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, PGI2 ) and its analogs have raised much pharmacological interest. In this review we detail how the PGI2 signaling pathway is much more complex than was initially anticipated, involving peroxisome proliferator-activated receptors (PPARs), prostaglandin transporters (PGTs), and PGI2 –thromboxane A2 (TXA2 ) receptor (IP TP) heterodimerization. We discuss the distinct affinities of PGI2 analogs for prostanoid receptors. In addition, we introduce the new direct and indirect pharmacological approaches to targeting the PGI2 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.
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.
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.
Subgroups of capillaroscopic scleroderma landscape have been correlated with stages of SSc: two groups for Maricq's classification (slow and active), and three for Cutolo's classification (early, ...active and late). We report inter- and intra-observer agreement for these classifications as a preliminary step in the multicentre prospective SCLEROCAP study, which aims to assess the classification and single capillaroscopic items as prognostic tools for SSc.
SCLEROCAP included 385 patients. Agreement was studied in the first 100 patients, who were independently rated twice by two observers, blind to patients' characteristics; 30 of the patients were rated once by six observers. After consensus meetings, these ratings were held again. Kappa and intraclass correlation coefficients were used to assess agreement.
Interobserver agreement on 100 patients was moderate for Maricq and Cutolo classifications κ 0.47 (0.28, 0.66) and 0.49 (0.33, 0.65), respectively, and became substantial after consensus meetings 0.64 (0.50, 0.77) and 0.69 (0.56, 0.81). Intra-observer agreement between two observers was moderate to substantial: κ 0.54 (0.33, 0.75) and 0.70 (0.57, 0.83) for Maricq's classification; 0.57 (0.38, 0.77) and 0.76 (0.65, 0.87) for Cutolo's. Thirty patients were rated once by each of six observers, and agreement was moderate to substantial: κ 0.57 ± 0.10 (Maricq) and 0.61 ± 0.12 (Cutolo). Agreement was substantial for bushy, giant capillaries and microhaemorrhages, moderate for capillary density and low for oedema, disorganization and avascular areas.
The moderate reproducibility of Maricq and Cutolo classifications might hamper their prognostic value in SSc patients. Consensus meetings improve reliability, a prerequisite for better prognostic performances. A focus on giant capillaries, haemorrhages and capillary density might be more reliable.
Lower-limb ulcers in systemic sclerosis patients are rarely reported. The aim of this study was to describe the main causes and outcomes of lower-limb ulcers in systemic sclerosis patients and to ...assess factors associated with ischemic causes (arterial disease and/or microvascular impairment). A retrospective, multicentre, case-control study was conducted in 2013 and 2014, including 45 systemic sclerosis patients presenting lower-limb ulcers between 2008 and 2013. The estimated prevalence of lower-limb ulcers among systemic sclerosis patients was 12.8%. Ulcers were related to venous insufficiency in 22 cases (49%), ischemic causes in 21 (47%) and other causes in 2 (4%). Complete healing was observed in 60% of cases in a mean time of 10.3 months; 59% relapsed during a mean follow-up of 22 months. Ischemic lower-limb ulcers outcomes were poor, with a 28.6% amputation rate. Logistic-regression multivariate analyses between ischemic lower-limb ulcers cases and matched systemic sclerosis-controls identified past or concomitant digital ulcer and cutaneous sclerosis of the feet as independent risk factors associated with ischemic lower-limb ulcers.
Background Apart from compression therapy, physical therapy has scarcely been evaluated in the treatment of chronic venous disorders (CVDs). Spa treatment is a popular way to administer physical ...therapy for CVDs in France, but its efficacy has not yet been assessed in a large trial. The objective was to assess the efficacy of spa therapy for patients with advanced CVD (CEAP clinical classes C4-C5). Methods This was a single-blind (treatment concealed to the investigators) randomized, multicenter, controlled trial (French spa resorts). Inclusion criteria were primary or post-thrombotic CVD with skin changes but no active ulcer (C4a, C4b, or C5). The treated group had the usual 3-week spa treatment course soon after randomization; the control group had spa treatment after the 1-year comparison period. All patients continued their usual medical care including wearing compression stockings. Treatment consisted of four balneotherapy sessions per day for 6 days a week. Follow-up was performed at 6, 12 and 18 months by independent blinded investigators. The main outcome criterion was the incidence of leg ulcers at 12 months. Secondary criteria were a modified version of the Venous Clinical Severity Score, a visual analog scale for leg symptoms, and the Chronic Venous Insufficiency Questionnaire 2 and EuroQol 5D quality-of-life autoquestionnaires. Results Four hundred twenty-five subjects were enrolled: 214 in the treatment group (Spa) and 211 in the control group (Ctr); they were similar at baseline regarding their demographic characteristics, the severity of the CVD, and the outcome variables. At 1 year, the incidence of leg ulcers was not statistically different (Spa: +9.3%; 95% confidence interval CI, +5.6 - +14.3; Ctr: +6.1%; 95% CI, +3.2 - +10.4), whereas the Venous Clinical Severity Score improved significantly in the treatment group (Spa: −1.2; 95% CI, −1.6 - −0.8; Ctr: −0.6; 95% CI, −1.0 - −0.2; P = .04). A significant difference favoring spa treatment was found regarding symptoms after 1 year (Spa: −0.03; 95% CI, −0.57 - +0.51; Ctr: +0.87; 95% CI,+0.46 - +1.26; P = .009). EuroQol 5D improved in the treatment group (Spa: +0.01; 95% CI, −0.02 - +0.04) while it worsened (Ctr: −0.07; 95% CI, −0.10 - −0.04) in the control group ( P < .001). A similar pattern was found for the Chronic Venous Insufficiency Questionnaire 2 scale (Spa: −2.0; 95% CI, −4.4 - +0.4; Ctr: +2.4; 95% CI, +0.2 - +4.7; P = .008). The control patients showed similar improvements in clinical severity, symptoms, and quality of life after their own spa treatment (day 547). Conclusions In this study, the incidence of leg ulcers was not reduced after a 3-week spa therapy course. Nevertheless, our study demonstrates that spa therapy provides a significant and substantial improvement in clinical status, symptoms, and quality of life of patients with advanced venous insufficiency for at least 1 year.
