Periodontal risk factors associated with medical treatment of elderly patients

Introduction

The purpose of this article is to review risk factors in periodontics that are associated with medications used for treating ailments suffered primarily by elderly individuals.

This article is divided into five segments. First, a review of the contemporary demographics of today's elderly population ; second, some details about the medications used by our elderly population ; third, considerations of the prevalence of the adverse effects these drugs can have in the oral cavity, specifically in the periodontium ; fourth, a brief review of some of the most common of these adverse reactions in the aging population. The article will conclude with a discussion of some of the new therapeutic challenges facing our profession as we attempt to treat clinical problems of this kind.

The aging population

^{Figure 1a} and ^1b , presents what are called « population pyramids » from two points in time for the country of Switzerland. For the purpose of this discussion, I chose Switzerland a) because it is a small country and b) because the Swiss have historically been exceptionally good at collecting data about their population. ^{Figure 1a} depicts the population pyramid for Switzerland in the year 1920, when the country had about 4,000,000 inhabitants. Notice the very even distribution of male and female young adults (ages 20-40) and a rapid tapering off toward the elderly categories, all the way up to 80. In 1920, there were very few 80- to 90-year-old individuals in Switzerland. In sharp contrast, ^{figure 1b} projects the population pyramid for the year 2000 in Switzerland, when the population is expected to be about 6,000,000. Evident here is a dramatically different pyramid dynamic. The shaded areas represent those persons who will be gainfully employed, while Swiss citizens depicted in the non-shaded segments of the graph are those who will be unemployed. Notice the large bulge in the middle of the age pyramid (ages 30 to 60 years), and also the dramatic increase in the numbers of persons who will be over the age of 65, some of whom are expected to be gainfully employed. The 70- to 90-year-old segment of the population now represents a significant proportion of the total population.

Switzerland can be taken as an excellent example of a highly developed Western country, and thus these population pyramids are likely to be comparable for other such countries. For example, the most recent figures from the United States census bureau show that the population of the USA is currently at about 250,000,000. Furthermore, the « over-60 » segment represents fully 17 percent of the population ; thus, almost 43,000,000 persons in the United States can today be categorized as « elderly ». The « over-65 » population represents 12-13 percent of the total US population.

What do we know about the elderly population in the industrialized Western countries ? The answer to that question is : Not nearly as much as we probably should know ; however, thanks to intensive research, our knowledge base is expanding very rapidly. We know that host systemic resistance is reduced in elderly persons, their strength and coordination are often compromised, their ability to adapt to new situations (e.g., dentures, partial dentures, implants, etc.) is impaired, and their short-term memory is often severely reduced. The proprioceptive mechanisms are often also impaired in the elderly population, as well as associative function, ability to learn, limitations obviously of sight and hearing, and - especially important for dentists and periodontists - the manual dexterity of elderly individuals is often severely compromised. This underscores the fact that patient compliance controls the outcome of periodontal therapy. It is well established that home-care (plaque control) tends to gradually but surely decrease between recall visits. For example, without recall, a patient will quickly reachieve about 30-40 percent plaque control levels, which are typical pre-therapy values (^{Leu, 1977}). This means that a dentist may be forced to shorten the recall interval for elderly patients if they are to maintain a level of plaque control that is above the critical 80 percent value.

Traditionally, the aging process has been synonymous with tooth loss, even to total edentulousness. As a relatively recent example, when young American men were conscripted into military service in the late 1930s and early 1940s, the most frequent cause for rejection was failure to meet the dental requirement, which was the presence of twelve teeth that more or less occluded (^{Ring, 1985}). Subsequently, an interesting series of clinical epidemiologic studies was performed, starting from 1957 and progressing up to the most recent one (in 1992), of edentulousness in the United States citizenry. In the 1957-58 study (^{Bersten, 1960}), almost 70 percent of persons over the age of 75 were completely edentulous. In the study that was performed in 1971, that figure had dropped to 60 percent (^{Burnham, 1974}). By 1983, the figure had gone all the way down to less than 50 percent edentulousness in the elderly population over age 75, and in the most recent epidemiologic study, the 75-and-over age group had stabilized at about 50 percent edentulousness (^{Marcus et al., 1996}). Looking at this data in a different way, in 1960, 36 percent of all Americans between the ages of 55 and 64 were edentulous. By 1985, that number had decreased to 12 percent. In a more recent study (in 1992), only 49 percent of Americans over the age of 80 were completely edentulous (^{Douglas et al., 1993}). It is clear that edentulousness is waning rapidly as a public health statistic, even in elderly populations.

