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The aim of this double-blind, placebo-controlled study was to evaluate the efficacy of 100 mg Pycnogenol daily (oral capsules) in a 3 month study in patients with osteoarthritis (OA). OA symptoms were evaluated by WOMAC scores, mobility by recording their walking performance (treadmill). Treatment (77 patients) and placebo group (79) were comparable for age, sex distribution, WOMAC scores, walking distances and use of antiinflammatory drugs. The global WOMAC score decreased by 56% (p < 0.05) in the treatment group versus 9.6% in the placebo group. Walking distance in the treadmill test was prolonged from 68 m at the start to 198 m after 3 months treatment (p < 0.05), under placebo, from 65 m to 88 m (NS). The use of drugs decreased by 58% in the treatment group (p < 0.05) versus 1% under placebo. Gastrointestinal complications decreased by 63% in the treatment group, but only 3% under placebo. Overall, treatment costs were reduced significantly compared with placebo. Foot edema was present in 76% of the patients of the treatment group at inclusion and in 79% of the controls. After 3 months edema decreased in 79% of Pycnogenol patients (p < 0.05) vs 1% in controls. In conclusion, Pycnogenol offers an option for reduction of treatment costs and side effects by sparing antiinflammatory drugs. [ABSTRACT FROM AUTHOR]

In 32 patients with chronic venous insufficiency and venous hypertension associated with ulcerations, the effects of the local application of a hydrogen peroxide cream (Crystacide) applied onto the skin was evaluated using a complex, proportional, microcirculatory model to assess and quantify venous microangiopathy after local treatment. A comparative group treated without Crystacide was included. Laser Doppler flowmetry was used to assess skin perfusion (flux and venoarteriolar response) in association with transcutaneous PO2 and PCO2 measurements. Local plasma free radicals were evaluated in the area surrounding the venous ulcer using the D-Roms test. Crystacide was applied around and on the ulcer for 10 days. Crystacide was more effective than the control treatments. PO2 was increased (improved, P < .05), and plasma free radicals, PCO2, and laser Doppler flowmetry were decreased (improving toward normal values, P < .05). Also, the ulcerated area was significantly smaller at 10 days in the Crystacide group in comparison with controls (P < .05). In the proportional microcirculatory model, all parameters indicated an important level of improvement significantly larger than in controls. In conclusion, in chronic venous insufficiency and venous ulcerations, local treatment with Crystacide (10 days) improves the microcirculation and decreases skin free radicals, thus improving healing. [ABSTRACT FROM AUTHOR]

The aim of this open study was the evaluation of the effects of HR (Venoruton) at a dose of 1 g/day on the prevention and control of flight microangiopathy and edema in subjects with varicose veins and moderate chronic venous insufficiency flying for more than 11 hours. Patients with varicose veins, edema, but without initial skin alterations or complications, were included. Measurements of skin laser Doppler (LDF) resting flux (RF) venoarteriolar response (VAR), ankle swelling (RAS), and edema were made within 12 hours before and within 3 hours after the flights. The resulting edema after the flights was evaluated with a composite edema score (analogue scale line). A group of 20 subjects was treated with HR (1 g/day, starting 2 days before the flight and 1 g for every 12 hours on day of travel). Another group of 18 subjects formed the control group. The length of the flights was between 11 and 13 hours; all seats were in coach class. Fifty patients were enrolled and 38 patients were evaluable at the end of the trial. The 2 groups (treatment and control) were comparable for age and sex distribution. The decrease in RF was significant in both groups with a higher flux at the end of the flight in the HR group (p < 0.05). The venoarteriolar response was decreased at the end of the flights; the decrease was lower in the HR group (p < 0.05). The increase in RAS and the edema score were significantly lower in the HR group. In conclusion HR is useful for reducing the level of microangiopathy and the increased capillary filtration and in controlling edema in patients with venous disease in long flights. The higher level of flux and VAR and the reduction in edema indicate a positive effect of HR on the microcirculation. This study confirms that HR prophylaxis is effective to control flight microangiopathy associated with edema. [ABSTRACT FROM AUTHOR]

Background: This retrospective registry study evaluated different managements on the development of post-thrombotic syndrome (PTS) and recurrent deep venous thrombosis (R-DVT). The effects of aspirin (100 mg/day), added to the "standard management" (SM) (IUA consensus), were observed in patients after a proximal DVT., Methods: The study started after the anticoagulant period. Comparable groups used the mild-antithrombotic agent Pycnogenol® (200 mg/day), ticlopidine (250 mg/day) or sulodexide (500 ULS/day)., Results: The groups were comparable for sex and age distribution and clinical pictures. In the SM group, 222 patients completed the follow-up (72 months). With SM, the percentage of patients with R-DVT (requiring anticoagulants) was 17.2%; 19.8% of SM patients had a PTS. In the aspirin group (202 subjects), R-DVT was observed in 14.8% of patients; 17.32% had a PTS. The reduction in R-DVT and PTS with aspirin was significant (P<0.05) vs. the SM. There was no tolerability problem in subjects using Pycnogenol® (137 patients); they had a much lower incidence of R-DVT (5.8%) and PTS (6.5%) vs. SM and aspirin (P<0.05). Ticlopidine (121 patients) reduced the incidence of R-DVT (12.4%) and PTS (19.8% of patients) (P<0.05 vs. SM). With sulodexide the incidence of R-DVT was 6.7% (P<0.05 vs. SM); the incidence of PTS was 16.6% (P<0.05 vs. SM). The combined R-DVT+PT syndrome was observed in 14.9% of subjects using SM and in 12.9% of subjects using aspirin (P<0.05 vs. SM), in 3.6% of subjects managed with Pycnogenol® (<0.05% vs. aspirin and all other managements). The incidence was 10.74% with ticlopidine and 6.7% with sulodexide (both significantly lower than SM)., Conclusions: Interaction between PTS and R-DVT are complex; recurrences cause more PTSs, and a post-thrombotic limb is prone to R-DVT. Aspirin, for patients that can tolerate it, reduces the occurrence of PTS and R-DVT. In addition, ticlopidine and sulodexide are effective. Pycnogenol® is the most effective and safe for R-DVT and particularly PTS. Its full range of anti-thrombotic activity is now under evaluation.

The aim of this registry study was to compare products used to control symptoms of CVI. Endpoints of the study were microcirculation, effects on volume changes, and symptoms (analogue scale). Pycnogenol, venoruton, troxerutin, the complex diosmin-hesperidin, Antistax, Mirtoselect (bilberry), escin, and the combination Venoruton-Pycnogenol (VE-PY) were compared with compressions. No safety or tolerability problems were observed. At inclusion, measurements in the groups were comparable: 1,051 patients completed the registry. Best performers : Venoruton, Pycnogenol, and the combination VE-PY produced the best effects on skin flux. These products and the combination VE-PY better improved PO 2 and PCO 2 . The edema score was decreased more effectively with the combination and with Pycnogenol. Venoruton; Antistax also had good results. Considering volumetry, the best performers were the combination PY-VE and the two single products Venoruton and Pycnogenol. Antistax results for edema were also good. The best improvement in symptoms score were obtained with Pycnogenol and compression. A larger decrease in oxidative stress was observed with Pycnogenol, Venoruton, and with the VE-PY combination. Good effects of Antistax were also observed. Parestesias were lower with Pycnogenol and with Antistax. Considering the need for interventions, the best performers were Pycnogenol, VE-PY, and compression. The efficacy of Pycnogenol and the combination are competitive with stockings that do not have the same tolerability in warmer climates. A larger and more prolonged evaluation is suggested to evaluate cost-efficacy (and non-interference with drugs) of these products in the management of CVI. The registry is in progress; other products are in evaluation.

The aim of this registry was to evaluate the management of initial symptoms of benign prostatic hyperthrophy (BPH) in otherwise healthy subjects, using Prostaquil® (Alchem) in a 8-week registry. Prostaquil was used at the dosage of 200 mg/day. The product includes Pygeum extract (100 mg) and Saw palmetto oil (35 mg). The two resulting groups standard management and supplement) were comparable., Results: No side effects or comparability problems were observed and compliance was optimal with more than 95% of the capsules correctly used. Empting, frequency, intermittency, urgency, weak flow, straining, nocturia were all significantly improved with Prostaquil (p<0.05) and the improvement - globally and evaluating any single item - was significantly superior to the one observed in controls (p<0.05). Quality of life with the supplement was also significantly better in comparison with controls (p<0.05). The residual vescical volume was 94.7;5,8 ml in the supplement group at inclusion and decreased to 39.3;5 ml (p<0.05) at 8 weeks. This decrease was equivalent to a reduction of 58.5%(vs a decrease of 27.9% in controls)(p<0.05; ANOVA). In conclusion, the most common symptoms of BPH are controlled by Prostaquil a new standardized supplement including Pygeum.

