Methods of evaluation and quantification of microangiopathy in high perfusion microangiopathy (chronic venous insufficiency and diabetic microangiopathy).

Noninvasive macro- and microcirculatory tests provide quantitative information that offers answers to most questions posed in venous diseases. Duplex scanning is used to assess the macrocirculation, and microcirculatory methods are used to assess and quantify venous microangiopathy. Laser Doppler flowmetry is used to assess perfusion. Transcutaneous Po(2) and Pco(2) measurements are used to study venous hypertension, and strain-gauge plethysmography is used to assess capillary filtration. In venous hypertension, fluid filtration into the extracapillary compartment is increased. The increase in filtration is associated with a decreased venoarteriolar response. To quantify capillary filtration, two methods have been developed: venous occlusion plethysmography and rate of ankle swelling. These methods quantify filtration into the extracapillary compartment and, therefore, are an indication of the formation of edema, the most frequent sign in venous hypertension. Other methods, such as the vacuum suction chamber and the edema tester, can be used to assess changes due to treatments in venous hypertension. The techniques described in this article should be used in controlled environmental conditions

HR (Paroven, Venoruton; 0-(beta-hydroxyethyl)-rutosides) in venous hypertensive microangiopathy: a prospective, placebo-controlled, randomized trial.

UNLABELLED: The aim of this study was to demonstrate whether HR (Paroven-Venoruton; 0-(beta-hydroxyethyl)-rutosides), was effective in improving the microcirculation in venous hypertension and microangiopathy. Sixty patients with severe venous hypertension due to chronic venous insufficiency, ankle swelling, and lipodermatosclerosis were included. After informed consent, patients were randomized into a treatment group and a placebo group. Patients in the treatment group received oral HR (2 g/day for 8 weeks); those in the placebo group received a comparable placebo. RESULTS: The two groups were comparable for age and sex distribution. The mean age was 45 years (SD 9) in the treatment group (31 patients) and 45.5 (SD 10) in the placebo group (29 patients). There were no differences between the placebo and treatment groups at inclusion. There was no change between inclusion and measurements at 8 weeks in the placebo group. A significant decrease (P < 0.05) in flux at rest and rate of ankle swelling was observed in the treatment group. The decrease in capillary filtration was associated with improvement in signs and symptoms (P < 0.05). The difference in flux, sign and symptoms, and filtration was clinically important at 8 weeks in the treatment group when compared with the placebo group. No adverse effects were observed. CONCLUSION: Venous microangiopathy was improved by HR treatment.

Treatment of diabetic microangiopathy and edema with HR (Paroven, Venoruton; 0-(beta-hydroxyethyl)-rutosides): a prospective, placebo-controlled, randomized study.

UNLABELLED: This study was planned to demonstrate in a prospective, placebo-controlled, randomized study, whether HR (Paroven, Venoruton; 0-(beta-hydroxyethyl)-rutosides), is effective in improving the microcirculation in subjects with diabetic microangiopathy and neuropathy. Patients with severe diabetic microangiopathy, neuropathy and edema, patients with microangiopathy, without neuropathy, and 20 healthy subjects were included. Microangiopathy was defined by laser Doppler flowmetry and capillary filtration (rate of ankle swelling (RAS)). Inclusion criteria were: increase in resting flux (RF) and RAS, a decrease in venoarteriolar response (VAR), and alterations in flux increase with temperature. The 2 groups of patients and the control group were randomized in a treatment sub-group which received HR (1 g, twice daily for 6 months); those in the placebo group received similar treatment. RESULTS: Groups were comparable; there were no drop-outs. There were no differences in the treatment and placebo groups at inclusion. Treatment was well tolerated; no adverse effects were reported. No variations were observed in healthy subjects at 6 months. In both groups of patients, significant decreases (P < 0.05) in RF and RAS were observed in the active treatment groups. The decrease in RAS was associated with a decrease in edema (P < 0.05) in both treatment groups. The decrease in RF and the increase in VAR were associated with a proportional decrease in RAS (P < 0.05). In patients without neuropathy, the variations in RF, VAR, and RAS were larger (P < 0.05) at 6 months. The variations in healthy subjects were limited and not significant. CONCLUSION: The decrease in capillary filtration and edema with HR is associated with symptomatic improvement. The action on edema is beneficial for the evolution of neuropathy. The effects of HR on flux, RAS, and edema are important in early stages of microangiopathy to avoid progression to clinical stages.