There are other interesting trends that are evident in the elderly population. For example, in a study (OHCC, 1993) performed from 1982 to 1986, it was found that elderly persons are visiting their dentists more frequently, a 30 percent increase in the 3 year period from 1983 to 1986. It is reasonable to speculate that this trend has continued in the decade since 1986 ; therefore, the patients in our dental practices now and in the future are going to be represented by a much higher number of elderly individuals.

With especial regard to the periodontal health of older individuals, there has been some controversy and discussion during the last few years about an epidemiologic survey (^{Loë, 1987}) that was sponsored by the US National Institute of Dental Research (NIDR) in the 1980s. One controversial conclusion from this study was that " periodontal disorders affect only a minority of the elderly population ". However, some contemporaneous clinical research (^{Fox et al., 1994}), performed by Dr C. Douglas and his coworkers (the " NEEDS " study : North East Elders Dental Study) has raised serious doubts about the NIDR conclusions. The NEEDS research was a study of over 1,000 elderly persons in the New England area. These were home-dwelling individuals ; they were not in nursing homes or institutions. In this sample population, 89 percent exhibited dental calculus accumulation, 85 percent had bleeding on probing, 39 percent exhibited moderate loss of periodontal attachment, and 56 percent exhibited severe loss of attachment. In these community-dwelling elders over age 70, 66 percent exhibited periodontal pockets of 4-6 mm and 21 percent had pockets greater than 6 mm in depth. ^{Table I} represents a comparison of some of the results from the NIDR study (N = 510) and the NEEDS study (N = 1150). In the latter, 28 percent of the sampled subjects still had 20 or more teeth, and in every category measured the findings of the NEEDS study showed much higher levels of periodontal involvement than the NIDR project. The myriad of factors that contributed to the disparity between the two studies is beyond the scope of this review. Nevertheless, one can conclude that the prevalence and severity of periodontal problems among older Americans has been underestimated by previous national studies.

Use of medications

The elderly comprise the fastest growing segment of our population, and they are maintaining their teeth longer than ever before in history. They also suffer from more chronic diseases than younger individuals, and therefore they also take significantly more medications. In 1988, doctor-prescribed medications accounted for almost 30 billion dollars of expenditure in the United States. « Over-the-counter » (OTC, non-prescription) drugs accounted for about $15 billion. Although the over-65 age category comprises only about 13 percent of the US population, it consumes 25 percent of all medical services ; furthermore, more than 40 percent of all the expenditures for medications (doctor-prescribed and OTC) are made by and for persons over the age of 65.

Viewed in another way, these figures become even more dramatic : 85 percent of all home-dwelling and ambulatory elderly individuals are on some type of long-term drug regimen, whereas 95 percent of all institutionalized elderly are on a long-term drug regimen. In summary, there is a large and fast-growing segment of the population that is consuming a disproportionately large share of medicines.

The most common category of drugs taken by the elderly is cardiovascular medications. ^{Table 2} lists the other seven types of medicine used most often by older persons : antihypertensives, analgesics, anti-arthritics, sedatives, tranquilizers and gastrointestinal medications. It is a startling fact that the average 70-year-old in the United States is taking about 14 different prescription medications. Unfortunately, a recent study (^{Nelson et al., 1987}) revealed that older patients who are admitted to hospitals could not identify 60 percent of the drugs that they were taking, could not identify their medications by name, and were not able to tell the physician why they were taking that particular drug. This fact is important for dentists and dental specialists, especially periodontists, who need to be able to cross-check the Physicians Desk Reference (PDR) or similar reference works to determine whether any intraoral side effects are associated with the medications.

