The word laxative is almost synonymous with Ex-Lax; the familiar, sweetened, chocolate flavored purgative know to several generations world-wide. So why is Ex-Lax in the news? Because the Food and Drug Administration has announced that it is considering a ban of this popular laxative from the market place. The words "proposed ban" is the death knell for most any product, when pronounced by the Government. Never mind that it is only a proposal, and the public and affected companies have thirty days to comment; after which the FDA will decide(?) to make the ban final.
One should look at the basis for the regulatory agencies action before concluding whether the action is justified or not. To wit, phenolthalein an organic chemical has been with us not only as a gentle cathartic but as a useful indicator of the alkalinity of solutions since its synthesis in 1880. There is no evidence that it has caused harm other than that expected when any medication is misused. Some people become dependent upon laxatives, which of course includes Ex-Lax. Others may become ill for a variety of reasons but this is not the damnation of Ex-Lax alone.
In defense of its actions, the Food and Drug Administration is quick to point out that they are not depriving the public of relief. No there are a number of alternative products on the market. Laxatives take several forms; either a bulking agent that when well hydrated passes easily through the intestines (examples are the metamucil gels and the magnesium sulfate type products), an irritant (many of the early "natural" laxatives fall in this category as well as castor oil(more on this later)), a peristaltic activating effect of compounds like phenolphthalein or perhaps the lubricating action of mineral oil. Thus no one need fear that constipation awaits without relief.
As a counter point, the FDA admits that after 90 years of use, phenolphthalein has a record of safety and acknowledges that it has no reports that phenolphthalein has caused cancer in people.
But, FDA hangs its decision upon "new" evidence that the p53 gene is damaged by phenolphthalein and consequently, persons using the products containing phenolphthalein may lose a degree of protection provided by this gene. Here we must ask a number of important questions; how firm is the evidence that the p53 gene in fact provides protection against cancer, and how substantial is the evidence that phenolphthalein acts on the gene in question and how dose sensitive are the results?
Let's address the p53 gene first. We are taught that there is a point of location on one of our chromosomes (number 17), where a particular encoding of genetic information resides. This encrypted message when translated by cellular mechanisms results in formation of a particular protein which is of some great size containing 393 amino acids. (For comparison, growth hormone has about 200 amino acids and is considered a very large protein). The name p53 is derive from the mol size of the protein, i.e. 53 kilodaltons. Now at first, it was believed that this gene product was capable of immortalizing cells and transforming them, thus the gene was identified as an oncogene (a cancer former). This proved to be false and in fact, just the reverse has been shown to be the case. It is now believed that p53 gene product is in fact a growth inhibitor or suppressor and thus stops the progression of cellular division and in turn tissue growth. First evidence of p53 as an oncogene is thought to be based on the erroneous observation that an alternative form, a mutant of p53, was inactive thus allowing dividing cells (immortalized lines) to avoid entering the stage of cell division arrest or death. In the absence of death, the cells gone astray can then divide and thus the cancer grows, with death, the cancer diminishes in size, or so it is thought. Future research is expected to clarify the exact mechanism by which p53 stops cell division, thus inducing cell death (apoptosis). At least this is our hope!
Now for the jump in faith taken by the FDA. Assuming that p53 is the sole mechanism by which the body avoids tumorigenesis and that various chemical substances can affect the expression of this gene and thus production of the gene product, it is logical that precautions should be taken to avoid exposure to those chemicals. Clearly if this is so, the actions taken by the FDA are warranted. But let us suppose that in the test-tube environment where exposure to all but the desired substance is carefully controlled, that there is no limit to the number of chemicals that affect expression of the p53 gene (some to the benefit and others to the detriment). What then are we to do, shall we ban all those suspect chemicals, or do we do as in the case of the use of LD50 and other toxicological date, decide where we care to place our bets. Some compounds are going to be clearly more dangerous (or beneficial) than others. This is the position at which FDA has placed us in a most compromised state. We simply do not know and to rush to judgement is perhaps the greatest error of all. I know, some will be quick to point to thalidomide as evidence of FDA's quick action that prevented needless tragedy in the United States. But, thalidomide was a "new" pharmaceutical, whereas, phenolphthalein has been around for over a century. Then there is the dose-dependent relationships - still unproven. And finally, where is the evidence that the biological system has been ineffective in blocking phenolphthalein's actions. In fact one could point to the possible exclusion of phenolpthalein from the system, by its stimulation of peristaltic action giving an element of safety not possible with other laxatives. (Just a thought.)
