Dermal Blood Flow Research Articles

Determination of Capsaicin Induced Increase in Dermal Blood Flow Using Laser Doppler Flowmetry Technique

In the present study, we evaluated laser Doppler flowmetry technique using LDF100C (Biopac systems) by determining blood flow changes following acute application of capsaicin on 12 healthy human subjects. Capsaicin applied locally (topical application) at a dose of 0.075% produced significant increase in mean dermal blood flow from 31.4 ± 3.1 Blood Perfusion Units (BPU) to 115. 7 ± 24.6 Blood Perfusion Units (BPU) after 30 minutes, also there was significant difference in dermal blood flow change between placebo (32.1 ± 2.7 BPU) and capsaicin (115.7 ± 24.6 BPU) applica- tion. Capsaicin application produced significant percentage change in dermal blood flow by 291.0 ± 85.3% from baseline, while the change was insignificant with placebo (13.2 ± 7.4%). Therefore, it is suggested that this technique which is technically sound, non-invasive and inexpensive can be adopted in various fields of research to determine blood flow changes and this technique can also be utilized to determine the antagonists of the mediators involved in capsaicin induced vasodilatation.

Clinical, power Doppler sonography and histological assessment of the psoriatic plaque: short-term monitoring in patients treated with etanercept

To date, the diagnosis of psoriasis is based on both clinical history and physical examination, and its severity is assessed by the Psoriasis Area and Severity Index (PASI). Continuous technological advances in the field of sonography have led to the development of equipment with high power Doppler frequency, which allows for very detailed morphological information regarding the dermal blood flow. To compare power Doppler sonography (PDS) with clinical and histological findings before and after etanercept treatment in patients with psoriasis. Twelve patients with a clinical diagnosis of psoriasis were enrolled in this study. The PASI, PDS and histological examinations were assessed in all patients on the same day at baseline, and after 12 weeks of biological treatment. PDS examination was performed by an experienced sonographer, using a sonographic system equipped with transducer ranging from 6 to 18 MHz and Doppler frequency ranging from 7 to 14 MHz. At follow up there was a significant decrease in PASI. A significant change was also detected for the PDS findings (P = 0·005). At baseline the median value for factor VIII staining was 1·5, and the median value for vascular endothelial growth factor (VEGF) staining was also 1·5. At follow up there was a significant decrease in both factor VIII and VEGF staining scores. Moreover, a positive correlation between reduction in PDS score and improvement in clinical and histological scores was found: Spearman's ρ = 0·639, P = 0·0022; Spearman's ρ = 0·619, P = 0·0013; Spearman's ρ = 0·765, P = 0·0002, respectively. Our results show a significant correlation between PDS findings and both PASI and histological degree of vascularization before and after etanercept treatment. These data provide evidence in favour of the validity of PDS in the assessment of dermal perfusional changes in patients with psoriatic plaques.

Pharmacological Properties of MK-3207, a Potent and Orally Active Calcitonin Gene-Related Peptide Receptor Antagonist

Calcitonin gene-related peptide (CGRP) has long been hypothesized to play a key role in migraine pathophysiology, and the advent of small-molecule antagonists has clearly demonstrated a clinical link between blocking the CGRP receptor and migraine efficacy. 2-[(8R)-8-(3,5-Difluorophenyl)-10-oxo-6,9-diazaspiro[4.5]dec-9-yl]-N-[(2R)-2'-oxo-1,1',2',3-tetrahydrospiro[indene-2,3'-pyrrolo[2,3-b]pyridin]-5-yl]acetamide (MK-3207) represents the third CGRP receptor antagonist to display clinical efficacy in migraine trials. Here, we report the pharmacological characterization of MK-3207, a potent and orally bioavailable CGRP receptor antagonist. In vitro, MK-3207 is a potent antagonist of the human and rhesus monkey CGRP receptors (K(i) = 0.024 nM). In common with other CGRP receptor antagonists, MK-3207 displays lower affinity for CGRP receptors from other species, including canine and rodent. As a consequence of species selectivity, the in vivo potency was assessed in a rhesus monkey pharmacodynamic assay measuring capsaicin-induced changes in forearm dermal blood flow via laser Doppler imaging. MK-3207 produced a concentration-dependent inhibition of dermal vasodilation, with plasma concentrations of 0.8 and 7 nM required to block 50 and 90% of the blood flow increase, respectively. The tritiated analog [3H]MK-3207 was used to study the binding characteristics on the human CGRP receptor. [3H]MK-3207 displayed reversible and saturable binding (K(D) = 0.06 nM), and the off-rate was determined to be 0.012 min(-1), with a t(1/2) value of 59 min. In vitro autoradiography studies on rhesus monkey brain slices identified the highest level of binding in the cerebellum, brainstem, and meninges. Finally, as an index of central nervous system penetrability, the in vivo cerebrospinal fluid/plasma ratio was determined to be 2 to 3% in cisterna magna-ported rhesus monkeys.