Flight microangiopathy in medium-to-long distance flights: prevention of edema and microcirculation alterations with HR (Paroven, Venoruton; 0-(beta-hydroxyethyl)-rutosides): a prospective, randomized, controlled trial.

This study evaluated the effects of HR (Paroven, Venoruton; 0-(beta-hydroxyethyl)-rutosides) on the prevention and control of flight microangiopathy, and particularly on edema, in subjects with varicose veins flying for more than 7 hours. Forty patients with varicose veins, edema, and initial skin alterations due to chronic venous hypertension were included. Measurements of skin laser Doppler flowmetry resting flux, Po(2) and rate of ankle swelling, were made before and after the flights (within 4 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 2 groups were comparable for distribution. The variation of Po(2) was significant in both groups. However, in subjects treated with HR, the decrease in Po(2) was smaller (P < 0.05). The decrease in laser Doppler flowmetry resting flux was also significant in both groups, with a higher flux at the end of the control period in the treated subjects (P < 0.05). The venoarteriolar response progressively decreased at 7 and 9 hours. The decrease was less evident in the treatment group (P < 0.05). The rate of ankle swelling was progressively increased in the control group; the increase was not significant in the HR group. In long-haul flights, HR is useful for reducing the increased capillary filtration and in controlling edema in patients with venous hypertension and is effective in controlling perfusion disorders and microangiopathy, particularly swelling and edema, due to flights.

Treatment of edema and increased capillary filtration in venous hypertension with HR (Paroven, Venoruton; 0-(beta-hydroxyethyl)-rutosides): a clinical, prospective, placebo-controlled, randomized, dose-ranging trial.

UNLABELLED: The variation of capillary filtration rate (CFR) and ankle edema (AE) were evaluated in three groups of patients with venous hypertension with ambulatory venous pressure > 42 mmHg and in healthy subjects before and after treatment for four weeks with HR (Paroven, Venoruton; 0-(beta-hydroxyethyl)-rutosides), a venoactive drug acting on the microcirculation and on capillary permeability. Group A (30 patients) was treated with HR 500 mg tid; group B (30 patients) was treated with 1 g tid; group C (30 patients) was treated with placebo; group D (10 healthy subjects) was treated with HR 1 g/day in a randomised study. CFR was assessed by venous occlusion plethysmography. Subjective symptoms of venous hypertension were assessed by an analogue scale line considering four symptoms: swelling sensation, restless lower extremity, pain and cramps, and tiredness. RESULTS: There were no significant differences for sex and age distribution among the groups; no significant differences were found for ambulatory venous pressure and refilling time and parameters of venous hypertension among groups. There was a significant difference between normal subjects and patients. There were no drop-outs and observed intolerance. In group A, there was a significant decrease of CFR (P < 0.01) after treatment. In group B (2 g/day), the decrease was greater than that in group A (P < 0.05). In group C (placebo) there was no significant difference before or after treatment. The variations in analogue score was higher with the higher dosage. The score of group A fell from 7.8 (SD 1.3) to 4 (1). Group B's score fell from 7.9 (2) to 3.1 (1.2). In group C (placebo) there was no change. The decrease in the score in the groups of patients was correlated with the variation in edema and CFR. CONCLUSION: HR is effective in venous edema and hypertension. Its effects are dose-related.

Variations in plasma free radicals in patients with venous hypertension with HR (Paroven, Venoruton; 0-(beta-hydroxyethyl)-rutosides): a clinical, prospective, placebo-controlled, randomized trial.

