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.

Increase in echogenicity of echolucent carotid plaques after treatment with total triterpenic fraction of Centella asiatica: a prospective, placebo-controlled, randomized trial.

The aim of this study was to evaluate whether total triterpenic fraction of Centella asiatica (TTFCA), was effective in modulating collagen production over 12 months, by producing an increase in echogenicity in echolucent carotid plaques. Part I was a pilot study aimed at evaluating the effects of TTFCA on different types of plaques. Part II was a prospective, randomized, placebo-controlled trial aimed at evaluating the effects of TTFCA on hypoechoic-echolucent plaques. The sonographic examination of carotid plaques was made with high-resolution ultrasound. Capturing, digital image processing, and normalization were standardized, interobserver, intrascanner, gain-level variability were standardized using as reference blood (black) for the most echolucent parts of the plaque and the adventitia (white) as the most echogenic part. Normalization of echo texture was obtained and plaque characterization differentiated echo-texture of plaque associated with events and those that did not cause embolization, thrombosis, or cardiovascular events. After identifying plaques at higher risk, patients were treated with TTFCA (oral tablets, 60 mg, thrice daily for 12 months) to evaluate whether this compound, by modulating collagen synthesis, could increase the echogenicity and therefore the stability of echolucent plaques. Part II was aimed at evaluating the effects of TTFCA on hypoechoic-echolucent plaques. Asymptomatic patients with echolucent plaques (GSM<18) were treated with TTFCA (60 mg, oral tablets three times daily for 12 months) or with comparable placebo after informed consent. All patients were also treated with antiplatelet agents. In part 1, at inclusion the GSC in the hypoechoic group was 15 (range, 12-18) while in the hyperechoic group it was 26 (range, 24-31); at 6 months it was increased in the hypoechoic group and at 12 months the increase was significant (19.5; p<0.05). There was a minor increase in GSM in the hyperechoic group (30; ns). In part II in the treatment group there was a significant difference in GSM (increase) at 12 months (p<0.05), improvement in texture (p<0.05) and a nonsignificant decrease in stenosis. No changes were observed in the placebo group. Events were observed in 6.5% of patients in the TTFCA group and in 11% in the control group (p<0.05). In conclusion these observations suggest a positive action of TTFCA on the stabilization of hypoechoic, low-density carotid plaques.

Treatment of diabetic microangiopathy and edema with total triterpenic fraction of Centella asiatica: a prospective, placebo-controlled randomized study.

The aim of this study was to demonstrate in a prospective, placebo-controlled, randomized study, whether total triterpenic fraction of Centella asiatica (TTFCA) is effective in improving the microcirculation in diabetic microangiopathy and neuropathy, Patients with severe diabetic microangiopathy, neuropathy, and edema; patients with microangiopathy without neuropathy; and healthy subjects were included. Microangiopathy was defined by laser Doppler and capillary filtration (rate on ankle swelling). Inclusion criteria were increase in resting flux and rate of ankle swelling; decrease in venoarteriolar response (VAR) and alteration in flux increase with temperature. Patients were randomized: the treatment group received TTFCA (tablets, 60 mg twice daily for 12 months); those in the placebo group received similar tablets. Healthy controls were followed up as a reference. Groups were comparable; there were no dropouts. There were no differences in the treatment and placebo groups at inclusion. Treatment was well tolerated; no side effects were reported. No variations were observed in normals at 12 months. In the neuropathy A-group, decreases (p<0.05) in RF and RAS were observed in the two treatment groups. The decrease in RAS was associated with a decrease in edema (p<0.05) in both treatment groups. The differences in flux (38%) and in VAR (38%) were associated with a decrease (28%) in the rate of ankle swelling (p<0.05). In patients without neuropathy (B-group) the decrease in flux was 22%, the VAR increased 22.7%, and the RAS decreased 9.5% at 12 months. The variations in normals and the progressive deterioration observed in untreated patients in both groups indicates the difference between treatment and placebo. In conclusion, the decrease in capillary filtration and edema is associated with symptomatic improvement. The action on edema is beneficial for the evolution of neuropathy. The effects of TTFCA 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 total triterpenic fraction of Centella asiatica.

