REDUCED CARDIOTOXICITY AND INCREASED CYTOTOXICITY IN A NOVEL ANTHRACYCLINE ANALOG, 4'-AMINO-3'-HYDROXY-DOXORUBICIN

The acute and chronic cardiotoxicity and cytotoxicity of the novel doxorubicin (DXR) derivative 4'-amino-3'-hydroxy-DXR were compared with those of 4'-deoxy-DXR and DXR. In the acute cardiotoxicity study, the ECG and hemodynamic changes recorded in anesthetized rats that had been treated i.v. with 10 mg/kg 4'-amino-3'-hydroxy-DXR or 8.6 mg/kg 4'-deoxy-DXR were significantly less severe than those caused by 13 mg/kg DXR. In the chronic cardiotoxicity study, rats received 3 weekly i.v. injections of 3 mg/kg DXR, 3 mg/kg 4'-amino-3'-hydroxy-DXR, or 2 mg/kg 4'-deoxy-DXR during the first 14 days of the study and were observed for an additional 35-day period. DXR induced severe cardiomyopathy that was characterized by ECG changes in vivo (S-alpha-T-segment widening and T-wave flattening) and by impairment of the contractile responses (F(max), +/- dF/dt(max)) to adrenaline of hearts isolated from treated animals. 4'-Deoxy-DXR caused a progressive enlargement of the S-alpha-T segment in vivo and a significant impairment of the - dF/dt(max) value in vitro, which were less severe than those produced by DXR. The least cardiotoxic drug was 4'-amino-3'-hydroxy-DXR, which induced minor ECG changes without causing significant alterations in the contractile responses of isolated hearts to adrenaline. On the basis of the drug concentration required to inhibit 50% of the colony formation (IC50) of cell lines in vitro, 4'-amino-3'-hydroxy-DXR was less active than 4'-deoxy-DXR but at least twice as active as DXR against human cancer and murine transformed cell lines. These data indicate that 4'-amino-3'-hydroxy-DXR is significantly less cardiotoxic and more cytotoxic than DXR

Comparative sem evaluation of three solvents used in endodontic retreatment: an ex vivo study

This study compared, by scanning electron microscopy (SEM), the efficacy of three solvents on the removal of filling materials from dentinal tubules during endodontic retreatment. Forty human maxillary canines with straight canals were prepared according to a crown-down technique and enlarged to a#30 apical file size, before obturation with gutta-percha and a zinc-oxide-eugenol based sealer. The samples were stored for 3 months before being randomly assigned to four groups: chloroform (n=10), orange oil (n=10), eucalyptol (n=10) and control (n=10). Solvents were applied to a reservoir created on the coronal root third using Gates Glidden drills. The total time for retreatment using the solvents was 5 minutes per tooth. Following retreatment the roots were split longitudinally for SEM evaluation. SEM images were digitized, analyzed using Image ProPlus 4.5 software, and the number of dentinal tubules free of filling material from the middle and apical thirds was recorded. No significant difference was found among the solvent groups regarding the number of dentinal tubules free of root filling remnants in the middle and apical root thirds (p>;0.05). However, the control group had fewer dentinal tubules free of filling material (

Development of Feline Immunodeficiency Virus ORF-A (tat) Mutants: In Vitro and in Vivo Characterization

AbstractA functional ORF-A is essential for efficient feline immunodeficiency virus replication in lymphocytes. We have characterized a series of mutants of the Petaluma strain, derived from p34TF10 and having different combinations of stop codons and increasingly long deletions in ORF-A. Six clones proved fully replicative in fibroblastoid Crandell feline kidney cells and monocyte-derived macrophage cultures but failed to replicate in T cell lines and primary lymphoblasts. Cats inoculated with three selected mutants had considerably milder infections than controls given intact ORF-A virus. In vivo, the mutants maintained growth properties similar to those in vitro for at least 7 months, except that replication in lymphoid cells was strongly reduced but not ablated. One mutant underwent extensive ORF-A changes without, however, reverting to wild-type. Antiviral immune responses were feeble in all cats, suggesting that viral loads were too low to represent a sufficiently powerful antigenic stimulus

