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In probing enhancement of the transdermal delivery of the anti-psychotic drug haloperidol, five prodrugs (ethanoate, propanoate, butanoate, octanoate and decanoate) were synthesised and their relative rates of hydrolysis determined in the presence of porcine liver esterase (PLE), a model for cutaneous esterases. (1)H NMR, MS and elemental analysis confirmed the successful synthesis of each prodrug in high purity, and each was found to hydrolyse in the presence of PLE with the hydrolytic rate reaching a maximum with haloperidol octanoate (C8) at 2.31 +/- 0.06 nmol ml(-1) h(-1) (p < 0.001).

Purpose: To determine the in vitro effects of simultaneously administered LY29400, PD98059, tamoxifen and eicosapentaenoic acid (EPA) on breast cancer cells, and determine their transcutaneous delivery., Methods: Growth assays were performed on MCF-7 cells challenged with IC(50) and permeated concentrations of PD98059, LY294002 and tamoxifen firstly in isolation then combined. Permeation studies were performed using PD98059 and LY294002 (singly or simultaneously) in DMSO then fish oil, with enhancers. Immunocytochemical detection of phospho-MAPK, phospho-Akt, total COX-2 and Ki-67 was performed., Results: When applied singly, fluxes of PD98059 and LY294002 were 0.09 +/- 0.008 and 0.14 +/- 0.045 microg cm(-2) h(-1), respectively; applied simultaneously, 0.18 +/- 0.045 and 0.49 +/- 0.051 microg cm(-2) h(-1). Permeated concentrations of PD98059 and LY294002 reduced growth to 13.78 +/- 0.63%. Fish oil plus 2.5% DMSO/ethanol allowed 5.96 +/- 0.9 and 7.7 +/- 1.2 microg cm(-2) of PD98059 and LY294002 to permeate after 48 h., Conclusions: PD98059 and LY294002 permeate excised skin at therapeutically useful rates, and also demonstrate growth inhibitory effects on MCF-7 cancer cells. Synergism was noted in co-transport across skin and activity against cancer cells. A formulation based on fish oil is potentially skin friendly; simultaneous permeation of EPA provides further anti-cancer action.

The feasibility of using 10% 1,8-cineole as an enhancer for transdermal delivery of haloperidol has been examined. In-vitro transdermal delivery across full-thickness human, rabbit and hairless mouse skins was measured from three polymer gel systems, hypromellose (hydroxypropylmethylcellulose), Carbomer (Carbopol) 940 and macrogol (polyethylene glycol) using Franz cells. Values for the permeability coefficient kp, calculated as the product (Kh)x(D/h2) where these two factors were obtained from curve fitting of the non-steady-state equation over 24 h, were similar from the three formulations. The value of kp from hypromellose was significantly enhanced by cineole by factors of 6.2 (4.6-8.1), 5.6 (5.0-6.2) and 3.0 (2.6-3.4) for human, rabbit and mouse, respectively (mean and 95% confidence intervals). Enhancement ratios for K: 13.3 (8.3-20), 3.1 (2.5-3.9) and 2.0 (1.5-2.6), were higher than those for D: 0.47 (0.41-0.55), 1.8 (1.6-2.1) and 1.5 (1.3-1.8). This suggested that the barrier function of the skin lipids was marginally affected and the main effect was to increase the thermodynamic activity of the drug in the barrier. The enhancement achieved in human skin suggested that delivery could be safely enhanced by terpenoids.

The potential of the administration of Harpagophytum procumbens extract via the topical route has not been studied previously. In the current work, the dermal and transcutaneous delivery of the major pharmacologically active constituents present in H. procumbens tuber extract were determined across porcine ear skin from four vehicles: de-ionised water, 30 % ethanol in water (v/v), PEG 400, 50 : 50 PEG 400 in 30 % EtOH (v/v). Permeation profiles were obtained under infinite conditions and tape stripping was performed at 24 h. The permeation of the compounds varied according to their physicochemical properties as well as the nature of the vehicle. The highest permeation was found from the ethanol/water saturated solutions and the lowest MW harpagide was obtained at significantly higher concentrations in the receptor phase compared to the rest of the compounds, with the permeability coefficient being inversely dependent on dielectric constant of the vehicle. Depth profiling revealed higher penetration of all compounds from ethanol/water; in addition, significantly higher amounts of the pro-inflammatory harpagide were present in the strips and the remaining epidermis compared to other compounds. This suggests that ethanol is not a suitable vehicle as it leads to more harpagide penetration, potentially counteracting the anti-inflammatory activity of the other compounds. The development of new systems for local cutaneous inflammation (e. g., psoriasis, eczema) and subcutaneous inflammation (e. g., arthritis) is supported.

The permeation enhancement of mefenamic acid by ethanol across full-thickness porcine skin, heat-separated epidermal membrane and heat-separated dermal membrane has been probed. Three donor phases saturated with mefenamic acid were used: (1) PEG400; (2) PEG400 with 10% ethanol; (3) mefenamic acid in PEG 400 with 30 mg ml(-1) cetrimide; these were applied to membranes mounted in Franz diffusion-type cells with 30 mg ml(-1) cetrimide as receptor phase (n > or =5). Across full-thickness skin, the flux was below the limit of detection from PEG400, but with the inclusion of 10% ethanol was 0.83 microg cm(-2)h(-1). When cetrimide was present in the donor (and receptor) phase the flux was very low 0.1 microg cm(-2)h(-1). Across heat-separated epidermal membrane the flux from PEG was 11.9+/-2.4 microg cm(-2)h(-1) with a 2.42 x increase in flux observed when 10% ethanol was present (p=0.0095). Across heat-separated dermal membrane the flux from PEG400 was 0.62+/-0.13 microg cm(-2)h(-1), with a 2.34 x increase in flux observed when 10% ethanol was present (p=0.0027). To conclude, complexation and co-permeation with ethanol via a pull effect was confirmed as the mechanism of enhanced skin permeation of mefenamic acid. Full thickness skin provides a more effective barrier than either isolated dermis or epidermis, casting doubt over the use of heat-separated epidermal membranes to model skin permeation and penetration. There was evidence that cetrimide does not cause skin barrier modulation, supporting its use as an effective receptor phase.

Many currently available drugs show unfavourable physicochemical properties for delivery into or across the skin and temporary chemical modulation of the penetrant is one option to achieve improved delivery properties. Pro-drugs are chemical derivatives of an active drug which is covalently bonded to an inactive pro-moiety in order to overcome pharmaceutical and pharmacokinetic barriers. A pro-drug relies upon conversion within the body to release the parent active drug (and pro-moiety) to elicit its pharmacological effect. The main drawback of this approach is that the pro-moiety is essentially an unwanted ballast which, when released, can lead to adverse effects. The term 'co-drug' refers to two or more therapeutic compounds active against the same disease bonded via a covalent chemical linkage and it is this approach which is reviewed for the first time in the current article. For topically applied co-drugs, each moiety is liberated in situ, either chemically or enzymatically, once the stratum corneum barrier has been overcome by the co-drug. Advantages include synergistic modulation of the disease process, enhancement of drug delivery and pharmacokinetic properties and the potential to enhance stability by masking of labile functional groups. The amount of published work on co-drugs is limited but the available data suggest the co-drug concept could provide a significant therapeutic improvement in dermatological diseases. However, the applicability of the co-drug approach is subject to strict limitations pertaining mainly to the availability of compatible moieties and physicochemical properties of the overall molecule.

