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The delayed-release tablet formulation of posaconazole (POS-tab) results in higher plasma POS trough concentrations (C min ) than the oral suspension (POS-susp), which raises the question of the utility of therapeutic drug monitoring (TDM). We aimed to compare the variability of the POS C min for the two formulations and identify determinants of the POS-tab C min and its variability. Demographic, biological, and clinical data from 77 allogeneic hematopoietic stem cell transplant patients (874 C min ) treated with POS-tab ( n  = 41), POS-susp ( n  = 29), or both ( n  = 7) from January 2015 to December 2016 were collected retrospectively. Interpatient and within-subject coefficients of variation (CVs) of the C min adjusted to dose (D) were calculated for each formulation. Between-group comparisons were performed using a linear mixed effects model. The POS C min was higher for the tablet than for the suspension (median [25th-75th percentile]: 1.8 [1.2-2.4] mg/liter versus 1.2 [0.7-1.6] mg/liter, P  < 0.0001). Interpatient CVs for the tablet and suspension were 60.8 versus 63.5% ( P  = 0.7), whereas within-subject CVs were 39.7 and 44.9%, respectively ( P  = 0.3). Univariate analysis showed that age and treatment by POS-tab were significantly and positively associated with the POS C min , whereas diarrhea was associated with a diminished POS C min Multivariate analysis identified treatment with POS-tab and diarrhea as independent factors of the POS C min , with a trend toward a lower impact of diarrhea during treatment with POS-tab ( P  = 0.07). Despite increased POS exposure with the tablet formulation, the variability of the POS C min was not significantly lower than that of the suspension. This suggests that TDM may still be useful to optimize tablet POS therapy., (Copyright © 2019 American Society for Microbiology.)

Objective: Although anti-inflammatory drugs are commonly used in acute discogenic sciatica, data regarding their efficacy are scarce and controversial. We compared the efficacy and safety of intravenous ketoprofen and methylprednisolone with placebo in sciatica., Design: Multicenter, double-blinded randomized controlled trial., Subjects: Patients with confirmed discogenic acute sciatica, without neurologic deficit, were randomized into three arms., Methods: Besides standard-of-care analgesic therapy, they received intravenous injections of methylprednisolone (60 mg/d) or ketoprofen (200 mg/d) or placebo for five days. The primary outcome was leg pain over five days. Secondary outcomes were clinical responses at days 3 and 5, lumbar pain, Straight Leg Raise Test and lumbar flexion index, analgesic consumption, realization of lumbar spine injections, and surgery during the study period., Results: Fifty-four patients were randomized, and 50 completed the study. In patients admitted to the hospital for pain control with acute lumbar radicular pain due to intervertebral disc herniation and receiving an oral analgesic protocol including paracetamol, nefopam, tramadol, and morphine, there was no additional analgesic effect seen between groups. There was no significant difference in leg pain between the three groups over the study period. In the methylprednisolone group, however, we observed a higher rate of clinically relevant responses at day 3. No difference was observed on other secondary efficacy outcomes and safety., Conclusion: No significant difference in leg pain was observed between groups. However, there was a higher proportion of patients relieved with intravenous methylprednisolone at day 3, compared with ketoprofen or placebo., (© 2018 American Academy of Pain Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

This study aimed to assess, for the first time, the change in vascular reactivity across the full spectrum of cardiometabolic health. Systematic searches were conducted in MEDLINE and EMBASE databases from their inception to March 13, 2017, including studies that assessed basal vascular reactivity in two or more of the following health groups (aged ≥18 years old): healthy, overweight, obesity, impaired glucose tolerance, metabolic syndrome, or type 2 diabetes with or without complications. Direct and indirect comparisons of vascular reactivity were combined using a network meta-analysis. Comparing data from 193 articles (7226 healthy subjects and 19344 patients), the network meta-analyses revealed a progressive impairment in vascular reactivity (flow-mediated dilation data) from the clinical onset of an overweight status (-0.41%, 95% CI, -0.98 to 0.15) through to the development of vascular complications in those with type 2 diabetes (-4.26%, 95% CI, -4.97 to -3.54). Meta-regressions revealed that for every 1 mmol/l increase in fasting blood glucose concentration, flow-mediated dilation decreased by 0.52%. Acknowledging that the time course of disease may vary between patients, this study demonstrates multiple continuums of vascular dysfunction where the severity of impairment in vascular reactivity progressively increases throughout the pathogenesis of obesity and/or insulin resistance, providing information that is important to enhancing the timing and effectiveness of strategies that aim to improve cardiovascular outcomes., (© 2019 World Obesity Federation.)

Background and Objective: Pain, a symptom often present in patients with Chronic Obstructive Pulmonary Disease (COPD), alters quality of life. COPD exacerbation augments several mechanisms that may cause pain (dyspnea, hyperinflation and inflammation) and therefore we hypothesized that pain might be increased during exacerbation., Methods: A prospective cohort study was conducted in patients admitted for acute exacerbations of COPD (AECOPD) in two emergency departments in France and Canada. Patients with cancer-related pain or recent trauma were not included. The Short Form McGill Pain Questionnaire (SF-MPQ) and the Brief Pain Inventory (BPI) scale were used to evaluate pain intensity and location. Patients also completed the Borg Dyspnea Scale and Hospital Anxiety and Depression Scale. The questionnaires were completed again during an outpatient assessment in the stable phase. The primary outcome was difference in pain intensity (SF-MPQ) between the exacerbation and stable phases., Results: Fifty patients were included. During exacerbation, 46 patients (92%) reported pain compared to 29 (58%) in the stable phase (p<0.001). Pain intensity was higher during exacerbation (SF-MPQ 29.7 [13.6-38.2] vs. 1.4 [0.0-11.2]; p<0.001). Pain was predominantly located in the chest during exacerbation and in the limbs during the stable phase. Pain intensity during exacerbation correlated with anxiety score., Conclusion: The frequency and intensity of pain were higher during AECOPD, with a specific distribution. Pain should therefore be routinely assessed and treated in patients with AECOPD., Competing Interests: MM reports grants from Mundipharma and Roche diagnostics outside the submitted work. MM also reports personal fees from Mundipharma and Purdue outside the submitted work. JLP is supported by the French National Research Agency in the framework of the "Investissements d’avenir” program (ANR-15-IDEX-02). DV reports research grants from AstraZeneca during the conduct of the study, outside the submitted work. All the other authors report no financial relationships with any organisations that might have an interest in the submitted work in the previous three years, and no other relationships or activities that could appear to have influenced the submitted work. These competing interests do not alter the authors’ adherence to PLOS ONE policies on sharing data and materials. There are no restrictions to the sharing of data from this study.