Aim: The aim of this open, observational registry was to evaluate the effects of antithrombotic treatment on the development of postthrombotic syndrome (PTS): the effects of "standard management" (SM; according to International Union of Angiology guidelines) were compared to SM in association with sulodexide or aspirin., Methods: Postthrombotic syndrome occurrence was observed in 3 nonparallel groups after deep venous thrombosis (DVT); the registry started after the end of the anticoagulation period. The target was to observe the occurrence of PTS in 5 years. Three possible options were suggested to the patients, and the patients and their caregivers defined the type of management. A group of 167 patients was involved in the SM with reevaluation every 6 months; the sulodexide group included 124 patients and the aspirin group included 48 patients., Results: The 3 groups were clinically similar and comparable for age and sex distribution. Of the 167 patients in the SM group, 154 patients completed 60 months of follow-up. The percentage of patients with PTS in the SM group ranged from 14.9% (1 year after the end of anticoagulation) to 19.5% (60 months). In the nonparallel group using sulodexide (124 comparable patients at inclusion; 115 at 60 months), the percentage of PTS was variable from 8.8% (1 year after anticoagulants) to 12.17% at 60 months. These percentages are significantly lower than those observed with SM. In the nonparallel aspirin group (48 patients at inclusion and 34 at 54 months), there was a PTS incidence of 23.5% at 54 months (vs 12.17% in the sulodexide group and 18.23% in the SM group). The incidence of PTS was significantly higher in comparison with the other 2 groups. The incidence of PTS was lower in the sulodexide group in comparison with the 2 other groups., Conclusions: Sulodexide administration after DVT appears to be effective in preventing PTS in association with recommended management and a number of recurrent DVTs. Modalities of treatment, dosages, and timing of administration should be explored in more comprehensive and complete studies., (© The Author(s) 2014.)

Aim: The aim of this registry study was to evaluate the efficacy of Pycnogenol® (Horphag Research Ltd.), a standardized extract from the French maritime pine bark, to control signs/symptoms and prevent complications associated with hemorrhoids in the months after delivery in healthy women., Methods: Women with hemorrhoids after their second pregnancy were included within the third month after pregnancy. Pycnogenol dosage was 150 mg/day for 6 months. Symptoms for 4th and 3rd degree hemorrhoids were evaluated., Results: The registry groups were comparable. For 4th degree hemorrhoids, main symptoms were reduced after 6 months in all patients, but the group using Pycnogenol in addition to standard best management showed more improvement. In patients with 3rd degree hemorrhoids, symptoms were reduced in both management groups at 6 months; with Pycnogenol the reduction in symptoms scores was significantly better. At 6 months 18/24 subjects (75%) in the Pycnogenol group were symptom-free in comparison with 14/25 (56%) in controls. In the 4th degree hemorrhoid group, 7/10 patients (70%) in the Pycnogenol group were symptom-free at 6 months in comparison with 4/11 subjects (36%) in the best management group. No significant side effects were observed., Conclusion: Pycnogenol appears to positively affect hemorrhoid signs and symptoms in the months after pregnancy.

Background: In the present study, the improvement of diabetic microangiopathy and retinopathy was evaluated in 38 diabetic patients treated with a novel curcumin phospholipids delivery form (Meriva®)., Methods: Diabetes was diagnosed at least 5 years before inclusion and all patients had signs of retinal oedema and of peripheral microangiopathy. Meriva® was administered at the dosage of 2 tablets/day (each tablet containing 500 mg Meriva® corresponding to 100 mg curcumin) for a period of at least 4 weeks in addition to the standard management plan, while a comparable group of subjects (n = 39) followed the standard management plan alone., Results: All subjects (treatment and controls) completed the follow-up period, there were no dropouts and Meriva® showed an optimal tolerability. At 4 weeks, microcirculatory and clinical evaluations indicated an improvement of microangiopathy. In terms of peripheral microangiopathy, in the Meriva® group, there was a significant improvement in the venoarteriolar response (p<0.05) and a decrease in the score of peripheral oedema (p<0.05), a sign typically associated with the failure of the venoarteriolar response. At the retinal level, high-resolution, duplex scanning, used to measure retinal flow, showed improvements in the Meriva® treated patients. The evaluation of retinal oedema (Steigerwalt's scale) showed an improvement associated with improved visual acuity (Snellen scale). There were no clinical or microcirculatory effects in controls., Conclusion: These preliminary observations, indicate the value of curcumin, when administered in a bioavailable form as with Meriva®, in the management of diabetic microangiopathy and retinopathy.

Aim: Intermittent claudication (IC) in peripheral vascular disease is characterized by lower limb pain appearing on effort. Treatment with PGE1 has been successfully used to manage IC patients. This registry has evaluated safety and costs of PGE1 in the management of IC., Methods: In this study a long-term treatment protocol (LTP), a short-term protocol (STP) and an outpatient (OP), "on-demand" treatment have been compared. A treadmill effort test has been used to evaluate walking distance. The follow up for these three protocols was 40 weeks. PGE1 treatment was associated to a risk reduction plan and to an exercise program., Results: The final analysis has included 252 LTP patients, 223 STP patients and 284 OP patients (total 659 valid cases). A group of 171 comparable patients not treated with PGE1 was used for a parallel comparison. Cardiovascular mortality and morbidity has been evaluated in 731 PGE1 patients completing 24 months of follow up. All protocols have been well tolerated. No side effects were observed. The lower cost has been observed for OP patients. In the long term, mortality and morbidity were lower in patients treated with PGE1 in comparison with patients not treated with PGE1., Conclusion: Considering costs and results (increase in walking distance) and improvement in Karnofsky scale the STP plan appears to be better than LTP for IC patients. The OP, "on-demand" treatment offers further improvements. This last treatment plan is simpler; the plan allows better timing for exercise. The treatment can be used even in non-specialized centers.

Aim: The aim of the present study was to evaluate the improvement of diabetic microangiopathy in patients suffering from this condition since at least five years, and whose disease was managed without insulin., Methods: Curcumin, the orange pigment of turmeric, has recently received increasing attention because of its antioxidant properties, mediated by both direct oxygen radical quenching and by induction of anti-oxidant responses via Nrf2 activation. This aspect, combined with the beneficial effects on endothelial function and on tissue and plasma inflammatory status, makes curcumin potentially useful for the management of diabetic microangiopathy. To further evaluate this, Meriva, a lecithinized formulation of curcumin, was administered at the dosage of two tablets/day (1 g Meriva/day) to 25 diabetic patients for four weeks. A comparable group of subjects followed the best possible management for this type of patients., Results: All subjects in the treatment and control group completed the follow-up period; there were no dropouts. In the treatment group, at four weeks, microcirculatory and clinical evaluations indicated a decrease in skin flux (P<0.05) at the surface of the foot, a finding diagnostic of an improvement in microangiopathy, the flux being generally increased in patients affected by diabetic microangiopathy. Also, a significant decrease in the edema score (P<0.05) and a corresponding improvement in the venoarteriolar response (P<0.05) were observed. The PO2 increased at four weeks (P<0.05), as expected from a better oxygen diffusion into the skin due to the decreased edema. These findings were present in all subjects using Meriva, while no clinical or microcirculatory effects were observed in the control group., Conclusion: Meriva was, in general, well tolerated, and these preliminary findings suggest the usefulness of this curcumin formulation for the management of diabetic microangiopathy, opening a window of opportunities to be evaluated in more prolonged and larger studies. The molecular mechanisms involved in the beneficial effects of curcumin on microcirculation and edema are also worth investigation.

Aim: The aim of this study was to test mf Odondovis Calcium® as a food supplement in a 3-month product evaluation study measuring how the low jaw bone density, could be improved. The upper jaw density was tested with an ultrasound method, evaluating the grey scale median of the images (GSM)., Methods: Seventy nine subjects were enrolled; 22 normal subjects (group A) and 57 with upper jaw osteoporosis (according to DEXA values). Patients were divided into 2 groups (group B and C, respectively 28 and 29 cases). These subjects were treated with what was considered the' best treatment' and in the group B only was added mf Odontovis Calcium®, consisting of calcium salts, Vitamin D and physiological modulators with antioxidant activity. This treatment continued for 3 months., Results: The GSM of osteoporotic patients was significantly lower in comparison with GSM in normal subjects. No changes were observed (between the inclusion and 3 month values) in normal subjects and minimal, non-significant changes were observed in control osteoporosis patients. Before-after treatment values of GSM in treatment patients showed a significant increase (P<0.022) at 3 months. The increase in GSM in these patients was significantly higher (P<0.05) in comparison with control patient with osteoporosis. The Tolerability of the product was very good and the compliance corresponded to 98%., Conclusion: the jaw density in patients with osteoporosis is increased in only 3 months with supplementation with mf Odontovis Calcium®. Long-term clinical implications should be observed in more prolonged studies.

