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It used to be that the word drug had a solid respectable meaning. But in recent years drug and abuse have been put together in the same sentence so often, without discrimination, that the word drug has come into disrepute. It’s confusing, and a shame. Today people brag, just before they ascend, “I never took a drug in my life.” As if St. Peter cared. Good drugs are a cheerful feature of our society. We should stop tarring them with the same brush we use on the bad ones and be grateful for them. With this general comment off my chest I would like to make some observations about PHT.
PHT would appear to be the most broadly useful drug in our pharmacopoeia (unless another is hidden in the literature). Paradoxically, this valuable feature, this versatility, has interfered with our understanding of the drug. The idea that one substance can have as many uses as PHT has been difficult to accept. And this is understandable. Not too long ago the thinking was a single drug for a single disorder.
A discussion of the basic mechanisms of action of PHT will help us understand how one drug can have so many uses. A basic mechanism of action study was the first study to demonstrate that PHT might be a therapeutic substance. In 1938 Putnam and Merritt tested PHT on cats in which convulsions were induced by electricity. Of a large group of substances, including the best-known anticonvulsants, it was the most effective in controlling the convulsions. Putnam and Merritt said, Eureka! Maybe we have a superior antiepileptic drug.
They did. And not only was PHT the most effective anticonvulsant but it was found to have another remarkable property. Unlike previously used substances it achieved its therapy without sedation. Let’s go back to Putnam and Merritt’s original study and apply hindsight. Suppose, instead of inferring that PHT would help the epileptic, Putnam and Merritt had drawn a broader inference from their data. Suppose they had inferred that PHT worked against inappropriate electrical activity. That also would have been a correct inference—but with far broader implications. And the properties of PHT would not have been obscured by the label “anticonvulsant.” Today basic mechanism scientists use broad terminology for PHT. They refer to it as a membrane stabilizer.
From the early basic mechanisms study of Toman, in 1949, PHT has been found to correct inappropriate electrical activity in groups of cells, and in individual cells. This includes nerve cells, brain cells, muscle cells—in fact, all types of cells that exhibit marked electrical activity. Whether a cell is made hyperexcitable by electrical impulse, calcium withdrawal, oxygen withdrawal, or by poisons, PHT has been shown to counteract this excitability. Further, it has been demonstrated that, in amounts that correct abnormal cell function, PHT does not affect normal function. (See The Broad Range of Clinical Use of Phenytoin—Basic Mechanisms of Action.)
When we understand that PHT is a substance that stabilizes the hyperactive cell, without affecting normal cell function, we see its therapeutic potential in the human body, a machine that runs on electrical impulse. It is estimated that there are a trillion cells in the body, tens of billions in the brain alone. Thinking is an electrical process, the rhythms of the heart are electrically regulated, the rhythms of the gut are electrically regulated, muscle movement is electrically regulated, messages of pain are electrically referred, and more.
It’s important to know that after a cell has been stimulated to fire a few times it becomes potentiated, easier to fire than a normal cell. This is called post-tetanic potentiation. If the stimulation is continued, the cell starts to fire on its own, and continues to fire until its energy is depleted—post-tetanic afterdischarge. PHT has a modifying effect on post-tetanic potentiation and a correcting effect on post-tetanic afterdischarge. This may account for PHT’s therapeutic effect on persistent and repetitive thinking and on unnecessary repetitive messages of pain.
PHT has a number of properties that set it apart from most substances. For ten distinctive characteristics see The Broad Range of Clinical Use of Phenytoin. For purposes here we should consider several of these properties. PHT is a nonhabit-forming substance. (This is not to be confused with the well-known fact that a person with epilepsy should not abruptly discontinue PHT.) The desirability of a nonhabit-forming drug that can calm and also relieve pain is apparent—it may be particularly useful during withdrawal from habit-forming substances.