The pathophysiology of pulmonary arterial hypertension (PAH) induced by protein kinase inhibitors (PKIs) remains unclear. To gain knowledge into this rare and severe pathology we performed a study combining a pharmacovigilance approach and the pharmacodynamic properties of PKIs.A disproportionality analysis on the World Health Organization pharmacovigilance database VigiBase using the reporting odds ratio (ROR) and 95% confidence interval was first performed. Then, we identified the most relevant cellular targets of interest through a systematic literature review and correlated the pharmacovigilance signals with the affinity for the different PKIs. We further performed a hierarchical cluster analysis to assess patterns of binding affinity.A positive disproportionality signal was found for dasatinib, bosutinib, ponatinib, ruxolitinib and nilotinib. Five non-receptor protein kinases significantly correlate with disproportionality signals: c-Src (r=0.79, p=0.00027), c-Yes (r=0.82, p=0.00015), Lck (r=0.81, p=0.00046) and Lyn (r=0.80, p=0.00036), all belonging to the Src protein kinase family, and TEC (r=0.85, p=0.00006). Kinases of the bone morphogenetic protein signalling pathway also seem to play a role in the pathophysiology of PKI-induced PAH. Interestingly, the dasatinib affinity profile seems to be different from that of other PKIs in the cluster analysis.The study highlights the potential role of the Src protein kinase family and TEC in PAH induced by PKIs. This approach combining pharmacovigilance and pharmacodynamics data allowed us to generate some hypotheses about the pathophysiology of the disease; however, the results have to be confirmed by further studies., Competing Interests: Conflict of interest: L. Cornet has nothing to disclose. Conflict of interest: C. Khouri has nothing to disclose. Conflict of interest: M. Roustit reports grants from United Therapeutics outside the submitted work. Conflict of interest: C. Guignabert has nothing to disclose. Conflict of interest: M-C. Chaumais reports nonfinancial support from Bayer and personal fees from Actelion, outside the submitted work. Conflict of interest: M. Humbert reports personal fees from Actelion, Bayer, GSK, Merck and United Therapeutics, during the conduct of the study. Conflict of interest: B. Revol has nothing to disclose. Conflict of interest: F. Despas has nothing to disclose. Conflict of interest: D. Montani reports grants and personal fees from Actelion and Bayer, and personal fees from BMS, GSK, MSD and Pfizer, outside the submitted work. Conflict of interest: J-L. Cracowski reports grants from Bioprojet and Topadur, outside the submitted work., (Copyright ©ERS 2019.)

Background: Treatment of Raynaud phenomenon (RP) with phosphodiesterase-5 inhibitors has shown moderate efficacy. Adverse effects decrease the risk-benefit profile of these drugs, and patients may not be willing to receive long-term treatment. On-demand single doses before or during exposure to cold may be a good alternative., Objective: To assess the efficacy and safety of on-demand sildenafil in RP., Design: Series of randomized, double-blind, n-of-1 trials. (ClinicalTrials.gov: NCT02050360)., Setting: Outpatients at a French university hospital., Participants: Patients with primary or secondary RP., Intervention: Each trial consisted of a multiple crossover study in a single patient. Repeated blocks of 3 periods of on-demand treatment were evaluated: 1 week of placebo, 1 week of sildenafil at 40 mg per dose, and 1 week of sildenafil at 80 mg per dose, with a maximum of 2 doses daily., Measurements: Raynaud Condition Score (RCS) and frequency and daily duration of attacks. Skin blood flow in response to cooling also was assessed with laser speckle contrast imaging. Mixed-effects models were used and parameters were estimated in a Bayesian framework to determine individual and aggregated efficacy., Results: 38 patients completed 2 to 5 treatment blocks. On the basis of aggregated data, the probability that sildenafil at 40 mg or 80 mg was more effective than placebo was greater than 90% for all outcomes (except for RCS with sildenafil, 80 mg). However, the aggregated effect size was not clinically relevant. Yet, substantial heterogeneity in sildenafil's efficacy was observed among participants, with clinically relevant efficacy in some patients., Limitation: The response to sildenafil was substantially heterogeneous among patients., Conclusion: Despite a high probability that sildenafil is superior to placebo, substantial heterogeneity was observed in patient response and aggregated results did not show that on-demand sildenafil has clinically relevant efficacy. In this context, the use of n-of-1 trials may be an original and relevant approach in RP., Primary Funding Source: GIRCI (Groupement Interrégional de Recherche Clinique et d'Innovation) Auvergne Rhône-Alpes (academic funding) and Pfizer.

Background: Recent guidelines recommend riociguat, a soluble guanylate cyclase (sGC) stimulator, and the type 5 phosphodiesterase inhibitor (PDE5i) tadalafil or sildenafil as treatments for pulmonary arterial hypertension. We compared the safety profiles of sildenafil, tadalafil, and riociguat in pulmonary hypertension., Methods: We combined two approaches. First, we performed a meta-analysis of safety data extracted from randomized controlled trials. Second, we conducted a disproportionality analysis of data from VigiBase, the World Health Organization's global database of individual case safety reports, to compare the safety profiles with real-life data., Results: In the meta-analysis, a significant difference between the three drugs was only detected for gastrointestinal disorders, in disfavor of riociguat (P < .01 for interaction). In the disproportionality analysis, the use of riociguat was associated with fewer reports of visual disorders but increased reporting of gastrointestinal, hemorrhagic, and musculoskeletal disorders compared with sildenafil and tadalafil. Pharmacovigilance signals of hearing/vestibular disorders were heterogeneous: vestibular disorders (dizziness) were reported more frequently for riociguat, whereas hearing disorders (deafness) were reported less frequently compared with PDE5is., Conclusions: The safety profiles of PDE5is and sGC stimulators significantly differ in pulmonary hypertension. Accordingly, there is a safety rationale in switching between PDE5is and sGC stimulators because of their different side effects., Trial Registry: PROSPERO; No.: CRD42016051986; URL: https://www.crd.york.ac.uk/prospero/., (Copyright © 2017 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Inhibitors of the sodium-glucose co-transporter-2 (SGLT-2) are a novel class of glucose-lowering agents that show promising results. However, the use of canagliflozin has been associated with an increased risk of lower-limb amputation. Whether this risk concerns other SGLT-2 inhibitors is unclear, and our objective was to address this issue. We performed a disproportionality analysis using the WHO global database of individual case safety reports (VigiBase). Among the 8 293 886 reports available between January 2013 and December 2017, we identified 79 reports of lower-limb amputation that were associated with SGLT-2 inhibitors. Among all blood glucose lowering drugs, the proportional reporting ratio (PRR) was increased only for SGLT-2 inhibitors (5.55 [4.23, 7.29]). While we observed an expected signal for canagliflozin (7.09 [5.25, 9.57]), the PRR was also high for empagliflozin (4.96 [2.89, 8.50]) and, for toe amputations only, for dapagliflozin (2.62 [1.33, 5.14]). In conclusion, our results reveal a positive disproportionality signal for canagliflozin, and also for empagliflozin, and, for toe amputations only, for dapagliflozin. However, our analysis relies on a limited number of cases and is exposed to the biases inherent to pharmacovigilance studies. Further prospective data are therefore needed to better characterize the risk of amputations with different SGLT-2 inhibitors., (© 2018 John Wiley & Sons Ltd.)