This influence of skin stretching and hair follicle sealing on the delivery of retinyl ascorbate (RA-AsA) to the epidermis was probed in vitro. Porcine ear skin was subjected to stretching by 2 and 4 mm (3.3 and 6.7%, respectively); the hair follicles of other skin sections were located and painstakingly sealed using adhesive. After mounting in Franz cells the skin was dosed with 100 microl of 2.5 mM RA-AsA in methanol/PBS with water as receptor phase. After 24 h the diffused areas were subjected to tape stripping, and the amount of RA-AsA was determined in 5 groups of 9 strips. Statistical analysis of the resulting depth profiles showed that there was no statistical difference between unstretched skin and the skin that had the follicles sealed across the 5 depth bands. Between 0 and 2 mm stretch there were generally significant differences; between 0 and 4 mm p < 0.001 was obtained at each depth. The data from this limited exercise suggest that in native skin the follicular route does not contribute to dermal absorption, but when disturbed (as when stretched) follicular delivery can substantially increase drug delivery into the skin by up to approximately 20-40%. Skin stretching becomes difficult beyond about 7%., ((c) 2007 S. Karger AG, Basel)

Background: The aim of this review was to determine whether dexmedetomidine alone provided satisfactory conditions for children undergoing magnetice resonance imaging (MRI)., Methods: A retrospective review of 21 patients was undertaken, (age range: 1-8 years, weight 10-27 kg) who received dexmedetomidine to provide deep sedation for an MRI procedure., Results: In the initial eight patients who received dexmedetomidine (bolus 0.5-1.5 mg.kg(-1) and infusion rate 1-1.5 mg.kg(-1).h(-1)) by itself, movement occurred in five of them, even when the maximum suggested dose was used (1 microg.kg(-1).h(-1)). Midazolam (0.1 mg.kg(-1)) i.v. was given as an adjunct to the following 13 patients (dexemdetomidine doses were lower: bolus 1 mg.kg(-1), infusion 0.5-1 mg.kg(-1).h(-1)). Only one patient moved within this group. The mean time to discharge postprocedure was 90 min. There were no differences with respect to recovery or discharge times between those who did or did not receive midazolam. No cardiac or respiratory complications were noted., Conclusions: The use of dexmedetomidine for MRI sedation by itself was more unpredictable than anticipated from the published case reports of its use.

Unexpected enhancement of the topical delivery of eicosapentaenoic acid (EPA) across porcine skin was observed previously when fish oil was co-formulated with ketoprofen. In the current work depth profile analysis was used to probe the epidermal conversion of EPA to its 15-hydroxy metabolite in the presence and absence of ketoprofen. Freshly excised full-thickness porcine skin in Franz diffusion cells was dosed (both infinite and finite) with simple formulations based on fish oil as source of EPA. After 24h the skin was subjected to tape stripping and depth profiles were constructed. Typical depth profiles were obtained, with an inverse relationship between depth and permeant concentration. 15-HEPE was generated in the skin when Hepes-modified Hanks' balanced salt solution was used, but none was detected when a cetrimide receptor phase was used, highlighting the importance of maintaining skin viability in such exercises. Ketoprofen had a direct influence on the metabolism of EPA and resulting in conversion to its 15-LOX metabolite 15-HEPE. However, this link appears to be only part of the solution of EPA enhancement however, as even in non-viable skin ketoprofen had an enhancing affect.

The n-3 fatty acids have demonstrable biological activities and have been associated with many health improvements from child brain development to arthritis. In this review we sought to pull together the works that have examined the potential use of n-3 fatty acids in psoriasis. The rationale of using EPA and/or its metabolites is supported by findings which suggest that it has anti-inflammatory properties and plays an important role in the resolution phase of inflammation. EPA use in psoriasis has also been demonstrated in trials using oral, intravenous, and topical preparations, with generally positive outcomes. Depth profile analysis revealed that EPA and its metabolite, 15-HEPE are deposited in the epidermis, particularly in the metabolically active basal layer. This is considered advantageous in psoriasis therapy. Currently there are many unknowns about psoriasis aetiology and the effects of blocking different cytokines have on the disease progression. Furthermore not enough is known about EPA effects on cellular immunity other than via prostaglandin and leukotriene synthesis to fully understand the mode of action of EPA. However, evidence so far suggests EPA does have a potential role in the treatment of psoriasis, in particular for topical treatments either as an active anti-inflammatory agent by itself, or as a dual action permeation enhancer for other anti-psoriatic treatments. The challenges include optimising the delivery of EPA to the skin and determining the derivatives of EPA which would give maximal effects, and overcoming pharmacokinetic and formulation problems to optimally deliver EPA to its intended target cells.

The complexation of EPA with ketoprofen was probed in order to rationalise co-operative skin permeation enhancement behaviour observed previously. The modulation of aromatic protons of ketoprofen was determined using (1)H NMR spectra from different formulations containing varying concentrations of fish oil and a control saturated triglyceride. Molecular modelling of possible complexes of ketoprofen with constituents of fish oil was performed. NMR data revealed a dose-dependent change in chemical shift in the aromatic protons of ketoprofen on addition of fish oil and/or EPA. Similar patterns were observed in both cases, although the free fatty acid induced changes in more protons. Molecular modelling results indicate quite large binding energies of all complexes considered, varying between ca. 90 and 160 kJ mol(-1). The geometries of these complexes shows strong O-H...O hydrogen bonds in all cases, and in the case of the complex of ketoprofen with free EPA there is also some evidence of C-H... pi and/or pi-pi interactions, giving rise to regiospecifically solvated complexes. If strongly bound ketoprofen:EPA complexes can form, then the permeation enhancement of EPA by ketoprofen could be attributed to such a complex. Once the complex is formed, the triglyceride/free fatty acid could aid permeation of associated ketoprofen into the lipophilic stratum corneum via the pull effect. Once permeated, the more hydrophilic ketoprofen could aid the permeation of the triglyceride/free fatty acid through the epidermis, again via the pull effect. This could explain the synergistic permeation enhancement seen with these compounds.

This work employed immunocytochemistry (ICC) techniques to study the effect of topically applied fish oil and ketoprofen on cyclooxygenase (COX-2) and lipoxygenase (LOX) within freshly excised porcine ear skin. Maintained in Hanks buffer immediately post excision, full thickness membranes were mounted in Franz diffusion cells and dosed with 1 ml of individual formulations containing ketoprofen, fish oil or both. At different timepoints, the diffused areas were recovered and relative activities of COX-2 and LOX determined. It was found that the fish oil formulation qualitatively inhibited the expression of both COX-2 and LOX enzymes. As expected, ketoprofen had no effect upon LOX expression but a significant decrease on COX-2 expression was observed. The formulation containing both fish oil and ketoprofen proved to be the most effective at inhibiting the expression of both COX-2 and LOX. Considered together with data from earlier papers, a mechanism of EPA permeation enhancement by ketoprofen may be elucidated and also show the ability of such a formulation to inhibit these enzymes and thus indicate the efficacy of such a formulation.

