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Chapter 11: Phenformin and Phenytoin, Two Drugs to Watch
In 1980 some very interesting new drugs joined the list of all those drugs which might increase lifespans in man. These are the drugs phenformin and diphenylhydantoin (sometimes called phenytoin or dilantin). The ability of both drugs to increase lifespan in at least one strain of mouse was first discovered and reported by VM Dilman and VN Anisimov of the Laboratory of Endocrinology at the NN Petrov Research Institute of Oncology at Leningrad (now St Petersburg) in Russia. Dilman is one of the leading Soviet researchers in aging; he has already contributed some quite significant ideas and papers, not just in the Soviet press but in the West. His general field of research, which is one which has been growing in the US also, is the endocrinology of aging: to work out how our hormones, particularly brain hormones, change with aging and find ways to reverse these changes.
To explain how Dilman came to his discovery, I shall review some of the endocrinology of aging according to Dilman. One part of our brain, located at the bottom of our brains above the back of our mouth, the hypothalamus plays a critical role in regulating our hormonal functions. It does this not by producing the hormones directly, but by producing other special hormones (usually present only in extremely small concentrations) which then directly or indirectly cause our glands (adrenals, thyroids, sex glands, and others) to actually produce the hormones needed. The regulation of any physiological state is a complex process: our bodies will require a certain level of hormone, which will cause harm if it is present either to excess or scarcity. The hypothalamus is therefore constructed so that it will measure the levels of these hormones and if levels are too high, it will cut back on the production of its own regulatory hormones. Regulation of hormone levels, of course, is not the only regulation which the hypothalamus performs; for instance, it also plays a role in appetites such as thirst (causing us to want to drink if we become too dehydrated) and the regulation of body temperature too.
Dilman's idea about aging, which he has expanded upon in a significant number of articles, is that one of the critical changes which happens with aging is that the threshold above which the hypothalamus will respond by trying to decrease the level of certain hormones, rather than increase them, is raised as people grow older. This means among other things that as we age our body will continually suffer from an excess of hormones necessary to health, particularly adrenal hormones.
Given this possibility, we would naturally become interested in drugs which might act upon the hypothalamus so as to lower its threshold for these hormones. At this point Dilman seems to have made an inductive leap: from observations that both phenformin and diphenylhydantoin lower the sensitivity of the hypothalamus to the single hormone estrogen, he decided that these drugs may have a similar activity with respect to other hormones whose output is ultimately controlled by the hypothalamus, and therefore undertook a study of both drugs for their influence in aging.
Dilman and Anisimov published the results of their study in GERONTOLOGY 26 (1980) 241-246. They tried three different drugs on 100 female mice of the C3H/Sn strain: phenformin, phenytoin, and L-dopa. They found that phenformin and phenytoin at a dose of 2 mg/day would prolong the mean lifespan of their treated mice by 23% and 25% respectively. The same dose of L-dopa did not appear to increase lifespans in the mice studied; Table I on the previous page gives their results in tabular form. The work of Dilman and Anisimov remains uncorroborated. On the other hand, their study appears both careful and thorough, and should be an accurate statement of what these two drugs do to the mouse populations studied.
 Both drugs appear quite different in their metabolic effects and the advantages or disadvantages of their use and their significance to us as immortalists. Phenformin has been withdrawn from the US market because of toxicity (described below). Phenytoin, however, still has significant interest for longevists. They both merit description.
Phenformin was once a very well known antidiabetic drug. Its most well known effect is the fact that it lowers blood levels of glucose sugar in diabetic patients. Rather curiously, it does not have any such effect in normal (nondiabetic) patients. Scientists have not worked out the exact process by which it has these effects. Besides its effect in lowering blood sugar content, phenformin may also increase the use of free fatty acids (FFA's) by the body. It may cause a loss of weight in the obese, particularly obese diabetics, by causing release of fats from the fat cells. It also decreased cholesterol levels, particularly in diabetics.