The aim of this study was to demonstrate whether HR (Paroven, Venoruton; 0-(beta-hydroxyethyl)-rutosides), was effective in improving levels of plasma free radicals (PFRs) in patients with chronic venous insufficiency (CVI) and venous microangiopathy. Patients were randomized into the treatment group, which received oral HR (1g sachets, twice daily, for 4 weeks), and a placebo group, which received comparable placebo. Below-knee Sigvaris stockings were used during the study. PFRs were measured with the D-Rom test at the finger and at a vein of the leg in an area of CVI. The mean age of included subjects was 46 years (SD 11) in the treatment group (20 patients; 6 females) and 46.4 (SD 8) in the placebo group (20 patients; 7 females). There were no differences between placebo and treatment groups at inclusion in age and sex distribution and in parameters indicating venous hypertension. The decrease of PFRs levels in the treatment group was significant, both at the finger and in the distal blood taken in areas of CVI. There there were no significant changes in the control group. In areas of venous hypertension, PFRs values were on average higher than at the finger (systemic) level (P < 0.05). In parallel with the progressive decrease in PFRs associated with treatment, the analogue score was significantly decreased at 2 (P < 0.05) and 4 weeks (P < 0.02) in the HR group. No changes were observed in the placebo group. No adverse effects were observed. In conclusion, HR treatment is effective in decreasing both the systemic and local values of PFRs and therefore may have a positive effect on the evolution of CVI.

'Real' epidemiology of varicose veins and chronic venous diseases: the San Valentino Vascular Screening Project.

The aim of this study was to evaluate the prevalence and incidence of venous diseases and the role of concomitant/risk factors for varicose veins (VV) or chronic venous insufficiency (CVI). The study was based in San Valentino in Central Italy and was a real whole-population study. The study included 30,000 subjects in eight villages/towns evaluated with clinical assessment and duplex scanning. The global prevalence of VV was 7%; for CVI, the prevalence was 0.86% with 0.48% of ulcers. Incidence (new cases per year) was 0.22% for VV and 0.18% for CVI; 34% of patients with venous disease had never been seen or evaluated. The distribution of VV and CVI in comparison with duplex-detected incompetence (DI) indicates that 12% of subjects had only VV (no DI), 2% had DI but no VV, 7.5% had DI associated with VV, 2% apparent CVI without DI, 3% DI only (without CVI), and 1.6% both CVI and DI. VV associated with DI are rapidly progressive and CVI associated with DI often progresses to ulceration (22% in 6 years). VV without significant DI (3%) and venous dilatation without DI tend to remain at the same stage without progression for a lengthy time. New cases per year appear to have a greater increase in the working population (particularly CVI) possibly as a consequence of trauma during the working period. In older age (>80 years), the incidence of CVI tends to decrease. Ulcers increase in number with age. Only 22% of ulcers can be defined as venous (due to venous hypertension, increased ambulatory venous pressure, shorter refilling time, obstruction and DI). Medical advice for VV or CVI is requested in 164 subjects of 1,000 in the population. In 39 of 1,000, there is a problem but no medical advice is requested and in only 61 of 1,000, the venous problem is real. In VV in 78% of limbs, there is only reflux, in 8% only obstruction, and in 14% both. In CVI, 58% of limbs have reflux, 23% obstruction, and 19% both. In conclusion, VV and CVI are more common with increasing age. The increase with age is linear. There was no important difference between males and females. These results are the basis for future real, whole population studies to evaluate VV and CVI.

Treatment of severe intermittent claudication with pentoxifylline: a 40-week, controlled, randomized trial.

The efficacy, safety, and cost of pentoxifylline (PXF) in the treatment of severe intermittent claudication were studied comparing PXF and placebo in a randomized 40-week study. A treadmill test was performed at inclusion and at the end of weeks 20 and 40. A progressive training plan and the control of risk factors (with antiplatelet treatment) were used in both groups. Of the 200 included patients, 178 completed the study: 88 in the PXF group and 90 in the placebo group. There were 22 dropouts. The two groups were comparable for age, sex distribution, and for the presence of risk factors and smoking. There was a significant increase in pain-free walking distance (PFWD) in both groups. The absolute and percent increase in PFWD was significantly greater in the PXF group (p<0.05). At 20 weeks, the increase was 360.5% in the PXF vs 252% in the placebo group. At 40 weeks, the increase was 386% in the PXF and 369% in the placebo group (p<0.02). Total walking distance (TWD) increased at 20 weeks (up to 254%) and up to 329% at 40 weeks. In the placebo groups the increase was 158% at 20 weeks and 183% at 40 weeks. The excess increase produced by PXF treatment was 30% at 20 weeks and 38% at 40 weeks (p<0.02). Unwanted effects treatment was well tolerated. No serious drug-related side effects were observed. In summary, between-group analysis favors PXF considering walking distance and costs. Results indicate good efficacy and tolerability.

