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Nifedipine – a calcium channel blocking drug given to treat cardiac angina, arrhythmias and hypertension, it produces fibrous hyperplasia of the gums. The gums on the outer surface of the front teeth are more severely affected than back teeth. Influence fibroblast function by folic acid depletion and decreasing its permeability to calcium therefore increasing collagen in gums. Changing the drug rarely possible therefore treatment is restricted to oral hygiene instructions and scaling of gumline. There is varying degree of metal handicap with mongoloid facial features, and individuals are prone to infections and 20 times incidence of leukemia.
Typically class III occlusion with anterior open bite seen and there is a large tongue and a lack of lip seal. This autosomal dominant trait with an incidence of 1:350,000 can occur singly or in association with other inherited syndromes though there is also a fairly common idiopathic version. Hereditary gingival fibromatosis is revealed on eruption of teeth, usually permanent teeth, with excessive production of collagen in the gums corium.
Crohn’s disease is a chronic inflammatory condition affecting any part of the gut from the mouth to the anus with regional enteritis primarily of the terminal ileum. Blood disorders are not causes of chronic periodontal disease but can be dramatic secondary factors. Leukemia is a malignant neoplastic disease of white blood cells-forming tissues, usually with increased number of leucocytes in the circulation included are developing blast cells and other tissues including lymph nodes are infiltrated. Bacterial, viral and fungal infections can lead to exacerbation of existing conditions such as acute necrotizing ulcerative gingivitis (ANUG) or increased in susceptibility to these gum disease. Effort should be made to provide treatment during remissions and professionally administered control is worthwhile.
Gingival overgrowth occurs mainly as a result of certain anti-seizure, immunosuppressive, or antihypertensive drug therapies.
Clinically detectable fibrotic overgrowth of gingiva is caused by a variety of etiological factors and is exacerbated by local bacterial plaque accumulation. There is now general agreement that gingival overgrowth lesions all contain fibrotic or expanded connective tissues with various levels of inflammation and an enlarged gingival epithelium. Drug-induced gingival overgrowth is a side-effect and unwanted outcome of systemic medication and is limited to gingival tissues. Dose-dependent correlations with the severity of gingival overgrowth are weak, but decreased drug use in general results in reduced severity of gingival pathology.
Therapy of drug-induced gingival overgrowth would seem to be most simply accomplished by the use of alternate medications that do not induce gingival overgrowth, and new medications are under development. Treatment of the gingival overgrowth lesion itself can be complicated due to the superimposed inflammation on the fibrotic tissue enlargement. Studies on the direct effects of phenytoin , nifedipine , and cyclosporin A on collagenous and non-collagenous extracellular matrix metabolism by gingival fibroblasts in culture have provided variable results. Gingival tissues are generally in a state of injury and repair that involves repetitive cycles of production of chemotactic factors, inflammatory cell recruitment, and tissue resorption, replacement, and remodeling .
There is a limited understanding of the mechanisms by which altered cytokine balances occur in drug-induced gingival overgrowth.
The occurrence of abnormal cytokine levels does not alone prove a functional relationship to gingival overgrowth. CTGF is found to occur at elevated levels in a variety of fibrotic pathologies, including the fibrous stroma of mammary tumors , chronic pancreatitis , cataract formation , nephropathy, systemic sclerosis , pulmonary fibrosis , inflammatory bowel disease , bladder fibrosis due to outlet obstruction , brain fibrosis following injury , atherosclerosis , and fibrotic skin disorders . CTGF is developmentally regulated , and interesting studies regarding the presence and function of CTGF in developing tooth germs have been reported . Clinical and histological characteristics of drug-induced gingival overgrowth include hyperplasia in junctional epithelium and hypertrophy in keratinized epithelium and excessive connective tissue accumulation. My classmate Marco and me , have decided to place a particular emphasis on communicating a proper perspective regarding the direct effects of phenytoin, nifedipine, and cyclosporin A on collagenous and non-collagenous extracellular matrix metabolism by gingival fibroblasts in culture,which have provided variable results . The mechanisms by which CTGF promotes fibrosis are being investigated by several different laboratories. In some respects, it is surprising that CTGF is elevated in phenytoin-induced gingival overgrowth tissues. Cyclosporin-A-induced gingival overgrowth is an interesting example of tissue-specific mechanisms that are not fully understood at this time. Diminished tissue resorption as a mechanism contributing to drug-induced gingival overgrowth has received some attention . Gingival overgrowth or enlargement, the currently accepted terminology for an increase in the size of the gingiva, is a common feature of gingival disease.
