Tadalafil analgesia in experimental arthritis involves suppression of intra-articular TNF release

BACKGROUND AND PURPOSE We investigated the effect of the phosphodiesterase-5 inhibitor, tadalafil, on the acute hypernociception in rat models of arthritis. EXPERIMENTAL APPROACH Rats were treated with either an intra-articular injection of zymosan (1 mg) or surgical transection of the anterior cruciate ligament (as an osteoarthritis model). Controls received saline intra-articular or sham operation respectively. Joint pain was evaluated using the articular incapacitation test measured over 6 h following zymosan or between 4 and 7 days after anterior cruciate ligament transection. Cell counts, tumour necrosis factor-alpha (TNF-alpha), interleukin-1 (IL-1), and the chemokine, cytokine-induced neutrophil chemoattractant-1 (CINC-1) were measured in joint exudates 6 h after zymosan. Groups received tadalafil (0.02-0.5 mg.kg(-1) per os) or saline 2 h after intra-articular zymosan. Other groups received the mu-opioid receptor antagonist naloxone or the cGMP inhibitor 1H-[1,2,4] oxadiazolo [4,3-a] quinoxalin-1-one (ODQ) before tadalafil. KEY RESULTS Tadalafil dose-dependently inhibited hypernociception in zymosan and osteoarthritis models. In zymosan-induced arthritis, tadalafil significantly decreased cell influx and TNF-alpha release but did not alter IL-1 or CINC-1 levels. Pretreatment with ODQ but not with naloxone prevented the anti-inflammatory effects of tadalafil. CONCLUSIONS AND IMPLICATIONS Therapeutic oral administration of tadalafil provided analgesia mediated by guanylyl cyclase and was independent of the release of endogenous opioids. This effect of tadalafil was associated with a decrease in neutrophil influx and TNF-alpha release in inflamed joints.

Effects of Lidocaine Infusion during Experimental Endotoxemia in Horses

Background The clinical efficacy of IV infusion of lidocaine for treatment of equine endotoxemia has not been studied. Hypothesis Lidocaine infusion after exposure to lipopolysaccharide (LPS) will inhibit the inflammatory response and have inhibitory effects on the hemodynamic and cytokine responses to endotoxemia. Animals Twelve horses. Methods Two equal groups (n = 6): saline (GI) and lidocaine (GII). In all animals, endotoxin (500 ng/kg body weight [BW]) was injected intraperitoneally over 5 minutes. Twenty minutes later, animals received a bolus of GI or GII (1.3 mg/kg BW) over 5 minutes, followed by a 6-hour continuous rate infusion of GI or GII (0.05 mg/kg BW/min). Treatment efficacy was judged from change in arterial blood pressure, peripheral blood and peritoneal fluid (PF) variables (total and differential cell counts, enzyme activities, and cytokine concentrations), and clinical scores (CS) for behavioral evidence of abdominal pain or discomfort during the study. Results Compared with the control group, horses treated with lidocaine had significantly lower CS and serum and PF tumor necrosis factor-alpha (TNF-alpha) activity. At several time points in both groups, total and differential cell counts, glucose, total protein and fibrinogen concentrations, and alkaline phosphatase, creatine kinase, and TNF-alpha activities were significantly different from baseline values both in peripheral blood and in PF. Conclusions and Clinical Importance Lidocaine significantly decreased severity of CS and inhibited TNF-alpha activity in PF.

Fructose-1,6-bisphosphate reduces inflammatory pain-like behaviour in mice: role of adenosine acting on A(1) receptors