Treatment of long-distance intermittent claudication with pentoxifylline: a 12-month, randomized trial.

The efficacy, safety, and cost of pentoxifylline (PXF) in long-range (>400 m interval) intermittent claudication was studied comparing PXF and placebo in a 12-month study. A standardized treadmill test was performed at inclusion and at 6 and 12 months. A training plan based on walking was associated with the control of risk factor levels. Of the 194 included patients, 135 completed the study: 75 in the PXF group and 60 in the placebo group. There were 59 dropouts (due to low compliance). The authors observed a 148% increase in total walking distance (TWD) at 6 months with PXF (vs 110% with placebo; p<0.05); at 12 months, the increase was 170% with PXF (vs 131% with placebo; p<0.02). There was a 38% difference at 6 months and 39% at 12 months in favor of PXF. Treatment was well tolerated. In conclusion, PXF improved walking distance significantly better than placebo.

Treatment of vascular inner ear disease in vascular patients with pentoxifylline: a controlled, randomized trial.

The efficacy of Pentoxifylline in vascular inner ear disease (VIED) was studied comparing PXF and placebo in a 4-week study; 40 patients with vascular disease and monolateral loss of hearing, vertigo, dizziness, tinnitus (analyzed with an analogue scale line), and cochlear flow reduction were included. The aims of the study were to study the effects of PXF (1600 mg daily) in VIED considering clinical outcome and cochlear flow. Of the 20 included patients, 19 completed the study. One dropout in the placebo group was due to low compliance. Intention-to-treat analysis indicated an improvement in cochlear flow (p<0.05) and a decrease in score in both groups. The cochlear flow increase was 287.5% in the PXF group vs 168% in the placebo group (119.5% difference; p<0.02). There was a difference in score decrease (44.1% larger) in the PXF group (p<0.05).Between-group analysis favors PXF considering blood flow and symptoms. Results indicate good efficacy and tolerability of PXF in VIED.

Treatment of vascular inner ear disease with pentoxifylline: a 4-week, controlled, randomized trial.

The efficacy of pentoxifylline (PXF) in vascular inner ear disease (VIED) was studied comparing PXF and placebo in a 4-week study; 60 patients with unilateral loss of hearing, vertigo, dizziness, tinnitus (analyzed with an analogue scale line), and cochlear flow reduction were included. The aim of the study was to study the effect of PXF (1800 mg/day) in VIED considering clinical outcome and cochlear flow. All patients completed the study. Improvement in cochlear flow (p<0.05) and a decrease in score in both groups were observed. The cochlear flow increase was 287.5% in the PXF group vs 168% in the placebo group (119.5% difference; p<0.02). There was a difference in score decrease (44.1% larger) in the PXF group (p<0.05). PXF was more effective considering flow and symptoms.

Short-range intermittent claudication and rest pain: microcirculatory effects of pentoxifylline in a randomized, controlled trial.

The efficacy of pentoxifylline (PXF) in severe intermittent claudication was studied comparing PXF and placebo. Patients were randomized into two treatment plans: PXF (2400 mg, four 600-mg tablets daily) or equivalent placebo was administered for 10 days. The exercise protocol associated with treatment was conducted under supervision. Skin flux (RF) was measured at rest and after 1 minute of exercise (AEF = after exercise flux; 3 km/hr, 12% inclination) with laser Doppler. PO2 and PCO2 were measured at the dorsum of the foot. All 20 included patients completed the study. The two groups were comparable. In the PXF group there was a significant increase in RF, AEF, and in PO2 (p<0.05); PCO2 was decreased (p<0.05). There were also changes in the placebo group, significantly lower than those observed in the PXF group (p<0.05). In conclusion high-dose PXF treatments improved all microcirculatory parameters in subjects with short-range claudication even with a short period of treatment.

Treatment of vascular retinal disease with pentoxifylline: a controlled, randomized trial.

