Formulation of microemulsion gel systems for transdermal delivery of celecoxib: In vitro permeation, anti-inflammatory activity and skin irritation tests.

The aim of this study was to develop suitable microemulsion gel systems for transdermal delivery that could assist dissolution enhancement of poorly water soluble celecoxib and thus improve its skin permeability. Long term oral administration of celecoxib causes serious gastrointestinal adverse effects, which makes it a good candidate for transdermal formulations, yet its low water solubility (4 mg/L) makes this challenging. Ternary phase diagrams were constructed using isopropyl myristate and oleic acid as oils, Tween 80 as surfactant, and Cremophor RH40 as cosurfactant. Microemulsion areas were identified and two systems each of 36 formulas were prepared and assessed for visual inspection, spreadability, pH measurements, and droplet size analysis. Drug release and in vitro permeation of celecoxib from microemulsion formulas through semi-permeable membranes and excised abdominal rabbit skin, respectively, were carried out and compared to celecoxib cream. In all tested formulas, celecoxib was released and permeation was at a higher rate than that from the corresponding cream. The optimized formula (F12) was found to be superior to all other formulas. This formula increased the permeation rate of celecoxib up to 11 times compared to that of the cream. Its stability was retained after one year of storage under ambient conditions and its anti-inflammatory effect was significantly higher than that of celecoxib cream and the oral commercial formula. Skin irritancy and histopathological investigation of rat skin revealed its safety. The results revealed that the developed microemulsion gel has great potential for transdermal delivery of celecoxib.

Preparation and characterization of oxybenzone-loaded solid lipid nanoparticles (SLNs) with enhanced safety and sunscreening efficacy: SPF and UVA-PF.

The objective of the current study was to formulate solid lipid nanoparticles of oxybenzone to enhance its sunscreening efficacy while reducing its side effects. Solid lipid nanoparticles (SLNs) of oxybenzone were prepared by the solvent diffusion method. A complete 2(4) factorial design was used to optimize preparations. The study design involves the investigation of four independent variables, namely lipid type (Glyceryl monostearate, GMS; and Witepsol E85, WE85), lipid concentration (5 and 10%), polyvinyl alcohol (PVA) concentration (1 and 2%), and ethanol/acetone ratios (1:1 and 3:1, v/v), in terms of their effect on the particle size and entrapment efficiency. GMS was found to significantly increase the p.s. and EE%. SLNs prepared using 10% lipid had slower drug release compared to those prepared using 5%. The candidate oxybenzone-loaded SLN formula (SLN2) consisting of 0.5% oxybenzone, 10% GMS, 1% PVA, and ethanol/acetone (1:1, v/v) was then formulated into a gel and compared to the corresponding free oxybenzone nanosuspension and placebo SLN. The formulations were evaluated for skin irritation, in vitro sun protection factor, and ultraviolet A protection factors. The incorporation of oxybenzone into solid lipid nanoparticles greatly increased the SPF and UVA protection factor of oxybenzone more than five-fold while providing the advantage of overcoming skin irritancy problems.

Transcriptome of angiopoietin 1-activated human umbilical vein endothelial cells.

Angiopoietin 1 (Ang-1) is the main ligand for endothelial cell-specific tyrosine kinase (Tie-2) receptors and it promotes migration and proliferation and inhibits apoptosis and vascular leakage. The exact mechanisms through which the Ang-1 exerts these effects remain unclear. The authors exposed human umbilical vein endothelial cells (HUVECs) to Ang-1 (300 ng/mL) for 4 h and conducted gene expression profiling using oligonucleotide microarrays. Real-time polymerase chain reaction (PCR) was also conducted to verify several of the genes that were regulated by Ang-1. Exposure to Ang-1 resulted in induction of 86 genes that are involved in endothelial cell (EC) proliferation, differentiation, migration, and survival. Thirty-six of these genes, including stanniocalcin, cyclin D1, vascular endothelial growth factor C, fms-related tyrosine kinase 1, interleukin 8, and CXCR4 have previously been shown to be induced by vascular endothelial growth factor (VEGF), suggesting significant similarities between VEGF and Ang-1 pathways. Ang-1 exposure also inhibited mRNA expressions of 49 genes, most of which are involved in cell cycle arrest, apoptosis, and suppression of transcription. These results indicate that Ang-1 triggers coordinated responses in endothelial cells designed to inhibit the expression of proapoptotic and antiproliferative genes and up-regulate proproliferative, proangiogenic, and antiapoptotic pathways. Moreover, we also found that the Erk1/2, phosphatidylinositol (PI) 3-kinase, and the mTOR pathways are involved in Ang-1-induced gene expression in HUVECs.

