SAFETY, EFFICACY & METABOLISM

To demonstrate the safety profile of Diosmin, the following section contains the articles cited in Nutratech's submission, as well as other articles, all of which confirm the safe use of Diosmin.

In Guilhou's study of diosmin+h for the treatment of venous ulcers, 107 men and women were enrolled in a multicenter, double-blind, randomised, placebocontrolled trial and received a 2-month treatment with diosmin+h 1000 mg daily. Ninety-nine patients completed the protocol . Six patients withdrew from the study far reasons other than ulcer healing. In the diosmin group 2 withdrew because of phlebitis and 1 because of noncompliance . In the placebo group, 3 individuals withdrew due to mild cutaneous eruptions and 1 for personal reasons. Treatment was well tolerated . Two venous thromboses were diagnosed in the diosmin group but investigators thought that they were unrelated to treatment. Other adverse events were eczema (2), urticaria (1), puritis of the scalp (1), and local pain (1) in the placebo group; and skin changes around ulcer (1), asthemia (1), headaches (1), and exacerbation of chronic colopathy (1) in the diosmin+h group".

Guillot and colleagues carried out a study to confirm the long term therapeutic efficiency of diosmin + hesperidin (Daflan 500 mg) and the safety of this agent in one year of continuous administration . They concluded that a long term treatment with diosmin+h was beneficial to patients suffering from chronic functional venous insufficiency . Two hundred and fifteen out-patients (28 males and 187 females) aged between 19 and 81 years were included in the study. All patients suffered from functional symptoms of venous insufficiency like leg heaviness, cramps, paresthesia, evening edema. Exclusion criteria included pregnancy and some others. The disease had been present for 1 to 3 years in 28.3%, 4 to 10 years in 42.3%, more than 10 years in 29 .3% . Each patient was given diosmin+h, 2 tablets daily for a year with regular controls every two months. The efficacy was clearly demonstrated with a rapid improvement of functional signs in the first months, being maintained till the end of the study. The reduction of ankle and calf circumferences is probably linked to a decrease in plasma filtration through capillary walls. This fact confirms the positive role of the drug on tissue microcirculation . The safety was demonstrated by the rareness and mildness of clinical side effects : gastralgia in 7 patients, dizziness in 4, gynaecological signs in 7 and cutaneous eruption in two eases. The side effects led to treatment withdrawal in 4 patients : nausea and gastralgia in two cases and an increase of the body weight in two others but probably not in relation with the treatment . No abnormal changes in laboratory parameters were observed'.

In a 1995 review article in Drugs of Today, Godeberge assesses studies conducted by Cospite, Cope, and Delmont that enrolled a total of 299 patients to test diosmin+h as a treatment far hemorrhoids . In all trials, diosmin+h was well tolerated . The side effects, generally transient and mild, were anxiety, shivering, oppressive feeling across the chest, and epigastric pain . The frecuency of side effects was similar in both treated and control groups and never required specific treatment. There was no evidence of drug interaction in any of the studies".

Diosmin+h 1000 mg was given daily for two months to 174 women and 26 men with either organic CVI (83) or functional CVI (117) in 2 double-blind randomised trials, placebo-controlled trials. Results showed that variations in blood parameters were within accepted physiological limits. There were no allergic reactions or drug interaction seen . Side effects were of the same type and frequency in both groups. In the diosmin group, 1 patient experienced hypotension, 4 patients complained of nausea, 1 of headache, 2 of gastric pain, 1 of insomnia. Only 3 patients dropped out: 1 in the diosmin group for epigastric pain and 2 in the control group for nausea and hypotension. In the placebo group, 1 patient experienced  metrorrhagia' .