Aim: This registry evaluation was conducted in post-thrombotic syndrome (PTS) patients (with a minimum five-year follow up). The study evaluated: 1) variations in peripheral edema with an analogue scoring system; 2) ankle circumference at the PTS limb in comparison with the normal contralateral limb., Methods: The difference was expressed in percent increase in circumference measured at the PTS limb; 3) other end-points were observed in a five-year follow-up that created a specific PTS registry. Subjects could follow a management system including: 1) compression; 2) compression and Venoruton® (1 g/day); 3) compression and Venoruton® (2 g/day)., Results: The groups of patients with chronic venous insufficiency (CVI) resulted comparable. The occurrence of a new deep venous thrombosis (DVT) episode was considered a drop out. At five years there were four new DVTs (in 90 patients) in the compression group. There was one case (90 patients included) in the compression and HR (1 g) group and no DVT in group 3. The outcome in groups 2 and 3 was significantly better (0.05) than in group 1. The need for surgery or sclerotherapy (for larger varicose veins), the occurrence of lipodermatosclerosis and ulcerations were significantly lower in the HR groups with a better outcome in the higher dose group (P<0.05). The number of ulcerations were also significantly reduced in the HR groups. The difference in ulcerations was significantly better in the higher dose group in comparison with the other groups (P<0.05). The edema score was significantly reduced at five years in the HR groups (P<0.05) in comparison with the compression group. The higher dose resulted more effective in controlling edema. Both edema score and ankle circumference at five years were significantly lower (P<0.05) in the HR-treated groups with a significant decrease in edema score and ankle circumference in the higher dosage group., Conclusion: The study confirms the long-term efficacy of HR in PTS, CVI patients. Controlling signs/symptoms and edema in CVI with HR prevents the most severe complications of CVI including lipodermatosclerosis and venous ulcerations. An early therapeutic program including exercise, risk factor controls, compression an edema-controlling treatment with HR is effective in decreasing the classic complications of PTS syndrome. The important restrictions and difficulties to the use of elastic stockings (in regions with warmer climates) are not applicable to HR that is well tolerated and can be used all the time alone or in association with compression.

Aim: The simplification of the management of asthma in the different clinical phases of this common chronic inflammatory disorder is the main goal of therapy. Pycnogenol®, a standardized extract of French maritime pine bark, inhibits expression of 5-lipoxygenase and consequently decreases leukotriene levels in asthmatic patients. Pycnogenol® anti-inflammatory activities may be supportive when taken in addition to inhalation corticosteroid (ICS), putatively allowing for a reduction in dosage and frequency of ICS administration., Methods: This study evaluated the efficacy of Pycnogenol® during a period of six months for improving allergic (mite in house dust) asthma management in patients with stable, controlled conditions. Pycnogenol® was used at a daily dosage of 100 mg, distributed as 50 mg in the morning at 9 am and again in the evening at 9 pm). An individual patient's asthma condition was graded in five steps based on the daily dosage of inhaled fluticasone propionate with step 1 indicating 0 µg and step 5 the maximum dose of 500 µg ICS twice daily., Results: A total 76 patients were enrolled for this study. The group taking Pycnogenol® in addition to ICS and the group taking only ICS were comparable for age, gender and clinical characteristics including FEV1. The analysis of therapeutic ranking steps showed that 55% of patients taking Pycnogenol® improved as judged by passing to a lower ICS dose step. In comparison, only 6% of patients depending exclusively on ICS progressed to a lower (ICS dose) therapeutic step. No deterioration (passage to a higher ICS therapeutic step) was observed in the Pycnogenol® group, whereas in 18.8% of patients depending exclusively on corticosteroids a deterioration requiring a higher dosage step was observed. The passage to different therapeutic steps was statistical significant between groups (P<0.05). Drop-outs were associated entirely to irregularities in follow-up and not due to medical reasons. No serious adverse events were observed in both groups and tolerability of Pycnogenol® was very good. The levels of asthma control in the 6 interventional months as compared to the same period in the previous year were compared. In the Pycnogenol® group, night-awakenings were less frequent, the number of days with PEF<80% were decreased, days with asthma score >1 were lower, requirement for salbutamol and additional asthma medication less frequent, and consultation of general practitioner and specialist required less commonly. All these parameters were statistical significantly improved in Pycnogenol® + ICS group versus the ICS control group where no considerable changes were observed. Various common signs and symptoms were evaluated by visual analog scale, (dry) cough, severity of chest symptoms, wheezing, dyspnea and daytime symptoms. In the ICS-only group values did not improve while they did improve significantly in the ICS + Pycnogenol® group (P<0.05 vs. ICS only group). A decrease by 15.2% of the specific IgE titer was found in the Pycnogenol® + ICS group, whereas the titer increased by 13.4% in the ICS-only group, while IgG1 and IgG4 remained unchanged in both groups., Conclusion: Pycnogenol® administration was effective for better control of signs and symptoms of allergic asthma and reduced the need for medication.

Aim: Venous ulcers are a common, chronic medical and social problem. These ulcers are difficult to heal in most patients with sustained venous hypertension. This pilot product evaluation registry study has evaluated the efficacy and safety of an antimicrobial silver oxide wound dressing ointment ("Silver Oxide Ointment") as part of the treatment of 'difficult' venous ulcerations., Methods: The study was conducted measuring the variations in the area of the ulceration and microcirculatory parameters., Results: After four weeks, treatment with the Silver Oxide Ointment proved more effective than the 'best management' used in controls. Transcutaneous PO2 was increased (improved); Laser Doppler skin flux and transcutaneous PCO2 were improved (decreased). Also in the silver oxide group a significantly higher number of venous ulcers were completely healed at four weeks. The silver oxide ointment improved both the microcirculation and the healing rate of their ulcers. No significant tolerability problems were observed., Conclusion: In difficult venous ulcerations, local treatment with this Silver Oxide Ointment, as one component of the total wound dressing, improved microcirculation measurements and healing rate. Most of the treatments were done at home by the patients or by their tutors. This study indicates the important role of this type of treatment and indicates the need to plan larger and more prolonged studies.

Aim: Post-thrombotic syndrome is a common complication following deep vein thrombosis. The aim of this twelve month registry study was to compare the efficacy of compression stockings and per oral administration of Pycnogenol® standardized pine bark extract on the severity and incidence of post thrombotic syndrome signs and symptoms., Methods: One hundred fifty-six patients with a single, major episode of proximal deep vein thrombosis (DVT) were assigned to one of three groups receiving treatment with either compression stockings (group 1), Pycnogenol® (group 2) or the combination of both (group 3) over an investigational period of one year. The study evaluated treatment on edema using a scoring system, the ankle circumference, and the limb volume as ratio to the healthy contralateral limb., Results: Two new incidents of DVT occurred in the group of 55 patients wearing compression stockings between the third and sixth months, whereas no DVT cases occurred in the two other groups which took Pycnogenol®. The edema symptom score was gradually decreased in all three groups during the one year treatment period. Pycnogenol® was significantly more effective from six months onwards than compression stockings for relieving edema symptoms (P<0.05). Symptoms were more effectively reduced with the combination of Pycnogenol® and compression stockings than with the individual regimen alone (P<0.05). Limb volume and ankle circumference were likewise more effectively reduced with Pycnogenol® plus stockings than with compression stockings alone after six months. Ambulatory venous pressure progressively decreased in all three groups after twelve months treatment as compared to baseline. Compression stockings and Pycnogenol® were of comparable efficacy, there were no significant differences of ambulatory venous pressure between groups following twelve months treatment. Laser Doppler flowmetry at the dorsum of feet showed improved micro-circulation which was further demonstrated by increased pO2 and decreased pCO2. Importantly, none of the patients developed ulcerations during the observational period., Conclusion: This study suggests that Pycnogenol® may have significant long-term protective efficacy for individuals following a thrombotic event. Moreover, Pycnogenol® appears to be at least as effective for post-thrombosis management as compression stockings, while the combination of both is superior. An important aspect is the patient compliance which was found to be much better in the Pycnogenol® group with two drop-outs due to non-medical reasons, whereas in the compression stockings group eighteen patients were lost to follow-up because wearing stockings at higher temperatures is bothersome.

Aim: This long-term (10-year) study evaluated the safety and efficacy of expanded polytetrafluoroethylene (ePTFE) external valve support (EVS) implants used for external valvuloplasty in the treatment of incompetence of the proximal long saphenous veins., Methods: During a 10-year follow-up, patients with superficial venous disease and venous hypertension due to pure superficial vein incompetence underwent an external valvuloplasty using an EVS with a PTFE suture. Forty-nine patients were included in the EVS group and 47 in the control group. Patients with superficial venous disease and venous hypertension due to pure superficial venous incompetence were randomised into two treatment groups. The first group was treated with what was considered "conventional treatment" (ligation or stripping) and the second with external valvuloplasty with EVS. This report deals with controls treated with ligation as only 6 cases (not mentioned in this report) were treated with stripping. There were no significant differences in the two groups concerning age, sex, or type of venous insufficiency. The procedures focused on only one single limb per patient., Results: 46.9% of limbs treated with EVS developed varices in comparison with 73% in the control group. New surgical procedures (localized ligation) were needed in 32.6% of the EVS patients vs. 55.3% in controls. Sclerotherapy was used in 42% of the EVS patients vs. 72.34% in controls. At 10 years the SFJ was incompetent (reflux) in 2 EVS patients (4%); one after 5 years and one after 7 years. There was no incompetence at the level of the ligated junction in controls. There were 62 incompetent venous sites (1.26 per limb) in the EVS group vs. 96 new incompetent venous sites (2.04 per limb) in controls. In controls 10.63% of the limbs developed minor discolorations and signs due to mild CVI; none was observed in the EVS group. In all ESV implants there was full restoration of competence at 1 year., Conclusion: EVS implants used to correct superficial venous incompetence at 10 years were well tolerated and produced good results on incompetence and on the evolution of varicose veins.