Background and purpose: D-Fructose-1,6-bisphosphate (FBP) is an intermediate in the glycolytic pathway, exerting pharmacological actions on inflammation by inhibiting cytokine production or interfering with adenosine production. Here, the possible antinociceptive effect of FBP and its mechanism of action in the carrageenin paw inflammation model in mice were addressed, focusing on the two mechanisms described above. Experimental approach: Mechanical hyperalgesia (decrease in the nociceptive threshold) was evaluated by the electronic pressure-metre test; cytokine levels were measured by elisa and adenosine was determined by high performance liquid chromatography. Key results: Pretreatment of mice with FBP reduced hyperalgesia induced by intraplantar injection of carrageenin (up to 54%), tumour necrosis factor alpha (40%), interleukin-1 beta (46%), CXCL1 (33%), prostaglandin E(2) (41%) or dopamine (55%). However, FBP treatment did not alter carrageenin-induced cytokine (tumour necrosis factor alpha and interleukin-1 beta) or chemokine (CXCL1) production. On the other hand, the antinociceptive effect of FBP was prevented by systemic and intraplantar treatment with an adenosine A(1) receptor antagonist (8-cyclopentyl-1,3-dipropylxanthine), suggesting that the FBP effect is mediated by peripheral adenosine acting on A(1) receptors. Giving FBP to mice increased adenosine levels in plasma, and adenosine treatment of paw inflammation presented a similar antinociceptive mechanism to that of FBP. Conclusions and implications: In addition to anti-inflammatory action, FBP also presents an antinociceptive effect upon inflammatory hyperalgesia. Its mechanism of action seems dependent on adenosine production but not on modulation of hyperalgesic cytokine/chemokine production. In turn, adenosine acts peripherally on its A(1) receptor inhibiting hyperalgesia. FBP may have possible therapeutic applications in reducing inflammatory pain.

Experimental selective choriocapillaris photothrombosis using a modified indocyanine green formulation

Background: This in vivo study assessed and compared the effectiveness of an aqueous indocyanine green (ICG) formulation (R-ICG) and a lipid ICG formulation (L-ICG) in occluding the rabbit choriocapillaris, and determined the singlet oxygen quantum yields and aggregation properties of both formulations in vitro. Methods: Singlet oxygen production and aggregation were compared. The eye fundus of 30 albino rabbits was irradiated 0-15 min after dye injection using an 810 nm diode laser. Fluorescein angiography and light microscopy were used to evaluate the safety and efficacy of R-ICG and L-ICG. Results: L-ICG decreased the dimerisation constant and the tendency of ICG to form aggregates, and increased the efficiency of ICG in generating singlet oxygen (R-ICG, Phi Delta= 0.120 and L-ICG, Phi Delta= 0.210). Using a 10 mg/kg dose, choriocapillaris occlusion was achieved at a light dose of 35.8 J/cm(2) with L-ICG and 71.6 J/cm(2) with R-ICG with minimal damage to the neurosensory retina. Conclusion: Restrictions to the use of ICG in aqueous solution, low singlet oxygen quantum yields and high aggregation tendency, were overcome with L-ICG. The lower laser irradiance required to obtain choriocapillaris occlusion may suggest that L-ICG is a more potent and selective photosensitiser than R-ICG.

Ethanolic extract of Casearia sylvestris and its clerodane diterpen (caseargrewiin F) protect against DNA damage at low concentrations and cause DNA damage at high concentrations in mice`s blood cells

Casearia sylvestris is used in Brazil as a popular medicine to treat ulcer, inflammation and tumour. Caseargrewiin F is a clerodane diterpene isolated from the ethanolic leaf extract of C.sylvestris. The aim of the study was to assess the capacity of the ethanolic extract of C.sylvestris leaves and caseargrewiin F to protect DNA and verify if both the compounds cause some DNA damage, using the micronucleus (MN) test and comet assay in mice. Balb-C mice were treated with the extract [3.13, 6.25, 12.5, 25, 50 and 75 mg/kg body weight (b.w.)] and caseargrewiin F (0.16, 0.32, 0.63, 1.3, 2.5 and 3.8 mg/kg b.w.) for 14 days. On day 15, DNA damage was induced by intra-peritoneal (i.p.) injection of cyclophosphamide (CP) (i.p.) at 50 mg/kg b.w. after the MN test and comet assay were performed. A protective effect of ethanolic extract was observed in MN test (6.25 and 12.5 mg/kg b.w.) and the comet assay (3.13 and 6.25, 12.5 and 25 mg/kg b.w.). Caseargrewiin F showed protective effect at 0.63, 1.3 and 2.5 mg/kg b.w. only in comet assay. We also tested the ability of compounds of C.sylvestris to induce MN and to increase the comet assay tail moment. The experimental design was similar to the DNA protection assay except that in test groups we omitted the CP challenge. We observed increased damage at 50 and 75 mg/kg b.w. of ethanolic extract of C.sylvestris and caseargrewiin F at 3.18 mg/kg b.w. in both the MN test and comet assay. We conclude that ethanolic extract of C. sylvestris and caseargrewiin F can protect cells against DNA damage induced by CP at low concentrations, but at high concentrations these compounds also induce DNA damage.