Gingivitis can usually be diagnosed from our own symptoms alone and, in most cases,we will not require any tests or procedures to confirm uour dentist's diagnosis. Many therapeutic agents can predispose to or precipitate diabetes, especially when pre-existing risk factors are present, and these may cause glucose control to deteriorate if administered to those with existing diabetes.
A wide range of therapeutic agents may affect glucose tolerance, and the list of known or suspected drugs is lengthy. A number of drugs used to reduce cardiovascular risk also predispose to the development of diabetes.
Thiazides: Thiazide diuretics revolutionized the treatment of hypertension in the 1960s, but were soon noted to increase the risk of diabetes[1].
Beta-blockers: These impair insulin release, especially agents that are not selective for the ?1-receptor subtype.
Statins: Meta-analysis has shown an excess risk of ~9% of progression to diabetes in those taking statins. Steroids: Steroid drugs can induce a form of iatrogenic Cushing's syndrome, and are probably the most widely used drugs which confer a high risk of diabetes. Anabolic steroids (synthetic androgens mimicking testosterone or dihydrotestosterone) should not be confused with glucocorticoids. Although the effect of anti-psychotic drugs in general may have been over-estimated by studies which have not corrected for underlying predisposition to diabetes, there is little doubt that they are associated with an increased risk of diabetes.
Since these drugs predispose to weight gain and are not known to affect insulin secretion, their diabetogenic effect was assumed to be due to weight gain and insulin resistance[6]. The agents most commonly implicated have been clozapine, olanzapine and risperidone; other agents should not however be assumed to be safer until more experience has been obtained concerning their use. Protease inhibitors such as ritonavir form an important element in highly active antiretroviral therapy (HAART) and strongly predispose to the development of diabetes by increasing insulin resistance and possibly by other direct effects upon the ?-cell. Pentamidine, used by iv injection for the treatment of _Pneumocystis carinii _pneumonia, can cause transient hyperinsulinaemia associated with hypoglycaemia, followed by persistent beta cell failure requiring insulin treatment. Nicotinic acid, used as a lipid-lowering agent, can induce diabetes secondary to increased insulin resistance.
Drug-induced diabetes is often relatively mild, because it is typically due to extra stress placed upon an otherwise healthy pancreas. Vaxeal focuses on developing advanced cancer immunotherapies to meet the growing need for improved anti-cancer treatments. Vaxeal’s core expertise in vaccine design, antigen formulation, delivery systems and immuno-modulatory drugs has allowed the management team to identify the optimal and innovative combined strategy for the design of fixed combined immunotherapies, overcoming the limitations of current cancer immunotherapy-based approaches. To design of Long Synthetic Peptides (LSP) containing several immunogenic peptides sequences, called T-cell epitopes, derived from relevant target protein. To optimize immunotherapy formulation with potent immuno-adjuvant, delivery systems to improve the polarization and longevity of the vaccine-induced T-cell responses. To use a synergistic combination with immunomodulatory drugs to limit tumor-mediated immuno-suppressive mechanisms. Vaxeal’s LSP-based immunotherapies can induce robust T-cell responses in the broad majority of patients while overcoming the limitations arising from conventional cancer vaccines, as well as some tumor immune escape mechanisms. The company’s strategy also overcomes tumor-induced immunosuppressive mechanisms developing in some tumour micro-environments that can greatly limit the therapeutic efficacy of other immunotherapeutic cancer vaccines. Chalasani N, Fontana RJ, Bonkovsky HL, Watkins PB, Davern T, Serrano J, Yang H, Rochon J; Drug Induced Liver Injury Network (DILIN).
The condition is however less common in patients on cyclosporine, but when it occurs it may be very severe. Nifedipine hyperplasia is less firm than the other two, and contains a higher proportion of ground substance. The swelling is fibrous – firm, pink and lobulated, and the swelling does not appear to be severe if oral hygiene is good. Local removal of overgrowth tissue can be done by gingivectomy however recurrence is common 3 to 6 months later.