Telomerase is the enzyme that maintains telomere length by adding telomeric repeats after each cell division. Numerous metabolic factors such as obesity, insulin resistance or physical inactivity have been associated with shortened telomeres. In the present study, we assessed telomerase activity in diabetic patients having or not foot ulcer. A total of 90 adult patients with type 2 diabetes mellitus (T2DM) were studied. Patients were allocated into two groups according to the absence or presence of active foot ulcers as follows: Νon-ulcer group (N=58) and ulcer group (N=32). Our data revealed that the patients with diabetic ulcers had significantly greater waist circumference and neuropathy disability score, while exhibiting lower telomerase activity, indicating the possible existence of a common clinical profile among ulcer-bearing diabetic patients. Validation of our findings by extending the study in larger patient groups may contribute to the understanding of T2DM pathophysiology and its main clinical implications.

Ischaemic digital ulcers (DUs) are an indicator of the severity of the microangiopathy in patients with systemic sclerosis (SSc). DUs are a frequent complication, affecting about 50% of patients with SSc, and are often recurrent. In cross-sectional studies involving patients with SSc, the frequency of ischaemic DUs was 12-16% with a major impact on hand function and quality of life. Effective therapy for DUs remains elusive. Intravenous iloprost has been demonstrated to have a positive effect on healing of active DUs. Bosentan, an oral endothelin receptor antagonist, only showed a benefit in preventing the occurrence of new DUs. Despite limited evidence, recent guidelines have recommended phosphodiesterase type 5 inhibitors as an option. Injection of botulinum toxin and digital sympathectomy have been increasingly used for ischaemic DUs. Here we present the complex case of a SSc patient already treated with sildenafil and bosentan in whom an active DU was successfully treated with botulinum toxin A. Despite the lack of a randomised controlled trial, results are encouraging for the use of botulinum toxin in the treatment of DUs and could perhaps help to avoid some amputations, as in the present case., (© 2017 Medicalhelplines.com Inc and John Wiley & Sons Ltd.)

Objective: Recent technical developments enable skin fluorescence to be quantified in vivo in humans. The present study aimed at determining whether flow mediated skin fluorescence was reproducible, sensitive to changes within an individual, and if it could differ between patients with coronary artery disease and healthy volunteers., Methods: First, forearm flow mediated skin fluorescence recorded during and after brachial artery occlusion was assessed following successive forearm occlusion periods (1, 2, 3 and 5min) and expressed as ischemic and hyperemic responses (as % of baseline). Secondly, 3min flow mediated skin fluorescence was assessed before and after 10min local cooling to 15°C. In a third protocol, the inter-day reproducibility of ischemic and hyperemic responses to 3min occlusion was tested at an interval of 7days, and compared between healthy controls and patients with coronary artery disease (CAD)., Results: In the first protocol, we observed a time dependent increase in the ischemic and hyperemic responses to occlusion. Next, we observed a lower hyperemic response after local cooling (9.8±4.2 versus 17.8±2.5% respectively, P<0.001), while in contrast, the ischemic response was higher and exhibited greater variability (23±15 versus 11.8±6.4%; P=0.028). In the third protocol, the inter-day reproducibility of flow mediated skin fluorescence for a 3min occlusion period was excellent. The ischemic response was significantly lower in CAD patients than in healthy controls (6.7±4.8% vs 14.7±6.8% respectively, P<0.001). Similarly, the hyperemic response was significantly decreased in the CAD group compared to healthy controls (11.6±3.6% vs 19.5±5.4% respectively, P<0.001)., Conclusion: We show that quantifying the ischemic and hyperemic flow mediated skin fluorescence is feasible, reproducible, sensitive to acute changes in skin blood flow, and distinguishes patients populations. However, more data are needed to evaluate the correlation with other methods or specific biochemical endothelial markers., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Aim: Iontophoresis of vasoactive agents is commonly used to assess cutaneous microvascular reactivity. However, it is known that iontophoresis can be limited by confounding non-specific vasodilatory effects. Despite this, there is still no standardization of protocols or data expression. Therefore, this study evaluated commonly used protocols of iontophoresis by assessing each for evidence of non-specific vasodilatory effects and examined the reproducibility of those protocols that are free of non-specific responses., Methods: Twelve healthy participants were administered doses of acetylcholine (ACh) 1-2% and sodium nitroprusside (SNP) 1%, diluted in sodium chloride 0.9% or deionized water, and insulin 100U/mL in a sterile diluent using iontophoresis coupled with laser speckle contrast imaging (LSCI). Increases in blood flux at a control electrode, containing the diluent only, indicated a non-specific response. Reproducibility of iontophoresis protocols that were free of non-specific vasodilatory effects were subsequently compared to that of post-occlusive reactive hyperemia (PORH), used as a standard, in 20 healthy participants., Results: Iontophoresis of ACh or SNP in sodium choloride (0.02mA for 200 and 400s, respectively) and ACh in deionized water (0.1mA for 30s) mediated the least non-specific vasodilatory effects. Microvascular responses to insulin were mediated mainly by non-specific effects. Compared to PORH, the intraday and interday reproducibility for iontophoresis of ACh and SNP (0.02mA for 200 and 400s, respectively) with LSCI was weaker, but still deemed good to excellent when data was expressed, in perfusion units or cutaneous vascular conductance, as the absolute peak blood flux response to the vascular reactivity test or as the change in blood flux between peak and baseline values., Conclusion: This study provides updated recommendations for assessing cutaneous microvascular function with iontophoresis., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Electrical stimulation (ES) has been tested for decades to improve chronic wound healing. However, uncertainty remains on the magnitude of the efficacy and on the best applicable protocol. We conducted an effect size meta-analysis to assess the overall efficacy of ES on wound healing, to compare the efficacy of the different modalities of electrical stimulation, and to determine whether efficacy differs depending on the wound etiology, size, and age of the chronic wound. Twenty-nine randomized clinical trials with 1,510 patients and 1,753 ulcers were selected. Overall efficacy of ES on would healing was a 0.72 SMD (95% CI: 0.48, 1) corresponding to a moderate to large effect size. We found that unidirectional high voltage pulsed current (HVPC) with the active electrode over the wound was the best evidence-based protocol to improve wound healing with a 0.8 SMD (95% CI: 0.38, 1.21), while evaluation of the efficacy of direct current was limited by the small number of studies. ES was more effective on pressure ulcers compared to venous and diabetic ulcers, and efficacy trended to be inversely associated with the wound size and duration. This study confirms the overall efficacy of ES to enhance healing of chronic wounds and highlights the superiority of HVPC over other type of currents, which is more effective on pressure ulcers, and inversely associated with the wound size and duration. This will enable to standardize future ES practices., (© 2017 by the Wound Healing Society.)

