Olive Leaf Complex [Discontinued] by Barlean's

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Athletic performance. Although there has been interest in using oral caffeic acid for athletic performance, there is insufficient reliable information about the clinical effects of caffeic acid for this purpose.
• Obesity. Although there has been interest in using oral caffeic acid for weight loss, there is insufficient reliable information about the clinical effects of caffeic acid for this purpose. More evidence is needed to rate caffeic acid for these uses.

(Read more about CAFFEIC ACID)

POSSIBLY EFFECTIVE

• Chronic venous insufficiency (CVI). Oral diosmin, as part of a micronized purified flavonoid fraction, seems to be beneficial for reducing symptoms of CVI. It is unclear if oral diosmin alone is beneficial. Details: Most clinical research shows that taking 2-3 tablets daily of a specific combination product (Daflon 500, Les Laboratoires Servier) containing micronized purified flavonoid fraction (MPFF), providing diosmin 450 mg and other flavonoids, such as hesperidin, 50 mg per tablet, for 2-6 months modestly improves symptoms of chronic venous diseases such as varicose veins and CVI, including leg pain, heaviness, swelling, and cramps, when compared with baseline or placebo (50892,54755,54799,98597,98609). Additionally, a large clinical study in patients with CVI shows that results are similar when a chewable form of this product taken 1000 mg daily (Daflon 1000, Les Laboratoires Servier) is compared with 500 mg tablets taken twice daily (112796). An observational study in adults with advanced CVI suggests that taking MPFF 1000 mg, consisting of 90% micronized diosmin and 10% other flavonoids, daily for 6 months in addition to conservative treatment, mainly compression therapy, is associated with improved symptoms (e.g., varicose veins, venous edema, pain) and reduced subcutaneous adipose tissue thickness when compared to baseline (112795). The validity of these findings is limited by a lack of a comparator group. In patients with mild to moderate pelvic venous disorder due to valvular incompetence, two preliminary clinical trials show that this same combination product is beneficial for reducing pain and other symptoms (105287,108150). In one study, taking 1000 mg daily for 2 months modestly improves quality of life and reduces most symptoms, including pain, tenderness, edema, heaviness, and discomfort, when compared with placebo (108150). Other preliminary clinical research shows that dosing based on severity as either 1000 mg daily for 2 months or 1000 mg twice daily for one month and then 1000 mg once daily for an additional month, reduces pelvic pain by a moderate and large amount, respectively, when compared to baseline. The average time to pain relief was 13.7 or 3.1 days, respectively, for each dosing group. Pelvic venous congestion was reduced more in the higher dose group as calculated following transvaginal and transabdominal duplex ultrasound scanning (DUS) and single-photon emission computed tomography (SPECT) of the pelvic veins (105287). Micronized diosmin in combination with other flavonoids has also been compared with non-micronized diosmin alone. Although taking non-micronized diosmin 900 mg daily modestly improved clinical symptoms when compared with baseline in early research, taking 1000 mg of micronized purified flavonoid fraction daily for 2 months was more effective (54935,54950). However, more recent preliminary clinical research in a well-defined patient population with pre-CVI symptoms shows that taking one tablet of a specific non-micronized diosmin (Flebodia, Laboratoire Innotech International) 600 mg daily for 6 months is as effective for reducing leg pain, fatigue, swelling, or tension as taking 1000 mg daily of micronized purified flavonoid fraction providing diosmin plus other flavonoids (Daflon, Laboratórios Servier do Brasil Ltda.) (105293). Also, in a mixed population with pre-CVI and CVI, clinical research shows that taking a specific diosmin (as µsmin Plus, Giellepi S.p.A.) 450 mg once daily for 8 weeks reduces edema by approximately 4% when compared with placebo. Additionally, 98% of patients taking this diosmin product experienced symptom relief, compared with only 29% of those taking placebo (105294). The discrepancy in these findings may be related to the different products used or the severity of disease in the included patient populations.
• Hemorrhoids. Oral diosmin, as part of a micronized purified flavonoid fraction or in combination with other compounds, seems to be beneficial for hemorrhoids. Details: A meta-analysis of the available research, as well as individual clinical trials, show that taking three tablets of a specific combination product (Daflon 500, Les Laboratoires Servier), containing diosmin 450 mg plus other flavonoids, such as hesperidin, 50 mg per tablet, twice daily for 4-5 days followed by two tablets of this same product twice daily for up to 3 months, improves signs and symptoms of internal hemorrhoids. The combination appears to stop acute bleeding in up to 92% of patients after 4 days of treatment. It may also reduce symptoms such as anal discomfort, pain, discharge, and local lesions within 2 days of treatment. The combination also seems to reduce the duration and intensity of hemorrhoidal flare-ups (4861,4900,8077,54970,105282) and improve recovery after hemorrhoidopexy or hemorrhoidectomy (54793,105284). Maintenance treatment with one tablet of this product twice daily for 2-3 months following acute treatment for hemorrhoids decreases the relapse rate and improves symptoms, including pain, itching, tenesmus, mucous discharge, redness, swelling, and bleeding (4861,54954). Diosmin has also been evaluated