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Reverse iontophoresis facilitated the extraction of phytochemicals from intact pomegranates in a non-destructive manner. These phytochemicals were subsequently identified using liquid chromatography coupled to untargeted mass spectrometry (LC-MS).

Medicines designed to deliver the active pharmaceutical ingredient either into or through the skin─often referred to as topicals and transdermals, respectively─are generally considered to be complex drug products. A particular challenge faced by these formulations is identifying a suitable method (ideally, in terms of specificity, accuracy, precision, and robustness) or combination of methods with which to assess the amount and rate of drug delivery to the target site. Significant research currently aims to identify and validate relevant and minimally invasive techniques that can be used to quantify both the levels of the drug attained within different parts of the skin and the kinetics with which the drug is taken up into the skin and cleared therefrom into the systemic circulation. Here, the application of confocal Raman microspectroscopy and imaging to interrogate events integral to the performance of topical and transdermal drug products at the formulation-skin interface is illustrated. Visualization, depth slicing, and profiling are used (a) to elucidate key chemical properties of both the delivery system and the skin that have impact on their interaction and the manner in which drug transfer from one to the other may occur, (b) for the transformation of a drug product from that manufactured into a residual phase post-application and inunction into the skin (including the potential for important changes in solubility of the active compound), and (c) for drug absorption into the skin and its subsequent '"clearance" into deeper layers and beyond. Overall, the Raman tools described offer both qualitative and potentially semi-quantitative insights into topical and transdermal drug product performance and provide information useful for formulation improvement and optimization.

Accurate preoperative staging of colorectal cancers is critical in selecting patients for neoadjuvant therapy prior to resection. Inaccurate staging, particularly understaging, may lead to involved resection margins and poor oncological outcomes. Our aim is to determine preoperative imaging accuracy of colorectal cancers compared to histopathology and define the effect of inaccurate staging on patient selection for neoadjuvant treatment(NT). Staging and treatment were determined for patients undergoing colorectal resections for adenocarcinomas in a single tertiary centre(2016–2020). Data were obtained for 948 patients. The staging was correct for both T and N stage in 19.68% of colon cancer patients. T stage was under-staged in 18.58%. At resection, 23 patients (3.36%) had involved pathological margins; only 7 of which had been predicted by pre-operative staging. However, the staging was correct for both T and N stage in 53.85% of rectal cancer patients. T stage was understaged in 26.89%. Thirteen patients had involved(R1)margins; T4 had been accurately predicted in all of these cases. There was a general trend in understaging both the tumor and lymphonodal involvement (T p p

Regulatory science underpins the objective evaluation of medicinal products. It is therefore imperative that regulatory science and expertise remain at the cutting edge so that innovations of ever-increasing complexity are translated safely and swiftly into effective, high-quality therapies. We undertook a comprehensive examination of the evolution of science and technology impacting on medicinal product evaluation over the next 5–10 years and this horizon-scanning activity was complemented by extensive stakeholder interviews, resulting in a number of significant recommendations. Highlighted in particular was the need for expertise and regulatory science research to fill knowledge gaps in both more fundamental, longer-term research, with respect to technological and product-specific challenges. A model is proposed to realise these objectives in Europe, comprising a synergistic relationship between the European Medicines Agency, the European Medicines Regulatory Network and academic research centres to establish a novel regulatory science and innovation platform.

For topical drug products that target sites of action in the viable epidermal and/or upper dermal compartment of the skin, the local concentration profiles have proven difficult to quantify because drug clearance from the viable cutaneous tissue is not well characterised. Without such knowledge, of course, it is difficult—if not impossible—to predict a priori whether and over what time frame a topical formulation will permit an effective concentration of drug within the skin ‘compartment’ to be achieved. Here, we test the hypothesis that valuable information about drug disposition, and specifically its clearance, in this experimentally difficult-to-access compartment (at least, in vivo) can be derived from available systemic pharmacokinetic data for drugs administered via transdermal delivery systems. A multiple regression analysis was undertaken to determine the best-fit empirical correlation relating clearance from the skin to known or easily calculable drug properties. It was possible, in this way, to demonstrate a clear relationship between drug clearance from the skin and key physical chemical properties of the drug (molecular weight, log P and topological polar surface area). It was further demonstrated that values predicted by the model correlated well with those derived from in vitro skin experiments.

An important question in the development of a dermatological drug product is whether a target concentration has been achieved in, for example, the viable epidermis following topical administration. When attempting to address this challenge, it is essential to consider the role of excipients in the formulation that may influence drug partitioning and diffusion in the different layers of the skin. The objective, therefore, was to correlate, in human subjects, the skin pharmacokinetics of diclofenac (specifically, its uptake into and clearance from the stratum corneum (SC)) from an approved drug product (Voltaren® medicated plaster) with the in vivo co-uptake of two key excipients, namely propylene glycol and butylene glycol. SC sampling was used to assess diclofenac input into the skin during patch application, and its subsequent clearance post-removal of the delivery system. In parallel the uptake of the two glycol excipients was also measured. Drug and excipient amounts in the SC increased with time of application up to 6 h and, for diclofenac, no further increase was observed when the administration was prolonged to 12 h. When the plaster was removed after 6 h of wear, diclofenac cleared relatively slowly from the SC suggesting that drug binding with a slow off-rate had occurred. The results indicate that the optimisation of drug delivery from a topical formulation must take into account the disposition of key excipients and their impact on dermato-pharmacokinetics in general.