Aim: In addition to contemporary compression therapy, one of the therapeutic approaches is the use of a topical wound care agent. The goal of this pilot registry study is to evaluate the efficacy and safety of a uniquely designed ointment containing multivalent silver oxide (Ag4O4) in the healing of difficult diabetic or venous ulcerations., Methods: Patients who had ulcers resulting from chronic venous insufficiency or diabetes participated in this open-label, randomized registry study. All patients were evaluated by measuring both the area of the ulceration and microcirculatory parameters. 148 patients were included in the study and categorized into two main groups: venous ulcers and diabetic ulcers. Each main group was then randomized into two sub-groups: topical treatment with silver oxide ointment and the control group (standard cleaning and compression management methods, without silver ointment). All patients were treated with accepted cleaning and compression management. RESULTS. In subjects with venous ulcers: After 4 weeks, the silver treatment was more effective than the control group treatment: Skin PO2 was increased 2.1 times more than the control group (17.4% to 8.2%) and skin flux (RF) was improved 1.6 times more than the control group (-38.7% to -24.2%). The total surface area of the ulcer was significantly reduced in the silver treatment group by 1.9 times the control group (-88.7% to -46.9%). In addition, in the silver treatment group we observed complete closure of the ulceration in 42% of subjects compared to 22% in the control group (P=<0.05). In subjects with diabetic ulcers: after 4 weeks, the silver treatment was more effective than the control group treatment: Skin PO2 increased 2.6 times more than the control group (23.3% to 9.1%) and skin flux (RF) was significantly improved 4.3 times more than the control group(-26.7% to -6.2%). The total surface area of the ulcer was significantly reduced in the silver treatment group by 3.7 times the control group (-89.0% to -23.9%). In addition, in the silver treatment group we observed complete closure of the ulceration in 39% of subjects compared to 16% in the control group (P

Aim: Vascular access for hemodialysis can be provided by a native arteriovenous fistula (AVF), a synthetic arteriovenous graft (AVG), or a central venous catheter. The mature, native fistula is considered the preferred type of vascular access. This study evaluates the results of a retrospective registry assessing topically applied heparin (added to antiplatelet therapy) efficacy in patients with newly created AVF., Methods: To the current "best treatment", a number of patients also added topical heparin spray, a formulation containing a high concentration of heparin sodium for topical administration. At present, the average followup time is 7.9 months (range 3-12)., Results: In all patients using topical heparin, AVF remained patent and suitable for dialysis at three months. One fistula occluded at six months, and one more become unsuitable for dialysis. In patients using only antiplatelets, three fistulas occluded at three months and another two at six months of follow-up. In all, after six months of follow-up, there were two patients using heparin for whom the dialysis access was not suitable for dialysis; in the group treated with antiplatelets only, the access could not be used any longer in six patients. Addition of heparin reduced the risk for patency loss by 16.7% at three months and by 22.2% at six months. The risk of reduced dialysis suitability of the fistula was reduced by 27.6% and 22.2%, respectively. The odds for the loss of fistula patency and dialysis suitability at six months follow-up in patients treated with antiplatelet versus combined treatment was 6.5 and 4, respectively. Also, the number of patients needed to treat (NNT) with the addition of heparin spray to achieve AVF patency and suitability at three and/or six months suggests the benefit of combined adjuvant medical treatments for prevention of early AV shunt failure. The safety and tolerability of both treatments were good., Conclusion: Considering these results, it appears that topically applied heparin may sustain AVF patency and suitability for dialysis.

Aim: This registry evaluated the result of treatment with Crystacide in 73 patients with chronic venous insufficiency (CVI) and ulcerations. The local application of a hydrogen peroxide cream (Crystacide, Sandoz) onto the skin was evaluated with clinical and microcirculatory parameters. After briefing, one group used Crystacide and standard management for ulcers, including compression. A comparable group that did not use Crystacide was also evaluated., Methods: Laser Doppler flowmetry (LDF) was used to measure skin perfusion in association with skin TcP02 and TcPCO2. Crystacide was applied around and on the ulcer area for a period between 6 and 9 weeks (with a target time of observation of 8 weeks)., Results: Treatment with Crystacide was more effective. The increased skin flux at inclusion (indicating venus hypertension and microangiopathy) decreased in both groups (improving); TcO2 was increased (P<0.05) and TcCO2 was decreased (P<0.05) in both groups. However, changes in the microcirculatory parameters were significantly larger in the Crystacide group. The average ulcer area was significantly smaller at the average target time of 8 weeks in the Crystacide group in comparison with controls (P<0.05). In the Crystacide group 64.86% of the ulcers were completely healed at 8 weeks versus 38.88% in controls. The difference (+25.98%) in the treatment group is significant (P<0.002)., Conclusion: Local treatment with Crystacide improves the healing of venous ulcerations by improving skin perfusion.

Ankle sprains mainly caused by accidents or strenuous sport activities can often be quite painful and impair motility. If not treated immediately and correctly, sprains may lead to severe complications. The aim of the present study was to compare the efficacy and safety of topically applied ketoprofen versus orally administered ketoprofen in 20 patients with grade I ankle sprain and 34 patients with grade II sprain. The patients were divide into in two treatment groups and received either topically applied ketoprofen treatment (ketoprofen 10% spray-gel; Prontoflex; 360 mg/die) or orally administered ketoprofen treatment (ketoprofen tablets; 3x50 mg/die). Treatment duration was one week. After 3 and 7 days of treatment, reduction of spontaneous pain and pain on active movement in the Prontoflex group was significantly bigger greater in the oral treatment group, irrespective of sprain severity. Regarding secondary parameters as mobility impairment and ankle swelling topically applied ketoprofen treatment turned out to be significantly superior to orally administered ketoprofen treatment. Additionally, Prontoflex was well tolerated, whereas ketoprofen tablets caused gastrointestinal side effects in some patients. The good efficacy in pain reduction and absence of side effects in the present study distinguished the topically applied ketoprofen as a favorable treatment for patients with accidental or sport soft tissue injuries.

Lymphedema is mainly characterized by swelling, fibrosis, and non-pitting edema. The aim of this study was evaluation of the long-term (10 years) effects of autologous lymphatic tissue implant in lymphedema. Lymphatic tissue from 9 patients (harvested form the same patient in areas not affected by lymphedema) was reimplanted into the affected limb, and these patients were followed for 10 years. Lymph nodes were harvested at the neck, axillary, or inguinal space (contralateral limb). Results showed that limb volume was decreased in the treatment group vs. controls. In ultrasound, black, low density, lymphatic spaces were visible in 100% of patients at inclusion but in only 23% of these subjects at 10 years. Thus, this early report proposes a new, minimally invasive method to improve lymphedema. Studies in progress will indicate the role of lymphatic transplant in the management of lymphedema and the best indications for this method.

In a previous, double-blind, placebo-controlled study we evaluated the efficacy of a 3-month treatment with Pycnogenol for 156 patients with osteoarthritis of the knee. Pycnogenol significantly decreased joint pain and improved joint function as evaluated using the WOMAC score and walking performance of patients on a treadmill. In this study, we further investigated the anti-inflammatory and antioxidant activity of Pycnogenol in a subset of the osteoarthritis patients presenting with elevated C-reactive protein (CRP) and plasma-free radicals. Elevated CRP levels have been suggested to be associated with disease progression in osteoarthritis. In our study, 29 subjects of the Pycnogenol group and 26 patients in the placebo group showed CRP levels higher than 3 mg/l at baseline. Comparison of blood specimens drawn at baseline and after 3-month treatment showed that Pycnogenol significantly decreased plasma free radicals to 70.1% of baseline values. Plasma CRP levels decreased from baseline 3.9 mg/l to 1.1 mg/l in the Pycnogenol group whereas the control group had initial values of 3.9 mg/l which decreased to 3.6 mg/l. The CRP decrease in the Pycnogenol was statistical significant as compared to the control group (P < 0.05). Fibrinogen levels were found to be lowered to 62.8% of initial values (P < 0.05) in response to Pycnogenol. No significant changes for plasma free radicals, CRP and fibrinogen were found in the placebo-treated group. The decrease of systemic inflammatory markers suggests that Pycnogenol may exert anti-inflammatory activity in osteoarthritic joints and patients did not present with other ailments or infections. The nature of the anti-inflammatory effects of Pycnogenol with regard to CRP warrants further investigation.

Superficial vein thrombosis is characterized by clotting of superficial veins (ie, following direct trauma) with minimal inflammatory components. Superficial thrombophlebitis is a minimally thrombotic process of superficial veins associated with inflammatory changes and/or infection. Treatments generally include analgesics, elastic compression, anti-inflammatory agents, exercise and ambulation, and, in some cases, local or systemic anticoagulants. It is better to avoid bed rest and reduced mobility. Topical analgesia with nonsteroidal, anti-inflammatory creams applied locally to the superficial vein thrombosis/superficial thrombophlebitis area controls symptoms. Hirudoid cream (heparinoid) shortens the duration of signs/symptoms. Locally acting anticoagulants/antithrombotics (Viatromb, Lipohep, spray Na-heparin) have positive effects on pain and on the reduction in thrombus size. Intravenous catheters should be changed every 24 to 48 hours (depending on venous flow and clinical parameters) to prevent superficial vein thrombosis/superficial thrombophlebitis and removed in case of events. Low molecular weight heparin prophylaxis and nitroglycerin patches distal to peripheral lines may reduce the incidence of superficial vein thrombosis/superficial thrombophlebitis in patients with vein catheters. In case of superficial vein thrombosis/superficial thrombophlebitis, vein lines should be removed. In neoplastic diseases and hematological disorders, anticoagulants may be necessary. Exercise reduces pain and the possibility of deep vein thrombosis. Only in cases in which pain is very severe is bed rest necessary. Deep vein thrombosis prophylaxis should be established in patients with reduced mobility. Antibiotics usually do not have a place in superficial vein thrombosis/superficial thrombophlebitis unless there are documented infections. Prevention of superficial vein thrombosis should be considered on the basis of patient's history and clinical evaluation.

