Intra-articular Injection of Baicalein Inhibits Cartilage Catabolism and NLRP3 Inflammasome Signaling in a Posttraumatic OA Model.

Baicalein has been shown to have chondroprotective potential in vitro. However, its effect on disease modification in osteoarthritis (OA) is largely unknown. The present study is aimed at determining whether baicalein could slow the progression of OA and inhibit OA-related inflammation in a rat model of destabilization of the medial meniscus (DMM) and the underlying mechanisms. The rats subjected to DMM surgery were treated with baicalein (0.8, 1.6, and 3.2 µg/L, 50 µL, once a week) by intra-articular injection for 6 weeks. Dexamethasone (0.4 mg/mL, 50 µL, once a week) was used as a positive control. Histologic grading of cartilage degeneration was performed using the Osteoarthritis Research Society International (OARSI) recommended grading system (on a scale of 0-6). The expression levels of molecules associated with cartilage homeostasis and inflammatory cytokines were analyzed; moreover, the NLRP3 inflammasome activation and cartilage oxidative stress-associated molecules were determined. Baicalein treatment reduced the OARSI score and slowed OA disease progression in a dose-dependent manner within a certain range. Compared with DMM rats, intra-articular injection of baicalein led to (1) reduced levels of inflammatory mediates such as IL-1ß and TNF-α, (2) reduced immunochemical staining of MMP-13 and ADAMTS-5, (3) suppressed immunochemical staining loss of type II collagen, (4) reduced expression of cartilage degradation markers including CTX-II and COMP in urine, and (5) inhibited NLRP3 inflammasome activation rather than regulated expression of SOD, GSH, and MDA. In contrast to the administration of baicalein, dexamethasone injection showed similar effects to slow OA progression, while dexamethasone inhibited NLRP3 inflammasome partly through decreasing levels of SOD, GSH, and MDA. This study indicated that baicalein may have the potential for OA prevention and exerts anti-inflammatory effects partly via suppressing NLRP3 inflammasome activation without affecting oxidative stress-associated molecules, and inhibition of cartilage catabolism enzymes in an OA rat model.

[Aspirin and preeclampsia]. / Aspirine et prééclampsie.

Indications for aspirin during pregnancy are a matter of debate and there is a recent trend to an extended prescription and an overuse of aspirin in pregnancy. Aspirin is efficient in secondary prevention of preeclampsia essentially in patients with a personal history of preeclampsia. The effect of aspirin on platelet aggregation and on the TXA2/PGI2 balance is dose-dependent. The optimum dosage, from 75mg/day to 150mg/day, needs to be determined. Fetal safety data at 150mg/day are still limited. The efficacy of aspirin seems to be subject to a chronobiological effect. It is recommended to prescribe an evening or bedtime intake. Aspirin, in primary prevention of preeclampsia, given to high-risk patients identified in the first trimester by screening tests, seems to reduce the occurrence of early-onset preeclampsia. Nevertheless, there are insufficient data for the implementation of such screening procedures in practice.

Prostaglandin antagonist relieves blood-retinal barrier breakdown induced by anterior segment intraocular surgery in a rat model.

PURPOSE: To evaluate the efficacy of prostaglandin antagonists on blood-retinal barrier breakdown induced by anterior segment intraocular simulated surgery. METHODS: Rats were randomly assigned to a negative control group, model group, nonsteroidal anti-inflammatory drugs prophylactic treatment group, nonsteroidal anti-inflammatory drugs treatment group, corticosteroid prophylactic treatment group, and corticosteroid treatment group. Four hours and 48h after modeling, the concentrations of PGE1, PGE2, and PGF2 α in the aqueous humor and vitreous body of the rat model were visualized using ELISA. The integrity of the blood-retinal barrier was quantitatively measured using Evan's blue as a tracer. RESULTS: Four hours after modeling, the concentrations of PGE1, PGE2, and PGF2α in the aqueous humor and vitreous body in the negative control group and the nonsteroidal anti-inflammatory drugs prophylactic treatment group were significantly lower than those in the model group. The concentrations of PGE1, PGE2, and PGF2α in the aqueous humor and vitreous body in the corticosteroid prophylactic treatment group were higher than those in the negative control group and the nonsteroidal anti-inflammatory drugs prophylactic treatment group. Forty-eight hours after modeling, the concentrations of PGE1, PGE2, and PGF2α in the aqueous humor and vitreous body in the nonsteroidal anti-inflammatory drugs prophylactic treatment group, nonsteroidal anti-inflammatory drugs treatment group, corticosteroid prophylactic treatment group, and corticosteroid treatment group were lower than those in the model group, but higher than those in the negative group. Retinal Evan's blue leakage in the nonsteroidal anti-inflammatory drugs prophylactic treatment group was higher than that in the negative control group, and lower than those in the nonsteroidal anti-inflammatory drugs treatment group, corticosteroid prophylactic treatment group, corticosteroid treatment group, and model group. Retinal Evan's blue leakage in the nonsteroidal anti-inflammatory drugs treatment group, corticosteroid prophylactic treatment group, and corticosteroid treatment group were lower than those in the model group. CONCLUSIONS: This study confirms that prostaglandin antagonists can relieve blood-retinal barrier breakdown in a rat model and that nonsteroidal anti-inflammatory drugs prophylactic treatment can achieve better efficacy.