The simultaneous skin permeation of drug and penetration enhancer have been studied in vitro. Simple formulations of mefenamic acid in PEG400 incorporating various proportions of ethanol or 1,8-cineole were prepared and applied to porcine ear skin in diffusion cells under infinite conditions. Receptor phases were assayed for mefenamic acid by HPLC and ethanol or 1,8-cineole by GC. Concentration-dependent permeation profiles were obtained for both ethanol or 1,8-cineole, in addition to concentration-dependent enhancement of mefenamic acid. When the steady state flux of mefenamic acid was plotted against ethanol or 1,8-cineole, linear relationships were observed with r2 values of 0.988 and 0.999, respectively. The close connection between rates of excipient and solute permeation is generally referred to as the 'pull' (or 'drag') effect, where in this case permeation of the enhancer facilitated permeation of the solute. This appears to be sufficient to account for the enhancing activity of ethanol and 1,8-cineole, notwithstanding initial modulations that may occur within the stratum corneum.

Extracts of guarana (Paullinia cupana) feature as putatively stimulating ingredients in a number of foods, drinks and dietary/herbal supplements. The objective of this work was to investigate in vitro the transdermal delivery of the major pharmacologically active compounds contained in guarana extract. Saturated solutions of guarana were prepared in polyethylene glycol 400 (PEG400), propylene glycol (PG) and H(2)O at 32 degrees C. Guarana extract was also formulated in Duro-tak 2287 transdermal adhesive in a range of concentrations and the diffusional release was determined in addition to adhesive properties. Transdermal delivery across full thickness pig ear skin was investigated in vitro using Franz-type diffusion cells, with reverse-phase HPLC being used for the quantification of the permeation of theobromine (TB), theophylline (TP), (+)-catechin (C) and caffeine (CF). Based upon a combination of release and adhesive property data a patch containing 5.55 mg guarana extract cm(-2) was deemed optimal. The general trend for the delivery of the 4 analytes was: water >5.55 mg cm(-2) patch approximately PG>PEG400. For CF the greatest steady state flux was obtained from the water vehicle: 19 microg cm(-2)h(-1), with approximately 420 microg cm(-2) permeating after 24h. This was some 6x times more than from the drug-in-adhesive patch and 10x greater than PG, a well-known penetration enhancer, and 50x that of the 'regular' excipient PEG400. A water vehicle also provided the greatest delivery of TB (0.45 microg cm(-2) h(-1)), TP (0.022 microg cm(-2) h(-1)), and C (0.10 microg cm(-2) h(-1)). An inverse relationship was noted between lipophilicity and k(p) in each vehicle. The simultaneous transdermal delivery of the major actives of guarana was established, with permeation rates being highly concentration and vehicle dependent.

This work explored the use of pluronic lecithin organogel (PLO) as a base for the delivery of bioactive polyunsaturated fatty acids from fish oil, eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) and ketoprofen. PLO was adapted to contain fish oil, ketoprofen, or both, and 1,8-cineole as penetration enhancer, and used to determine the in-vitro permeation from infinite and finite dosing protocols across full thickness porcine skin. Oruvail gel (2.5% ketoprofen) was included for comparison. No EPA or DHA was found to permeate skin when applied as an infinite dose. From multiple finite doses, small amount (max. 0.22%) of fish oil were found to permeate the skin. This indicates retention of fish oil within the gel matrix and that the viable domain of full thickness skin was a significant barrier. Greater amounts of EPA and DHA were delivered in the presence of ketoprofen indicating co-transport resulting from selective complexation, although no enhancement was observed using 1,8-cineole. Unlike EPA and DHA, substantial amounts of ketoprofen permeated when applied as infinite doses. Oruvail, a Carbopol 940-based hydrogel containing 2.5% ketoprofen and ethanol, delivered the greatest amount, although similar to the PLO gel containing 5% ketoprofen. The addition of propylene glycol enhanced permeation, although the presence of fish oil in the PLO gel inhibited ketoprofen permeation. When applied as multiple finite doses a maximum of 76 microm cm(-2) (1.12%) was delivered, which was reduced by the presence of 1,8-cineole. Greater permeation was again observed with Oruvail by a factor of two and with half the ketoprofen dose. To conclude, a PLO-based gel is capable of delivering EPA and DHA via a repeat finite dosing regimen, although there is evidence for the retention of these very lipophilic molecules within the gel matrix. Although to a lesser extent than EPA and DHA, ketoprofen was also substantially retained, as exemplified by the superior delivery rates from Oruvail. Finally, this work has highlighted the importance of using an appropriate topical dosing method to match the intended use of a product.

This work investigated the simultaneous permeation of ketoprofen and propylene glycol (PG) across pig ear skin from simple gel formulations administered under simulated in-use conditions. The aims were to quantify rates of permeation of both solvent and active, probe the effects of formulation drying and gain insight into drag/complexation interactions. Simple 3-component gels were formulated using a fixed amount of ketoprofen and hydroxypropyl cellulose thickener with decreasing content of solvent propylene glycol. Multiple finite (5 mg x 15 mg) doses were massaged over 24h into full thickness pig ear skin in vertical Franz-type diffusion cells. The permeation of ketoprofen was inversely proportional to the content of PG, whereas the permeation of PG was directly proportional, although the amount of PG permeated was always greater than ketoprofen, even from the driest gel practically achievable. In this state, the molar ratio of PG/ketoprofen was approximately 12, suggesting that this number of PG molecules constitutes the solvation cage of ketoprofen. Dragging/pulling effect extends throughout the skin and into the receptor compartment and probably the system, in an in vivo situation. Although PG may represent a worse case scenario given its well-documented skin permeation enhancement properties, it is probable that other solvents exert a similar effect on solutes across skin. A drying film will behave in different ways depending on the nature of both the thickener and solvent, where the outcomes are not readily predictable. It is important to account for the fate of all species administered from a topical formulation.

Chemical and enzymatic hydrolysis of the co-drug of retinoic acid (vitamin A) and ascorbic acid (vitamin C) - retinyl ascorbate (RA-AsA)--have been studied. Firstly, the amount of protein and ester hydrolysis activity was determined in crude cellular extracts from freshly excised porcine ear skin (<3 h) and stored porcine ear skin (frozen >6 months) using ethyl butyrate as model substrate. The stability of RA-AsA was then determined in the crude cell extracts with and without additional antioxidants. Lastly, the enzymatic hydrolysis of RA-AsA and retinyl-2-carboxy-2-hydroxy-ethanoate were determined by incubating with porcine liver esterase - retinol palmitate and ascorbyl palmitate were included for comparison. Freshly excised skin contained higher amounts of active proteins than previously frozen skin. RA-AsA underwent hydrolytic reduction causing the AsA moiety to disintegrate due to the presence of free radicals in the media. An intermediate was produced that seemed to be cleaved by enzymes. Addition of ascorbic acid, as antioxidant, to the media of crude protein extracts decelerated the hydrolysis rate. This was supported when RA-AsA and retinyl-2-carboxy-2-hydroxy-ethanoate were incubated separately with pure esterase. There was approximately 5-fold more soluble protein per ml of cytosol in the fresh skin compared to the stored skin. Therefore, the amount of protein present within approximately 1.5 cm(2) of skin (average diffusion area in the Franz cells used in our skin penetration studies) was 0.06 mg cm(-2) and 0.01 mg cm(-2) for fresh and stored extracts, respectively.