Oral side effects of medications

In 1991, Baker and coworkers published an interesting article about drug use by elders (N = 500), in the journal Special Care in Dentistry. Baker et al. reported that 51 percent of their sample were taking some type of diuretic drug, 17 percent were taking an antipsychotic drug, 13 percent were taking an antihistamine, 12 percent were on an antidepressant regimen, and 11 percent were ingesting antihypertensives regularly. All of these types of drugs exert adverse effects in the oral cavity. These effects fall into four categories (^{table III}). True allergic reactions or idiosyncratic reactions to drugs are quite rare. Overdose reactions are not uncommon with virtually all medications until the titer of the drug is stabilized in the bloodstream. However, of primary interest to the periodontist are the true side affects, the adverse intraoral reactions to drugs frequently taken by the elderly population. ^{Table IV} presents a list of the commonly occurring intraoral lesions that are the direct result of an adverse reaction to a drug taken by elderly individuals. These are just some of the oral manifestations of drugs commonly taken by the elderly population. In the study by Baker and colleagues in 1991 (^{table V}), 74 percent of those sampled were taking a drug known to cause xerostomia as a side effect. Fifty percent of the entire elder sample were taking one or more drugs known to cause a soft tissue reaction. Almost 40 percent of the sample were taking a drug that was associated with a side effect of abnormal hemostasis, e.g., gingival bleeding or petechial hemorrhage. Almost 40 percent of the elderly individuals studied by Baker's group were taking a drug that has been associated with overgrowth or hyperplasia of the gingiva, and 15 percent were taking drugs that would alter host resistance to infection.

The first task of the periodontist is to determine the cause-and-effect relationship between medications and oral changes. It is necessary to establish a temporal relationship between the use of the drug and the onset of an adverse oral reaction. For example, not everyone who takes a drug that might cause xerostomia actually develops xerostomia. Furthermore, patients may develop xerostomia for reasons other than taking a particular drug or combination of drugs. The intraoral reactions may be due to a systemic effect, rather than or in addition to the particular medication that is being taken on a chronic regimen. It is important to clarify such relationships before establishing a definitive diagnosis.

Of interest in this regard is a clinical study performed by McClain and coworkers, which was published in Special Care in Dentistry in 1991. This was a study of 90 Caucasian dental patients in North Carolina ; all were 65 years of age or older. The protocol included a comprehensive dental exam including the gingival index (GI), the plaque index (PI), the calculus index (CI), and the community periodontal index of treatment needs (CPITN or PSR). From their study results, McClain et al. concluded that " clinically evident medication effect is a relatively infrequent phenomenon in elderly individuals ". Now, this conclusion appears to contradict other studies. However, when one looks carefully at the Materials and Methods section of the article, one finds that McClain and colleagues excluded from their survey all patients with diabetes, epilepsy, hypertension or antibiotic treatment. These are the four categories of patients who would be most likely to take drugs that are associated with oral side effects !

This particular clinical study is a good example to show how important it is to read carefully and understand our professional literature. How could McClain and coworkers study drug side effects in the elderly if they excluded the population most likely to manifest such effects ?

Probably the most frequent drug side effect observed in older patients is xerostomia (« dry mouth ») (^{table V}). Many classes of medication can be associated with xerostomia (^{table VI}). The question is : Is it a problem for the patient ? Some patients with mild xerostomia experience no perceptible difficulties whatever. Other patients, suffering severe xerostomia, may have significant difficulties. They may have difficulties wearing dentures, difficulties with oral hygiene at home, difficulties with mastication of food, and even difficulties with speaking. These are the patients to whom we must target treatment. What might that treatment consist of ? Obviously, if xerostomia is associated with a drug that the patient is taking, the first choice of action would be to simply remove or replace that drug with some other drug, in consultation with the patient's physician. There are several commercially available " artificial saliva " products, and some patients do get relief from such products. Recent research has demonstrated that routine home use of a high-speed powered toothbrush (sonicare, Bellevue, WA) can enhance saliva flow rate by up to 250 percent in patients with xerostomia (^{Papas et al., 1998}).

Common oral drug adverse reactions

Presented in this section are some of the medications that are generally acknowledged to cause adverse reactions in the oral cavity, and clinical illustrations of the appearance of such side effects is also presented.

Acetyl salicylic acid (aspirin)

This is an OTC drug that is commonly taken for pain, but also as one component of a cardiac prophylactic regimen. A common intraoral adverse reaction to long-term aspirin use is hemorrhage of oral mucosa and gingiva. ^{Figure 2} depicts an area of petechial hemorrhage in an edentulous patient who was taking aspirin on a chronic regimen and a high dose. In dentulous patients, aspirin-induced gingival bleeding can confound clinical investigations where the parameter " bleeding on probing " (BOP) is measured, or when BOP is used to monitor home care compliance or efficacy.