However phenformin had two side effects which were not at all minor. The first of these was lactic acidosis. This is a condition in which the level of lactic acid in the blood increases over normal levels and the blood becomes acid (pH decreased). Patients developing this condition often died of it; they needed intensive hospital care to recover. Lactic acidosis in patients taking phenformin killed 27% of those who developed it. Several cases of attempted suicide also showed quite definitively that even NONdiabetics taking phenformin could get lactic acidosis.
The second major problem, very serious to longevists in particular, came from the fact that patients taking phenformin had significantly shorter lifespans. An 8-year study of two antidiabetic drugs, tolbutamide and phenformin, showed that the percentage of patients dying in the phenformin group was about twice the percentage dying in groups treated with either insulin or PLACEBOS. a
full report of this study is in DIABETES 24 (SUPPL 1)(1975) 65-184. Significantly more patients taking phenformin had blood pressures greater than 160/95, in the hypertension range. More patients on phenformin developed some kind of cardiovascular condition.
These studies ultimately caused phenformin to be withdrawn from the US market entirely. Even though Dilman and Anisimov's results with phenformin may tell students of aging something significant, it does not make a useful treatment for our aging.
Phenytoin
The second drug of interest is diphenylhydantoin (or phenytoin for short). Phenytoin has many side effects both common and uncommon; like phenformin, some of them are fatal. On the other hand, some of them are also favorable and very interesting from the standpoint of aging. Adult epileptics take between 50 and 100 mg of phenytoin three times daily, depending on the amounts needed to control their convulsions. They maintain these doses of phenytoin for their entire lives.
To deal with relatively benign side effects first, phenytoin can cause nausea. vomiting, headache, dizziness, tremor, and insomnia. These effects tend to disappear with continued use. Secondly, phenytoin seems to cause tenderness and excessive growth of the gum tissue. This side effect is very common; one paper by a dentist (LA Klar, JOUR PUBLIC HEALTH DENTISTRY 33(3) (1973) 180) reports the results of his study of 312 patients, the majority of them children; 38 percent of the patients had moderate to severe excess growth of the gums. One study found excess growth of the gums in 78 percent of patients studied (Gardner, AF et al EXP MED SURG 20 (1952) 133). References about phenytoin (such as the US PHYSICIANS DESK REFERENCE) suggest that "good oral hygiene" (ie. brushing one's teeth) can control this symptom, but Klar found from his own studies, and other papers also find, no indications that frequent toothbrushing prevented the gum growth caused by phenytoin.
Of the major possible side effects (and risks for those who take it) perhaps the most dangerous, though not the most common (it is rare) is its toxicity to the liver. This disorder usually begins with many different symptoms, easily mistaken for other problems: it begins with a constellation of problems among which are fever, skin rash, swollen lymph glands, and blood abnormalities. The patients then show signs of liver damage, which then causes coma; in one study 7 out of 17 patients with this disorder grew worse until they died of it soon after its appearance.
People usually show this reaction after they have only taken phenytoin for a few weeks. One reason why this problem is so serious is that its early symptoms resemble so many other diseases, such as rubella or mononucleosis, so that doctors may not really realize the seriousness and nature of the reaction until their patient has almost died of it. The problem seems to arise in patients who are genetically predisposed to it through an inherited deficiency of enzymes needed to metabolize the drug. As the liver metabolizes phenytoin, it produces special free radicals, the arene oxides, in the liver, and patients who show liver damage seem to lack enzymes to metabolize these.
Some significant prospect exists that a blood test can distinguish people who are likely to show this very toxic reaction to phenytoin from others who will not. A recent paper by SP Spielberg et al of the Johns Hopkins School of Medicine showed that white blood cells from people subject to phenytoin liver damage would show clear signs of toxicity at levels of phenytoin which left similar cells from normal controls unharmed. However this test is not yet a test we can order as part of normal "diagnostic workup".
