Pharmacological topics of bone metabolism: a novel bisphosphonate for the treatment of periodontitis

It has been reported that the pharmacological characteristics of bisphosphonates vary depending on the side chain attached to the carbon atom of the P-C-P bond. TRK-530 is a novel synthetic bisphosphonate with an anti-oxidant methylthio-phenylthio side chain. This compound has been suggested to have both anti-inflammatory and anti-bone-resorbing effects. Such a compound could be effective for the treatment of diseases with excessive bone resorption accompanied by inflammation. We have been studying this compound as a potential therapeutic agent for periodontitis. To date, we have found that 1) TRK-530 inhibited osteoclastic bone resorption in animals and in bone organ culture, 2) both systemic and topical administration of TRK-530 prevented alveolar bone loss in animals with experimental periodontitis, 3) TRK-530 prevented prostaglandin E(2) synthesis by inhibiting the expression of cyclooxygenase (COX)-2 mRNA, and 4) TRK-530 inhibited the formation of dental calculus. The above results suggest that TRK-530 might be useful for the treatment of alveolar bone loss in periodontitis.     

Non-antibacterial tetracyclines modulate mediators of periodontitis and atherosclerotic cardiovascular disease: A mechanistic link between local and systemic inflammation

Periodontitis, one of the most common chronic inflammatory diseases afflicting man, is increasingly being recognized as a risk factor for atherosclerotic cardiovascular disease (ASCVD). Non-antimicrobial tetracyclines are known to have inhibitory effects on inflammatory mediators and effector molecules, including cytokines and matrix metalloproteinases (MMPs), associated with both diseases. In this paper, we discuss the evidence that doxycycline and related non-antibiotic chemically modified tetracyclines (e.g., CMT-3) can effectively reduce cytokine (TNF-α, IL-6, and MCP-1) production by human mononuclear inflammatory cells when stimulated either by endotoxin (LPS) or by a complex of C-reactive protein/oxidized LDL cholesterol relevant to the pathogenesis of periodontal disease and ASCVD, respectively. This inhibition by tetracycline compounds appears to be mediated at least in part by a suppression of the phosphorylation/activation of the NFκB cell signaling pathway. We are currently conducting clinical trials on patients who exhibit both diseases, and our preliminary data suggest that virtually all acute coronary syndrome (ACS) patients exhibit moderate-to-severe periodontitis, a higher incidence of this oral inflammatory disease than that seen in the population at large. In other studies, a non-antimicrobial formulation of doxycycline (SDD) has been found to dramatically reduce hsCRP, IL-6 and MMP-9 levels in plasma of ACS patients, and SDD has also been found to significantly increase serum levels of both cardio-protective HDL cholesterol and its core molecule apolipoprotein A-I in ASCVD-vulnerable patients with periodontitis. Our current research suggests that one mechanism involved may be the ability of SDD to inhibit MMP-mediated HDL loss by protecting apolipoprotein A-I from proteinase attack. These pleiotropic mechanisms of non-antimicrobial tetracyclines provide significant therapeutic potential to treat chronic inflammatory diseases including both periodontitis and ASCVD.     

The use of ketorolac tromethamine oral rinse for the treatment of periodontitis in adults

Periodontitis is a chronic infectious and inflammatory disease which afflicts approximately three quarters of the world’s adult population over the age of thirty-five. Recently published studies have demonstrated that long-term administration (>-6 months) of non-steroidal anti-inflammatory drugs (NSAIDs) can halt the progressive loss of alveolar bone associated with this disease. The safe and efficacious twice daily use for six months of 0.1% ketorolac tromethamine oral rinse for the prevention of periodontal disease progression in adults has recently been demonstrated. This presentation summarizes our results to date regarding the pharmacokinetics, pharmacodynamics, safety and efficacy of the topical oral rinse form of this potent NSAID in patients with periodontitis.     

