are sitting at the breakfast table in the morning staring at a big bunch of prescription pills and capsules, plus an additional handful of vitamins. Do you ever wonder how all those chemicals that are supposed to be helping us, ever get to the right place at the right time in our bodies and do what they are supposed to do? Well, I hope you find the following article helpful in answering that question.

HOW DRUGS WORK By Harold J. DeMonaco, M.S. Massachusetts General Hospital

What started out as a little twinge in the back of your neck has blossomed into a full, head-pounding ache. You grab the aspirin bottle, pour out two tablets, pop them into your mouth and wash 'em down with a glass of water. Half an hour later you realize the headache is gone.

How did the aspirin get into your system? How did it know to go after the headache? Moreover, just how did it turn off the pain?

It isn't magic. Instead, it's the end result of an amazing system designed not for drugs but for allowing things into the body that the body needs and keeping out things that are harmful. Drugs (and drug designers) co-opt this intricate transport and delivery system to ease pain and treat a host of other problems.

Here's what happens with aspirin: It sits in your stomach and intestines for a bit, dissolving under the onslaught of stomach acids and digestive enzymes. Molecules of aspirin slip into tiny pores that tunnel through the gut wall and into nearby blood vessels. Fast-flowing blood whisks the aspirin to all parts of the body. The aspirin molecules quell pain signals by turning off production of a hormone like substance (prostaglandin) that generates pain signals and causes inflammation. It's also at work elsewhere around the body - making blood platelets less sticky and so less likely to form clots, and turning off production of a substance that helps to protect the lining of the stomach from acids and digestive enzymes. While all of this is going on, the body is busy getting rid of the aspirin via the kidney.

It's much the same story for other drugs. Each one follows a somewhat precarious route into the body, and each one has effects throughout the body, even if its intended target is a particular tissue or organ.

Keep in mind that this is as true for herbal remedies as it is for the highest high-tech drug. After all, the body doesn't know "natural" from "manufactured."

HOW DO DRUGS GET WHERE THAY NEED TO GO?
When you choke down a slug of foul-tasting syrup or get jabbed with what looks like a foot-long needle, do you ever wonder why all drugs aren't as easy to take (or as tasty) as a Flintstones vitamin?

For a drug to work, it has to reach its target. This takes some doing, because the body is essentially a series of barriers between the hostile outside world and the carefully regulated internal environment. The skin, the corrosive mix of stomach acids and digestive enzymes, the selectively permeable walls of the digestive system and blood vessels, the membranes of tissues, and the rapidly deployed immune system are all designed to allow only certain substances to reach vital tissues. So drug molecules must either be able to mimic substances the body is used to handling, or be able to penetrate and withstand its defenses and use the bloodstream as a kind of public transportation system to get where they need to go. Different routes of administration help to bypass some of these barriers.

Because swallowing a pill or syrup is the most common way to take medications, we'll use it as an example to describe how drugs work. Let's look at penicillin.

When a drug lands in your stomach, corrosive stomach acids and aggressive digestive enzymes attack it. In the case of penicillin, some of the drug is destroyed by the acid in the stomach. As the tablet dissolves, molecules of the drug must travel from your stomach or intestines into the bloodstream. This means crossing two critical barriers - the stomach (or intestinal) wall, and the wall of a blood vessel. Both of these contain heavily guarded pores, or channels, that allow only substances with the right shapes and electrical charges to slip through.

Food plays an important role in this step. You've probably seen warnings on drug labels telling you to take a medication with, or without, food. Sometimes that's for your stomach's sake, and sometimes it's for the drug's. Food can either help or hinder drug absorption. It depends on the drug and its physical and chemical characteristics.

Once inside the bloodstream, drug molecules aren't free to wander. Instead, like tourists in totalitarian countries, they are often met at their point of entry and linked to proteins floating in the blood. Such protein-bound molecules usually have little drug effect. For example, about 99 percent of the blood-thinning medication coumadin is bound to protein, leaving only 1 percent free and able to prevent blood clotting. Protein binding can be affected by many things, including diet, infection, other medications, and illness. This variability is one reason for drug overdoses and underdoses, as well as for adverse reactions.

Getting into the bloodstream is only half the journey. The other half is getting into the target tissue. Blood passing the digestive system immediately flows through the liver. Think of this organ as the body's garbage disposal. One of its jobs is to detoxify potentially harmful substances (such as drugs) that might accumulate in the blood. It does this either by breaking the drug down or by putting an electrical charge on the drug molecule using enzymes. Each of us breaks down drugs at our own pace. Genes affect the process. So does age. The presence of other drugs or herbal medications also can speed up or slow down drug metabolism.