Furthermore there is an increased incidence of chronic periodontitis and increased susceptibility to acute necrotizing ulcerative gingivitis (ANUG). Good plaque control and frequent scaling are important and the caretakers may have to finish off the plaque control. The condition can be generalized or localized, delaying tooth eruption and the cause seems to be permanently activated fibroblasts.
There is stenosis (abnormal narrowing of a bodily canal or passageway) with necrotic breakdown and scarring of gastrointestinal tract and other gastrointestinal areas are also affected including the mouth. For example severe gum bleeding is a common feature in acute leukemia and it can be the presenting feature of the disease. Chlorhexidine rinse regardless of staining should be used with antibiotic cover for invasive treatment and frank infections. Gingival overgrowth can be inherited (hereditary gingival fibromatosis), or is of idiopathic origin, or is sometimes associated with other systemic diseases. The degrees of inflammation, fibrosis, and cellularity depend on the duration, dose, and identity of the drug, on the quality of oral hygiene, and on individual susceptibility that stems from genetic factors and environmental influences.
Drug-induced gingival overgrowth does not originate in the periodontium, but it occurs exclusively in periodontal tissues and is generally not of the same magnitude in other tissues. For example, phenytoin was reported to effuse into crevicular fluid without any correlation to the incidence of overgrowth ,while no direct link was shown between overgrowth and the concentrations of phenytoin and metabolites . Traditionally, periodontal therapy offers removal of the inflammatory component of the overgrowth through scaling and gingival curettage, followed by excision of the overgrown gingiva . Collagen turnover is unusually high in periodontal tissues .Wound healing and connective tissue turnover are largely controlled by chemokines and cytokines secreted by inflammatory cells such as macrophages and lymphocytes and, to a lesser degree, by fibroblasts.
Studies have begun to investigate functional relationships between cytokines and gingival extracellular matrix metabolism.


Inhibition of CTGF with a blocking antibody in murine tooth germ organ cultures inhibited tooth germ development and differentiation.
The hypothesis was developed that CTGF could play a role in gingival overgrowth and fibrosis.
In human and rodent fibroblast cell lines, PGE2 is a potent and rapid down-regulator of CTGF, and this effect is mediated by elevated cAMP levels. Connective tissue turnover in gingival tissues is high, and destruction of the extracellular matrix occurs as a result of elaboration of extracellular proteinases, reduced MMP activity, and by phagocytosis and intracellular destruction of extracellular matrix components by lysozomal enzymes. If your doctor suspects that we have gingivitis and periodontitis, they will refer us to a specialist. The most common is chronic inflammatory gingival enlargement, when the gingiva presents clinically as soft and discolored.
They may act by increasing insulin resistance, by affecting the secretion of insulin, or both.
Subsequent experience showed that that this risk is greatly reduced by low-dose therapy, whose benefits therefore outweigh its risks.
Several studies have linked chronic use of ?-blockers with an increased risk for the development of diabetes. A Canadian paediatric study found that 0.4% of childhood diabetes was ascribed to medication, and 55 of 56 children in this category were on steroids. Diabetes is, for example, considered to be 2-3 times as common in people with schizophrenia as in the background population, probably because of lifestyle factors such as obesity and lack of exercise, although a family history of diabetes is common in those with schizophrenia. An unexplained feature of their action is that presentation in diabetic ketoacidosis is relatively common in individuals who otherwise appear to have type 2 diabetes[4]. Weight gain does not in itself provide a sufficient explanation of the phenomenon, however, and a unified mechanistic explanation is still lacking[4]. The most potent of these are the calcineurin inhibitors, which also affect the nuclear factor of activated T-cells (NFAT) pathway; examples are tacrolimus and ciclosporin A.
Your case is unusual, in that small replacement doses of hydrocortisone (in contrast to the large doses of steroids used to treat other medical conditions) would not be expected to stress the pancreas. I developed drug induced diabetes after I developed adrenal insufficiency and had to start taking the replacement steroid hydrocortisone.
They address a large spectrum of cancer patients as they target broadly expressed tumour antigens, which cover almost all solid tumors.
