Analgesic and antiinflammatory effects of two novel kappa-opioid peptides

BACKGROUND: This study investigates two new kappa-agonist tetrapeptides, FE 200665 and FE 200666, with high peripheral selectivity as a result of poor central nervous system penetration. METHODS: Four days after administration of Freund adjuvant into the hind paw of male Wistar rats, antinociceptive effects of intraplantar and subcutaneous injection of FE 200665 and FE 200666 were measured by paw pressure algesiometry and compared with the kappa-agonist U-69,593. Peripheral and kappa-receptor selectivity was assessed by the antagonists naloxone methiodide (NLXM) and nor-binaltorphimine, respectively. Antiinflammatory effects were evaluated by paw volume plethysmometry and histologic score. RESULTS: Similar to intraplantar U-69,593, intraplantar FE 200665 (3-100 microg) and FE 200666 (1-30 microg) resulted in significant and dose-related increases of paw pressure thresholds. Higher doses of FE 200665 (0.2-20 mg) and FE 200666 (0.06-6 mg) were required by subcutaneous route to produce similar antinociceptive responses, supporting a peripheral site of action. nor-Binaltorphimine dose-dependently antagonized this effect, implying kappa-opioid selectivity. Analgesic effects of subcutaneous FE 200665 and FE 200666 were abolished by intraplantar nor-binaltorphimine, and both subcutaneous and intraplantar effects were dose-dependently antagonized by subcutaneous NLXM, further demonstrating a peripheral site of action. One to 6 days after Freund adjuvant inoculation, single and repeated intraplantar injections of FE 200665, FE 200666, and U-69,593 significantly reduced paw volume and histologic scores. Both changes were reversed by intraplantar nor-binaltorphimine and subcutaneous NLXM. CONCLUSION: FE 200665 is a peripherally selective kappa-agonist with potent analgesic and antiinflammatory properties that may lead to improved analgesic-antiinflammatory therapy compared with centrally acting opioids or standard nonsteroidal antiinflammatory drugs.     

Do practice guidelines guide practice? A prospective audit of induction of labor three years experience

BACKGROUND: To examine the effect of implementation of guidelines for induction of labor on the process of care and outcome measures. METHOD: Guidelines for induction of labor were implemented in January 1996 following an audit report identifying inconsistency in clinical practice. A prospective audit was carried out following the implementation of a new strategy directed towards pre-induction cervical ripening in nulliparae with unfavorable cervices and the use of low dosages of vaginal prostaglandin E2 for induction of labor. Level of compliance and outcome measures were compared before and after implementation of guidelines. RESULTS: In the period of January 1995 to November 1997, 1,230 women were induced with a singleton viable pregnancy in a cephalic presentation with a gestational age > or = 37 weeks with no history of rupture of membranes or cesarean section. Completed forms were available for 1,147 women (370, 421 and 356 in 1995, 1996 and 1997, respectively). Among nulliparous women, there was a reduction in the number of women who were admitted with cervical score of < or = 4 (24%, 40%, and 54% in 1997, 1996, and 1995, respectively; p=0.0001), an increase in the number of women who had amniotomy on admission (32%, 25% and 12% in 1997, 1996, and 1995, respectively; p=0.0001) and a shorter induction-delivery interval. No change in outcome measures was noted among multiparous women despite reduced dose of prostaglandin E2 used for induction of labor. A marginal reduction of both Cesarean section and failed induction rates were noted in both nulliparae and multiparae. Level of compliance improved with successive rounds of audit. CONCLUSION: Explicit guidelines do improve clinical practice, when introduced and monitored in the context of rigorous evaluations. However, the size of improvement could vary.     

Copper levels in women using intrauterine devices or oral contraceptives

A study was undertaken to explore the role of the copper IUD (Cu-200) in contraception and to lower its side effects. Endometrial and plasma concentrations of copper were determined spectrographically in the late proliferative and late secretory phases in 15 women wearing the copper IUD, in 6 short-term Lippes loop users, in 23 long-term Lippes loop users, in 17 patients on oral contraception, and in 32 women who were not using contraception,y The last group of women served as controls. The findings showed a decrease in the endometrial copper level in the secretory phase but no change in the plasma concentration of copper in the control group. Both Cu-200 and Lippes loops produced a rise in endometrial copper which was significant during the secretory phase. The possibility of a local foreign body reaction is noted. Combined steroid pills caused variable degrees of increase of endometrial and plasma copper in both phases. Endometrial copper levels were elevated in both phases of the cycle, while plasma copper showed a probably significant rise in the proliferative phase only. The change in plasma copper may be explained by changes occurring in hormonal pattern during pill therapy.     

