Assessment of the Effectiveness of Different Fluoride-releasing Bonding Agents on Prevention of Enamel Demineralization around Orthodontic Bracket: An In Vitro Study.

AIM: The aim of the current research was to evaluate the efficacy of different fluoride-releasing bonding products in preventing enamel demineralization around orthodontic brackets by using a scanning electron microscope (SEM). MATERIALS AND METHODS: This research was performed using 80 healthy human premolar teeth that were extracted in course of orthodontic therapy. Until use, the sample premolars were subjected to storage in 0.1% thymol. Each premolar was thereafter cleansed with pumice for 10 seconds. Stainless steel brackets for premolars were employed. The 80 samples were allocated at random to one of the four groups (20 in each) as follows: Group I, control; group II, Transbond Plus color change adhesive; group III, GC Fuji Ortho LC; and group IV, Vitremer. An hour following bonding, all samples were subjected to pH cycling at a temperature of 37°C for a 14-day period. The premolar teeth were assessed below SEM. Analysis was performed with the one-way analysis of variance. Statistical significance was set at a p-value less than 0.05. RESULTS: The extreme area of demineralization was abridged by the use of Transbond™ Plus color change adhesive (108.19 ± 0.68), trailed by GC Fuji Ortho LC (119.24 ± 0.37) use, Vitremer (121.56 ± 0.92) as well as the control group (141.88 ± 1.09) in that order. And there was a statistically significant difference found between the groups (p <0.001). Tukey's honestly significant difference (HSD) was employed in an overall comparison of mean areas of enamel demineralization, which depicted that differences were significant statistically with the exception of group III and group IV. CONCLUSION: The current research came to a conclusion that the Transbond Plus color change adhesive group was more potent in significant inhibition of demineralization areas in comparison to GC Fuji Ortho LC group and Vitremer group. CLINICAL SIGNIFICANCE: In course of fixed orthodontic therapy, demineralization of enamel is an inherent occurrence. Multiple approaches are being continually developed to avoid the formation of white spot lesions (WSLs) that compromise esthetics and cause deprived remineralization that enhances the menace of dental caries. Bonding agents that can release fluorides are thus considered highly efficacious.

Cost-effectiveness of tiotropium versus glycopyrronium in moderate to very severe chronic obstructive pulmonary disease in Canada, Spain, Sweden, and the UK.

OBJECTIVES: Tiotropium (TIO), Spiriva® Handihaler®, is a well-established bronchodilator, LAMA (long acting muscarinic antagonist), for the treatment of moderate to very severe chronic obstructive pulmonary disease (COPD). Clinical evidence from the SPARK trial suggests that TIO is superior to glycopyrronium (GLY), Seebri® Breezhaler®, in terms of severe exacerbations. This modeling study assessed the cost-effectiveness of TIO versus GLY for Canada (CAN), Spain (ESP), Sweden (SWE), and the UK, making use of this new clinical evidence. METHODS: A Markov cohort model, with moderate to very severe (Global Initiative for Chronic Obstructive Lung Disease II-IV) COPD patients, was populated with efficacy data from the Understanding Potential Long-term Impacts on Function with Tiotropium (UPLIFT) and SPARK trials as well as costs, utilities, and epidemiological data relevant for each country. Treatment efficacy was modeled as improvements in lung function, quality-adjusted life years (QALYs), and as a lowering of the risk of exacerbations (rate of exacerbations). Risks of exacerbations differed between cohorts based on data from SPARK. Health and cost outcomes were simulated over an approximate lifetime horizon, starting from the age of 65 years. Robustness of results was validated in deterministic sensitivity analyses. RESULTS: Over the lifetime horizon, patients treated with TIO accumulated -623 (CAN), 1,066 (ESP), 1,137 (SWE), and -169 (UK), respectively, in incremental costs (€2014). TIO generated better health outcomes compared to GLY in all countries, 0.21 (CAN), 0.25 (ESP), 0.23 (SWE), and 0.23 (UK) in incremental QALYs. The cost per QALY gained was found to be €4,281 and €1,137 for ESP and SWE, respectively, while TIO was found to be cost saving in CAN and the UK. The results were mainly driven by the relative risk of severe exacerbations found in SPARK (GLY/TIO relative risk: 1.43, 95% confidence interval: 1.05-1.97, P=0.025). CONCLUSION: The results from this study show that TIO is a cost-effective treatment compared to GLY in moderate to very severe COPD. The cost per QALY is well below the existing implicit and explicit willingness-to-pay thresholds.

