Research Update:Citrus aurantium.

  seminal trace...Synephrine,M.F.C9H13NO2.CAS No.94-07-5.Bitter Orange Extract,Citrus Aurantium Extract,Synephrine 6%~98%.Synephrine 6%.Synephrine 8%10%.Synephrine 30%.Synephrine 95%.Bitter Orange,Seville Orange, Zhi Shi, Chongcao,Orange Bitters, Naranja Agria, Neroli, Petitgrain,Seville Orange,Citrus Amara,Citrus Bergamia,Citrus Bigaradia,and Citrus Vulgaris...

 


   Phytochemical info of Citrus aurantium

 Product Name:
 Synonym:
 Definition:Citrus aurantium are majorly composed of
 Chemical information disclosed as following table:


   Research Update:Citrus aurantium.

  Mass spectrometric determination of the predominant adrenergic protoalkaloids in bitter orange (Citrus aurantium).:J Agric Food Chem. 2007 Nov 28;55(24):9769-75. Epub 2007 Oct 30.Nelson BC, Putzbach K, Sharpless KE, Sander LC.Analytical Chemistry Division, Stop 8392, National Institute of Standards and Technology, 100 Bureau Drive, Gaithersburg, Maryland 20899-8392, USA. bryant.nelson@nist.gov

 The predominant adrenergic protoalkaloid found in the peel and fruit of bitter orange, Citrus aurantium, is synephrine. Synephrine is reputed to have thermogenic properties and is used as a dietary supplement to enhance energy and promote weight loss. However, there exists some concern that the consumption of dietary supplements containing synephrine or similar protoalkaloids may contribute to adverse cardiovascular events. This study developed and validated a positive-ion mode liquid chromatography/tandem mass spectrometry (LC/MS/MS) method for the quantitative determination of the major (synephrine) and minor (tyramine, N-methyltyramine, octopamine, and hordenine) adrenergic protoalkaloids in a suite of National Institute of Standards and Technology (NIST) bitter orange Standard Reference Materials (SRMs): SRM 3258 Bitter Orange Fruit, SRM 3259 Bitter Orange Extract, and SRM 3260 Bitter Orange Solid Oral Dosage Form. The limit of quantitation (LOQ) for all protoalkaloids is approximately 1 pg on-column, except for octopamine (20 pg on-column). Additionally, the method has a linear dynamic range of > or =3 orders of magnitude for all of the protoalkaloids. Individual, as well as "total", protoalkaloid levels (milligrams per kilogram) in the NIST SRMs were determined and compared to the levels measured by an independent liquid chromatography/fluorescence detection (LC/FD) method. Satisfactory concordance between the LC/MS/MS and LC/FD protoalkaloid measurements was demonstrated. LC/MS/MS analysis of the protoalkaloids in the SRMs resulted in mean measurement imprecision levels of < or =10% coefficient of variation (% CV).

  Simultaneous determination of flavonoid and alkaloid compounds in Citrus herbs by high-performance liquid chromatography-photodiode array detection-electrospray mass spectrometry.:J Chromatogr B Analyt Technol Biomed Life Sci. 2007 Oct 1;857(2):202-9. Epub 2007 Jul 14.

 The major active biological constituents in Citrus herbs are flavonoids, especially hesperidin, naringin and alkaloids, mainly synephrine, with beneficial medical effects on human health. They are used as the markers to control the quality of Citrus herbs. In this paper, a new ion pairing chromatographic method was developed to exclude the most polar solute (synephrine) from the viod volume and to maintain selectivity between the two other solutes (hesperidin and naringin). Perfluorinated carboxylic acids, which are appropriate for MS detection due to their volatility, were used as ion-pairing agents. The problems of the synephrine separation, such as band tailing and low retention, were solved successfully by using perfluorinated carboxylic acids. The effect of heptafluorobutyric acid (HFBA) was the best in the three investigated perfluorinated carboxylic acids. For the flavanone glycosides, the influence of the perfluorinated acids on retention time was rather weak. The two different kinds of the analytes were separated satisfactorily in one run using an isocratic eluent and the total analysis time takes less than 10 min. The abundance of pseudomolecular ions was recorded using selected ion monitoring (SIM) mode of m/z 135.1, 273.1 and 303.1 for synephrine, naringin and hesperidin, respectively. The contents of hesperidin, naringin and synephrine in several Citrus herbs were simultaneously determined by the proposed method.

