Topical delivery of retinyl ascorbate co-drug. 1. Synthesis, penetration into and permeation across human skin

A novel synthetic technique was used to synthesise the co-drug retinyl ascorbate (RA-AsA) ester from all-trans-retinyl chloride (RA) and L-ascorbic acid (AsA) suspended in ethanol at low temperature. Its log P, solubility in a Me:PBS, 50/50 at pH 4.8 and degradation constant were determined. The flux and permeation coefficient were determined using heat separated human skin membrane, and skin penetration was determined by tape stripping using full thickness human. All experiments were performed in parallel with retinyl palmitate (Rol-Pal) and ascorbyl palmitate (AsA-Pal), which are used in commercial topical formulations. RA-AsA exhibited favourable log P (2.2), with stability much greater than RA and AsA, but similar stability to Rol-Pal and AsA-Pal. The flux of RA-AsA was lower than for Rol-Pal and AsA-Pal. RA-AsA also demonstrated higher skin retention than the other two esters, but delivered more RA and AsA to the viable epidermis than retinol from Rol-Pal and ascorbic acid from AsA-Pal. Overall, the data suggest the potential value of RA-AsA co-drug for the purpose of treating damage to skin resulting from UV-induced production of free radicals.     

Comparisons of hypertension-related costs from multinational clinical studies

BACKGROUND: This study identifies and compares the individual cost components of hospital and ambulatory services that manage the care of hypertensive patients in eight countries: the US, the UK, France, Spain, Germany, Italy, Canada and Australia. METHODS: Hypertension-related costs are classified according to four major cardiovascular events: (i) acute myocardial infarction; (ii) congestive heart failure; (iii) stroke; and (iv) renal failure, which was subdivided into renal failure treated by dialysis and renal failure treated by kidney transplantation. To make cross-country costs comparisons, we used the DRG codes used in the US and DRG-like codes from each country. US cost information was obtained from hypertension data available from the literature and health economics researchers. For costs in other countries, we consulted with national health economics experts in each country, used analyses by the Research Triangle Institute, and performed Medline and international literature searches. When available, we obtained information from the countries' public and private nationally representative data sources. For cross-country currency adjustments, all currencies were converted using the Purchasing Power Parities from the Organisation for Economic Cooperation and Development, and then converted into inflation-adjusted year 2000 US dollars. RESULTS: There exists considerable variation in hypertension-related costs from multinational clinical studies. This study documents that costs are generally higher in the US than in other countries; however, this is not always true. In particular, costs of treating heart failure in France and the costs of renal failure without transplantation in Germany and the UK are relatively high. DISCUSSION: While analysing multinational hypertensive cost data, this study also addresses the impact of cross-country cost variations on cost analyses. During the last decade, drug-development researchers have drawn extensively upon multinational trials to resolve enrollment problems and drug-registration issues. At the same time, formulary decision-makers are increasingly demanding multinational cost-effectiveness analyses of the clinical differences found between drug-treatment regimens. Since these data are typically not captured by randomised clinical trials, standard cost estimates must be applied to the clinical trials' resource data, although such standardised calculations do not necessarily account for clinical and cost variations between countries. CONCLUSION: This paper serves as an instrument for identifying which national and event cost data are comparable for analysis as well as highlighting specific problem areas for cost data integration. Although the study focuses on hypertension-related costs, its results may provide insight for multinational cost comparisons of other diseases where similar hospitalisation costs may be analysed.     

Enhancement of bone formation in rat calvarial bone defects using low-level laser therapy

OBJECTIVE: To evaluate the effect of low-level laser therapy (LLLT), using a GaAlAs diode laser device, on bone healing and growth in rat calvarial bone defects. STUDY DESIGN: An animal trial of 4 weeks' duration was conducted using a randomized blind, placebo-controlled design. Standardized round osseous defects of 2.7 mm diameter were made in each parietal bone of 20 rats (n=40 defects). The animals were randomly divided into an experimental and a control group of 10 animals each. In the experimental group, a GaAlAs diode laser was applied immediately after surgery and then daily for 6 consecutive days. The control group received the same handling and treatment, but with the laser turned off. Five rats from each group were killed on day 14 and the remainder on day 28 postoperatively. From each animal, tissue samples from one defect were prepared for histochemistry and samples from the contralateral defect for histology. Levels of calcium, phosphorus, and protein were determined by using atomic absorption spectrometry, colorimetry, and photometry, respectively. Student t-test and Mann-Whitney were used for statistical analyses. RESULTS: At both time points the tissue samples from the experimental animals contained significantly more calcium, phosphorus, and protein than the controls. Similarly, histological analyses disclosed more pronounced angiogenesis and connective tissue formation, and more advanced bone formation in the experimental group than in the controls. CONCLUSION: LLLT may enhance bone formation in rat calvarial bone defects.     