in combination with hesperidin and troxerutin. Clinical research in adults with acute hemorrhoidal crisis shows that taking a combination product (Triade H, Omikron Italia Srl) providing these ingredients in tapered doses over 43 days reduces progressive pain in approximately 88% of patients, bleeding in 64% of patients, and anal itching in 56% of patients. These changes are significant when compared with placebo (93885). This product was given as one sachet of powdered diosmin 300 mg, troxerutin 300 mg, hesperidin 300 mg, and vitamin C 12 mg mixed in water orally three times daily for 3 days, then two sachets daily for 2 days, then one sachet daily for seven days, followed by one tablet containing diosmin 300 mg, troxerutin 300 mg, and hesperidin 100 mg daily for one month. Diosmin has also been evaluated in combination with bulk laxatives. Diosmin 600 mg three times daily for 4 days, then 300 mg twice daily for 10 more days in conjunction with psyllium 11 grams daily, seems to modestly improve symptoms after 4 days of treatment (4898). However, this combination does not seem to be as effective as the use of micronized purified flavonoid fraction.
• Venous leg ulcers. Oral diosmin, as part of a micronized purified flavonoid fraction, seems to be beneficial for venous leg ulcers. Details: Clinical research in adults with venous leg ulcers up to 10 cm in size shows that taking two tablets daily of a specific combination product (Daflon 500, Les Laboratoires Servier), containing diosmin 450 mg plus other flavonoids, such as hesperidin, 50 mg per tablet for 2 months in conjunction with compression dressing more than doubles the number of patients with complete healing of ulcers when compared with placebo. Also, the time to healing was reduced. However, in one study there was no effect on the ulcer surface area, symptoms, or healing of ulcers greater than 10 cm in size (10229,54972,54984).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Back pain. It is unclear if oral diosmin is beneficial for back pain. Details: Preliminary clinical research in patients with radicular low back pain shows that taking diosmin (Nanjing Chia Tai Tianqing Pharmaceutical Co., Ltd) moderately improves subjective pain scores after 8 weeks and reduces the use of rescue analgesics after 24 months similarly to intravenous dexamethasone every 3 days with monthly administration of mannitol. Diosmin was administered at doses of 900 mg orally three times daily for 2 weeks, then 900 mg twice daily for 2 weeks, then 450 mg twice daily for one month (95043).
• Chronic prostatitis and chronic pelvic pain syndrome (CP/CPPS). It is unclear if oral diosmin, as part of a micronized purified flavonoid fraction, is beneficial for CPPS. Details: Preliminary clinical research shows that taking one tablet daily of a specific combination product containing diosmin 450 mg plus other flavonoids, such as hesperidin, 50 mg per tablet (Daflon) for 8 weeks in combination with standard treatment involving antibiotics and anti-inflammatory drugs improves overall symptoms of CPPS at 6 months similarly to taking alfuzosin, an alpha-blocker, along with standard treatment for 12 weeks. However, there was no benefit when the diosmin product was used alone, without standard treatment. At 12 months, symptoms were modestly more improved in those taking alfuzosin (105297).
• Coronary artery bypass graft (CABG) surgery. It is unclear if oral diosmin, as part of a micronized purified flavonoid fraction, is beneficial for patients undergoing CABG surgery. Details: In patients about to undergo CABG for impaired left ventricular function, clinical research shows that a specific combination product containing diosmin 450 mg plus other flavonoids, such as hesperidin, 50 mg per tablet (Daflon 500, Les Laboratoires Servier), taken as 3000 mg daily for 4 days, followed by 1000 mg daily for 3 days preoperatively, does not reduce the postoperative length of stay in the intensive care unit or hospital, inotropic medication requirements, or left ventricular ejection fraction when compared with placebo. However, levels of troponin I and lactate were lower, and patient status based on the New York Heart Association (NYHA) classification was modestly improved (105285).
• Diabetes. It is unclear if oral diosmin, as part of a micronized purified flavonoid fraction or in combination with other compounds, is beneficial for diabetes. Details: Preliminary clinical research in females with type 2 diabetes shows that taking one tablet of a specific combination product containing diosmin 450 mg plus other flavonoids, such as hesperidin, 50 mg per tablet (Daflon 500, Les Laboratoires Servier) twice daily for 45 days modestly decreases glycated hemoglobin (HbA1c) and serum glucose when compared to baseline (54977). However, a prospective observational study in patients with type 1 or type 2 diabetes has found that taking a specific product (Flebotrofine, AMNOL Chimica Biologica) containing diosmin for 3 months is not associated with improvements in HbA1c, cholesterol, or triglyceride levels when compared with baseline. Other ingredients in this product included L-arginine, troxerutin, hesperidin, black currant extract, and gotu kola extract (108151). The validity of these findings is limited by the lack of a comparator group.
• Diabetic neuropathy. It is unclear if oral diosmin is beneficial for diabetic neuropathy. Details: A small clinical study in adults with type 2 diabetes, peripheral neuropathy, and metabolic syndrome on oral antidiabetic therapy shows that taking diosmin 1 gram daily (Dioven, Amryia Pharmaceutical Co.) for 12 weeks, with or without hesperidin 1 gram daily, improves diabetic neuropathy as measured by the Michigan Neuropathy Screening Instrument (MNSI) when compared with standard care alone. In addition, the improvements in measures of diabetic neuropathy were greater when diosmin and hesperidin are taken together compared with either supplement alone, suggesting a synergistic effect (112797). However, the validity of this study is limited by inadequate blinding.