Imaging dermal blood flow through the intact rat skin with an optical clearing method

Noninvasive detection of skin microcirculation is very significant for clinical diagnosis and therapy of peripheral vascular disease. In this study, an optical clearing method enables a laser speckle contrast imaging (LSCI) technique to image dermal blood flow through intact rat skin. The optical clearing effect of rat skin in vitro caused by a mixture of PEG-400 and Thiazone is evaluated by a commercially available spectrophotometer with an integrating sphere. A LSCI system is applied to image the dermal blood flow of in vivo rat skin after topical treatment of the agents. The results show that the reduced scattering coefficient (630 nm) is down to 60% of the initial value after 40 min of topical treatment of the mixture on skin in vitro. In vivo experimental results show that a 12-min treatment of the mixture on the epidermis can make the skin transparent and dermal vessels can be observed, while treatment with pure PEG-400 cannot. The process of skin optical clearing lasts, and the skin can be recovered by treatment of saline solution. Because optical clearing decreases the temporal contrast, dermal blood flow can be obtained by the laser speckle contrast imaging technique.

Inhibition of capsaicin‐induced increase in dermal blood flow by the oral CGRP receptor antagonist, telcagepant (MK‐0974)

* Calcitonin gene-related peptide (CGRP) was first described as a potent vasodilator. * CGRP is also increasingly recognized as a key player in the pathophysiology of migraine, and CGRP receptor antagonists potentially offer a new approach for treating migraine. * A novel pharmacodynamic assay to measure CGRP receptor antagonist activity non-invasively in humans has been developed, which involves measuring the increase in dermal blood flow induced by topical application of capsaicin on the forearm. * This study shows that the novel oral CGRP receptor antagonist, telcagepant, inhibits the increases in dermal blood flow induced by the topical application of capsaicin on the human forearm. * This experimental medicine model may have utility to assist in dose selection for the development of CGRP receptor antagonists. To evaluate inhibition of capsaicin-induced increase in dermal blood flow (DBF) following telcagepant (MK-0974), a potent and selective orally bioavailable calcitonin gene-related peptide (CGRP) receptor antagonist being developed for the acute treatment of migraine. A three-period crossover study in 12 healthy adult men. Each subject received a single oral dose of telcagepant 300 mg, telcagepant 800 mg or placebo at 0 h, followed 0.5 and 3.5 h later by two topical doses of 300 and 1000 microg capsaicin per 20 microl water-ethanol mixture. Capsaicin was applied at two sites on the volar surface of the subjects' left and right forearms. DBF was assessed by laser Doppler perfusion imaging immediately before ('baseline'), and 0.5 h after each capsaicin application at 1 and 4 h. Plasma samples to determine telcagepant concentrations were collected immediately after laser Doppler perfusion imaging. A pharmacodynamic model was developed to explore the relationship between plasma concentration and inhibition of capsaicin-induced increase in DBF. Geometric mean plasma concentrations after dosing with 300 mg and 800 mg telcagepant were 720 and 1146 nm, respectively, at 1 h, vs. 582 and 2548 nm, respectively, at 4 h. The pharmacodynamic model suggested that the EC(90) for telcagepant inhibition of capsaicin-induced increases in DBF was 909 nm. Telcagepant inhibits the increases in DBF induced by the topical application of capsaicin on the human forearm. This experimental medicine model may have utility to assist in dose selection for the development of CGRP receptor antagonists.