  A case of severe exercise-induced rhabdomyolysis associated with a weight-loss dietary supplement.: Mil Med. 2007 Jun;172(6):656-8.Burke J, Seda G, Allen D, Knee TS.Regional Support Organization Norfolk, Norfolk, VA 23511, USA.

 In response to questions about the safety of ephedra-based dietary products, ephedra-free products are now available. Many contain synephrine, a sympathomimetic amine with structural similarities to ephedra. We present a 22-year-old, previously healthy, African American male with sickle cell trait who developed rhabdomyolysis after ingestion of a synephrine-containing dietary supplement. The patient developed fatigue, dehydration, and myalgias while exercising. He developed severe rhabdomyolysis, with a peak creatine phosphokinase level of 2.8 million U/L, complicated by pulmonary edema, acute renal failure, disseminated intravascular coagulation, and bilateral compartment syndromes in his lower extremities. He required prolonged hospitalization for hemodialysis, multiple wound debridements, hyperbaric oxygen therapy, and physical therapy. He has permanent sensory and motor neurological deficits in his distal lower extremities. Military physicians should routinely inquire about the use of dietary supplements, educate patients about the potential adverse reactions associated with these agents, and encourage healthy diets and exercise for weight loss.

  Chromatographic and electrophoretic methods for the analysis of phenethylamine [corrected] alkaloids in Citrus aurantium.:J Chromatogr A. 2007 Aug 17;1161(1-2):71-88. Epub 2007 Jun 7. Review. Erratum in: J Chromatogr A. 2007 Sep 14;1164(1-2):334. Pellati F, Benvenuti S.Department of Pharmaceutical Sciences, University of Modena and Reggio Emilia, Via G. Campi 183, 41100 Modena, Italy. pellati.federica@unimore.it

 Citrus aurantium (bitter orange) is a plant belonging to the family Rutaceae, whose fruit extracts have been used recently for the treatment of obesity. The most important biologically active constituents of the C. aurantium fruits are phenethylamine alkaloids (i.e. octopamine, synephrine, tyramine, N-methyltyramine and hordenine). Synephrine is a primary synthesis compound with pharmacological activities such as vasoconstriction, elevation of blood pressure and relaxation of bronchial muscle. Synephrine is present in the peel and the edible part of Citrus fruit. Of the adrenergic amines of natural origin, synephrine has been found to be the main constituent of C. aurantium fruits and extracts; the other alkaloids are either absent or present in only low concentrations. It is known that synephrine and the other amines found in C. aurantium have adverse effects on the cardiovascular system, owing to adrenergic stimulation. In light of the great commercial proliferation of C. aurantium herbal medicines in recent years, this review provides an overview of various extraction, separation and detection techniques employed for the qualitative and quantitative determination of the alkaloids in C. aurantium and related species. The application of chromatographic and electrophoretic methods for the separation and determination of these active components in C. aurantium plant material and derivatives are described. Since synephrine is a chiral compound, enantioselective chromatographic and electrophoretic techniques for the analysis of synephrine enantiomers in natural products are presented. Furthermore, examples of identification of these active compounds in complex matrices by hyphenated methods, such as gas chromatography-mass spectrometry and high-performance liquid chromatography-mass spectrometry, are described. The advantages and limitations of these separation and identification methods are assessed and discussed.

  Simultaneous analysis of adrenergic amines and flavonoids in citrus peel jams and fruit juices by liquid chromatography: part 2.:J AOAC Int. 2007 May-Jun;90(3):633-40.Avula B, Upparapalli SK, Khan IA.National Center for Natural Products Research, Research Institute of Pharmaceutical Sciences, The University of Mississippi, MS 38677, USA. bavula@olemiss.edu

 Citrus species are rich sources for various bioactive compounds such as flavonoids, adrenergic amines, limonoids, and coumarins. Six adrenergic amines and 20 flavonoids in the jams and juices of Citrus species were analyzed by high-performance liquid chromatography with a C18 reversed-phase column using gradient mobile phase of sodium acetate buffer (pH 5.5) and acetonitrile at a flow rate of 1.0 mL/min with detection at 254, 280, and 330 nm. Synephrine was present in levels from 3.65 to 60.66 mg/L in 48 Citrus juices and 0.018-1.02 mg per serving in 32 Citrus jams. The content of these amines and flavonoids varied to a large extent depending on the type of the Citrus species used. The method has been successfully applied to the determination of adrenergic amines and flavonoids in several samples of Citrus fruit juices and jams.