Aim An audit of rib fracture (RF) patients admitted to an EGS unit to determine demographics, injury mechanisms & outcomes. Methods Retrospective analysis was undertaken of all RF patients admitted between 1st Jan & 31st Dec 2019. Patient demographics, injury mechanism, comorbidities, length of stay (LOS) & outcomes were recorded. Analysis of age-related differences was undertaken using Mann Whitney U & Chi Squared tests. Results There were 115 patients (67 males) with median age 74 (38 patients 65 yrs). Seventy-three patients (63.5%) sustained injury after a fall. Eighty (69%) patients had cardiorespiratory, cerebrovascular or metabolic conditions, of whom 62 (54%) were >65 yrs, & 31 (27%) were on antiplatelets or anticoagulants. Thirty-eight (33%) had a pneumothorax or haemothorax, 19 (5.4%) flail chest & 39 (34%) additional bony injuries. Some 107 (93%) were managed on a rib fracture pathway. Thirty-seven (32%) patients developed pulmonary complications (infection 27, effusion 5, contusion 5) & 8 (7%) died. Subgroup analysis revealed a significant difference in LOS (median 3 vs 6.5 days, p = 0.00144) for age 65 years & gender (females 9.5 vs males 3.5 days, p = 0.00114), as well as for age 65 & injury mechanism (no fall vs fall, p = 0.042). Conclusion RFs are commonly sustained in frail elderly patients following a fall & are associated with significant pulmonary consequences in around a third, with potentially long hospital stay. Close collaboration with Pain Teams and specialists in Medicine for the Elderly is essential.

Optical poration, or drilling, of the human nail has the potential to drastically improve transungual drug delivery. However, this approach is accompanied by thermal damage to the nail tissue surrounding the laser radiation-created pore. In this paper, fluorescence microscopy has been employed to quantitatively evaluate thermal damage to the nail induced by laser ablation with 80 MHz, nanojoule, femtosecond pulses delivered via a hollow-core fibre. An empirical relation has been established between the intensity of the resulting fluorescence signal and temperature to which the nail was exposed. Using this relationship, detailed temperature maps have been created of the areas surrounding the pores, enabling the mechanism of poration to be better understood. It was deduced that plasma-mediated ablation is primarily responsible for nail tissue ablation at the centre of the pore, while cumulative photothermal processes dominate at the pore edges. It is concluded, furthermore, that temperature mapping represents a useful new tool with which to optimise the process of nail poration. The method is potentially generic and may be applicable to other biological materials.

Prediction of skin absorption and local bioavailability from topical formulations remains a difficult task. An important challenge in forecasting topical bioavailability is the limited information available about local and systemic drug concentrations post-application of topical drug products. Commercially available transdermal patches, such as Scopoderm® (Novartis Consumer Health UK), offer an opportunity to test these experimental approaches as systemic pharmacokinetic data is available with which to validate a predictive model. The long-term research aim, therefore, is to develop a physiologically-based pharmacokinetic model (PBPK) to predict the dermal absorption and disposition of actives included in complex dermatological products. This work explored whether in vitro release and skin permeation tests (IVRT and IVPT, respectively), and in vitro and in vivo stratum corneum (SC) and viable tissue (VT) sampling data, can provide a satisfactory description of drug “input rate” into the skin and subsequently into the systemic circulation. In vitro release and skin permeation results for scopolamine were consistent with the previously reported performance of the commercial patch investigated. New skin sampling data on the dermatopharmacokinetics (DPK) of scopolamine also reflected accurately the rapid delivery of a “priming” dose from the patch adhesive, superimposed on a slower, rate-controlled input from the drug reservoir. The scopolamine concentration versus time profiles in SC and VT skin compartments, in vitro and in vivo, taken together with IVRT release and IVPT penetration kinetics, reflect the input rate and drug delivery specifications of the Scopoderm® transdermal patch and reveal the importance of skin binding with respect to local drug disposition. Further data analysis and skin PK modelling are indicated to further refine and develop the approach outlined.

This chapter describes biological and physicochemical parameters which determine the rate and extent of chemical penetration across human skin. It discusses how these parameters interact with the physicochemical properties of the dermally contacting chemical to determine the kinetics and degree of penetration. When the skin is treated with volatile solvents, the barrier to chemical transport is reduced, presumably because of lipid extraction. If the chemical is in a solid state then the particle size and polymorphism of the material may contribute to the kinetics of this first step in absorption. Chemicals which are extremely lipophilic will be severely rate limited by this process due to their low solubility in the viable tissue and the resultant slow interfacial transfer kinetics at the lipid-aqueous boundary. It is possible that certain chemicals may induce significant changes in cutaneous blood flow. For a topically applied chemical to reach the systemic circulation requires that it transports through both lipophilic and aqueous regions.

Background Iatrogenic ureteric injury is a serious complication of colorectal surgery. Incidence is estimated to be between 0.3 and 1.5%. Of all ureteric injuries, 9% occur during colorectal procedures. Ureteric stents are utilised as a method to reduce the risk of injury; however, these are not without risk and do not guarantee prevention of injury. Fluorescence is a safe and effective alternative for intraoperative ureteric localisation. This proof of principle study aims to assess the use of methylene blue to fluoresce the ureter during colorectal surgery. Method Patients undergoing elective colorectal surgery were included in this open label, non-randomised study. Methylene blue was administered intravenously at varying doses (0.25–1 mg/kg) over 5 min, 10–15 min prior to entering ‘ureteric territory.’ Fluorescence was assessed using the PINPOINT Deep Red laparoscopic system at fixed time points by the surgeon and an independent observer. Results 42 patients received methylene blue; 2 patients were excluded from analysis. Of the 69 ureters assessed, 64 were seen under fluorescence. Of these, 14 were not visible under white light. 50 ureters were observed with both fluorescence and white light with 14 of these being seen earlier with fluorescence. In ten cases, fluorescence revealed the ureter to be in a different location than suspected. Conclusion Fluorescence is a promising method to allow visualisation of the ureter, where it is not identified easily under standard operative conditions, thereby improving safety and reducing operative time and difficulty. Electronic supplementary material The online version of this article (10.1007/s00464-018-6219-8) contains supplementary material, which is available to authorized users.