Coumadin

Many elderly patients take coumadin (sodium warfarin) and similar anticoagulants. These are often used for treatment of venus thrombosis, and also very frequently in postmyocardial infarction patients. This drug is associated with hemorrhagic petechia, which can be observed on the palate of the coumadin treated individual depicted in ^{figure 3} .

Colchicine

This anti-uric acid drug is used in the treatment of gout, and also in the treatment of gouty arthritis. It is associated with adverse reactions including " sore gums " and thrombocytopenia. Gingival bleeding is a common sequella. ^{Figure 4} depicts spontaneous hemorrhage in the soft palate area, in a colchicine treated patient whose platelet count was below 50,000.

Septra

This is an antibacterial agent that is used most frequently for urinary tract infections, but also for other types of infections. Chronic ingestion of septra is often associated with glossitis, stomatitis and gingival bleeding (^{fig. 5}) associated with thrombocytopenia, which is a direct side effect of septra medication. Thrombocytopenia, and the resultant intraoral hemorrhage, is a common side effect of many medications (see ^{table VII} ). The periodontist must be cognizant of these drugs, and be alert when encountering a patient with what appears to be an elevated level of gingival bleeding on probing, or spontaneous gingival hemorrhage.

Tetracycline

This is an antibiotic, obviously, and one of the several such drugs that are being used more and more frequently today in the treatment of some periodontitis patients. In general, systemic antibiotic therapy is often associated with the adverse reaction of candidiasis (^{fig. 6}), also known as « thrush reaction ». This is an overgrowth of fungal organisms in the oral cavity, primarily Candida albicans. Virtually any other antibiotic taken by the elderly on a chronic regimen may result in a candidiasis reaction.

Aldomet

This is an antihypertensive drug, an alpha methyldopa derivative that is associated with numerous oral side effects in a relatively high percentage of patients who take the drug on a chronic regimen. Among the adverse reactions are so-called « black tongue » (^{fig. 7}), xerostomia, and the gingival hemorrhage associated with thrombocytopenia.

5-Fluorouracil

An anti-neoplastic agent used in the treatment of colon and breast carcinoma, this drug is often associated with stomatitis and oral ulceration in patients who are taking this drug on a chronic regimen (^{fig. 8}).

Bleomycin

This is an interesting drug in many respects. Bleomycin (^{fig. 9}) is an anti-neoplastic agent that is used in patients with mid- to late-stage carcinoma. Possible adverse reactions include connective tissue fibrosis and gingival overgrowth, but the intraoral side effects are very poorly documented, probably because bleomycin-treated patients are usually severely debilitated by their cancer, and the gingival condition, be it overgrowth or inflammation, is secondary and often not documented at all. However, when gingival fibroblasts from 50-year-old individuals were exposed to bleomycin in culture there was a 400 percent increase in protein and collagen synthesis by those cells. Interestingly, the most commonly documented adverse effect of bleomycin is fibrosis of the lung and other internal organs. Thus, Neomycin stimulates fibroblasts not only in the gingiva but also in the lung. Since bleomycin-treated cancer patients often die due to lung fibrosis and not to the cancer itself, it is likely that such patients also manifest gingival overgrowth.

Cyclosporine-A

The transplantation of organs is not uncommon today, as it was 25 years ago. The transplantation of kidneys, livers, lungs and hearts is routine today. To prevent rejection of such transplants, the drug of choice is Cyclosporine-A, marketed under the trade name Sandimmune. Many periodontal patients are also organ transplant patients, and almost all of them are taking Cyclosporine. The periodontal literature has been filled recently with articles about the gingival overgrowth that is elicited by Cyclosporine (^{fig. 10}), in 25-40 % of all patients who take this drug (^{Hefti et al., 1994}). The lesions are histologically identical to those elicited by the antiepileptic drug phenytoin : An accumulation of redundant collagen matrix elements. The tissue regrows very rapidly after it is surgically resected. Because solid organ transplantation has become such a common medical procedure, dentists and periodontists are going to have to deal with gingival overgrowth much more frequently.