Cost-effectiveness of tiotropium versus usual care and glycopyrronium in the treatment of chronic obstructive pulmonary disease in Sweden.

BACKGROUND: Tiotropium (TIO) is a well-established bronchodilator, LAMA (long-acting anticholinergic), for the treatment of moderate to very severe chronic obstructive pulmonary disease (COPD). Clinical evidence suggests that tiotropium is superior to usual non-LAMA care (UC) but may also have benefits compared to other LAMAs in preventing and limiting the effects of severe exacerbations. The primary objective of this study was to undertake a cost-effectiveness analysis of adding tiotropium to usual care versus usual care alone. A secondary objective was to assess the cost-effectiveness of tiotropium compared to glycopyrronium (GLY), another LAMA. The study was conducted with a Swedish setting in mind. METHODS: A Markov cohort model, incorporating the effects of exacerbations, was populated with efficacy data from the UPLIFT and SPARK trials and epidemiological data relevant for a Swedish patient population. Treatment efficacy of tiotropium was modelled as a lowering of the risk of exacerbations and as a slow-down of overall disease progression. The model followed patients over their remaining life-time. RESULTS: The base case analysis showed that patients treated with tiotropium gained 0.07 quality-adjusted life years (QALYs) compared to usual care alone at an incremental cost of SEK 15,041, resulting in a cost per QALY gained of SEK 224,850. Compared to glycopyrronium the QALY gained was estimated to 0.23 QALYs in favour of tiotropium at an incremental cost of SEK 2423, yielding a cost per QALY gained of SEK 10,456. The results were mainly driven by differences in the risk of severe exacerbations. CONCLUSION: At the current implicit willingness-to-pay (WTP) per QALY threshold in Sweden, the results from this study indicate that tiotropium is a highly cost-effective intervention when added to usual non-LAMA care in the treatment of moderate to very severe COPD in Sweden. In addition, tiotropium is a highly cost-effective intervention when compared to glycopyrronium monotherapy.

Differential regulation of C-type natriuretic peptide-induced cGMP and functional responses by PDE2 and PDE3 in failing myocardium.

Recently, we showed C-type natriuretic peptide (CNP)-induced negative inotropic (NIR) and positive lusitropic response (LR) in failing rat heart. We wanted to study whether, and if so, how phosphodiesterases (PDEs) regulate CNP-induced cyclic 3',5'-guanosine monophosphate (cGMP) elevation and functional responses. Inotropic and lusitropic responses were measured in left ventricular muscle strips and cyclic nucleotide levels, PDE activity and phospholamban (PLB) and troponin I (TnI) phosphorylation were measured in ventricular cardiomyocytes from Wistar rats with heart failure 6 weeks after myocardial infarction. CNP-mediated increase in global cGMP was mainly regulated by PDE2, as reflected by a marked amplification of the cGMP increase during PDE2 inhibition and by a high PDE2 activity in cardiomyocytes. PDE3 inhibition, on the other hand, caused no significant cGMP increase by CNP. The functional consequences did not correspond to the changes of cGMP. PDE3 inhibition increased the potency of the CNP-induced NIR and LR, while PDE2 inhibition desensitized the CNP-induced NIR, but not LR. A role for PDE2 on the maximal LR and PDE5 on the maximal NIR to CNP was revealed in the presence of PDE3 inhibition. CNP increased PLB phosphorylation about 25- to 30-fold and tended to increase TnI phosphorylation about twofold. As a whole, CNP-induced functional responses were only modestly regulated by PDEs compared to the cAMP-mediated functional responses to ß1-adrenoceptor stimulation, which are highly regulated by PDEs. There is a mismatch between the CNP-induced cGMP increase and functional responses. Global cGMP levels are mainly regulated by PDE2 after CNP stimulation, whereas the functional responses are modestly regulated by both PDE2 and PDE3, indicating cGMP compartmentation by PDEs affecting CNP-induced responses in failing hearts.