Topical effects of heparins on the skin need deeper investigations. The lack of evidence is mainly due to the lack of large investments in this field. Three main local actions of heparin on the skin can be defined: (a) the anticoagulant action, (b) the microcirculatory-modulatory action determining important control of the microcirculation in case of excessive vasoconstriction or vasodilatation, and (c) the 'facilitatory action' on skin permeability allowing other drugs to diffuse better and faster into the skin (producing a therapeutic effect). These aspects have to be evaluated more extensively in both experimental and clinical conditions. Recent experimental studies demonstrate these effects of locally applied heparin. Therefore, key questions on local heparin administration such as skin penetration and the action on the local thrombi have promising answers. These observations suggest important clinical applications for local liposomal heparin. Both the potentials of local applications of heparin, particularly with new formulations, and some new aspects in the management of superficial vein thrombosis (SVT) can focus on locally applied heparin. SVT is an important clinical condition considering its frequency and the potentially heavy use of local heparin in this clinical problem. Results from new studies and observations presented in this issue of Angiology could be a window for suggesting new significant clinical applications and therapeutic solutions.

Diabetic microangiopathy leads to lower limb ulcers that are very slow to heal. Pycnogenol was evaluated on diabetic ulcers in a controlled trial. Ulcer medications were used in 4 groups (30 patients): (1) systemic Pycnogenol and local application; (2) local Pycnogenol only; (3) oral Pycnogenol; and (4) medications only (control group). Ulcerated areas and symptom scores were more reduced with the combined oral and local treatment (P < .05). Oral and local treatment were less effective, but still improved compared with the controls. Combined treatment produced 89% complete healing at 6 weeks versus 84% with local treatment and 85% with oral treatment; healing in controls was 61%. The combined treatment group and oral only group had better microcirculation after the combined treatment. Combined local and systemic application of Pycnogenol may offer a new treatment of diabetic ulcers. Local treatment also speeds ulcer healing.

Chronic venous insufficiency (CVI) causes a well-defined microangiopathy described as venous hypertensive microangiopathy (VHM) leading to venous ulcerations. VHM is mainly observed in the distal part of the leg, in the perimalleolar region. In VHM edema is the consequence of increased capillary pressure and reduced local clearance, and this affects local perfusion. The healing of venous ulcers is usually very slow. Many treatments are available, but there is still no standard. Oral Pycnogenol is effective in venous disease and particularly in controlling edema. The aim of this study was the evaluation of the local effects of Pycnogenol on ulcers healing associated with venous hypertension. The study lasted 6 weeks including 18 patients (16 completed the study) with venous ulcerations. The oral treatment with Pycnogenol was compared with a combination treatment including oral and local treatment. In subjects treated with the combination treatment (oral and local), venous ulcers healed better (there was a faster reduction in ulcerated area) in comparison with oral treatment only. According to this pilot study Pycnogenol appears to have an important role in local treatment of venous ulcers improving healing and signs/symptoms.

Shock waves (SW) are used to control pain in different clinical conditions (eg, painful knee, elbow, and shoulder, etc). The effects of SWs may be due to cellular ;;stunning'' (particularly nervous components). It may also be the consequence of unknown metabolic actions on tissues, which may include changes in cellular permeability, the liberation of proteins and mediators locally acting on pain and nerve endings. The aim of this study was to evaluate the reduction in pain and the improvement in microcirculation induced by SW treatment in a 2-week study in patients with chronic limb ischemia (CLI). Of the 32 patients with CLI, 30 (20 with rest pain only, 10 with necrosis) completed the study. The treatment was well tolerated. Foot radiographs performed before and after treatment indicate no bone damage after treatment. Foot (tibial arteries) blood pressure was unchanged after 2 weeks. The increase in laser Doppler flux was significant (p <0.05) after treatment. The ORACLE score at 2 weeks was decreased (p <0.05). The same trend was observed with the analogue scale line for pain (p <0.05). Partial pressure of oxygen (PO2) increased (p <0.05) and partial pressure of carbon dioxide (PCO2) decreased (p <0.05). In all patients an increase in pain-free walking distance was observed (the distance increased on average 2.4 times). Flux improvement was still present after 1 month. The outcome at 3 months in these patients indicates that the improvement (concerning the survival of the limbs) was persistent. In conclusion SWs treatment in CLI produced changes both on the microcirculation and pain. These results are very interesting, confirming previous observations, and opening new treatment options in CLI. The skin flow improvement did not relate to an increase in pressure.

The aim of this study was to evaluate the prevention of edema during long-haul flights with an oral, anti-edema and antithrombotic agent (Pycnogenol, Horphag, Research Management SA, Geneva, Switzerland) in asymptomatic subjects. The assessment of edema was performed by evaluating an analogue scale, the rate of ankle swelling by strain-gauge derived rate of ankle swelling (RAS), and by assessing the ankle circumference variation. The study included 211 subjects; 169 completed the study (88 in the control group and 81 in the Pycnogenol group). There were no important differences between the two groups (comparable for age, gender, weight, body mass index, and pattern distribution). The edema score, the RAS, and the circumference at inclusion were also comparable. After the flight in those treated with Pycnogenol, the edema score was increased only by 17.9% (vs. an increase of 58.3% in the control group) (p<0.05). The RAS, evaluated in 22 subjects in the Pycnogenol group (age 44.5; SD 8) and in 23 in the control group (age 45; SD 9) was increased on average by 91% in the control group and 36% in the Pycnogenol group (p<0.05). The variation on circumference at the ankle was 6% in the Pycnogenol group (11% in the control group; p<0.05). These results indicate a positive effect of Pycnogenol on edema during long flights when considering subjective and objective data. No unwanted effects were observed.

The aim of this open study was the evaluation of the effects of HR (Venoruton) at a dose of 1 g/day on the prevention and control of flight microangiopathy and edema in subjects with varicose veins and moderate chronic venous insufficiency flying for more than 11 hours. Patients with varicose veins, edema, but without initial skin alterations or complications, were included. Measurements of skin laser Doppler (LDF) resting flux (RF) venoarteriolar response (VAR), ankle swelling (RAS), and edema were made within 12 hours before and within 3 hours after the flights. The resulting edema after the flights was evaluated with a composite edema score (analogue scale line). A group of 20 subjects was treated with HR (1 g/day, starting 2 days before the flight and 1 g for every 12 hours on day of travel). Another group of 18 subjects formed the control group. The length of the flights was between 11 and 13 hours; all seats were in coach class. Fifty patients were enrolled and 38 patients were evaluable at the end of the trial. The 2 groups (treatment and control) were comparable for age and sex distribution. The decrease in RF was significant in both groups with a higher flux at the end of the flight in the HR group (p < 0.05). The venoarteriolar response was decreased at the end of the flights; the decrease was lower in the HR group (p < 0.05). The increase in RAS and the edema score were significantly lower in the HR group. In conclusion HR is useful for reducing the level of microangiopathy and the increased capillary filtration and in controlling edema in patients with venous disease in long flights. The higher level of flux and VAR and the reduction in edema indicate a positive effect of HR on the microcirculation. This study confirms that HR prophylaxis is effective to control flight microangiopathy associated with edema.

The aim of this study was to evaluate the occurrence of deep venous thrombosis (DVT) and superficial vein thrombosis (SVT) and its prophylaxis with an oral anti-edema and antithrombotic agent (Pycnogenol, Horphag, Research Management SA, Geneva, Switzerland) in long-haul flights, in subjects at moderate to high-risk of DVT and SVT. The study pre-included 244 pre-selected subjects; 211 were included (33 were excluded for several reasons due to logistic problems) and 198 completed the study; 13 subjects were lost for follow-up at the end of the flight, all for non-medical problems (i.e., for difficult connections). All subjects were scanned within 90 minutes before the flight and within 2 hours after disembarking. Subjects were supplemented with 100 mg Pycnogenol per capsule. Treatment subjects received two capsules between 2 and 3 hours before flights with 250 mL of water; two capsules were taken 6 hours later with 250 mL of water and one capsule the next day. The control group received comparable placebo at the same intervals. The flight duration was on average 8 hours and 15 minutes (SD 55 min) (range, 7.45-12.33). In the control group there were five thrombotic events (one DVT and four superficial thromboses) while only nonthrombotic, localized phlebitis was observed in the Pycnogenol group (5.15% vs. no events; p<0.025). The ITT (intention to treat) analysis detects 13 failures in the control group (eight lost to follow up + five thrombotic events) of 105 subjects (12.4%) vs. five failures (4.7%; all lost, no thrombotic events) in the treatment group (p<0.025). No unwanted effects were observed. In conclusion, this study indicates that Pycnogenol treatment was effective in decreasing the number of thrombotic events (DVT and SVT) in moderate-to-high risk subjects, during long-haul flights.