A second possibly serious side effect of phenytoin is cancer. The risk of cancer is not absolute; what happens is that prolonged treatment with phenytoin may increase the frequency of Hodgkin's disease, a very serious form of cancer of the lymph glands. FP Li et al report in CANCER (36 (1975) 1359-1362) that 8 out of 516 patients with lymphatic cancers reported that they had taken phenytoin longterm, as compared to 3 out of 516 patients with other cancers and 2 out of 516 people without any tumors. This suggests that the risk of lymphatic cancer is increased on the order of 4 times. These authors cite other papers suggesting that phenytoin may promote lymph gland cancer.
Related to these cancers is another kind of side effect, the pseudolymphoma of phenytoin. This is a very characteristic reaction to phenytoin involved swelling of the lymph nodes and the adenoids, fever, skin rash, and swollen liver. Usually it only occurs within a few weeks after commencing phenytoin, and doctors for a long time believed that this reaction did no serious damage to a patient, even though it closely resembled lymphatic cancers such as Hodgkin's disease. However doctors have subsequently noted that patients who show this reaction also show a later tendency to get the full-blown cancer (AM J MED 32 (1962) 286). On the other hand, one Danish study of cancer among people taking "anticonvulsants" (including phenytoin but not limited to it) found no evidence of an excess risk of cancer overall. The study involved 4201 men and 3957 women; unfortunately the study does not distinguish those patients taking phenytoin longterm from other patients taking other anticonvulsant drugs (for instance, phenobarbitone), so that its conclusions aren't quite as strong as we would like.
Two other side effects of phenytoin relate to its effect on absorption and metabolism of two essential vitamins, Vitamin D and Folic Acid. Vitamin D is involved in control of calcium levels in the blood and therefore in bone growth (in children) and maintenance (in adults). Many doctors using phenytoin on their patients have reported that these patients showed signs of bone weakness and some report that patients on phenytoin show increased susceptibility to rickets; although scientists haven't yet worked out the exact nature of the fault some derangement of Vitamin D metabolism seems responsible. For instance, one study found that out of 91 epileptics taking phenytoin, 42 showed signs on x-rays of severe bone changes and moderate changes in 28; 30% of these patients had abnormally low levels of blood calcium. (EA Sotaniemi et al ANN INTERN MED 77 (1972) 389). Another study found that in 226 patients with epilepsy, bone mineral mass was only 87% of normal and blood calcium levels were lower than normal. Calcium supplements together with Vitamin D helped to PARTIALLY restore bone mass, from 87% up to 91% of normal.
Phenytoin also disturbs Folic Acid metabolism. Prolonged deficiency in Folic Acid causes a characteristic anemia, megaloblastic anemia; many doctors have reported finding this anemia in their epileptic patients. One paper reports that out of 14 patients taking anticonvulsants, of which 13 took phenytoin, 11 had evidence of megaloblastic anemia. Patients who develop megaloblastic anemia generally tend to recover after treatment with Folic Acid and sometimes with Vitamin B12 also. (SN Wickramasinghe et al BRIT MED J 4 (1974) 136).
Finally among the major side effects, phenytoin, particularly when taken to overdose, also causes brain damage. This effect often happens from overdoses, but it can also happen to patients taking therapeutic amounts of phenytoin. Even in therapeutic doses some of the side effects of phenytoin come from its action on the nervous system: they include eye trembling when the eyes are moved sharply, coordination difficulties, slurred speech and blurred vision. The part of the brain most affected is the cerebellum, which controls motion and coordination. Usually these signs of incoordination disappear when the patient takes less phenytoin, but they are sometimes irreversible. In animal studies large doses of phenytoin will cause atrophy of the cerebellum and widespread destruction of critical neurons. Human patients taking overdoses of phenytoin will show similar destruction; some doctors have reported identical brain damage in some patients taking doses in the therapeutic range (JB Selhorst et al ARCH NEUROL (CHICAGO) 27 (1972) 453).