The kidney also plays an important role in eliminating drugs. It basically filters out drugs that have an electrical charge, usually courtesy of the liver. So the liver and kidney work hand in hand metabolizing and eliminating drugs.

Because of the mechanics of blood flow in the liver and the way some of the enzymes work, not all of the drug is changed as it passes through the liver. So penicillin molecules that pass through the liver unscathed and evade the kidney are the ones that ultimately fight infection.

WHAT DO DRUGS DO WHEN THEY GET WHERE THEY NEED TO GO?
A few drugs work very simply. An antacid, for example, turns stomach acids into water and salt by neutralizing them with a straightforward chemical reaction. Most drugs, though, get results in a more complicated lock-and-key arrangement.

Proteins called receptors poke out from the surface of every cell. Each type of receptor has a particular shape (lock) that will fit one particular drug (key). When the right drug meets the right receptor, a physical change occurs that triggers a reaction.

Some drugs are designed to activate a receptor. These are called agonists. Albuterol, a drug used to relieve asthma attacks, is one example of an agonist. Albuterol activates receptors called beta-adrenergic receptors that relax and open the airways. Other drugs are designed to inactivate a receptor. These are called antagonists or blockers. Propranolol, a drug used to control blood pressure and erratic heart rhythms, is a good example of an antagonist. It blocks beta-adrenergic receptors, which also control blood pressure and heart rate. Because these receptors are also found in the airways, propranolol can also trigger attacks in people with asthma.

Receptors aren't just fixed grabbers of passing drug molecules. Instead, the body constantly regulates their number and sensitivity. Morphine is a good example. At first, small doses of morphine are usually enough to stop pain. Over time, though, the body makes more morphine receptors, and so it takes increasingly larger doses to quell the same amount of pain.

GETTING DRUGS INTO THE BODY
There are many different ways to take, or to be given, a drug. The method used depends on the chemical composition of the drug, the dose and speed with which it needs to work, and the person getting the medication.

Oral - Swallowing a pill is probably the easiest way to take a medication. But it's only good for drugs that can survive a bath in stomach acid and that can get through the lining of the stomach or intestines. Sublingual - Letting a drug dissolve under the tongue, where there is a rich supply of blood vessels, gets it into the bloodstream quickly. Rectal - Inserting a suppository into the rectum is a good way to give a medication to a child or someone who is vomiting and can't keep an oral medication down.

Intravenous - Delivering a medication directly into a vein is usually the fastest way to get a drug to work. But it is usually reserved for medications that dissolve in water.

Intramuscular - Some drugs are injected into a muscle. From there, they pass into blood vessels running through the muscle.

Subcutaneous - Some drugs are injected just beneath the skin, where they can enter the network of blood vessels supplying the skin.

Inhaled - Breathing in a mist or fine powder is a good way to get a medication to the lungs. Since the lungs are so richly supplied with blood vessels, medications delivered this way also get into the bloodstream.

Topical - Some medications are placed right where they are needed, such as eye drops to relieve pressure in the eyes or creams to soothe a skin rash. Transdermal - A medication-soaked patch on the skin can also deliver drugs. The medication seeps through the skin and into the bloodstream.

DON'T GO THERE
Certain parts of the body are protected more than others from potentially harmful substances. Three of the most important are the brain, the placenta of a developing baby, and milk-making glands. While this discrimination offers important protection, it also makes it difficult to get drugs into these tissues if the need arises.

The brain - The delicate nerve cells in the brain have special nutritional needs. They are also easily disrupted by hormones and other substances that the rest of the body requires. The blood/brain barrier is the body's way of feeding and protecting the brain - it lets sugar and other nutrients into the brain and waste products out. It sees drugs as foreign substances that should be filtered out, so few drugs commonly used today actually enter the brain. For a drug to get into the brain it must have special properties. Anesthetic drugs like propofol or thiopental (also known as Pentothal) are examples of drugs that can get into brain tissue very easily.

The placenta - Given the incredible number of complicated steps needed to go from a simple fertilized egg to a complex, trillion-celled baby complete with sparkling eyes, 20 fingers and toes, and a pumping heart, it's no wonder that mother and baby work together to keep potentially harmful substances out of the developing system. The placenta acts much like the blood/brain barrier, allowing nutrients and wastes to cross while keeping out most unfamiliar substances, but it isn't quite as good a barrier. Because a developing baby is very vulnerable to chemical actions (because of the huge number of cellu lar changes going on) and the inability of the placenta to absolutely screen out all but essential nutrients, the use of medications during pregnancy requires special precautions. Not all medications get across the placenta in amounts large enough to potentially cause harm but some do. So, it is important to take special precautions.