  Determination of bitter orange alkaloids in dietary supplement Standard Reference Materials by liquid chromatography with atmospheric-pressure ionization mass spectrometry.: Anal Bioanal Chem. 2007 Sep;389(1):197-205. Epub 2007 Jun 20.Putzbach K, Rimmer CA, Sharpless KE, Wise SA, Sander LC.RCC Ltd., Zelgliweg 1, CH-4452, Itingen, Switzerland.

 A liquid chromatographic atmospheric-pressure ionization electrospray mass spectrometry (LC-API-ES-MS) method has been developed for the determination of five bitter orange alkaloids (synephrine, octopamine, n-methyltyramine, tyramine, and hordenine) in bitter orange-containing dietary supplement standard reference materials (SRMs). The materials represent a variety of natural, extracted, and processed sample matrices. Two extraction techniques were evaluated: pressurized-fluid extraction (PFE) and sonication extraction. The influence of different solvents, extraction temperatures, and pH were investigated for a plant material and a processed sample. The LC method uses a new approach for the separation of highly polar alkaloids. A fluorinated, silica-based stationary phase separated the five alkaloids and the internal standard terbutaline in less than 20 min. This method enabled the determination of the dominant alkaloid synephrine and other minor alkaloids in a variety of dietary supplement SRMs.

  Determination of synephrine in weight-loss products using high performance liquid chromatography with acidic potassium permanganate chemiluminescence detection.:Anal Chim Acta. 2007 Jun 12;593(1):98-102. Epub 2007 Apr 24.Slezak T, Francis PS, Anastos N, Barnett NW.School of Life and Environmental Sciences, Deakin University, Geelong, Victoria 3217, Australia.

 Adrenergic amines found in extracts of Citrus aurantium (bitter orange) evoke analytically useful chemiluminescence with acidic potassium permanganate in the presence of polyphosphates. From corrected chemiluminescence spectra, the wavelength of maximum intensity for these reactions was 680+/-5 nm and, using flow injection analysis methodology, limits of detection for synephrine, octopamine, tyramine and hordenine were found to be between 1x10(-9) and 1x10(-8) M. We have applied this method of detection to the rapid determination of synephrine in dietary supplements using monolithic column chromatography.

  Determination of Bitter Orange alkaloids in dietary supplements standard reference materials by liquid chromatography with ultraviolet absorbance and fluorescence detection.: J Chromatogr A. 2007 Jul 13;1156(1-2):304-11. Epub 2007 May 23.Putzbach K, Rimmer CA, Sharpless KE, Sander LC.Analytical Chemistry Division, National Institute of Standards and Technology, Gaithersburg, MD 20899, USA. putzbach.karsten@rcc.ch

 Four adrenergic amines [synephrine, octopamine, tyramine, and n-methyltyramine] were determined in a variety of Bitter Orange containing dietary supplements. Two extraction techniques were evaluated in detail: Soxhlet extraction and sonication extraction. A liquid chromatographic separation using a reversed-phase C(18) stationary phase and the ion-pairing reagent sodium dodecyl sulfate was developed to separate the Bitter Orange alkaloids. Ultraviolet absorbance detection at 220 nm and fluorescence detection with excitation at 273 nm and emission at 304 nm were used for the alkaloid detection. The method described was used for the assignment of the levels of the predominant alkaloids in three candidate standard reference materials containing Bitter Orange.