There is also some evidence that phenytoin causes neurological problems in all or most patients taking it for their epilepsy. Many epileptics have complained that phenytoin seems to slow them down or make them function less well than when they are not on the drug. In 1974 Carl B Dodrill of the Seizure Clinic at the University of Washington studied 70 adult epileptics to try to assess whether or not phenytoin impaired their mental function. Dosage of phenytoin depends very much on the patient, some patients responding on much smaller doses than others; he therefore assessed their level of dosage not by the amount of phenytoin they were taking but by the level of phenytoin in their bloodstream. Out of his work he found quite clear evidence that phenytoin in therapeutic doses definitely impaired the motor coordination of all patients studied: patients with higher blood levels of phenytoin showed increasingly impaired motor skills. But phenytoin seems to impair the higher intellectual functions also; differences here were not statistically significant but definitely seemed to appear from the data (CB Dodrill EPILEPSIA 16 (1975) 593). Other papers have also reported evidence of intellectual impairment from taking phenytoin.
These are all serious side effects of phenytoin, but they aren't close to a
complete list. Doctors have described many other side effects of this drug, on the blood, the vascular system, ability to metabolize glucose, blood fat levels, skin reactions, and effects on the ability of the lungs to absorb and retain oxygen. Readers who want to make a full study of phenytoin with a view to possibly taking it should consult the references given.
Technically speaking, a "side effect" is simply a drug effect for which the drug is not commonly prescribed or used, and COULD turn out to be favorable rather than unfavorable. With this in mind I'll end my review of phenytoin by pointing out that it also has many relatively little known effects which could be FAVORABLE. In the first place, even though it may make younger people more stupid and more slow, it may also actually IMPROVE intellectual abilities in the old. A very interesting paper in the JOUR AMER GERIATRICS SOC (23(5) (1975) 207), by WL Smith and JB Lowrey, reports that phenytoin at a dose of 100 mg two times a day in subjects of average age 69 years would actually improve their intelligence. These subjects were normal (nonsenile) elderly people, but the possibilities with phenytoin in aging and senility seem very suggestive indeed. To confuse the issue, these two scientists also report that phenytoin would improve the intelligence of younger people also. The reason for the improvement in both cases, according to these authors, is that phenytoin improves mental concentration. We might reconcile the conflicts between this study and the others in several ways: phenytoin may improve memory for people who suffer from poor concentration but also cause other effects, which worsen memory for those whose concentration is optimal. Alternatively phenytoin may cause a normalization in the old but worsen the condition of younger people by raising the level of some vital substance too high.
Besides work suggesting that phenytoin may help memory in older people animal experiments have also shown improved memory in older animals. Work by P Gordon (RECENT ADVANCES BIOL PSYCHIATRY 10 (1968) 121-133) is the best study of this kind.
A second very interesting side effect from the standpoint of aging is the ability of phenytoin to improve wound healing. This effect seems to stem from the fact that phenytoin promotes the growth of collagen, the connective protein which binds us together, and this same effect of phenytoin probably causes the excessive growth of the gums mentioned above. In 1976 JW Frymoyer reported his work with phenytoin in the healing of bone fractures in rats. He gave his rats doses similar to the normal amounts given to human patients, and looked at healing of the wound at intervals of 5, 10, 15, 20, 25, and 30 days afterwards. Rats given phenytoin then showed markedly improved rates of healing; degree of healing by several different measures in phenytoin- treated animals exceeded that for controls. By Frymoyer's index of rate of healing, healing took place 40% faster in treated rats. Several studies in human beings found that phenytoin promotes the healing of leg ulcers, some of which had persisted for years (GM Simpson et al NEW YORK MED J 65 (1965) 886-888).
Finally any article on phenytoin should mention the evidence that phenytoin has markedly favorable effects on many neurological disorders, including migraine, anxiety (phenytoin acts as a sedative without any tendency to cause sleepiness), neuralgias, and movement disorders, including Parkinson's disease. Doctors also often use phenytoin to treat heart arrhythmias.
Although I have intensively discussed toxic reactions to phenytoin, readers should see these in proportion. The vast majority of epileptics take phenytoin without meeting problems, and our detailed knowledge of the toxicology of phenytoin comes as much from the large number of people who have taken it for a long time as it does from any propensity of phenytoin to cause problems.