The aim of this study was the evaluation of microcirculatory alterations associated with edema in passengers travelling for more than 3 hours and the study of the effects of TTFCA (total triterpenic fraction of Centella asiatica) on the development of microcirculation alterations and edema, in a prospective, randomized study. Laser Doppler flowmetry (LDF), transcutaneous PO2 and PCO2, rate of ankle swelling (RAS) were used. Subjects were randomized after informed consent into two groups: one control group (no drug or other treatment), and a treatment group (TTFCA 60 mg thrice daily for 2 days before the flight, the day of the flight, and for another day after the flight). Inclusion criteria were age range between 30 and 50, mild-moderate superficial venous disease with varicose veins. Subjects traveled in economy class. In controls there was a progressive increase in CO2, RAS, and edema score and a progressive decrease in flux (RF) and venoarteriolar response with flying time. The variations in all parameters were milder (p>0.05) in the TTFCA group. RAS and edema were significantly lower in the TTFCA-treated group (p<0.025). The progressive increase in RAS, PCO2, and the decrease in VAR and O2 were linearly associated with flight time (up to 10 hours). These results are very interesting and indicate an option for patients prone to edema and microcirculation disturbances during long flights.

Capillary filtration in venous hypertension: evaluation with the vacuum suction chamber device and strain-gauge plethysmography.

The aim of this study was to evaluate local capillary filtration with the vacuum suction chamber (VSC) and the rate of ankle swelling (RAS) in patients with ankle edema due to venous hypertension before and after treatment with oral TTFCA (60 mg tablets twice daily) for 4 weeks. Strain-gauge plethysmography (SGP) was used to assess RAS and local capillary filtration was studied with the VSC (applied on the perimalleolar region); the disappearance of the weal was measured (minutes). Fifty patients with chronic venous insufficiency and edema were included (M:F= 25:25) after informed consent and randomized into a treatment (mean age 43; SD 7) and a control (mean age 44; SD 8) group. Compliance was very good (100% completed the 4-week trial); no side effects were observed. The two groups were comparable for age/sex distribution. Values of RAS and VSC time were comparable in the two groups, at inclusion. After 4 weeks there were no changes in the control group. A significant reduction was observed in the treatment (RAS decreased to 34% of the initial value; the VSC time decreased 48%; p<0.02). Treatment with TTFCA in chronic venous insufficiency is useful as soon as edema is detected to control the progressive alterations leading to ulcerations. This action is produced by complex actions on the microcirculation reducing and controlling edema and modulating collagen synthesis. This results in an improvement of the microcirculation, skin and subcutaneous tissue perfusion and functions.

Microcirculatory effects of total triterpenic fraction of Centella asiatica in chronic venous hypertension: measurement by laser Doppler, TcPO2-CO2, and leg volumetry.

The aim of this prospective, randomized study was to demonstrate whether an oral preparation of TTFCA was effective in improving the microcirculation and edema (leg volume) in venous microangiopathy. Forty patients with venous hypertension were included. Treatment was prescribed for 6 weeks (tablets, 60 mg twice daily). Patients were randomized into a treatment and a placebo group. There were 20 patients in each group. In the treatment group the mean age was 42 (SD 7; M:F = 10:10); in the placebo group, the mean age was 40 (SD 9; M:F = 10:10). Tolerability and compliance were very good; there were no dropouts. At inclusion there were no differences between placebo and treatment group. After treatment there was a decrease in resting flux (29%) and an improvement (increase) in venoarteriolar response (52%); PO2 was increased (7.2%) and PCO2 decreased (9.6%). There was an important decrease in leg volume (66 mL decrease; 1.3% volume variation). The difference in flux, O2-CO2 and volume parameters were significant and clinically important at 6 weeks in the treatment group. In conclusion, TTFCA improves microcirculation and leg volume in venous hypertension. The effects of TTFCA are observed even in a limited sample of patients.

Evaluation of treatment of diabetic microangiopathy with total triterpenic fraction of Centella asiatica: a clinical prospective randomized trial with a microcirculatory model.

Fifty patients with diabetic microangiopathy were studied by laser Doppler flowmetry (measuring skin blood flow at rest) (RF) and the venoarteriolar response (VAR), by transcutaneous PO2 and PCO2 measurements, and by capillary permeability evaluation (rate of ankle swelling [RAS]). Thirty of these patients were treated for 6 months with total triterpenic fraction of Centella asiatica (TTFCA) (60 mg twice daily), a drug active on microcirculation and capillary permeability. A control group of ten patients was treated with placebo and another group of ten patients was left without treatment thus acting as a second control group. After six months there were no significant changes in the two control groups. There was a significant improvement of microcirculatory parameter in patients treated with TTFCA. RF (abnormally increased at the beginning of the treatment) decreased, and the VAR (impaired at the beginning of the study) improved. PO2 increased and PCO2 decreased the abnormally increased capillary permeability was also improved (decreased). According to these data, TTFCA is useful in diabetic microangiopathy by improving microcirculation and decreasing capillary permeability. Also TTFCA protects against the deterioration of microcirculation due to diabetic microangiopathy.