Summary Background Acute lower gastrointestinal bleeding is a common reason for emergency hospital admission, and identification of patients at low risk of harm, who are therefore suitable for outpatient investigation, is a clinical and research priority. We aimed to develop and externally validate a simple risk score to identify patients with lower gastrointestinal bleeding who could safely avoid hospital admission. Methods We undertook model development with data from the National Comparative Audit of Lower Gastrointestinal Bleeding from 143 hospitals in the UK in 2015. Multivariable logistic regression modelling was used to identify predictors of safe discharge, defined as the absence of rebleeding, blood transfusion, therapeutic intervention, 28 day readmission, or death. The model was converted into a simplified risk scoring system and was externally validated in 288 patients admitted with lower gastrointestinal bleeding (184 safely discharged) from two UK hospitals (Charing Cross Hospital, London, and Hammersmith Hospital, London) that had not contributed data to the development cohort. We calculated C statistics for the new model and did a comparative assessment with six previously developed risk scores. Findings Of 2336 prospectively identified admissions in the development cohort, 1599 (68%) were safely discharged. Age, sex, previous admission for lower gastrointestinal bleeding, rectal examination findings, heart rate, systolic blood pressure, and haemoglobin concentration strongly discriminated safe discharge in the development cohort (C statistic 0·84, 95% CI 0·82–0·86) and in the validation cohort (0·79, 0·73–0·84). Calibration plots showed the new risk score to have good calibration in the validation cohort. The score was better than the Rockall, Blatchford, Strate, BLEED, AIMS65, and NOBLADS scores in predicting safe discharge. A score of 8 or less predicts a 95% probability of safe discharge. Interpretation We developed and validated a novel clinical prediction model with good discriminative performance to identify patients with lower gastrointestinal bleeding who are suitable for safe outpatient management, which has important economic and resource implications. Funding Bowel Disease Research Foundation and National Health Service Blood and Transplant.

Assessment of the bioavailability of topically applied drugs designed to act within or beneath the skin is a challenging objective. A number of different, but potentially complementary, techniques are under evaluation. The objective of this work was to evaluate in vitro skin penetration and stratum corneum tape-stripping in vivo as tools with which to measure topical diclofenac bioavailability from three approved and commercialized products (two gels and one solution). Drug uptake into, and its subsequent clearance from, the stratum corneum of human volunteers was used to estimate the input rate of diclofenac into the viable skin layers. This flux was compared to that measured across excised porcine skin in conventional diffusion cells. Both techniques clearly demonstrated (a) the superiority in terms of drug delivery from the solution, and (b) that the two gels performed similarly. There was qualitative and, importantly, quantitative agreement between the in vitro and in vivo measurements of drug flux into and beyond the viable skin. Evidence is therefore presented to support an in vivo − in vitro correlation between methods to assess topical drug bioavailability. The potential value of the stratum corneum tape-stripping technique to quantify drug delivery into (epi)dermal and subcutaneous tissue beneath the barrier is demonstrated.

Purpose To examine the potential of stratum corneum (SC) sampling via tape-stripping in humans to assess bioequivalence of topical acyclovir drug products, and to explore the potential value of alternative metrics of local skin bioavailability calculable from SC sampling experiments. Methods Three acyclovir creams were considered in two separate studies in which drug amounts in the SC after uptake and clearance periods were measured and used to assess bioequivalence. In each study, a “reference” formulation (evaluated twice) was compared to the “test” in 10 subjects. Each application site was replicated to achieve greater statistical power with fewer volunteers. Results SC sampling revealed similarities and differences between products consistent with results from other surrogate bioequivalence measures, including dermal open-flow microperfusion experiments. Further analysis of the tape-stripping data permitted acyclovir flux into the viable skin to be deduced and drug concentration in that ‘compartment’ to be estimated. Conclusions Acyclovir quantities determined in the SC, following a single-time point uptake and clearance protocol, can be judiciously used both to objectively compare product performance in vivo and to assess delivery of the active into skin tissue below the barrier, thereby permitting local concentrations at or near to the site of action to be determined.

The opioids buprenorphine hydrochloride (BUP) and naltrexone hydrochloride (NTX) show promise as a combination treatment for addiction, but no means of delivering the two compounds in one medicine currently exist. In this paper, we report sufficient input rates of both these drugs from one iontophoretic transdermal drug delivery system. Experiments were performed using dermatomed pig skin mounted in glass side-bi-side cells. BUP and NTX were iontophoretically delivered together from the anode using direct constant current from Ag/AgCl electrodes. The transdermal drug fluxes and the masses of drugs in both the stratum corneum and the underlying epidermis/dermis were measured. The apparent electroosmotic flow was quantified using a neutral marker (acetaminophen). The effects of donor composition (drug concentration/molar fraction and pH), current density and profile, and the choice of receptor solution were assessed. Iontophoresis dramatically increased the flux of both drugs compared to passive control values. Target fluxes (calculated from literature clearance values and required therapeutic plasma concentrations) were greatly exceeded for NTX and were met for BUP. The latter accumulated in the skin and suppressed electroosmotic flow, inhibiting both its own flux and that of NTX. NTX, in turn, negatively influenced the flux of BUP via co-ion competition. Lowering current density by increasing the delivery area resulted in increased electroosmotic flow but did not significantly affect current-normalized drug fluxes. Delivering the drugs from both electrodes and reversing the polarity for every 2 h did not increase the flux of either compound. In summary, during iontophoresis, BUP and NTX inhibited each other's flux by two distinct mechanisms. While the more complex behavior of BUP complicates the optimization of this drug combination, iontophoresis nevertheless appears to be a feasible approach for the controlled codelivery of NTX and BUP through the skin.

ObjectivesSociety is confronted with the rapid emergence of innovation in science and technology. To manage this, horizon scanning is being adopted globally to identify, assess and prioritise innovations and trends at an early stage of their development. This enables decision-makers to be better informed and to prepare for change. The aim of this paper is to systematically identify and evaluate horizon scanning methodologies employed in the healthcare and biomedical fields.MethodsA systematic literature review was performed using PubMed and Embase and was supplemented with grey literature searches (2008–2018). The principal methodologies used in horizon scanning were extracted.ResultsApproximately 100 articles were summarised in a literature map. The search revealed many examples of horizon scanning across disciplines. Challenges, such as the need to refine prioritisation criteria, manage uncertainty inherent in the findings and improve the dissemination of identified issues, have been highlighted.ConclusionHorizon scanning, when performed appropriately, is a flexible and potentially reliable tool, with a wide variety of methods. Horizon scanning can inform and influence decision-making, through identifying opportunities and challenges, from an organisational to an international level. Further research to identify the most effective methodologies available would add depth to this landscape and enable the evolution of best practice to most efficiently anticipate novel developments and innovations.

