I. Drug and Supplement Interactions
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Clinical Trials of Drug or Supplement Interactions
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No clinical trials of drug or supplement interactions were identified.
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Case Reports of Suspected Drug or Supplement Interactions
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No case reports of drug or supplement interactions were identified.
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Animal Trials of Drug or Supplement Interactions
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In rats orally administered ciprofloxin with or without 2 g/kg of an aqueous extract of fennel, decreases in the maximum plasma concentration, area under the curve, and urinary recovery of ciprofloxin were observed after coadministration with fennel. The volume of distribution and terminal elimination half-life of ciprofloxin were increased (Zhu et al. 1999).
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An increase in pentobarbital-induced sleeping time was observed in mice intraperitoneally administered 50 mg/kg of fennel essential oil (Marcus and Lichtenstein 1982).
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Case Reports of Adverse Events
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A case series of premature thelarche (isolated breast development with no other clinical signs of sexual maturation) was reported in four girls ages 5 months to 5 years who had been administered two to three cups of fennel tea daily for 4 months to 2 years. Age-specific serum estradiol levels were 15 to 20 times higher than normal. All of the girls had been breast-fed for their first 9 months, and none had a history of prolonged drug intake that would account for the elevation in hormone levels. After cessation of administration, premature thelarche resolved within 3 to 6 months and hormone levels decreased to the normal range (Turkyilmaz et al. 2008).
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A case series of methemoglobinemia with respiratory distress, cyanosis, and tachycardia was reported in four infants, 7 to 9 months old, that had been fed purées of fennel (part and dose used not specified). Purées administered to two of the infants were analyzed for nitrate content and found to contain high (2550 mg/kg) levels of nitrates. In two cases, the purées were combined with carrot, a vegetable that is high in nitrates. Nitrates are the most common cause of acquired methemoglobinemia (Murone et al. 2005).
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Rare cases of allergic reaction to fennel have been reported (Bensky et al. 2004; De Smet 1992; Ottolenghi et al. 1995). Allergic reactions are reported to have been associated with symptoms such as shortness of breath, facial pallor, low blood pressure, excessive sweating, accelerated pulse, and impaired consciousness (Bensky et al. 2004).
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In patch testing of persons with birch-mugwort-celery syndrome, cross-sensitivity to fennel was relatively high as compared to other allergens tested (Jensen-Jarolim et al. 1997; Stager et al. 1991).
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III. Pharmacology and Pharmacokinetics
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Human Pharmacological Studies
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In a study of women with idiopathic hirsutism (excessive male pattern hair growth in women with normal levels of serum androgens), involving topical application of a cream containing 1 or 2% fennel ethanol extract daily for 8 or 12 weeks, a dose-dependent reduction in hair diameter was observed. The authors of the article indicated that estrogenic activity of fennel was responsible for this reduction (Javidnia et al. 2003).
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Animal Pharmacological Studies
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In rats orally administered an acetone extract of fennel at doses of 0.5 to 2.5 mg/kg daily for 14 days, dose-dependent induction of the estrus cycle and increased weights of mammary glands, endometrium, cervix, and vagina were observed in females. In males, a decrease in total protein concentration in the testes and vas deferens and an increase in the seminal vesicles and prostate gland were observed after doses of 1.5 or 2.5 mg/kg (Malini et al. 1985).
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A decrease in the weight of testes, epididymis, seminal vesicle, ventral prostate, and vas deferens was observed in male rats orally administered 250 or 500 mg/kg of fennel aqueous extract daily for 60 days. A decrease in sperm motility was also observed along with a decrease in fertility (Agarwal et al. 2006).
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Antithrombotic activity was observed in mice orally administered 30 mg/kg fennel essential oil daily for 5 days. At that dose, prevention of paralysis induced by collagen-epinephrine injection was observed and did not cause any prohemorrhagic side effects (Tognolini et al. 2007).
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No effects on blood glucose levels were observed in diabetic mice intraperitoneally administered fixed oil of fennel daily for 7 days (Ozbek et al. 2003).