Pioneering work demonstrated that an unstable substance isolated from rabbit and pig aortas could relax arterial smooth muscle and inhibit platelet aggregation. Since then, prostacyclin (prostaglandin I2, PGI 2 ) and its analogs have raised much pharmacological interest. In this review we detail how the PGI 2 signaling pathway is much more complex than was initially anticipated, involving peroxisome proliferator-activated receptors (PPARs), prostaglandin transporters (PGTs), and PGI 2 -thromboxane A 2 (TXA 2 ) receptor (IP TP) heterodimerization. We discuss the distinct affinities of PGI 2 analogs for prostanoid receptors. In addition, we introduce the new direct and indirect pharmacological approaches to targeting the PGI 2 pathway within the systemic circulation, including non-prostanoid agonists of the prostacyclin receptor (IP) and PGT inhibitors, as well as transcutaneous pathways using iontophoresis and nanostructured lipid carriers., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Context: The dipeptidyl peptidase-4 inhibitor, linagliptin, possesses pleiotropic vasodilatory, antioxidant, and anti-inflammatory properties in animals, independent of its glucose-lowering properties. Although large, randomized clinical trials are being conducted to better evaluate the efficacy and safety of linagliptin on cardiovascular outcomes, little is known about its effects on vascular function in humans., Objective: This study sought to evaluate the effect of linagliptin on surrogates of vascular and mitochondrial function., Design and Setting: This was a randomized, double-blind, placebo-controlled trial at a tertiary care center with a large type 2 diabetes referral base., Patients and Intervention: Forty participants with type 2 diabetes were included in a 12-wk treatment of either linagliptin 5mg/d or placebo., Main Outcome Measures: Micro- and macrovascular functions were assessed using laser Doppler coupled with iontophoresis and with brachial flow-mediated dilation, respectively. Mitochondrial function was assessed by phosphorus-31 metabolites changes in the calf muscle measured by magnetic resonance spectroscopy. Circulating endothelial progenitor cells, as well as inflammatory cytokines, growth factors, and biomarkers of endothelial function were also quantified., Results: Linagliptin was associated with an increase in axon reflex-dependent vasodilation, a marker of neurovascular function (P = .05). A trend indicating increased endothelium-dependent microvascular reactivity was observed (P = .07). These were associated with decreases in concentrations of IFNγ (P < .05), IL-6 (P = .03), IL-12 (P < .03), and MIP-1 (P < .04) following linagliptin treatment when compared with placebo., Conclusions: This study demonstrates that linagliptin tends to improve endothelial and neurovascular microvascular function and is associated with decreased markers of inflammation in patients with type 2 diabetes. There was no significant effect of linagliptin on mitochondrial function, macrovascular function, or endothelial progenitor cells.

Introduction: Diabetic peripheral neuropathy (DPN) is one of the most common complications of diabetes and has been associated with cardiovascular disease, the leading cause of mortality in diabetes. As asymptomatic myocardial ischemia (MI) is frequent in diabetes, we hypothesized that DPN may be associated with MI in patients with type 2 diabetes mellitus and no history of cardiovascular events., Methods: Eighty-two patients with DPN (n = 41) or without DPN (n = 41) were included. Among the DPN group, 15 had active foot ulcers. All subjects underwent Technetium-99 m sestamibi single-photon emission computed tomographic imaging for the estimation of myocardial ischemia, expressed as Summed Stress Score (SSS). The Neuropathy Disability Score (NDS) was used to quantify DPN and abnormal ratio of the longest electrocardiographic RR interval between the 28th and 32nd beats, after standing to the shortest interval between the 13th and 17th beats (RR ratio) was used as an index of cardiovascular autonomic neuropathy (CAN)., Results: Abnormal SSS was observed in 9.8% of patients without DPN and in 46.3% of patients with DPN (p < 0.001). In the multivariate analysis, NDS was the strongest predictor for SSS (β = 0.32, p = 0.003). When excluding patients with abnormal RR ratio (β = 0.32, p = 0.003) or with foot ulcers (β = 0.24, p = 0.04), this association remained significant. The RR ratio was also significantly associated with SSS in univariate (ρ = -0.30, p = 0.005) and multiple regressions (β = 0.24, p = 0.02)., Conclusions: MI was strongly associated with DPN, and this association remained significant in patients with normal RR ratio. These results suggest that DPN assessment could help in identifying patients at risk of cardiovascular disease (CVD).

Background: Physician attitude influences the way patients cope with diagnosis and therapy in chronic severe diseases such as cancer. Previous studies showed that such an effect exists in HIV care; it is likely that it begins with the first contact with a physician., Objective: We aimed to explore in HIV-infected persons their perception of the first consultation they had with an HIV specialist (PFC-H), and whether this perception correlates with adherence to antiretroviral therapy., Method: The study was conducted in Grenoble University Hospital, France, a tertiary care center. Every antiretroviral-experienced patient was asked to freely complete a self-reported, anonymous questionnaire concerning retrospective PFC-H, present adherence (Morisky scale), and present perceptions and beliefs about medicine (BMQ scale)., Results: One hundred and fifty-one questionnaires were available for evaluation. PFC-H score and adherence were correlated, independently from age, gender, and numbers of pill(s) and of pill intake(s) per day. BMQ score also correlated with adherence; structural equation analysis suggested that the effect of PFC-H on adherence is mediated by positive beliefs., Conclusion: These results suggest that for HIV-infected persons, the perceptions remaining from the first consultation with an HIV specialist physician influence important issues such as adherence and perception about medicine. Physicians must be aware of this potentially long-lasting effect.

Context: Cardiovascular risk factors are well-known predictors of the development of diabetic peripheral neuropathy (DPN), which has traditionally been considered as a manifestation of diabetes-associated microangiopathy. Because endothelial dysfunction is strongly associated with all cardiovascular risk factors, we hypothesized that it may be a link between cardiovascular risk factors and DPN., Objective: The primary objective of this study was to test whether endothelial dysfunction is a predictor of DPN., Design and Setting: This is a cross-sectional analysis of a cohort composed of patients followed at the Microcirculatory Laboratory, Beth Israel Deaconess Medical Center., Patients: Participants with diabetes without DPN (n = 192) and with DPN (n = 166), subjects with prediabetes (n = 75), and nondiabetic controls (n = 59) were included., Interventions: Endothelial function was assessed with flow-mediated dilation (FMD) of the brachial artery. Inflammatory cytokines and biomarkers of endothelial function (soluble intercellular and vascular cell adhesion molecules) were quantified using a multiplex bead-based immunoassay. Neurological assessment included the neuropathy disability score (NDS)., Main Outcome Measure: The relationship between FMD and NDS assessed using multiple linear regression., Results: In addition to already known risk factors of DPN, FMD was strongly associated with NDS (β = -0.24; P < .001). Sensitivity analysis that removed FMD from the model provided similar results for soluble intercellular cell adhesion molecule-1, another biomarker of endothelial function. Confirmatory factor analysis further showed that endothelial dysfunction is a significant mediator between glycosylated hemoglobin and diabetes duration and diabetic complications., Conclusions: This study shows that endothelial dysfunction occurs early in the pathophysiology of diabetes and is a link between cardiovascular risk factors and DPN.