亚抗菌剂量多西环素治疗牙周炎的临床评价

目的：评价亚抗菌剂量多西环素（subantimicrobial dose doxycycline,SDD）在牙周炎治疗中的安全性和有效性.方法：对文献报告的SDD用于牙周炎临床治疗的多个大型、多中心、安慰剂对照试验结果进行分析总结.结果：在刮治＋根面平整术的基础上再给予SDD治疗牙周炎,能有效提高牙周组织的临床附着水平,降低探诊深度,改善牙周袋内位点数目,且不良反应发生率低,也不易产生细菌耐药性.结论：SDD是牙周炎临床治疗中安全有效的给药方法.     

Growth factor delivery to re-engineer periodontal tissues

Repair of tooth-supporting structures destroyed by the chronic inflammatory disease periodontitis is a major goal of oral therapy. The field of tissue engineering combines materials science and biology to repair tissues and organs. Periodontal tissue engineering has been achieved with limited success by the utilization of guiding tissue (cell occlusive) membranes and bone grafting techniques. Over the past decade investigators have begun to utilize signaling molecules such as growth factors to restore lost tooth support due to periodontitis, the most common bone disease affecting humans. This review will provide information on the status of growth factor therapies being applied in periodontology to treat advanced alveolar bone loss.     

Effects of calcium gluconate on experimental periodontitis and alveolar bone loss in rats

We examined the effects of calcium gluconate, an anti-inflammatory calcium salt, on ligature-induced experimental periodontitis and related alveolar bone loss. Calcium gluconate was orally administered daily for 10 days at 250, 125 or 62.5 mg/kg, beginning 1 day after ligation. We recorded changes in body-weight and alveolar bone loss and quantified the anti-inflammatory effects of calcium gluconate by measuring levels of myeloperoxidase (MPO), IL-1β and TNF-α. We also evaluated inducible nitric oxide synthase (iNOS) activity and malondialdehyde (MDA) concentration as a measure of antioxidant effects. Ligature placement produced a marked decrease in body-weight, increased alveolar bone loss, and led to increased MPO, IL-1β, TNF-α and MDA concentrations, as well as elevated iNOS activity, increased inflammatory cell infiltration and decreased collagen fibre content in gingival tissue. Histopathology revealed decreased alveolar bone volume, increased osteoclast cell numbers and activity, and an elevated percentage of osteclasts on the alveolar bone surface. The effects of ligature placement were significantly and dose-dependently inhibited by 10 days of daily oral treatment with 250 and 125 mg/kg of calcium gluconate. The results suggest that 10 days daily oral treatment with calcium gluconate effectively inhibits ligature placement-induced periodontitis and related alveolar bone loss via antioxidant effects.     

治疗牙周炎所致牙槽骨吸收的前景药物

牙周炎是成人牙齿丧失的首要原因,以牙周组织的炎症和牙槽骨的吸收为主要临床表现。现今治疗牙周炎的药物主要是硝基咪唑类、青霉素类和四环素类,用于控制菌斑、消除炎症;但缺乏能够改建牙槽骨、促进牙槽骨再生的药物,因此影响了临床疗效。寻找促进成骨的药物尤为重要,通过查阅文献,很多研究表明辛伐他汀、贝尼地平、柚皮苷和蛇床子素具有成骨作用,能够修复牙槽骨缺失,并可制成多种缓控释剂型,可提高药效并避免全身用药引起的不良反应。联合抗菌药物与成骨药物制成缓控释制剂并采用局部用药的方式为牙周炎的治疗提供了新的治疗策略。     

Pleiotropic effects of statins on the treatment of chronic periodontitis – a systematic review

Aim

Statins are inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase and are an important group of hypolipidaemic drugs, widely used in the treatment of hypercholesterolaemia and cardiovascular disease. Some studies have shown that statins are able to modulate inflammation and alveolar bone loss.

