Multi-ingredient preparations: Alvenor, Ardium, Arventum 500, Capiven, Daflon 500, Detralex, Dios, Variton, Venitrol



Common Forms

Available as effervescent granules for oral solution and as tablets (50 mg with diosmin 450 mg [flavone derivative]).

Source

The herb is extracted from Aurantii fructus immaturi, also known as unripe orange, and Aurantii pericarpium, or dried bitter-orange peel, both of which are derived from Citrus aurantium. It is also extracted from Citri pericarpium, known as dried lemon peel, which is derived from Citrus limon.

Chemical components

The agent is a crystalline flavonoid glycoside. Other chemical constituents include limonene (essential oil), pectin, coumarin derivatives, carotenoids, citric acid, and various other glycosidic flavonoids.

Actions

Reports describing the physiologic mechanisms of action have been

largely based on the use of micronized purified flavonoid fraction (MPFF), composed of 90% diosmin and 10% hesperidin, as a phlebotropic agent. Clinical data have consistently shown a number of effects on venouS hemodynamic parameters, including a reduction in venouS emptying time, venous capacitance, venous distensibility, and increases in venous tone. Data from human trials also indicate that MPFF can exert effects on the microcirculation by modulating leukocyteendothelial interactions and inhibiting proinflammatory mediators. One small clinical study demonstrated a reduction in surface expression of CD62L in neutrophils, monocytes, and the endothelial markers intercellular adhesion molecule-1 and vascular cell adhesion molecule1, thus decreasing leukocyte chemotaxis and activation . MPFF has also been shown to inhibit the release of prostaglandins and free radicals, resulting in decreased capillary permeability and increased capillary resistance.

Reported Uses

Hesperidin is purported to be useful for treating chronic venous insufficiency (CVI). Numerous clinical studies have reported efficacy of the drug (as MPFF) in reducing the symptoms of CVI. The results of four randomized, double-blind, controlled trials showed significant reductions in subjective symptoms, including heaviness, nocturnal cramps, pain, and swelling and significant decreases in leg circumferences at the levels of the ankle and calf, after 2 to 3 months of therapy . Similar efficacy was noted after a 1year period of administration. Hesperidin's ability to influence healing in patients with venous ulceration was assessed in a relatively small, double-blind, randomized, placebo-controlled trial, which reported that a significantly larger number of patients had complete ulcer healing at 2 months compared with placebo and a statistically shorter healing time. All patients were treated with a standard compression stocking, and it was among those patients with an ulcer size less than or equal to 10 cm that the results reached statistical significance. The ability of the drug to expedite ulcer healing is attributed to its effects on the microcirculation . One clinical study suggested that hesperidin may be valuable in patients with upper limb lymphedema secondary to breast cancer therapy, especially those with more severe lymphedema. Another role for this drug in the short-term treatment of hemorrhoids of pregnancy was suggested in an open study. Animal data from one source proposed a role for hesperidin in inhibiting neoplastic transformation in murine fibroblasts.

Dosage

Most trials that assessed the use of flavonoids for CVI and lymphedema secondary to breast cancer therapy tested Daflon 500. Patients received 2 tablets P.O. each day, equivalent to 1,000 mg.

Adverse Reactions

CNS: anxiety, asthenia, dizziness, drowsiness, headache, insomnia, vertigo.

CV: hypotension, palpitations.

GI: abdominal cramps and pain, diarrhea, dyspepsia, epigastric discomfort, nausea, vomiting.

Skin: rash.

Interactions

None reported.

Contraindications and precautions

Use cautiously in patients taking anticoagulants. Adverse outcomes on human reproduction and lactation are unclear, but birth weight, fetal development, infant growth and feeding, and pregnancy were unaffected in an open study of 50 women with acute hemorrhoids. No teratogenic effects were observed among the offspring of rats treated with doses up to 8 g/kg/day. Photosensitization may occur because C. aurantium is known to contain furanocoumarins.

Special considerations

Urge the patient to report unusual bleeding or bruising.

Inform the patient that products containing hesperidin may cause photosensitization.

Caution the patient not to self-treat symptoms of CVI before seeking appropriate medical evaluation because this may delay diagnosis of a serious medical condition.

Although no known chemical interactions have been reported in clinical studies, consideration must be given to the pharmacologic properties of the herbal product and the potential for exacerbation of the intended therapeutic effect of conventional drugs.

Commentary

The preponderance of available clinical data comes from foreign studies evaluating MPFF (450 mg of diosmin and 50 mg of hesperidin). The most convincing human trial data suggest a role for hesperidin in managing CVI. Evidence indicates that this drug is efficacious in improving venous hemodynamic parameters and mitigating the microcirculatory changes underlying CVI, thereby ultimately reducing the symptoms of the disease and even accelerating complete healing of ulcers. Much of this evidence is based on double-blind, randomized, placebo-controlled trials, but sample size was consistently small and treatment duration was restricted to 1 year or less. Furthermore, these studies did not compare hesperidin with standard-of-care treatments. Although evidence seems to suggest that hesperidin is relatively benign with regard to adverse effects, it is important to note that available data are based on relatively small patient numbers. Overall, it seems that this agent could be considered a reasonable adjunct to current treatment modalities for CVI, including surgery, compression therapy, and pharmacotherapy.