Comparative reproducibility of dermal microvascular blood flow changes in response to acetylcholine iontophoresis, hyperthermia and reactive hyperaemia

Laser Doppler fluxmetry (LDF) can non-invasively measure skin microvascular changes in response to acetylcholine (ACh), local heating of the skin and reactive hyperaemia following arterial occlusion. Various studies have used microvascular changes in response to these stimuli, especially ACh iontophoresis and local heating, as a surrogate marker of endothelial function. There are few data in the literature regarding the comparative reproducibility of microvascular perfusion changes induced by the three stimuli. The aim of this study was to systematically assess and compare the reproducibility of skin microcirculatory function in response to each of these challenges. Ten healthy non-smoking subjects (seven males) median age 36 years (range 23–46), with no history of hypertension, diabetes, coronary artery disease or any connective tissue disorder, were studied. Changes in skin microcirculation in response to ACh iontophoresis, local heating of the skin and post-occlusive reactive hyperaemia, on two separate days (median 31, range 11–42 days), were assessed in all subjects. We measured three parameters: the change in perfusion from baseline perfusion (peak minus baseline perfusion), the relative percentage change in perfusion from baseline (peak − baseline)/baseline × 100 (%) and also the time-to-peak perfusion. The reproducibility of the change in perfusion had coefficients of variation (CV) of 9.3% for local skin heating, 19.4% for reactive hyperaemia and 25.5% for ACh iontophoresis. The relative percentage change in perfusion from baseline was more variable with CVs ranging from 23% to 39%. The coefficient of variation of time-to-peak perfusion was 7.0% for heating, 15.1% for reactive hyperaemia and 10.4% for ACh iontophoresis. We have shown that microcirculatory changes measured by the change in perfusion from baseline and time-to-peak perfusion in response to ACh, post-occlusive reactive hyperaemia and local skin heating had good reproducibility when carried out in a controlled environment with a standardized protocol. Relative change in perfusion had relatively poor reproducibility. The change in perfusion and time-to-peak perfusion for local skin heating were the most reproducible overall.

The effect of simvastatin on the survival of ischaemic skin flap: An experimental study in rats

Thrombomodulin (TM) is down-regulated from the vascular endothelial surfaces and corresponds to disturbed dermal blood flow and microthrombus formation in the ischaemic skin flap. We examined the therapeutic potential of simvastatin which up-regulates endothelial cell TM expression and activity in the dorsal ischaemic skin flap model. The study was carried out on 30 rats, divided into three groups. Group 1 was treated with simvastatin at a dose of 5mgkg(-1) day(-1) by intraperitoneal injection. Group 2 was treated with 1mgkg(-1) day(-1) with a phosphate-buffered saline for 7 days. Group 3 was the control group. Tissue blood flow, vascularisation and the survival rate of the skin flaps from each group were compared. The mean surviving area of group 1 was higher than groups 2 and 3 (p<0.05). The blood flow change rate did not decrease in the treatment group in contrast to the control groups at 3cm and 5cm (p<0.05). Microangiography demonstrated decreased flap vascularity in groups 2 and 3. There was no evidence of necrosis or positive peroxidase staining for TM in group 1 at 3cm and 5cm., although it was negative in groups 2 and 3. In this study, it was demonstrated that simvastatin prevented shedding of endothelial TM and contributed to flap survival.

Plasties en Z basse tension

Performing a conventional Z-plasty on postburn scar tissue frequently leads to varying degrees of necrosis of the tips of the transposed flaps. In the conventional technique, the flaps are transposed first by anchoring the tips and then by performing the other sutures. In this order, the tips are subjected to a high degree of tension. Again, according to the conventional technique, perpendicular incisions are performed along the tips, which do not ensure the effective vascularisation of the tips in this context of postburn scarring tissue with loss of dermal blood flow. Two technical modifications are proposed: a different approach to the tension by first of all anchoring the base of the flaps and not by classical first suturing of the tips and the performance of oblique incisions away from the tips to ensure a maximum vascularisation of the subdermal fatty tissue. These two elements have allowed us to improve the results of our plasties.