Objective To examine whether in vitro and ex vivo measurements of topical drug product performance correlate with in vivo outcomes, such that more efficient experimental approaches can be reliably and reproducibly used to establish (in)equivalence between formulations for skin application. Materials and Methods In vitro drug release through artificial membranes, and drug penetration into porcine skin ex vivo, were compared with published human in vivo studies. Two betamethasone valerate (BMV) formulations, and three marketed econazole nitrate (EN) creams were assessed. Results For BMV, the stratum corneum (SC) uptake of drug in 6 h closely matched data observed in vivo in humans, and distinguished between inequivalent formulations. SC uptake of EN from the 3 creams mirrored the in vivo equivalence in man (both clinically and via similar tape-stripping experiments). However, EN clearance from SC ex vivo did not parallel that in vivo, presumably due to the absence of a functioning microcirculation. In vitro release of BMV from the different formulations did not overlap with either ex vivo or in vivo tape-stripping data whereas, for EN, a good correlation was observed. No measurable permeation of either BMV or EN was detected in a 6-h in vitro skin penetration experiment. Conclusions In vitro and ex vivo methods for topical bioequivalence determination can show correlation with in vivo outcomes. However, these surrogates have understandable limitations. A “one-size-fits-all” approach for topical bioequivalence evaluation may not always be successful, therefore, and the judicious use of complementary methods may prove a more effective and reliable strategy.

Introduction The identification and characterisation of cellular metabolites has now become an important strategy to obtain insight into functional plant biology. However, the extraction of metabolites for identification and analysis is challenging and, at the present time, usually requires destruction of the plant. Objective To detect different plant metabolites in living plants with no pre-treatment using the combination of iontophoresis and ion-chromatography with mass spectrometry detection. Methodology In this work, the simple and non-destructive method of reverse iontophoresis has been used to extract in situ multiple plant metabolites from intact Ocimum basilicum leaves. Subsequently, the analysis of these metabolites has been performed with ion chromatography coupled directly to high resolution mass spectrometric detection (IC-MS). Results The application of reverse iontophoresis to living plant samples has avoided the need for complex pre-treatments. With this approach, no less than 24 compounds, including organic acids and sugars as well as adenosine triphosphate (ATP) were successfully detected. Conclusion The research demonstrates that it is feasible to monitor, therefore, a number of important plant metabolites using a simple, relatively fast and non-destructive approach. Copyright © 2016 John Wiley & Sons, Ltd.

The delivery of ibuprofen into and through the skin from novel formulations containing TEMPO-oxidized cellulose nanofibril-based (TOCN) gels was compared to that from two conventional and commercially available products. The gels were evaluated in-vitro (using both silicone membranes, and pig skin) and in-vivo in human volunteers. All gels showed consistent behaviour in a standard in vitro release test. The stratum corneum (SC) uptake and skin penetration of ibuprofen in vitro from the novel gels and the marketed formulations were generally comparable even though the drug loading in the TOCN-based vehicles was only 20% of that in the ‘reference’ products. In vivo, the new gels appeared to enhance drug uptake into the SC following a relatively short application time, again matching the performance of the commercial formulations. Taken together, the results of this research provide proof-of-concept for the idea that the sustainable, oxidised cellulose gels may provide more efficient drug delivery into and through the skin, thereby improving drug utilisation and reducing potential adverse effects when such formulations are applied chronically over large skin areas.

Current guidance for dermal exposure assessment of plant protection products typically uses in vitro skin penetration data for the active ingredient when applied as both the concentrated product and relevant spray dilutions thereof. However, typical re-entry scenarios involve potential skin exposure to a "dried residue" of the spray dilution, from which the absorption of a pesticide may be quite different. The research reported in this paper has shown: (1) The method to assess the transfer of dried pesticide residues from a surface to the skin is reproducible for four active ingredients of diverse physicochemical properties, after their application in commercially relevant formulations. (2) Skin absorption of all four pesticides examined was significantly less from a dried residue than from a spray dilution; the difference, in general, was of the order of a factor of 2. (3) Decontamination experiments with one of the active ingredients tested (trinexapac-ethyl) showed that, post-exposure to a spray dilution, skin surface cleaning must be performed within 1 h to significantly reduce potential systemic exposure (relative to continual contact for 24 h); in contrast, after contact with a dried residue, the sooner decontamination was performed, the greater the decrease in exposure achieved, even when the time of contact was as long as 8 h.

Acute severe colitis requires surgery in around 30% of the cases. Total colectomy with ileostomy is the standard procedure with distinct advantages to a laparoscopic approach. Less agreement exists regarding the formation or configuration of the retained rectal stump and its short-term and long-term management. In this review, aspects of management of the rectal remnant, including perioperative considerations, potential complications, medical treatment, surveillance and implications for proctectomy and reconstructive surgery are explored.A thorough literature review exploring the PubMed and EMBASE databases was undertaken to clarify the evidence base surrounding areas of controversy in the surgical approach to acute severe colitis. In particular, focus was given to evidence surrounding management of the rectal remnant.There is a paucity of high quality evidence for optimal management of the rectal stump following colectomy, and randomised trials are lacking. Establishment of laparoscopic colectomy has been associated with distinct advantages as well as the emergence of unique considerations, including those specific to rectal remnant management.Early surgical involvement and a multidisciplinary approach to the management of acute severe colitis are advocated. Laparoscopic subtotal colectomy and ileostomy should be the operation of choice, with division of the rectum at the pelvic brim leaving a closed intraperitoneal remnant. If the rectum is severely inflamed, a mucus fistula may be useful, and an indwelling rectal catheter is probably advantageous to reduce the complications associated with stump dehiscence. Patients electing not to proceed to proctectomy should undergo surveillance for dysplasia of the rectum.