This is achieved through synergistic fixed combinations with existing immunomodulatory drugs known to limit such tumor-mediated mechanisms. Clinico-pathologic correlation of liver damage in patients treated with 6-mercaptopurine and Adriamycin. High rate of long-term survivals in AML treated by chemotherapy and androgenotherapy: a pilot study.
Liver calcifications following hepatic artery infusion with 5-fluorouracil, adriamycin and mitomycin C(FAM). A randomized study of the efficacy of consolidation therapy in adult acute nonlymphocytic leukemia. A comparative pathological study of liver injury after different combination chemotherapies for leukemia. Oral idarubicin plus cytosine arabinoside in the treatment of acute non lymphoblastic leukemia in elderly patients. Randomized study for the treatment of adult advanced Hodgkin's disease: epirubicin, vinblastine, bleomycin, and dacarbazine(EVBD) versus mitoxantrone, vinblastine, bleomycin, and dacarbazine(MVBD). Idarubicin in patients with diffuse large cell lymphomas: a randomized trial comparing VACOP-B(A = doxorubicin) vs VICOP-B(I = idarubicin). Phase-II trial of idarubicin, fludarabine, cytosine arabinoside, and filgrastim(Ida-FLAG) for treatment of refractory, relapsed, and secondary AML. Induction therapy with idarubicin alone significantly influences event-free survival duration in patients with newly diagnosed hypergranular acute promyelocytic leukemia: final results of the GIMEMA randomized study LAP 0389 with 7 years of minimal follow-up.
Acute toxicity of adjuvant doxorubicin and cyclophosphamide for early breast cancer - a retrospective review of Chinese patients and comparison with an historic Western series.
Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States.
With superimposed inflammation the gums, swelling can become soft and red and bleed when provoked. Effective oral hygiene is compromised in the presence of gingival overgrowth, and it is now recognized that this may have negative implications for the systemic health of affected patients.
Many professors regard the importance of gingival overgrowth as a clinical problem, and highlights recent advances in the identification of molecular and cellular processes that are leading to an enhanced understanding of the biological mechanisms underlying the overgrowth. Patients who receive anti-epileptic therapy through the systemic use of phenytoin, or immunosuppressive therapy with systemic cyclosporin A ,or anti-hypertensive treatment with systemic nifedipine develop gingival overgrowth with various degrees of prevalence. A more recent study supports a correlation between diminished metabolism of phenytoin in affected individuals and overgrowth, but this has not been confirmed. Cyclosporin A, for example, increases the rates of survival of most organ transplant patients, although the more recently developed immunosuppressant FK506 (tacrolimus) can be substituted in some patients .
For patients with severe gingival overgrowth and who require continuous drug therapy for medical reasons, gingivectomy must be repeated periodically due to the recurrent nature of drug-induced gingival overgrowth . While cyclosporin A was found to increase glycosaminoglycan secretion by fibroblasts , and nifedipine and phenytoin increased heparan levels ,other studies failed to report any differences in vivo . Proliferation and differentiation of connective tissue cells and production of extracellular matrix are controlled by cytokines that initiate signaling cascades mediated by specific receptors. These studies seem likely to result in a greater understanding of the biological mechanisms that may be unique to human gingival tissues and may be relevant to the development of therapeutic strategies for either the prevention or treatment of gingival overgrowth. This is illustrated by experiments in which the simultaneous application of CTGF and TGF-?1 is required for sustained skin fibrosis; neither factor alone was effective .
These factors have a highly conserved structure that consists of four domains containing 38 conserved cysteine residues. Studies of CTGF regulation were initiated in vitro in human gingival fibroblast cultures, because increased collagen and lysyl oxidase biosynthesis induced by TGF-?1 occurred only at modest levels and with slow kinetics compared with effects seen in other cell types.
