Bitter orange: Difference between revisions
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In [[the Americas]], the juice from the ripe fruit is used as a [[marinade]] for meat in [[Nicaraguan cuisine|Nicaraguan]], [[Cuban cuisine|Cuban]], [[Cuisine of the Dominican Republic|Dominican]] and [[Haitian cuisine|Haitian]] cooking, as it is in [[Peru]]vian [[ceviche]]. In Yucatán (Mexico), it is a main ingredient of the [[cochinita pibil]]. |
In [[the Americas]], the juice from the ripe fruit is used as a [[marinade]] for meat in [[Nicaraguan cuisine|Nicaraguan]], [[Cuban cuisine|Cuban]], [[Cuisine of the Dominican Republic|Dominican]] and [[Haitian cuisine|Haitian]] cooking, as it is in [[Peru]]vian [[ceviche]]. In Yucatán (Mexico), it is a main ingredient of the [[cochinita pibil]]. |
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==HerbalThermogenic== |
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==Herbal stimulant== |
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[[File:Bitter oranges.jpg|thumb|left|Bitter oranges]] |
[[File:Bitter oranges.jpg|thumb|left|Bitter oranges]] |
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Bitter orange extracts are aqueous/ethanolic extracts of the dried immature fruits of ''Citrus aurantium''. Contrary to popular belief, bitter orange extract and p-synephrine do not act as stimulants at commonly used doses, and p-synephrine does not augment the cardiovascular effects of caffeine [Ratamess, N.A., Bush, J.A., Stohs, S.J., Ellis, N.L., Vought, I.T., O’Grady, E.A., Kuper, J.D., Hasan, S., Kang, J., Faigenbaum, A.D. 2017. Acute cardiovascular effects of caffeine and p-synephrine alone and in combination: A placebo-controlled, double-blind study. Phytother. Res. doi: 10.1002/ptr.5953.; Shara, M., Stohs, S.J., Smadi, M.M. 2017. Safety evaluation of bitter orange (p-synephrine) extract following oral administration for 15 days to healthy human subjects: A clinical trial. Phytother. Res. doi: 10.1002/ptr.5956.] Over 30 human studies regarding p-synephrine and bitter orange extracts have been conducted and published regarding their safety and efficacy [Stohs, S.J. 2017. Safety, efficacy and molecular studies regarding Citrus aurantium (Bitter orange) extract and p-synephrine. Phytother. Res. doi: 10.1002/ptr.5879.]. |
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The [[solvent extraction|extract]] of bitter orange (and bitter orange peel) has been marketed as [[dietary supplement]] purported to act as a weight-loss aid and [[appetite suppressant]]. Bitter orange contains the [[tyramine]] metabolites [[N-Methyltyramine|''N''-methyltyramine]], [[octopamine (drug)|octopamine]] and [[synephrine]],<ref name="pmid18700609"/> substances similar to [[epinephrine]], which act on the [[alpha-1 adrenergic receptor|α<sub>1</sub> adrenergic receptor]] to [[vasoconstriction|constrict blood vessels]] and increase [[blood pressure]] and [[heart rate]].<ref>{{cite journal |vauthors=Bui LT, Nguyen DT, Ambrose PJ |title=Blood pressure and heart rate effects following a single dose of bitter orange |journal=[[The Annals of Pharmacotherapy]] |volume=40 |issue=1 |pages=53–7 |date=January 2006 |pmid=16317106 |doi=10.1345/aph.1G488 }}</ref><ref>{{cite journal |vauthors=Hess AM, Sullivan DL |title=Potential for toxicity with use of bitter orange extract and guarana for weight loss |journal=The Annals of pharmacotherapy |volume=39 |issue=3 |pages=574–5 |date=March 2005 |pmid=15657116 |doi=10.1345/aph.1E249}}</ref> Several low-quality clinical trials have had results of p-Synephrine (alone or in combination with caffeine or some other substances) increasing weight loss slightly.<ref name="stohs">{{cite journal |vauthors=Stohs SJ, Preuss HG, Shara M |title=A review of the human clinical studies involving Citrus aurantium (bitter orange) extract and its primary protoalkaloid p-synephrine. |journal=Int J Med Sci |volume=9 |issue=7 |pages=527–538 |date=August 2012 |pmid= 22991491 |doi= 10.7150/ijms.4446|pmc=3444973}}</ref> |
