NLC-Based Sunscreen Formulations with Optimized Proportion of Encapsulated and Free Filters Exhibit Enhanced UVA and UVB Photoprotection.

The topical use of sunscreens is recommended for avoiding the damaging effects of UV radiation. However, improvements are still needed in the existing products to enhance their photoprotection effectiveness and safety. This involves minimizing the use of chemical UV filters while providing enhanced and prolonged photoprotection. This work investigated novel sunscreen formulations and their UV protection effects by encapsulating Uvinul® A, Tinosorb® S, and Uvinul® T150 into nanostructured lipid carriers (NLCs) based on bacuri butter and raspberry seed oil. First, the impact of critical formulation and process parameters on NLCs' particle size was evaluated using a 22 Face Centered Central Composite Design. Then, formulations were evaluated in terms of critical quality factors, in vitro skin permeation, and in vitro and in vivo photoprotection activities. The developed NLCs-containing formulations exhibited appropriate size (122-135 nm), PdI (<0.3), encapsulation efficiency (>90%), and drug content (>80%), which were preserved for at least 90 days under different stability conditions. Moreover, these NLCs-based formulations had equivalent skin permeation to emulsion-based controls, and the addition of NLCs into sunscreen cream bases in the optimum proportion of 20% (w/w) resulted in enhanced UVA and UVB photoprotection levels, despite a 10% reduction in the total filters content. Altogether, these results describe the application of nanoencapsulated organic UV filters in innovative sunscreen formulations to achieve superior photoprotection and cosmeceutical properties.

Pulmonary endothelium dependent vasodilation emerges after birth in mice.

At birth, with the first breath, pulmonary vessels undergo profound adaptive processes. A failure in the ability of pulmonary vessels to adapt at birth results in persistent pulmonary hypertension of the new born. The mechanisms regulating pulmonary adaptation at birth are still unclear. Progress in this area is slow, not least because genetically modified mice have not yet been used to address questions in this area of research, principally because pulmonary vessels in new born mice are very small making the study of dilator response in vitro difficult. In the current study we have used precision cut lung slices to characterise the functional vasomotor changes in lung vessels of new born mice (1-4 days old), 8-15 day old mice or adult mice. The internal luminal area of pulmonary artery and airways was measured digitally. Vasoconstriction and vasodilatation were expressed as the percentage change in internal luminal area compared with the control area. The thromboxane A(2) mimetic U-46619 (3x10(-7) M) caused a significant vasoconstriction in vessels of all groups. However, acetylcholine (3x10(-5) M) induced arterial dilation only in the 8-15 days, and adult groups. By contrast, sodium nitroprusside, which acts independently of the endothelium, was an effective vasodilator in lung vessels from neonates. These data are the first to characterise the development of endothelium dependent vasodilatation in lung after birth in mice. This approach can be used with genetically modified mice, which is important to further our understanding of the physiology in this area.

Pharmacokinetics and pharmacodynamics of a nitric oxide-releasing derivative of enalapril in male beagles.

1. Pharmacological compounds that release nitric oxide (NO) have been useful tools in the evaluation of the broad role of NO in physiopathology and therapeutics. The present study compared the pharmacokinetics and pharmacodynamics of enalapril and an NO-releasing enalapril molecule (NCX899) in conscious male beagles. The effects of both enalapril and NCX899 in the arterial hypertension and bradycardia induced by acute NO inhibition in anaesthetized dogs were also investigated. 2. Dogs received either NCX899 (4 micromol/kg, i.v.) or enalapril (4 micromol/kg, i.v.), after which plasma concentrations of the analytes and metabolites were quantified by liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS). 3. In the NCX899 group, the area under the time-course curve (AUC(0-24h)) was 29.18 +/- 4.72, 229.37 +/- 51.32 and 5159.23 +/- 514.88 microg.h/L for the analytes nitro-enalapril, enalapril and enalaprilat, respectively. In the enalapril group, the AUC(0-24h) was 704.53 +/- 158.86 and 4149.27 +/- 847.30 microg.h/L for the analytes enalapril and enalaprilat, respectively. Statistical analysis of data from both groups showed a significant difference for the analyte enalapril, but not for enalaprilat. Moreover, NCX899 and enalapril were equally effective in inhibiting the activity of serum angiotensin-converting enzyme. 4. In anaesthetized dogs, i.v. administration of the NO synthase (NOS) inhibitor N(G)-nitro-l-arginine methyl ester (l-NAME; 0.1-10 mg/kg) significantly elevated arterial blood pressure, with concomitant bradycardia. The compound NCX899 significantly attenuated both arterial hypertension and bradycardia, whereas enalapril had no significant effect. 5. In conclusion, the present results showed that the NO-releasing derivative of enalapril NCX899 presents a pharmacokinetic/pharmacodynamic relationship similar to its parent compound enalapril. Moreover, NCX899 (but not enalapril) was effective in protecting against the cardiovascular changes induced by acute NOS inhibition.