Prostaglandin antagonist relieves blood-retinal barrier breakdown induced by anterior segment intraocular surgery in a rat model / O antagonista das prostaglandinas alivia a ruptura da barreira sanguínea retiniana induzida pela cirurgia intraocular do segmento anterior em um modelo em ratos

ABSTRACT Purpose: To evaluate the efficacy of prostaglandin antagonists on blood-retinal barrier breakdown induced by anterior segment intraocular simulated surgery. Methods: Rats were randomly assigned to a negative control group, model group, nonsteroidal anti-inflammatory drugs prophylactic treatment group, nonsteroidal anti-inflammatory drugs treatment group, corticosteroid prophylactic treatment group, and corticosteroid treatment group. Four hours and 48h after modeling, the concentrations of PGE1, PGE2, and PGF2 α in the aqueous humor and vitreous body of the rat model were visualized using ELISA. The integrity of the blood-retinal barrier was quantitatively measured using Evan's blue as a tracer. Results: Four hours after modeling, the concentrations of PGE1, PGE2, and PGF2α in the aqueous humor and vitreous body in the negative control group and the nonsteroidal anti-inflammatory drugs prophylactic treatment group were significantly lower than those in the model group. The concentrations of PGE1, PGE2, and PGF2α in the aqueous humor and vitreous body in the corticosteroid prophylactic treatment group were higher than those in the negative control group and the nonsteroidal anti-inflammatory drugs prophylactic treatment group. Forty-eight hours after modeling, the concentrations of PGE1, PGE2, and PGF2α in the aqueous humor and vitreous body in the nonsteroidal anti-inflammatory drugs prophylactic treatment group, nonsteroidal anti-inflammatory drugs treatment group, corticosteroid prophylactic treatment group, and corticosteroid treatment group were lower than those in the model group, but higher than those in the negative group. Retinal Evan's blue leakage in the nonsteroidal anti-inflammatory drugs prophylactic treatment group was higher than that in the negative control group, and lower than those in the nonsteroidal anti-inflammatory drugs treatment group, corticosteroid prophylactic treatment group, corticosteroid treatment group, and model group. Retinal Evan's blue leakage in the nonsteroidal anti-inflammatory drugs treatment group, corticosteroid prophylactic treatment group, and corticosteroid treatment group were lower than those in the model group. Conclusions: This study confirms that prostaglandin antagonists can relieve blood-retinal barrier breakdown in a rat model and that nonsteroidal anti-inflammatory drugs prophylactic treatment can achieve better efficacy.