The Kock pouch procedure is an operation to construct a continent ileostomy which the patient self- catheterises several times a day. The procedure is not widely performed owing to the technical difficulty and the high complication rate associated with the procedure but there is renewed interest in this technique for patients with a failed ileoanal pouch or where an ileoanal pouch is not an option. Patient motivation and expectation must be considered in the preoperative phase as the Kock pouch requires significant patient engagement. This chapter highlights the selection, techniques, post-operative care and complications associated with the Kock pouch.

PURPOSE: The study was conducted to investigate the impact of charge and molecular weight (MW) on the iontophoretic delivery of a series of dipeptides. METHODS: Constant current iontophoresis of lysine and 10 variously charged lysine- and tyrosine-containing dipeptides was performed in vitro. RESULTS: Increasing MW was compensated by additional charge; for example, Lys (MW = 147 Da, +1) and H-Lys-Lys-OH (MW = 275 Da, +2) had equivalent steady-state fluxes of 225 +/- 48 and 218 +/- 40 nmol cm(-2) h(-1), respectively. For peptides with similar MW, e.g., H-Tyr-D-Arg-OH (MW = 337 Da, +1) and H-Tyr-D-Arg-NH(2) (MW = 336 Da, +2), the higher valence ion displayed greater flux (150 +/- 26 vs. 237 +/- 35 nmol cm(-2) h(-1)). Hydrolysis of dipeptides with unblocked N-terminal residues, after passage through the stratum corneum, suggested the involvement of aminopeptidases. The iontophoretic flux of zwitterionic dipeptides was less than that of acetaminophen and dependent on pH. CONCLUSIONS: For the series of dipeptides studied, flux is linearly correlated to the charge/MW ratio. Data for zwitterionic peptides indicate that they do not behave as neutral ("charge-less") molecules, but that their iontophoretic transport is dependent on the relative extents of ionization of the constituent ionizable groups, which may also be affected by neighboring amino acids.

Introduction: Dosing regimens requiring multiple daily applications frequently result in poor patient compliance, especially in the treatment of chronic skin diseases. Consequently, development of sustained delivery systems for topical drugs permitting less frequent dosing is of continuing interest for dermatological therapy. Areas covered: This potential of polymeric film-forming systems (FFS), created in situ on the skin, as sustained delivery platforms for topical drug delivery is reviewed. Key formulation parameters that determine delivery efficiency are considered focussing on those that permit a drug reservoir to be established in the upper layers of the skin and/or on the skin surface from which release can be sustained over a prolonged period. The advantageous and superior cosmetic attributes of FFS (compared to conventional semi-solid formulations) that offer significantly improved patient compliance are also addressed. Expert opinion: The promise of polymeric FFS as convenient and aesthetic platforms for sustained topical drug delivery is clear. Manipulation of the formulation allows the delivery profile to be customized and optimized to take advantage of both a rapid, initial input of drug into the skin (likely due to a transient period of supersaturation) and a slower, controlled release over an extended time from the residual film created thereafter.

This study demonstrates the potential of polymeric nanoparticles as drug reservoirs for sustained topical drug delivery into microneedle-treated human nail. Laser scanning confocal microscopy was used to image the delivery of a fluorescent model compound from nanoparticles into the nail. A label-free imaging technique, stimulated Raman scattering microscopy, was applied, in conjunction with two-photon fluorescence imaging, to probe the disposition of nanoparticles and an associated lipophilic 'active' in a microneedle-porated nail. The results provide clear evidence that the nanoparticles function as immobile reservoirs, sequestered on the nail surface and in the microneedle-generated pores, from which the active payload can be released and diffuse laterally into the nail over an extended period of time.

Laser poration of the skin locally removes its outermost, barrier layer, and thereby provides a route for the diffusion of topically applied drugs. Ideally, no thermal damage would surround the pores created in the skin, as tissue coagulation would be expected to limit drug diffusion. Here, a femtosecond pulsed fiber laser is used to porate mammalian skin ex vivo. This first application of a hollow core negative curvature fiber (HC-NCF) to convey a femtosecond pulsed, visible laser beam results in reproducible skin poration. The effect of applying ink to the skin surface, prior to ultra-short pulsed ablation, has been examined and Raman spectroscopy reveals that the least, collateral thermal damage occurs in inked skin. Pre-application of ink reduces the laser power threshold for poration, an effect attributed to the initiation of plasma formation by thermionic electron emission from the dye in the ink. Poration under these conditions significantly increases the percutaneous permeation of caffeine in vitro. Dye-enhanced, plasma-mediated ablation of the skin is therefore a potentially advantageous approach to enhance topical/transdermal drug absorption. The combination of a fiber laser and a HC-NCF, capable of emitting and delivering femtosecond pulsed, visible light, may permit a compact poration device to be developed.

The feasibility of targeting drugs to hair follicles by a combination of microencapsulation and iontophoresis has been evaluated. Minoxidil sulphate (MXS), which is used in the treatment of alopecia, was selected as a relevant drug with respect to follicular penetration. The skin permeation and disposition of MXS encapsulated in chitosan microparticles (MXS-MP) was evaluated in vitro after passive and iontophoretic delivery. Uptake of MXS was quantified at different exposure times in the stratum corneum (SC) and hair follicles. Microencapsulation resulted in increased (6-fold) drug accumulation in the hair follicles relative to delivery from a simple MXS solution. Application of iontophoresis enhanced follicular delivery for both the solution and the microparticle formulations. It appears, therefore, that microencapsulation and iontophoresis can act synergistically to enhance topical drug targeting to hair follicles.