Milk-producing glands - Precautions are also necessary for breast-feeding - many drugs pass directly from the bloodstream into breast milk, so an infant could receive a full dose of the drug by breast-feeding. Because of the thalidomide disaster of the early 1960s, all drugs must now be tested for their ability to produce injury to the developing infant and their ability to get into breast milk. The U.S. Food and Drug Administration has a formal system for rating the safety of different drugs during pregnancy.

HOW DRUGS GET TO THE MARKET
Pharmaceutical companies develop new drugs in a very systematic way, at least at the outset. Because we know a good deal about many diseases right down to the molecular level, we can use computer modeling to design drugs to work in very specific ways. So, if the drug company is interested in developing drugs to treat heart disease (angina, for example), they can design drugs that will, at least theoretically, act directly where they want them to.

For example, we know that people with angina have a problem with blood flow to the heart muscle. This reduced blood flow is caused by cholesterol buildup in and/or an abnormal, abrupt narrowing of the blood vessels that supply the heart (called coronary artery vasospasm). We know that by blocking some enzymes or enhancing the effects of others we can change the way blood vessels work. Drug companies use this kind of information to design new drugs.

Some new drugs aren't designed but are found in nature. For example, in 1958 the National Cancer Institute began a screening program of 35,000 plants, looking for anticancer agents. In the bark of the Pacific yew tree researchers found a substance that is now a drug called paclitaxel (also known as Taxol), used in the treatment of breast, ovarian and lung cancers.

And just plain old luck sometimes leads to drug discoveries. The anticonvulsant valproic acid (also known as Depakote and Depakene) was discovered quite by accident - it was being used as a solvent for another drug being tested.

Once a drug is identified and purified, it is tested in animals. These early tests are used to see if the drug does what we think it should do and if it is safe. Many people have questioned the need for this kind of testing, but it is essential, at least at the moment, because as good as our understanding of disease is, there are always surprises. Computer models aren't foolproof, and only testing in living systems such as animals or humans can give definitive answers. Testing new drugs for their ability to produce birth defects is also done in early animal studies.

If the drug seems to work and seems safe in the animal tests, the drug company applies to the U.S. Food and Drug Administration for approval for testing in humans. The approval is called an Investigational New Drug Exemption and allows the drug company to test the drug under a specified set of conditions. The testing is done in very structured phases, each designed to answer different questions.

Phase 1 - These studies help define the dose of the new drug and its toxicity (negative effects). Phase 1 studies test the drug for the first time in a small group of volunteers to ensure safety of the drug.

Phase 2 - These studies further define the safety and evaluate the effectiveness of the new drug in a larger group of patients with a particular disease or disorder.

Phase 3 - These studies are carefully designed to show that the drug works as intended, has a low incidence of toxicity and can be taken safely by patients. The testing is done in a larger group of volunteers and compares drug's effectiveness with that of other treatments being used.

Phase 4 - This phase of testing occurs after the drug already has been approved for use and is being prescribed to the general population. These studies continue to monitor the effects of the drug, along with any side effects, that occur with long-term use.

If a new drug makes it through all of the required Phase 3 testing, drug companies can apply to the FDA to obtain market approval. This process is called a New Drug Application. The time period from discovery to the NDA can be as short as three to five years or as long as decades, with recently estimated drug-company costs of up to $500 million. Only a small minority of drugs actually make it to the NDA step. Most drugs tested fail to live up to expectations somewhere in the process.

The FDA relies on volunteer medical specialists to review the NDAs, in addition to career scientists in the agency itself. The volunteers serve on scientific advisory committees that make recommendations to the FDA on drug approvals. The actual approval of the drug is made by a dedicated group of scientists at the FDA.

It is important to remember that the testing of new drugs is done on no more than a couple of thousand research subjects and under very controlled settings. Only when used in large numbers of patients will the true value of a new drug be realized. Regardless of how testing is done, the true risks and benefits of a new drug can be seen only after months, if not years, of use.