Inhibition of cytochrome P450omega-hydroxylase: a novel endogenous cardioprotective pathway

Cytochrome P450s (CYP) and their arachidonic acid (AA) metabolites have important roles in regulating vascular tone, but their function and specific pathways involved in modulating myocardial ischemia-reperfusion injury have not been clearly established. Thus, we characterized the effects of several selective CYPomega-hydroxylase inhibitors and a CYPomega-hydroxylase metabolite of AA, 20-hydroxyeicosatetraenoic acid (20-HETE), on the extent of ischemia-reperfusion injury in canine hearts. During 60 minutes of ischemia and particularly after 3 hours of reperfusion, 20-HETE was produced at high concentrations. A nonspecific CYP inhibitor, miconazole, and 2 specific CYPomega-hydroxylase inhibitors, 17-octadecanoic acid (17-ODYA) and N-methylsulfonyl-12,12-dibromododec-11-enamide (DDMS), markedly inhibited 20-HETE production during ischemia-reperfusion and produced a profound reduction in myocardial infarct size (expressed as a percent of the area at risk) (19.6+/-1.7% [control], 8.4+/-2.5% [0.96 mg/kg miconazole], 5.9+/-2.2% [0.28 mg/kg 17-ODYA], and 10.8+/-1.8% [0.40 mg/kg DDMS], P<0.05, respectively). Conversely, exogenous 20-HETE administration significantly increased infarct size (26.9+/-1.9%, P<0.05). Several CYPomega-hydroxylase isoforms, which are known to produce 20-HETE such as CYP4A1, CYP4A2, and CYP4F, were demonstrated to be present in canine heart tissue and their activity was markedly inhibited by incubation with 17-ODYA. These results indicate an important endogenous role for CYPomega-hydroxylases and in particular their product, 20-HETE, in exacerbating myocardial injury in canine myocardium. The full text of this article is available online at http://circres.ahajournals.org.     

The general anesthetic propofol increases brain N-arachidonylethanolamine (anandamide) content and inhibits fatty acid amide hydrolase

1. Propofol (2,6-diisopropylphenol) is widely used as a general anesthetic and for the maintenance of long-term sedation. We have tested the hypothesis that propofol alters endocannabinoid brain content and that this effect contributes to its sedative properties. 2. A sedating dose of propofol in mice produced a significant increase in the whole-brain content of the endocannabinoid, N-arachidonylethanolamine (anandamide), when administered intraperitoneally in either Intralipid or emulphor-ethanol vehicles. 3. In vitro, propofol is a competitive inhibitor (IC(50) 52 micro M; 95% confidence interval 31, 87) of fatty acid amide hydrolase (FAAH), which catalyzes the degradation of anandamide. Within a series of propofol analogs, the critical structural determinants of FAAH inhibition and sedation were found to overlap. Other intravenous general anesthetics, including midazolam, ketamine, etomidate, and thiopental, do not affect FAAH activity at sedative-relevant concentrations. Thiopental, however, is a noncompetitive inhibitor of FAAH at a concentration of 2 mM. 4. Pretreatment of mice with the CB(1) receptor antagonist SR141716 (1 mg kg(-1), i.p.) significantly reduced the number of mice that lost their righting reflex in response to propofol. Pretreatment of mice with the CB(1) receptor agonist, Win 55212-2 (1 mg kg(-1), i.p.), significantly potentiated the loss of righting reflex produced by propofol. These data indicate that CB(1) receptor activity contributes to the sedative properties of propofol. 5. These data suggest that propofol activation of the endocannabinoid system, possibly via inhibition of anandamide catabolism, contributes to the sedative properties of propofol and that FAAH could be a novel target for anesthetic development.     

Is laparoscopic cholecystectomy safe and acceptable as a day case procedure?

BACKGROUND: This study reviewed the results of performing day case laparoscopic cholecystectomy to assess the feasibility and safety of the procedure as a day case. MATERIALS AND METHODS: This is a prospective study of 150 day case laparoscopic cholecystectomies performed between September 1999 and December 2004 under the care of the senior author. The results of a follow-up questionnaire to assess post-discharge clinical course and patient satisfaction were analyzed. All patients had commenced eating and drinking and were fully mobile before discharge home. The length of hospital stay was 4-8 hours. RESULTS: The mean age of the patients was 43 years; 134 patients had an American Society of Anesthesiologists grade I, the remaining 16 patients were grade II. The mean operative time was 41 minutes. There were no conversions to open procedures. There was no bleeding, no visceral injury, and no mortality. There was one admission directly from the day surgical unit (admission rate of 0.6%), but no readmission following discharge. No patients were admitted due to postoperative nausea or pain. Ninety-nine (66%) of 150 patients responded to our questionnaire: 97% were satisfied about the information they had received. Patients rated their satisfaction with the procedure as follows: 75% excellent, 21% good, 3% satisfied, and 1 patient un-satisfied. Ninety-four percent of the patients would recommend the procedure as a day case. CONCLUSION: Day case laparoscopic cholecystectomy is safe, feasible, and cost-effective when patients are carefully selected. It provides good patient satisfaction.