While cyclosporin A was found to increase glycosaminoglycan secretion by fibroblasts ,and nifedipine and phenytoin increased heparan levels , other studies failed to report any differences in vivo . Phenytoin stimulates prostaglandin E2 (PGE2) production by gingival fibroblasts, and it is well-known that human gingival tissues accumulate significant levels of prostaglandins including PGE2 . In vitro studies have shown that phenytoin and cyclosporin A inhibit production of the lysozomal proteinase cathepsin L, but not cathepsin B, by human gingival fibroblasts . This is caused by tissue edema and infective cellular infiltration caused by prolonged exposure tobacterial plaque, and is treated with conventional periodontal treatment, such as scaling and root planing. For convenience, these agents may be subdivided into widely used medications that are weakly diabetogenic, and drugs used for special indications that are more strongly diabetogenic. It should however be appreciated that these are commonly offered to individuals who are at increased risk of diabetes by virtue of risk factors such as obesity and hypertension, and that risk association does not necessarily mean causation. The Atherosclerosis Risk in Communities (ARIC) study found that the risk of diabetes in was increased by 28% in those taking a beta-blocker for hypertension over a 6-year period, as compared with other medications[2].
This increase in baseline risk must be taken into account when considering the effect of any anti-psychotic agent upon risk of diabetes[4]. I don't know if I am typical of the drug-induced type of this disease, but I have a very mild case of it.
A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in the chemotherapy of cancer. The gum enlargement can almost cover the teeth though the size of the swelling not related directly to drug dosage. Recent studies indicate that cytokine balances are abnormal in drug-induced forms of gingival overgrowth. These medications include the anti-seizure drug phenytoin, the immune suppressor cyclosporin A, and certain anti-hypertensive dihydropyridine calcium-channel-blockers, most notably nifedipine. Many recent genetic studies on hereditary gingival fibromatosis are beginning to identify the unique cell biology and extracellular matrix metabolism that occur in human gingiva. While the incidence of this side-effect can be as high as 65% in epileptics, 70% in transplant patients, and 30% in hypertension subjects, variation exists in the reported prevalence and severity of the clinical problem . Age, gender, concomitant medication with multiple drugs, local factors such as plaque accumulation, and genetic disposition are additional complicating risk factors in drug-induced gingival overgrowth . Tacrolimus has not yet been associated with gingival overgrowth, but does cause other side-effects that are important for some patients. In addition, extracellular matrix elements interact with cell-surface receptors, including integrins, that initiate or modulate signaling cascades .Recent studies demonstrate abnormally high levels of specific cytokines in gingival overgrowth tissues.
In contrast, macrophages in highly inflamed tissues express predominantly the 27E10 marker .
TGF-?1 is a cytokine secreted by many cell types, including macrophages, and it has an important regulatory function in collagen metabolism in connective tissues. CTGF is rapidly and potently induced by TGF-?1 in fibroblastic cells from a variety of different tissues, and contributes to the regulation of extracellular matrix genes . The working hypothesis was that TGF-?1 might induce CTGF, which in turn would stimulate extracellular matrix production in gingival fibroblasts.
While the incidence of this side-effect can be as high as 65% in epileptics, 70% in transplant patients, and 30% in hypertension subjects, variation exists in the reported prevalence and severity of the clinical problem.
The fact that CTGF is elevated in phenytoin-induced gingival overgrowth tissues, therefore, is unexpected and raises the notion that human gingival tissues may be metabolically unique in their response to PGE2. Situations in which the chronic inflammatory gingival enlargement include significant fibrotic components that do not respond to and undergo shrinkage when exposed to scaling and root planing are treated with surgical removal of the excess tissue, most often with a procedure known as gingivectomy.
This effect is so marked in one member of the family, diazoxide, that this is used to control excessive insulin secretion by unresectable insulinomas. The risk conferred by non-selective beta blockers may be enhanced if these are combined with a thiazide diuretic. PubMed Citation  (Among 283 patients with acute non-lymphocytic leukemia treated with daunorubicin, cytarabine and thioguanine, 77 also received consolidation therapy, 6 [8%] of whom developed severe hepatotoxicity, but no details given). PubMed Citation  (Overview of hepatotoxicity of antineoplastic agents, mentions that hepatotoxicity was not detected in single agent trials of doxorubicin and daunorubicin, but evidence implicates them when used in combination with mercaptopurine, cisplatin, cyclophosphamide, and etoposide, possibly due to sinusoidal obstruction syndrome).
PubMed Citation  (Description of two different patterns of liver injury associated with cancer chemotherapy).
PubMed Citation  (Among 18 elderly patients with leukemia treated with cytarabine and oral idarubicin, 2 developed severe liver injury [bilirubin >20 times ULN] and one died, but few details given).