• Lymphedema. It is unclear if oral diosmin, as part of a micronized purified flavonoid fraction or in combination with other compounds, is beneficial for lymphedema. Details: Clinical research shows that taking two tablets of a specific combination product (Daflon 500, Les Laboratoires Servier) containing diosmin 450 mg plus other flavonoids, such as hesperidin, 50 mg per tablet daily for 6 months may improve drainage of lymph from the arms after breast cancer surgery, but does not reduce arm swelling or other clinical signs of lymphedema, when compared with placebo (10227). A small clinical study in patients with severe breast cancer-related lymphedema shows that taking a specific combination product (Linfaden, OMEGA PHARMA Srl) containing diosmin 200 mg, coumarin 30.6 mg, and arbutin 3.7 mg twice daily for 2 weeks and then once daily for 4 weeks, in addition to complex congestive therapy (CDT), reduces upper limb excess volume by 521 mL, compared with a 256 mL reduction in the CDT-only group (101646). It is unclear if the effects are due to diosmin, other ingredients, or the combination.
• Metabolic syndrome. It is unclear if oral diosmin is beneficial for metabolic syndrome. Details: A small clinical study in adults with metabolic syndrome, type 2 diabetes, and peripheral neuropathy on oral antidiabetic therapy shows that taking diosmin 1 gram daily (Dioven, Amryia Pharmaceutical Co.) for 12 weeks, with or without hesperidin 1 gram daily, reduces body mass index, fasting blood glucose, triglycerides, and low-density lipoprotein cholesterol but does not change systolic blood pressure, diastolic blood pressure, or high-density lipoprotein cholesterol when compared with standard care alone. These effects are enhanced when diosmin is taken in combination with hesperidin compared with either supplement taken alone or control (112797). However, the validity of this study is limited by inadequate blinding.
• Minor bleeding. It is unclear if oral diosmin, as part of a micronized purified flavonoid fraction, is beneficial for minor bleeding. Details: Preliminary clinical research in patients with idiopathic epistaxis shows that taking a specific combination product containing diosmin 450 mg plus other flavonoids, such as hesperidin, 50 mg (Daflon, Servier) daily for 1-3 months modestly reduces emergency room visits and need for cauterization due to failure of light nasal packing when compared with no treatment (101644). The validity of this study is limited by the lack of blinding.
• Ovarian hyperstimulation syndrome. It is unclear if oral diosmin is beneficial for reducing the occurrence of ovarian hyperstimulation syndrome. Details: Observational research in patients at high risk of ovarian hyperstimulation syndrome (OHSS) following a previous cancellation of embryo transfer has found that taking diosmin 1000 mg twice daily for 10 days after oocyte retrieval is associated with a 6.2% incidence of moderate to severe OHSS, compared to 13.4% in the patients that had not received diosmin. Also, there were no cases of severe OHSS (105295). This study is limited by its retrospective, observational design.
• Varicose veins. It is unclear if oral diosmin, as part of a micronized purified flavonoid fraction, is beneficial for varicose veins. Details: In patients with mild varicose veins such as spider veins or reticular veins, some observational research has evaluated the use of a specific combination product (Detralex; Servier France) containing diosmin 450 mg plus other flavonoids, such as hesperidin, 50 mg per tablet, taken as one tablet twice daily for 6 weeks, starting 2 weeks before sclerotherapy. This research has found that taking this product is associated with decreased leg heaviness, pain, swelling sensation, night cramps, and itching after sclerotherapy when compared with patients not using this treatment. It is also associated with a reduction in pain and swelling sensation from before sclerotherapy when compared with those not using this treatment. Additionally, the use of this product is associated with a slight reduction in hyperpigmentation following sclerotherapy, although there were no benefits on other sclerotherapy-related adverse effects, including phlebitis and necrosis (105283). In patients with varicose veins of greater severity, observational research has found that taking this same product 1000 mg daily for 30 days, starting on the day of mechanochemical ablation with mini-phlebectomy or foam sclerotherapy, is associated with a modest reduction in the severity of varicose veins, such as swelling, heaviness, and itching, after 30 days, but not after 7 or 14 days, when compared with no treatment (105286). For more information on the use of diosmin for chronic venous insufficiency (CVI), which can occur concomitantly with varicose veins, refer to the CVI discussion.
• Venous thromboembolism (VTE). It is unclear if oral diosmin is beneficial for prevention of VTE. Details: In patients experiencing their first femoropopliteal deep vein thrombosis (DVT), preliminary clinical research shows that taking diosmin 600 mg daily for 12 months, in addition to rivaroxaban and elastic compression stockings, reduces the frequency of post-thrombotic syndrome to 9%, compared to 49% in those not taking diosmin. There were also fewer patients with chronic venous disease or DVT recurrence at 12 months (105296). More evidence is needed to rate diosmin for these uses.