Influence of blood flow and millimeter wave exposure on skin temperature in different thermal models

Recently we showed that the Pennes bioheat transfer equation was not adequate to quantify mm wave heating of the skin at high blood flow rates. To do so, it is necessary to incorporate an "effective" thermal conductivity to obtain a hybrid bioheat equation (HBHE). The main aim of this study was to determine the relationship between non-specific tissue blood flow in a homogeneous unilayer model and dermal blood flow in multilayer models providing that the skin surface temperatures before and following mm wave exposure were the same. This knowledge could be used to develop multilayer models based on the fitting parameters obtained with the homogeneous tissue models. We tested four tissue models consisting of 1-4 layers and applied the one-dimensional steady-state HBHE. To understand the role of the epidermis in skin models we added to the one- and three-layer models an external thin epidermal layer with no blood flow. Only the combination of models containing the epidermal layer was appropriate for determination of the relationship between non-specific tissue and dermal blood flows giving the same skin surface temperatures. In this case we obtained a linear relationship between non-specific tissue and dermal blood flows. The presence of the fat layer resulted in the appearance of a significant temperature gradient between the dermis and muscle layer which increased with the fat layer thickness.

121 Laser Speckle Perfusion Imaging of Wound Healing in a Porcine Model

A Laser Speckle Perfusion Imaging (LSPI) system has been developed to achieve rapid, high-resolution, noninvasive imaging of tissue blood flow. This study was designed to evaluate LSPI for monitoring dermal blood flow during the wound healing process in a well-established porcine model. Full-thickness excisional wounds (2 × 2 cm) were created on the dorsal skin of 11 juvenile female red Duroc pigs. The skin wounds were imaged weekly with the LSPI system until day 49 postwounding. Blood flow values for the wounds were normalized using the values from the surrounding healthy skin to account for variations in systemic perfusion from one scan date to the next. An average normalized perfusion value was obtained from the scans of all animals for each time point. Wound perfusion at the time of reepithelialization reached ∼165% of the surrounding skin (p < 0.001). This elevation in wound perfusion slowly and steadily decreased over time, until day 49 postwounding, at which time the values returned to normal. This trend toward decreased wound perfusion over time has previously been reported in human burn wounds using the LSPI instrument. Further, the LSPI data from this study and from other human studies correlates well with data generated using the more widely established Laser Doppler Imaging (LDI) technique. The faster scan time and higher resolution of the LSPI method provides a distinct clinical advantage, both in terms of patient comfort and for reliably matching perfusion characteristics to their associated anatomical features. The fast temporal response of the LSPI instrument could be used to monitor vascular responses to mechanical or pharmacological interventions to study dynamic vascular changes to damaged tissues. This study validates LSPI as a tool to measure blood flow in skin wounds and further supports the use of the juvenile female pig as a model of excisional wound healing, yielding results comparable to healing in humans. Acknowledgments: Funding provided by CIHR, AHFMR, and NSERC

Chronic ethanol ingestion alters xenobiotic absorption through the skin: Potential role of oxidative stress

Alcohol ingestion is correlated with several skin disorders and it has been proposed that changes in skin properties may be an early indicator of alcohol misuse. Topically applied ethanol is an effective transdermal penetration enhancer; however, little is known about the effects of chronic ethanol ingestion on skin. Rats were pair fed a diet containing 36% ethanol for twelve weeks. The animals were then switched to a non-ethanol diet and were monitored for up to four weeks. Non-invasive measurements for changes in dermal blood flow using laser Doppler velocimetry (LDV), damage to skin barrier via transepidermal water loss (TEWL) and changes in skin moisture content were obtained for the experimental duration. At 0, 1 day or 1, 2, 3, 4 weeks after alcohol removal rats were euthanized and their skin was analyzed for alcohol and aldehyde dehydrogenase, and lipid peroxidation. Transdermal penetration of the herbicide paraquat, industrial solvent dimethyl formamide (DMF), insect repellant N,N-diethyl-m-toluamide (DEET) and herbicide 2,4-dichlorophenoxyacetic acid (2,4-D) was also determined. Transdermal absorption, LDV, TEWL, skin alcohol and aldehyde dehydrogenase, as well as lipid peroxidation significantly increased after continuous ethanol exposure (p<0.05). These factors remain elevated for up to four weeks after termination of ethanol consumption, showing that skin changes induced by alcohol are not immediately reversible and reflect fundamental changes in the skin itself. This work provides a starting point for examining the link between ethanol ingestion and skin disorders associated with alcohol use.