Phenytoin

This anti-seizure drug was first marketed in 1938 (by Parke Davis Co., as " dilantin "). The gingival enlargement and overgrowth caused by chronic phenytoin ingestion is well documented clinically, histologically and pathogenetically (^{Hassell, 1981}). Only recently, however, have new articles (^{McCord et al., 1992}) appeared in the professional literature, which describe phenytoin-induced fibrous hyperplasia of edentulous oral tissues (^{fig. 11}), and fibrous gingival hyperplasia surrounding teeth that serve as abutments for partial dentures. These observations have been made mainly in older persons. Until these recent reports, the phenytoin-induced gingival lesions were perceived as being a problem primarily of young persons, up to the age of about 25 or 30 (^{Hefti et al., 1994}). Until the appearance of this more recent literature, I think that practitioners and clinical scientists were not looking for phenytoin-induced soft tissue enlargement in the elderly, and therefore did not see it and did not report it. Needed now are some well-designed clinical studies of the elder population who are still taking phenytoin, to see what the prevalence of soft tissue problems truly is in the elderly population.

The substituted dihydropyridines

In the early 1980s, the European pharmaceutical industry introduced nifedipine as the newest and most effective antihypertensive medication. This drug is also used in post-myocardial syndrome and other cardiovascular cases. In 1983, in the Journal of Cardiology, it was first reported that nifedipine (marketed as Procardia in the USA and by many other trade names worldwide, e.g., Adalat in Germany) is associated with the development of gingival overgrowth (^{Ramon et al., 1984}). ^{Figure 12} presents a 56-year-old Black female with a very generalized case of Procardia-induced gingival overgrowth, also associated with abscesses and advanced periodontitis. For the first time since 1938, a new class of drugs was implicated in the pathogenesis of gingival enlargement and overgrowth. These exuberant lesions are being observed more and more frequently in the elderly population, because hypertension and cardiovascular events are most common in this age category. For over 60 years, all of our gingival overgrowth patients (phenytoin patients) were young ; now, we are observing gingival enlargements in about 25-30 % of adult elderly individuals who ingest dihydropyridine-type medications regularly.

These new drugs are almost 100 times more effective than the previous " standards of care " for hypertension (beta blockers, diuretics, ace inhibitors). The revolution began with nifedipine, but now there is a large family of substituted dihydropyridines on the world market (^{table VIII}), including felodipine, nicardipine, nimodipine, nitrendipine, nisoldipine and others, and the patients in our periodontal practices are taking these drugs routinely and on a chronic regimen. All of the drugs in this family of medicaments elicit the side effect of gingival overgrowth in the elderly population at a prevalence rate of about 25-30 %. We are going to continue to see these patients in our periodontal practices, because of the gingivalside effects.

Sometimes the overgrowth lesions are very localized lesions, but often also generalized throughout the oral cavity. The clinical picture and the histological picture are identical to a phenytoin-induced case, and the in vitro reactions of gingival fibroblast cells are similar (^{Willershausen-Zoennchen et al., 1994}). For over 60 years, because " gingival hyperplasia " has been a problem of younger persons, we haven't seen any associated bone loss, and the patients have always healed quickly because they're young. However, suddenly we are faced with a patient who comes in looking like the Caucasian female depicted in ^{figure 13a} : She was wearing a temporary anterior bridge, and had started taking Procardia about eight months before this photograph was taken. She presented in the periodontist's office with sincere concerns about the condition and appearance of her gingivae. After a thorough diagnostic appointment, it became evident that - in addition to her gingival enlargement - she was also suffering from moderate-to-advanced adult periodontitis with significant alveolar bone loss in the anterior segments. The periodontist was faced with a very unusual situation : A patient with excessive gingival tissue and inadequate alveolar bone. How shall we approach cases like this surgically ? This, today, remains an unanswered question. To treat the periodontitis, we have available the classical osseous resective procedures or osteoplastic procedures that are common in flap-and-osseous periodontal surgery today (^{fig. 13b} and ^13c) . However, in cases like this, we often end up with a less than satisfactory esthetic result in patients who come to us with the superimposition of gingival overgrowth onto pre-existing periodontitis. The clinical picture presented here as ^{figure 13d} was take 10 days after the surgery. One might question whether or not this was a " successful " therapy. It was certainly successful in the sense that the tissue is healthy and there aren't any residual pockets. But is this success in terms of esthetics ? In terms of patient satisfaction ?

In the future, how shall we treat patients with dihydropyridine-induced gingival overgrowth ? A great deal more research, both in the laboratory and the clinic, is required before we can answer that question. Can we combine, for example, regenerative procedures (for bone) and resective procedures (for gingivae) ?

