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Calcium channel blockers-induced gingival hyperplasia
378
ORAL SURGERY ORAL MEDICINE ORAL PATHOLOGY
Letters to the editor
April 1996 bin time ratio (PTR) monitoring systems themselves, I must take issue with the following points. The authors state, " A PTR of 2 to 2.5 is considered the therapeutic range," but then in Table I show a different therapeutic range from 1.3 to 1.8. Actually, the therapeutic range for PTR for oral anticoagulant therapy is dependent on the ISI value but will generally range from (no lower than) PTR 1.3 to (no higher than) PTR 2.0, not 2.0 to 2.5. Table I shows the 1989 recommendations for therapeutic range of oral anticoagulation, but these recommendations were updated in 19922 and later endorsed by the American Heart Association) The table shows recurrent systemic embolism and atrial fibrillation with systemic emboli as conditions with recommended INR from 3 to 4.5, but it is now recommended that patients with these conditions be anticoagulated between INR 2.0 and 3.0. Patients with mechanical heart valves should now be anticoagulated between INR 2.5 and 3.5, not 3.0 to 4.5. In summary, for most conditions that require continuous anticoagulation, the therapeutic range of anticoagulation is from INR 2.0 to 3.0. Only with mechanical heart valves is a higher INR (INR 2.5 to 3.5) recommended. These levels generally correspond to I ~ R s no higher than 2.0. The latest recommended levels of continuous oral anticoagulation are simpler and lower than ever before. They are therefore more understandable for physicians, patients, and dentists, and are less likely to be associated with bleeding problems after surgery. Michael J. Wahl DDS Wilmington, Delaware
REFERENCES
1. Steinberg MJ, Moores JF. Use of INR to assess degree of anticoagulation in patients who have dental procedures. OrAL SURC ORALMED ORALPAa~qOLORALRADIOLENDO 1995; 80:175-7. 2. Hirsh J, Dalen JE, Deykin D, Poller L. Oral anticoagulants: mechanism of action, clinical effectiveness, and optimal therapeutic range. Chest 1992;102(suppl):312S-326S. 3. HirshJ, Fuster V. Guide to anticoagulant therapy. Part 2: oral anticoagulants. Circulation 1994;89:1469-80.
Calcium channel blockers-induced gingival hyperplasia To the editor: W e have read with great interest the article by Harel-Raviv et al. entitled, Nifedipine-induced gingi-
val hyperplasia: A comprehensive review and analysis,. published in the June issue of this Journal (1995;79:715-22). Because some of our work was quoted, we feel the need to clarify our position on the subject. Our group is working on an animal model of gingival hyperplasia induced in dogs treated with oxodipine, a dihydropyridine-type calcium antagonist. 1 T h e authors of the aforementioned article are probably unaware of the existence of an animal model that has been recognized as pathologically similar to that noted in human beings treated with calcium antagonists and that is used today to investigate the mechanism, of gingival hyperplasia. 1 We have noticed that there is a direct relationship between the dosage of the drug and the appearance of the gingival hyperplasia. Almost complete recovery of the gingival change was noted after a 2-month drug withdrawal period. We have investigated the collagen fibers of the hyperplastic gingiva by measuring the polarization colors from Picrosirius-red stained paraffin sections. 2 There was a difference in the polarization colors of the thick collagen fibers (1.6-2.4 lam diameter) between the genders, and it has been proposed that this difference may indicate gender variation in the genesis of gingival hyperplasia in dogs. 2 The difference in the hyperplastic collagens between genders may be explained by the fact that the gingiva is an androgen target tissue containing receptors for 5-oLdihydrotestosterone. These receptors are implicated in the stimulation of fibroblasts to proliferate and synthesize collagen, as the authors mention in their article (Fig. 3). However, it is of interest to note that they cited such mechanism connected with the administering of phenatoin (see "Possible mechanisms"). W e wonder why the authors are not aware of the connection between administering a calcium channel blocker and the increase in the number of hyperplastic gingiva, particularly in male patients treated with nifedipine. 3 On the basis of our findings that oxodipine induces hyperplasia of the adrenal zona glomerulosa, we recently proposed a mechanism by which calcium antagonists induce gingival hyperplasia in dogs. 4 In brief, the calcium antagonist induces blockage of the aldosterone synthesis in the zona glomerulosa of the adrenal cortex, because this pathway is calciumdependent. This may produce a feed-back stimulation of an increase in pituitary secretion of A C T H that affects zona glomerulosa hyperplasia. This hyperplasia is merely related by accumulation of steroid intermediate products (androgens) that are transformed to testosterone because of an increase in 17-oL-hy-