The maximum effective dose of retinyl ascorbate and its potential therapeutic benefits against induced oxidative damage were assessed in vitro using cultured human epidermal keratinocytes. RA-AsA exhibited toxic effects at concentrations >6 microM. The findings indicate to the potency of RA-AsA as free radical scavenger and cell proliferation regulator.

The effect of different proportions of borage oil on the in vitro transcutaneous delivery of tamoxifen were studied, with the aim of developing a gel capable of the simultaneous delivery of tamoxifen and gamma linolenic acid across (breast) skin. Supplementary work probed 1H NMR spectral data for tamoxifen in the presence of different proportions of polyunsaturated or unsaturated fatty acids. Typical, non-aqueous gels were modified to contain 1% tamoxifen and three levels of borage oil ( approximately 25% gamma linolenic acid) and the transcutaneous delivery of both tamoxifen and GLA across full thickness skin determined in vitro. Both tamoxifen and gamma linolenic acid permeated the skin with the ratio of moles being consistent at approximately 4:1. This was irrespective of time, amount of borage oil contained in the formulation (above a minimum) and the presence of other (unsaturated) excipients: mineral oil, Miglyiol 810N, white soft paraffin, PEG400 and Cabosil M5. Dose-dependent downfield shifts of tamoxifen aromatic protons were observed in the presence of borage oil and linolenic acid (gamma and alpha), but not saturated triacyl glycerol. The permeation data suggested vehicular complexation between tamoxifen and polyunsaturated constituents of borage oil and that such complexes permeated the skin intact. The 1H NMR data supported the hypothesis that such complexation was a consequence of preferential pi-pi orbital interactions between the phenyl groups of tamoxifen and the multiple double bonds of GLA. The mechanism for the permeation of intact complexes across skin remains to be elucidated.

The effects of decreasing solvent content and macroviscosity of simple topical gel formulations on the transcutaneous delivery and distribution of ketoprofen through skin were studied. Simple topical gels, based on ketoprofen, PEG 400 and either Cabosil M-5 or hydroxypropylcellulose were formulated and applied to freshly excised pig ear skin in vitro. Receptor phase samples were taken to determine permeation and depth profiles of ketoprofen were constructed, following tape stripping and membrane separation. Reduction of solvent from the Cabosil-thickened gels resulted in a rank order reduction in the permeation and distribution of ketoprofen. Reduced amounts of ketoprofen were distributed through the skin, particularly the dermis, with decreasing solvent. Two gels sharing the same macroviscosity exhibited significantly different skin permeation and distribution characteristics. The rank order reduction in both permeation and distribution of ketoprofen was attributed to the physiochemical properties of the formulation and how they may change after application, in particular the increased adsorptivity of ketoprofen to the Cabosil relative to the amount of solvent present in the system. This effect appeared to be predominant over any interactions occurring between the formulation and the skin. The data provided further evidence that adsorption to the thickener, rather than changes in viscosity, were primarily responsible for reduced permeation and distribution in the system examined., (Copyright (c) 2005 S. Karger AG, Basel.)

In this study, we compared the effect of isoflurane and desflurane on the posterior tibial somatosensory evoked potential recorded by scalp electrodes during correction of idiopathic scoliosis in pediatric patients. Depth of sedation was controlled by maintaining bispectral index (BIS) at 60 throughout the study. Comparison of patients breathing desflurane and isoflurane showed an evoked cortical amplitude (N37-P45) of 0.53 +/- 0.3 microV versus 1.3 +/- 0.8 microV (P = 0.014), respectively. In addition to this comparison, a crossover design was included whereby the desflurane or isoflurane received in the first part of the study was changed to the other anesthetic. Substituting one anesthetic for another confirmed our initial finding that the cortical evoked amplitude is greater with isoflurane than with desflurane. No differential effect was found between desflurane and isoflurane on the evoked subcortical (N31-P34) amplitude or the P37 latency.

The free radical scavenging properties of retinyl ascorbate (RA-AsA) were determined by monitoring the decomposition of 2,2-diphenyl-1-picrylhydrazyl (DPPH) as a function of time and in comparison with ascorbic acid (AsA), ascorbic acid palmitate (AsA-Pal), retinoic acid (RA), retinol (ROL) and retinol palmitate (Rol-Pal). The rate constant of RA-AsA (mean3+/-SD) was 4.9+/-0.3 M(-1) s(-1), and indicated greater potency as an antioxidant compared to the rest of the test compounds (AsA 3.4+/-0.4 M(-1) s(-1), AsA-Pal, 2.9+/-0.2 M(-1) s(-1), RA 1.4+/-0.3 M(-1) s(-1), ROL 1.3+/-0.1 M(-1) s(-1), Rol-Pal exhibited insignificant activity). The decomposition rate constant of DPPH, 5+/-0.6 x 10(-8) M(-1) s(-1), in ethanol and BHA, 154+/-3 M(-1) s(-1) were both used as control. The compound RA-2-carboxy-2-hydroxy-ethanoate was isolated by prep-TLC and was identified, by 13C and 1HNMR spectroscopy, as the major by-product from the reaction of RA-AsA with DPPH, which was also found to be potent antioxidant, 2.1+/-0.2 M(-1) s(-1). This suggests that oxidation of AsA moiety did not lead to the production of erythrulose species, which could cause deleterious modifications of cellular proteins.

In vitro measurements of skin absorption are an increasingly important aspect of regulatory studies, product support claims, and formulation screening. However, such measurements are significantly affected by skin variability. The purpose of this study was to determine inter- and intralaboratory variation in diffusion cell measurements caused by factors other than skin. This was attained through the use of an artificial (silicone rubber) rate-limiting membrane and the provision of materials including a standard penetrant, methyl paraben (MP), and a minimally prescriptive protocol to each of the 18 participating laboratories. "Standardized" calculations of MP flux were determined from the data submitted by each laboratory by applying a predefined mathematical model. This was deemed necessary to eliminate any interlaboratory variation caused by different methods of flux calculations. Average fluxes of MP calculated and reported by each laboratory (60 +/- 27 microg cm(-2) h(-1), n = 25, range 27-101) were in agreement with the standardized calculations of MP flux (60 +/- 21 microg cm(-2) h(-1), range 19-120). The coefficient of variation between laboratories was approximately 35% and was manifest as a fourfold difference between the lowest and highest average flux values and a sixfold difference between the lowest and highest individual flux values. Intralaboratory variation was lower, averaging 10% for five individuals using the same equipment within a single laboratory. Further studies should be performed to clarify the exact components responsible for nonskin-related variability in diffusion cell measurements. It is clear that further developments of in vitro methodologies for measuring skin absorption are required., (Copyright 2005 Wiley-Liss, Inc. and the American Pharmacists Association.)