RESUMO Objetivos: Avaliar a eficácia do antagonista de prostaglandinas no rompimento da barreira hemato-retiniana induzida por cirurgia simulada intraocular do segmento anterior. Métodos: Os ratos foram divididos aleatoriamente em grupo controle negativo, grupo modelo, grupo de tratamento profilático com drogas anti-inflamatórias não esteroides, grupo de tratamento com anti-inflamatórias não esteroides, grupo de tratamento profilático com corticosteroides e grupo de tratamento com corticosteroides. Quatro e 48h após a modelagem, as concentrações de PGE1, PGE2 e PGF2 α no humor aquoso e no corpo vítreo em modelo em ratos foram detectadas através de Elisa. A integridade da barreira hemato-retiniana foi quantitativamente mensurada utilizando o azul de Evans como marcador. Resultados: Quatro horas após a modelagem, as concentrações de PGE1, PGE2 e PGF2α no humor aquoso e no corpo vítreo no grupo controle negativo e no grupo de tratamento profilático com anti-inflamatórias não esteroides foram significativamente menores do que as do grupo modelo. As concentrações de PGE1, PGE2 e PGF2α no humor aquoso e no corpo vítreo no grupo de tratamento profilático com corticosteroides foram maiores do que as observadas no grupo controle negativo e no grupo de tratamento profilático com anti-inflamatórias não esteroides. 48h após a modelagem, as concentrações de PGE1, PGE2 e PGF2α no humor aquoso e no corpo vítreo no grupo de tratamento profilático com anti-inflamatórias não esteroides, no grupo de tratamento com anti-inflamatórias não esteroides, no grupo de tratamento profilático com corticosteroides e no grupo de tratamento com corticosteroides foram menores do que as observadas no grupo modelo e maiores que as observadas no grupo negativo. O extravasamento retinal de azul de Evans no grupo de tratamento profilático com anti-inflamatórias não esteroides foi maior que no grupo controle negativo e menor que nos grupos de tratamento com anti-inflamatórias não esteroides, de tratamento profilático com corticosteroides, de tratamento com corticosteroides e no grupo modelo. O extravasamento retinal de azul de Evans observado nos grupos de tratamento com anti-inflamatórias não esteroides, de tratamento profilático com corticosteroides e de tratamento com corticosteroides foi inferior ao observado no grupo modelo. Conclusões: Este estudo valida que o antagonista das prostaglandinas pode aliviar a ruptura da barreira hemato-retiniana em um modelo em ratos e que o tratamento profilático com anti-inflamatórias não esteroides pode alcançar melhor eficácia.

Role of the water-drinking test in medically treated primary open angle glaucoma patients.

PURPOSE: The water-drinking test (WDT) has recently re-emerged as a possible way to determine the competency of the trabecular meshwork. We performed a prospective interventional study to test the hypothesis that the WDT could be useful in assessing fluctuations in patients undergoing treatment for primary open angle glaucoma (POAG). METHODS: We included 122 patients; 62 on medical treatment for POAG (n=123 eyes) and 60 controls (n=120 eyes). The study group had been on intraocular pressures (IOP) lowering treatment continuously for at least 3months with stable IOP. The WDT was performed during fasting and was considered positive if it fluctuated ≥6mmHg. RESULTS: The patients on medical treatment had a mean age of 50.56±18.45 years vs. 51.35±11.22 for the controls (P=0.34); with 71% being female in the study group and 77% in the control group. In the study group; 52% were on beta blockers (n=64), 27% combination of two or more medications (n=33), 19% prostaglandin analogues (n=24) and 2% alpha agonists (n=2). The WDT was positive in 17.07% (n=21) in the study group and 2.5% (n=3) in the control group (P=0.0001). The mean fluctuation was 7.14±2.15mmHg in the study group and 6.00±0mmHg in the controls (P=0.33). A positive WDT was found in 33.33% (n=11) of those on combination therapy; 12.5% (n=3) prostaglandin analogues and 10.94% (n=7) beta blockers (P=0.03). Combination therapy had the highest positive WDT fluctuation (7.54±2.87) followed by prostaglandin analogues (7.00±1.00) and beta blockers (6.57±0.78) with a P value of 0.44. CONCLUSIONS: The WDT can identify significant fluctuations in eyes with POAG that are medically treated.

Prostaglandins mediate zymosan-induced sickness behavior in mice.