No, Food and Drug Administration actions smell of something entirely different from that of protecting the public from a potential health hazard. Congress empowered the agency to regulate pharmaceuticals but they have been carefully excluded from taking action against the over-the-counter products. Their actions strike at the heart of Congresses control. If FDA is able to accuse without proof, ban without limitation, and expand their control into yet another agenda, Congress will have lost yet another of its mandates from the people.
FDA has already have won this battle as the companies with phenolphthalein products have withdrawn them from the market and are reformulation with alternative chemicals. The question is whether FDA will now expand their new found entitlement to oversee the rest of the over-the-counter products. Time will tell.
Before we leave this subject, it is interesting to see how the problem of constipation was addressed some 100 or so years ago. First, when a person was ill, it was thought that the best thing to do was to "cleanse" the system thus purgatives and emetics were the front line of defense against disease. "Constipation of the bowels. This is one of the most troublesome of all complaints, and if allowed to become confirmed, often leads to serious consequences. It can never be cured by pills or other medicines taken into the stomach. On the contrary, the tendency of these things is inevitable to make it worse. The only permanent cure is a proper system of diet and regimen. But if not cured, immediate relief may be obtained by using injections. The best instrument for this purpose is the common syringe, which cost but a trifle. For injection, pure water in many cases will answer, milk warm. Throw up as much as to make the stomach feel a little uncomfortable, and if one injection does not answer, try another, and even a third.
Constipation in some persons becomes a habit, by carelessness and by suffering the bowels to remain for several days or more without an operation, and thereby is the cause of other affections, such as Colic, Dyspepsia, &c., of which diseases it is the general accompaniment. It is therefore of the utmost importance to attend to this matter strictly, as a neglect of the daily evacuations from carelessness, or excess of food and want of proper exercise, will sooner or later produce a diseased state of the system.
The treatment is very simply, and merely requires a dose of Salts or Rhubarb, or Seidlitz Powder, to relieve the bowels, and attention to the quality and quantity of food. Pills or drastic purgatives of ever description, all more or less containing Aloes, should be strictly avoided, as they only increase the debility of the intestines, which is the cause of the complaint, and they likewise irritate the rectum, and strongly tend to the production of Piles.... (pp 218, Gunn's Family Physician, 1875)
Cathartic and Anti-bilious - Take Podophyllin, Leptandrin, and Aloes, each, 30 grains; Cayenne, 10 grains; make into thirty pills, with Extract of Dandelion. This is a very good Cathartic pill for ordinary purposes. Dose: two to three pills.
Cathartic and Liver - Take Podophyllin, 30 grains; Leptandrin, Sanguinarin, Ipecac, and pure Cayenne, each, 15 grains; make into sixty pills, with a little soft Extract of Mandrake or Dandelion. This is the best pill I have ever used, as a Cathartic and Liver pill, and to act on secretions generally. As a Purgative, the dose is from two to four pills, for a grown person; and as an alternative and substitute for Blue Mass, and to act on the liver, one pill once a day, or ever other day. (As a point of information: Blue Mass is a mixture of honey, licorice, glycerol and 32-34 percent mercury metal with other minor ingredients and is still listed in the latest edition of the Merck Index) pp 1134, Gunn's Family Physician, 1875.
Cathartic Syrup - Best senna leaf 1 oz.; jalap � oz.; butternut, inner bark of the root, dried and bruised, 2 oz.; peppermint leaf � oz.; fennel seed � oz.; alcohol � pint.; water 1 � pint; sugar 2 lbs.; put all into the spirit and water, except the sugar, and let it stand 2 weeks, then strain, pressing out from the dregs, adding the sugar and simmering a few minutes only, to form a syrup. If it should cause griping in any case, increase the fennel seed and peppermint leaf. Dose - one tablespoon, once a day, or less often if the bowels become too loose, ...
This is a mild purgative and especially pleasant. Most persons, after a trial of it will adopt it for their general cathartic, and especially for children. Increase or lessen the dose, according to the effect desired. (pp106, Dr. Chase's Information for Everyone. 1886)
I suppose the FDA will want to examine each of these "natural" ingredients, especially the constituent oils, alkaloids, esters &c. for their effect on p53 and either give a clean bill of health to each or ban them from the market place (of course after going through the Federal Register to announce that all those opposed please step forward.) Does anyone really care? I wonder.
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