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No adverse events have ever been associated with the consumption of p-synephrine and bitter orange extract in any of the controlled human studies or associated with consumption of food products containing bitter orange [Stohs, S.J. 2017. Safety, efficacy and molecular studies regarding Citrus aurantium (Bitter orange) extract and p-synephrine. Phytother. Res. doi: 10.1002/ptr.5879]. Adverse events have been reported in poorly documented case reports involving complex products that may have contained bitter orange extract. These products contained numerous alkaloidal ingredients and the presence of bitter orange extract was never confirmed [Stohs, S.J. 2010. A review and assessment of the FDA adverse events reports and clinical case reports between April 2004 and October 2009. J. Funct. Foods 2:235-238; Stohs, S.J. 2017. Safety, efficacy and molecular studies regarding Citrus aurantium (Bitter orange) extract and p-synephrine. Phytother. Res. doi: 10.1002/ptr.5879.] |
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===Safety studies=== |
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Following bans on the herbal stimulant [[ephedra]] in the [[United States|U.S.]], [[Canada]], and elsewhere, bitter orange has been substituted into "ephedra-free" herbal weight-loss products by dietary supplement manufacturers.<ref name="nyt">{{cite news | publisher = ''[[New York Times]]'' |url = https://www.nytimes.com/2005/10/11/health/policy/11cons.html | title = Bitter Orange Under Scrutiny as New Ephedra | last = Duenwald | first = Mary | date = 2005-10-11 | accessdate = 2008-11-03}}</ref> Like most dietary supplement ingredients, bitter orange has not undergone formal safety testing, but it is believed to cause the same spectrum of [[adverse events]] (harmful side-effects) as ephedra.<ref name="jordan">{{cite journal|date=October 2004|title=Products containing bitter orange or synephrine: suspected cardiovascular adverse reactions|url=https://www.researchgate.net/publication/8220292_Products_containing_bitter_orange_or_synephrine_Suspected_cardiovascular_adverse_reactions|format=pdf|journal=[[Canadian Medical Association Journal]]|volume=171|issue=8|pages=993–4|doi=|pmid=15497209|vauthors=Jordan S, Murty M, Pilon K}}</ref> The U.S. [[National Center for Complementary and Integrative Health]] found that "there is currently little evidence that bitter orange is safer to use than ephedra."<ref name="nccam">{{cite web | publisher = [[National Center for Complementary and Integrative Health]] | title = Bitter Orange | url = http://nccih.nih.gov/health/bitterorange/ | date = April 2008 | accessdate = 2008-11-03}}</ref> |
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Studies in rats indicate that the oral LD50 (lethal dose for 50 % of a rat population) of a bitter orange extract standardized to 50 % p-synephrine is greater than 5000 mg/kg, demonstrating a high degree of safety [Deshmukh, N.S., Stohs, S.J., Magar, C.C., Kale, A. 2017a. Citrus aurantium (bitter orange) extract: Acute 14-day study in rats and the reverse mutation Ames test. J. Reg. Toxicol. Pharmacol. doi: 10.1016/j.yrtph.2017.09.027]. A 90 day subchronic toxicity study in rats demonstrated that the oral no-adverse-effect-level (NOAEL) of a bitter orange extract standardized to 50 % p-synephrine was 1000 mg/kg [Deshmukh, N.S., Stohs, S.J., Magar, C.C., Kale, A., Sowmya B. 2017b. Bitter orange (Citrus aurantium L.) extract subchronic 90-day safety study in rats. Tox. Reports. 4: 598-613.]. Bitter orange extract and p-synephrine have been shown to be non-mutagenic and non-teratogenic [Deshmukh, N.S., Stohs, S.J., Magar, C.C., Kale, A. 2017a. ''Citrus aurantium'' (bitter orange) extract: Acute 14-day study in rats and the reverse mutation Ames test. J. Reg. Toxicol. Pharmacol. doi: 10.1016/j.yrtph.2017.09.027.;Hansen DK, Juliar BE, White GE, Pellicore LS. 2011. Developmental toxicity of Citrus aurantium in rats. Birth Defects Res. (Part B) 92: 216-223. ]. A bitter orange extract standardized up to 50 % p-synephrine has been determined to be Generally Recognized as Safe (GRAS) by an expert panel. |