  Determination of synephrine in bitter orange raw materials, extracts, and dietary supplements by liquid chromatography with ultraviolet detection: single-laboratory validation.: J AOAC Int. 2007 Jan-Feb;90(1):68-81.Roman MC, Betz JM, Hildreth J.ChromaDex, 13161 56th Ct, Suite 201, Clearwater, FL 33760, USA. mroman@tampabayanalytical.com

 A method has been developed to quantify synephrine in bitter orange raw material, extracts, and dietary supplements. Single-laboratory validation has been performed on the method to determine the repeatability, accuracy, selectivity, limit of detection/limit of quantification (LOQ), ruggedness, and linearity for p-synephrine and 5 other biogenic amines: octopamine, phenylephrine (m-synephrine), tyramine, N-methyltyramine, and hordenine, which may be present in bitter orange. p-Synephrine was found to be the primary biogenic amine present in all materials tested, accounting for >80% of the total biogenic amine content in all samples except a finished product. Repeatability precision for synephrine was between 1.48 and 3.55% RSD. Synephrine recovery was between 97.5 and 104%. The minor alkaloids were typically near the LOQ of the method (300-900 microg/g) in the test materials, and between-day precision for the minor compounds was poor because interferences could sometimes be mistakenly identified as one of the minor analytes. Recoveries of the minor components ranged from 99.1 to 103% at approximately 6000 microg/g spike level, to 90.7 to 120% at 300 microg/g spike level.

  Determination of three chemical components in Fructus aurantii immaturus.:Zhongguo Zhong Yao Za Zhi. 2006 Sep;31(17):1425-7. Chinese.

 


  A rapid and simple procedure for the determination of synephrine in dietary supplements by gas chromatography-mass spectrometry..: J Pharm Biomed Anal. 2006 Jun 16;41(4):1468-72. Epub 2006 May 15.Marchei E, Pichini S, Pacifici R, Pellegrini M, Zuccaro P.Drug Control and Evaluation Department, Istituto Superiore di Sanit¨¢, V.le Regina Elena 299, 00161, Rome, Italy.

 A simple and rapid procedure based on gas chromatography-mass spectrometry (GC-MS) is described for determination of synephrine, active principle of Citrus aurantium plant, in solid and liquid dietary supplements. After the addition of 3,4-methylenedioxypropylamphetamine as internal standard (I.S.), a liquid-liquid extraction procedure in alkaline conditions with chloroform/isopropanol (9:1, v/v) was applied to the samples prior to analysis. Chromatography was performed on a fused capillary column and synephrine and I.S., derivatized with pentafluoropropionic anhydride, were determined in the selected-ion-monitoring (SIM) mode. The method was validated in the range 0.1-50 microg/mg or microg/mL synephrine. Mean recovery ranged between 89.3% and 90.5% in both solid and liquid dietary supplements. The quantification limit was 0.1 microg/mg or microg/ml. The method was applied to analysis of various dietary supplements promoted for aiding weight control containing, among other constituents such as ephedrine alkaloids and methylxanthines, Citrus aurantium. Amount of synephrine present in such products ranged from 3.1 microg/mg solid product to 480.2 microg/mL liquid product.

  Citrus aurantium and synephrine alkaloids in the treatment of overweight and obesity: an update.: Obes Rev. 2006 Feb;7(1):79-88. Review.Haaz S, Fontaine KR, Cutter G, Limdi N, Perumean-Chaney S, Allison DB.Division of Rheumatology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

 Obesity is a major health problem facing the developed and developing world. Efforts by individuals, health professionals, educators, and policy makers to combat the escalating trend of growing obesity prevalence have been multifaceted and mixed in outcome. Various dietary supplements have been marketed to reduce obesity. These products have been suggested to accomplish this by decreasing energy intake and energy absorption, and/or increasing metabolic rate. Ephedra, one such supplement, was banned from sale in the US market because of concerns about adverse events. Another substance, Citrus aurantium, which contains several compounds including synephrine alkaloids, has been suggested as a safe alternative. This review examines the evidence for safety and efficacy of C. aurantium and synephrine alkaloids as examined in animal studies, clinical weight loss trials, acute physiologic studies and case reports. Although at least three reviews of C. aurantium have been published, our review expands upon these by: (i) distinguishing and evaluating the efficacy of C. aurantium and related compounds; (ii) including results from previously unreviewed research; (iii) incorporating recent case reports that serve to highlight, in an anecdotal way, potential adverse events related to the use of C. aurantium and related compounds; and (iv) offering recommendations to guide the design of future trials to evaluate the safety and efficacy of C. aurantium. While some evidence is promising, we conclude that larger and more rigorous clinical trials are necessary to draw adequate conclusions regarding the safety and efficacy of C. aurantium and synephrine alkaloids for promoting weight loss.