Pain and distress reactivity and recovery as early predictors of temperament in toddlers born preterm

Background: Pain reactivity may reflect underlying mechanisms of constitutional aspects of temperament. Aim: To examine whether the neonatal biobehavioral reactivity and recovery responses from pain and distress, as well as the gestational age, the illness severity and the amount of painful procedures undergone the Neonatal Intensive Care Unit (NICU) stay, predict temperament later in toddlerhood, in vulnerable children born preterm. Study design: Prospective-longitudinal study. Subjects: Twenty-six preterm and very low birth weight infants followed from birth to toddlerhood. Outcome measures: Illness severity was assessed with the Clinical Risk Index for Babies (CRIB) score. The medical charts were reviewed prospectively for obtaining the amount of pain exposure in NICU. For assessing the behavioral and cardiac reactivity and recovery from pain and distress, the neonates were evaluated during routine blood collection in the NICU in the first 10 days of life. Pain and distress reactivity and recovery was measured using the Neonatal Facial Coding System score, the duration of crying. and the magnitude of average heart rate. At toddlerhood, mothers answered the Early Childhood Behavior Questionnaire. Results: Higher biobehavioral reactivity to pain and distress predicted higher temperamental Negative Affect, above and beyond gestational age, illness severity and amount of pain exposure in NICU. However, we did not find a predictive relation between gestational age, CRIB score and number of painful procedures undergone NICU and toddler`s temperament. Conclusions: The findings highlight the relevance of the neonatal individual characteristics of reactivity for identifying more vulnerable infants for future problems in biobehavioral regulation. (C) 2009 Elsevier Ireland Ltd. All rights reserved.

Development of chronic cardiomyopathy in canine Chagas disease correlates with high IFN-gamma, TNF-alpha, and low IL-10 production during the acute infection phase

When infected with Trypanosoma cruzi, Beagle dogs develop symptoms similar to those of Chagas disease in human beings, and could be an important experimental model for a better understanding of the immunopathogenic mechanisms involved in chronic chagasic infection. This study evaluates IL-10, IFN-gamma and TNF-alpha production in the sera, culture supernatant, heart and cervical lymph nodes and their correlation with cardiomegaly, cardiac inflammation and fibrosis in Beagle dogs infected with T. cruzi. Pathological analysis showed severe splenomegaly, lymphadenopathy and myocarditis in all infected dogs during the acute phase of the disease, with cardiomegaly, inflammation and fibrosis observed in 83% of the animals infected by T. cruzi during the chronic phase. The data indicate that infected animals producing IL-10 in the heart during the chronic phase and showing high IL-10 production in the culture supernatant and serum during the acute phase had lower cardiac alterations (myocarditis, fibrosis and cardiomegaly) than those with high IFN-gamma and TNF-alpha levels. These animals produced low IL-10 levels in the culture supernatant and serum during the acute phase and did not produce IL-10 in the heart during the chronic phase of the disease. Our findings showed that Beagle dogs are a good model for studying the immunopathogenic mechanism of Chagas disease, since they reproduce the clinical and immunological findings described in chagasic patients. The data suggest that the development of the chronic cardiac form of the disease is related to a strong Th1 response during the acute phase of the disease, while the development of the indeterminate form results from a blend of Th1 and Th2 responses soon after infection, suggesting that the acute phase immune response is important for the genesis of chronic cardiac lesions. Crown Copyright (C) 2009 Published by Elsevier B.V. All rights reserved.