Aim: Peripheral vasoconstriction has long been described as a vascular adverse effect of β-adrenoceptor blockers. Whether β-adrenoceptor blockers should be avoided in patients with peripheral vascular disease depends on pharmacological properties (e.g. preferential binding to β1 -adrenoreceptors or intrinsic sympathomimetic activity). However, this has not been confirmed in experimental studies. We performed a network meta-analysis in order to assess the comparative risk of peripheral vasoconstriction of different β-adrenoceptor blockers., Method: We searched for randomized controlled trials (RCTs) including β-adrenoceptor blockers that were published in core clinical journals in the Pubmed database. All RCTs reporting peripheral vasoconstriction as an adverse effect of β-adrenoceptor blockers and controls were included. Sensitivity analyses were conducted including possibly confounding covariates (latitude, properties of the β-adrenoceptor blockers, e.g. intrinsic sympathomimetic activity, vasodilation, drug indication, drug doses). The protocol and the detailed search strategy are available online (PROSPERO registry CRD42014014374)., Results: Among 2238 records screened, 38 studies including 57 026 patients were selected. Overall, peripheral vasoconstriction was reported in 7% of patients with β-adrenoceptor blockers and 4.6% in the control groups (P < 0.001), with heterogeneity among drugs. Atenolol and propranolol had a significantly higher risk than placebo, whereas pindolol, acebutolol and oxprenolol had not., Conclusion: Our results suggest that β-adrenoceptor blockers have variable propensity to enhance peripheral vasoconstriction and that it is not related to preferential binding to β1 -adrenoceptors. These findings challenge FDA and European recommendations regarding precautions and contra-indications of use of β-adrenoceptor blockers and suggest that β-adrenoceptor blockers with intrinsic sympathomimetic activity could be safely used in patients with peripheral vascular disease., (© 2016 The British Pharmacological Society.)

Objectives: To assess the feasibility of intraparotid facial nerve (VIIn) tractographic reconstructions in estimating the presence of a contact between the VIIn and the tumour, in patients requiring surgical resection of parotid tumours., Methods: Patients underwent MR scans with VIIn tractography calculated with the constrained spherical deconvolution model. The parameters of the diffusion sequence were: b-value of 1000 s/mm(2); 32 directions; voxel size: 2 mm isotropic; scan time: 9'31'. The potential contacts between VIIn branches and tumours were estimated with different initial fractional anisotropy (iFA) cut-offs compared to surgical data. Surgeons were blinded to the tractography reconstructions and identified both nerves and contact with tumours using nerve stimulation and reference photographs., Results: Twenty-six patients were included in this study and the mean patient age was 55.2 years. Surgical direct assessment of VIIn allowed identifying 0.1 as the iFA threshold with the best sensitivity to detect tumour contact. In all patients with successful VIIn identification by tractography, surgeons confirmed nerve courses as well as lesion location in parotid glands. Mean VIIn branch FA values were significantly lower in cases with tumour contact (t-test; p ≤ 0.01)., Conclusions: This study showed the feasibility of intraparotid VIIn tractography to identify nerve contact with parotid tumours., Key Points: • Diffusion imaging is an efficient method for highlighting the intraparotid VIIn. • Visualization of the VIIn may help to better manage patients before surgery. • We bring new insights to future trials for patients with VIIn dysfunction. • We aimed to provide radio-anatomical references for further studies.

Several noninvasive techniques have been developed using laser light interaction in the skin to explore the skin's microcirculation. Combined with laser Doppler or LSCI, reactivity tests are used to explore skin endothelial and neurovascular function in humans, including PORH, LTH, PIV, and iontophoresis of vasodilators. Recent advances in our comprehension of the physiological pathways underlying these reactivity tests have been possible through topical or intradermal delivery of drugs that produce elevated local concentrations. Skin microvascular function has also been proposed as a prognostic biomarker or for evaluating the effect of drugs. Comprehension of the physiological pathways, together with recent technological improvements in microcirculation imaging, has provided reliable and reproducible tools to study skin microcirculation., (© 2015 John Wiley & Sons Ltd.)

Aim: Drug-induced Raynaud's phenomenon (RP) has long been associated with the use of different drugs, including cancer chemotherapy or β-adrenoceptor blockers. However, sources report extremely variable prevalence and the level of evidence for each class is heterogeneous. Moreover, new signals are emerging from case reports and small series. Our objective was therefore to review available evidence about this adverse drug effect and to propose a mechanistic approach of drug-induced RP., Methods: A systematic review of English and French language articles was performed through Medline (1946-2015) and Embase (1974-2015). Further relevant papers were identified from the reference lists of retrieved articles., Results: We identified 12 classes of drugs responsible for RP, with a variety of underlying mechanisms such as increased sympathetic activation, endothelial dysfunction, neurotoxicity or decreased red blood cell deformability. Cisplatin and bleomycin were associated with the highest risk, followed by β-adrenoceptor blockers. Recent data suggest a possible involvement of tyrosine kinase inhibitors (TKI), through an unknown mechanism., Conclusion: Drug-induced RP is a probably underestimated adverse drug event, with limited available evidence regarding its prevalence. Although rare, serious complications like critical digital ischaemia have been reported. When these treatments are started in patients with a history of RP, careful monitoring must be made and, if possible, alternative therapies that do not alter peripheral blood flow should be considered., (© 2016 The British Pharmacological Society.)

Mont Blanc, the summit of Western Europe, is a popular but demanding high-altitude ascent. Drug use is thought to be widespread among climbers attempting this summit, not only to prevent altitude illnesses, but also to boost physical and/or psychological capacities. This practice may be unsafe in this remote alpine environment. However, robust data on medication during the ascent of Mont Blanc are lacking. Individual urine samples from male climbers using urinals in mountain refuges on access routes to Mont Blanc (Goûter and Cosmiques mountain huts) were blindly and anonymously collected using a hidden automatic sampler. Urine samples were screened for a wide range of drugs, including diuretics, glucocorticoids, stimulants, hypnotics and phosphodiesterase 5 (PDE-5) inhibitors. Out of 430 samples analyzed from both huts, 35.8% contained at least one drug. Diuretics (22.7%) and hypnotics (12.9%) were the most frequently detected drugs, while glucocorticoids (3.5%) and stimulants (3.1%) were less commonly detected. None of the samples contained PDE-5 inhibitors. Two substances were predominant: the diuretic acetazolamide (20.6%) and the hypnotic zolpidem (8.4%). Thirty three samples were found positive for at least two substances, the most frequent combination being acetazolamide and a hypnotic (2.1%). Based on a novel sampling technique, we demonstrate that about one third of the urine samples collected from a random sample of male climbers contained one or several drugs, suggesting frequent drug use amongst climbers ascending Mont Blanc. Our data suggest that medication primarily aims at mitigating the symptoms of altitude illnesses, rather than enhancing performance. In this hazardous environment, the relatively high prevalence of hypnotics must be highlighted, since these molecules may alter vigilance.