Methods

In order to evaluate whether statins could influence periodontal treatment, improving the clinical and radiographic parameters in chronic periodontitis, a systematic review was conducted in the databases PUBMED and BIREME, searching for articles in English and Portuguese, published between the years 2004 and 2014, using the combined keywords statin, periodontal disease, periodontitis and alveolar bone. Studies regarding the treatment of chronic periodontitis in humans, blind or double-blind, retrospective cohort or randomized controlled trials that used statins topically or systemically were selected.

Results

Statins have important anti-inflammatory and immune effects, reducing levels of C-reactive protein and matrix metalloproteinases and their intermediate products, such as tumour necrosis factor-α, and are also able to inhibit the adhesion and extravasation of leukocytes, which block the co-stimulation of T cells. Statins reduce bone resorption by inhibiting osteoclast formation and lead to increased apoptosis of these cells. The effect of statins on bone formation is related to the increased gene expression of bone morphogenetic protein in osteoblasts.

Conclusion

Although we found biological mechanisms and clinical results that show lower alveolar bone loss and reduction of clinical signs of inflammation, further studies are needed to evaluate the clinical applicability of statins in the routine treatment of chronic periodontitis.     

黄芪注射液治疗大鼠牙周炎作用研究

目的:研究黄芪注射液对大鼠牙周炎的治疗作用。方法:采用牙龈划割剥离加高糖饲料和高糖饮水喂养的方法复制大鼠牙周炎模型,以血液生化指标和临床观察指标考察黄芪注射液8.0g·kg-1剂量下连续给药10d的治疗作用。结果:黄芪注射液能显著降低牙周炎大鼠的血清白细胞、中性粒细胞等指标含量,对红细胞、血小板、血红蛋白无降低作用;同时能显著降低牙周炎大鼠的龈沟出血指数、菌斑指数、牙槽骨吸收值、牙齿松动度,而对探针深度、丧失值、牙周骨支持率等指标无明显改善。结论:黄芪注射液对大鼠牙周炎有一定的治疗作用。     

骨碎补总黄酮对牙周炎大鼠龈沟液骨钙素及牙槽骨骨密度的影响

目的：观察骨碎补总黄酮对牙周炎大鼠龈沟液骨钙素（OC）和牙槽骨骨密度的影响,探讨其治疗牙周炎的机制。方法成功建立 SD 大鼠牙周炎模型之后,使用完全随机分组方法将大鼠分为正常组、牙周炎组、骨碎补总黄酮组,每组18只。建模4周后分别灌服生理盐水和骨碎补总黄酮240 mg／（kg·d）。各组大鼠分别在建模后第4,6,8周各处死6只。放射免疫分析法测定龈沟液 OC 水平,显微 CT 测定大鼠牙槽骨骨密度。结果牙周炎组龈沟液 OC 水平显著高于正常组和骨碎补总黄酮组（P ＜0．05）;骨碎补总黄酮组龈沟液 OC 水平在6周和8周时显著低于牙周炎组（P ＜0．05）,8周时与正常组龈沟液 OC 水平相比差异无统计学意义（P ＞0．05）。牙周炎组牙槽骨骨密度显著低于正常组和骨碎补总黄酮组（P ＜0．05）;骨碎补总黄酮组牙槽骨骨密度在 6 和8周时显著高于牙周炎组（P ＜0．05）。结论骨碎补总黄酮可降低牙周炎大鼠龈沟液骨钙素水平,增加牙槽骨骨密度,对大鼠牙周炎具有一定治疗作用。     

Sub-antimicrobial doxycycline for periodontitis reduces hemoglobin A1c in subjects with type 2 diabetes: A pilot study