Protective effects of BAY 41-2272 (sGC stimulator) on hypertension, heart, and cardiomyocyte hypertrophy induced by chronic L-NAME treatment in rats.

This study evaluated the effects of BAY 41-2272 (BAY), a specific activator of sGC NO-independent action on changes of mean arterial blood pressure, heart and left ventricle weight indexes, cardiomyocyte hypertrophy (Vv) and fibrosis area induced by chronic N-nitro-L-arginine methyl ester (L-NAME) treatment in rats. The animals were divided into (a) control group, (b) L-NAME group, (c) L-NAME+BAY group, and (d) BAY group. Eight weeks of L-NAME treatment caused a significant increase in mean arterial blood pressure when compared with untreated rats (173 +/- 11.1 and 109 +/- 5.0 mm Hg, respectively; P < 0.01). L-NAME + BAY cotreatment abolished the L-NAME-induced hypertension (112 +/- 5.1 mm Hg; P < 0.01). Significant increases in heart and left ventricle weight indexes and in Vv were observed in the L-NAME-treated animals compared with control group, and concomitant treatment with BAY significantly attenuated this hypertrophic effect. Treatment with L-NAME presented several areas of repairing fibrosis in left ventricles, and this effect was also abolished by BAY cotreatment. Our results demonstrate that BAY 41-2272 inhibits hypertension and prevents heart abnormalities (cardiac hypertrophy and increased fibrosis areas) induced by NO synthase inhibition.

Role of endothelin-1 and thromboxane A2 in the pulmonary hypertension induced by heparin-protamine interaction in anesthetized dogs.

This study aimed to study the role of thromboxane A2 (TXA2) and endothelin-1 (ET-1) in the pulmonary hypertension induced by interaction of heparin-protamine in anesthetized dogs. The effect of inhaled nitric oxide (NO) was also investigated in this model. Dogs were anesthetized and instrumented for acquisition of mean arterial blood pressure, mean arterial pulmonary pressure (MPAP), and pulmonary pressure gradient (PPG). Cardiac index (CI), heart rate, and index of systemic vascular resistance were also obtained. Intravenous administration of heparin (500 IU/kg) 3 minutes before protamine (10 mg/kg) caused marked pulmonary hypertension, as evaluated by the increase in MPAP and PPG. This was accompanied by systemic hypotension, CI decrease, and tachycardia. Indomethacin (10 mg/kg), dazoxiben (10 mg/kg), or tezosentan (10-mg/kg bolus plus 10-mg/kg/h infusion) significantly reduced the increase in MPAP and PPG, but had no effect on the systemic hypotension. Similar results were obtained with inhaled NO (3 ppm). Plasma TXB2 levels were markedly elevated during the pulmonary hypertension, and this was abolished in indomethacin-treated dogs. Our study shows that interaction of heparin-protamine in anesthetized dogs lead to TXA2- and ET-1-mediated pulmonary hypertension. Drugs that interfere with the synthesis of these mediators as well as inhaled NO may be of beneficial value to control this disorder.

Relaxing effects induced by the soluble guanylyl cyclase stimulator BAY 41-2272 in human and rabbit corpus cavernosum.

5-Cyclopropyl-2-[1-(2-fluoro-benzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-pyrimidin-4-ylamine (BAY 41-2272) is a potent soluble guanylyl cyclase stimulator in a nitric oxide (NO)-independent manner. The relaxant effect of BAY 41-2272 was investigated in rabbit and human corpus cavernosum in vitro. BAY 41-2272 (0.01-10 microM) relaxed both rabbit (pEC(50)=6.82+/-0.06) and human (pEC(50)=6.12+/-0.10) precontracted cavernosal strips. The guanylyl cyclase inhibitor (ODQ, 10 microM) caused significant rightward shifts in the concentration-response curves for BAY 41-2272 in rabbit (4.7-fold) and human (2.3-fold) tissues. The NO synthesis inhibitor (N-nitro-L-arginine methyl ester (L-NAME), 100 microM) also produced similar rightward shifts, revealing that BAY 41-2272 acts synergistically with endogenous NO to elicit its relaxant effect. The results also indicate that ODQ is selective for the NO-stimulated enzyme, since relaxations evoked by BAY 41-2272 were only partly attenuated by ODQ. The present study shows that both BAY 41-2272 and sildenafil evoke relaxations independent of inhibition of haem in soluble guanylate cyclase. Moreover, there is no synergistic effect of the two compounds in corpus cavernosum.

Endogenous myocardial angiogenesis and revascularization using a gastric submucosal patch.