Previous studies have demonstrated that zymosan, a cell wall component of the yeast Saccharomyces cerevisiae, induces inflammation in experimental models. However, few studies have evaluated the potential of zymosan to induce sickness behavior, a central motivational state that allows an organism to cope with infection. To determine whether zymosan administration results in sickness behavior, mice were submitted to the forced swim (FST) and open field (OFT) tests 2, 6, and 24 h after treatment with zymosan (1, 10, or 100 mg/kg). Additionally, to evaluate the possible relationship between zymosan-induced sickness behavior and prostaglandin synthesis, mice were pretreated with the cyclooxygenase inhibitors indomethacin (10 mg/kg) and nimesulide (5 mg/kg) and the glucocorticoid drug dexamethasone (1 mg/kg). Zymosan induced time-dependent decreases in locomotor activity in the OFT, and an increase in immobility in the FST, and increased plasma levels of corticosterone at 2 h. Pretreatment with indomethacin, nimesulide, or dexamethasone blocked zymosan-induced behavioral changes in both the FST and OFT at 2 h post administration. These findings confirm previous observations that zymosan induces sickness behavior. Furthermore, our results provide new evidence that prostaglandin synthesis is necessary for this effect, as anti-inflammatory drugs that inhibit prostaglandin synthesis attenuated zymosan-induced behavioral changes.

Female Sex Hormones Influence the Febrile Response Induced by Lipopolysaccharide, Cytokines and Prostaglandins but not by Interleukin-1ß in Rats.

There are differences in the immune response, and particularly fever, between males and females. In the present study, we investigated how the febrile responses induced by lipopolysaccharide (LPS) and different endogenous pyrogens were affected by female gonadal hormones. The febrile response to i.p. injection of LPS (50 µg/kg) was 40% lower in female rats compared to male or ovariectomised (OVX) female rats. Accordingly, oestrogen replacement in OVX animals reduced LPS-induced fever. Treatment with the prostaglandin synthesis inhibitor indomethacin (2 mg/kg, i.p. 30 min before) reduced the febrile response induced by LPS in both OVX (88%) and sham-operated (71%) rats. In line with the enhanced fever in OVX rats, there was increased expression of cyclooxygenase-2 (COX-2) in the hypothalamus and elevated levels of prostaglandin E2 (PGE2 ). In addition, OVX rats were hyper-responsive to PGE2 injected i.c.v. By contrast to the enhanced fever in response to LPS and PGE2 , the febrile response induced by i.c.v. injection of interleukin (IL)-1ß was unaffected by ovariectomy, whereas the responses induced by tumour necrosis factor (TNF)-α and macrophage inflammatory protein (MIP)-1α were completely abrogated. These results suggest that the mediators involved in the febrile response in females are similar to males, although the reduction of female hormones may decrease the responsiveness of some mediators such as TNF-α and MIP-1α. Compensatory mechanisms may be activated in females after ovariectomy such as an augmented synthesis of COX-2 and PGE2 .

Diameter changes of retinal arterioles during acute hypoxia in vivo are modified by the inhibition of nitric oxide and prostaglandin synthesis.

PURPOSE: Inhibition of cyclooxygenase (COX) and nitric oxide synthesis (NOS) has previously been shown to modify hypoxia-induced relaxation of retinal arterioles in vitro. The purpose of the present study was to investigate whether these findings can be reproduced in vivo. METHODS: Twenty healthy persons aged 20-55 years were examined. Using the dynamic vessels analyzer (DVA), the resting diameter and diameter changes during isometric exercise and flicker stimulation were studied before and during breathing of a hypoxic gas mixture. The examinations were carried out before and during intravenous infusion of the NOS-inhibitor l-NMMA, and were repeated on a second study day after topical administration of the COX-inhibitor diclofenac. RESULTS: The resting diameter of retinal arterioles increased significantly during hypoxia and decreased significantly during l-NMMA infusion (p < 0.0001) which compensated for changes in the blood pressure. During hypoxia and l-NMMA infusion together contraction of retinal arterioles could not compensate for the increased blood pressure as assessed by a gain factor significantly lower than one (p = 0.002). The arteriolar contraction induced by isometric exercise was significantly reduced by diclofenac and flicker-induced dilatation of retinal arterioles was increased during l-NMMA infusion (p < 0.0001). CONCLUSION: Diameter changes of retinal vessels during acute hypoxia in vivo are modified by inhibiting NO and prostaglandin synthesis. The evidence points to possible new targets of intervention on the diameter regulation of retinal arterioles in diseases where retinal hypoxia is part of the disease pathogenesis.

In vivo investigations on luteotropic activity of prostaglandins during early diestrus in nonpregnant bitches.