Harold J. DeMonaco, M.S., is the director of Drug Therapy Management and the chair of the Human Research Committee at Massachusetts General Hospital. He is an author of over 20 publications in the pharmacy and medical literature and routinely reviews manuscript submissions for eight medical journals

*****************************************

STAGES OF CHANGE: GETTING TO WHERE YOU WANT TO BE Harvard Heart Letter - Harvard Health Publications

So often, we give you advice on how to get heart-healthy: eat right, lose weight, exercise, and stop smoking. For many of us, this means dropping a bad habit or instituting a new, healthy one; in other words, change. However, change is difficult. Simply knowing that something is or isn't good for you doesn't make it any easier to actually start or stop that behavior. Yet, some people do. We all know someone who quit smoking or lost weight. What enabled these people to change and how did they summon the will to maintain their new, healthier behaviors?

In navigating the road to understanding successful change, psychologists James Prochaska, John Norcross, and Carlo DiClemente asked these very same questions. But rather than analyzing academic theory and expert opinion, they studied the strategies of thousands of people who changed a behavior without "outside help," such as therapy or formal programs. Instead of trying to determine what people should do to successfully make a change, they studied what people actually did do to change. The result of this analysis is a behavioral model called Stages of Change. The basic principle behind it is that most successful self-changers go through each of the following six stages:

This "theory" has been applied to helping people change - and it works. The Stages of Change model is a general guideline that you can apply to almost any habit that you want to change, from quitting smoking to controlling your anger to developing an active lifestyle. Try to thoroughly work your way through each step before proceeding to the next.

1. Precontemplation
   If you are in the precontemplation stage, you may still be in denial of your problem, or you simply don't want to change. Though you admit that you smoke, you are unwilling to admit that it has any negative consequences for you or the people around you. You might still be waiting for the "definitive" study to prove that smoking causes lung cancer, or you might cite the example of a grandfather who smoked and lived to be 85. People who are in this stage are also likely to defend their behavior or blame others for their problems. If you know someone in this stage, the best thing to do is to raise his or her consciousness. Finding out what the "barrier" is (that is, what might help make a person want to change) can assist as well. If a friend is obese, for example, ask if he or she knows that being overweight significantly increases the risk of developing heart disease. The goal at this stage is to get the individual (or yourself) to acknowledge the negative consequences of his or her action, and to think about changing it. When you've let your defenses down and become aware of the facts and consequences of your behavior, it's more difficult to reverse the process.
2. Contemplation
   Once you become aware that you have a problem and have started thinking and learning about it, you've entered the contemplation stage. For example, you now admit that regular exercise is essential to a healthy lifestyle, or that it's not alright to have four to five alcoholic drinks every evening. In this stage, you are actively collecting information in preparation for change and are seriously thinking about making that change within the next six months. You should get to the point where you are convinced that your life would be substantially better if you altered your behavior. But don't fall into the trap of chronic contemplation. Someone who wants to become active could spend months trying to figure out which would be the best exercise program for him or her. On the other hand, it's also important not to jump too quickly into action, because premature action is likely to lead to failure.
3. Preparation
   Preparation is the transition from deciding to change to planning exactly how to go about changing. You're still learning, but rather than collecting information about the problem, you're gathering data about a solution. The first step is to determine what action would solve your problem. For example, if smoking or troubled drinking were the problem, then abstinence would be the solution. If a high-fat diet is the problem, the goal should be to get fewer than 30% of your total calories from fat. But the planning process involves more than just making a list of low-fat foods to substitute for the high-fat ones. First, you must prepare yourself to make this change a priority in your life. Adding exercise to your schedule might mean missing out on an extra hour of sleep. It's also important to prepare those around you for the change. If you're giving up smoking, for example, you should warn family, friends, and colleagues that your mood might be unpredictable. Mental preparation is just as important as physical preparation. If you are giving up alcohol, know what you're going to tell coworkers if they ask you to join them for a drink. And be aware that once you make your change, others might begin to see you differently. And you may view yourself in a completely new light.
   Another thing you should do is to go public with your decision to change. Meeting the expectation of others can be a far more potent motivator than keeping a promise to yourself. Finally, set a date to begin your change and stick to it.
4. Action
   When you're fully committed to taking action, go for it! Join the gym, start counting calories, or swear off those cigarettes. Though this may be the most rewarding time, it will also be challenging. At first, avoid temptation. Don't join your colleagues for a smoking break and expect that you will be able to resist lighting up. Fill up the hours that you might otherwise have spent going to the local bar. Call a friend, learn to cook, or take up piano lessons. You might also find it helpful to reward yourself for good behavior in this stage. If you stick to your exercise regimen for a month, allow yourself to splurge on a new outfit. Ask family and friends for positive reinforcement when you follow through on a change. While it isn't unusual to slip up a few times during this stage, do your best not to. It can undermine your commitment to change. But if you do, don't let one mistake obliterate your efforts.
5. Maintenance
   After about six months in the action stage, you will find yourself transitioning into maintenance. Maintenance is the long haul, for most people, a lifetime commitment. Successful maintenance of change depends on more than avoiding temptation and rewarding yourself for good behaviors. You must rethink what you found appealing about the habit in the first place. You may remember that having a cigarette calmed your nerves after a stressful day at work. Now is the time to find new, less self-destructive ways to deal with that stress. Don't delude yourself into thinking that you're strong enough to have one drink, cigarette, or brownie, and then control yourself from having another. Also, expect and be prepared for social pressure and special situations. A friend is bound to offer you a piece of cake, "now that you've lost all that weight," or a new client, unaware of your former drinking problem, might order a bottle of wine during a business dinner. Just think back to all the reasons why you stopped your negative behavior in the first place, and remember how hard it was to quit the first time. Again, relapses are not uncommon and in fact may be different for different problems. Many people cycle through the stages more than once before effecting a permanent change. Even so, work hard to prevent relapses.
6. Termination
   Although psychologists disagree about whether anyone actually terminates the process of change, Prochaska and his colleagues view it as a point where you are no longer tempted to return to the way things were. Someone at this stage would not even want a cigarette if it were offered to him or her. They also note, however, that few "changers" reach this stage (permanent change) - p erhaps only 20% - and the final success rates vary depending on the behavior change undertaken. For example, most smokers who quit eventually do reach the termination stage. Relapses, while discouraging, offer the chance to try again and often individuals find they can refine and improve what they've learned about themselves and the process of change as they re-cycle through the action and maintenance stages. In the face of repeated relapses, some people decide to seek professional help in their efforts. It is not unusual, however, for many people to remain in the maintenance stage, still tempted by old habits, but resolved not to give in to them. And in terms of heart-health, this is truly a worthy accomplishment.