Pain and tactile stimuli during arterial puncture in preterm neonates

The purpose of this study was to assess the behavioral and physiological reactivity of preterm neonates during different phases of a blood collection procedure involving arterial puncture. The sample consisted of 43 preterm and very low birth weight neonates with a postnatal age of 1 to 21 days who were hospitalized in the Neonatal Intensive Care Unit. The neonates were evaluated during the whole blood collection procedure. The assessment was divided into five consecutive phases: Baseline (BL); Antispsis (A), covering the period of handling of the neonate for antisepsis prior to puncture; Puncture (P): Recovery-Dressing (RD), covering the period of handling of the neonate for dressing until positioning for rest in the isolette; and Recovery-Resting (RR). Facial activity was videotaped and analyzed using the National Facial Coding System (NFCS). The sleep-wake state and heart rate were registered at the bedside. There was a significant increases in NFCS score and heart rate, and more active behavior during phases A, P, and RD relative to BL. Regarding the tactile stimulation of the infant in pre-puncture (A) and post-puncture (RD), it was observed increased NFCS score, heart rate, and active behavior in comparison to the BL an BR phases. There was evidence of distress responses immediately before and after a painful event, quite apart form the pain reaction to the puncture procedure. Published by Elsevier B.V. on behalf of International Association for the Study of Pain.

Is pain relief equally efficacious and free of side effects with repeated doses of oral sucrose in preterm neonates?

The aim of the present study was to examine the efficacy and potential side effects of repeated doses of oral sucrose for pain relief during procedures in NICU. Thirty-three preterm neonates were randomly allocated in blind fashion into two groups, the sucrose group (SG = 17) and the control group (CG = 16). The responses of neonates to pain and distress were assessed during blood collection on four consecutive assessment (ass.) days. For the first assessment, the neonates did not receive any solution before the blood collection procedure. During the next three days, the SG received oral sucrose (25%; 0.5 ml/kg) and the CG received sterile water, 2 min before each minor acute painful procedure. The neonates were evaluated during blood collection each morning. The assessment was divided into five phases: Baseline (BL), Antisepsis (A), Puncture (P), Dressing (D), and Recovery (R). The neonates` facial activity (NFCS), behavioral state, and heart rate were evaluated. The data analysis used cut-off scores for painful and distressful responses. No side effects of using sucrose were detected. There were significantly fewer SG neonates with facial actions signaling pain than CG neonates in P (ass.2) and in A (ass.3). We found significantly fewer SG neonates in the awake state than CG neonates in P (ass.2 and ass.4). There were significantly fewer SG neonates crying during A (ass.2), P (ass.2 and ass.4), and D (ass.3). There was no statistical difference between-groups for physiological response. The efficacy of sucrose was maintained for pain relief in preterm neonates with no side effects. (C) 2007 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

Effect of laser phototherapy on recurring herpes labialis prevention: an in vivo study

Alternative treatment for recurrent labial infection by herpes simplex virus (HSV) have been considered. The aim of this study was to evaluate the effectiveness of laser phototherapy in prevention and reduction of severity of labial manifestations of herpes labialis virus. Seventy-one patients, divided into experimental (n = 41) and control (n = 30) groups were followed up for 16 months. Patients in the control group were treated topically with aciclovir and patients in the experimental group were subjected to laser phototherapy (one session per week, 10 weeks): 780 nm, 60 mW, 3.0 J/cm(2) or 4.5 J/cm(2) on healthy (no HSV-1 infection) and affected (with HSV-1 infection) tissues. Patients in the experimental group presented a significant decrease in dimension of herpes labialis lesions (P = 0.013) and inflammatory edema (P = 0.031). The reduction in pain level (P = 0.051) and monthly recurrences (P = 0.076) did not reach statistical significance. This study represents an in vivo indication that this treatment should be further considered as an effective alternative to therapeutic regimens for herpes labialis lesions.