(Read more about DIOSMIN)

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Dyspepsia. Oral olive leaf extract has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small study in healthy adults shows that taking a specific combination product containing olive leaf extract 24% and prickly pear cactus 33% (Mucosave, Bionap S.R.L.) 400 mg daily for 8 weeks seems to improve dyspepsia and other gastrointestinal symptoms when compared with placebo (105904). It is unclear if this benefit would occur in patients with clinically diagnosed dyspepsia.
• Exercise-induced respiratory infections. It is unclear if oral olive leaf extract is beneficial for reducing respiratory infections from exercise. Details: A small clinical study in high school athletes shows that taking one tablet of olive leaf extract providing eleuropein 100 mg daily for 2 months during training season does not reduce the incidence of the common cold when compared with placebo. While it may reduce the number of sick days by 28%, a sub-group analysis suggests that this reduction is only evident in female athletes (101860).
• Gastroesophageal reflux disease (GERD). Although there is interest in using oral olive leaf for GERD, there is insufficient reliable information about the clinical effects of olive for this condition.
• Herpes zoster (shingles). Although there is interest in using oral olive leaf for shingles, there is insufficient reliable information about the clinical effects of olive for this condition.
• Influenza. Although there is interest in using oral olive leaf for influenza, there is insufficient reliable information about the clinical effects of olive for this condition.
• Metabolic syndrome. It is unclear if oral olive leaf extract is beneficial for improving body composition and cardiovascular risk factors in patients with metabolic syndrome. Details: A small clinical trial in overweight, middle-aged males at risk for metabolic syndrome shows that taking four capsules of olive leaf extract providing oleuropein 51.1 mg and hydroxytyrosol 9.7 mg daily for 12 weeks improves insulin sensitivity by 15% when compared with placebo. However, body composition, blood pressure, cholesterol levels, and other cardiovascular risk factors were not improved (92245).
• Osteoarthritis. It is unclear if oral olive fruit or leaf extract is beneficial for improving osteoarthritis. Details: Preliminary clinical research shows that taking a freeze-dried aqueous extract of olive fruit 400 mg daily for 8 weeks decreases pain and increases mobility in people with osteoarthritis (14844). Other preliminary clinical research in adults with knee osteoarthritis shows that taking olive leaf extract 50.1 mg daily for 4 weeks improves overall pain measurements by 14%, compared to only 4% in the placebo group. However, many individual measurements of pain are not improved (92252).
• Osteoporosis. It is unclear if oral olive leaf extract is beneficial for osteoporosis. Details: Clinical research shows that taking olive leaf extract (Bonolive, BioActor BV) 250 mg daily for 12 months, along with elemental calcium 400 mg daily, increases osteocalcin levels by about 32% when compared to baseline; this increase was significant when compared to those taking calcium 400 mg plus placebo, who showed a 6% decrease in osteocalcin levels. However, taking olive leaf extract does not significantly increase bone mineral density of the lumbar spine or femur neck when compared with placebo (92247).
• Rheumatoid arthritis (RA). It is unclear if oral olive fruit extract is beneficial for improving RA symptoms. Details: Preliminary clinical research in adults with RA shows that taking an aqueous freeze-dried extract of olive fruit 400 mg daily for 8 weeks does not improve symptoms when compared with control (14844). More evidence is needed to rate the effectiveness of olive for these uses.