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In Vitro Pharmacological Studies
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Fennel essential oil inhibited platelet aggregation induced by arachidonic acid, ADP, thromboxane A2, and U46619 in guinea pig and rat plasma (Tognolini et al. 2006). The compound anethole, the main component of fennel essential oil, inhibited platelet aggregation induced by arachidonic acid, collagen, ADP, and U46619, and prevented thrombin-induced clot retraction in guinea pig plasma (Tognolini et al. 2007).
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Studies on the effects of fennel methanol extracts on the activity of the human drug-metabolizing isoenzyme CYP3A4 have shown differing results, with one study indicating significant inhibition (Subehan et al. 2006, 2007) and another study showing no activity (Usia et al. 2006). No significant effects of a methanol extract of fennel seed were observed on the human drug-metabolizing isoenzyme CYP2D6 (Subehan et al. 2006; Usia et al. 2006).
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IV. Pregnancy and Lactation
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German authorities have indicated that while fennel essential oil and alcohol extracts should not be taken during pregnancy, water-based extracts of fennel are regarded as safe (Wichtl 2004).
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A review of the safety of fennel indicated that, while fennel essential oil, like many other essential oils, has been reported to cause excitation of the gravid uterus, this effect has not been verified and is not likely to occur with therapeutic doses of fennel. The review also indicated that no cases of successfully self-induced abortions from fennel or fennel essential oil have been reported (De Smet 1992).
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An in vitro test using limb bud cells from day 13 rat embryos indicated some evidence of toxicity of fennel essential oil to fetal cells but no evidence of teratogenicity. After 5 days of incubation in concentrations of 0.93 mg/ml and above, a significant reduction in the number of stained differentiated foci were observed. This reduction was thought to be due to cell loss rather than to a decrease in cell differentiation (Ostad et al. 2004).
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The compound trans-anethole, isolated from fennel essential oil, exhibited dose-dependent anti-implantation activity in rats administered doses of 50 to 80 mg/kg on days 1 to 10 of pregnancy. At the 80 mg/kg dose level, administration on days 1 and 2 of pregnancy did not cause any changes in fertility, while with the same dose administered on days 3 to 5 of pregnancy, no implantation occurred. The same dose administered on days 6 to 10 of pregnancy caused a reduction in the number of pregnancies. No malformations were observed in any of the animals born from treated mothers (Dhar 1995).
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In isolated rat uteri, treatment with fennel essential oil reduced the intensity of contractions induced by oxytocin and prostaglandin E2. The oil also reduced the frequency of contractions induced by prostaglandin E2 but not by oxytocin (Ostad et al. 2001).
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A risk-benefit analysis on the use of fennel tea as a colic remedy for infants indicated that studies regarding carcinogenicity of the compound estragole in animal studies were difficult to interpret, as direct translation of animal experimental data to humans is problematic for numerous reasons. The analysis concluded that, based on available clinical and epidemiological data, any cancer risk is negligible and fennel seed is safe for use in infants (Iten and Saller 2004).
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The LD50 of orally administered fennel oil in rats is 3.8 ml/kg, whereas that of bitter fennel oil is 5.42 ml/kg (Opdyke 1979). The dermal LD50 of fennel oil and bitter fennel oil in rabbits could not be determined at doses up to 5 ml/kg (Opdyke 1979). The LD50 of an ethanol extract of fennel orally administered in mice and rats could not be determined at doses up 3 g/kg (Shah et al. 1991; Tanira et al. 1996).
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The LD50 of orally administered fennel essential oil in rats has also been reported as 1.3 mg/kg (Ostad et al. 2001). In mice, the intraperitoneal LD50 of fennel essential oil is 1.04 ml/kg whereas the oral LD50 is 5.52 ml/kg (Ozbek et al. 2003, 2006).
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No adverse morphological, hematological, or spermatogenic changes were observed in mice orally administered 100 mg/kg of an aqueous extract of fennel daily for 90 days (Shah et al. 1991).
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Some mutagenic activity of a fennel extract was observed in Salmonella typhimurium strains TA98 and TA102 (Mahmoud et al. 1992). Fennel essential oil exhibited mutagenic activity in the Ames test with Salmonella typhimurium strains TA98 and TA100, with activity potentiated by metabolic activation with S13 (Marcus and Lichtenstein 1982).