The aim of this study was to test for the postulated luteotropic effect of prostaglandin E2 during early diestrus in the dog in an in vivo study. This study was performed on 30 bitches which were randomly assigned to a treatment group (TG) and a control group. Starting on the day of ovulation (Day 0), dogs of the TG were treated for 5, 10, 20, or 30 days with 10 mg firocoxib/kg body weight per day (Previcox, a selective PTGS2 inhibitor) and ovariohysterectomized for collection of corpora lutea on the last day of treatment. Similarly, dogs of the control group were ovariohysterectomized on Days 0, 5, 10, 20, and 30. Blood samples for progesterone measurement were collected every second day; additionally, the area of luteal cell nuclei and the expression of 3ß-hydroxysteroid-dehydrogenase at the mRNA and the protein levels were assessed. Mean P4 concentrations were lower in TGs; however, a significant difference was only observed on Day 10. This observation is in line with the finding that treatment with firocoxib reduced expression of 3ß-hydroxysteroid-dehydrogenase mRNA and protein (P < 0.05) and the area of luteal cell nuclei (P < 0.05). The results of this study further point to the postulated luteotropic function of prostaglandin E2.

Efficacy of paracetamol on patent ductus arteriosus closure may be dose dependent: evidence from human and murine studies.

BACKGROUND: We evaluated the clinical effectiveness of variable courses of paracetamol on patent ductus arteriosus (PDA) closure and examined its effect on the in vitro term and preterm murine ductus arteriosus (DA). METHODS: Neonates received one of the following three paracetamol regimens: short course of oral paracetamol (SCOP), long course of oral paracetamol (LCOP), and intravenous paracetamol (IVP) for 2-6 d. Pressure myography was used to examine changes in vasomotor tone of the preterm and term mouse DA in response to paracetamol or indomethacin. Their effect on prostaglandin synthesis by DA explants was measured by mass spectroscopy. RESULTS: Twenty-one preterm infants were included. No changes in PDA hemodynamics were seen in SCOP infants (n = 5). The PDA became less significant and eventually closed in six LCOP infants (n = 7). PDA closure was achieved in eight IVP infants (n = 9). On pressure myograph, paracetamol induced a concentration-dependent constriction of the term mouse DA, up to 30% of baseline (P < 0.01), but required >1 µmol/l. Indomethacin induced greater DA constriction and suppression of prostaglandin synthesis (P < 0.05). CONCLUSION: The clinical efficacy of paracetamol on PDA closure may depend on the duration of treatment and the mode of administration. Paracetamol is less potent than indomethacin for constriction of the mouse DA in vitro.

The role of prostaglandin and antioxidant availability in recovery from forearm ischemia-reperfusion injury in humans.

BACKGROUND: Endothelial dysfunction, manifesting as attenuated flow-mediated dilation (FMD), is clinically important. Antioxidants may prevent this dysfunction; however, the acute effects of oral administration in humans are unknown. Low flow-mediated constriction (L-FMC), a further parameter of endothelial health, is largely unstudied and the mechanisms for this response unclear. METHODS: Twelve healthy participants (five women and seven men) completed three test conditions: control; antioxidant cocktail (α-lipoic acid, vitamins C and E); and prostaglandin inhibitor ingestion (ibuprofen). Ultrasound measurements of brachial artery responses were assessed throughout 5 min of forearm ischemia and 3 min after. Subsequently, an ischemia-reperfusion injury was induced by a 20-min upper arm occlusion. Further, vascular function protocols were completed at 15, 30, and 45 min of recovery. RESULTS: Endothelial dysfunction was evident in all conditions. FMD was attenuated at 15 min after ischemia-reperfusion injury (Pre: 6.24 ± 0.58%; Post15: 0.24 ± 0.75%; mean ± SD, P < 0.05), but recovered by 45 min. Antioxidant administration did not preserve FMD compared with control (P > 0.05). The magnitude of L-FMC was augmented at 15 min (Pre: 1.44 ± 0.27%; Post15: 3.75 ± 1.73%; P < 0.05) and recovered by 45 min. Ibuprofen administration produced the largest constrictive response (Pre: -1.13 ± 1.71%; Post15: -5.57 ± 3.82%; time × condition interaction: P < 0.05). CONCLUSION: Results demonstrate ischemia-reperfusion injury causes endothelial dysfunction and acute oral antioxidant supplementation fails to reduce its magnitude. Our results also suggest that a lack of shear stress during occlusion combined with suppression of prostaglandin synthesis magnifies L-FMC, possibly due to augmented endothelin-1 expression.