(Read more about OLIVE)

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Aging skin. It is unclear if topical rutin is beneficial for aging skin. Details: Preliminary clinical research shows that topical application of a cream containing rutin 2% twice daily for 4 weeks reduces signs of skin aging around the eye in females aged 30-50 years. Skin dermal density is improved by 20%, area of crow's feet is reduced by 26%, and the number of wrinkles under the eye is reduced by 53% when compared with placebo (92236).
• Autism spectrum disorder. Oral rutin has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in children 4-10 years-old with autism spectrum disorder shows that taking a product containing rutin 3 mg/kg, luteolin 10 mg/kg, and quercetin 7 mg/kg daily for 26 weeks improves aspects of behavior, such as hyperactivity, irritability, and lethargy, by a moderate to large amount when compared to baseline. It also seems to improve some indices of functioning, such as daily living and social behavior, by a small amount. These improvements were considered to be greater than expected when taking aging into consideration; however, no placebo was used in this study (96765).
• Diabetes. It is unclear if oral rutin is beneficial for diabetes. Details: A small clinical study in adults with type 2 diabetes conducted in Iran shows that taking rutin 500 mg twice daily for 3 months reduces fasting blood glucose and glycated hemoglobin by approximately 40 mg/dL and 1%, respectively, and modestly reduces triglycerides and total and low-density lipoprotein cholesterol when compared with placebo (112182). The interpretation of these findings is limited by the omission of data regarding concurrent diabetes medications. A small observational study in patients with a family history of type 1 diabetes shows that taking a specific product (Mucos Pharma) containing rutin 100 mg, trypsin 48 mg, and bromelain 90 mg daily for 24 months is not associated with reduced incidence of type 1 diabetes at 8 years (99472).
• Exercise-induced respiratory infections. Oral rutin has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in non-elite male runners shows that taking a combination product (Wobenzym Plus, Mucos Pharma) providing rutin 600-1200 mg, trypsin 288-576 mg, and bromelain 540-1080 mg daily for 3 weeks, starting one week before a marathon, does not reduce the risk of a post-race respiratory tract infection when compared with placebo (96766).
• Hemorrhoids. Although there is interest in using oral rutin for hemorrhoids, there is insufficient reliable information about the clinical effects of rutin for this condition.
• Inflammatory bowel disease (IBD). Although there is interest in using oral rutin for IBD, there is insufficient reliable information about the clinical effects of rutin for these conditions.
• Lymphedema. Oral rutin has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Some clinical research in patients who have undergone a mastectomy shows that taking a specific combination product containing rutin, pancreatin, papain, bromelain, trypsin, and chymotrypsin (Wobenzym N, Mucos Pharma) daily for 7 weeks reduces arm swelling associated with lymphedema when compared with diuretics (24560). Also, preliminary clinical research in patients with primary or secondary lymphedema of the upper or lower limbs shows that taking a combination product containing rutin 300 mg, bromelain 100 mg, and sweet clover 100 mg daily for 6 months decreases pitting, limb volume, pain, and quality of life when compared to baseline (103298). The validity of these findings is limited by the lack of a comparator group. Also, it is unclear if these effects are due to rutin, other ingredients, or the combination.
• Multiple sclerosis (MS). Oral rutin has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A preliminary clinical study in patients with relapsing-remitting MS shows that taking an enzyme combination containing rutin 100 mg, trypsin 48 mg, and bromelain 90 mg per tablet for at least 3 months does not affect the progression of disability, relapse rate, or central nervous system lesions when compared with placebo (99468). The validity of these results are limited by the short duration of treatment.
• Obesity. It is unclear if oral rutin is beneficial for obesity. Details: In Japanese adults with a body mass index (BMI) of 23-30 kg/m2, a small clinical trial shows that taking a specific monoglucosyl rutin ( αG Rutin PS) 200 mg or 400 mg daily for 8 weeks reduces the area of visceral fat by 2.4 cm and 3.5 cm, respectively, compared with an increase of 5.2 cm in those taking placebo. However, there were no differences between groups in the actual value of visceral fat, changes in total fat or subcutaneous fat, BMI, body weight, abdominal circumference, or cholesterol or triglyceride levels (105298).
• Oral mucositis. Although there is interest in using oral rutin for oral mucositis, there is insufficient reliable information about the clinical effects of rutin for this condition.
• Osteoarthritis. Oral rutin has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research shows that taking a specific combination product (Wobenzym PS, formerly Phlogenzym, Mucos Pharma) at a dose providing up to 600 mg rutin, 288 mg trypsin, and 540 mg bromelain daily for 3-12 weeks, is as effective as diclofenac for relieving pain and improving knee function in patients with painful osteoarthritis of the knee. This product also reduces the need for rescue medication by 95% when compared with placebo (6252,91104,99467,99477).
• Postoperative swelling. Oral rutin has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small preliminary clinical study in patients undergoing surgery of the jaw shows that taking an enzyme combination of rutin 200 mg, trypsin 96 mg, and bromelain 180 mg twice daily for 5 days in addition to standard treatment reduces soft-tissue thickness (indicating the amount of swelling) at most of the nine assessed facial points when compared to control (99476).
• Sprains. Oral rutin has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A clinical study in patients with a sprained ankle shows that taking a specific enzyme combination (Phlogenzym, Mucos Pharma) containing rutin 100 mg, trypsin 48 mg, and bromelain 90 mg, or taking different combinations of the individual enzymes three times daily for 10 days, is no more effective for relieving pain than placebo (99473).
• Stroke. Although there is interest in using oral rutin for stroke prevention, there is insufficient reliable information about the clinical effects of rutin for this purpose.
• Sunburn. Although there is interest in using topical rutin for sunburn prevention, there is insufficient reliable information about the clinical effects of rutin for this purpose.
• Varicose veins. Although there is interest in using oral rutin for varicose veins, there is insufficient reliable information about the clinical effects of rutin for this condition. More evidence is needed to rate rutin for these uses.