The effect of incorporating the lipidic medium-chain triglyceride (MCT) into polymeric film-forming systems (FFS) for topical drug delivery has been evaluated. First, the in vitro release of betamethasone-17-valerate (BMV), a representative dermatological drug, was determined from FFS comprising either hydrophobic polyacrylate co-polymers, or hydrophilic hydroxypropyl cellulose, with and without MCT. Release was enhanced from both polymers in the presence of MCT. Atomic force microscopy imaging and nanoindentation of FFS with MCT revealed two-phase structured films with softer inclusions (0.5 to 4 μm in diameter) surrounded by a more rigid structure. Chemical mapping with Raman micro-spectroscopy showed that MCT was primarily confined to the inclusions within the polymer, which predominated in the surrounding film. BMV was distributed throughout the film but was more concentrated outside the inclusions. Furthermore, while BMV dissolved better into the hydrophobic films, it was more soluble in the MCT inclusions in hydrophilic films, suggesting its increased availability for diffusion from these softer regions of the polymer and explaining the release enhancement observed. Second, ex vivo skin penetration studies clearly revealed that uptake of BMV was higher from hydrophobic FFS than that from the more hydrophilic polymer due, at least in part, to the superior anti-nucleation efficiency of the former. Drug was quickly taken up into the SC from which it then diffused continuously over a sustained period into the lower, viable skin layers. In the presence of MCT, the overall uptake of BMV was increased and provides the basis for further optimisation of FFS as simple, convenient and sustained formulations for topical therapy.

BACKGROUND: Eczema affects ~20% of children but multiple different outcome measures have hampered research into the effectiveness of different treatments.OBJECTIVES: To compare the change in scores and correlations within and between five measures of eczema severity: Patient Orientated Eczema Measure (POEM), Eczema Area Severity Index (EASI), Six Area Six Sign Atopic Dermatitis (SASSAD), Three Item Severity (TIS), and skin hydration (corneometry).METHODS: Data from a feasibility trial that randomised young children with eczema to one of four emollients were used. Participants were followed for three months (84 days). Descriptive statistics (by emollient over time) and Spearman's correlation coefficients comparing scores at each time-point and absolute change (between adjacent time-points) for each outcome measure were calculated.RESULTS: 197 children, mean age (SD) of 21.7 (12.8) months, were randomised. POEM and TIS appeared to capture a range of eczema severity at baseline but only POEM had close approximation to normal distribution. Mean POEM, EASI, SASSAD and TIS scores improved month-by-month, with POEM showing the greatest sensitivity (effect size 0.42). Correlations within POEM, EASI, SASSAD and TIS were moderate-to-good, decreasing over time. Correlations between measures were strongest for EASI, SASSAD and TIS. By contrast, corneometry scores were more variable, correlated less well over time, and were poorly correlated with the other measures.CONCLUSIONS: Except for corneometry, all measures appear to change in relation to emollient use over time and correlate well with themselves. POEM demonstrated the greatest range of scores at baseline and change in eczema severity over the first 28 days. This article is protected by copyright. All rights reserved.

The topical bioavailabilities of metronidazole from a commercially available ‘reference’ product (Rozex®) and two extemporaneous test formulations were compared. With the reference drug product, a full skin pharmacokinetic profile, in vivo in human volunteers (following a 6-h uptake and clearance over the subsequent 22 h), was obtained using an improved stratum corneum (SC) sampling procedure. Then, a two-time point SC sampling method enabled the bio(in)equivalence of the test formulations to Rozex® to be evaluated. One test formulation was shown to be bioequivalent to Rozex®, both for uptake and clearance, whereas the other (more viscous and less spreadable) formulation was not. The delivery of metronidazole into the underlying viable epidermal tissue from Rozex® and from the equivalent test formulation was 2.5 to 3.5-fold higher than that from the inequivalent extemporaneous vehicle. The results highlight that the quantitative composition of a formulation, as well as its physical properties that influence events that take place at the vehicle-skin interface, can have a dramatic impact on the delivery of drug into the SC and subsequently to the viable skin layers below. The reproducible, sensitive and facile in vivo methodology employed may prove of particular value where regulatory approval of generic formulations lacks objective rigour.

Patient: Male, 49 Final Diagnosis: Anal squamo cell carcinoma Symptoms: Inguinal mass • inflammation • perineal tumor Medication: — Clinical Procedure: Abdominoperineal resection (APR) • groin dissection and closure of the inguinal defect with oblique rectus abdominis myocutaneous (ORAM) flap Specialty: Surgery Objective: Unusual setting of medical care Background: Anal squamous cell carcinoma accounts for about 2–4% of all lower gastrointestinal malignancies, with a distant disease reported in less than 5%. Although surgical treatment is rarely necessary, this often involve large dissections and difficult reconstructive procedures. Case Report: We present a complex but successful case of double-flap reconstruction after abdominoperineal resection and groin dissection for anal squamous cell carcinoma (cT3N3M0) with metastatic right inguinal lymph nodes and ipsilateral threatening of femoral vessels. A multi-specialty team was involved in the operation. A vascular and plastic surgeon performed the inguinal dissection with en bloc excision of the saphenous magna and a cuff of the femoral vein, while colorectal surgeons carried out the abdominoperineal excision. The 2 large tissue gaps at the groin and perineum were covered with an oblique rectus abdominis myocutaneous flap and a gluteal lotus flap, respectively. A partially absorbable mesh was placed at the level of the anterior sheath in order to reinforce the abdominal wall, whereas an absorbable mesh was used as a bridge for the dissected pelvic floor muscles. The post-operative period was uneventful and the follow-up at 5 months showed good results. Conclusions: An early diagnosis along with new techniques of radiochemotherapy allow patients to preserve their sphincter function. However, a persistent or recurrent disease needs major operations, which often involve a complex reconstruction. Good team-work and experience in specialized fields give the opportunity to make the best choices to perform critical steps during the management of complex cases.