Calcitonin Gene-Related Peptide8-37 Antagonizes Capsaicin-Induced Vasodilation in the Skin: Evaluation of a Human in Vivo Pharmacodynamic Model

The purpose of this study was to identify the mediators involved in capsaicin-induced vasodilation in the human skin and to evaluate a pharmacodynamic model for the early clinical evaluation of calcitonin gene-related peptide (CGRP) receptor antagonists. Dermal blood flow (DBF) response of the forearm skin to topically applied capsaicin was measured using laser Doppler perfusion imaging in 22 subjects. The effect of intra-arterially administered CGRP(8-37) (1200 ng . min(-1) . dl(-1) forearm), indomethacin (5 mug . min(-1) . dl(-1) forearm), and N(G)-monomethyl-l-arginine (l-NMMA; 0.2 mg . min(-1) dl(-1) forearm), and orally administered aprepitant (375 mg) on capsaicin-induced dermal vasodilation was assessed. Furthermore, the diurnal variation of the DBF response to capsaicin was studied. CGRP(8-37) inhibited the capsaicin-induced DBF increase: 217(145, 290)% in infused versus 370 (254, 486)% in the noninfused arm [mean (95% CI); p = 0.004]. In contrast, indomethacin, l-NMMA, aprepitant, and the time of assessment did not affect the DBF response to capsaicin. Thus, capsaicin-induced vasodilation in the human forearm skin is largely mediated by CGRP, but not by vasodilating prostaglandins, nitric oxide, or substance P. The response to capsaicin does not display a circadian rhythm. A pharmacodynamic model is proposed to evaluate CGRP receptor antagonists in humans in vivo.

O86. Nitric oxide-releasing hydrogels for increasing dermal blood flow: Concentration and diffusion effects

O86. Nitric oxide-releasing hydrogels for increasing dermal blood flow: Concentration and diffusion effects

Pharmacological Characterization of MK-0974 [N-[(3R,6S)-6-(2,3-Difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)azepan-3-yl]-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxamide], a Potent and Orally Active Calcitonin Gene-Related Peptide Receptor Antagonist for the Treatment of Migraine

Calcitonin gene-related peptide (CGRP) is a potent neuropeptide that plays a key role in the pathophysiology of migraine headache. CGRP levels in the cranial circulation are increased during a migraine attack, and CGRP itself has been shown to trigger migraine-like headache. The correlation between CGRP release and migraine headache points to the potential utility of CGRP receptor antagonists as novel therapeutics in the treatment of migraine. Indeed, clinical proof-of-concept in the acute treatment of migraine was demonstrated with an intravenous formulation of the CGRP receptor antagonist BIBN4096BS (olcegepant). Here we report on the pharmacological characterization of the first orally bioavailable CGRP receptor antagonist in clinical development, MK-0974 [N-[(3R,6S)-6-(2,3-difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)azepan-3-yl]-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxamide]. In vitro, MK-0974 is a potent antagonist of the human (K(i) = 0.77 nM) and rhesus (K(i) = 1.2 nM) CGRP receptors but displays >1500-fold lower affinity for the canine and rat receptors as determined via (125)I-human CGRP competition binding assays. A rhesus pharmacodynamic assay measuring capsaicin-induced changes in forearm dermal blood flow via laser Doppler imaging was utilized to determine the in vivo activity of CGRP receptor antagonism. MK-0974 produced a concentration-dependent inhibition of dermal vasodilation, generated by capsaicin-induced release of endogenous CGRP, with plasma concentrations of 127 and 994 nM required to block 50 and 90% of the blood flow increase, respectively. In conclusion, MK-0974 is a highly potent, selective, and orally bioavailable CGRP receptor antagonist, which may be valuable in the acute treatment of migraine.