Comparison of primary human gingival fibroblasts from an older and a young donor on the evaluation of cytotoxicity of denture adhesives

Denture adhesives (DA) improve the retention and stability of ill-fitting dentures, especially for older adults. These materials should be biocompatible, i.e., they cannot cause undesired biological responses and be non-cytotoxic to oral tissues. However, in vitro testing of DA biocompatibility employing primary cell culture may possibly be affected by other factors, such as the donor age. Objective To compare the cytotoxicity of three different denture adhesives when assessed in primary gingival fibroblasts from a young donor or from an older donor, as well as the release of the basic fibroblast growth factor (bFGF), and the inflammatory response marker interleukin-6 (IL-6). Material and Methods Gingival fibroblasts isolated from a 30- and a 62-year-old donor were assayed for proliferation (1-7 days) and sensitivity to latex (positive control). Fibroblasts were indirectly exposed to Corega Ultra (cream), Corega powder and Fixodent Original for a 24 h period and assayed by XTT and Crystal Violet tests. The release of IL-6 and bFGF by exposed cells was determined by ELISA. Results While cells from the young donor presented higher cell growth after 7 days, the sensitivity to increasing concentrations of latex extracts was very similar between young and older cells. Both XTT and CVDE detected no difference between the DA and the control group. All materials induced higher levels of IL-6 and bFGF compared to control. Cells from the older donor exposed to Corega Ultra released lower levels of cytokine and growth factor. Conclusions All materials were considered non-cytotoxic, but affected cytokine and growth factor release. The biological differences found between fibroblasts from both donors could be due to individual or age-related factors. The authors suggest the use of cells from older donors on studies of dental products aimed at older patients, to better simulate their physiological response

CAN METABOLIC SYNDROME AFFECT THE EFFICACY OUTCOMES OF COMBINATION THERAPY WITH DAILY TADALAFIL 5MG PLUS TAMSULOSIN 0.4MG IN MEN WITH LUTS AND ED?

INTRODUCTION AND OBJECTIVE: Metabolic Syndrome (METS) has a high prevalence (26.5%–55.6%) in men with LUTS and erectile dysfunction (ED). Daily tadalafil 5mg intake is currently recognized as an effective pharmacological treatment for male LUTS, alone or in combination with alpha-lithics such as tamsulosin 0,4mg, ensuring a greater LUTS relieve. Aim of this study is to assess if METS could affect the efficacy of combination therapy with daily tadalafil 5mg plus tamsulosin 0,4mg in men with LUTS and ED. METHODS: Across 12 months, fifty consecutive patients aged >40 to 80 years, with moderate to severe LUTS (IPSS >7) and mild to severe ED (IIEF-5 <22) were enrolled and treated with the previous combination therapy for 12 weeks. The assessment of patients included age, body mass index (BMI), METS features - waist circumference (WC), blood pressure, clinical laboratory parameters- digital rectal examination, IPSS, OABq, uroflowmetry and postvoid residual (PVR) volume, IIEF-5. METS was defined according to NCEP ATP III. Differences were calculated by unpaired sample t-test at baseline and 12 weeks. The analysis of variance (ANOVA) was used for between-group differences. RESULTS: Among 50 patients enrolled, 31 (62.0%) had METS. Mean age was similar with 65.5 years (9.1) in patients without METS and 67.1 years (7.2) in METS patients, p=0.133. Baseline IPSS, OAB-q and IPSS QoL were significantly higher in patients with METS (p<0.05), while IIEF was higher in patients without METS (p=0.039) at baseline (Table1). After 3 months of combination therapy, IIEF, total IPSS and subscores, OAB-q and Qmax significantly improved in both groups. DeltaIPSS, deltaQMax and deltaIIEF were similar between groups (p>0.05). However, total IPSS, IPSS QoL, IPSS Voiding and IPSS Storage were significantly better at the end of the trial in men without METS. Conversely, 12wks IIEF was similar in patients with or without METS (16.3 vs 17.7 p=0.238) (Table2). CONCLUSIONS: Tadalafil plus tamsulosin combi therapy represents an effective LUTS treatment in male, independently from METS. Despite a similar improvement of LUTS (delta), patients without METS obtained a significantly better LUTS relieve. Interestingly, the efficacy in ED was greater in men with METS and, at the end of trial, IEEF-5 scores were similar in the two groups