What is the meaning of phenytoin and phenformin to us?
Even a cursory reading of this article shows that both phenytoin and phenformin have many side effects, so many that we might seriously wonder whether or not we would like to take them for our aging. Furthermore, the lifespan increases caused by either phenytoin or phenformin seem relatively small compared to their risk: both drugs may produce as much as a 25% increase, comparable to other less toxic drugs such as Deaner or BHT, and nowhere near the possible increases due to L-dopa, which also has many possibly dangerous side effects.
However drugs can be interesting for other reasons than the immediately practical. Phenformin is interesting for what it may tell us about aging and the cardiovascular system. Dilman and Anisimov suggest, in fact, that phenformin increases the lifespan of their mice by affecting their metabolism of FFAs (free fatty acids). Phenformin may tell us that heart disease, at least when it appears in the old, connects closely to the deteriorations of aging itself, so that we could not seriously expect to cure or help heart disease in such patients without affecting their basic aging. I believe that gerontologists would do well to study phenformin and the reasons for its action closely, because such study may tell us a great deal about heart disease, aging, and their relationships.
Phenytoin is perhaps even more interesting than phenformin, though for very different reasons. In the first place, even though I've listed an impressive and even horrifying set of side effects from phenytoin, many people take it all their lives without encountering any of the severe effects I have listed. I feel that phenytoin is therefore not a drug which we want to exclude from consideration. Future developments may help to make it much safer, particularly if the test for whether or not it will damage our liver and ways of reducing the bone weakness are worked out. So many epileptics take phenytoin that we can reasonably expect that doctors will find solutions to both of these problems. High doses of Vitamin D can already help to reduce bone loss, for instance.
The second reason why we want to watch phenytoin very closely is BASIC. Phenytoin was discovered, and epileptics started to use it, in 1939. Epilepsy is a common condition which does not (unlike diabetes) seem to threaten lifespan in any serious way: even before drug treatment epileptics could survive, although of course their seizures caused them many other problems. WE THEREFORE HAVE A LARGE POPULATION OF PEOPLE WHO HAVE BEEN TAKING AN ANTIAGING DRUG FOR OVER 30 YEARS. This period is longer, in fact, than the period for which people have taken GH-3. I have not, myself, found any report of the longevity of patients on phenytoin; despite this, they would provide an ideal population to study the possible ability of an antiaging drug to prolong lifespan IN HUMAN BEINGS. Phenytoin bears watching because we might actually be able to prove this drug increases human lifespans, and in the relatively near future.
Dosage and Availability
There seems little reason not to choose the standard dosage taken by epileptics, about 300 mg per day. Phenytoin does require a prescription, but because epilepsy isn't a rare condition all pharmacies will keep it in stock.
TO LEARN MORE:
About possible antiaging effects:
Dilman, VM; Anisimov, VN, "Increase in the lifetime and decrease in the frequency of tumors in C3H/Sn mice under the influence of phenformin and diphenin", DOKLADY BIOLOGICAL SCIENCES (ACAD NAUK SSR) 245(3) (1979) 841-844. Diphenin is a synonym for phenytoin. Dilman, VM; Anisimov, VN, "Effect of treatment with phenformin, diphenylhydantoin, or L-Dopa on life span and tumor incidence in C3H/Sn mice", GERONTOLOGY 26 (1980) 241-246
Dilman, V, "Age-associated elevation of hypothalamic threshold to feedback control and its role in development, aging, and death", LANCET (i) (1971) 1211-1219
The two best references for quickly getting a good idea of risks and benefits of these two drugs are the PHYSICIANS DESK REFERENCE and the MARTINDALE (EXTRA) PHARMACOPEIA (27th ed, 1977. A Wade (ed)). Recent editions of MARTINDALE do not discuss phenformin.