  Blood pressure and heart rate effects following a single dose of bitter orange.: Ann Pharmacother. 2006 Jan;40(1):53-7. Epub 2005 Nov 29.Bui LT, Nguyen DT, Ambrose PJ.School of Pharmacy, University of California, San Francisco, CA, USA.

 BACKGROUND: The ingredients of numerous "ephedra-free" dietary supplements used for weight loss include bitter orange, which contains sympathomimetic alkaloids such as synephrine. Due to the similarity in chemical structure to ephedrine and the potential sympathomimetic effects of synephrine, it is hypothesized that bitter orange may increase blood pressure (BP) and heart rate (HR). OBJECTIVE: To determine the effects on BP and HR after a single dose of bitter orange in healthy adults. METHODS: In a prospective, randomized, double-blind, placebo-controlled, crossover study, 15 young, healthy, adult subjects received either a single dose of Nature's Way Bitter Orange--a 900 mg dietary supplement extract standardized to 6% synephrine--or matching placebo, with a one week washout period. Systolic BP (SBP), diastolic BP (DBP), and HR were measured at baseline and every hour for 6 hours after administration. RESULTS: SBP after bitter orange was significantly increased versus placebo at hours 1-5 (p < 0.0001); the peak difference was 7.3 +/- 4.6 mm Hg. Although the baseline DBP was higher than after administration of both placebo and bitter orange, DBP after bitter orange was significantly increased versus placebo at hours 4 and 5 (p < or = 0.02); the peak difference was 2.6 +/- 3.8 mm Hg. HR was significantly increased after bitter orange versus placebo for hours 2-5 (p < 0.01); the peak difference was 4.2 +/- 4.5 beats/min. CONCLUSIONS: SBP, DBP, and HR were higher for up to 5 hours after a single dose of bitter orange versus placebo in young, healthy adults.

  Absence of QTc-interval-prolonging or hemodynamic effects of a single dose of bitter-orange extract in healthy subjects.:Pharmacotherapy. 2005 Dec;25(12):1719-24.Min B, Cios D, Kluger J, White CM.School of Pharmacy, University of Connecticut, Storrs, and Division of Cardiology, Hartford Hospital, Hartford, Connecticut 06102-5037, USA.

 STUDY OBJECTIVE: To evaluate the hemodynamic and electrocardiographic effects of a single dose of commercially available bitter-orange dried-fruit extract, which is increasingly being used in dietary supplements. DESIGN: Randomized, double-blind, placebo-controlled, crossover study. SETTING: University of Connecticut, Storrs Campus. SUBJECTS: Eighteen healthy volunteers aged 18 years or older. INTERVENTION: Subjects were given either placebo or bitter-orange dried-fruit extract (450 mg standardized to 27 mg of m- or p-synephrine) in phase 1. The opposite treatment was given during phase 2 after a washout period of at least 7 days. MEASUREMENTS AND MAIN RESULTS: The rate-corrected QT (QTc) interval and blood pressure were measured before dosing and at 1, 3, 5, and 8 hours after dosing. Mean+/-SD values of the maximum postdose values were compared between groups. Subjects receiving bitter-orange extract versus those receiving placebo had similar postdose QTc intervals (402+/-29 vs 403+/-24 msec, p=0.653), systolic blood pressure (114+/-10 vs 115+/-8 mm Hg, p=0.686) and diastolic blood pressure (68+/-9 vs 68+/-8, p=0.879). CONCLUSION: Bitter-orange dried-fruit extract standardized to m- or p-synephrine 27 mg did not significantly alter the QTc interval or blood pressure after a single dose was administered. Future studies are necessary to ensure the safety of this herbal product with multiple doses.

  Exactly which synephrine alkaloids does Citrus aurantium (bitter orange) contain?.: Int J Obes (Lond). 2005 Apr;29(4):443-6.Allison DB, Cutter G, Poehlman ET, Moore DR, Barnes S.Department of Nutritional Sciences, Section on Statistical Genetics, Clinical Nutrition Research Center, Montreal, Quebec, Canada. Dallison@UAB.edu