The aim of this study was to evaluate the effect of PXF (1800 mg daily) in patients with sudden loss of vision (SLV) in a 4-week trial, evaluating clinical outcome and retinal flow parameters. Inclusion criteria were SLV associated with thrombosis of the retinal artery; decrease in retinal blood flow (PSF: peak-systolic flow; EDF: end-diastolic flow velocity) and asymmetry between the two retinal arteries (>40%) documented by duplex scanning. All 10 included patients completed the study. The groups were comparable. No side effects were reported. A significant improvement in flow velocity (p<0.05) and a decrease in analogue score in both groups were observed. PSF increase was 550% in the PXF group vs 288% in the placebo group (262% difference). EDF increase was 400% in the PXF group vs 200% in the placebo group (200% difference). There was a significant difference in the analogue score decrease (33.3% difference larger in the PXF group; p<0.05). In conclusion, PXF treatment improved retinal flow after retinal artery occlusion better than placebo and should be considered as an important option in this condition.

Treatment of retinal vein thrombosis with pentoxifylline: a controlled, randomized trial.

The aim of this study was to evaluate PXF (pentoxifylline; 1600 mg daily vs placebo) in patients with retinal vein thrombosis (RVT) in a 4-week trial, evaluating clinical outcome and retinal flow. Inclusion criteria were sudden loss of vision (SLV); retinal vein thrombosis (RVT); decrease in retinal vein flow; asymmetry between retinal veins (>40%) documented by duplex scanning (retinal vein thrombosis flow = RVTF). All 18 included patients completed the study. The groups were comparable. No side effect was observed. An improvement in arterial flow (p<0.05) and a decrease in analogue score (p<0.05) were observed in both groups (due to the spontaneous evolution with partial thrombus lysis in 4 weeks). The increase in arterial flow (PSF and EDF) were greater (p<0.05) in the PXF group. The RVFV increase was better in the PXF group (350% increase vs 200% increase in the placebo group; p<0.05). There was a significant difference in the analogue score decrease (4 vs 7) in the PXF group (p<0.05). In conclusion, PXF improved retinal flow after RVT better than placebo. It should be considered as an important treatment option.

Treatment of venous ulcers with pentoxifylline: a 6-month randomized, double-blind, placebo controlled trial.

The aim of this study was the evaluation of treatment with pentoxifylline in patients with venous ulcers in a 6-month, randomized, controlled trial. Treatment with placebo or pentoxifylline (PXF; 400 mg, 3 times daily) lasted 6 months and was associated to elastic bandaging. The endpoints were the number of limbs with complete healing and the variation in the area of ulceration. A group of 172 patients were included: 82 in the PXF group and 88 in the placebo group; 82 completed the study in the PXF group and 78 in the placebo group. Results. The two groups were comparable for age and sex distribution. The treatment was well tolerated. Complete healing was obtained in 67% of patients in the PXF group and 30.7% in the placebo group (p<0.02). The variations in the average area of ulceration were 86.7% (decrease) in the PXF group and 47% in the placebo group. The cost of treatment increased 21% with PXF but the cost due to non-healing of the ulcer was equivalent to a 44% increase (in comparison with the PXF group). In conclusion PXF is effective and cost-effective in improving ulcer healing in patients with chronic venous hypertension.

Treatment of venous ulcers with pentoxifylline: a 12-month, double-blind, placebo controlled trial. Microcirculation and healing.

The aim of this study was the evaluation of the treatment of venous ulcers with pentoxifylline (PXF) in 12 months. This double-blind, placebo-controlled trial was conducted in GCP. Patients were included after consent and randomized for PXF (400 mg three times daily) or placebo. The number of healed ulcers, the variation in the area of ulceration, and the variation in microcirculatory parameters (laser-Doppler flux and skin PO2) were considered as endpoints. Of the 85 patients included, 80 completed the study (41 in the PXF and 39 in the placebo group). The groups were comparable. Healing occurred in 88% of limbs in the PXF and in 44% in the placebo group (44% difference; p<0.02). The average area reduction was 93% in the PXF and 56% in the placebo group. Microcirculation was significantly improved in both groups at 12 months. The decrease in flux and the increase in PO2 were greater in the PXF group (p<0.05). Considering the proportion of healed ulcers a better outcome was observed with PXF (p<0.02; 12% of nonhealed ulcers in the PXF vs 56% in the placebo group). The ulcerated area decreased 93% in the PXF vs 56% in the placebo group (40% difference; p<0.02). Tolerability was comparable (6% in the PXF group and 5% in the placebo group complained for treatment). No important side effects were observed. In conclusion, treatment with PXF in venous ulcers improves healing and microcirculation and should be considered in slow-healing venous ulcers.