Prenatal effects of maternal consumption of polyphenol-rich foods in late pregnancy upon fetal ductus arteriosus.

Fetal circulation has characteristic features, being morphologically and functionally different from extrauterine circulation. The ductus arteriosus plays a fundamental role in directing the blood flow to fetal inferior body parts. Basically, the ductus arteriosus directs 80-85% of the right ventricular output arising from the superior vena cava, coronary sinus, and a small part from the inferior vena cava to descending aorta. Its histological structure is made up predominantly by a thick muscular layer, differently from the aorta and the pulmonary artery, which increases with gestational age. The fibers have a circumferential orientation, especially at the external layers, facilitating and making effective ductal constriction. These factors may generate lumen alterations which may cause fetal and neonatal complications, such as heart failure, hydrops, neonatal pulmonary hypertension, and even death. Classically, maternal administration of indomethacin and/or other antiinflammatory drugs interfere in prostaglandins metabolism, causing ductal constriction. However, many cases of fetal ductal constriction, as well as of persistent neonatal pulmonary artery hypertension, remain without an established etiology, being referred as "idiopathic." In recent years, a growing body of evidence has shown that herbs, fruits, nuts, and a wide diversity of substances commonly used in daily diets have definitive effects upon the metabolic pathway of inflammation, with consequent inhibition of prostaglandins synthesis. This antiinflammatory action, especially of polyphenols, when ingested during the third trimester of pregnancy, may influence the dynamics of fetal ductus arteriosus flow. The goal of this review is to present these new observations and findings, which may influence dietary orientation during pregnancy.

Aspirin use and risk of colorectal cancer according to BRAF mutation status.

IMPORTANCE: Aspirin use reduces the risk of colorectal carcinoma. Experimental evidence implicates a role of RAF kinases in up-regulation of prostaglandin-endoperoxide synthase 2 (PTGS2, cyclooxygenase 2), suggesting that BRAF-mutant colonic cells might be less sensitive to the antitumor effects of aspirin than BRAF-wild-type neoplastic cells. OBJECTIVE: To examine whether the association of aspirin intake with colorectal cancer risk differs according to status of tumor BRAF oncogene mutation. DESIGN AND SETTING: We collected biennial questionnaire data on aspirin use and followed up participants in the Nurses' Health Study (from 1980) and the Health Professionals Follow-up Study (from 1986) until July 1, 2006, for cancer incidence and until January 1, 2012, for cancer mortality. Duplication-method Cox proportional cause-specific hazards regression for competing risks data was used to compute hazard ratios (HRs) for colorectal carcinoma incidence according to BRAF mutation status. MAIN OUTCOMES AND MEASURES: Incidence of colorectal cancer cases according to tumor BRAF mutation status. RESULTS: Among 127,865 individuals, with 3,165,985 person-years of follow-up, we identified 1226 incident rectal and colon cancers with available molecular data. Compared with nonuse, regular aspirin use was associated with lower BRAF-wild-type cancer risk (multivariable HR, 0.73; 95% CI, 0.64 to 0.83; age-adjusted incidence rate difference [RD], -9.7; 95% CI, -12.6 to -6.7 per 100,000 person-years). This association was observed irrespective of status of tumor PTGS2 expression or PIK3CA or KRAS mutation. In contrast, regular aspirin use was not associated with a lower risk of BRAF-mutated cancer (multivariable HR, 1.03; 95% CI, 0.76 to 1.38; age-adjusted, incidence RD, 0.7; 95% CI, -0.3 to 1.7 per 100,000 person-years: P for heterogeneity = .037, between BRAF-wild-type vs BRAF-mutated cancer risks). Compared with no aspirin use, aspirin use of more than 14 tablets per week was associated with a lower risk of BRAF-wild-type cancer (multivariable HR, 0.43; 95% CI, 0.25 to 0.75; age-adjusted incidence RD, -19.8; 95% CI, -26.3 to -13.3 per 100,000 person-years). The relationship between the number of aspirin tablets per week and colorectal cancer risk differed significantly by BRAF mutation status (P for heterogeneity = .005). CONCLUSIONS AND RELEVANCE: Regular aspirin use was associated with lower risk of BRAF-wild-type colorectal cancer but not with BRAF-mutated cancer risk. These findings suggest that BRAF-mutant colon tumor cells may be less sensitive to the effect of aspirin. Given the modest absolute risk difference, further investigations are necessary to determine clinical implications of our findings.