PubMed Citation  (4 Chinese patients [ages 29-55 years] with HBsAg developed fatal reactivation of hepatitis B after intensive chemotherapeutic regimens that included doxorubicin).
PubMed Citation  (Comparison of different cytotoxic antibiotics combined with bleomycin, vincristine and dacarbazine for Hodgkin disease, found that 6 of 35 given mitoxantrone, but none of 35 treated with epirubicin, developed liver toxicity [AST >3 times ULN], that persisted in 2). PubMed Citation  (Comparison of VACOP vs VICOP induction therapy in 104 patients with lymphoma, found hepatotoxicity occurred in 4% on doxorubicin vs 12% on idarubicin). PubMed Citation  (Among 85 women with breast cancer treated with doxorubicin and cyclophosphamide, severe hepatotoxicity occurred only in HBsAg positive patients). PubMed Citation  (Among 300 cases of drug induced liver disease in the US collected between 2004 and 2008, several cases were attributed to antineoplastic agents [such as mercaptopurine, cyclophosphamide, docetaxel, temozolomide, bortezomib and imatinib], but none to the cytotoxic antibiotics such as doxorubicin or daunorubicin). Data supporting molecular and cellular characteristics that distinguish different forms of gingival overgrowth are summarized, and aspects of gingival fibroblast extracellular matrix metabolism that are unique to gingival tissues and cells are reviewed. Clinical and histological characteristics of drug-induced gingival overgrowth include hyperplasia in junctional epithelium and hypertrophy in keratinized epithelium and excessive connective tissue accumulation.
The literature on the effective substitution of cyclosporin A with tacrolimus is relatively new. These findings are inconsistent with the in vivo characteristics of drug-induced gingival overgrowth. These findings are of great interest, and suggest that substances that cause gingival overgrowth may do so by altering the normal balance of cytokines in gingival tissues. TGF-?1 slowly stimulates collagen and lysyl oxidase biosynthesis in early-passage human gingival fibroblast cell cultures , whereas IL-1?, IL-6, and PDGF-BB have little or no effect, and FGF-2 is inhibitory .
Findings indicate that CTGF is rapidly and potently up-regulated by TGF-?1, and that CTGF stimulates insoluble collagen accumulation in human gingival fibroblast cultures . In addition, extracellular matrix elements interact with cell-surface receptors, including integrins, that initiate or modulate signaling cascades(Comprehensive dermatologic drug therapy, Wolverton, 2000). Similarly, phenytoin, cyclosporin A, and nifedipine gingival overgrowth tissues contain subpopulations of macrophages and other inflammatory cells that differ from those in healthy control gingival tissues(Da Silva,1998). A possible role in the inhibition of cell-cycle progression by intracellular CTGF has been suggested.
The effects of PGE2 on fibroblasts are mediated principally by four receptors, EP1-EP4 PGE2 stimulation of cAMP levels is mediated primarily by the EP2 receptor .Future studies will determine which PGE2 receptors are expressed by gingival fibroblasts, and whether phenytoin regulates either the function or the expression of prostaglandin receptors in gingiva in novel ways.
Consistent results were found in cathepsin-L-deficient mice that exhibited enlarged gingival epithelial and connective tissues .
Gingivitis and gingival enlargement are often seen in mouth breathers as a result of irritation brought on by surface dehydration, but the manner in which it is caused has not been demonstrated. Abnormal cytokine balances derived principally from lymphocytes and macrophages, and unique aspects of gingival extracellular matrix metabolism, are elements of a working model presented to facilitate our gaining a better understanding of mechanisms and of the tissue specificity of gingival overgrowth. In addition to being disfiguring and uncomfortable for affected individuals, moderate to severe forms of gingival overgrowth impair oral hygiene and may lead to increased accumulation of micro-organisms. Cyclosporin A continues to be the most commonly prescribed drug for the prevention of graft rejection. Taken together, these studies support the conclusion that direct regulation of extracellular matrix metabolism or proliferation of gingival fibroblasts by these drugs is probably not the primary mechanism responsible for gingival overgrowth.