 Following the withdrawal of ephedrine from the dietary supplement marketplace sales of products containing Citrus aurantium (CA) (bitter orange) for weight loss are believed to have increased dramatically. CA contains a number of constituents speculated to lead to weight loss, of which the most frequently cited constituent is synephrine. Concerns have been raised about the safety of products containing synephrine. To develop an adequate basis for clinical and public health recommendations, it is necessary to understand the nature of the synephrine alkaloids in CA. There are six possible isomers of synephrine (para, meta, ortho; and for each a d or l form). Some authors have stated that CA contains only p-synephrine, whereas other authors have stated that CA contains m-synephrine. This is an important distinction because the two molecules have different pharmacologic properties, which may differentially affect safety and efficacy. We are unable to identify published data that explicitly show whether CA contains p-synephrine, m-synephrine, or both. In this brief report, we show that at least one product purportedly containing synephrine alkaloids from CA contains both p-synephrine and m-synephrine. We believe this justifies further investigation into which synephrine alkaloids are present in CA and products purportedly containing synephrine alkaloids from CA and the relative quantities of each of the different isomers.


  Safety and efficacy of citrus aurantium for weight loss.:Am J Cardiol. 2004 Nov 15;94(10):1359-61. Review.Bent S, Padula A, Neuhaus J.Osher Center for Integrative Medicine at the University of California, San Francisco, USA. bent@itsa.ucsf.edu

 To examine the safety and efficacy of citrus aurantium, an herb now commonly used as a substitute for ** in dietary supplements marketed to promote weight loss, we conducted a systematic review. An extensive search of MEDLINE, EMBASE, BIOSIS, and the Cochrane Collaboration Database identified only 1 eligible randomized placebo controlled trial, which followed 20 patients for 6 weeks, demonstrated no statistically significant benefit for weight loss, and provided limited information about the safety of the herb.

  Citrus aurantium, an ingredient of dietary supplements marketed for weight loss: current status of clinical and basic research.: Exp Biol Med (Maywood). 2004 Sep;229(8):698-704. Review. Haaz S, Fontaine KR, Cutter G, Limdi N, Perumean-Chaney S, Allison DB.Division of Rheumatology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

 Obesity is a major health problem facing the developed and developing world. Efforts by individuals, health professionals, educators, and policy makers to combat the escalating trend of growing obesity prevalence have been multifaceted and mixed in outcome. Various dietary supplements have been marketed to reduce obesity. These products have been suggested to accomplish this by decreasing energy intake and energy absorption, and/or increasing metabolic rate. Ephedra, one such supplement, was banned from sale in the US market because of concerns about adverse events. Another substance, Citrus aurantium, which contains several compounds including synephrine alkaloids, has been suggested as a safe alternative. This review examines the evidence for safety and efficacy of C. aurantium and synephrine alkaloids as examined in animal studies, clinical weight loss trials, acute physiologic studies and case reports. Although at least three reviews of C. aurantium have been published, our review expands upon these by: (i) distinguishing and evaluating the efficacy of C. aurantium and related compounds; (ii) including results from previously unreviewed research; (iii) incorporating recent case reports that serve to highlight, in an anecdotal way, potential adverse events related to the use of C. aurantium and related compounds; and (iv) offering recommendations to guide the design of future trials to evaluate the safety and efficacy of C. aurantium. While some evidence is promising, we conclude that larger and more rigorous clinical trials are necessary to draw adequate conclusions regarding the safety and efficacy of C. aurantium and synephrine alkaloids for promoting weight loss.

  High-performance liquid chromatography methods for the analysis of adrenergic amines and flavanones in Citrus aurantium L. var. amara.:Phytochem Anal. 2004 Jul-Aug;15(4):220-5.Bui LT, Nguyen DT, Ambrose PJ.School of Pharmacy, University of California, San Francisco, CA, USA.

 BACKGROUND: The ingredients of numerous "ephedra-free" dietary supplements used for weight loss include bitter orange, which contains sympathomimetic alkaloids such as synephrine. Due to the similarity in chemical structure to ephedrine and the potential sympathomimetic effects of synephrine, it is hypothesized that bitter orange may increase blood pressure (BP) and heart rate (HR). OBJECTIVE: To determine the effects on BP and HR after a single dose of bitter orange in healthy adults. METHODS: In a prospective, randomized, double-blind, placebo-controlled, crossover study, 15 young, healthy, adult subjects received either a single dose of Nature's Way Bitter Orange--a 900 mg dietary supplement extract standardized to 6% synephrine--or matching placebo, with a one week washout period. Systolic BP (SBP), diastolic BP (DBP), and HR were measured at baseline and every hour for 6 hours after administration. RESULTS: SBP after bitter orange was significantly increased versus placebo at hours 1-5 (p < 0.0001); the peak difference was 7.3 +/- 4.6 mm Hg. Although the baseline DBP was higher than after administration of both placebo and bitter orange, DBP after bitter orange was significantly increased versus placebo at hours 4 and 5 (p < or = 0.02); the peak difference was 2.6 +/- 3.8 mm Hg. HR was significantly increased after bitter orange versus placebo for hours 2-5 (p < 0.01); the peak difference was 4.2 +/- 4.5 beats/min. CONCLUSIONS: SBP, DBP, and HR were higher for up to 5 hours after a single dose of bitter orange versus placebo in young, healthy adults.