(Read more about RUTIN)

There is insufficient reliable information available about the safety of caffeic acid.

PREGNANCY AND LACTATION:
Insufficient reliable information; avoid using.

(Read more about CAFFEIC ACID)

LIKELY SAFE ...when used orally in amounts found in foods.

POSSIBLY SAFE ...when supplements are used orally and appropriately, short-term. Diosmin seems to be safe when used alone or in combination with other flavonoids in doses of up to 1350 mg daily for up to 6 months (4861,4898,10227,10229,93885,105283,105286,105287,105293,105294)(105296,108150).

PREGNANCY AND LACTATION: LIKELY SAFE
when used orally in amounts found in foods.

PREGNANCY AND LACTATION: POSSIBLY SAFE
when used orally in doses of up to 900 mg daily for 30 days in combination with other flavonoids, such as hesperidin. Some evidence suggests that taking this combination may be associated with placental insufficiency when used during the third trimester of pregnancy; however, the combination does not seem to induce fetal abnormalities, retard fetal growth, increase the risk of intrauterine death, or affect birth weight. Also, when breastfeeding, this combination does not seem to affect infant growth or feeding (54970).

(Read more about DIOSMIN)

LIKELY SAFE ...when olive fruit is used orally and appropriately in amounts commonly found in foods.

POSSIBLY SAFE ...when olive leaf extract is used orally and appropriately. Olive leaf extract providing 51-100 mg oleuropein daily has been used with apparent safety for 6-8 weeks (92245,92247,101860). There is insufficient reliable information available about the safety of olive fruit extract when used in amounts greater than those found in foods.

PREGNANCY AND LACTATION:
Insufficient reliable information available; stick with amounts commonly found in foods.

(Read more about OLIVE)

LIKELY SAFE ...when used orally in amounts found in foods, such as fruits and vegetables.

POSSIBLY SAFE ...when used orally in medicinal amounts, short-term. Rutin has been used with apparent safety at doses of up to 600 mg daily for up to 12 weeks (6252,24560,91104,96766,105298). ...when applied topically as a cream (92236,99258,99260).

PREGNANCY AND LACTATION: LIKELY SAFE
when used orally in amounts commonly found in foods. There is insufficient reliable information available about the use of supplemental rutin; avoid amounts greater than those found in foods.

(Read more about RUTIN)

LEVODOPA Interaction Rating = Minor Be watchful with this combination. Severity = Insignificant •  Occurrence = Possible •  Level of Evidence = D Theoretically, caffeic acid might increase the levels and clinical effects of levodopa.  Details In an animal model, caffeic acid 10 mg/kg seems to significantly decrease conversion of levodopa to 3-O-methyldopa by about 22%. Caffeic acid also decreased the maximum concentration (Cmax) of 3-O-methyldopa by about 31% (18044). There is speculation that this interaction could be beneficial for Parkinson disease patients. However, the clinical significance of this potential interaction in humans is not known.

ORGANIC ANION TRANSPORTER 1 (OAT1) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, caffeic acid might increase the levels and clinical effects of OAT1 substrates.  Details In vitro, caffeic acid inhibits OAT1. This drug transport protein is involved in renal tubular uptake of some drugs from the blood and then elimination in the urine. Inhibition of this transporter decreases renal elimination and increases drug levels in the body (18041). Although caffeic acid inhibits OAT1 in vitro, the clinical significance of this in humans is not known.