PHT, in therapeutic amounts, has a calming effect without being a sedative. This characteristic is unusual, and clinical observations, supported by basic mechanisms studies, show that PHT does not affect normal function. Not only does PHT not sedate but it has been shown to improve concentration and effect a return of energy. This can be attributed, at least in part, to the fact that an overactive brain (hyperexcitable cells) wastes energy compounds. (PHT has been shown to increase energy compounds in the brain. See The Broad Range of Clinical Use of Phenytoin—Basic Mechanisms of Action.) One can conjecture that when thoughts with negative emotions are diminished, the effect of these “down” emotions is eliminated, and “psychic” energy may return.
Now that preventive medicine is being given more and more consideration, PHT may be of special interest because of its general properties and its versatility. PHT, as do other drugs, has side effects. Safety and Toxicology of PHT is reviewed in The Broad Range of Clinical Use of Phenytoin. A replication of Parke-Davis’s package insert is included in the Physicians’ Desk Reference. It should be noted that PHT is not on the government’s list of Controlled Drugs.
PHT can be used on a regular basis or on an occasional basis by the nonepileptic—depending on need. In the nonepileptic, effective doses tend to be lower than those used for epilepsy. The reader is reminded that PHT is a prescription drug and should be obtained from a physician.
When the Dreyfus Medical Foundation was preparing The Broad Range of Clinical Use of Phenytoin, in 1970, there were many published studies to draw on—1,900 by the time of publication. Seven hundred and fifty references were selected and over 300 of them were summarized. These summaries were presented chronologically in order to show in sequence how the information about PHT developed.
Five years later when PHT, 1975 was published, there were more than twice the number of studies to review, and the interrelationship between the clinical effects and basic mechanisms of action of PHT was in better perspective. In this bibliography the medical material was arranged according to subject matter for the convenience of the reader. Examples of this are found under such headings as Stabilization of Bioelectrical Activity, Anti-anoxic Effects, Antitoxic Effects, Treatment of Pain, and others.
As an instance, under Anti-anoxic Effects of PHT, ten studies are grouped. (This was in 1975. In the present Bibliography, there are forty-one studies.) They were published in nine different journals, over a span of twenty years. Each of them is interesting but, by itself, would not carry much weight. But when these studies are reviewed together, the evidence that PHT has an offsetting effect against oxygen lack in animals is highly significant.
These basic studies furnish rationale for the clinical findings first made by Shulman in 1942, New England Journal of Medicine, that PHT is effective in asthma—and other studies in asthma, by Sayer and Polvan, Lancet (1968), and Shah, Vora, Karkhanis, and Talwalkar, Indian Journal of Chest Diseases (1970). (The latter authors give an additional rationale, PHT’s potential usefulness against the paroxysmal outbursts of asthma by its ability to stop repetitive afterdischarge.) They also furnish rationale for exploration of new uses.
Since Putnam and Merritt’s discoveries in 1938 that phenytoin was a therapeutic substance, a steadily increasing number of uses for it have been found. The probabilities are high that there are more to come. Evidence from existing clinical and basic mechanisms of action studies furnishes clues for further exploration.
PHT has been reported effective in a wide variety of severely painful conditions. Its usefulness as a nonhabit-forming analgesic in many forms of pain has been established. (See The Broad Range of Clinical Use of Phenytoin.) The antiahypoxic effects of PHT point to its possible usefulness in stroke, emphysema, shock, and, in fact, in any condition where oxygen lack is a problem. There are a number of references in the literature to beneficial effects of PHT on hypertension. Recently, in a study of mildly hypertensive patients, treatment with PHT was reported effective. (See The Broad Range of Clinical Use of Phenytoin.) Further study of PHT in hypertension, both by itself and in combination with hypertensive drugs, seems indicated.
A use of PHT that has received little attention, and that may have great potential, is its use topically, for the treatment of pain and for the promotion of healing.
Systemic PHT has been reported useful in healing in a variety of disorders—in leg ulcers, stomach ulcers, scleroderma, pruritus ani, and epidermolysis bullosa. (See The Broad Range of Clinical Use of Phenytoin.) The foregoing was written sixteen years ago. Since then there has been substantial evidence from at least six countries that, used topically, PHT is rapidly effective against the pain of burns, ulcers, wounds and other surface conditions, and that it speeds healing time. In recent years, its effectiveness against intractable ulcers of leprosy has been established.
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