  Determination of naringin and synephrine in fructus aurantii from different habitats by HPLC.:Zhong Yao Cai. 2000 May;23(5):268-70. Chinese.Min B, Cios D, Kluger J, White CM.School of Pharmacy, University of Connecticut, Storrs, and Division of Cardiology, Hartford Hospital, Hartford, Connecticut 06102-5037, USA.

 STUDY OBJECTIVE: To evaluate the hemodynamic and electrocardiographic effects of a single dose of commercially available bitter-orange dried-fruit extract, which is increasingly being used in dietary supplements. DESIGN: Randomized, double-blind, placebo-controlled, crossover study. SETTING: University of Connecticut, Storrs Campus. SUBJECTS: Eighteen healthy volunteers aged 18 years or older. INTERVENTION: Subjects were given either placebo or bitter-orange dried-fruit extract (450 mg standardized to 27 mg of m- or p-synephrine) in phase 1. The opposite treatment was given during phase 2 after a washout period of at least 7 days. MEASUREMENTS AND MAIN RESULTS: The rate-corrected QT (QTc) interval and blood pressure were measured before dosing and at 1, 3, 5, and 8 hours after dosing. Mean+/-SD values of the maximum postdose values were compared between groups. Subjects receiving bitter-orange extract versus those receiving placebo had similar postdose QTc intervals (402+/-29 vs 403+/-24 msec, p=0.653), systolic blood pressure (114+/-10 vs 115+/-8 mm Hg, p=0.686) and diastolic blood pressure (68+/-9 vs 68+/-8, p=0.879). CONCLUSION: Bitter-orange dried-fruit extract standardized to m- or p-synephrine 27 mg did not significantly alter the QTc interval or blood pressure after a single dose was administered. Future studies are necessary to ensure the safety of this herbal product with multiple doses.

  Determination of adrenergic agonists from extracts and herbal products of Citrus aurantium L. var. amara by LC.:J Pharm Biomed Anal. 2002 Aug 1;29(6):1113-9.Pellati F, Benvenuti S, Melegari M, Firenzuoli F.Department of Pharmaceutical Sciences, University of Modena and Reggio Emilia, Via Campi 183, Modena, Italy.

 The purpose of this study was to set up a HPLC method to separate adrenergic amines (dl-octopamine, dl-synephrine and tyramine) and to determine their content in fruits, extracts and herbal products of Citrus aurantium L. var. amara. A rapid method for the quantitative analysis of these amines is described, based on their separation by RP-HPLC technique with UV detection. The analysis were conducted on a Lichrospher RP-18 column at room temperature, using a mobile phase consisting of 0.02 M citric acid-0.02 M NaH2PO4 (7:3 v/v) and adjusted to a final pH of 3. The detection was at 220 nm. Since some of these amines are chiral compounds and their enantiomers showed different pharmacological activity, the direct separation of synephrine enantiomers was carried out with HPLC on a beta-cyclodextrin stationary phase. The mobile phase consisted of methanol-NaH2PO4 25 mM pH 3.5 (20:80 v/v) and tetrabutylammonium hydrogen sulfate 10 mM in ratio of 30:70 v/v in isocratic condition and the detection was at 220 nm. The two proposed methods were applied to the analysis of fruits, extracts and herbal products of C. aurantium L. var. amara. Taking into account that some authors have reported that l-synephrine may be converted into its d-form by high temperature, this optical isomerization was monitored by the same HPLC method used for the separation of enantiomers.