Intergroup conflict management strategies from a nobel peace laureate: The case of Jose Ramos-Horta

We report on the case of Dr. José Ramos-Horta (JRH), a 1996 Nobel Peace Laureate, former President of East Timor, and current envoy of the United Nations to Guinea-Bissau. JRH agreed to an interview detailing the peace building strategies he has used to manage conflicts. The transcript of his Nobel Laureate acceptance speech was also analysed to strengthen the overall narrative. Our findings suggest two higher-order themes: (1) psycho-social skills, and (2) social networking. Specifically, JRH uses active listening, mindful breaks, and awareness of media trends to create personal and strategic networking contacts, which are critical elements in managing conflict

Glyphosate efficacy, absorption and translocation for Eragrostis plana control.

Abstract: Background: Glyphosate is the most effective herbicide to control the invasive and perennial Eragrostis plana in Southern Brazil. However, one application has not been sufficient to prevent the regrowth of plants. Objective: The aim of this research was to evaluate the efficacy of glyphosate sprayed alone or mixed with fluazifop-p-butyl or flumioxazin on E. plana control and to investigate 14C-glyphosate absorption and translocation. Methods: Plants with 2-3 tillers were treated with glyphosate (700 g a.e. ha- 1), fluazifop-p-butyl (47 g a.i. ha-1), flumioxazin (100 g a.i. ha-1), glyphosate + fluazifop-p-butyl (700 g a.e. ha-1 + 47g a.i. ha-1), glyphosate + flumioxazin (700 g a.e. ha-1 +100 g a.i. ha-1). Weed control was evaluated visually for 28 d after treatment (DAT) when plants were harvested for shoot dry biomass determination. 14C-glyphosate absorption and translocation were measured at 24 and 72 h after treatment. Results: Glyphosate at 700 g a.e. ha-1 controlled E. plana plants at 2-3 tillers. The mixture with fluazifop-p-butyl or flumizin did not significantly increase the level of control (87 and 86% at 7 DAT, respectively) but increased 14C-glyphosate translocation to the roots. Conclusions: Glyphosate is effective on E. plana. However, applied with fluazifop-p-butyl could improve the control of this weed, especially when perennial plants of E. plana dominate the field, preventing their fast regrowth. Keywords: 14C-glyphosate; fluazifop-p-butyl; forage grass; invasive plant; tough lovegras

New form discovery for the analgesics flurbiprofen and sulindac facilitated by polymer-induced heteronucleation

The selection and discovery of new crystalline forms is a longstanding issue in solid-state chemistry of critical importance because of the effect molecular packing arrangement exerts on materials properties. Polymer-induced heteronucleation has recently been developed as a powerful approach to discover and control the production of crystal modifications based on the insoluble polymer heteronucleant added to the crystallization solution. The selective nucleation and discovery of new crystal forms of the well-studied pharmaceuticals flurbiprofen (FBP) and sulindac (SUL) has been achieved utilizing this approach. For the first time, FBP form III was produced in bulk quantities and its crystal structure was also determined. Furthermore, a novel 3:2 FBP:H 2 O phase was discovered that nucleates selectively from only a few polymers. Crystallization of SUL in the presence of insoluble polymers facilitated the growth of form I single crystals suitable for structure determination. Additionally, a new SUL polymorph (form IV) was discovered by this method. The crystal forms of FBP and SUL are characterized by Raman and FTIR spectroscopies, X-ray diffraction, and differential scanning calorimetry. © 2007 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 96: 2978–2986, 2007Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/57336/1/20954_ftp.pd