Introduction: Severe Raynaud's syndrome and DUs are the most prevalent manifestations of SSc peripheral microvascular disease. We tested whether treprostinil iontophoresis on the finger pad of patients with SSc would improve digital blood flow during hand cooling., Methods: Eleven patients with limited cutaneous SSc underwent a double-blinded iontophoresis of treprostinil (2.56 × 10(-4) M during two hours) and placebo (NaCl 0.9%) on two finger pads. Then, the hand was inserted for 30 minutes in a fenestrated cooling box at 8 °C, and skin blood flow was recorded continuously using LSCI., Results: During the local cooling, CVC was significantly higher at the treprostinil site than at the placebo site and remained higher 30 minutes after the test., Conclusions: In patients with SSc, digital treprostinil iontophoresis shifts skin blood flow upward during local cooling of the hand and during the initial rewarming phase. Digital treprostinil iontophoresis should now be tested in larger scale studies., (© 2016 John Wiley & Sons Ltd.)

Objective: Concerns have been raised about nonadherence behavior among patients with chronic inflammatory rheumatic diseases (CIRD) receiving biologics. This nonadherence may be caused by various factors. The main objective was to explain why patients discontinue their biologics of their own accord., Methods: A quantitative and descriptive study was performed using a self-report questionnaire that was sent through the Internet to members of different patient associations. Sociodemographic data, medical and therapeutic history, management of biologic administration, previous experiences, and patients' beliefs and perceptions about treatment efficacy and side effects were studied to explain self-discontinuation (SD)., Results: A total of 581 patients answered the questionnaire between June 16, 2012, and July 4, 2012, including patients with ankylosing spondylitis (351/581, 60.4%), rheumatoid arthritis (196/581, 33.7%), psoriatic arthritis (30/581, 5.2%), and other CIRD (4/581, 0.7%). More than 1000 different biologics were described by the 581 patients, with a median of 2 lines per patient. Eighty-six patients discontinued their biologics of their own accord (14.8%). In a multivariate analysis, factors that were significantly related to SD were low level of pain, more than 1 line of biologics tried, self-administration of biologics, negative beliefs about the treatment, and a lack of medical and social support., Conclusion: Five predictive factors of this SD were identified, which should be assessed in routine with patients with CIRD receiving biologic treatment: pain, treatment history, self-administration of injections, negative beliefs about treatment, and a lack of perceived medical and social support.

Background: Peripheral skin blood flow (SBF) changes during and after spinal mobilization (SM), evaluated with laser Doppler flowmetry, may document physiological responses associated with SM., Objectives: To document variations in SBF during and after application of an SM and evaluate influence of pressure on SBF by applying the same standardized SM with 3 different nonnoxious pressures., Design: Cross-over design with 4 interventions on 4 different days: control (no touch) and 3 SMs applied rhythmically at 5%, 40%, or 80% of pain pressure threshold (sham SM, low-pressure SM, or high-pressure SM, respectively)., Method: Thirty-two individuals participated. The inspiratory gasp (IG) test was our positive control of vasoconstriction through excitation of the skin sympathetic nervous activity (SSNA). Each session comprised 5 phases: (1) baseline at the end of a 20-min acclimatization, (2) IG test, (3) post-IG phase, (4) SM phase or no manual contact for control, and (5) post-SM phase. A Biopac MP36 system collected SBF data, and a Novel Pliance-X system recorded pressure data., Results/findings: Equal and significant bilateral vasodilation occurred during application of unilateral sham SM, low-pressure SM, and high-pressure SM. Post-SM significant vasodilation persisted after high-pressure SM., Conclusions: The current study is the first to describe bilateral peripheral SBF changes occurring during and 5 min after application of standardized SMs. Our post-SM vasodilation suggests involvement of mechanisms other than the putative SSNA-excitatory mechanism proposed with skin conductance measurements. Persistence of post-SM vasodilation following only high-pressure SM suggests possible pressure-dependent mechanisms. However, further research is warranted to clarify our findings., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Several mediators contribute to postocclusive reactive hyperaemia (PORH) in the skin, including sensory nerves and endothelium-derived hyperpolarizing factors. The main objective of this study was to investigate the specific involvement of prostanoids in human skin PORH. We tested the effect of the inhibition of cyclo-oxygenases (COX) by 4 mm ketoprofen, infused through microdialysis fibers inserted into the healthy volunteers forearm skin, following 5 min brachial artery occlusion. Skin microvascular blood flux was recorded using two-dimensional Laser Speckle Contrast Imaging. Maximal cutaneous vascular conductance (CVCmax ) was obtained following the perfusion of 29 mm sodium nitroprusside. A systematic review of the effects of COX inhibitors on skin peak PORH was also performed. We observed no significant difference between ketoprofen and placebo for the PORH peak (78 ± 8 and 71 ± 19% CVCmax , respectively) and area under the curve (2951 ± 721 and 2490 ± 936% CVCmax .s). A meta-analysis showed a substantial heterogeneity between studies, with overall a neutral effect of COX inhibition on peak PORH. Cyclo-oxygenase inhibition does not alter skin PORH, suggesting no involvement of prostanoids in cutaneous postocclusive vasodilatation in healthy humans., (© 2015 Société Française de Pharmacologie et de Thérapeutique.)

Skin microvascular endothelial function is impaired in many cardiovascular diseases, and could be therefore considered as a representative vascular bed. However, today, available evidence allows considering skin microvascular endothelial function neither as a diagnostic biomarker nor as a prognostic biomarker in cardiovascular diseases. Large follow-up studies using standardized methods should now be conducted to assess the potential predictive value of skin microvascular function in cardiovascular diseases., (Copyright © 2015 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.)