Laser Phototherapy as Topical Prophylaxis Against Head and Neck Cancer Radiotherapy-Induced Oral Mucositis: Comparison Between Low and High/Low Power Lasers

Background and Objective: Oral mucositis is a dose-limiting and painful side effect of radiotherapy (RT) and/or chemotherapy in cancer patients. The purpose of the present study was to analyze the effect of different protocols of laser phototherapy (LPT) on the grade of mucositis and degree of pain in patients under RT. Patients and Methods: Thirty-nine patients were divided into three groups: G1, where the irradiations were done three times a week using low power laser; G2, where combined high and low power lasers were used three time a week; and G3, where patients received low power laser irradiation once a week. The low power LPT was done using an InGaAlP laser (660 nm/40 mW/6 J cm(-2)/0.24 J per point). In the combined protocol, the high power LPT was done using a GaAlAs laser (808 nm, 1 W/cm(2)). Oral mucositis was assessed at each LPT session in accordance to the oral-mucositis scale of the National Institute of the Cancer-Common Toxicity criteria (NIC-CTC). The patient self-assessed pain was measured by means of the visual analogue scale. Results: All protocols of LPT led to the maintenance of oral mucositis scores in the same levels until the last RT session. Moreover, LPT three times a week also maintained the pain levels. However, the patients submitted to the once a week LPT had significant pain increase; and the association of low/high LPT led to increased healing time. Conclusions: These findings are desired when dealing with oncologic patients under RT avoiding unplanned radiation treatment breaks and additional hospital costs. Lasers Surg.Med. 41:264-270,2009. (C) 2009Wiley-Liss, Inc.

Tailoring of physical properties in highly filled experimental nanohybrid resin composites

Objectives. To assess the elastic modulus (EM), volumetric shrinkage (VS), and polymerization shrinkage stress (PSS) of experimental highly filled nanohybrid composites as a function of matrix composition, filler distribution, and density. Methods. One regular viscosity nanohybrid composite (Grandio, VOCO, Germany) and one flowable nanohybrid composite (Grandio Flow, VOCO) were tested as references along with six highly filled experimental nanohybrid composites (four Bis-GMA-based, one UDMA-based, and one Ormocer (R) -based). The experimental composites varied in filler size and density. EM values were obtained from the ""three-point bending"" load-displacement curve. VS was calculated with Archimedes` buoyancy principle. PSS was determined in 1-mm thick specimens placed between two (poly) methyl methacrylate rods (empty set = 6 mm) attached to an universal testing machine. Data were analyzed using oneway ANOVA, Tukey`s test (alpha = 0.05), and linear regression analyses. Results. The flowable composite exhibited the highest VS and PSS but lowest EM. The PSS was significantly lower with Ormocer. The EM was significantly higher among experimental composites with highest filler levels. No significant differences were found between all other experimental composites regarding VS and PSS. Filler density and size did not influence EM, VS, or PSS. Significance. Neither the filler configuration nor matrix composition in the investigated materials significantly influenced composite shrinkage and mechanical properties. The highest filled experimental composite seemed to increase EM by keeping VS and PSS low; however, matrix composition seemed to be the determinant factor for shrinkage and stress development. The Ormocer, with reduced PSS, deserves further investigation. Filler size and density did not influence the tested parameters. (C) 2011 Academy of Dental Materials. Published by Elsevier Ltd. All rights reserved.

Effect of Different Fluoride Concentrations of Experimental Dentifrices on Enamel Erosion and Abrasion

It has been suggested that fluoride products are able to reduce erosive tooth wear. Thus, the purpose of this in vitro study was to evaluate the effect of dentifrices with different fluoride concentrations as well as of a low-fluoridated dentifrice supplemented with trimetaphosphate (TMP) on enamel erosion and abrasion. One hundred twenty bovine enamel blocks were assigned to the following experimental dentifrices: placebo, 1,100 mu g F/g, 500 mu g F/g plus 3% TMP and 5,000 mu g F/g. The groups of enamel blocks were additionally subdivided into conditions of erosion (ERO) and of erosion plus abrasion (ERO + ABR). For 7 days, the blocks were subjected to erosive challenges (immersion in Sprite (R) 4 times a day for 5 min each time) followed by a remineralizing period (immersion in artificial saliva between erosive challenges for 2 h). After each erosive challenge, the blocks were exposed to slurries of the dentifrices (10 ml/sample for 15 s). Sixty of the blocks were additionally abraded by brushing using an electric toothbrush (15 s). The alterations of the enamel were quantified using the Knoop hardness test and profilometry (measurements in micrometers). The data were analyzed using a 2-way ANOVA test followed by a Bonferroni correction (p < 0.05). In in vitro conditions, the 5,000 mu g F/g and 500 mu g F/g plus 3% TMP dentifrices had a greater protective effect when compared with the 1,100 mu g F/g dentifrice, under both ERO and ERO + ABR conditions. The results suggest that dentifrices alone are not capable of completely inhibiting tooth wear. Copyright (C) 2010 S. Karger AG, Basel