Tsouderos presented the results of a study that included 20 patients who had been suffering from CVI for at least one year. This study evaluated the activity of 1000 mg Diosmin Complex as a single dose, compared to a placebo. The results showed that there was no significant change in cardiac index, capillary filtration index, blood pressure, cardiac or respiratory rate. Tsouderos also reported the results of a double blind randomised controlled trial of the effect of Diosmin Complex (1000 mg/day) compared to placebo, over a two-month treatment period. Eighteen patients with functional venous insufficiency were examined in each group. Assessments were undertaken for capillary filtration, arterial output, respiratory and cardiac rates and systolic and diastolic blood pressure . There was no statistically significant difference between Diosmin Complex and placebo groups".

Cesarone et al. reported the results of a pilot study in which 43 patients with venous hypertension were administered Diosmin Complex at a daily dose of 1500 mg or 1000 mg . In addition, ten healthy subjects were also administered Diosmin Complex at a daily dose of 1500 mg . The duration of administration was 4 weeks. After treatment with Diosmin Complex, a dose-related decrease in capillary filtration was observed . The treatments were well tolerated and the patients did not raport!any unwanted effects".

Meyer conducted a review in the use of diosmin+h (Daflon 500 mg) in which they paint out that clinical trials fulfil international scientific requirements and have collected more than 2850 patients treated with diosmin+h at the dosage of two tablets per day for six weeks to one year. The proportion of patients with side effects (10% of those treated), essentially of a gastrointestinal or autonomic nature and leading to a rare of only 1 .1% trial dropouts, is less than described in 225 patients given a placebo (13 .9%) in controlled trials. Satisfactory clinical acceptability already confirmed in the short term was equally found in long term treatment. Hemodynamic parameters as well as laboratory parameters were uninfluenced even by prolonged treatment for one year at the dosage of two tablets per day. No contraindications have been found, even in the elderly and in pregnant women.

Belcaro and colleagues reported the results of a three-month double-blind randomised study, which allocated patients into three groups with different daily doses of Diasmin Complex: 500 mg (n=34), 1000 mg (n=33) or 2000 mg (n=37) . All 104 patients included in the trial were affected with mild CVI . Fourteen patients dropped out of the study: nine for reasons not related to treatment, 2 lost to followup and 3 because of an adverse event. Side effects leading to withdrawal occurred in one patient in group 1 (inguinal pain) and in 2 patients in group 3 (gastralgia and cystitis) . The treatment was discontinued and the adverse events disappeared. For all patients, haematological and biochemical parameters remained stable over the study period.

In a safety and efficacy study of micronized diosmin+h for the treatment of internal haemorrhoids of pregnancy, Buckshee and co-workers showed that treatment was safe, acceptable, and effective in the treatment of haemorrhoids of pregnancy. In an open study on hospital outpatients, they studied therapy with diosmin+h for a median of 8 weeks before delivery and 4 weeks after delivery, in 50 women with

acute haemorrhoids . The outcome measures were symptoms and signs of haemorrhoids, adverse effects, and acceptability of treatment. 66% of the patients had relief from acute symptoms by the fourth day, 53.6% fewer patients had relapse in the antenatal period . Treatment was well accepted, and did not affect pregnancy, fetal development, birth weight, infant growth and feeding.

In a double-blind, placebo-controlled trial of a flavonoid fraction (consisting of 90% diosmin and 10% hesperidin) in the treatment of symptomatic capillary fragility, Galley andThiollet concluded that the flavonoid fraction increased to a large extent the capillary resistance in patients with abnormal capillary fragility without significant side-effects. The treatment was performed in 100 patients with symptomatic capillary fragility in a double-blind, randomised, placebo-controlled trial . Treatment lasted 6 weeks and consists of 2 daily tablets of either diosmin+h or placebo. Patients were examined at weeks 0, 2, 4 and 6. Compared to placebo, capillary resistance, assessed by the negative suction cup method, was significantly higher in the diosrmin+h group at week 4 and week 6 . This resulted in a significant improvement of symptoms of capillary fragility in the treated patients. The drug was well tolerated. The rate of side-effects spontaneously volunteered by the patients was similar in both groups'.