Reduced Vascular Endothelial Growth Factor Expression and Intra-Epidermal Nerve Fiber Loss in Human Diabetic Neuropathy

To assess the relevance of vascular endothelial growth factor (VEGF) in the maintenance of peripheral nerve integrity in diabetic neuropathy we have assessed the expression of VEGF and intra-epidermal nerve fiber density (IENFD) in skin biopsy samples from diabetic patients. Fifty-three diabetic patients and 12 nondiabetic control subjects underwent neurological evaluation, electrophysiology, quantitative sensory, and autonomic function testing. Dermal blood flow responses were evaluated with laser Doppler flowmetry. Skin biopsies were performed on the dorsum of the foot, and IENFD was quantified and compared with the expression of vascular endothelial growth factor A (VEGF-A), its receptor vascular endothelial growth factor receptor 2 (VEGFR-2), hypoxia-inducible factor 1alpha (HIF-1alpha), and microvessel density. IENFD decreased progressively with increasing severity of diabetic neuropathy (P < 0.001). The dermal blood flow response to acetylcholine was reduced in diabetic patients with mild and moderate neuropathy (P < 0.01), and the intensity of staining for epidermal VEGF-A was significantly reduced in diabetic patients compared with control subjects (P < 0.01). Epidermal HIF-1alpha and VEGFR-2 expression did not differ between groups. Progressive endothelial dysfunction, a reduction in VEGF expression, and loss of intra-epidermal nerve fibers occurs in the foot skin of diabetic patients with increasing neuropathic severity.

Reproducibility of the capsaicin‐induced dermal blood flow response as assessed by laser Doppler perfusion imaging

Part I: to establish the dose and appropriate application site of capsaicin on the human forearm in order to produce a robust and reproducible dermal blood flow (DBF) response. Part II: to evaluate the within-subject arm-to-arm and period-to-period reproducibility. Both parts consisted of two study visits. In part I, placebo and 100, 300 and 1000 microg capsaicin were applied at four predefined sites on the volar surface of both forearms. Placebo and capsaicin doses were randomized and balanced by site between subjects. Changes in DBF were assessed by laser Doppler perfusion imaging up to 60 min after capsaicin application. In part II, only 1000 microg capsaicin was applied on the proximal forearm and changes in DBF assessed up to 30 min (t(30)). DBF response was expressed as percent change from baseline +/- SD and the corresponding AUC(0-30). Reproducibility assessment included calculation of the concordance correlation coefficient (CCC). Part I (n = 12 subjects): compared with placebo, 300 and 1000 microg capsaicin increased DBF (P < 0.05) at all time points except at 10 min. This increase was reproducible at the two most proximal sites from the 30-min time point onwards when compared between arms (CCC >or= 0.8, i.e. substantial to almost perfect reproducibility). In part II (n = 11), t(30) averaged 390 +/- 120% and arm-to-arm reproducibility was almost perfect (CCC = 0.91) for AUC(0-30). Capsaicin induces a reproducible within-subject arm-to-arm increase in DBF. We provide a non-invasive pharmacodynamic model in humans to test antagonists of mediators involved in capsaicin-induced dermal vasodilation, including calcitonin gene-related peptide antagonists.

Potential mechanisms by which a single drink of alcohol can increase transdermal absorption of topically applied chemicals