ORAL SURGERY ORAL MEDICINE ORAL PATHOLOGY
Letters to the editor
379
Volume 81, Number 4 droxylase enzyme activity. The testosterone then acts on the gingival tissue~4 At present, the role of testosterone in the genesis of gingival hyperplasia is under investigation (Dayan et al., manuscript in preparation). Dr. Abraham Nyska, D V M Kimron Veterinary Institute PO Box 12 Beit Dagan 50250, Israel Fax: 972-8-408951 Prof. Dan Dayan, DMD, MSc Section of Oral Pathology and Oral Medicine The Maurice and Gabriela Goldschleger School of Dental Medicine Tel Aviv University Tel Aviv 69978, Israel Fax: 972-3-6409250 REFERENCES 1. Nyska A, Waner T, Zlotogorski A, Pirak M, Scolnik M, Nyska M, Galliano A. Animal model of human disease: oxodipineinduced gingival hyperplasia in beagle dogs. Am J Pathol 1990; 137:737-9. 2. Dayan D, Waner T, Tal H, Nyska A. Polarization microscopy of Picrosirius red-stained collagen from oxodipine-induced hyperplastic gingiva of beagle dogs. Int J Exp Pathol 1993; 74:225-8. 3. Sooriyamoorthy M, Gower DB, Eley BM. Androgen metabolism in gingival hyperplasia induced by nifedipine and cyclosporin. J Periodontal Res 1990;25:25-30. 4. Nyska A, Shemesh M, Tal H, Dayan D. Gingival hyperplasia induced by calcium channel blockers: mode of action. Med Hypotheses 1994;43:115-8.
In reply The letter to the editor from Dr. Abraham Nyska and Professor Dan Dayan of Tel Aviv University related to our article is informative, and the authors should be complimented for their continued interest and involvement in identifying the possible mechanism for nifedipine-induced gingival hyperplasia. It is true that we were unaware of the existence of an animal model as we had been researching the dental literature and the references supplied by the authors of the letter were not included in our Medline search for perusal. Their continued research and future publication will be a welcome addition to the understanding of the mode of action of dihydropyridine-type calcium antagonists in causing gingival hyperplasia. We obviously are well aware of the connection between calcium channel blockers and hyperplastic gingiva, and the reason for this article was to present to the dental community an overview and comprehensive review of the dental literature. The use of
calcium channel blockers for the treatment of hypertension and angina pectoris is increasing, especially with the introduction of second generation dihydropyridine type calcium antagonists. This article should bring to the dental profession an increased awareness of an altered state that is induced by a drug in common use. Dr. Mervyn Gornitslcy Peofessor, Faculty of Dentistry Dr. Mili-Harel Raviv Assistant Professor, Faculty of Dentistry McGill university Montreal, Qu6bec, Canada
Cause of m e d i a n r h o m b o i d glossitis To the editor: In reflecting on possible etiologic factors for the development of median rhomboid glossitis (MRG), it has come to our attention that perhaps there are indeed sufficient local factors to promote lesional development. Although many theories have been proffered, it does appear that the idea of persistance of the tuberculum impar has fallen away and given rise to a localized candidal infection. 1, 2 Attempts have been made to ascertain the cause for candidal proliferation in this area alone; however, none have been completely all conclusive) We would like to make a comparison with another common candial infection and offer a " n e w " theory for M R G development. Cases of denture-induced candidiasis (denture sore mouth) are thought to arise because the organisms are in a warm moist environment that is protected from the antimicrobial, enzymatic, and physical cleansing actions of saliva. In similar fashion, it could well be that in many instances, candidal organisms of the mid to posterior dorsal tongue are also shielded from these same actions. Arendorf and Walker 3 suggested that the tongue is the primary oral reservoir for Candida Albicans and stated that perhaps the large surface area of the lingual papillae possibly shelter the organisms from removal during eating and swallowing. Furthermore, it was suggested that the concentration of these organisms about the lingual midline might explain the reason for the development of MRG. It was suggested, however, that other factors may also play a role. As such, we would like to comment on another possible element that may be involved in the causation of MRG. In reviewing the physiologic actions of