Clinical efficacy and safety of a multimodality skin brightener composition compared with 4% hydroquinone.

There are numerous common skin disorders involving hyperpigmentation, including solar lentigines, postinflammatory hyperpigmentation, melasma, freckles, and dyschromia from photoaging. While these conditions are of an aesthetic nature, there is great interest in newer, safer, and more effective treatment modalities. Topical hydroquinone (HQ) has been the gold standard of skin lighteners for many years. However, regulatory authorities around the world are now questioning its safety. A randomized, double-blind, half-face study was conducted in females with moderate to severe facial hyperpigmentation to assess the efficacy and tolerability of 3 new skin brightener formulations containing SMA-432, a prostaglandin E2 inhibitor, compared with 4% HQ. Each subject was assigned 2 of the 4 test materials and was instructed to apply the product on the assigned side of the face twice daily for 12 weeks. Evaluation visits were conducted at baseline and at 4, 8, and 12 weeks. At each visit, subjects were evaluated by a blinded investigator for clinical efficacy and tolerability using grading scales. Standardized digital photography and Chroma Meter assessments were also taken. Self-assessment questionnaires were completed at weeks 4, 8, and 12. Sixty-eight Caucasian subjects (136 half faces) completed the study. All test materials significantly reduced Overall Hyperpigmentation and improved the Investigator's Global Hyperpigmentation Improvement rating at weeks 4, 8, and 12 compared with baseline. SMA-432 exhibited a dose-dependent improvement in hyperpigmentation. There were no major tolerability issues with any of the test materials. Self-assessments were generally favorable for all test materials. At the completion of the trial, subjects rated one of the tested multimodality brightener compositions as the most favorable product and 4% HQ as the least favorable. This study demonstrated that the new non-HQ-containing skin brightener formulations were as effective and equally well tolerated as the gold standard, 4% HQ, in females with facial hyperpigmentation.

Pharmacokinetics after intravenous administration of flunixin meglumine in budgerigars (Melopsittacus undulatus) and Patagonian conures (Cyanoliseus patagonus).

OBJECTIVE: To investigate the disposition kinetics of flunixin meglumine when administered IV to budgerigars (Melopsittacus undulatus) and Patagonian conures (Cyanoliseus patagonus). DESIGN: Prospective cohort study. ANIMALS: 8 adult Patagonian conures and 24 adult budgerigars. PROCEDURES: Injectable flunixin meglumine (50 mg/mL) was diluted to 10 and 1. 0 mg/mL and administered IV at a dose of 5.0 mg/kg (2.3 mg/lb) to Patagonian conures and budgerigars, respectively. RESULTS: In budgerigars, the elimination half-life was 0.72 hours and the mean residence time was 0.73 hours. In Patagonian conures, the elimination half-life was 0.91 hours and the mean residence time was 1.20 hours. The concentration of flunixin was below the assay's limit of quantification (0.5 µg/mL) at 3 and 6 hours in budgerigars and Patagonian conures, respectively. A single budgerigar developed adverse effects (lethargy and signs of depression) for approximately 15 minutes following drug administration. CONCLUSIONS AND CLINICAL RELEVANCE: The half-life of flunixin in Patagonian conures and budgerigars was short following IV administration; however, results of this study suggested that IV administration of injectable flunixin meglumine at 5.0 mg/kg resulted in plasma concentrations that could potentially be anti-inflammatory and analgesic in budgerigars and Patagonian conures.

Bilateral sequential nonarteritic anterior ischemic optic neuropathy: a comparison of visual outcomes in fellow eyes using quantitative analysis of goldmann visual fields.