ORGANIC ANION TRANSPORTER 3 (OAT3) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, caffeic acid might increase the levels and clinical effects of OAT3 substrates.  Details In vitro, caffeic acid inhibits OAT3. This drug transport protein is involved in renal tubular uptake of some drugs from the blood and then elimination in the urine. Inhibition of this transporters decreases renal elimination and increases drug levels in the body (18041). Although caffeic acid inhibits OAT3 in vitro, the clinical significance of this in humans is not known.

(Read more about CAFFEIC ACID)

ANTICOAGULANT/ANTIPLATELET DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, diosmin may increase the risk of bleeding if used with anticoagulant or antiplatelet drugs.  Details A case of spontaneous intraventricular hemorrhage has been reported for a 77-year-old female after 6 weeks of warfarin therapy, despite an international normalized ratio (INR) of only 1.8. The patient had also been taking aspirin and diosmin for several years. Experts speculate that chronic intake of diosmin predisposed the patient to spontaneous intraventricular hemorrhage by inducing chronic microcirculatory hypertension and inhibiting platelet aggregation. The presence of aspirin was also thought to play a role in this event (93886).

CARBAMAZEPINE (Tegretol) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Theoretically, diosmin might reduce the effects of carbamazepine and increase the risk for convulsions.  Details A pharmacokinetic study in humans shows that taking diosmin (Venex) 500 mg daily for 10 days prior to oral administration of carbamazepine 200 mg increases blood levels of carbamazepine by approximately 58% and decreases carbamazepine clearance by 42%. It also decreases the formation of carbamazepine's active metabolite. It is speculated that diosmin reduces the metabolism of carbamazepine by inhibiting cytochrome P450 3A4 (CYP3A4) (95041).

CHLORZOXAZONE (Parafon Forte, Paraflex) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Theoretically, diosmin might increase the levels and clinical effects of chlorzoxazone.  Details A pharmacokinetic study in humans shows that taking diosmin (Venex 500) 500 mg daily for 9 days prior to oral administration of chlorzoxazone 250 mg increases blood levels of chlorzoxazone by 53% and decreases chlorzoxazone clearance by 40%. It is speculated that diosmin reduces the metabolism of chlorzoxazone by inhibiting cytochrome P450 2E1 (CYP2E1) (93889).

CYTOCHROME P450 2C9 (CYP2C9) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, diosmin might inhibit the metabolism of CYP2C9 substrates.  Details Diclofenac is metabolized by CYP2C9 enzymes. Clinical and laboratory research shows that diosmin inhibits the metabolism of diclofenac (93888,98596). A pharmacokinetic study in humans shows that taking diosmin (Venex 500) 500 mg daily for 9 days prior to oral administration of diclofenac 100 mg increases blood levels of diclofenac and decreases diclofenac clearance (93888).

CYTOCHROME P450 2E1 (CYP2E1) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, diosmin might inhibit the metabolism of CYP2E1 substrates.  Details Chlorzoxazone is metabolized by CYP2E1 enzymes. A pharmacokinetic study in humans shows that taking diosmin (Venex 500) 500 mg daily for 9 days prior to oral administration of chlorzoxazone (Paraflex 250) 250 mg increases blood levels of chlorzoxazone by 34% and decreases chlorzoxazone clearance by 40%. It is speculated that diosmin reduces the metabolism of chlorzoxazone by inhibiting CYP2E1 (93889).

CYTOCHROME P450 3A4 (CYP3A4) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, diosmin might inhibit the metabolism of CYP3A4 substrates.  Details Laboratory research is conflicting with respect to the effects of diosmin on CYP3A4. Some research suggests that diosmin does not affect CYP3A4 activity (95040). However, other research suggests that diosmin alters the metabolism of carbamazepine, a CYP3A4 substrate. Laboratory and animal research show that oral administration of diosmin for 7 days prior to oral administration of carbamazepine increases plasma concentrations of carbamazepine, decreases the clearance of carbamazepine, and decreases the formation of carbamazepine's active metabolite (95039). Additionally, pharmacokinetic research in healthy male subjects shows that taking diosmin (Venex) 500 mg daily for 10 days prior to oral administration of carbamazepine 200 mg increases blood levels of carbamazepine by approximately 58% and decreases carbamazepine clearance by 42% (95041). It is speculated that diosmin reduces the metabolism of carbamazepine by inhibiting CYP3A4 (95039,95041). Diosmetin, a metabolite of diosmin, may also inhibit CYP3A4 (95041).

DICLOFENAC (Voltaren, others) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Theoretically, diosmin might increase the levels and clinical effects of diclofenac.  Details Clinical and laboratory research shows that diosmin inhibits the metabolism of diclofenac (93888,98596). A pharmacokinetic study in humans shows that taking diosmin (Venex 500) 500 mg daily for 9 days prior to oral administration of diclofenac 100 mg increases blood levels of diclofenac and decreases diclofenac clearance. It is speculated that diosmin reduces the metabolism of diclofenac by inhibiting cytochrome P450 2C9 (CYP2C9) (93888).