Agents increasing cyclic GMP amplify 5-HT4-elicited positive inotropic response in failing rat cardiac ventricle.

Activation of 5-HT(4) receptors in failing ventricles elicits a cAMP-dependent positive inotropic response which is mainly limited by the cGMP-inhibitable phosphodiesterase (PDE) 3. However, PDE4 plays an additional role which is demasked by PDE3 inhibition. The objective of this study was to evaluate the effect of cGMP generated by particulate and soluble guanylyl cyclase (GC) on the 5-HT(4)-mediated inotropic response. Extensive myocardial infarctions were induced by coronary artery ligation in Wistar rats, exhibiting heart failure 6 weeks after surgery. Contractility was measured in left ventricular preparations. Cyclic GMP was measured by EIA. In ventricular preparations, ANP or BNP displayed no impact on 5-HT(4)-mediated inotropic response. However, CNP increased the 5-HT(4)-mediated inotropic response as well as the ß(1)-adrenoceptor (ß(1)-AR)-mediated response to a similar extent as PDE3 inhibition by cilostamide. Pretreatment with cilostamide eliminated the effect of CNP. Inhibition of nitric oxide (NO) synthase and soluble GC by L-NAME and ODQ, respectively, attenuated the 5-HT(4)-mediated inotropic response, whereas the NO donor Sin-1 increased this response. The effects were absent during PDE3 inhibition, suggesting cGMP-dependent inhibition of PDE3. However, in contrast to the effects on the 5-HT(4) response, Sin-1 inhibited whereas L-NAME and ODQ enhanced the ß(1)-AR-mediated inotropic response. cGMP generated both by particulate (NPR-B) and soluble GC increases the 5-HT(4)-mediated inotropic response in failing hearts, probably through inhibition of PDE3. ß(1)-AR and 5-HT(4) receptor signalling are subject to opposite regulatory control by cGMP generated by soluble GC in failing hearts. Thus, cGMP from different sources is functionally compartmented, giving differential regulation of different G(s)-coupled receptors.

Differential regulation of ß2 -adrenoceptor-mediated inotropic and lusitropic response by PDE3 and PDE4 in failing and non-failing rat cardiac ventricle.

BACKGROUND AND PURPOSE: ß-Adrenoceptors play a major role in regulating myocardial function through cAMP-dependent pathways. Different phosphodiesterases (PDEs) regulate intracellular cAMP-pools and thereby contribute to the compartmentalization of cAMP-dependent effects. We explored the involvement of PDEs in limiting the ß(2) adrenoceptor-mediated positive inotropic (PIR) and lusitropic (LR) responses in sham-operated (Sham) and failing rat hearts. EXPERIMENTAL APPROACH: Extensive myocardial infarctions were induced by coronary artery ligation in Wistar rats. Rats developing heart failure were studied 6 weeks after surgery. Contractility was measured in left ventricular strips from failing and Sham hearts. cAMP was quantified by RIA. KEY RESULTS: In ventricular strips, stimulation of ß(2) -adrenoceptors with (-)-adrenaline (300 nM CGP20712A present) exerted a small PIR and LR. In Sham hearts, ß(2) -adrenoceptor-mediated as well as ß(1) -adrenoceptor-mediated PIR and LR were increased by selective inhibition of either PDE3 (1 µM cilostamide) or PDE4 (10 µM rolipram). In failing rat hearts, PDE3 inhibition enhanced PIR and LR to both ß(1) - and ß(2) -adrenoceptor stimulation while PDE4 inhibition had no effect on these responses despite a significant increase in cAMP levels. Combined PDE3/4 inhibition further enhanced the PIR and LR of ß(2) - and ß(1) -adrenoceptor activation both in Sham and failing hearts, compared with PDE3 inhibition alone. PDE4 enzyme activity was reduced in failing hearts. CONCLUSIONS AND IMPLICATIONS: Both PDE3 and PDE4 attenuated ß(2) - and ß(1) -adrenoceptor-mediated contractile responses in Sham hearts. In failing hearts, these responses are attenuated solely by PDE3 and thus even selective PDE3 inhibitors may provide a profound enhancement of ß-adrenoceptor-mediated responses in heart failure.