Cytokines and growth factors found at elevated levels in human drug-induced gingival overgrowth include interleukin-6 (IL-6), IL-1?, platelet-derived growth factor-B (PDGF-B), fibroblast growth factor-2 (FGF-2), transforming growth factor-? (TGF-?), and connective tissue growth factor CTGF. Similarly, phenytoin, cyclosporin A, and nifedipine gingival overgrowth tissues contain subpopulations of macrophages and other inflammatory cells that differ from those in healthy control gingival tissues. In contrast, PDGF-BB and FGF-2 are potent mitogenic factors and contribute to the proliferation of gingival connective tissue and epithelial cells. The biological functions of this family of proteins include positive and negative regulation of proliferation and differentiation of connective tissue cells, and regulation of extracellular matrix accumulation. Moreover, a clinical study indicates that CTGF is present at elevated levels in phenytoin- and nifedipine-induced gingival overgrowth tissues, but not in cyclosporin-A-stimulated gingival overgrowth . It is very interesting to note that other recent studies support the notion that gingival fibroblast extracellular matrix metabolism has unique aspects.
The authors note that humans lacking lysozomal enzymes as a result of the rare genetic disease I-cell disease or mucolipidosis also have gingival overgrowth .
Oral infections can potentially impair systemic health ,and elevated oral infections stemming from gingival overgrowth could possibly compromise the general health of patients. Similarly, although several new anti-seizure drugs have been introduced and its prescription is markedly reduced, phenytoin remains the drug of choice for certain types of grand mal epileptic seizures .
As noted below, deregulated cytokine balances may contribute more significantly to the development and maintenance of gingival overgrowth. Studies on T- and B-lymphocytes showed that T-cells are increased in the peripheral blood of organ transplant patients with no apparent shift of subpopulations and nifedipine increased lymphocyte counts in blood , although these findings were not found in gingival tissues .
The effects of TGF-?1 on gingival collagen and lysyl oxidase regulation are notable because the magnitude and kinetics of regulation are unexpectedly smaller and slower compared with studies on other connective tissue cells performed under the same conditions . The finding of elevated CTGF in phenytoin-induced gingival overgrowth was obvious and clear, even after adjustment for the level of inflammation determined by histomorphometric analyses . Deregulated cytokine balances may contribute more significantly to the development and maintenance of gingival overgrowth.
At this time, however, there is no consensus regarding functional relationships between and among drug therapies, the distribution of specific immune system cell subpopulations, and altered cytokine balances (Simpson,2003).
It binds to the extracellular matrix protein fibulin and is proposed to participate in extracellular matrix deposition and cell adhesion . In healing adult human gingiva, MMP-13, and not MMP-1, is highly expressed by gingival fibroblasts. These findings are surprising and indicate that oral bacteria and gingival cells and tissues must interact in unique ways in subjects receiving cyclosporin A that results in relatively greater inflammation and cellularity compared with other forms of gingival overgrowth. This is most obvious in the case of organ transplant recipients who require continuous therapy with cyclosporin A, thereby being rendered critically susceptible to life-threatening systemic infections, and who concomitantly develop gingival overgrowth. Finally, although hypertension cases are now being treated by alternative calcium-channel-blockers that either do not predictably cause gingival overgrowth or are linked to isolated cases of gingival pathologies, nifedipine remains a highly effective agent in the management of patients who do not respond sufficiently well to other anti-hypertensive medications .In summary, it should be anticipated that drug-induced gingival overgrowth will continue to be a problem until safe and equally reliable medications to control these systemic conditions are developed and fully utilized. A reduction in the number of Langerhans cells in nifedipine and cyclosporin A gingival overgrowth occurs and suggests a modification of an inflammatory reaction that influences the level of helper T-lymphocytes and cytokine profiles. To understand the unexpectedly slow kinetics of TGF-?1 on extracellular matrix synthesis in gingival fibroblasts, investigators in recent studies have focused on the presence and role of connective tissue growth factor (CTGF) as a possible matrix-stimulatory factor downstream of TGF-?1 in gingival overgrowth tissues.
CTGF is expressed by endothelial cells, granulosa cells , fibroblasts , mesangial cells , chondrocytes , and osteoblast, and occurs in biological fluids and tissues in low-molecular-weight forms that contain domains 3 and 4 that retain mitogenic activity .