Transcutaneous administration of nonsteroidal anti-inflammatory drugs and essential fatty acids from fish oil, principally eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), may simultaneously lead to increased cyclooxygenase inhibition and the production of less potent inflammatory mediators within joints. The objective of our study was to determine the permeation of ketoprofen, EPA, and DHA (from fish oil) across pig ear skin in vitro in the presence of the enhancer 1,8-cineole. Formulations containing 2.5% ketoprofen in fish oil with varying concentrations of 1,8-cineole were prepared and applied to full-thickness pig ear skin mounted in all glass Franz-type diffusion cells. Simultaneous permeation of ketoprofen and EPA and DHA from these formulations was determined by reverse phase HPLC over a 48-hr period (n = 6). We found that fish oil alone enhanced the permeation of ketoprofen across pig ear by a factor of 1.72 relative to a water vehicle. There was a dose-dependent increase in the rate of permeation of ketoprofen relative to the concentration of 1,8-cineole. The highest Q24 and Q48 was obtained with a 20% 1,8-cineole formulation with values of 355.78 +/- 50.73 microg cm(-2) and 963.29 +/- 136.69 microg cm(-2), respectively. Surprisingly, no clear effect upon the permeation of EPA and DHA by 1,8-cineole was observed, with the highest Q24 and Q48 values seen in a formulation containing no 1,8-cineole. This may have been due to differential solvation effects prior to or during the permeation process or modulation of the skin during the permeation process.

Retinyl ascorbate (RA-AsA), an ester co-drug of vitamins A (RA) and C (AsA), is proposed as a topical antioxidant/cell division regulator for reducing UV-induced generation of free radicals and disrupted dermal cell growth. The efficacy of dermatological agents is influenced by their retention within the skin, which is increased by the interaction with skin components. Keratin is the major protein (approximately 95%) in the skin, and this paper reports the binding of RA-AsA, RA, AsA, retinol, ascorbic acid palmitate and retinol palmitate to three tissues-human callus, pig ear skin and bovine horn keratin. Tissue samples were incubated with solutions of compounds and the uptake measured as the ratio of bound/free compound at equilibrium. Binding to keratin was assessed using delipidised tissue, and was much higher for the polar compounds, suggesting dipolar/H-bonding interaction. Binding strength was ranked as human > porcine > bovine, but there was no distinction for highly lipophilic compounds. The binding characteristic of native tissues was complicated by lipid content of the tissues. There seemed to be a dual effect. The binding of very lipophilic materials increased with lipid content, implying that a substantial amount is dissolved in the lipid matrix. For highly polar AsA, lipid content decreased the binding, suggesting that the lipid reduced the strong polar interactions with skin protein/keratin., (2004 S. Karger AG, Basel.)

The objective of this study was to examine the effects of ethanol and 1,8-cineole on the transcutaneous delivery of tamoxifen and gamma-linolenic acid (GLA) as a two-pronged anti-breast cancer therapy. Formulations containing tamoxifen and varying concentrations of borage oil (approximately 25% GLA), 1,8-cineole and ethanol were prepared and the simultaneous permeation of tamoxifen and GLA determined across full-thickness pig skin using Franz-type diffusion cells over 48 h. Analysis of tamoxifen and GLA (as methyl ester) were by reverse-phase HPLC. The highest flux of tamoxifen of 488.2 +/- 191 x 10(-3) microg cm(-2) h(-1) was observed with a formulation containing 20% 1,8-cineole and 20% ethanol. The same formulation also provided the greatest flux of GLA, 830.6 x 10(-3) microg cm(-2 )h(-1). The findings from this work demonstrate the ability of 1,8-cineole and ethanol to enhance the in-vitro permeation of tamoxifen and GLA across the skin and support the plausibility of simultaneously delivering tamoxifen and GLA transcutaneously as a two-pronged anti-breast cancer system.

The aim of this study was to investigate the feasibility of the transdermal delivery of catechins and caffeine from green tea extract. Drug-in-adhesive patches containing 1.35, 1.03, 0.68, and 0.32 mg cm(-2) green tea extract were formulated and the dissolution of (-)-epigallocatechin gallate (EGCg), (-)-epigallocatechin (EGC) and (-)-epicatechin (EC) from these was determined. Transdermal delivery was determined across full thickness pig ear skin from saturated solutions of green tea extract in pH 5.5 citrate-phosphate buffer, polyethylene glycol 400 and a 50:50 mixture of the citrate phosphate buffer and polyethylene glycol in addition to patches containing 1.35 mg cm(-2) green tea extract. Dissolution experiments indicated first order release which was dose dependent in respect of the loading level, although the amounts permeated were not always proportional to the amounts in the formulation. The highest percentage permeation of EGCg was found to be from the patch formulation. EGCg, EGC and EC were all successfully delivered transdermally from saturated solutions and adhesive patches containing green tea extract in this study. There was some evidence for the dermal metabolism of EGCg, but after 24 h 0.1% permeated from the patches containing 1.35 mg cm(-2) green tea extract. This was equivalent to the percentage absorbed after intragastric administration of green tea extract in rats. In addition, the concentration of EGCg in the Franz cell receptor chamber after 24 h permeation from the 0.9 cm diameter patch containing 1.35 mg cm(-2) was within the range of Cmax plasma levels achieved after oral dosing of 2.2-4.2 gm(-2) green tea extract. Caffeine was also delivered at concentrations above those previously reported.

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.

Purpose: To determine the in-vitro dermal delivery of a new class of lipophilic, highly potent and uniquely selective anti-VZV nucleoside analogues in comparison with aciclovir., Methods: Three test compounds (Cf1698, Cf1743, Cf1712) and aciclovir were formulated into propylene glycol/aqueous cream BP formulations and finite doses applied to full-thickness pig ear skin for 48 hours in vertical Franz-type diffusion cells. Receptor phase samples were taken at specific intervals to determine permeation, and depth profiles were constructed following tape stripping and membrane separation., Results: All three test compounds reached the target basal epidermis in concentrations suggesting they would be highly efficacious in reducing viral load. Furthermore, the data showed that each of the test compounds would perform in a far superior manner to aciclovir, the current treatment of choice., Conclusions: The dermatomal site of viral replication during secondary infection--the basal epidermis--was successfully targeted. Topical delivery of these compounds is highly promising as a new first line treatment of VZV infections. By attacking the virus at the first sign of reactivation, it is proposed that the extent of damage caused by the virus would be significantly lowered, thereby limiting the extent and severity of post-herpetic neuralgia.

Tamoxifen is the hormonal treatment of choice in women who have hormone-dependent breast cancer and its efficacy in those women considered to have a high risk of developing breast cancer, has also been established. Gamma linolenic acid (GLA) has been shown to decrease the invasion of breast cancer and recent studies have demonstrated that GLA can enhance the oestrogen receptor down-regulation induced by tamoxifen. However, tamoxifen is associated with serious side-effects due mainly to systemic delivery, and targeted delivery of both tamoxifen and GLA would be highly beneficial. This work was a preliminary study for the development of a transcutaneous system to simultaneously deliver both tamoxifen and GLA directly to the breast. Full thickness human skin was dosed with 500 microl saturated solution of tamoxifen in borage oil (25% GLA) and the simultaneous permeation of the two actives determined. There was rapid flux with minimal lag time, the cumulative permeation at 24 h was 764.3 +/- 94.2 microg cm(-2) for GLA and 5.44 +/- 0.67 microg cm(-2) for tamoxifen: the latter being comparable to the amount of tamoxifen associated with cancerous breast tissue from a 20 mg oral dose. The ratio of GLA/tamoxifen permeated at different timepoints was quite consistent, both in terms of mass (mean 138, S.D. 15.1) and mols (mean 184, S.D. 20.3). It was determined that 2.5 molecules of GLA were associated with each molecule of tamoxifen in the permeation process, equating to a solvation cage of three molecules of triacylglycerol. This study has demonstrated the feasibility of administering simultaneously tamoxifen and GLA using borage oil as vehicle, which warrants further investigation as a novel topical two-component system in relation to or prophylaxis of those perceived at high risk of developing breast cancer. The study also provides further evidence of the permeation of solvated complexes across skin, rather than discrete penetrant molecules.