In vitro and animal studies suggest a possible role for the tetracycline class of drugs in the inhibition of non-enzymatic protein glycation. We conducted a 3-month, randomized placebo-controlled pilot clinical trial of conventional sub-gingival debridement (periodontal therapy), combined with either a three month regimen of sub-antimicrobial-dose doxycycline (SDD), a two week regimen of antimicrobial-dose doxycycline (ADD), or placebo in 45 patients with long-standing type 2 diabetes (mean duration 9 years) and untreated chronic periodontitis. Subjects were taking stable doses of oral hypoglycemic medications and/or insulin. Treatment response was assessed by measuring hemoglobin A1c (HbA1c), plasma glucose, and clinical periodontal disease measures. At one-month and three-month follow-up, clinical measures of periodontitis were decreased in all groups (data to be presented elsewhere). At three months, mean HbA1c levels in the SDD group were reduced 0.9% units from 7.2% units ± 2.2 (±SD), to 6.3% units ± 1.1, which represents a 12.5% improvement. In contrast, there was no significant change in HbA1c in the ADD (7.5% ± 2.0 to 7.8% ± 2.1) or placebo (8.5% ± 2.0 to 8.5% ± 2.6) groups. Mean HbA1c change from baseline was significantly greater in the SDD group compared with the ADD group (p = 0.04) but not placebo (p = 0.22). Moreover, a larger proportion of subjects in the SDD group experienced improvement (p < 0.05) compared to the ADD or placebo groups. Mean plasma glucose levels were not significantly different between or within the groups. The results of this pilot study suggest that the treatment of periodontitis with sub-gingival debridement and 3-months of daily sub-antimicrobial-dose doxycycline may decrease HbA1c in patients with type 2 diabetes taking normally prescribed hypoglycemic agents.     

A novel inhibitor of vacuolar ATPase, FR202126, prevents alveolar bone destruction in experimental periodontitis in rats

An acidic microenvironment formed by vacuolar ATPase (V-ATPase) expressed in plasma membranes of osteoclasts is thought to be indispensable for bone resorption. This study examined the efficacy of a novel V-ATPase inhibitor, FR202126, in reducing alveolar bone loss caused by experimental periodontitis in rats. FR202126 inhibited H+ transport in plasma membrane vesicles of murine osteoclasts, whereas FR202126 exerted no effect on H+ transport of mitochondrial ATPase or gastric H+,K+-ATPase, indicating that FR202126 is a specific inhibitor of V-ATPase. As expected from the mechanism, FR202126 remarkably inhibited in vitro bone resorption whatever bone resorptive factors were added. Moreover, FR202126 was also able to exert an inhibitory effect on in vivo bone resorption. Experimental periodontitis was induced by ligature wire tied around the contact between the first and second maxillary molars. Insertion of ligature wire for 7 days induced alveolar bone destruction by activating osteoclasts. Oral administration of FR202126 (u.i.d.) significantly prevented alveolar bone loss in experimental periodontitis which may offer a new approach to treatment of periodontal disease.     

Baicalin inhibits toll-like receptor 2/4 expression and downstream signaling in rat experimental periodontitis

Periodontitis is a severe inflammatory response, leading to characteristic periodontal soft tissue destruction and alveolar bone resorption. Baicalin possesses potent anti-inflammatory activity; however, it is still unclear whether baicalin regulates toll-like receptor (TLR) 2/4 expression and downstream signaling during the process of periodontitis. In this study, the cervical area of the maxillary second molars of rats was ligated and inoculated with Porphyromonas gingivalis (P. gingivalis) for 4 weeks to induce periodontitis. Some rats with periodontitis were treated intragastrically with baicalin (50, 100 or 200 mg/kg/day) or vehicle for 4 weeks. Compared with the sham group, the levels of TLR2, TLR4 and MyD88 expression and the p38 MAPK and NF-κB activation were up-regulated in the experimental periodontitis group (EPG), accompanied by marked alveolar bone loss and severe inflammation. Treatment with 100 or 200 mg/kg/day baicalin dramatically reduced the alveolar bone loss, the levels of HMGB1, TNF-α, IL-1β, and MPO expression, and the numbers of inflammatory infiltrates in the gingival tissues. Importantly, treatment with 100 or 200 mg/kg/day baicalin mitigated the periodontitis-up-regulated TLR2, TLR4 and MyD88 expression, and the p38 MAPK and NF-κB activation. Hence, the blockage of the TLR2 and TLR4/MyD88/p38 MAPK/NF-κB signaling by baicalin may contribute to its anti-inflammatory effects in rat model of periodontitis. In conclusion, these novel findings indicate that baicalin inhibits the TLR2 and TLR4 expression and the downstream signaling and mitigates inflammatory responses and the alveolar bone loss in rat experimental periodontitis. Therefore, baicalin may be a potential therapeutic agent for treatment of periodontitis.     