******************************************

FDA OKS NEW RHEUMATOID ARTHRITIS DRUG
January 2, 2003 WASHINGTON (AP)

The government has approved sale of a new drug for rheumatoid arthritis that works like two older competitors -- but may prove easier to take.

Abbott Laboratories' Humira works by blocking an immune system protein called tumor necrosis factor, or TNF, that is responsible for much of the pain and inflammation of rheumatoid arthritis.

It requires patients to give themselves one shot every two weeks.

Two other TNF blockers, Enbrel and Remicade, have long been sold. Enbrel requires two shots a week, and is so difficult to manufacture that it's often in short supply. Remicade requires an infusion in a doctor's office.

All three drugs have similar side effects, including serious, sometimes fatal, infections thought linked to the suppression of the immune protein.

About 2 million Americans have rheumatoid arthritis, where the immune system goes awry and destroys patients' joints.

Abbott plans to begin the first shipments of Humira next week, with nationwide sales by the end of January. The company said Humira's wholesale price will be identical to Enbrel's, at a little over $1,100 a month. Copyright 2003 The Associated Press.

**********************************

CONCERNS OVER DRUG INDUSTRY CREATION OF NEW DISEASES
January 3, 2003 (British Medical Journal)

Drug companies are sponsoring creation of a new medical disorder known as female sexual dysfunction in order to build markets for drugs among women, despite controversy surrounding the medicalisation of sexual problems, finds an article in this week's BMJ.

Over the past six years, researchers with close ties to the pharmaceutical industry have been developing and defining the new disorder at company sponsored meetings, writes journalist, Ray Moynihan.

One of the milestones in the making of the new disorder was a JAMA article in February 1999, which suggested that 43% of women aged 18-59 have female sexual dysfunction. However, leading researchers have raised serious concerns about this figure, describing it as misleading and potentially dangerous.

Many researchers believe that portraying sexual difficulties as a dysfunction will encourage doctors to prescribe drugs that change sexual function, when attention should be paid to other aspects of the woman's life. It's also likely to make women think they have a malfunction when they do not. But perhaps the greatest concern is the ever-narrowing definitions of "normal" which help turn the complaints of the healthy into the conditions of the sick, says the author.

Although the corporate sponsored creation of a disease is not a new phenomenon, the role of drug companies in the construction and promotion of new conditions needs more public scrutiny, he concludes.

*********************************************

Good Health to All,

Jack Nicholas
Newsletter Editor
Cornishpro@aol.com
Issue 2003 1/15/03-01