Treatment of edema and increased capillary filtration in venous hypertension with total triterpenic fraction of Centella asiatica: a clinical, prospective, placebo-controlled, randomized, dose-ranging trial.

The variation of capillary filtration rate (CFR), ankle circumference (AC), and ankle edema (AE) was evaluated in three groups of patients with venous hypertension (ambulatory venous pressure >42 mm Hg) and in a group of normal subjects before and after treatment for 4 weeks with total triterpenic fraction of Centella asiatica (TTFCA), a venoactive drug acting on the microcirculation and on capillary permeability. Group A (20 patients)was treated with TTFCA 60 mg thrice daily, group B (20 patients) was treated with 30 mg thrice daily; group C (12 patients) was treated with placebo; and group D (10 normal subjects) was treated with TTFCA 60 mg thrice daily in a randomized study. Capillary filtration rate was assessed by venous occlusion plethysmography, ankle edema by a new system called AET (ankle edema tester). 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. CFR, AC, and AE were significantly higher in patients in comparison with normal subjects. After 4 weeks of TTFCA treatment, there was a significant decrease of CFR, AC, and AET time in patients. This was also greater in the higher dose group. No significant change was observed in the placebo group and in normal subjects treated with TTFCA. Symptoms were also significantly improved in the two groups treated with the active drug according to the dose. No significant changes were observed in the placebo group. In conclusion, the improvement of signs and symptoms by TTFCA observed in patients with venous hypertension was well correlated with the improvement of CFR and ankle edema. Dose ranging showed that 180 mg/day is more effective in improving symptoms and CFR.

Total triterpenic fraction of Centella asiatica in the treatment of venous hypertension: a clinical, prospective, randomized trial using a combined microcirculatory model.

A single-blind, placebo-controlled, randomized study was performed on the effects of different doses of the total triterpenic fraction of Centella asiatica (TTFCA) in patients with venous hypertensive microangiopathy. A combined microcirculatory model that considers laser Doppler flowmetry (LDF) and transcutaneous oxygen (PO2), transcutaneous carbon dioxide tension (PCO2) measurements was combined with the symptom evaluation. LDF tests included the baseline resting flow, the venoarteriolar reflex, and the variation of flow related to the temperature increase. All tests provided a significant difference between drug-treated groups and the placebo group, thereby allowing a distinction to be made between the higher (120 mg daily) and the lower (60 mg daily) dose of TTFCA. Transcutaneous PO2-PCO2 measurements were significantly modified by drug treatments, while no variation could be detected in the placebo group. Important symptomatologic effects (evaluated by subjective scores) followed TTFCA administration, especially at the higher dose level, while no effect was obtained with placebo. The trend of symptom evaluation paralleled the results of objective tests of our microcirculatory model, providing evidence that this model can reveal effects of venoactive drugs on venous hypertensive microangiopathy. TTFCA displays a significant activity. Doses as high as 120 mg daily may be safely used in venous hypertension.

Modification of the echogenicity of femoral plaques after treatment with total triterpenic fraction of Centella asiatica: a prospective, randomized, placebo-controlled trial.

The aim of this study was to evaluate whether TTFCA (total triterpenic fraction of Centella asiatica), was effective, by modulating collagen production, in a period of 12 months, increasing the echogenicity of echolucent plaques at the femoral bifurcation. Hypoechoic atherosclerotic plaques have been found to be associated with an increased evidence of cerebrovascular events. In this type of plaques stromal composition is limited as the collagen component is generally very low; the plaque composition is mainly due to lipid accumulation or thrombosis. The aim of this study was the evaluation of echogenicity of hyperechoic plaques and how it could be modified by a drug acting on the modulation of collagen synthesis. Antiplatelet agents were used in all patients; cholesterol-lowering agents were used in 34% of patients in the treatment group and in 36% in the placebo group. TTFCA was used at the dose of 60 mg thrice daily (oral tablets). Of the 60 included subjects 26 completed the study in the treatment group and 24 in the placebo group. At inclusion the average GSM in the treatment group was 14 (SD 3) and 14.3 (SD 3) in controls. At 12 months GSM was increased up to 22.8 (SD 4) in the treatment group and it was 15 (SD 3) in controls. Considering texture no significant changes were observed in controls while a qualitative increase in homogenicity was observed in the TTFCA group. Plaque size measured at the beginning and at the end of the study showed a median increase in size, in controls (23%; range 0%-44%); it was unchanged in the TTFCA group (variation 7%; 4%-26%). In conclusion in the treatment group plaques increased in echogenicity and in homogenicity; size and stenosis remained unchanged. Modulating the scarring process within echolucent plaques (low echogenicity, high echolucency, with a very low collagen/stromal component), possibly by collagen modulation, makes plaques more stable. This has been achieved and documented in the present study by an increase in the gray-scale median (plaques become more echogenic, more 'white'). The variation in GSM is generally associated with a lower risk of wall thrombosis, rupture and embolization. These observations indicate a positive action of TTFCA on the stabilization of hypoechoic, low-density femoral plaques.