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[[Case report]]s have linked bitter orange supplements to [[stroke]]s,<ref>{{cite journal |vauthors=Bouchard NC, Howland MA, Greller HA, Hoffman RS, Nelson LS |title=Ischemic stroke associated with use of an ephedra-free dietary supplement containing synephrine |journal=Mayo Clinic Proceedings |volume=80 |issue=4 |pages=541–5 |date=April 2005 |pmid=15819293 |doi= 10.4065/80.4.541|url=}}</ref><ref>{{cite journal |vauthors=Holmes RO, Tavee J |title=Vasospasm and stroke attributable to ephedra-free xenadrine: case report |journal=[[Military Medicine (journal)|Military Medicine]] |volume=173 |issue=7 |pages=708–10 |date=July 2008 |pmid=18700609 |doi=}}</ref> [[angina]],<ref name="pmid18700609">{{cite journal |doi=10.4065/81.4.545 |vauthors=Gange CA, Madias C, Felix-Getzik EM, Weintraub AR, Estes NA |title=Variant angina associated with bitter orange in a dietary supplement |journal=[[Mayo Clinic Proceedings]] |volume=81 |issue=4 |pages=545–8 |date=April 2006 |pmid=16610576 }}</ref> and [[ischemic colitis]].<ref>{{cite journal |vauthors=Sultan S, Spector J, Mitchell RM |title=Ischemic colitis associated with use of a bitter orange-containing dietary weight-loss supplement |journal=Mayo Clinic Proceedings |volume=81 |issue=12 |pages=1630–1 |date=December 2006 |pmid=17165643 |doi= 10.4065/81.12.1630|url=}}</ref> Following an incident in which a healthy young man suffered a [[myocardial infarction]] (heart attack) linked to bitter orange, a case study found that dietary supplement manufacturers had replaced ephedra with its analogs from bitter orange.<ref>{{cite journal |vauthors=Thomas JE, Munir JA, McIntyre PZ, Ferguson MA |title=STEMI in a 24-Year-Old Man after Use of a Synephrine-Containing Dietary Supplement: A Case Report and Review of the Literature |journal=Tex Heart Inst J. |year=2009 |volume=36|issue=6 |pages=586–90 |pmid= 20069086 |pmc=2801940}}</ref> |
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===Mechaniams of action=== |
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Although p-synephrine has structural similarities to ephedrine, it cannot be equated with ephedrine and the effects of ephedrine cannot be extrapolated to p-synephrine due to structural differences which greatly alter receptor binding characteristics, pharmacokinetic properties and the pharmacological/physiological effects produced. The cardiovascular effects of epedrine and other catecholamines are due to direct and/or indirect interaction with α-1, α-2, β-1 and β-2 adrenergic receptors. Various receptor binding studies have shown that p-synephrine exhibits very poor binding to these receptors [Stohs SJ, Preuss HG, Shara M. 2011. A review of the receptor-binding properties of p-synephrine as related to its pharmacological effects. Oxid. Med. Cell. Longev. Vol. 2011: 1-9]. Because p-synephrine exhibits little or no binding, p-synephrine exerts metabolic enhancement without acting as a central nervous system or cardiovascular stimulant at commonly used doses, and therefore does not increase heart rate or blood pressure. As a consequence, p-synephrine functions as a non-stimulant thermogenic agent without altering blood chemistries, blood cell counts, ECGs or other cardiovascular parameters [Stohs, S.J., Badmaev, V. 2016. A review of stimulant and non-stimulant thermogenic agents. Phytother. Res 30:733-740.; Shara, M., Stohs, S.J., Mukattash, T.L. 2016. Cardiovascular safety of oral p-synephrine (bitter orange) in human subjects: A randomized placebo-controlled cross-over clinical trial. Phytother. Res 30:842-847; Shara, M., Stohs, S.J., Smadi, M.M. 2017. Safety evaluation of bitter orange (p-synephrine) extract following oral administration for 15 days to healthy human subjects: A clinical trial. Phytother. Res. doi: 10.1002/ptr.5956]. |
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p-Synephrine, the primary active constituent in bitter orange extracts, at least in part exerts its effects through multiple mechanisms including its binding to β-3 adrenergic receptors which regulate lipid and carbohydrate metabolism, neuromedin U2 receptors, as well as AMPK, cAMP and Ca(2+)-dependent mechanisms. p-Synephrine stimulates glycogenolysis, glycolysis, gluconeogenesis, oxygen uptake, lypolysis and increases glucose consumption without increasing heart rate or blood pressure [Stohs, S.J. 2017. Safety, efficacy and molecular studies regarding Citrus aurantium (Bitter orange) extract and p-synephrine. Phytother. Res. doi: 10.1002/ptr.5879]. |