BACKGROUND: The gastrointestinal submucosa physiologically produces angiogenic proteins. We examined whether these properties could lead to endogenous myocardial angiogenesis in a swine model of chronic ischemia. METHODS: Fifteen Yorkshire swine underwent ameroid constrictor placement around the circumflex artery and either lateral epicardial abrasion, creation of a gastroepiploic artery (GEA) based gastric patch, mucosal avulsion, transdiaphragmatic transfer, and apposition of the patch against the circumflex myocardial territory (number = 8; test animals), or lateral epicardial abrasion alone (number = 7; controls). Seven weeks later, lateral myocardial perfusion, endothelial cell density, and expression of VEGFR-1 and VE-cadherin were determined using isotope-labeled microsphere assays, immunohistochemistry, and immunoblotting, respectively. RESULTS: Microsphere assays showed equivalent lateral/anterior myocardial perfusion indices at rest (1.10 +/- 0.49 vs 0.95 +/- 0.23, test vs control animals; p = 0.54), but higher perfusion in test animals versus controls during pacing (1.05 +/- 0.29 vs 0.69 +/- 0.09, test vs controls; p = 0.02). Increased myocardial endothelial cell density (42.6 +/- 8.5 vs 26.1 +/- 11.6 cells per 3850 microm2, test vs controls; p = 0.02) and expression of VE-cadherin (3.10 +/- 0.60-fold change, test vs controls; p = 0.001) were also observed in the lateral territory of test animals versus controls. Reconstitution of the proximally occluded circumflex artery from patch collaterals was demonstrated on gastroepiploic arteriography in a subset of test animals. CONCLUSIONS: This model results in an angiogenic process of significantly greater magnitude than that resulting from chronic myocardial ischemia alone, without the need for exogenous angiogenic agents.

A novel peroxynitrite decomposer catalyst (FP-15) reduces myocardial infarct size in an in vivo peroxynitrite decomposer and acute ischemia-reperfusion in pigs.

BACKGROUND: Reactive oxygen and nitrogen species generated after reperfusion injury result in organ dysfunction. Peroxynitrite, a reactive nitrogen molecule produced from the reaction of superoxide anions and nitric oxide, is thought to be a causative agent in oxidative reperfusion injury. The aim of this study was to investigate the effects of a novel peroxynitrite decomposition catalyst (FP-15) in an acute myocardial ischemia/reperfusion model. METHODS: Pigs were subjected to 60 minutes of regional ischemia by reversibly ligating the left anterior descending coronary artery followed by 180 minutes of reperfusion. In the treatment group (n = 6), an FP-15 (1 mg/kg) bolus was infused through the jugular vein after 30 minutes of ischemia followed by a continuous infusion (1 mg x kg(-1) x h(-1)) during reperfusion. Vehicle was infused in the control group (n = 6). Coronary flow was recorded by an ultrasonic flow probe and infarct size determined by tetrazolium staining. Arterial and left ventricular pressures were monitored continuously and regional myocardial function determined by sonomicrometry. RESULTS: No significant differences were observed in either hemodynamics or ischemic area at risk. However, the infarct size was significantly reduced (35.3% +/- 3.5% versus 21.6% +/- 2.6% of the ischemic area, control versus FP-15-treated groups, respectively, p < 0.05). +dP/dt was transiently improved in the FP-15-treated groups while during most of the reperfusion period coronary flow, and was significantly lower in the FP-15-treated group as compared to the control group (p < 0.01). CONCLUSIONS: FP-15 administration reduces myocardial infarct size and reactive hyperemia. These data support the pathogenic role of endogenously produced peroxynitrite and that FP-15 is effective in preventing myocardial reperfusion injury.

Myocardial protection by PJ34, a novel potent poly (ADP-ribose) synthetase inhibitor.

BACKGROUND: The activation of poly (ADP-ribose) synthetase plays an important role in the pathogenesis leading to myocardial ischemia-reperfusion injury. The aim of this study was to determine if a novel potent inhibitor of poly (ADP-ribose) synthetase, PJ34, provides myocardial protection. METHODS: Pigs were subjected to 60 minutes of regional ischemia followed by 180 minutes of reperfusion. Ten mg/kg of PJ34 (PJ34; n = 6) was administrated intravenously (treated group) from 15 to 5 minutes before reperfusion followed by 3 mg/kg/hour of PJ34 from 5 minutes before reperfusion to the end of 180 minutes reperfusion. Control pigs (n = 7) received vehicle only. Arterial and left ventricular pressure and coronary flow were monitored. RESULTS: The PJ34 showed significant reduction on infarct size (37.5%+/-4.5% and 50.5%+/-4.8% of the area at risk) for PJ34 and control pigs groups, respectively, (p < 0.05). Significant reduction in postsystolic shortening, as well as improvement on segment shortening, and positive first derivative of pressure over time (+dP/dt) maximum were also observed in PJ34 versus control pigs (p < 0.05). CONCLUSIONS: Our results suggest that PJ34 provides cardioprotection by decreasing myocardial infarct size and enhancing postischemic regional and global functional recovery.