In summary, what do we know today about our potential patient population, and their periodontal requirements ? We know that persons over 70 are the fastest growing segment of the population. We know that these individuals are keeping their teeth much longer than ever before in history. We know that they have more chronic diseases than the younger population. And we know that they take significantly higher amounts of medications. We know these medications have numerous adverse side effects, and that many of these side effects are reflected in the oral cavity. We know that many of those oral side effects are directly periodontally-related, and that we will continue to see these patients on a more frequent basis in the years to come.

It is incumbent upon our profession to dedicate our energy and our research efforts in this growing aspect of daily practice.

The author wishes to thank Drs Gregg Gilbert, Ann Jones and Teresa Dolan for fruitful discussions during the preparation of this article.

BIBLIOGRAPHY

• LEU M. Nachsorge parodontalbehandelter Patienten. Dtsch Zahnaerztl Z 1977;32:38-43.
• RING ME. Dentistry : An Illustrated History. New York : Harry N Abrams, Inc. and St Louis : The CV Mosby Co., 1985, 294.
• BERGSTEN JW. US Department of Health, Education and Welfare, Public Health Service. Health Statistics from the US National Health Survey. Loss of Teeth, United States, July 1957- June 1958. PHS Publication No. 584B22. Washington, DC : US Government Printing Office, 1960.
• BURNHAM CE. National Center for Health Statistics, Edentulous Persons : United States- 1971. Vital and Health Statistics, Series 10-#89. DHEW Publication No. (HRA) 74-1516. Health Resources Administration. Rockville, MD : US Government Printing Office, June 1974.
• MARCUS S, DRURY T, BROWN L, ZION G. Tooth retention and tooth loss in the permanent dentition of adults : United States, 1988-1991. J Dent Res 1996;75 (spec. lss.):684-695.
• DOUGLAS C, JETTE A, FOX C, TENNSTEDT S, JOSHI A, FELDMAN H, MCGUIRE S, MCKINLAY J. Oral health status of the elderly in New England. J Gerontol 1993;48:M39-M46.
• Toward improving the oral health of Americans ; overview of oral health, services and methods. Public Health Reports, No. 108, volume 6, pp. 652-672. Oral Health Coordinating Committee (OHCC), United States Public Health Service, 1993.
• LÖE H (ED). Oral Health of United States Adults. The national survey oral health in US employed adults and seniors : 1985-1986. US Department of Health and Human Services, Public Health Service, National Institutes of Health, 1987. NIH Publication No. 87-2868.
• FOX C, JETTE A, MCGUIRE S, FELDMAN H, DOUGLAS C. Periodontal disease among New England elders. J Periodontol 1994;65:676-684.
• NELSON J, BARNES G, TOLLEFSBOL R, PARKER W. Prevalence and significance of prescription medication usage among gerodontic patients. Gerodontology 1987;6:17-22.
• BAKER K, LEVY S, CHRISCHILLES E. Medications with dental significance : usage in a nursing home population. Spec Care Dentist 1991;11(1):19-25.
• MCCLAIN D, BADER J, DANIEL S, SAMS D. Gingival effects of prescription medications among adult dental patients. Spec Care Dentist 1991;11(1):15-18.
• PAPAS A, STACK K, SPODAK D. Sonic toothbrushing increases saliva flow rate in Sjögrens Syndrome patients. J Dent Res 1998 (in press).
• HEFTI A, ESHENAUR A, HASSELL T, STONE C. Gingival overgrowth in cyclosporine-A treated multiple sclerosis patients. J Periodontol 1994;65:744-749.
• HASSELL T. Epilepsy and the Oral Manifestations of Phenytoin Therapy Basel. Basel : Karger Publishers, 1981, 206 p.
• MCCORD J, SLOAN P, QUALE A, HUSSEY DJ. Phenytoin hyperplasia occurring under complete dentures : a clinical report. J Prosthet Dent 1992;68:569-572.
• RAMON Y, BEHAR S, KISHON Y ET COLL. Gingival hyperplasia caused by nifedipine - a preliminary report. Int J Cardiol 1984;5:195-204.
• WILLERSHAUSEN-ZOENNCHEN B, LEMMEN C, ZOENNCHEN B ET COLL. Influence of nifedipine on the metabolism of gingival fibroblasts. Biol Chem Hoppe Syler 1994;375:299-303.