FEXOFENADINE (Allegra) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Theoretically, diosmin might increase the levels and clinical effects of fexofenadine.  Details A pharmacokinetic study in humans shows that taking diosmin (Venex) 500 mg daily for 10 days prior to oral administration of fexofenadine 120 mg increases blood levels of fexofenadine by approximately 49% and decreases the apparent oral clearance of fexofenadine by 41%. The time taken to reach maximum plasma concentration, the half-life, and the apparent renal clearance of fexofenadine are not affected. For this reason, it is speculated that diosmin alters the pharmacokinetics of fexofenadine via inhibition of P-glycoprotein in the intestine, but not in the kidney or liver (95042).

P-GLYCOPROTEIN SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, diosmin might increase levels of drugs that are substrates of P-glycoprotein (P-gp).  Details Preliminary laboratory research suggests that diosmin inhibits P-gp (93890). Additionally, pharmacokinetic research in healthy male subjects shows that taking diosmin (Venex) 500 mg daily for 10 days prior to oral administration of fexofenadine 120 mg increases blood levels of fexofenadine, a P-gp substrate, by approximately 49% and decreases the apparent oral clearance of fexofenadine by 41%. The time taken to reach maximum plasma concentration, the half-life, and the apparent renal clearance of fexofenadine are not affected. For this reason, it is speculated that diosmin inhibits P-gp in the intestine, but not in the kidney or liver (95042).

(Read more about DIOSMIN)

(Read more about OLIVE)

ANTIDIABETES DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, taking rutin with antidiabetes drugs might increase the risk of hypoglycemia.  Details Animal research suggests that rutin has hypoglycemic effects (105299).

(Read more about RUTIN)

General ...No adverse effects have been reported. However, a thorough evaluation of safety outcomes has not been conducted.

(Read more about CAFFEIC ACID)

General ...Orally, diosmin is generally well tolerated.
Most Common Adverse Effects:
Orally: Abdominal pain, diarrhea, dizziness, gastritis, nausea, skin inflammation, and skin redness.
Serious Adverse Effects (Rare):
Orally: Cardiac arrhythmias and hemolytic anemia.

Cardiovascular ...Orally, diosmin can cause cardiac arrhythmias (93887,105293).

Dermatologic ...Orally, diosmin can cause skin redness, hives, itchiness, and inflammation (93887).

Gastrointestinal ...Orally, diosmin can cause gastrointestinal side effects, including abdominal pain, diarrhea, nausea, flatulence, and gastritis (4861,4898,4900,10229,54935,54970,93887,105287,105293,105296)(112796). In one case, exacerbation of chronic colopathy was reported after taking a specific diosmin-containing product (Daflon 500, Les Laboratoires Servier) (10229).

Hematologic ...Orally, diosmin can cause hemolytic anemia (93887).

Musculoskeletal ...Orally, one case report of muscle pain was thought to be related to diosmin use (93887).

Neurologic/CNS ...Orally, diosmin can cause headache, low energy, and dizziness in some patients (4861,4898,4900,10229,93887,105293,112796).

(Read more about DIOSMIN)

General ...Orally, olive fruit is well tolerated when used in typical food amounts. Olive leaf extract seems to be well tolerated.
Most Common Adverse Effects:
Orally: Headache and stomach discomfort.

Dermatologic ...Orally, one patient in one clinical trial reported bad skin and acne after using olive leaf extract (101860).

Gastrointestinal ...Orally, three patients in one clinical trial reported stomach ache after using olive leaf extract (101860).

Neurologic/CNS ...Orally, three patients in one clinical trial reported headache after using olive leaf extract (101860).

Psychiatric ...In one case report, a 67-year-old female experienced irritability, anger, a lack of control, and feelings of sadness and negativity after consuming a multi-ingredient product containing olive leaf extract 5 grams, horseradish root, and eyebright daily for 38 days. All psychiatric symptoms disappeared within days of stopping the combined product. It is hypothesized that the hydroxytyrosol component of olive leaf extract contributed to these symptoms due to its chemical similarity to dopamine; however, it is not clear if these symptoms were due to the olive leaf extract or to the other ingredients (96245).

Pulmonary/Respiratory ...Olive tree pollen can cause seasonal respiratory allergy (1543).

(Read more about OLIVE)

General ...Orally, rutin is generally well tolerated.

Dermatologic ...Orally, rutin may cause flushing and rashes in some people (313).

Gastrointestinal ...Orally, rutin may cause gastrointestinal disturbance in some people (313).

Neurologic/CNS ...Orally, rutin may cause headache in some people (313).

(Read more about RUTIN)