Slow-flow superficial vascular malformations (VMs) are rare congenital anomalies that can be responsible for pain and functional impairment. Currently, we have no guidelines for their management, ...which can involve physical bandages, sclerotherapy, surgery, anti-inflammatory or anti-coagulation drugs or no treatment. The natural history is progressive and worsening. Mammalian target of rapamycin (mTOR) is a serine/threonine kinase that acts as a master switch in cell proliferation, apoptosis, metabolism and angio/lymphangiogenesis. Sirolimus directly inhibits the mTOR pathway, thereby inhibiting cell proliferation and angio/lymphangiogenesis. Case reports and series have reported successful use of sirolimus in children with different types of vascular anomalies, with heterogeneous outcomes.
The objective of this trial is to evaluate the efficacy and safety of sirolimus in children with complicated superficial slow-flow VMs.
This French multicenter randomized observational-phase, phase 2 trial aims to include 50 pediatric patients 6 to 18 years old who have slow-flow (lymphatic, venous or lymphatico-venous) voluminous complicated superficial VM. Patients will be followed up for 12 months. All patients will start with an observational period (no treatment). Then at a time randomly selected between month 4 and month 8, they will switch to the experimental period (switch time), when they will receive sirolimus until month 12. Each child will undergo MRI 3 times: at baseline, at the switch time, and at month 12. For both periods (observational and treatment), we will calculate the relative change in volume of the VM divided by the study period duration. This relative change weighted by the study period duration will constitute the primary endpoint. VM will be measured by MRI images, which will be centralized and interpreted by the same radiologist who will be blinded to the study period. Hence, each patient will be his/her own control. Secondary outcomes will include assessment of safety and efficacy by viewing standardized digital photographs and according to the physician, the patient or proxy; impact on quality of life; and evolution of biological makers (coagulation factors, vascular endothelial growth factor, tissue factor).
The main benefit of the study will be to resolve uncertainty concerning the efficacy of sirolimus in reducing the volume of VMs and limiting related complications and the safety of the drug in children with slow-flow VMs. This trial design is interesting in these rare conditions because all included patients will have the opportunity to receive the drug and the physician can maintain it after the end of the protocol if is found efficient (which would not be the case in a classical cross-over study).
ClinicalTrials.gov Identifier: NCT02509468 , first received: 28 July 2015. EU Clinical Trials Register EudraCT Number: 2015-001096-43.
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.
The treatment of systemic sclerosis-related digital ulcers is challenging. Although the only effective drugs are prostacyclin analogs, their use is limited by vasodilation-related adverse reactions. ...In this study, we assessed the local iontophoresis administration of three soluble guanylate cyclase (A-350619 3-2-(4-chlorophenyl)thiophenyl-N-4-(dimethylamino)butyl-2-propenamide hydrochloride, SIN-1 amino-3-morpholinyl-1,2,3-oxadiazolium chloride, and CFM 1571 3-3-(dimethylamino)propoxy-N-(4-methoxyphenyl)-1-(phenylmethyl)-1H-pyrazole-5-carboxamide hydrochloride) and two nonprostanoid prostaglandin I2 (prostacyclin) receptor agonists (MRE-269 4-(5,6-diphenylpyrazinyl)(1-methylethyl)aminobutoxy-acetic acid and BMY 45778 3-(4,5-diphenyl2,4'-bioxazol-5'-yl)phenoxyacetic acid) to induce vasodilation onto the hindquarters of anesthetized rats. Skin blood flow was quantified using laser Doppler imaging during the whole experience, and safety was assessed by continuous recording of blood pressure and histopathological examination. Anodal iontophoresis of A-350619 (7.54 mM) induced a sustained increase in cutaneous blood flow (P = 0.008 vs. control). All other drugs exhibited poor or no effect on skin blood flow. Vasodilation with A-350619 iontophoresis was concentration-dependent (7.5, 0.75, and 0.075 mM; P < 0.001, Jonckheere-Terpstra trend test), and repeated administrations do not suggest any risk of tolerance. This study also compared continuous versus intermittent iontophoresis protocols. Continuous anodal iontophoresis of A-350619 at 7.5 mM increases cutaneous blood flow with good local tolerance. Iontophoresis of soluble guanylate cyclase stimulators should be investigated as potential local therapy for digital ulceration in patients with scleroderma.
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