Background Decreasing anastomotic leak rates remain a major goal in colorectal surgery. Assessing intraoperative perfusion by indocyanine green (ICG) with near‐infrared (NIR) visualization may assist in selection of intestinal transection level and subsequent anastomotic vascular sufficiency. This study examined the use of NIR‐ICG imaging in colorectal surgery. Methods This was a prospective phase II study (NCT02459405) of non‐selected patients undergoing any elective colorectal operation with anastomosis over a 3‐year interval in three tertiary hospitals. A standard protocol was followed to assess NIR‐ICG perfusion before and after anastomosis construction in comparison with standard operator visual assessment alone. Results Five hundred and four patients (median age 64 years, 279 men) having surgery for neoplastic (330) and benign (174) pathology were studied. Some 425 operations (85·3 per cent) were started laparoscopically, with a conversion rate of 5·9 per cent. In all, 220 patients (43·7 per cent) underwent high anterior resection or reversal of Hartmann's operation, and 90 (17·9 per cent) low anterior resection. ICG angiography was achieved in every patient, with a median interval of 29 s to visualization of the signal after injection. NIR‐ICG assessment resulted in a change in the site of bowel division in 29 patients (5·8 per cent) with no subsequent leaks in these patients. Leak rates were 2·4 per cent overall (12 of 504), 2·6 per cent for colorectal anastomoses and 3 per cent for low anterior resection. When NIR‐ICG imaging was used, the anastomotic leak rates were lower than those in the participating centres from over 1000 similar operations performed with identical technique but without NIR‐ICG technology. Conclusion Routine NIR‐ICG assessment in patients undergoing elective colorectal surgery is feasible. NIR‐ICG use may change intraoperative decisions, which may lead to a reduction in anastomotic leak rates., Appears to reduce leaks

Purpose: To develop topical formulations of Clerodendrum petasites S. Moore (CP), and to optimize the skin permeability and topical bioavailability of the active phenolic compounds therein. Methods: The skin uptake and delivery of active compounds from two formulations, an oil-in-water cream and a lotion (both containing 10% w/w CP extracts), were examined (a) invitro using pig skin, and (b) invivo in human volunteers. Stratum corneum (SC) was collected by tape stripping and the compounds were detected and quantified by high performance liquid chromatography coupled with either mass spectrometry (HPLC-MS) or ultraviolet and photodiode array (HPLC-UV-PDA) detection. Results: From the invitro results, vanillic acid, verbascoside, nepetin and hispidulin, were chosen as potential phenolic actives for topical delivery optimization from the formulations. Invivo, vanillic acid, nepetin and hispidulin were appreciably taken up into the SC within 6 h, while verbascoside did not penetrate beyond the most superficial layers. No significant differences in delivery were observed between the two formulations, both of which were well tolerated. Conclusions: The detected topical absorption of hispidulin, nepetin, and vanillic acid, from the cream and lotion vehicles investigated, suggest that these compounds are potentially active compounds in Thai traditional medicine for the treatment of a wide range of skin diseases.

Background and study aims Investigations for lower gastrointestinal bleeding (LGIB) include flexible sigmoidoscopy, colonoscopy, computed tomographic angiography (CTA), and angiography. All may be used to direct endoscopic, radiological or surgical treatment, although their optimal use is unknown. The aims of this study were to determine the diagnostic and therapeutic yields of endoscopy, CTA, and angiography for managing LGIB, and their influence on rebleeding, transfusion, and hospital stay. Patients and methods A systematic search of MEDLINE, PubMed, EMBASE, and CENTRAL was undertaken to identify randomized controlled trials (RCTs) and nonrandomized studies of intervention (NRSIs) published between 2000 and 12 November 2015 in patients hospitalized with LGIB. Separate meta-analyses were conducted, presented as pooled odds (ORs) or risk ratios (RR) with 95 % confidence intervals (CIs). Results Two RCTs and 13 NRSIs were included, none of which examined flexible sigmoidoscopy, or compared endotherapy with embolization, or investigated the timing of CTA or angiography. Two NRSIs (57 – 223 participants) comparing colonoscopy and CTA were of insufficient quality for synthesis but showed no difference in diagnostic yields between the two interventions. One RCT and 4 NRSIs (779 participants) compared early colonoscopy ( Conclusions In LGIB there is a paucity of high-quality evidence, although the limited studies on the timing of colonoscopy suggest increased rates of diagnosis and therapy with early colonoscopy.

Drug treatment of diseases of the human nail remains a difficult challenge; topical therapy, in particular, is limited by very poor transport of active agents across the nail itself. The objective of this research was to examine the potential of controlled, and fibre-optic delivered, femtosecond laser light pulses to provide new pathways and opportunities for drug access to targets within and beneath the nail plate. Optical, confocal fluorescence and scanning electron microscopies demonstrated partial and complete laser poration of human nail samples, with the energy per pore and the exposure duration being the key modulating parameters that determined the extent of ablation achieved. Parallel measurements of the penetration of a model drug across laser-treated nails showed that complete poration resulted in essentially complete circumvention of the diffusion barrier, an array of 100 pores in 0.2 cm2 area of nail permitting a 103-fold increase in initial drug uptake. Partial ablation of the nail created pores that extended to a range of depths; the nail material adjacent to the ablated area was rendered porous in appearance presumably due to local thermal perturbation of the nail structure. These openings offer, as a result, potential sites in which topical drug formulations might be sequestered post-poration and from which slow, sustained delivery of the active agent into and through the nail may be envisaged.

Currently, there is no available needle-free approach for diabetics to monitor glucose levels in the interstitial fluid. Here, we report a path-selective, non-invasive, transdermal glucose monitoring system based on a miniaturized pixel array platform (realized either by graphene-based thin-film technology, or screen-printing). The system samples glucose from the interstitial fluid via electroosmotic extraction through individual, privileged, follicular pathways in the skin, accessible via the pixels of the array. A proof of principle using mammalian skin ex vivo is demonstrated for specific and ‘quantized’ glucose extraction/detection via follicular pathways, and across the hypo- to hyper-glycaemic range in humans. Furthermore, the quantification of follicular and non-follicular glucose extraction fluxes is clearly shown. In vivo continuous monitoring of interstitial fluid-borne glucose with the pixel array was able to track blood sugar in healthy human subjects. This approach paves the way to clinically relevant glucose detection in diabetics without the need for invasive, finger-stick blood sampling.