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===Similarities to ephedra=== |
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===Drug interactions=== |
===Drug interactions=== |
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Bitter orange may have serious [[Statin#Drug interactions|drug interactions]] with drugs such as [[statin]]s in a similar way to the long list of [[grapefruit–drug interactions]].<ref>[http://www.mayoclinic.com/health/food-and-nutrition/AN00413 Mayo clinic: article on interference between grapefruit and medication]</ref> |
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Drug interactions due to grapefruit are primarily due to furanocoumarins (bergapten, bergamottin, and 6’,7’-dihydroxybergamottin) that are present which inhibit the metabolism of drugs by inhibiting cytochrome P-450 [Greenblatt DJ, Zhao Y, Hanley MJ, Chen C, Harmatz JS, Cancalon PF, Gmitter FG Jr; Bailey DG. 2010.Fruit juice inhibition of the uptake transport: a new type of food-drug interaction. Br. J. Clin. Pharmacol. 70; 645-655; Bailey DG, Arnold JMO, Spence JD.1998. Grapefruit-drug interactions. Br. J. Clin. Pharmacol. 46; 101-110]. Lower levels of furanocoumarins are present in bitter orange juice which may alter drug metabolism [Edwards DJ, Fitzsimmons ME, Schuetz EG, Yusuda K, Ducharme MP, Warbasse LH, Woster PM, Schuetz JD, Watkins P. 1999. 6’,7’-Dihydroxybergamottin in grapefruit and Seville orange juice: effects on cyclosporine disposition, enterocyte CYP3A4, and P-glycoprotein. Clin. Pharmacol. Ther. 65; 237-244; Malhotra S., Bailey DG, Paine Mf, Watkins PB. 2001. Seville orange juice-felodipine interaction: comparison with dilute grapefruit juice and involvement of furanocoumarins. Clin. Pharmacol. Ther. 69; 14-23; DiMarco MP, Edwards DJ, Wainer IW, Ducharme MP.2002. The effect of grapefruit juice and Seville orange juice on the pharmacokinetics of dextromethorphan: the role of gut CYO3A and P-glycoprotein. Life Sci. 71; 1149-1160: 2002]. However, no clinically relevant drug or supplement interactions are expected with bitter orange extracts in which the furocoumarins that are naturally-occurring in the fruit are not present in the extracts of dried immature fruits. The amounts of furanocoumarins present in p-synephrine-standardized bitter orange extracts are insufficient to exert significant effects on the metabolism of susceptible drugs in human subjects [Stohs SJ, Miller H, Romano F. 2014. Absence of furanocoumarins in Advantra Z (Citrus aurantium, bitter orange) extracts. J. Diet. Suppl. 11: 288-293]. |
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==Other uses== |
==Other uses== |
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Revision as of 22:47, 15 January 2018
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| Species: | C. × aurantium
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| Citrus × aurantium | |
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List
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Bitter orange, Seville orange, sour orange, bigarade orange, or marmalade orange refers to a citrus tree (Citrus × aurantium) and its fruit. It is native to southeast Asia, and has been spread by humans to many parts of the world.[3] Wild trees are found near small streams in generally secluded and wooded parts of Florida and The Bahamas after it was introduced to the area from Spain[3] where it had been introduced and cultivated heavily beginning in the 10th century by the Moors.[4][5]
It is a hybrid between Citrus maxima (pomelo) and Citrus reticulata (mandarin).[6]
Usage
Many varieties of bitter orange are used for their essential oil, and are found in perfume, used as a flavoring or as a solvent. The Seville orange variety is used in the production of marmalade.