ORAL SURGERY ORAL MEDICINE ORAL PATHOLOGY
Letters to the editor
April 1996 bin time ratio (PTR) monitoring systems themselves, I must take issue with the following points. The authors state, " A PTR of 2 to 2.5 is considered the therapeutic range," but then in Table I show a different therapeutic range from 1.3 to 1.8. Actually, the therapeutic range for PTR for oral anticoagulant therapy is dependent on the ISI value but will generally range from (no lower than) PTR 1.3 to (no higher than) PTR 2.0, not 2.0 to 2.5. Table I shows the 1989 recommendations for therapeutic range of oral anticoagulation, but these recommendations were updated in 19922 and later endorsed by the American Heart Association) The table shows recurrent systemic embolism and atrial fibrillation with systemic emboli as conditions with recommended INR from 3 to 4.5, but it is now recommended that patients with these conditions be anticoagulated between INR 2.0 and 3.0. Patients with mechanical heart valves should now be anticoagulated between INR 2.5 and 3.5, not 3.0 to 4.5. In summary, for most conditions that require continuous anticoagulation, the therapeutic range of anticoagulation is from INR 2.0 to 3.0. Only with mechanical heart valves is a higher INR (INR 2.5 to 3.5) recommended. These levels generally correspond to I ~ R s no higher than 2.0. The latest recommended levels of continuous oral anticoagulation are simpler and lower than ever before. They are therefore more understandable for physicians, patients, and dentists, and are less likely to be associated with bleeding problems after surgery. Michael J. Wahl DDS Wilmington, Delaware
REFERENCES
1. Steinberg MJ, Moores JF. Use of INR to assess degree of anticoagulation in patients who have dental procedures. OrAL SURC ORALMED ORALPAa~qOLORALRADIOLENDO 1995; 80:175-7. 2. Hirsh J, Dalen JE, Deykin D, Poller L. Oral anticoagulants: mechanism of action, clinical effectiveness, and optimal therapeutic range. Chest 1992;102(suppl):312S-326S. 3. HirshJ, Fuster V. Guide to anticoagulant therapy. Part 2: oral anticoagulants. Circulation 1994;89:1469-80.
Calcium channel blockers-induced gingival hyperplasia To the editor: W e have read with great interest the article by Harel-Raviv et al. entitled, Nifedipine-induced gingi-
val hyperplasia: A comprehensive review and analysis,. published in the June issue of this Journal (1995;79:715-22). Because some of our work was quoted, we feel the need to clarify our position on the subject. Our group is working on an animal model of gingival hyperplasia induced in dogs treated with oxodipine, a dihydropyridine-type calcium antagonist. 1 T h e authors of the aforementioned article are probably unaware of the existence of an animal model that has been recognized as pathologically similar to that noted in human beings treated with calcium antagonists and that is used today to investigate the mechanism, of gingival hyperplasia. 1 We have noticed that there is a direct relationship between the dosage of the drug and the appearance of the gingival hyperplasia. Almost complete recovery of the gingival change was noted after a 2-month drug withdrawal period. We have investigated the collagen fibers of the hyperplastic gingiva by measuring the polarization colors from Picrosirius-red stained paraffin sections. 2 There was a difference in the polarization colors of the thick collagen fibers (1.6-2.4 lam diameter) between the genders, and it has been proposed that this difference may indicate gender variation in the genesis of gingival hyperplasia in dogs. 2 The difference in the hyperplastic collagens between genders may be explained by the fact that the gingiva is an androgen target tissue containing receptors for 5-oLdihydrotestosterone. These receptors are implicated in the stimulation of fibroblasts to proliferate and synthesize collagen, as the authors mention in their article (Fig. 3). However, it is of interest to note that they cited such mechanism connected with the administering of phenatoin (see "Possible mechanisms"). W e wonder why the authors are not aware of the connection between administering a calcium channel blocker and the increase in the number of hyperplastic gingiva, particularly in male patients treated with nifedipine. 3 On the basis of our findings that oxodipine induces hyperplasia of the adrenal zona glomerulosa, we recently proposed a mechanism by which calcium antagonists induce gingival hyperplasia in dogs. 4 In brief, the calcium antagonist induces blockage of the aldosterone synthesis in the zona glomerulosa of the adrenal cortex, because this pathway is calciumdependent. This may produce a feed-back stimulation of an increase in pituitary secretion of A C T H that affects zona glomerulosa hyperplasia. This hyperplasia is merely related by accumulation of steroid intermediate products (androgens) that are transformed to testosterone because of an increase in 17-oL-hy-