OBJECTIVE: To better define the concordance of visual loss in patients with nonarteritic anterior ischemic optic neuropathy (NAION). METHODS: The medical records of 86 patients with bilateral sequential NAION were reviewed retrospectively, and visual function was assessed using visual acuity, Goldmann visual fields, color vision, and relative afferent papillary defect. A quantitative total visual field score and score per quadrant were analyzed for each eye using the numerical Goldmann visual field scoring method. RESULTS: Outcome measures were visual acuity, visual field, color vision, and relative afferent papillary defect. A statistically significant correlation was found between fellow eyes for multiple parameters, including logMAR visual acuity (P=.01), global visual field (P<.001), superior visual field (P<.001), and inferior visual field (P<.001). The mean deviation of total (P<.001) and pattern (P<.001) deviation analyses was significantly less between fellow eyes than between first and second eyes of different patients. CONCLUSIONS: Visual function between fellow eyes showed a fair to moderate correlation that was statistically significant. The pattern of vision loss was also more similar in fellow eyes than between eyes of different patients. These results may help allow better prediction of visual outcome for the second eye in patients with NAION.

A new approach to reducing postsurgical cancer recurrence: perioperative targeting of catecholamines and prostaglandins.

Surgery is a crucial intervention in most cancer patients, but the perioperative period is characterized by increased risks for future outbreak of preexisting micrometastases and the initiation of new metastases-the major cause of cancer-related death. Here we argue that the short perioperative period is disproportionately critical in determining long-term recurrence rates, discuss the various underlying risk factors that act synergistically during this period, and assert that this time frame presents an unexplored opportunity to reduce long-term cancer recurrence. We then address physiologic mechanisms that underlie these risk factors, focusing on excess perioperative release of catecholamines and prostaglandins, which were recently shown to be prominent in facilitating cancer recurrence through their direct impact on the malignant tissue and its microenvironment, and through suppressing antimetastatic immunity. The involvement of the immune system is further discussed in light of accumulating evidence in cancer patients, and given the recent identification of endogenously activated unique leukocyte populations which, if not suppressed, can destroy autologous "immune-resistant" tumor cells. We then review animal studies and human correlative findings, suggesting the efficacy of blocking catecholamines and/or prostaglandins perioperatively, limiting metastasis and increasing survival rates. Finally, we propose a specific perioperative pharmacologic intervention in cancer patients, based on simultaneous ß-adrenergic blockade and COX-2 inhibition, and discuss specific considerations for its application in clinical trials, including our approved protocol. In sum, we herein present the rationale for a new approach to reduce long-term cancer recurrence by using a relatively safe, brief, and inexpensive intervention during the perioperative period.

Effects of sodium diclofenac on the concentration function in animals with different neurohypophyseal status.

The characteristics of the osmotic concentration system under conditions of sodium diclofenac treatment were studied in Wistar rats with normally functioning vasopressin gene and homozygotic Brattleboro rats completely lacking endogenous vasopressin. Blockade of prostaglandin synthesis in rats with different neurohypophyseal status stimulated urinary osmolality to a different degree. Different contribution of sodium cations and urea to osmotic concentration was revealed.

Inhibition of prostaglandin biosynthesis during postluteolysis and effects on CL regression, prolactin, and ovulation in heifers.

The beginning of postluteolysis (progesterone, <1 ng mL(-1)) in heifers was targeted by using 8 h after ultrasonic detection of a 25% decrease in CL area (cm2) and was designated Hour 0. Flunixin meglumine (FM; n=10) to inhibit PGF2α secretion or vehicle (n=9) were given intramuscularly at Hours 0, 4, 8, 16, 24, 32, and 40. The dose of FM was 2.5 mg/kg at each treatment. Blood sampling and measurement of the CL and dominant follicle were done every 8 h beginning 14 days postovulation in each group. Blood samples for detection of pulses of PRL and pulses of a metabolite of PGF2α (PGFM) were obtained every hour for 24 h beginning at Hour 0. Pulse concentrations of both PGFM and PRL were lower in the FM group than in the vehicle group. Concentration of PRL was greatest at the peak of a PGFM pulse. Neither CL area (cm2) nor progesterone concentration differed between groups during Hours 0 to 48 (postluteolysis). Ovulation occurred in nine of nine heifers in the vehicle group and in three of 10 heifers in the FM group. The anovulatory follicles in the FM group grew to 36.2±2.9 mm, and the wall became thickened from apparent luteinization. The hypothesis that PGF2α was involved in the continued P4 decrease and structural CL regression during postluteolysis was not supported. However, the hypotheses that pulses of PGFM and PRL were temporally related and that systemic FM treatment induced an anovulatory follicle were supported.