Inflammatory bone loss: pathogenesis and therapeutic intervention

Bone is a tissue undergoing continuous building and degradation. This remodelling is a tightly regulated process that can be disturbed by many factors, particularly hormonal changes. Chronic inflammation can also perturb bone metabolism and promote increased bone loss. Inflammatory diseases can arise all over the body, including in the musculoskeletal system (for example, rheumatoid arthritis), the intestine (for example, inflammatory bowel disease), the oral cavity (for example, periodontitis) and the lung (for example, cystic fibrosis). Wherever inflammatory diseases occur, systemic effects on bone will ensue, as well as increased fracture risk. Here, we discuss the cellular and signalling pathways underlying, and strategies for therapeutically interfering with, the inflammatory loss of bone.     

Tamibarotene modulates the local immune response in experimental periodontitis

Tamibarotene (Am80), a synthetic retinoic acid receptor (RAR), is an agonist with high specificity for RARα and RARβ. Retinoid agonists have been shown to inhibit Th17 cell polarization and to enhance forkhead box P3 (Foxp3) expression during the course of inflammatory diseases. The aim of this study was to evaluate the previously unrecognized role of Am80 in regulating the immune responses of periodontitis within the oral microenvironment. The experimental model of periodontitis in mice was induced by oral infection with Porphyromonas gingivalis (P. gingivalis) W83. Our results indicated that Am80 effectively suppressed alveolar bone resorption induced by P. gingivalis W83 and decreased the number of osteoclasts. We clarified that these effects were closely associated with the reduced percentage of CD4⁺ retinoid-related orphan receptor (ROR)γt⁺ cells and increased the percentage of CD4⁺ Foxp3⁺ cells in the gingival tissues, cervical lymph nodes (CLNs), and spleen. Furthermore, in P. gingivalis-infected mice, Am80 down-regulated mRNA expression levels of interleukin-17A (IL-17A), receptor activator of nuclear factor-kappa beta ligand (RANKL), monocyte chemotactic protein-1 (MCP-1), IL-6, and IL-1β. Simultaneously, Am80 up-regulated expression levels of IL-10 and transforming growth factor-β1 (TGF-β1) in gingival tissues and the CLNs. Our results suggest that Am80 could protect against periodontal bone resorption, primarily through the modulation of immune responses in the oral microenvironment, and demonstrate the potential of Am80 as a novel clinical strategy for preventing periodontitis.     

Emerging concepts in periodontal therapy

Conventional periodontal therapy consists of mechanical scaling and root planing, and surgical treatment. This is still the mainstay of periodontal treatment. Adjunctive antimicrobial treatments, both systemic and local delivery, are becoming more sophisticated and useful in the treatment of recurrent periodontitis. Also very promising are adjunctive treatments that modulate the host response and decrease levels of destructive pro-inflammatory cytokines or matrix metalloproteinases. Smoking is a major risk factor for periodontitis and has a profound impact on the progression of periodontal bone and attachment loss. In the interest of improved periodontal health patients should be encouraged to stop smoking. Finally bacterial endotoxins that stimulate the release of pro-inflammatory cytokines can have systemic effects and may lead to pre-term, low birthweight babies, and cardiovascular diseases such as atherosclerosis, myocardial infarction and stroke. Health professionals need to be cognisant of the effect dental health can have on systemic diseases and refer for treatment when appropriate to ensure that optimum oral and systemic health is achieved for their patients.     