Background Both chronic and acute ethanol consumption increase transdermal penetration of topically applied xenobiotics. The mechanisms by which this enhancement occurs are unknown. We hypothesized that either the vasodilatory effects of ethanol or its ability to disrupt the lipid bilayer via lipid peroxidation, may be contributing to the increased transdermal absorption observed in alcohol consuming animals. Methods Male Wistar rats were gavaged with 1.5, 3, 4.3, 6 or 10 g/kg ethanol or saline control or were treated with either the vasoconstrictor epinephrine or with the vasodilator prilocaine. Dermal blood flow, transepidermal water loss (TEWL), and skin moisture were non-invasively measured. Transdermal penetration was then determined for four xenobiotics (paraquat, dimethyl formamide (DMF), 2,4-dichlorophenoxyacetic acid (2,4-D) and N, N-diethyl- m-toluamide (DEET)). Lipid peroxidation was also determined by monitoring the formation of malondialdehyde. Results Dermal blood flow increased by approximately 27% ( p < 0.05), TEWL increased 1.12 ± 0.2-fold while skin lipid peroxidation increased 1.4-fold ( p < 0.05) 2 h after gavage with 10 g/kg alcohol. Transdermal penetration of paraquat was increased by prilocaine (ER = 2.1 ± 0.4, p < 0.05), but the absorption of DEET, 2,4-D and DMF were not influenced by greater blood flow. Reducing dermal blood flow with epinephrine did not cause any significant changes in transdermal penetration. Conclusions Vasodilation triggered by a single episode of ethanol ingestion is not responsible for the observed increase in transdermal absorption. Ethanol induced changes in lipid peroxidation and TEWL demonstrate that drinking alcohol induces transdermal absorption of xenobiotics.

S-nitrosoglutathione-containing hydrogel increases dermal blood flow in streptozotocin-induced diabetic rats

Endothelial dysfunction is characterized by decreased vasodilatory capacity of the arterioles mainly due to the reduced release of nitric oxide (NO). Application of NO donors may prevent or even reverse the consequences of endothelial dysfunction, such as diabetic leg ulcers. To investigate the vasodilatory capacity and the possible side-effects of topical application of an NO donor-containing hydrogel in diabetic rats. S-nitrosoglutathione (GSNO) was incorporated in Pluronic F127 hydrogel and applied on the foot sole skin of healthy and streptozotocin-induced diabetic rats. Blood flow was monitored using a laser-Doppler probe. Nitrotyrosine formation, a possible side-effect of GSNO action, was evaluated by Western blotting of skin protein extracts. Systemic circulatory side-effects were investigated by monitoring blood pressure and heart rate during the application. The hydrogel alone did not induce any changes in microvascular flow, while GSNO-containing hydrogel caused a twofold increase in perfusion. This effect was similar in diabetic and healthy animals. Topical GSNO application did not increase the nitrotyrosine content of skin proteins, nor did it have any effect on blood pressure or heart rate. Dermal application of GSNO may be an effective treatment for promoting the local vasodilation in both healthy and diabetic states, without inducing protein nitration or alterations in blood pressure or heart rate.

Consumption of flavanol-rich cocoa acutely increases microcirculation in human skin

Long term cocoa ingestion leads to an increased resistance against UV-induced erythema and a lowered transepidermal water loss. To investigate the acute effects of a single dose of cocoa rich in flavanols on dermal microcirculation. In a crossover design study, 10 healthy women ingested a cocoa drink (100 ml) with high (329 mg) or low (27 mg) content of flavanols. The major flavanol monomer in both drinks was epicatechin, 61 mg in the high flavanol, and 6.6 mg in the low flavanol product per 100 ml. Dermal blood flow and oxygen saturation of hemoglobin were examined by laser Doppler flowmetry and spectroscopically at 1 mm skin depth at t = 0, 1, 2, 4, and 6 h. At the same time points, plasma levels of total epicatechin (free compound plus conjugates) were measured by means of HPLC. Subsequent to the intake of high flavanol cocoa, dermal blood flow was significantly increased by 1.7-fold at t = 2 h and oxygen saturation was elevated 1.8-fold. No statistically significant changes were found upon intake of low flavanol cocoa. Maximum plasma levels of total epicatechin were observed 1 h after ingestion of the high flavanol cocoa drink, 11.6 +/- 7.4 nmol/l at baseline, and 62.9 +/- 35.8 nmol/l at 1 h. No change of total epicatechin was found in the low flavanol group. Flavanol-rich cocoa consumption acutely increases dermal blood flow and oxygen saturation.

Allergies and the skin, an interdisciplinary approach in GA2LEN and EAACI activities

Allergies and the skin, an interdisciplinary approach in GA²LEN and EAACI activities