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No mutagenic activity of aqueous and methanolic extracts of fennel were observed in the Ames test for mutagenicity in Salmonella typhimurium strains TA98 or TA100 with or without metabolic activation (Morimoto et al. 1982; Yamamoto et al. 1982). No mutagenic activity of the same extract was found in the Bacillus subtilis rec assay (Morimoto et al. 1982).
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In the Bacillus subtilis DNA-repair test, sweet fennel essential oil showed some mutagenic activity, while in the chromosomal aberration test in Chinese hamster fibroblast cells (Sekizawa and Shibamoto 1982), fennel essential oil showed no mutagenic activity (Ishidate et al. 1984).
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Agarwal, M., T. Gehani, B. Sharma, and A. Chauhan. 2006. Antifertility effect of Foeniculum vulgare seeds (aqueous extract) on the reproductive organs of male rats, Rattus norvegicus. J. Exp. Zool. India 9(2):269-274.
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Bensky, D., S. Clavey, and E. Stöger. 2004. Chinese herbal medicine: Materia medica. 3rd ed. Seattle: Eastland Press.
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De Smet, P.A.G.M. 1992. Adverse effects of herbal drugs, Volume 1. Berlin: Springer.
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Dhar, S.K. 1995. Anti-fertility activity and hormonal profile of trans-anethole in rats. Indian J. Physiol. Pharmacol. 39(1):63-67.
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ESCOP. 2003. ESCOP monographs: The scientific foundation for herbal medicinal products. 2nd ed. Exeter, U.K.: European Scientific Cooperative on Phytotherapy.
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Ishidate, M., T. Sofuni, K. Yoshikawa, et al. 1984. Primary mutagenicity screening of food additives currently used in Japan. Food Chem. Toxicol. 22(8):623-636.
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Iten, F., and R. Saller. 2004. Fennel tea: Risk assessment of the phytogenic monosubstance estragole in comparison to the natural multicomponent mixture. Forsch. Komplementarmed. Klass. Nat. 11(2):104-108.
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Javidnia, K., L. Dastgheib, S. Mohammadi Samani, and A. Nasiri. 2003. Antihirsutism activity of fennel (fruits of Foeniculum vulgare) extract. A double-blind placebo controlled study. Phytomedicine 10(6-7):455-458.
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Jensen-Jarolim, E., A. Leitner, R. Hirschwehr, et al. 1997. Characterization of allergens in Apiaceae spices: Anise, fennel, coriander and cumin. Clin. Exp. Allergy 27(11):1299-1306.
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Mahmoud, I., A. Alkofahi, and A. Abdelaziz. 1992. Mutagenic and toxic activities of several spices and some Jordanian medicinal plants. Int. J. Pharmacogn. 30(2):81-85.
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Malini, T., G. Vanithakumari, N. Megala, et al. 1985. Effect of Foeniculum vulgare Mill. seed extract on the genital organs of male and female rats. Indian J. Physiol. Pharmacol. 29(1):21-26.
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Marcus, C., and E.P. Lichtenstein. 1982. Interactions of naturally occurring food plant components with insecticides and pentobarbital in rats and mice. J Agric. Food. Chem. 30(3):563-568.
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Morimoto, I., F. Watanabe, T. Osawa, T. Okitsu, and T. Kada. 1982. Mutagenicity screening of crude drugs with Bacillus subtilis rec-assay and Salmonella/microsome reversion assay. Mutat. Res. 97(2):81.
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Murone, A.J., P. Stucki, M.G. Roback, and M. Gehri. 2005. Severe methemoglobinemia due to food intoxication in infants. Pediatr. Emerg. Care 21(8):536-538.
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Opdyke, D.L.J. 1979. Monographs on fragrance raw materials. New York: Pergamon.
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Ostad, S.N., B. Khakinegad, and O. Sabzevari. 2004. Evaluation of the teratogenicity of fennel essential oil (FEO) on the rat embryo limb buds culture. Toxicol. In Vitro 18 (5):623-627.