Deciphering the toxicological role of Porphyromonas gingivalis derived endotoxins in liver diseases

Periodontitis is a most prevalent and infectious multifactorial inflammatory disease and is characterized by the progressive destruction of the tooth-supporting tissues. Porphyromonas gingivalis, a Gram‑negative oral anaerobe, mainly causes periodontitis and it is one of the most important risk factors responsible for aggravation of existing systemic diseases. Several experimental and clinical studies have shown the positive association between periodontitis and different forms of liver disease. Periodontal diseases increase the prevalence of non-alcoholic fatty liver diseases and cirrhosis. Infected periodontium and pathogens in the periodontal microenvironments release pathogen-associated molecular patterns such as peptidoglycan, lipopolysaccharides, gingipain, fimbria, bacterial DNA, etc, and damage-associated molecular patterns such as interleukins-1α, β, − 8, and galectin-3, etc. These virulence factors and cytokines enter the bloodstream, disseminate into the whole body, and induce a variety of systemic pathological effects, including liver diseases (steatosis and fibrosis). Maintaining oral hygiene by scaling and root planning significantly improves liver damage in patients with periodontitis. Dentists and physicians should have more awareness in understanding the bidirectional nature of the relationship between oral and systemic diseases. Importantly, periodontitis condition aggravates simple fatty liver into fibrotic disease and therefore, the aim of this review is to understand the possible link between periodontitis and liver diseases.     

Laquinimod in the treatment of relapsing remitting multiple sclerosis

Introduction: Laquinimod is a new once-daily oral administrable agent, which is under investigation in a phase 3 clinical trial for relapsing remitting multiple sclerosis (RRMS) and in a phase 2 clinical trial for primary progressive MS (PPMS).

Areas covered: The pharmacokinetic, pharmacodynamic and the safety profiles of laquinimod are covered in this review. In preclinical studies, the ability to prevent both experimental autoimmune encephalomyelitis and experimental autoimmune neuritis has been demonstrated. Reduced cell infiltration, demyelination, axonal damage and a shift of T-helper cell responses have been shown. Accordingly, in human studies, a decrease of pro-inflammatory and an increase of anti-inflammatory cytokines have been measured and a significant reduction of disease progression and a decrease in brain volume loss has been demonstrated. During all clinical studies a favorable safety profile was observed for 0.6mg laquinimod. New information about cardiovascular events is prompting the discontinuation of higher dosing regimens in both ongoing trials.

Expert opinion: Laquinimod is a first in class oral agent with high potential to reduce disease progression in RRMS and PPMS. Owing to its favorable safety profile, a combination with 0.6mg laquinimod and other disease modifying therapies could be an option in future MS therapy.     

Cannabidiol decreases bone resorption by inhibiting RANK/RANKL expression and pro-inflammatory cytokines during experimental periodontitis in rats

Cannabidiol (CBD) is a cannabinoid component from Cannabis sativa that does not induce psychotomimetic effects and possess anti-inflammatory properties. In the present study we tested the effects of CBD in a periodontitis experimental model in rats. We also investigated possible mechanisms underlying these effects. Periodontal disease was induced by a ligature placed around the mandible first molars of each animal. Male Wistar rats were divided into 3 groups: control animals; ligature-induced animals treated with vehicle and ligature-induced animals treated with CBD (5 mg/kg, daily). Thirty days after the induction of periodontal disease the animals were sacrificed and mandibles and gingival tissues removed for further analysis. Morphometrical analysis of alveolar bone loss demonstrated that CBD-treated animals presented a decreased alveolar bone loss and a lower expression of the activator of nuclear factor-κB ligand RANKL/RANK. Moreover, gingival tissues from the CBD-treated group showed decreased neutrophil migration (MPO assay) associated with lower interleukin (IL)-1β and tumor necrosis factor (TNF)-α production. These results indicate that CBD may be useful to control bone resorption during progression of experimental periodontitis in rats.