Bitter orange extracts have been used as dietary supplements for weight management, sports performance, energy and appetite control. p-Synephrine is the primary active constituent in bitter orange extract, constituting 90-95 % of the total protoalkaloids. Other related substances include p-octopamine (0-1 %), L-tyramine (1-2 %) and N-methyltyramine (3-4 %) [Stohs, S.J. 2017. Safety, efficacy and molecular studies regarding Citrus aurantium (Bitter orange) extract and p-synephrine. Phytother. Res. doi: 10.1002/ptr.5879.
Stohs, S.J., Badmaev, V. 2016. A review of stimulant and non-stimulant thermogenic agents. Phytother. Res 30:733-740.] Standard reference materials are released concerning the properties in bitter orange by the National Institute of Standards and Technology (NIST), for ground fruit, extract and solid oral dosage form, along with those packaged together into one item.[7][8]
Varieties
- Citrus × aurantium subsp. amara is a spiny evergreen tree native to southern Vietnam, but widely cultivated. It is used as grafting stock for citrus trees, in marmalade, and in liqueur such as triple sec, Grand Marnier and Curaçao. It is also cultivated for the essential oil expressed from the fruit, and for neroli oil and orange flower water, which are distilled from the flowers.
- Citrus × aurantium var. myrtifolia is sometimes considered a separate species, Citrus myrtifolia, the myrtle-leaved orange. A selection known as Chinotto is used for the namesake Italian soda beverage.[9]
- Citrus × aurantium var. daidai, Daidai, is used in Chinese medicine and Japanese New Year celebrations. The aromatic flowers are added to tea.[3]
- Citrus bergamia, the Bergamot orange, is probably a bitter orange and limetta hybrid; it is cultivated in Italy for the production of bergamot oil, a component of many brands of perfume and tea, especially Earl Grey tea.[10]
- Citrus × aurantium subsp. currassuviencis, Laraha, grows on the Caribbean island of Curaçao. The dried peels are used in the creation of Curaçao liqueur.
Cooking
Seville orange (or bigarade) is a widely known, particularly tart orange which is now grown throughout the Mediterranean region. It has a thick, dimpled skin, and is prized for making marmalade, being higher in pectin than the sweet orange, and therefore giving a better set and a higher yield. It is also used in compotes and for orange-flavored liqueurs. Once a year, oranges of this variety are collected from trees in Seville and shipped to Britain to be used in marmalade.[11] However, the fruit is rarely consumed locally in Andalusia.[12]
The Seville orange—when preserved in sugar — is the principal ingredient in traditional British marmalade, reflecting the historic Atlantic trading relationship with Portugal and Spain: the earliest recipe for 'marmelat of oranges' dating from 1677.[13][page needed] The peel can be used in the production of bitters. The unripe fruit, called narthangai, is commonly used in Southern Indian cuisine, especially in Tamil cuisine. It is pickled by cutting it into spirals and stuffing it with salt. The pickle is usually consumed with yoghurt rice called thayir sadam. The fresh fruit is also used frequently in pachadis.
The Belgian Witbier (white beer) is made from wheat beer spiced with the peel of the bitter orange. The Finnish and Swedish use bitter orange peel in gingerbread (pepparkakor), some Christmas bread and in mämmi. It is also used in the Nordic mulled wine glögg. In Greece and Cyprus, the nerántzi or kitrómilon, respectively, is one of the most prized fruits used for spoon sweets, and the C. aurantium tree (nerantziá or kitromiliá) is a popular ornamental tree. In Albania as well, "nerënxa" or "portokalli i hidhur" is used commonly in spoon sweets. The blossoms are collected fresh to make a prized sweet-smelling aromatic jam ("Bitter orange blossom jam" Morabba Bahar-Narendj), or added to brewing tea.