Human alphavbeta3 integrin potency and specificity of TA138 and its DOTA conjugated form (89)Y-TA138

The present study was undertaken to define the alphavbeta3-binding potency and specificity of TA138, a nonpeptide integrin antagonist, and its conjugated form, 89Y-TA138. Various integrin-specific binding and functional assays as well as cell-adhesion assays were used to determine the potency and integrin specificity for TA138 and 89Y-TA138. Both TA138 and 89Y-TA138 inhibited alphavbeta3-mediated [125I]echistatin binding to 293-beta3-transfected cells, with IC50 values of 0.046 and 0.059 microM, respectively, and IC50 values of 0.012 and 0.018 microM, respectively, in inhibiting an alphavbeta3 integrin-mediated 293-beta3-transfected cell adhesion to fibrinogen. TA138 inhibited human umbilical vein endothelial cell adhesion to fibrinogen, with an IC50 value of 0.052 +/- 0.006 microM. Both TA138 and 89Y-TA138 demonstrated a relatively high degree of specificity for human alphavbeta3 integrin as compared with other human integrins, including alphavbeta5, alphaIIbbeta3, and alpha5beta1 (IC50 > 10 microM). Both 89Y-TA138 and TA138 demonstrated comparable alphavbeta3 affinity and specificity as compared with other closely related human integrins such as alphavbeta5, alphaIIbbeta3, or alpha5beta1.     

Effect of resveratrol on angiogenesis and platelet/fibrin-accelerated tumor growth in the chick chorioallantoic membrane model

We carried out this investigation to examine the effects on angiogenesis-mediated processes and to define anti-angiogenesis mechanisms for flavonoids. We examined the effects and mechanisms of the flavonoid resveratrol on angiogenesis and tumor growth using the chick chorioallantoic membrane (CAM) model of angiogenesis, the CAM tumor growth model, and the effect on p53 in fibroblast growth factor-2 (FGF2) stimulated human endothelial cells using immunoassay. Resveratrol demonstrated potent inhibition (effective dose50=0.7+/-0.1 microM) of FGF2-induced angiogenesis and tumor growth. Furthermore, resveratrol significantly (P<0.01) inhibited platelet/fibrin clot-promoted human colon and fibrosarcoma tumor growth in the CAM tumor model. Resveratrol in a concentration-dependent (1-3 microM) manner significantly promoted apoptosis in FGF2-stimulated endothelial cells by increasing p53 protein production. These data indicated potent anti-angiogenesis efficacy, inhibition of tumor growth, and clot-mediated enhanced tumor growth. These data suggest potential anticancer benefits as a chemopreventive and chemotherapeutic for the flavonoid resveratrol.     

Periodontal diseases and the risk of coronary heart and cerebrovascular diseases: a meta-analysis

BACKGROUND: This meta-analysis was conducted to examine the relationship between periodontal diseases and coronary heart diseases (CHD) and cerebrovascular diseases (CVD) in observational studies. METHODS: This study was based on seven cohort studies and four studies of other designs that met prestated inclusion criteria. Information on study design, year of publication, study location, sample size, study population, participant characteristics, measurement of risk factors, exposure and outcome measures, matching, controlling for confounders, and risk estimates was abstracted independently by two investigators using a standard protocol. RESULTS: Subjects with periodontitis had an overall adjusted risk of CHD that was 1.15 times (95% confidence interval [CI]: 1.06 to 1.25; P = 0.001) the risk for healthy subjects. There was no heterogeneity among the studies in the overall relative risk estimate (P = 0.472). As compared to healthy subjects, those with periodontitis had an overall adjusted relative risk of CVD of 1.13 (95% CI: 1.01 to 1.27; P = 0.032). CONCLUSIONS: Findings indicated that periodontal infection increases the risk of CHD and CVD. However, this meta-analysis provided no evidence for the existence of strong associations between periodontitis and CHD and CVD. Larger and better-controlled studies involving socially homogeneous populations and measuring specific periodontal pathogens are required to identify a definite association between periodontal disease and the risk of coronary heart disease and cerebrovascular disease.