Treatment of intermittent claudication with pentoxifylline: a 12-month, randomized trial--walking distance and microcirculation.

The efficacy, safety and cost of pentoxifylline (PXF) in severe intermittent claudication was studied comparing PXF and placebo in a 12-month study. A treadmill test and microcirculatory evaluation with laser Doppler flowmetry were performed at inclusion and at the end of 6 and 12 months. A physical training plan (based on walking) and reduction in risk factor levels plan was used in both groups. Of the 120 included patients, 101 completed the study: 56 in the PXF group and 45 in the placebo group. There were 19 dropouts (due to low compliance). The two groups were comparable for age, sex distribution, walking distance, and the presence of risk factors and smoking. Intention-to-treat analysis indicated a 268% increase in walking distance in the PXF group (vs 198% in the placebo group; p<0.05) at 6 months and an increase of 404% (vs 280% in the placebo group; p<0.02) at 12 months. The absolute and percent increase in pain-free walking distance (PFWD) was greater in the PXF group (p<0.05). Treatment was well tolerated. No serious drug-related side effects were observed. Microcirculatory evaluation indicated an increase in flux (p < 0.05) in the PXF group (not significant in the placebo group); the after-exercise flux (AEF) was increased (p<0.05) in both groups at 6 months but the increase in AEF was greater in the PXF group at 12 month. In conclusion, between-group analysis favors PXF considering walking distance and microcirculatory parameters. Results indicate good efficacy and tolerability.

Intermittent claudication in diabetics: treatment with exercise and pentoxifylline--a 6-month, controlled, randomized trial.

The aims of this study were to evaluate the effect of PXF (1600 mg daily) in diabetic patients with intermittent claudication. Of the 60 included patients, 53 completed the study (27 in the PXF group). There were seven dropouts. The groups were comparable for age, sex distribution, and total walking distance (TWD), and risk factors. There was an increase in TWD at 3 and 6 months in both groups (p<0.05) possibly due to exercise. However the increase (both absolute and percentage) in TWD was significantly larger in the PXF group. At 6 months, PXF produced a 292% increase in TWD (vs 180% produced by placebo) (p<0.02). The excess increase produced by PXF treatment was 112% at 6 months in comparison with placebo (p<0.02). Treatment was well tolerated. Between-group analysis favors PXF considering TWD, and results indicate good efficacy and tolerability.

Effects of the total triterpenic fraction of Centella asiatica in venous hypertensive microangiopathy: a prospective, placebo-controlled, randomized trial.

The aim of this study was to demonstrate whether total triterpenic fraction of Centella asiatica (TTFCA), was effective in improving the microcirculation in venous hypertension and microangiopathy. Forty patients with severe venous hypertension, ankle swelling, lipodermatosclerosis were included. After informed consent, patients were randomized into a treatment and a placebo group: those in the treatment group received TTFCA (tablets, 60 mg, twice daily for 8 weeks). The two groups of subjects were comparable for age and sex distribution. The mean age was 48 years (SD 9; M:F= 11:11) in the treatment group (22 patients) and 47.6 (SD 7; M:F= 10:8) in the placebo group (18 patients). There were no differences between placebo and treatment group at inclusion; there was no change between inclusion and measurements at 8 weeks in the placebo group. A decrease (p < 0.05) in RF (flux at rest) and RAS (rate of ankle swelling) were observed in the treatment group. The decrease in capillary filtration was associated with improvement in signs and symptoms (p < 0.05). The difference in flux, signs and symptoms, and filtration was clinically important at 8 weeks. No side effects were observed. In conclusion venous microangiopathy was improved by TTFCA treatment.