In Turkey, juice of the ripe fruits can be used as salad dressing, especially in Çukurova region. However, in Iraqi cuisine, a bitter orange or "raranj" in Iraqi is used to compliment dishes like Charred Fish "samak/simach maskouf", tomato stew "morgat tamata", "Qeema", a dish that has the same ingredients as an Iraqi tomato stew with the addition of minced meat, boiled chickpeas "lablabi", salads, as a dressing, and on essentially any dish one might desire to accompany bitter orange. Iraqis also consume it as a citrus fruit or juice it to make bitter orange juice "'aseer raranj". Throughout Iran (commonly known as narenj), the juice is popularly used as a salad dressing, souring agent in stews and pickles or as a marinade.
In the Americas, the juice from the ripe fruit is used as a marinade for meat in Nicaraguan, Cuban, Dominican and Haitian cooking, as it is in Peruvian ceviche. In Yucatán (Mexico), it is a main ingredient of the cochinita pibil.
HerbalThermogenic
Bitter orange extracts are aqueous/ethanolic extracts of the dried immature fruits of Citrus aurantium. Contrary to popular belief, bitter orange extract and p-synephrine do not act as stimulants at commonly used doses, and p-synephrine does not augment the cardiovascular effects of caffeine [Ratamess, N.A., Bush, J.A., Stohs, S.J., Ellis, N.L., Vought, I.T., O’Grady, E.A., Kuper, J.D., Hasan, S., Kang, J., Faigenbaum, A.D. 2017. Acute cardiovascular effects of caffeine and p-synephrine alone and in combination: A placebo-controlled, double-blind study. Phytother. Res. doi: 10.1002/ptr.5953.; Shara, M., Stohs, S.J., Smadi, M.M. 2017. Safety evaluation of bitter orange (p-synephrine) extract following oral administration for 15 days to healthy human subjects: A clinical trial. Phytother. Res. doi: 10.1002/ptr.5956.] Over 30 human studies regarding p-synephrine and bitter orange extracts have been conducted and published regarding their safety and efficacy [Stohs, S.J. 2017. Safety, efficacy and molecular studies regarding Citrus aurantium (Bitter orange) extract and p-synephrine. Phytother. Res. doi: 10.1002/ptr.5879.].
No adverse events have ever been associated with the consumption of p-synephrine and bitter orange extract in any of the controlled human studies or associated with consumption of food products containing bitter orange [Stohs, S.J. 2017. Safety, efficacy and molecular studies regarding Citrus aurantium (Bitter orange) extract and p-synephrine. Phytother. Res. doi: 10.1002/ptr.5879]. Adverse events have been reported in poorly documented case reports involving complex products that may have contained bitter orange extract. These products contained numerous alkaloidal ingredients and the presence of bitter orange extract was never confirmed [Stohs, S.J. 2010. A review and assessment of the FDA adverse events reports and clinical case reports between April 2004 and October 2009. J. Funct. Foods 2:235-238; Stohs, S.J. 2017. Safety, efficacy and molecular studies regarding Citrus aurantium (Bitter orange) extract and p-synephrine. Phytother. Res. doi: 10.1002/ptr.5879.]