This study furthermore indicates that the more fibrotic tissues appear to contain the highest levels of CTGF. Several studies more consistently show that cultured human gingival fibroblasts treated with phenytoin, cyclosporin A, and nifedipine increase production of fibroblast cytokines and prostaglandin E2 ,although lymphocytes and macrophages may be important sources of these factors in vivo (Comprehensive dermatologic drug therapy, Wolverton, 2000). The biological mechanisms responsible for this phenomenon must be unique to gingival tissues and cells and are currently under investigation. The effective management of these patients clearly requires the active involvement of both dental and medical professionals to minimize the possibility of complications.(Thomason JM, Seymour RA, Ellis JS, Kelly PJ, Parry G, Dark J, et al. In addition, because the administration of these medications in general is beyond the control of the dental professional, clinical management of the gingival overgrowth presents a continuous challenge. Cyclosporin A, nifedipine and phenytoin: comparative effects on gingival fibroblast metabolism. Inflammatory cell populations that are altered as a result of drug therapy are likely to modify the gingival tissue response.
CTGF has been proposed to mediate the effects of TGF-? on extracellular matrix metabolism .Before studies performed in gingival cells and tissues are summarized, information on CTGF and the emerging related CCN family of factors is first offered as background information. It seems possible that the pleiotropic nature of the CCN family of factors may be related to proteolytic processing events that unmask latent activities encoded by different functionally independent domains.
Analysis of the data obtained supports the notion that cyclosporin-A-induced gingival overgrowth tissues are significantly more inflamed and less fibrotic than phenytoin- or nifedipine-induced gingival overgrowth. At this time, however, there is no consensus regarding functional relationships between and among drug therapies, the distribution of specific immune system cell subpopulations, and altered cytokine balances. Moreover, recent studies indicate that CTGF binds to other growth factors, resulting in either inhibition or stimulation of their activity. Taken together, these findings identify clear and consistent molecular and cellular distinctions between and among phenytoin-, nifedipine-, and cyclosporin-A-induced gingival overgrowth tissues.
Taken together, these findings identify clear and consistent molecular and cellular distinctions between and among phenytoin-, nifedipine-, and cyclosporin-A-induced gingival overgrowth tissues .It is apparent that gingival overgrowth is a clinical phenomenon that is heterogeneous with respect to the underlying biological mechanisms. MMP-13 is a collagenase with wide substrate specificity, whereas MMP-1 is a collagenase more restricted to hydrolyzing fibrillar collagens. Thus, CTGF binds to vascular endothelial growth factor (VEGF) and bone morphogenetic protein-4 (BMP-4), resulting in inhibition of VEGF and BMP-4 activity, respectively; whereas CTGF binding to TGF-?1 is reported to be stimulatory .
Future studies will be necessary to identify additional molecular markers unique to specific forms of gingival overgrowth that will likely prove to be of functional significance in the etiology of different forms of this condition. Differential regulation of these two MMP genes is likely to be of biological importance, and may be related to the generally lower tendency for scar formation in oral tissues .In addition, integrin expression patterns differ between gingival fibroblasts and dermal fibroblasts, whereas periodontal ligament fibroblasts and gingival fibroblasts are more similar to each other in this respect . It is interesting to note that human gingival fibroblasts and periodontal ligament fibroblasts express a variety of different genes differentially, including members of the CCN family of genes . CTGF binds to V?3, 6?1, and other ?3 integrins on different cell types and activates signaling cascades .
Unique aspects of gingival fibroblast extracellular matrix metabolism seem likely to contribute to the etiology of gingival overgrowth. Taken together, these studies support the idea that CTGF is a ‘matricellular’ factor that works in concert with growth factors, growth factor receptors, extracellular matrix, and extracellular matrix receptors .
In addition, metabolic uniqueness of gingival cells may help explain the striking tissue specificity of drug-induced gingival overgrowth.
This view is consistent with the relatively weak direct stimulatory effects of CTGF on extracellular matrix production compared with the effects of pro-fibrogenic cytokines such as TGF-?1, and may account for the requirement for the simultaneous presence of both CTGF and TGF-? for sustained fibrosis .
Integrin receptor-mediated signals in combination with growth factor receptor-mediated signals seem likely to work together to result in tissue fibrosis (Cley C, Javisk K, Hassell T.



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