Background: A synergistic effect has been described when rocuronium (Roc) and mivacurium (Miv) are combined in equal (i.e. 1:1) ED95 proportions at various total doses. We have investigated the effect of Roc or Miv alone and four different ratios (1:4, 2:3, 3:2 and 4:1) of Roc and Miv mixed to a total dose of 1.33 x ED95. The primary outcome is the ratio producing the maximum enhancement of duration of clinical effect., Methods: Sixty-eight healthy children were anaesthetized with propofol, nitrous oxide and fentanyl. They then randomly received either Roc 0.4 (mg.kg(-1)), Miv 0.133 (mg.kg(-1)) or one of four Roc + Miv combinations (mg.kg(-1)): Roc 0.32 + Miv 0.027; Roc 0.24 + Miv 0.053; Roc 0.16 + Miv 0.08; and Roc 0.08 + Miv 0.106. The mechanical response of the adductor pollicis muscle to supramaximal stimulation of the ulnar nerve at the wrist was recorded., Results: Duration of effect was greater in the combination groups than that predicted from the duration of Roc or Miv used alone. Duration was maximally increased around a 1:1 ratio (2:3 and 3:2) of Roc and Miv. The likelihood of achieving 100% block was greater in combination groups compared with Roc or Miv used alone., Conclusions: Combinations of Roc and Miv show a synergistic effect, which appears maximal as the mixture approaches a 1:1 ratio of their ED95s. This combination acted as if a larger effective dose of a single (new) drug had been given, but did not offer the advantage of both rapid onset and short duration of effect.

The migration of ketoprofen through a series of simple gels that varied in solvent composition to simulate snapshots of a dynamically drying topical formulation was studied. Firstly, the release rate of ketoprofen was determined from formulations based on Cabosil and PEG 400, the proportion of which was varied to mimic progressively dryer states. Secondly, the apparent permeability of ketoprofen across the corresponding blank Cabosil gels was determined. Thirdly, the effect of macro viscosity on these data was probed by comparing permeation of ketoprofen across Cabosil and hydroxypropyl cellulose (HPC) gels of equal viscosity. Linear release profiles were produced for all formulations suggesting first-order release and the rate of ketoprofen liberated was inversely to the proportion of Cabosil, suggesting that the drier the film, the slower the rate of release. At the lowest level of thickener used (5%) the release rate was reduced to 45% of the control. At 25% the release rate was reduced to 24% of the control. The presence of the Cabosil had an even more dramatic effect on the apparent permeability of ketoprofen across the gels. At 5% Cabosil the apparent steady state flux was reduced to 4% of the control. At 25% the apparent steady state flux was reduced to < 1% of the control. Although the 0.5% HPC gel and the 1% Cabosil gel possessed identical macro viscosities, the permeation of ketoprofen through the HPC gel was almost double that of the Cabosil gel. The data from these experiments demonstrated that migration of active molecules through a gel is significantly affected by the amount of solvent present in, or lost from, the system. It is proposed that increased adsorption of active to the thickener plays a more important role than increased macro viscosity for reduced active release as the formulation becomes increasingly dry. Furthermore, such affects are profoundly influenced by the chemical nature of the thickener.

Background: Opioids are frequently used for sedation in the Paediatric Intensive Care Unit (PICU). With time the dosing often increases because of tolerance. On cessation of the sedation there is a risk of the opioid withdrawal syndrome. The aim of our study was to evaluate methadone dosing as a risk factor for opioid withdrawal and to determine optimal dose and efficacy of methadone to prevent withdrawal., Method: We undertook a clinical, retrospective, chart review study. Data were analysed from the quality improvement initiative database of a tertiary-care 18 bed PICU., Results: Data from 30 children who received an opioid infusion for >/=7 days and subsequently received methadone for opioid withdrawal (between January 2000 and July 2001) were analysed. Nurses documented the presence or absence of withdrawal signs daily. Our unit protocol has recommended converting the patient's opioid dose into fentanyl equivalents and a dose of methadone equal to the total daily dose of fentanyl to be given three times a day. Twenty patients had no or minimal withdrawal symptoms and 10 experienced significant withdrawal. Age, weight, PRISM score, lorazepam dose, muscle relaxant use and fentanyl dose were not statistically significantly between these groups. Receiver Operator Characteristics analysis showed that 80% of the suggested methadone dose was effective in minimizing withdrawal symptoms. The odds ratio for withdrawal with <80% of the predicted methadone dose was 21., Conclusions: Inadequate methadone is a risk factor for opioid withdrawal. A daily starting methadone dose equivalent to 2.5 times the daily fentanyl dose is effective in minimizing withdrawal symptoms.

As part of our investigations into novel dual action topical anti-arthritis systems, the permeation of ibuprofen or ketoprofen plus eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) were determined from a fish oil vehicle across pig ear skin in vitro. The steady state fluxes of ibuprofen and ketoprofen were 9.17+/-1.98 microgram cm(-2)h(-1) and 6.12+/-2.39 microgram cm(-2)h(-1), respectively. At 24h, 5.7 microgram cm(-2) EPA and 3.1 microgram cm(-2) DHA permeated when the solute was ibuprofen; 1.4 microgram cm(-2) EPA and 1.0 microgram cm(-2) DHA when ketoprofen was the solute. At 12h, the ketoprofen/ibuprofen ratio of the moles permeated was 0.27, the ratio of EPA permeated simultaneously with ketoprofen and ibuprofen was 0.22 and the ratio of DHA permeated simultaneously with ketoprofen and ibuprofen was 0.24. We believe this is the first time that simultaneous permeation across skin of a solute and its vehicle has been determined purposefully. The data successfully demonstrated that simultaneous permeation of NSAIDs and essential fatty acids, EPA and DHA from a formulation containing fish oil is feasible. In addition, for both NSAIDs, the relative rates of permeation of EPA and DHA, were in proportion to their levels in the fish oil and the permeation rate of either fatty acid was higher when the permeation rate of the solute was greater. This suggested that the greater the rate of permeation of the NSAID, the greater the rate of permeation of the vehicle, and that a solute permeates skin complete with its vehicular solvation cage. This apparent relationship between solute and vehicle fluxes may be of more widespread significance to skin permeation experimentation.

The enantiomeric resolution of certain 2-arylpropionic acids was achieved on thin silica gel plates impregnated with optically pure L-(-)-serine as chiral selector. The mobile phase enabling successful resolution of (+/-)-ibuproxam and (+/-)-ketoprofen was acetonitrile-methanol-water (16:4:0.5, v/v/v) and (16:3:0.5, v/v/v) for (+/-)-tiaprofenic acid. The spots were detected with iodine vapors and the detection limits were found to be different for each of the 2-arylpropionic acid, ranging between 0.25 and 0.50 microg/ml. The effect of concentration of the impregnating chiral selector, temperature and pH on resolution has been studied. The procedure was applied successfully to resolve commercial ampoules of ketoprofen dosage formulation.