Safety studies
Studies in rats indicate that the oral LD50 (lethal dose for 50 % of a rat population) of a bitter orange extract standardized to 50 % p-synephrine is greater than 5000 mg/kg, demonstrating a high degree of safety [Deshmukh, N.S., Stohs, S.J., Magar, C.C., Kale, A. 2017a. Citrus aurantium (bitter orange) extract: Acute 14-day study in rats and the reverse mutation Ames test. J. Reg. Toxicol. Pharmacol. doi: 10.1016/j.yrtph.2017.09.027]. A 90 day subchronic toxicity study in rats demonstrated that the oral no-adverse-effect-level (NOAEL) of a bitter orange extract standardized to 50 % p-synephrine was 1000 mg/kg [Deshmukh, N.S., Stohs, S.J., Magar, C.C., Kale, A., Sowmya B. 2017b. Bitter orange (Citrus aurantium L.) extract subchronic 90-day safety study in rats. Tox. Reports. 4: 598-613.]. Bitter orange extract and p-synephrine have been shown to be non-mutagenic and non-teratogenic [Deshmukh, N.S., Stohs, S.J., Magar, C.C., Kale, A. 2017a. Citrus aurantium (bitter orange) extract: Acute 14-day study in rats and the reverse mutation Ames test. J. Reg. Toxicol. Pharmacol. doi: 10.1016/j.yrtph.2017.09.027.;Hansen DK, Juliar BE, White GE, Pellicore LS. 2011. Developmental toxicity of Citrus aurantium in rats. Birth Defects Res. (Part B) 92: 216-223. ]. A bitter orange extract standardized up to 50 % p-synephrine has been determined to be Generally Recognized as Safe (GRAS) by an expert panel.
Mechaniams of action
Although p-synephrine has structural similarities to ephedrine, it cannot be equated with ephedrine and the effects of ephedrine cannot be extrapolated to p-synephrine due to structural differences which greatly alter receptor binding characteristics, pharmacokinetic properties and the pharmacological/physiological effects produced. The cardiovascular effects of epedrine and other catecholamines are due to direct and/or indirect interaction with α-1, α-2, β-1 and β-2 adrenergic receptors. Various receptor binding studies have shown that p-synephrine exhibits very poor binding to these receptors [Stohs SJ, Preuss HG, Shara M. 2011. A review of the receptor-binding properties of p-synephrine as related to its pharmacological effects. Oxid. Med. Cell. Longev. Vol. 2011: 1-9]. Because p-synephrine exhibits little or no binding, p-synephrine exerts metabolic enhancement without acting as a central nervous system or cardiovascular stimulant at commonly used doses, and therefore does not increase heart rate or blood pressure. As a consequence, p-synephrine functions as a non-stimulant thermogenic agent without altering blood chemistries, blood cell counts, ECGs or other cardiovascular parameters [Stohs, S.J., Badmaev, V. 2016. A review of stimulant and non-stimulant thermogenic agents. Phytother. Res 30:733-740.; Shara, M., Stohs, S.J., Mukattash, T.L. 2016. Cardiovascular safety of oral p-synephrine (bitter orange) in human subjects: A randomized placebo-controlled cross-over clinical trial. Phytother. Res 30:842-847; Shara, M., Stohs, S.J., Smadi, M.M. 2017. Safety evaluation of bitter orange (p-synephrine) extract following oral administration for 15 days to healthy human subjects: A clinical trial. Phytother. Res. doi: 10.1002/ptr.5956].
p-Synephrine, the primary active constituent in bitter orange extracts, at least in part exerts its effects through multiple mechanisms including its binding to β-3 adrenergic receptors which regulate lipid and carbohydrate metabolism, neuromedin U2 receptors, as well as AMPK, cAMP and Ca(2+)-dependent mechanisms. p-Synephrine stimulates glycogenolysis, glycolysis, gluconeogenesis, oxygen uptake, lypolysis and increases glucose consumption without increasing heart rate or blood pressure [Stohs, S.J. 2017. Safety, efficacy and molecular studies regarding Citrus aurantium (Bitter orange) extract and p-synephrine. Phytother. Res. doi: 10.1002/ptr.5879].