The aim of this study was to evaluate the prevention of recurrent deep vein thrombosis (R-DVT) with an oral antithrombotic agent (sulodexide) in moderate to high-risk subjects. A group of 405 patients was included into the multicenter registry. Both compression and an exercise program were used as well as a risk-factors control plan. After diagnosis of DVT, patients were treated with oral anticoagulants for 6 months. At the end of this period a coagulation study was made and patients started treatment with oral sulodexide capsules for a period of 24 months. The femoral, popliteal, tibial, and superficial veins were scanned with high-resolution ultrasound at inclusion;scans were repeated at 6, 12, 18, and 24 months. Of the 405 subjects included into the registry 178 in the control group (mean age 52.2; SD 11; M:F=90:88) and 189 in the treatment group (mean age 53.2; SD 10.3; M:F=93:96) completed the analysis period of 24 months. At 6 and 12 months the incidence of R-DVT was lower (p<0.05) in the treatment group. At 24 months the global incidence of R-DVT was 17.9% in the control group and 7.4% in the sulodexide group (p<0.05), 2.42 times lower than in controls. The 2 groups were comparable for age and sex distribution and for the localization of the thrombi at inclusion. Also the 2 groups of dropouts were comparable. In the control group there were 32 recurrent DVTs and 24 subjects lost to follow-up (total of 56) of 202 included subjects (27.7%) in comparison with 28 failures (14 recurrent DVTs and 14 lost subjects) of 203 subjects (13.8%) in the treatment group. This difference was statistically significant. In this analysis the incidence of DVT in controls was 2.07 times higher than in the treatment group subjects. In conclusion sulodexide was effective in reducing recurrent thrombotic events in high-risk subjects.

The aim of this study was to evaluate the development of edema, and superficial and deep vein thrombosis (DVT) prophylaxis with an oral profibrinolytic agent (Flite Tabs, 150 mg pinokinase, Aidan, Tempe, AZ, USA) in long-haul flights (7-8 hours), in high-risk subjects. A group of 300 subjects was included; 76 were excluded for several problems including concomitant treatments; 204 were randomized into 2 groups (active treatment or placebo) to evaluate the effects of prophylaxis with Flite Tabs. An exercise program was used in both groups. The femoral, popliteal, tibial, and superficial veins were scanned with ultrasound before and within 90 minutes after flights. Of the included subjects, 92 of 103 controls and 94 of 101 treated subjects completed the study. Dropouts were due to connection problems. Age, gender, and risk distribution were comparable in the groups. In the treatment group, no DVT was observed. In the control group, 5 subjects (5.4%) had a DVT and there were 2 superficial thromboses (7 events in 92 subjects; 7.6%). At inclusion, edema was comparable in the 2 groups. After flights there was an increase in score in controls (+12%) in comparison with a decrease (-15%) in the Flite Tabs group (the difference in variation was statistically significant). Intention-to-treat analysis for thrombotic events shows 18 failures in controls (11 lost to follow-up + 7 thrombotic events) of 92 subjects (19.6%) in comparison with 7 failures (of 94 subjects, equivalent to 7.4%) in the treatment group (p < 0.05). Events were asymptomatic. In conclusion, Flite Tabs were effective in reducing thrombotic events and in controlling edema in high-risk subjects in long flights.

The aim of this study was to evaluate deep venous thrombosis (DVT) prophylaxis with specific elastic stockings in long-haul flights (11-13 hours), in high-risk subjects. A group of 300 subjects was included; 76 were excluded for several problems including concomitant treatments; 224 were randomized into two groups (stockings vs. controls) to evaluate prophylaxis with below-knee stockings. An exercise program was used in both groups. Scholl (UK) Flight Socks (14-17 mmHg of pressure at the ankle) were used. DVT was diagnosed with ultrasound scanning. The femoral, popliteal, and tibia] veins were scanned before and within 90 minutes after the flights. Of the 205 included subjects, 102 controls and 103 treated subjects completed the study. Drop-outs were due to flight connection problems. Age, gender, and risk distributions were comparable in the two groups. In the treatment group (103 subjects; mean age, 42; SD 9; M:F, 55:48), one limited, distal DVT was observed (0.97%). In the control group (102 subjects; mean age, 42.1; SD 10.3; M:F, 56:46), six subjects (5.8%) had a DVT. There were no superficial thromboses. The difference in DVT incidence is significant (p<0.0025; six times greater in the control group). Intention-to-treat analysis counts 18 failures in the control group (12 lost to follow-up + six thromboses) of 112 subjects (15.8%) versus eight failures (7.3%) in the treatment group (p<0.05). The tolerability of the stockings was very good and there were no complaints or side effects. All events were asymptomatic. Considering these observations, Scholl Flight Socks are effective in reducing the incidence of DVT in high-risk subjects.

The study compared, by a prospective, randomized method, 6 treatment options: A: Sclerotherapy; B: High-dose sclerotherapy; C: Multiple ligations; D: Stab avulsion; E: Foam-sclerotherapy; F: Surgery (ligation) followed by sclerotherapy. Results were analyzed 10 years after inclusion and initial treatment. Endpoints of the study were variations in ambulatory venous pressure (AVP), refilling time (RT), presence of duplex-reflux, and number of recurrent or new incompetent venous sites. The number of patients, limbs, and treated venous segments were comparable in the 6 treatment groups, also comparable for age and sex distribution. The occurrence of new varicose veins at 5 years varied from 34% for group F (surgery + sclero) and ligation (C) to 44% for the foam + sclero group (E) and 48% for group A (dose 1 sclero). At 10 years the occurrence of new veins varied from 37% in F to 56% in A. At inclusion AVP was comparable in the different groups. At 10 years the decrease in AVP and the increase in RT (indicating decrease in reflux), was generally comparable in the different groups. Also at 10 years the number of new points of major incompetence was comparable in all treatment groups. These results indicate that, when correctly performed, all treatments may be similarly effective. "Standard," low-dose sclerotherapy appears to be less effective than high-dose sclero and foam-sclerotherapy which may obtain, in selected subjects, results comparable to surgery.

The aim of this study was the evaluation of the effects of Venoruton (HR) on the prevention and control of flight microangiopathy and edema in subjects with varicose veins flying for more than 7 hours. A group of 80 patients with varicose veins, edema, and initial skin alterations due to chronic venous hypertension were included. Measurements of skin laser Doppler (LDF) resting flux (RF), PO2 and rate of ankle swelling (RAS), were made before and after the flights (within 2 hours before the flights and within 2 hours after the flights). The length of the flights was between 7 and 9 hours; all seats were in coach class. The two groups (treatment and control) were comparable for age and sex distribution. The variation (decrease) in PO2 was significant in both groups. In subjects treated with HR the decrease in PO2 was smaller (p < 0.05). The decrease in LDF-RF was significant in both groups with a higher flux at the end of the flight in the treated subjects (p < 0.05). The venoarteriolar response was decreased at the end of the flights. The decrease was less evident in the treatment group (p < 0.05). The increase in RAS was significant in the control group while it was limited in the HR group. In conclusion, HR is useful for reducing the increased capillary filtration and in controlling edema in patients with chronic venous disease in long-haul flights. HR is effective to control flight microangiopathy associated with edema.

Background: The LONFLIT1+2 studies have established that in high risk subjects after long flights (> 10 hours) the incidence of deep venous thrombosis (DVT) is between 4% and 6%. The LONFLIT4 study was designed to evaluate the control of edema and DVT in low-medium risk subjects. The aim of this study was to evaluate edema and its control with specific stockings (ankle pressure between 20 and 30 mm Hg) in long-haul flights. The first part of the study included flights lasting 7-8 hours and the second part included flights lasting 11-12 hours. Ultrasound scans were used to assess thrombosis before and after the flights and a composite edema score was used to evaluate edema and swelling. A group of patients with microangiopathy associated to edema (diabetes, venous hypertension, anti-hypertensive treatment) were also included to evaluate the preventive effects of stockings during flight. Part I: DVT evaluation: Of the 74 subjects in the stocking group and 76 in the control group (150), 144 completed the study. Dropouts were due to low compliance or traveling and connection problems. Age and gender distribution were comparable in the 3 groups as was risk factor distribution. In this part of the study there were no DVTs. Edema Evaluation: The level of edema at inclusion was comparable in the two groups of subjects. After the flight there was an average score of 6.9 (1) in the control group. In the stocking group, the score was on average 2.3 (1), three times lower than in the control group (p < 0.05). Part II: DVT evaluation: Of the 66 included subjects in the stocking group and 68 in the control group (134), 132 completed the study. Dropouts were due to low compliance or connection problems. Age and gender distribution were comparable in the two groups. In the stocking group no DVT was observed. In the control group, 2 subjects had a popliteal DVT and 2 subjects had superficial venous thrombosis (SVT); in total 4 subjects (6%) in the control group had a thrombotic event; the incidence of DVT was 3%. The difference (p < 0.02) is significant., Edema Evaluation: The composite edema score at inclusion was comparable in the two groups. After the flight there was a score of 7.94 (2) in the control group, while in the treatment group the score was 3.3 (1.2)., Microangiopathy Study: In all these subjects, the level of edema was very high in the control group and significantly lower in the compression stocking group. Stockings are effective in controlling edema during flights even in subjects with microangiopathy and edema. Compression was well tolerated in normal subjects and in patients., Conclusion: The Kendall Travel Socks (Tyco Healthcare, Mansfield, MA, USA) which provide 20-30 mm Hg pressure at the ankle, are effective in controlling edema and reducing the incidence of DVT in both low-medium-risk subjects and in patients with microangiopathy and edema in long-haul flights (7-11 hours).