A possible mechanism of low molecular weight protein tyrosine phosphatase (LMW-PTP) activity modulation by glutathione action during human osteoblast differentiation

Objective: Low molecular weight protein tyrosine phosphatases (LMW-PTPs) are a family of enzymes strongly involved in the regulation of cell growth and differentiation. Since there is no information concerning the relationship between osteoblastic differentiation and LMW-PTP expression/activity, we investigated its involvement during human osteoblast-like cells (hFOB 1.19) differentiation. It is known that LMW-PTP is regulated by an elegant redox mechanism, so we also observed how the osteoblastic differentiation affected the reduced glutathione levels. Design: hFOB 1.19 cells were cultured in DMEM/F12 up to 35 days. The osteoblast phenotype acquisition was monitored by measuring alkaline phosphatase activity and mineralized nodule formation by Von Kossa staining. LMW-PTP activity and expression were measured using the p-nitrophenylphosphate as substrate and Western blotting respectively. Crystal violet assay determined the cell number in each experimental point. Glutathione level was determined by both HPLC and DNTB assays. Results: LMW-PTP modulation was coincident with the osteoblastic differentiation biomarkers, such as alkaline phosphatase activity and presence of nodules of mineralization in Vitro. Likewise LMW-PTP, the reduced glutathione-dependent microenvironment was modulated during osteoblastic differentiation. During this process, LMW-PTP expression/activity, as well as alkaline phosphatase and glutathione increased progressively up to the 21st day (p < 0.001) of culturing, decreasing thereafter. Conclusions: Our results clearly suggest that LMW-PTP expression/activity was rigorously modulated during osteoblastic differentiation, possibly in response to the redox status of the cells, since it seems to depend on suitable levels of reduced glutathione. in this way, we pointed out LMW-PTP as an important signaling molecule in osteoblast biology and bone formation. (C) 2009 Elsevier Ltd. All rights reserved.

Low Intensity Laser Therapy in Temporomandibular Disorder: a Phase II Double-Blind Study

The purpose of this study was to evaluate the analgesic effect of Low Intensity Laser Therapy (LILT) and its influence on masticatory efficiency in patients with temporomandibular dysfunction (TMD). This study was performed using a random, placebo-controlled, and double-blind research design. Fourteen patients were selected and divided into two groups (active and placebo). Infrared laser (780 nm, 70 mw, 60s, 105J/cm(2)) was applied precisely and continuously into five points of the temporomandibular joint (TMJ) area: lateral point (LP), superior point (SP), anterior point (AP), posterior point (PP), and posterior-inferior point (PIP) of the condylar position. This was performed twice per week, for a total of eight sessions, To ensure a double-blind study, two identical probes supplied by the manufacturer were used: one for the active laser and one for the inactive placebo laser. They were marked with different letters (A and B) by a clinician who did not perform the applications. A Visual Analogue Scale (VAS) and a colorimetric capsule method were employed. Data were obtained three times: before treatment (Ev1), shortly after the eighth session (Ev2), and 30 days after the first application (Ev3). Statistical tests revealed significant differences at one percent (1%) likelihood, which implies that superiority of the active group offered considerable TMJ pain improvement. Both groups presented similar masticatory behavior, and no statistical differences were found. With regard to the evaluation session, Ev2 presented the lowest symptoms and highest masticatory efficiency throughout therapy. Therefore, low intensity laser application is effective in reducing TMD symptoms, and has influence over masticatory efficiency [Ev2 (0.2423) and Ev3 (0.2043), observed in the interaction Evaluations x Probes for effective dosage].