Interplay between nitric oxide and vasoactive intestinal polypeptide in inducing fluid secretion in rat jejunum.

Nitric oxide (NO) and vasoactive intestinal polypeptide (VIP) interact in the regulation of neuromuscular function in the gut. They are also potent intestinal secretogogues that coexist in the enteric nervous system. The aims of this study were: (1) to investigate the interaction between NO and VIP in inducing fluid secretion in the rat jejunum, and (2) to determine whether the NO effect on intestinal fluid movement is neurally mediated. The single pass perfusion technique was used to study fluid movement in a 25 cm segment of rat jejunum in vivo. A solution containing 20 mM L-arginine, a NO precursor, was perfused into the segment. The effect of the NO synthase inhibitors (L-NAME and L-nitroindazole (L-NI)) and the VIP antagonist ([4Cl-D-Phe6,Leu17]VIP (VIPa)) on L-arginine-induced changes in fluid movement, expressed as microl min(-1) (g dry intestinal weight)(-1), was determined. In addition, the effect of neuronal blockade by tetrodotoxin (TTX) and ablation of the myenteric plexus by benzalkonium chloride (BAC) was studied. In parallel groups of rats, the effect of L-NAME and L-NI on VIP-induced intestinal fluid secretion was also examined. Basal fluid absorption in control rats was (median (interquartile range)) 65 (45-78). L-Arginine induced a significant fluid secretion (-14 (-20 to -5); P<0.01). This effect was reversed completely by L-NAME (60 (36-65); P<0.01) and L-NI (46 (39-75); P<0.01) and partially by VIPa (37 (14-47); P<0.01). TTX and BAC partially inhibited the effect of L-arginine (22 (15-32) and 15 (10-26), respectively; P<0.05). The effect of VIP on fluid movement (-23 (-26 to -14)) was partially reversed by L-NAME (24 (8.4-35.5); P<0.01) and L-NI (29 (4-44); P<0.01). The inhibition of VIP or NO synthase prevented L-arginine- and VIP-induced intestinal fluid secretion through a neural mechanism. The data suggest that NO enhances the release of VIP from nerve terminals and vice versa. Subsequently, each potentiates the other's effect in inducing intestinal fluid secretion.

[24-hour esophageal pH monitoring in adults. Apropos of a series of 116 patients]. / La pH-metrie oesophagienne de 24 heures chez l'adulte. A propos d'une série de 116 malades.

Between June 1994 and June 1996, we performed a 24-hour oesophageal pH monitoring in 116 adult patients. A retrospective analysis of the data is hereby presented. The principal indications include a chronic cough, recurrent laryngitis and noncardiac chest pain. In 65.5% of our cases, a pathological gastroesophageal reflux was found during pH monitoring. The symptom-index (SI) concerning the digestive and ENT symptoms did correlate in 1/3 of the cases while it was significant in only 15% of the cases with pulmonary and cardiac symptoms. 24-hour pH monitoring remains the method of choice for the study of gastroesophageal reflux and analysis of the SI is indispensable to evaluate the correlation of symptoms with episodes of reflux.

[Detection of Helicobacter pylori by the urease test in 244 patients]. / Recherche d'Hélicobacter pylori chez 244 patients par le test à l'uréase.

The authors report the results of the detection of Helicobacter Pylori (HP) in gastric mucosa by the urease test, in 244 patients between January 1989 and August 1991. The overall prevalence of HP was 38.1%. It was 19.5% in patients with normal upper gastrointestinal endoscopy (UE), 61% in duodenal ulcer (p < 0.001) and 68.7% in congestive antritis (p < 0.001), significantly higher than in controls. There was no significant difference between controls and patients with erosive antritis or healed duodenal ulcers. The prevalence of HP rises with age in all patients and in those with lesions at UE but not in those with normal UE. A rise of this prevalence seems to exist in the months of June and December. The authors conclude by pointing out the rise of the overall prevalence of HP in congestive antritis compared with erosive antritis, the similarity of prevalence in normal subjects and those with healed ulcer and the lack of influence of age on this prevalence in subjects with normal UE. These conclusions are in need of confirmation by further studies on much more longer series.