Diabetic foot ulcers are one of the most common and serious complications of diabetes mellitus. Few drugs are effective in enhancing the healing of microvascular skin ulcers. The main objective of the present study was to determine whether iontophoresis of treprostinil, a prostacyclin analog, increases skin microvascular blood flux in the malleolus area of healthy subjects and diabetic patients. We recruited 12 healthy subjects and 12 type 2 diabetic patients. Cathodal iontophoresis (40mC/cm²) of treprostinil 250µM and NaCl 0.9% was performed in the malleolus area. Skin hyperemia was quantified using non-invasive laser speckle contrast imaging, and expressed as the area under the curve (AUC) of cutaneous vascular conductance (CVC). In healthy controls and diabetic patients, treprostinil 250µM induced a significant increase in CVC compared with NaCl (for diabetic patients, AUC0-6h was 19970±8697; versus 2893±5481%BL.min, respectively; P=0.002). In both groups, the peak flux was obtained between 30min and 1h after the end of treprostinil iontophoresis and flux remained higher than baseline up to 6h after ending of iontophoresis. No significant side-effect occurred. Cutaneous iontophoresis of 250µM treprostinil increases microvascular blood flux in the malleolus area in healthy volunteers and diabetic patients, without inducing systemic or local side-effects. Treprostinil cathodal iontophoresis should be further investigated as a new local therapy for diabetic ulcers., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Introduction: Systemic sclerosis (SSc) is a rare disease affecting digital microcirculation, leading to finger ulcers and in some cases to amputation. Prostacyclin analogues can be used intravenously but their therapeutic effect is counterbalanced by potentially serious vasodilatation-induced side effects. Iontophoresis of treprostinil could be a promising local therapeutic alternative for SSc-related digital ulcers. Iontophoretic drug delivery is complex, and whether continuous or periodic current should be used remains debated. The objective of the present work is to compare the effect of continuous vs pulsed iontophoresis of treprostinil in rats., Materials and Methods: Treprostinil (0.64 mM and 0.064 mM) and NaCl were delivered by cathodal iontophoresis onto the hindquarters of anaesthetized rats. Three protocols delivering the same quantity of current were compared: one was continuous (100 μA during 20 min) and two were periodic (B: twenty 1-min cycles with 200 μA during 30 s followed by 30 s Off; and C: twenty 1-min cycles with 600 μA during 10s followed by 50s Off) (n=8 for each protocol with each concentration). Skin blood flow was quantified using laser Doppler imaging and skin resistance was calculated with Ohm's law., Results: All protocols induced a significant increase in skin blood flow. At the lower concentration (0.064 mM treprostinil) the pulsed 10/50 sequence significantly enhanced cutaneous blood flow (Table 1; Fig. 1B) compared to continuous iontophoresis or the 30/30 sequence. We noted that the pulsed iontophoresis of NaCl (10/50 sequence) induced a significant early increase in cutaneous blood flow in comparison with continuous iontophoresis. Skin resistance measures were negatively correlated with current intensity delivered., Conclusion: In conclusion, pulsed iontophoresis of treprostinil with a 10 s/50 s (On/Off) protocol at 600 μA increases the efficacy of iontophoresis at 0.064 mM but not at a tenfold higher concentration. Pulsed iontophoresis could be used to optimize treprostinil iontophoresis, to provide similar efficacy with decreased costs, and should now be tested on humans., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Skin blood flow (SBF) indexes have been used to describe physiological mechanisms associated with spinal manual therapy (SMT). The aims of the current review were to assess methods for data collection, assess how investigators interpreted SBF changes, and formulate recommendations to advance manual medicine research. A database search was performed in PubMed, Cochrane Library, the Physiotherapy Evidence Database, and the Cumulative Index to Nursing and Allied Health Literature through April 2014. Articles were included if at least 1 outcome measure was changes in 1 SBF index following SMT. The database search yielded 344 records. Two independent authors applied the inclusion criteria. Twenty studies met the inclusion criteria. Selected studies used heterogeneous methods to assess short-term post-SMT changes in SBF, usually vasoconstriction, which was interpreted as a general sympathoexcitatory effect through central mechanisms. However, this conclusion might be challenged by the current understanding of skin sympathetic nervous activity over local endothelial mechanisms that are specifically controlling SBF. Evaluation of SBF measurements in peripheral tissues following SMT may document physiological responses that are beyond peripheral sympathetic function. Based on the current use of SBF indexes in clinical and physiological research, 14 recommendations for advancing manual medicine research using laser Doppler flowmetry are presented., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

In kidney transplantation, conversion to mammalian target of rapamycin (mTOR) inhibitors may avoid calcineurin inhibitor (CNI) nephrotoxicity, but its impact on post-transplant allo-immunization remains largely unexplored. This retrospective cohort study analyzed the emergence of donor-specific antibodies (DSA) in kidney transplant recipients relative to their immunosuppressive therapy. Among 270 recipients without pretransplant immunization who were screened regularly for de novo DSA, 56 were converted to mTOR inhibitors after CNI withdrawal. DSA emergence was increased in patients who were converted to mTOR inhibitors (HR 2.4; 95% CI 1.06-5.41, P = 0.036). DSA were mainly directed against donor HLA-DQB1 antigens. The presence of one or two DQ mismatches was a major risk factor for DQ DSA (HR 5.32; 95% CI 1.58-17.89 and HR 10.43; 95% CI 2.29-47.56, respectively; P < 0.01). Rejection episodes were more likely in patients converted to mTOR inhibitors, but this difference did not reach significance (16% vs. 7.9%, P = 0.185). Concerning graft function, no significant change was observed one year after conversion (P = 0.31). In conclusion, conversion to mTOR inhibitors may increase the risk of developing class II DSA, especially in the presence of DQ mismatches: this strategy may favor chronic antibody-mediated rejection and thus reduce graft survival., (© 2014 Steunstichting ESOT.)

Introduction: Nonadherence to immunosuppressive (IS) therapy is associated with poor outcomes. Identifying factors predicting poor adherence is therefore essential. The primary objective of this study was to test whether parameters of a model adapted from the theory of planned behavior, and more specifically attitudes that are influenced by beliefs and satisfaction with medication, could predict adherence in solid organ transplant patients., Methods: Adherence was assessed with a self-reported medication adherence scale and IS blood trough concentrations over 6 months, in four transplant units. Satisfaction and beliefs were assessed using the Treatment Satisfaction with Medicines Questionnaire (SATMED-Q) and Beliefs about Medicines Questionnaire (BMQ), respectively. Theory of planned behavior was assessed with a specific questionnaire exploring intentions, subjective norms, attitudes and perceived behavioral control. Treatment characteristics and socioeconomic data were also collected., Results: One hundred and fifty-three solid organ transplant patients were enrolled, including lung (n=33), heart (n=43), liver (n=42), and kidney (n=44) patients. Satisfaction and positive beliefs about medication were higher in adherent than those in nonadherent patients. Factors independently associated with an increased risk of nonadherence were negative general beliefs about medications (odds ratio [OR]=0.89 [0.83-0.97]), living alone (OR=2.78 [1.09-7.09]), heart transplantation (OR=3.49 [1.34-9.09]), and being on everolimus (OR=5.02 [1.21-20.8])., Conclusion: Negative beliefs toward medications were shown to be an independent risk factor of poor adherence. Therefore, the BMQ could be an effective, easy to implement tool, for use in everyday practice, to identify patients needing interventions to improve adherence to IS.