Similarities to ephedra
Drug interactions
Drug interactions due to grapefruit are primarily due to furanocoumarins (bergapten, bergamottin, and 6’,7’-dihydroxybergamottin) that are present which inhibit the metabolism of drugs by inhibiting cytochrome P-450 [Greenblatt DJ, Zhao Y, Hanley MJ, Chen C, Harmatz JS, Cancalon PF, Gmitter FG Jr; Bailey DG. 2010.Fruit juice inhibition of the uptake transport: a new type of food-drug interaction. Br. J. Clin. Pharmacol. 70; 645-655; Bailey DG, Arnold JMO, Spence JD.1998. Grapefruit-drug interactions. Br. J. Clin. Pharmacol. 46; 101-110]. Lower levels of furanocoumarins are present in bitter orange juice which may alter drug metabolism [Edwards DJ, Fitzsimmons ME, Schuetz EG, Yusuda K, Ducharme MP, Warbasse LH, Woster PM, Schuetz JD, Watkins P. 1999. 6’,7’-Dihydroxybergamottin in grapefruit and Seville orange juice: effects on cyclosporine disposition, enterocyte CYP3A4, and P-glycoprotein. Clin. Pharmacol. Ther. 65; 237-244; Malhotra S., Bailey DG, Paine Mf, Watkins PB. 2001. Seville orange juice-felodipine interaction: comparison with dilute grapefruit juice and involvement of furanocoumarins. Clin. Pharmacol. Ther. 69; 14-23; DiMarco MP, Edwards DJ, Wainer IW, Ducharme MP.2002. The effect of grapefruit juice and Seville orange juice on the pharmacokinetics of dextromethorphan: the role of gut CYO3A and P-glycoprotein. Life Sci. 71; 1149-1160: 2002]. However, no clinically relevant drug or supplement interactions are expected with bitter orange extracts in which the furocoumarins that are naturally-occurring in the fruit are not present in the extracts of dried immature fruits. The amounts of furanocoumarins present in p-synephrine-standardized bitter orange extracts are insufficient to exert significant effects on the metabolism of susceptible drugs in human subjects [Stohs SJ, Miller H, Romano F. 2014. Absence of furanocoumarins in Advantra Z (Citrus aurantium, bitter orange) extracts. J. Diet. Suppl. 11: 288-293].
Other uses
This orange is used as a rootstock in groves of sweet orange.[3] The fruit and leaves make lather and can be used as soap.[3] The hard white or light yellow wood is used in woodworking and made into baseball bats in Cuba.[3]
References
- ^ "Citrus × aurantium". Germplasm Resources Information Network. Agricultural Research Service, United States Department of Agriculture. Retrieved 2010-01-05.
- ^ "The Plant List: A Working List of All Plant Species". Retrieved 29 September 2015.
- ^ a b c d e f C. aurantium. Purdue Horticulture.
- ^ Morton, Julia (1987). Fruits of warm climates. Miami: Morton, J. 1987. Sour Orange. p. 130–133. In: Fruits of warm climates. Julia F. Morton, Miami, FL. pp. 130–133. ISBN 0-9610184-1-0.
- ^ Trillo San Jose, Carmen (2004). Agua y Paisaje en Granada: Una Herencia de Al-Andalus. Granada, Spain: DIP. PROV. de Granada. ISBN 9788478073528.
- ^ "Plant Profile for Citrus ×aurantium L. (pro sp.), http://plants.usda.gov/java/profile?symbol=CIAU8
- ^ "NIST Bitter Orange Reference Material Now Available". National Institute of Health. Retrieved 2017-10-08.
- ^ "Material Details: SRM 3261 - Bitter Orange Dietary Supplemental Suite". National Institute of Standards and Technology. Retrieved 2017-10-08.
- ^ Roger M. Grace. "Cadbury Schweppes Reigns Supreme Over Orange Soda Market". metnews.com.
- ^ "Citrus bergamia". Germplasm Resources Information Network. Agricultural Research Service, United States Department of Agriculture. Retrieved 2017-12-12.
- ^ Campaña de recogida de la naranja amarga.[permanent dead link] sevilla.org.
- ^ Apenas se aprovechará la naranja que se recoja en la capital este año. 20minutos.es.
- ^ Henry, Diana (2012). Salt sugar smoke : how to preserve fruit, vegetables, meat and fish. London: Mitchell Beazley. ISBN 978-1845336752.
External links
Data related to Citrus aurantium at Wikispecies- Bitter Orange: Information from the National Center for Complementary and Integrative Health
- Bitter Orange List of Chemicals (Dr. Duke's Databases)