Total triterpenic fraction of Centella asiatica in chronic venous insufficiency and in high-perfusion microangiopathy.

Total triterpenic fraction of Centella asiatica (TTFCA) is effective in improving venous wall alterations in chronic venous hypertension and in protecting the venous endothelium. TTFCA is active on connective tissue modulation, improves the synthesis of collagen and other tissue proteins by modulating the action of fibroblasts in the vein wall, and stimulates collagen remodeling in and around the venous wall. This is due to the modulating action of TTFCA on fibroblasts as shown by experiments on the growth of human embryonal fibroblasts. TTFCA has a moderate in-vitro and in-vivo stimulating effect on collagen synthesis and, at higher dosages, an inhibition on the synthesis of collagen and acid mucopolysaccharides. Studies have indicated the role of TTFCA on the synthesis of specific venous wall elements by cell cultures of human embryonal fibroblasts. The tissue-stimulating action is shown by the increased collagen production independent from the stimulation of cell proliferation (this differentiates the action of TTFCA from cell growth factors). TTFCA is active on the microcirculation in venous and diabetic microangiopathy. Signs and symptoms of venous hypertension and edema are improved by treatment. The remodeling on collagen synthesis could be one of the possible mechanisms of actions of TTFCA in the remodeling of echolucent (soft; therefore, with risk of thrombosis and embolization) plaques at the carotid and femoral bifurcation. This compound is safe and well tolerated. In conclusion, several actions of TTFCA in vascular diseases makes the use of this compound very interesting in venous and arterial problems.

Treatment of superficial vein thrombosis with standardized application of Essaven gel--a placebo-controlled, randomized study.

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 4-week study evaluated the average skin temperature and an analogue symptomatic score. Below-knee SVT was associated with large varicose veins. In patients treated with active EG the decrease in score and in the average, composite skin temperature was significantly larger than in the placebo and control groups. No intolerance was observed. The decrease in score and temperature in the placebo group was mainly due to skin manipulation and massage. In conclusion, treatment with EG in SVT improves symptoms and decreases skin temperature faster. This study confirms earlier observations on the effective use of EG in SVT.

Treatment of superficial vein thrombophlebitis of the arm with Essaven gel--a placebo-controlled, randomized study.

The aim of this randomized, placebo-controlled study was to evaluate the effect of local treatment with Essaven gel (EG), in comparison with placebo and with a group of controls in 23 patients with superficial vein thrombophlebitis (SVTPH) of the arms. SVTPH was consequent to infusional treatment with an intravenous catheter. The 4-week study evaluated the average skin temperature and an analogue symptomatic score. In patients treated with active EG, the decrease in score and in composite skin temperature was significantly larger than in the placebo and control groups. No intolerance was observed. The decrease in score and temperature in the placebo group was mainly due to skin manipulation and massage and to spontaneous resolution. In conclusion treatment with EG in arm SVTPH improves signs /symptoms and decreases skin temperature faster. This study confirms earlier observations on the effective, local use of EG in SVTPH.

Treatment of superficial vein thrombosis: clinical evaluation of Essaven gel--a placebo-controlled, 8-week, randomized study.

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 microcirculatory activity of Centella asiatica in venous insufficiency. A double-blind study]. / Attività microcircolatoria della Centella asiatica nell'insufficienza venosa. Studio in doppio cieco.

In 87 patients with chronic venous hypertensive microangiopathy the efficacy of oral FTTCA (Centella asiatica) administered for 60 days was tested. The microcirculatory effects of two dosages (30 mg bid and 60 mg bid) versus placebo was assessed in a double blind study. The compound was well tolerated and no unwanted effects were observed. Microcirculatory parameters--peri-malleolar skin flux at rest (RF) and transcutaneous PO2 and PCO2--improved as did the abnormally increased RF, PCO2 decreased and PO2 increased in comparison with values measured at inclusion. These results confirm the efficacy of FTTCA in venous hypertensive microangiopathy. Furthermore the effects of FTTCA appear to be dose-related.