Objectives: Postocclusive reactive hyperemia is mediated by two major mediators: sensory nerves and endothelium-derived hyperpolarizing factors. We hypothesized that the skin microvascular response to 5 min ischemia would differ depending upon the hand location in patients with systemic sclerosis (SSc), primary Raynaud's phenomenon (PRP) and healthy controls., Methods: Fifteen patients with SSc, 15 sex- and age-matched patients with PRP and healthy controls were enrolled. Their right hands were subjected to 5 min ischemia followed by a postocclusive hyperemia test, with local microcirculation monitoring by laser speckle contrast imaging on the dorsal face of the hand., Results: Postocclusive reactive hyperemia was abnormal in terms of peak and area under the curve (AUC) on all fingers except the thumb in patients with SSc and PRP compared with controls. In contrast, the kinetics of the response was longer only in SSc patients, with mean (SD) time to peak on the index, middle and ring finger were respectively 72 (58), 73 (51) and 67 (47) s for SSc; 40 (20), 40 (20) and 36 (19) s for PRP; and 34 (30), 34 (30) and 29 (24) s for controls (P=0.009 for interaction)., Conclusions: We observed decreased distal digital microvascular perfusion following 5 min of ischemia in patients presenting with PRP or SSc, while the kinetics was prolonged only in SSc. A dynamic assessment of digital skin blood flow using laser speckle contrast imaging following 5 min ischemia could be used as a tool to assess microvascular abnormalities in patients with Raynaud's phenomenon secondary to SSc., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Objectives: One of the most important skin complications in systemic sclerosis (SSc) is digital ulceration. Local thermal hyperemia (LTH) in the skin is a biphasic response to local heating involving both neurovascular and endothelial responses. Since LTH is abnormal in SSc patients, we aimed at testing whether LTH could be a prognostic tool for the onset of digital ulcers., Methods: We prospectively enrolled 51 patients with SSc. Nailfold capillaroscopy and LTH were recorded at baseline, and patients were followed for 3 years., Results: No patient with a LTH peak/plateau ratio ≥1 (n=19) developed digital ulcerations during the 3 year follow-up (100% negative predictive value), while 6 out of 32 patients with a LTH peak/plateau ratio <1 at enrolment presented with finger pad ulcerations within 3 years (p=0.05). In contrast, when lidocaine/prilocaine was applied to the finger pad, no relationship between thermal hyperemia and digital ulcerations was observed., Conclusions: A LTH peak/plateau ratio on the finger pad greater than 1, which can easily be determined in routine clinical practice, could be used to reassure patients, whatever the subtype of SSc, about the low probability of future digital ulceration. However, the prognostic value of this parameter should be confirmed in a larger cohort., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Bosentan is an endothelin receptor antagonist used as a first-line treatment in pulmonary arterial hypertension (PAH). Its main adverse effect is a dose-dependent liver toxicity. CYP2C9*2 has recently been shown to be associated with hepatotoxicity in PAH patients. We conducted a nested case-control study to further explore the relationship between functional polymorphisms of gene products involved in bosentan pharmacokinetics (OATP1B1, OATP1B3, and CYP2C9) or hepatobiliary transporters affected by bosentan (ABCB11) and bosentan-induced liver toxicity.

Ischemic digital ulcer (DU) is a serious complication of systemic sclerosis (SSc). Intravenous prostanoids are the only approved treatment for active DUs, but they induce dose-limiting side effects and require hospitalization. Our objective was to evaluate the effect of iontophoresis (a noninvasive drug delivery method) of treprostinil in SSc patients. Three studies were conducted: a pharmacokinetic study in 12 healthy volunteers showed that peak dermal concentration was reached at 2 hours, whereas plasma treprostinil was undetected. Then, a placebo-controlled, double-blind incremental dose study assessed the effect of treprostinil on digital skin blood flow in 22 healthy subjects. The effect of the highest dose was then compared with that of placebo in 12 SSc patients. Treprostinil significantly increased skin blood flow in healthy subjects (P = 0.006) and in SSc patients (P = 0.023). In conclusion, digital iontophoresis of treprostinil is feasible, is well tolerated, and increases digital skin perfusion. It could be tested as a treatment for SSc-related DUs.

Raynaud's phenomenon (RP) is characterised by transient ischaemia in the extremities in response to cold or emotions. It can be primary (idiopathic) or secondary to an underlying disease. The pathophysiology of RP is multifactorial and complex. Microvascular impairment is a hallmark of the disease. The objective of this work is to review the different pharmacological treatments currently used in the management of RP, from their mechanism of action to the available evidence regarding their efficacy. We also propose to discuss potential pharmacological targets such as the potentiation of the nitric oxide pathway, or the inhibition of the RhoA-Rho kinase pathway. The last part of this review deals with drug-induced RP. Among various medications, beta-blockers, interferons, tyrosine-kinase inhibitors or cytotoxic agents such as bleomycin are involved., (© 2014 Société Française de Pharmacologie et de Thérapeutique.)

Iontophoresis is a method of non-invasive transdermal drug delivery based on the transfer of charged molecules using a low-intensity electric current. Both local and systemic administration are possible; however, the skin pharmacokinetics of iontophoretically delivered drugs is complex and difficult to anticipate. The unquestionable theoretical advantages of the technique make it attractive in several potential applications. After a brief review of the factors influencing iontophoresis, we detail the current applications of iontophoresis in therapeutics and the main potential applications under investigation, including systemic and topical drugs and focusing on the treatment of scleroderma-related ulcerations. Finally, we address the issue of safety, which could be a limitation to the routine clinical use of iontophoresis., (© 2013 The British Pharmacological Society.)

Introduction: Recent controlled trials have assessed the efficacy of phosphodiesterase-5 (PDE-5) inhibitors in secondary Raynaud's phenomenon (RP). However, the conclusions are conflicting, and whether these drugs are effective remains unclear. The objective of this meta-analysis was to determine the efficacy of PDE-5 inhibitors on Raynaud's Condition Score (RCS) and frequency and duration of attacks., Methods: A systematic review of articles was performed (sources included Medline, Embase, Web of Science, the Cochrane Central Register of Controlled Trials). Only double-blind, randomised controlled trials (RCTs) were included. Studies were selected independently by two authors using predefined data fields, including study quality indicators., Results: Six RCTs were included (one with sildenafil, one with modified-release sildenafil, three with tadalafil and one with vardenafil). PDE-5 inhibitors significantly decreased mean RCS by -0.46 (-0.74 to -0.17) (p=0.002), the daily frequency of ischaemic attacks by -0.49 (-0.71 to -0.28) (p<0.0001), and daily duration of RP attacks by -14.62 (-20.25 to -9.00) min (p<0.0001)., Conclusions: PDE-5 inhibitors appear to have significant but moderate efficacy in secondary RP. A further large RCT is needed.