The aim of this randomized, placebo-controlled study was to evaluate the effect of local treatment with Essaven gel (EG), in comparison with placebo in 30 patients with superficial vein thrombosis (SVT). The 8-week study evaluated SVT with an analogue clinical/symptomatic score. SVT was associated with varicose veins. In patients treated with active EG the decrease in score was significantly larger (p< 0.02) than in the placebo group. No intolerance was observed. The decrease in score in the placebo group was due to spontaneous resolution and to skin manipulation and massage. In conclusion local treatment with EG in SVT improves signs/symptoms much faster than placebo. This study confirms earlier observation on the effective, local use of EG in SVT.

The authors evaluated the long-term safety of expanded polytetrafluoroethylene (ePTFE) implants used in external valvuloplasty for treatment of incompetence of the long saphenous and common and superficial femoral veins. During a 15-year period patients with superficial and/or deep venous disease and hypertension due to pure superficial or deep vein incompetence underwent an external valvuloplasty with ePTFE sutures, or an ePTFE cardiovascular patch placed as a sleeve around the incompetent vein segment, or an ePTFE tubular graft placed around the venous segment. Postoperative follow-up evaluations consisted of clinical examinations, high-resolution ultrasonography, and color duplex scanning, and a complete blood count performed at 1, 3 and 6 months, and repeated for at least 4 years, every 2 years after the procedure. A total of 101 patients (38 men and 63 women; mean [+/- sd] age, 44+/-12 years) underwent external valvuloplasty between January 1983 and December 1998; 82 of them completed the 4-year follow-up. Forty of the 82 patients had been operated on for superficial vein incompetence, 42 for deep vein incompetence. Overall, the mean follow-up time was 7.8+/-3.6 years (range, 4 to 13). There were no infections, thromboses,foreign-body reactions to the ePTFE implants, or other prosthesis-related complications requiring explantation. One granuloma (noninfected) developed in association with a tubular ePTFE implant around a long saphenous vein, but it did not necessitate implant removal. Seven patients required (at least after 4 years) a second procedure for recurrent or new venous incompetence. Therefore, in this observational study, ePTFE implants used to treat or correct venous incompetence were well tolerated on a long-term basis.

The efficacy, safety, and cost of prostaglandin E1 (PGE1) in the treatment of severe intermittent claudication was studied comparing a long-term treatment protocol (LTP) with a short-term treatment protocol (STP) in a randomized 20-week study. The study included 980 patients (883 completed the study) with an average total walking distance of 85.5 +/-10 m (range 22-119). Phase 1 was a 2-week run-in phase (no treatment) for both protocols. In LTP, phase 2 was the main treatment phase. In the LTP, treatment was performed with 2-hour infusions (60 microg PGE1, 5 days each week for 4 weeks. In phase 3 (4-week interval period) PGE1 was administered twice a week (same dosage). In phase 4 (monitoring lasting 3 months, from week 9 to 20) no drugs were used. In STP phase 2 treatment was performed in 2 days by a 2-hour infusion (first day: morning 20 microg, afternoon 40 microg; second day morning and afternoon 60 microg). The reduced dosage was used only at the first cycle (week 0) to evaluate tolerability or side effects. Full dosage (60 microg bid) was used for all other cycles. The same cycle was repeated at the beginning of weeks 4, 8, and 12. The observation period was between weeks 12 and 20. A treadmill test was performed at inclusion, at the beginning of each phase, and at the end of 20th week. A similar progressive physical training plan (based on walking) and a reduction in risk factors levels plan was used in both groups. Intention-to-treat analysis indicated an increase in walking distance, which improved at 4 weeks and at 20 weeks in the STP more than in the LTP group. At 4 weeks the variation (increase) in pain-free walking (PFWD) was 167.8% (of the initial value) in the LTP group and 185% in the STP group (p<0.05). At 4 weeks the variation (increase) in total walking distance (TWD) was 227.6% of the initial value in the LTP group and 289% in the STP group (p<0.05). At 20 weeks the increase in PFWD was 496% of the initial value in the LTP group vs 643% in the STP group (147% difference; p<0.02). The increase in TWD was 368% in the LTP group and 529% in the STP group (161% difference; p<0.02). In both groups there was a significant increase in PFWD and TWD at 4 and 20 weeks, but results obtained with STP are better considering both walking distances. No serious drug-related side effects were observed. Local, mild adverse reactions were seen in 6.3% of the treated subjects in the LTP and 3% in the STP. Average cost of LTP was 6,664 Euro; for STP the average costs was approximately 1,820 E. The cost to achieve an improvement in walking distance of 1 m was 45.8 E with the LTP and 8.5 E with the STP (18% of the LTP cost; p<0.02). For an average 100% increase in walking distance the LTP cost was 1,989 E vs. 421 E with STP (p<0.02). Between-group analysis favors STP considering walking distance and costs. Results indicate good efficacy and tolerability of PGE, treatment. With STP less time is spent in infusion and more in the exercise program. STP reduces costs, speeds rehabilitation, and may be easily used in a larger number of nonspecialized units.

Infusional, cyclic PGE1 treatment is effective in patients with intermittent claudication and critical limb ischemia (CLI). One of the problems related to chronic PGE1 treatment in vascular diseases due to atherosclerosis is to evaluate the variations of clinical conditions due to treatment in order to establish the number of cycles per year or per period (in severe vascular disease reevaluation of patients should be more frequent) needed to achieve clinical improvement. In a preliminary pilot study a group of 150 patients (mean age 67+/-12 years) with intermittent claudication (walking range from 0 to 500 m) and a group of 100 patients with CLI (45% with rest pain, and 55% gangrene; mean age 68 +/-11 years) the number of PGE1 cycles according to the short-term protocol (STP) needed to produce significant clinical improvement was preliminarily evaluated. Considering these preliminary observations, the investigators established a research plan useful to produce nomograms indicating the number of cycles of PGE1-STP per year needed to improve the clinical condition (both in intermittent claudication and CLI). A significant clinical improvement was arbitrarily defined as the increase of at least 35% in walking distance (on treadmill) and/or the disappearance of signs and symptoms of critical ischemia in 6 months of treatment in at least 75% of the treated patients. With consideration of the results obtained with the preliminary nomograms a larger validation of the nomograms is now advisable. A cost-effectiveness analysis is also useful to define the efficacy of treatment on the basis of its costs. The publication of this report in two angiological journals (Angeiologie and Angiology) will open the research on nomograms to all centers willing to collaborate to the study. The data are being collected in the ORACL.E database and will be analyzed within 12 months after the publication of this report.

The aim of this international multicenter trial was to evaluate the effects of a new surgical device (Gore External Valve Support-EVS) and technique for external valvuloplasty of the long saphenous vein (LSV). Patients with superficial venous disease and venous hypertension due to pure superficial venous incompetence were randomized into two treatment groups, the first treated with "conventional treatment" (ligation or stripping) and the second with external valvuloplasty with the EVS. Patients with uncomplicated varicose veins within the age range of 35-65 years were included. Incompetence with presence of functional cusps at the saphenofemoral junction (SFJ), with vein dilatation were the main inclusion criteria. The EVS comprised of a GORE-TEX patch material (including a nitinol frame) that is placed around the vein, producing a reduction in the caliber of the vein. Also the vein section becomes elliptical. These combined actions are aimed to reduce incompetence, allowing a better closure of the cusps. The EVS was placed at the SFJ after limited dissection of the vein and ligation of collaterals. The procedure was randomized as an alternative to simple ligation or stripping (according with the procedure commonly used in the center). The associated ligation of distal incompetent veins was allowed. The main outcome measures of the study were evaluated by color-duplex (morphologic findings and evaluation of reflux) and with ambulatory venous pressure (AVP) or air-plethysmography (APG). Main endpoints of the first year of the study and main subject of this report (mainly concerning safety within the first year of follow-up) were considered presence/absence of reflux; patency of the veins; mobility/function of vein cusps; occurrence of thrombosis; tolerability of the device; and increased complexity and operating time needed for the EVS. At 1 year 30 patients had been randomized (14 EVS implanted, 16 controls). Reflux was absent in all EVS patients, all treated veins were patent, and all cusps were mobile. No thrombosis had been observed and the tolerability of the device was very good. The increased complexity required by placing the EVS was limited (5-12 minutes more). In conclusion results of the first year show efficacy and tolerability of the EVS. In selected patients (superficial LSV incompetence, reflux-dilatation, functional SFJ cusps, incompetence mainly due to enlargement of the vein), the EVS could be an effective alternative to "destructive" ligation and/or stripping of the vein. Prolonged follow-up will indicate the clinical potentials of the EVS.