Varicella zoster virus (VZV) is responsible for causing chickenpox and shingles infections, the latter of which can lead to long-term post-herpetic neuralgia (PHN), the most common complication of VZV infections. A class of anti-VZV nucleoside analogues has been synthesised that shows up to 30,000 times the potency of aciclovir in vitro. The relatively high lipophilicities exhibited by the compounds led them to be selected for dermal delivery. The aim was to assess the relative penetration and permeation of the compounds into and through the skin, ideally targeting the region of skin in which the reactivated virus replicates. By targeting the skin it should be possible to reduce the viral load that causes damage to the nerves, thereby limiting zoster-associated pain, in particular PHN. Three compounds, as saturated solutions or as ethanol-based creams, were applied to full-thickness pig ear skin in Franz-type diffusion cells. An ethanolic and water receptor phases were compared. Samples of the receptor phase were taken at specific intervals, followed by tape stripping and separation of the remaining membrane at the end of the experiment. Analysis of the samples showed that all three compounds penetrated into the ethanolic receptor phase to a considerable degree, while only the least lipophilic compound entered the water receptor phase. The effects of the organic solvent in the receptor phase were visible in both the penetration and permeation of the compounds. All three compounds were distributed throughout the membrane in a manner that indicates that the site of viral replication in the skin is reached.

Impregnated silica TLC plates with L-(-)-serine and L-(-)-threonine and a mixture of L-(-)-serine and L-(-)-threonine (1:1) as chiral selectors were prepared to use as chiral stationary phases (CSPs) in thin layer chromatography. The resolution of the enantiomers of 2-arylpropionic drugs, including ibuprofen, ibuproxam, ketoprofen, pranoprofen, benoxaprofen, flurbiprofen and tiaprofenic acid was investigated on these CSPs. A mobile phase system of acetonitrile-methanol-water (16:4:0.5, v/v/v) was used. The spots were detected with iodine vapours and the detection limits were found to range between 0.25 and 0.5 micro g/mL for all racemic compounds investigated. The effect of temperature, pH and concentration of the impregnating chiral selectors on resolution has been studied., (Copyright 2003 John Wiley & Sons, Ltd.)

The aim of this study was to test the hypothesis that the most appropriate model for studying the diffusional release of an active from a topical formulation is one in which the membrane offers minimal resistance to release and involves a receptor phase that presents the least possible interfacial discontinuity. Using ketoprofen as the active, a series of simple gels were prepared consisting of PEG400 thickened with Cabosil M5. Using Franz-type diffusion cells, three different types of membrane (two porous and one non-porous) were compared, as were receptor phases of PEG400 (component of formulation) and PBS. Of the membranes tested only 0.2 microm nylon provided consistent first order kinetics for a range of gel consistencies, indicating negligible influence of the membrane. The non-porous silicone membrane did not show first order kinetic profile confirming the diffusional nature of such a membrane. From the non-thickened formulations, diffusional release into a receptor phase of PEG400 was some 3x that into PBS, whereas from the formulation thickened with 5% Cabosil M5, diffusional release into a receptor phase of PEG400 was 6x lower than that into PBS. Diffusional release into PBS did not follow first order kinetics while diffusion into PEG400 did, suggesting that the existence of a discontinuity affected the release process. Although the importance of zero-resistance membranes is of perhaps obvious importance, it is often not stated in the literature. The existence of phase/hydrodynamic boundaries in release studies can be a source of significant inaccuracy.

The localisation of primaquine was studied within epidermal membranes following the application of a topical dose. A depth profile was constructed by tape-stripping human epidermis following permeation of a 70 mgml(-1) solution of primaquine in Miglyol 840. Comparative binding studies of primaquine were carried out on isolated human stratum corneum and whole epidermis, using normal and delipidised tissue. An additional study was undertaken using bovine keratin powder as a model of human keratin. The depth profile showed that primaquine decreased with depth and decreasing keratin content, and the total primaquine recovered (15.5 mgcm(-2)) was 300 x the amount of extractable lipid. Binding to delipidised skin was saturable, whereas binding to normal skin was unsaturable, reflecting the high miscibility of drug in the lipid domains as opposed to a finite, but large number of binding sites on the corneocytes. Binding was greater for stratum corneum than stratum corneum plus viable epidermis, probably due to greater accessibility of corneocytes keratin. Binding was dose dependent, although binding to delipidised skin was far greater than to normal skin, demonstrating that primaquine had an affinity for lipoidal regions and an even higher affinity for the proteinaceous domains of the stratum corneum. This was supported by high saturable levels of primaquine binding to bovine horn keratin. The results indicated extensive binding to corneocyte keratin has a significant effect on reservoir formation and the permeability of primaquine across human skin. It is speculated that the large amount of keratin presented at the skin surface may be an evolutionary protective process for the sequestration of ingressing molecules.

Objectives: To evaluate carbon dioxide clearance in normal rabbits during high-frequency oscillatory ventilation with helium-oxygen mixtures by using a low bias flow oscillation (LBFO) system designed to conserve expensive gas., Design: A prospective, paired-controlled, interventional, in vivo animal laboratory study., Setting: Animal laboratory of a health science university., Subjects: Twelve New Zealand White rabbits., Interventions: Juvenile rabbits were anesthetized, paralyzed, and ventilated through a tracheostomy. LBFO was performed with a modified high-frequency oscillatory ventilation circuit that uses low bias flow (100 mL/kg) and a soda lime cartridge to clear carbon dioxide. LBFO-heliox trials were performed with 20%, 40%, 50%, 60%, and 70% helium (balanced with oxygen) for 30 mins. Each heliox trial was preceded by a paired control trial with 40% oxygen and 60% nitrogen for 30 mins. Ventilator settings in control and heliox trials were identical. During the second part of the study, four rabbits were made hypercapnic by decreasing the power (amplitude), and LBFO was performed with 70% helium against paired-control trials of 40% oxygen and 60% nitrogen. Arterial blood gases were measured at 15-min intervals and airway pressure amplitude was recorded. PaCO2 of control and heliox trials, alveolar PO2-PaO2 gradient of control, and 60% helium trials were compared by paired Student's t-test., Measurements and Main Results: At constant power, amplitude was unaffected by helium. Helium concentrations of 40%, 50%, 60%, and 70% decreased PaCO2 by 12%, 33%, 36%, and 46%, respectively. Alveolar PO2-PaO2 gradient was decreased by 40% during ventilation with 60% helium. Under hypercapnic conditions, 70% helium decreased PaCO2 by 20%., Conclusion: Helium concentrations > or = 40% facilitate carbon dioxide clearance from lungs of normal rabbits during LBFO. This could be accomplished inexpensively with LBFO due to preservation of heliox when using this device.