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Ostad, S.N., M. Soodi, M. Shariffzadeh, N. Khorshidi, and H. Marzban. 2001. The effect of fennel essential oil on uterine contraction as a model for dysmenorrhea, pharmacology and toxicology study. J. Ethnopharmacol. 76(3):299-304.
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Ottolenghi, A., A. De Chiara, S. Arrigoni, L. Terracciano, and M. De Amici. 1995. Diagnosis of food allergy caused by fruit and vegetables in children with atopic dermatitis. Pediatr. Med. Chirurg. 17(6):525.
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Ozbek, H., M. Ozturk, I. Bayram, S. Ugras, and G.S. Citoglu. 2003. Hypoglycemic and hepatoprotective effects of Foeniculum vulgare Miller seed fixed oil extract in mice and rats. Eastern J. Med. 8(2):35-40.
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Ozbek, H., A. Tas, F. Ozgokce, et al. 2006. Evaluation of median lethal dose and analgesic activity of Foeniculum vulgare Miller essential oil. Int. J. Pharmacol. 2(2):181-183.
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Sekizawa, J., and T. Shibamoto. 1982. Genotoxicity of safrole-related chemicals in microbial test systems. Mutat. Res. 101(2):127.
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Shah, A.H., S. Qureshi, and A.M. Ageel. 1991. Toxicity studies in mice of ethanol extracts of Foeniculum vulgare fruit and Ruta chalepensis aerial parts. J. Ethnopharmacol. 34(2-3):167-172.
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Stager, J., B. Wuthrich, and S.G.O. Johansson. 1991. Spice allergy in celery-sensitive patients. Allergy 46(6):475-478.
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Subehan, T. Usia, H. Iwata, S. Kadota, and Y. Tezuka. 2006. Mechanism-based inhibition of CYP3A4 and CYP2D6 by Indonesian medicinal plants. J. Ethnopharmacol. 105(3):449-455.
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Subehan, S.F. Zaidi, S. Kadota, and Y. Tezuka. 2007. Inhibition on human liver cytochrome P450 3A4 by constituents of fennel (Foeniculum vulgare): Identification and characterization of a mechanism-based inactivator. J. Agric. Food. Chem. 55(25):10162-10167.
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Tanira, M.O.M., A.H. Shah, A. Mohsin, A.M. Ageel, and S. Qureshi. 1996. Pharmacological and toxicological investigations on Foeniculum vulgare dried fruit extract in experimental animals. Phytother. Res. 10(1):33-36.
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Tognolini, M., V. Ballabeni, S. Bertoni, et al. 2007. Protective effect of Foeniculum vulgare essential oil and anethole in an experimental model of thrombosis. Pharmacol. Res. 56(3):254-260.
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Tognolini, M., E. Barocelli, V. Ballabeni, et al. 2006. Comparative screening of plant essential oils: Phenylpropanoid moiety as basic core for antiplatelet activity. Life Sci. 78(13):1419-1432.
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Turkyilmaz, Z., R. Karabulut, K. Sonmez, and A. Can Basaklar. 2008. A striking and frequent cause of premature thelarche in children: Foeniculum vulgare. J. Pediatr. Surg. 43(11):2109-2111.
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Usia, T., H. Iwata, A. Hiratsuka, et al. 2006. CYP3A4 and CYP2D6 inhibitory activities of Indonesian medicinal plants. Phytomedicine 13(1-2):67-73.
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Wichtl, M. 2004. Herbal drugs and phytopharmaceuticals: A handbook for practice on a scientific basis. 3rd ed. Boca Raton, FL: CRC Press.
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Yamamoto, H., T. Mizutani, and H. Nomura. 1982. Studies on the mutagenicity of crude drug extracts. I. Yakugaku Zasshi 102(6):596-601.
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Zhu, M., P.Y.K. Wong, and R.C. Li. 1999. Effect of oral administration of fennel (Foeniculum vulgare) on ciprofloxacin absorption and disposition in the rat. J. Pharm. Pharmacol. 51(12):1391-1396.
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