Jean and Bodinier studied the mediators involved in inflammation and the effects of diosmin + hesperidin on their release . They concluded that the anti-inflammatory effects of these drugs have been observed in a variety of in vivo models. Diosmin + hesperidin inhibit the formation of arachidonic acid derivatives and free radicals. This results in a decrease of membrane permeability and then in a protection against the development of the edema. These properties may explain, at least in part, the clinical activity of diosrnin + h and justify its therapeutic use .

Cospite conducted a study of 100 patients undergoing an acute hemorrhoidal attack who were treated with either diosmin + hesperidin and placebo . Diosmin + h was given for 7 days at the dosage of six tablets daily during the first four days and four tablets daily during the following three days. One patient in the diosmin group and five in the placebo one withdrew from the treatment because of dissatisfaction with the therapeutic results. 4 patients in the diosmin group and three in the placebo group experienced mild digestive side effects. No patient stopped due to major side effects . Blood pressure remained normal and showed no modification attributable to treatment . There was no statistically significant difference between groups . A significant improvement of signs and symptoms was demonstrated in the diosmin group. Moreover, a reduction in duration and intensity of attacks and a improvement of the local anatomic lesions were observed, both of which were mare important in the diosmin group than in the placebo group

Ho and colleagues performed a prospective randomised controlled trial on the effects of a flavonoid fraction containing 450 mg diasmin and 50 mg hesperidin on bleeding after haemorrhoidectomy . In all, 228 consecutive patients with prolapsed irreducible piles were recruited . Elective haemorrhoidectorny was performed with a standardized diathermy excision method. Some 114 patients were randomised to

receive diosmin + h for 1 week after operation (group one), and there were 114 controls (group two) . Postoperative analgesia and laxative prescription as well as hospital stay were otherwise the same . One patient from group one and seven from the placebo group had postoperative bleeding. All bleeding occurred from 6 to 15 days after haemorrhoidectomy . There were no side-effects from the use of

diosmin + h . The risk of secondary bleeding from haemorrhoidectomy is reduced with postoperative diosmin + hesperidin's.

Ramelet studied the clinical benefits of a flavonoid fraction (diosmin + hesperidin) in the most severe stages of CVI, and concluded that this fraction, thanks to its comprehensive mode of action on the veins, lymphatics, and microcirculation, is the method of choice not only in the early stages of CVI treatment, but also in the severe stages of this condition, in combination with compression treatment, sclerotherapy, and surgery if appropriate" .

Geroulakos and colleagues performed three controlled studies in CVI using Daflon 500 mg (diosmin + hesperidin) . This substance could play a greater role in the management on functional venous insufficiency. Patients with this condition have no clinically detectable anatomic abnormality in their veins, but they complain of intermittent functional symptoms such as leg heaviness, cramps, paraesthesia, and

evening edema. Approximately 5% of the patients who present in the varicose clinic of their hospital have functional venous insufficiency. Diosmin + h has been demonstrated to significantly improve the symptoms and the plethysmagraphic parameters in these patients. It also decreases the ankle circumference, indicating an effect on the fluid leakage rate from the capillaries . In these patients, treatment with diosmin + h is far more acceptable than elastic compression".

Cova and colleagues performed a pharmacokinetic studies of diosmin after oral administration to healthy volunteers . Diosmin and its aglycone, diosmetin, were determined using different analytical techniques. Diosmin was not present in the plasma but only diosmetin. Analysis of the pharmacokinetic parameters showed that the drug was rapidly absorbed . Diosmetin presents a long plasma elimination half-life ranging from 26 to 43 hours (which suggests an enterohepatic circulation which is known to have the effect of slowing down the complete elimination of the drugs) . Their data showed the total absence of urinary elimination for both diosmin and diosmetin, while its minor metabolites are eliminated in the urine, mainly as glucoronic acid conjugates. The presence of degradation products such as alkylphenolic acids confirms a metabolic pattern similar to other flavonoids.