Objective: To compare the Bispectral Index with clinical sedation assessment using the Ramsay score in normal sedated and paralyzed critically ill children., Design: Prospective observational study., Setting: Multidisciplinary 18-bed pediatric intensive care unit at a university-affiliated children's hospital., Patients: A total of 48 pediatric intensive care unit patients requiring mechanical ventilation and sedation. Of these, 24 patients were not paralyzed., Measurements and Main Results: Twenty-four pediatric intensive care unit children with normal mentation who were sedated and being ventilated in the intensive care unit were included in the study. The Ramsay score as assessed by the nurses was compared with the blinded Bispectral Index score. The regression coefficient between the Bispectral Index score and Ramsay score was 0.77 (p < 0.0001). The second group of patients included normal children similar to the previous group but paralyzed. The Ramsay score, as expected, was a poor tool for sedation assessment in a paralyzed patient. The nurse assessment only detected 8% of those patients at risk for awareness and recall (Bispectral Index score, > or = 80). Nurse assessment for oversedation (Bispectral Index score, < 40) was better with a sensitivity of 89.7% but a poor specificity of 38.6%., Conclusions: The Bispectral Index correlates well with the Ramsay score in the normal sedated child. The Ramsay score and bedside nurse assessment are inadequate for monitoring the depth of sedation in paralyzed children. The Bispectral Index is a useful adjunct in assessing sedation in a paralyzed patient.

Malarial resistance is an escalating global problem and consequently new and more efficacious treatments to combat malaria are urgently needed. The transdermal delivery of anti-malarials may provide an effective alternative or adjunct to conventional regimens. Triclosan is widely used as an anti-bacterial agent and it has recently been demonstrated that this compound has anti-malarial properties. Its high lipophilicity makes it a potential candidate for delivery across the skin and this paper examines in vitro the potential for the transdermal delivery of triclosan from 'drug-in-glue' formulations. Model patches were prepared using DuroTak 2287, 2516 and 2051 acrylic polymer adhesives loaded with 0, 30 and 50 mg per 0.785 cm(-2) triclosan and dissolution was measured over a 12-h period. There was no apparent difference between the adhesives at the 30 mg patch loading, but at 50 mg, the trend for increased release was 2051>2516>2287. No significant burst effect was apparent. Patches of 50 mg per 0.785 cm2 were then used to determine the permeation of triclosan across heat-separated human epidermal membranes in Franz diffusion cells, over a period of 48 h. The above general trend was reflected in the steady state flux values obtained: 2051:16.91 microg x cm(-2) x h(-1) (S.E.M. 1.29), 2516:15.05 microg x cm(-2) x h(-1) (S.E.M. 1.00), 2287 12.83 microg x cm(-2) x h(-1) (S.E.M. 2.81). Although pharmacokinetic data are not currently available to permit calculation of an efficacious patch size, the transdermal delivery of triclosan is feasible.

Doxycycline is licensed for the prophylaxis of malaria and recent research has indicated the feasibility of delivering this drug across the skin. The binding of doxycycline to keratin could influence skin permeation rates and it has been suggested that the interaction of anti-malarials with melanin may contribute to side effects, such as retinal damage. Doxycycline HCl was incubated with keratin (bovine horn), melanin (Sepia officinalis) and human epidermal samples (native and delipidised). Dose dependent binding of doxycycline to keratin and melanin was observed, and was of similar magnitude for each protein. However, the binding of doxycycline to melanin was lower by an order of magnitude relative to data previously reported for some other anti-malarials, and may indicate reduced side-effects. Doxycycline also demonstrated significantly greater affinity for native epidermal skin than for delipidised skin showing that doxycycline, a charged polar molecule, has affinity for the intercellular lipid matrix in addition to the proteinaceous domain. For native skin it was estimated that saturation would be reached at approximately 140 microg x cm(-2); for delipidised skin it was estimated to be 60 microg x cm(-2). Overall, the data suggested that the partition-diffusion steps that are involved in transcellular permeation are possible.

Molecular imprinted polymers (MIPs) of S-timolol were prepared as chiral stationary phases (CSPs) in thin layer chromatography (TLC). The resolution of the enantiomers of some cardiovascular drugs, including propranolol, atenolol, timolol, nadolol, nifedipine and verapamil were investigated on these CSPs. A mobile phase system of either methanol or acetonitrile was used and the effects of acetic acid content of the mobile phases were also investigated. The best resolution was achieved for enantioseparation of propranolol, timolol and atenolol on plates based on MIP of (-)-S-timolol using methacrylic acid as functional monomer (alpha = 1.52, 1.6, 1.59) respectively, using acetonitrile containing 5% acetic acid and (alpha = 1.47, 1.52, 1.5) in methanol containing 1% acetic acid as mobile phases. The results obtained show that TLC based on MIPs could be applied in the direct separation of several beta-adrenergic drugs. As the side chains on beta-blockers are similar, it is possible that this method could also be used for the resolution of other racemates in this family of drugs. Racemic drugs structurally related to print molecule, were completely resolved into two spots with the MIP plates. In general the retention of (+)-R-isomers was greater than that of (-)-S-isomers, indicating lower stereoselectivity of the MIPs to the dextrorotatory isomers. The method offers a rapid, sensitive and reliable method for quality control for these drugs.

Objective: To determine the incidence of physiologic deterioration in critically ill and injured pediatric patients during interhospital transport with air and ground ambulance, Design: Prospective, descriptive study, Setting: All children were treated in regional hospitals and then transported to a pediatric tertiary care center., Patients: Children (n = 100) with a median age of 1.4 years (range 1 week to 18 years), Main Results: Three sets of physiologic scores were calculated: at the time of referral, on departure from the referring hospital, and arrival at the tertiary care center. The incidence of significant physiologic deterioration based on the calculated physiologic scores was 5.6% (n = 4) during ground and 3.4% (n = 1) during air ambulance transports. Critical events occurred in 15% of ground and 31% of air ambulance transports., Conclusion: No difference existed in the incidence of adverse events or physiologic deterioration when air ambulance transports were compared with ground ambulance transports for critically ill children by our team. The physiologic scoring system we chose is simple and easy to use for quality assurance.

Objective: To document the safety and efficacy of an anaesthetic technique in paediatric patients undergoing transoesophageal echocardiography (TOE)., Methods: Prospective descriptive study performed in a children's hospital with all patients undergoing TOE. Topical analgesia of the pharynx was achieved with lidocaine. Anaesthesia was induced with midazolam (25 microg.kg-1), fentanyl (1 microg.kg-1), and propofol (0.5-1 mg.kg-1), followed by a continuous infusion of propofol (5-10 mg.kg-1.h-1)., Results: Thirty patients are reported. The mean age was 11.4 +/- 5.1 years (range 1-22) and weight 40.5 +/- 22.1 kg (range 10-110). All the patients tolerated the procedure well. Two patients experienced brief oxygen desaturations during induction, 10 patients coughed during the procedure, and six patients had significant muscle activity requiring supplemental doses of propofol. None of the patients experienced nausea or vomiting., Conclusion: We conclude that our anaesthetic technique in spontaneously breathing paediatric patients during TOE is effective and appears to be safe in children with heart disease.

We describe a neonate on venoarterial extracorporeal membrane oxygenation (ECMO) with acute renal failure associated with extensive aortic and bilateral renal artery thrombosis. Concurrent anticoagulation and continuous systemic thrombolytic therapy with tissue plasminogen activator (t-PA) resulted in complete thrombolysis as evaluated by Doppler flow. The relative risk and benefits of thrombolytic therapy in heparinized patients undergoing ECMO needs to be further studied.