For Phenytoin:
Clemmesen, J et al, "Are anticonvulsants oncogenic?", LANCET 20 April 1974, p. 705-707
Dodrill, CB, "Diphenylhydantoin serum levels, toxicity, and neuropsychological performance in patients with epilepsy", EPILEPSIA 16 (1975) 593-600
Frymoyer, JW, "Fracture healing in rats treated with diphenylhydantoin", JOUR OF TRAUMA 16(5) (1976) 368-370
Jubiz, W et al, "Plasma 1,25 dihydroxyvitamin D levels in patients receiving anticonvulsant drugs" JOURNAL CLIN ENDOCRIN METAB 44(4) (1977) 617-621
Klar, LA, "Gingival hyperplasia during dilantin therapy: a survey of 312 patients", JOUR PUBLIC HEALTH DENTISTRY 33(3) (1973) 180
Li, FP et al, "Malignant lymphoma after diphenylhydantoin therapy", CANCER 36 (1975) 1359-1362
Lindall, AW, "The multiple system effects of diphenylhydantoin (dilantin)", MINN MED 52 (1969) 337-344
Parker, WA; Shearer, CA, "Phenytoin hepatotoxicity: a case report and review", NEUROLOGY 29 (1979) 175-178
Palmer, KT et al, "Anticonvulsant-induced osteomalacia", AGE AND AGEING 6(4) (1977) 228-231
Smith, WL; Lowrey, JB, "Effects of diphenylhydantoin on mental abilities in the elderly", JOUR AMER GERIATRIC SOC 23(5) (1975) 207-211
Spielberg, SP et al, "Predisposition to phenytoin hepatotoxicity assessed in vitro", NEW ENGL J MED 305 (1981) 722-727
Ziegler, DK, "Toxicity to the nervous system of diphenylhydantoin: a review", INT JOUR NEUROLOGY 11(4) (1978) 383-400
The MARTINDALE (EXTRA) PHARMACOPEIA contains an excellent and very detailed account of the side effects of dilantin in the entry "Phenytoin". A second bibliography and review of the literature, oriented to the positive effects of dilantin on nervous system disorders, is:
Bogoch, J Dreyfus THE BROAD RANGE OF USE OF DIPHENYLHYDANTOIN 1970, Dreyfus Medical Foundation.
Phenformin:
Benoit, R et al, "Acidose lactique et phenformine", BULL UN MED CANADA 105(12) (1976) 1810-1814
Bingle, JP et al, "Fatal self-poisoning with phenformin", BRIT MED J 3 (1970) 752
Coronho, V et al, "Acute self-poisoning with phenformin", ACTA DIABET LATINA 13(3-4) (1976) 130-133
Manzo, L et al, "The interaction between alcohol, chlorpropamide, and phenformin in a severe combined poisoning: a case report", TOXICOL EUROP RES 1(4) (1978) 267-272
Prasannan K; Augusti, KT, "Effects of longterm feeding of tolbutamide and phenformin on normal rats", INDIAN J MED RES 61(7) (1973) 1072-1081
University Group Diabetes Program, I, DIABETES 19 (suppl 2) (1970) 747-783; II (Mortality results) DIABETES 19 (suppl 2) (1970) 789-830; III JAMA 218 (1971) 1400-1410; IV JAMA 217 (1971) 777-784; V (Evaluation of phenformin therapy) DIABETES 24 (1975) (suppl 1) (1975) 65-184
Williams, RH; Palmer, JP, "Farewell to phenformin for treating diabetes mellitus", ANN INTERN MED 83(4) (1975) 567-568
Note: The chemical diagram at the front of this Chapter shows phenytoin.
| This article contains chapters from the book, A GUIDE TO ANTIAGING DRUGS, published by PERIASTRON.
Dr. Donaldson aimed to provide, in the GUIDE, a discussion of both the good points and the bad points, of every drug shown by experiment to prolong the healthy lifespan of some mammal. The mammals involved must normally reach at least the average lifespan of their species.
This Web Site provides only samples of only part of the GUIDE, which discusses other drugs also. | |