ORAL SURGERY ORAL MEDICINE ORAL PATHOLOGY
Letters to the editor
379
Volume 81, Number 4 droxylase enzyme activity. The testosterone then acts on the gingival tissue~4 At present, the role of testosterone in the genesis of gingival hyperplasia is under investigation (Dayan et al., manuscript in preparation). Dr. Abraham Nyska, D V M Kimron Veterinary Institute PO Box 12 Beit Dagan 50250, Israel Fax: 972-8-408951 Prof. Dan Dayan, DMD, MSc Section of Oral Pathology and Oral Medicine The Maurice and Gabriela Goldschleger School of Dental Medicine Tel Aviv University Tel Aviv 69978, Israel Fax: 972-3-6409250 REFERENCES 1. Nyska A, Waner T, Zlotogorski A, Pirak M, Scolnik M, Nyska M, Galliano A. Animal model of human disease: oxodipineinduced gingival hyperplasia in beagle dogs. Am J Pathol 1990; 137:737-9. 2. Dayan D, Waner T, Tal H, Nyska A. Polarization microscopy of Picrosirius red-stained collagen from oxodipine-induced hyperplastic gingiva of beagle dogs. Int J Exp Pathol 1993; 74:225-8. 3. Sooriyamoorthy M, Gower DB, Eley BM. Androgen metabolism in gingival hyperplasia induced by nifedipine and cyclosporin. J Periodontal Res 1990;25:25-30. 4. Nyska A, Shemesh M, Tal H, Dayan D. Gingival hyperplasia induced by calcium channel blockers: mode of action. Med Hypotheses 1994;43:115-8.
In reply The letter to the editor from Dr. Abraham Nyska and Professor Dan Dayan of Tel Aviv University related to our article is informative, and the authors should be complimented for their continued interest and involvement in identifying the possible mechanism for nifedipine-induced gingival hyperplasia. It is true that we were unaware of the existence of an animal model as we had been researching the dental literature and the references supplied by the authors of the letter were not included in our Medline search for perusal. Their continued research and future publication will be a welcome addition to the understanding of the mode of action of dihydropyridine-type calcium antagonists in causing gingival hyperplasia. We obviously are well aware of the connection between calcium channel blockers and hyperplastic gingiva, and the reason for this article was to present to the dental community an overview and comprehensive review of the dental literature. The use of
calcium channel blockers for the treatment of hypertension and angina pectoris is increasing, especially with the introduction of second generation dihydropyridine type calcium antagonists. This article should bring to the dental profession an increased awareness of an altered state that is induced by a drug in common use. Dr. Mervyn Gornitslcy Peofessor, Faculty of Dentistry Dr. Mili-Harel Raviv Assistant Professor, Faculty of Dentistry McGill university Montreal, Qu6bec, Canada
Cause of m e d i a n r h o m b o i d glossitis To the editor: In reflecting on possible etiologic factors for the development of median rhomboid glossitis (MRG), it has come to our attention that perhaps there are indeed sufficient local factors to promote lesional development. Although many theories have been proffered, it does appear that the idea of persistance of the tuberculum impar has fallen away and given rise to a localized candidal infection. 1, 2 Attempts have been made to ascertain the cause for candidal proliferation in this area alone; however, none have been completely all conclusive) We would like to make a comparison with another common candial infection and offer a " n e w " theory for M R G development. Cases of denture-induced candidiasis (denture sore mouth) are thought to arise because the organisms are in a warm moist environment that is protected from the antimicrobial, enzymatic, and physical cleansing actions of saliva. In similar fashion, it could well be that in many instances, candidal organisms of the mid to posterior dorsal tongue are also shielded from these same actions. Arendorf and Walker 3 suggested that the tongue is the primary oral reservoir for Candida Albicans and stated that perhaps the large surface area of the lingual papillae possibly shelter the organisms from removal during eating and swallowing. Furthermore, it was suggested that the concentration of these organisms about the lingual midline might explain the reason for the development of MRG. It was suggested, however, that other factors may also play a role. As such, we would like to comment on another possible element that may be involved in the causation of MRG. In reviewing the physiologic actions of