PurposeTo explore the potential of non-invasive reverse iontophoresis transdermal extraction of iohexol as a marker of glomerular filtration rate.MethodsA series of in vitro experiments were undertaken to establish the feasibility of iohexol reverse iontophoresis and to determine the optimal conditions for the approach. Subsequently, a pilot study in paediatric patients was performed to provide proof-of-concept.ResultsThe iontophoretic extraction fluxes of iohexol in vitro were proportional to the marker subdermal concentration and the reverse iontophoretic technique was able to track changes dynamically in simulated pharmacokinetic profiles. Reverse iontophoresis sampling was well tolerated by the four paediatric participants. The deduced values of the iohexol terminal elimination rate constant from transdermal reverse iontophoresis sampling agreed with those estimated by conventional blood sampling.ConclusionsReverse iontophoretic transdermal extraction fluxes mirrored the subdermal concentration profiles of iohexol, a relatively large neutral marker of glomerular filtration both in vitro and in vivo. The efficiency of extraction in vivo was well predicted by the in vitro model used.

Purpose To characterise skin barrier function in vivo at two distinct anatomic sites using minimally invasive bioengineering and biophysical tools. Methods In healthy human volunteers, the quantities of stratum corneum (SC) per unit area of skin on the forearm and forehead were quantified by gravimetric and imaging techniques. Organisation of the SC intercellular lipids was evaluated as a function of position using attenuated total reflectance infrared spectroscopy (ATR-IR). The constituents of natural moisturising factor (NMF) were extracted from tape-stripped samples of the SC and by reverse iontophoresis; 21 components were identified and quantified by liquid chromatography with mass spectrometric detection. Results SC was quantified more accurately by imaging and was significantly thinner on the forehead than on the forearm. Intercellular lipids were more disordered near the skin surface at both sites; however, throughout forearm SC, the lipids were substantially better organised than those in the forehead. Compositionally, the NMF from forearm and forehead SC was similar, but the total amount extractable from the forehead was smaller. Conclusion Taken together, the bioengineering and biophysical techniques employed demonstrate, in a complementary, objective and quantitative fashion, that SC barrier function on the forehead is less competent than that on the forearm.

Background Anastomotic leakage is a devastating complication of colorectal surgery. However, there is no technology indicative of in situ perfusion of a laparoscopic colorectal anastomosis. Methods We detail the use of near-infrared (NIR) laparoscopy (PinPoint System, NOVADAQ, Canada) in association with fluorophore [indocyanine green (ICG), 2.5 mg/ml] injection in 30 consecutive patients who underwent elective minimally invasive colorectal resection using the simultaneous appearance of the cecum or distal ileum as positive control. Results The median (range) age of the patients was 64 (40–81) years with a median (range) BMI of 26.7 (20–35.5) kg/m2. Twenty-four patients had left-sided resections (including six low anterior resections) and six had right-sided resections. Of the total, 25 operations were cancer resections and five were for benign disease [either diverticular strictures (n = 3) or Crohn’s disease (n = 2)]. A high-quality intraoperative ICG angiogram was achieved in 29/30 patients. After ICG injection, median (range) time to perfusion fluorescence was 35 (15–45) s. Median (range) added time for the technique was 5 (3–9) min. Anastomotic perfusion was documented as satisfactory in every successful case and encouraged avoidance of defunctioning stomas in three patients with low anastomoses. There were no postoperative anastomotic leaks. Conclusion Perfusion angiography of colorectal anastomosis at the time of their laparoscopic construction is feasible and readily achievable with minimal added intraoperative time. Further work is required to determine optimum sensitivity and threshold levels for assessment of perfusion sufficiency, in particular with regard to anastomotic viability. Electronic supplementary material The online version of this article (doi:10.1007/s00464-014-3432-y) contains supplementary material, which is available to authorized users.

Ethnopharmacological relevance Clerodendrum petasites S. Moore (CP) has been widely prescribed in Thailand and neighbouring countries for both oral and topical administration to treat asthma, fever, cough, vomiting and skin diseases, for at least 30 years. However, the nature of the active species remains poorly characterized and there have been no clinical trials concerning the topical delivery of this medicine. The study aims to characterise polyphenolic compounds in the plant, to predict the feasibility of their topical absorption and to test their ability to penetrate the skin. Materials and methods Identification and quantification of flavonoids and phenolic acid derivatives in an ethanolic extract of the aerial parts of the plant were carried out using high performance liquid chromatography (HPLC) with photodiode array (PDA) and mass spectrometry (MS) detection. Ambiguous isomeric compounds were distinguished by nuclear magnetic resonance (NMR) spectroscopy. The feasibility of the compounds' topical permeability was evaluated by predicting their maximum fluxes from their physicochemical properties. The skin penetration of compounds in the plant extract was measured in vitro over 24 h. Results Vanillic acid, verbascoside, 4-coumaric acid, ferulic acid, nepetin, luteolin, apigenin, naringenin, hispidulin, hesperetin and chrysin, were identified in CP. All compounds except apigenin and hispidulin are reported in this species for the first time. Hispidulin is the predominant compound (1.2% w/w in a dried ethanolic extract) followed by nepetin, verbascoside, vanillic acid, and apigenin. Across mammalian skin, hispidulin was percutaneously absorbed within 3 h and vanillic acid and nepetin permeated the skin after 6 h. These experimental observations were consistent with the predicted maximum fluxes of these compounds calculated from their physicochemical properties. Conclusions Many of the phenolic compounds reported in this study are well-known to possess antimicrobial, anti-inflammatory and anti-oxidant activities. The skin permeation studies reported here support traditional topical uses of the plant in skin treatments and are useful for further topical formulation optimisation.