The study was planned to evaluate efficacy and costs of endovascular sclerotherapy (ES) in comparison with surgery and surgery associated with sclerotherapy in a prospective (10-year follow-up), good-clinical-practice study. Patients with varicose veins and pure, superficial venous incompetence were included. Of the patients randomized into the three groups 39 (group A) were treated with ES, 40 (B) with surgery + sclerotherapy, and 42 with surgery only (C). Surgery consisted of ligation of the SFJ (saphenofemoral junction) and of incompetent veins detected with color duplex. Of the preselected 150 patients, 121 subjects entered the study; 96 completed the 10-year follow-up (mean age 52.6 +/- 6 years; 51 men, 45 women). Dropouts were due to nonmedical problems. At 10 years no incompetence was observed in subjects treated with SPJ ligation (B and C). In the ES group 18.8% of the SFJs were patent and incompetent and in 43.8% of limbs the distal (below-knee) venous system was still incompetent [16.1% in the surgery + sclerotherapy group (p < 0.05) and 36% in the group treated with surgery only (p < 0.05 vs B and 0.05 vs A)]. Color duplex of the long saphenous vein indicated atrophy or obstruction of a segment (average 6.7 cm) after SFJ ligation (4.2 cm after ES). The cost of ES was 68% of surgery while the cost of surgery and sclerotherapy was 122% of surgery only. Endovascular sclerotherapy is an effective, cheaper treatment option, but surgery after 10 years is superior.

A group of 24 patients were considered for noninvasive shock waves thrombolysis (NISWT). Of these, 15 patients gave their informed consent. NISWT was attempted in eight patients (while seven patients were randomized for follow-up only). NISWT was possible in six of seven patients. In one patient randomized for NISWT, local inguinal scarring, due to previous surgery, made impossible the visualization of the femoral vein, and therefore focusing of shock waves (SWs). No side effects were reported in the days after SWs administration during the 4-month follow-up. In patients treated with NISWT it was possible to observe just after the SWs session the presence of echolucent "acoustic holes" and flow (by color and power Doppler) within the "holes." All "echolucent holes" produced at the first session were still present at 4 months, and color flow imaging also detected new flow channels in echogenic areas of thrombi previously not visible. In one patient thrombolysis was achieved after the first treatment, but at 3 and 4 months the thrombus was completely avascular. In conclusion, thrombolysis using SWs was obtained in selected cases and it was still persisting at 4 months in six of the seven treated patients. NISWT appears feasible and promising. These results should be confirmed by larger, prospective trials.

The aim of this study was to evaluate the effects after 10 years of external valvuloplasty of the femoral vein (limited anterior plication or LAP). After informed consent patients with venous hypertension due to deep and superficial venous incompetence were randomized into two treatment groups. Both groups were treated with superficial vein surgery (ligation and section of the major incompetent superficial veins). Group 2 was treated with the same procedure and with LAP. External valvuloplasty of the superficial femoral vein was performed with plication of the anterior vein wall after limited dissection of the vein. Results were evaluated with color-duplex scanning and ambulatory venous pressure (AVP) measurements. Endpoints were AVP, refilling time (RT), presence/absence of reflux at the superficial femoral vein, the variation in the diameter of the vein, and quality of life score (QLS). No complications were observed. All femoral veins treated with LAP were competent after 10 years. Significantly lower AVP and longer RT were observed in the LAP group. Also the average diameter of the vein was smaller in the LAP group. Moreover, QLS was significantly better in the LAP group after 10 years. In conclusion, in selected subjects, with moderate deep venous incompetence, functional cusps, or incompetence mainly due to relative enlargement of the femoral vein, LAP may be an effective alternative to external valvuloplasty.

The aim of the present study was to evaluate the effects of different treatment plans (compression only, early surgery, low-dose subcutaneous heparin [LDSH], low-molecular-weight heparin [LMWH], and oral anticoagulant [OC] treatment) in the management of superficial thrombophlebitis (STP), by considering efficacy and costs in a 6-month, randomized, follow-up trial. Patients with STP, with large varicose veins without any suspected/documented systemic disorder, were included. Criteria for inclusion were as follows: presence of varicose veins; venous incompetence (by duplex); a tender, indurated cord along a superficial vein; and redness and heat in the affected area. All patients were ambulatory. Exclusion criteria were obesity, cardiovascular or neoplastic diseases, bone/joint disease, problems requiring immobilization, and age > 70 years. Patients with superficial thrombophlebitis without varicose veins and patients under treatment with drugs at referral were also excluded. Color duplex (CD) was used to detect concomitant deep vein thrombosis (DVT) and to evaluate the extension or reduction of STP at 3 and 6 months. Venography was not used. Of 562 patients included, 3.5% had had a recent DVT in the same limb affected by SVT and 2.1% in the contralateral limb. In six patients DVT was present in both limbs. These patients were treated with anticoagulants and excluded from the follow-up. After 3 and 6 months the incidence of STP extension was higher in the elastic compression and in the saphenous ligation groups (p < 0.05). There was no significant difference in DVT incidence at 3 months among the treatment groups. Stripping of the affected veins was associated with the lowest incidence of thrombus extension. The cost for compression alone was the lowest and the cost including LMWH was the highest. The average cost was 1,383 US$. However the highest social cost (lost working days, inactivity) was observed in subjects treated only with stockings.

The efficacy, safety, and cost of prostaglandin E1 (PGE1) in the treatment of severe intermittent claudication was studied by comparing a long-term treatment protocol (LTP) with a short-term treatment protocol (STP) in a randomized 20-week study. The study included 109 patients (96 completed the study) with an average total walking distance of 65.5 +/- 8 m (range 20-109). Phase 1 was a 2-week run-in phase (no treatment) for both protocols. In LTP, phase 2 was the main treatment phase. In the LTP, treatment was performed with 2-hour infusions (60 microg PGE1, 5 days each week for 4 weeks). In phase 3 (4-week interval period) PGE1 was administered twice a week (same dosage). In phase 4 (monitoring lasting 3 months, from week 9 to 20) no drugs were used. In STP, phase 2 treatment was performed in 2 days by a 2-hour infusion (1st day: morning 20 microg, afternoon 40 microg; 2nd day morning and afternoon 60 microg). The reduced dosage was used only at the first cycle (week 0) to evaluate reduced tolerability or side effects. Full dosage (60 microg b.i.d.) was used for all other cycles. The same cycle was repeated at the beginning of weeks 4, 8, and 12. The observation period was between weeks 12 and 20. A treadmill test was performed at inclusion, at the beginning of each phase, and at the end of the 20th week. A similar progressive physical training plan (based on walking) and a reduction in risk factors levels plan was used in both groups. Intention-to-treat analysis indicated an increase in walking distance, which improved at 4 weeks (101.5% in STP vs 78.3% in LTP), at 8 weeks (260.9% STP vs 107.3% LTP), and at 20 weeks (351% STP vs 242% LTP). Comparable increases in pain-free walking distance were observed in the two groups. No serious drug-related side effects were observed. Local, mild adverse reactions were seen in 7% of the treated subjects in the LTP and 5% in the STP. Average cost of LTP was approximately 6,588 ECU; for STP the average cost was approximately 1,881 ECU. The cost to achieve an improvement in walking distance of 1 m was 35.6 ECU with the LTP and 9.45 ECU with the STP (26% of the LTP cost; p<0.02). For an average 100% increase in walking distance the LTP cost was 1,937 ECU vs 550 ECU with STP (p<0.02). The cost of PGE1 (including infusion and operative costs) was 25% of the total cost for LTP (24.9% for STP). In summary, between-group-analysis favors STP, in terms of walking distance and costs. Results indicate good efficacy and tolerability of PGE1 treatment. With STP less time is spent in infusion and more can be spent in the exercise program. STP reduces costs, speeds up rehabilitation, and may be used in a larger number of nonspecialized units available to follow the protocol.

Carnitine is associated with lipid synthesis and its deficiency may lead to cardiomegaly with parenchymal lipid in the heart, kidney and liver. In our study we found that pretreatment of peripheral blood mononuclear cells (PBMC) with serial dilutions of L-Carnitine (100 micrograms/ml-1 pg/ml) inhibits, in a dose-dependent manner, lymphocyte DNA synthesis stimulated with PHA (20 micrograms/ml). L-Carnitine did not have any effect on resting PBMC. The maximum inhibition was found at 10 micrograms/ml of L-Carnitine. Moreover, in a time-course study and using an enzymatic analysis (ATP monitoring reagent), L-Carnitine enhanced ATP production on PBMC treated and untreated with PHA, reaching a maximum effect at 30 min incubation. In another set of experiments PBMC were treated with L-Carnitine alone and in combination with PHA, and the percent of receptors CD3, CD4, and CD8 were calculated with flow cytometry. After the cell incubation with L-Carnitine, the percent of all receptors studied did not change compared to L-Carnitine-untreated cells (controls). These data suggest that L-Carnitine inhibits, in a dose-dependent manner, lymphocyte blastogenesis induced by PHA, probably through the enhancement of ATP synthesis, which is considered an inhibitor of phospholipase C activity and a suppressor in lymphocyte cultures.