  Studies on chemical constituents from the flower of Citrus aurantium.: Zhong Yao Cai. 2001 Dec;24(12):865-7. Chinese.Huang S, Hu S, Shi J, Yang Y.Institute of Chinese Materia Medica, Chinese Academy of TCM, Beijing 100700

 The chemical constituents from the flower of Citrus aurantium were studied. 11 compounds were isolated and identified including neohesperidin(I), synephrin(II), 5,8-epidioxyergosta-6,22-dien-3 beta-ol(III), adenosine(IV), asparagine(V), tyrosine(VI), valine(VII), isoleucine(VIII), alanine(IX),beta-sitosterol(X) and beta-daucosterol(XI).

  Seville (sour) orange juice: synephrine content and cardiovascular effects in normotensive adults.:J Clin Pharmacol. 2001 Oct;41(10):1059-63.Penzak SR, Jann MW, Cold JA, Hon YY, Desai HD, Gurley BJ.Department of Pharmacy Practice, Mercer University, Southern School of Pharmacy, Atlanta, Georgia 30341-4155, USA.

 The Seville orange extract Citrus aurantium contains m-synephrine (phenylephrine) and octopamine; it causes cardiac disturbances in animals and is used by humans for weight loss. Juice from the orange (Seville orange juice [SOJ]) is used to "knock out" intestinal cytochrome P450 (CYP) 3A4 in bioavailability studies. The purpose of this study was to determine synephrine and octopamine concentrations in SOJ and SOJ's cardiovascular effects in normotensive humans. Subjects consumed 8 ounces of SOJ and water in crossover fashion followed by a repeat ingestion 8 hours later. Hemodynamic (heart rate; systolic, diastolic, and mean arterial pressure) measurements followed. Synephrine and octopamine were determined by high-performance liquid chromatography. Hemodynamics did not differ significantly between water and SOJ groups. Mean synephrine concentration of SOJ samples was 56.9 +/- 0.52 microg/ml; octopamine was not detected. SOJ ingestion by normotensive subjects is expected to be safe. Individuals with severe hypertension, tachyarrhythmias, and narrow-angle glaucoma and monoamine oxidase inhibitor recipients should avoid SOJ consumption. Persons taking decongestant-containing cold preparations should also refrain from SOJ intake.


  Studies on chemical constituents from the flower of Citrus aurantium.:

 The chemical constituents from the flower of Citrus aurantium were studied. 11 compounds were isolated and identified including neohesperidin(I), synephrin(II), 5,8-epidioxyergosta-6,22-dien-3 beta-ol(III), adenosine(IV), asparagine(V), tyrosine(VI), valine(VII), isoleucine(VIII), alanine(IX),beta-sitosterol(X) and beta-daucosterol(XI).

  Determination of octopamine, synephrine and tyramine in Citrus herbs by ionic liquid improved 'green' chromatography.:

 Without adding any volatile organic solvents, aqueous solutions of room temperature ionic liquids (RTILs) were used as 'green' mobile phases to determine octopamine, synephrine and tyramine by liquid chromatography. The problems of the adrenergic amines separation, such as band tailing, low retention and low resolution were solved successfully by using RTIL. The effect of 1-ethyl-3-methylimidazolium tertafluoroborate ([EMIM][BF(4)]) was the best in the six investigated RTILs. The concentration of [EMIM][BF(4)], mobile phase pH and column temperature, which influenced the chromatographic behaviors of the analytes, were investigated in detail. The change of retention factors caused by pH shift was obviously suppressed by [EMIM][BF(4)]. The sensitivity, accuracy and repeatability of this method were found to be satisfactory. The contents of adrenergic amines in several Citrus herbs and extracts, such as Fructus aurantii immaturus, were simultaneously determined by this 'green' chromatographic method.

  A rapid and simple procedure for the determination of synephrine in dietary supplements by gas chromatography-mass spectrometry.:

 A simple and rapid procedure based on gas chromatography-mass spectrometry (GC-MS) is described for determination of synephrine, active principle of Citrus aurantium plant, in solid and liquid dietary supplements. After the addition of 3,4-methylenedioxypropylamphetamine as internal standard (I.S.), a liquid-liquid extraction procedure in alkaline conditions with chloroform/isopropanol (9:1, v/v) was applied to the samples prior to analysis. Chromatography was performed on a fused capillary column and synephrine and I.S., derivatized with pentafluoropropionic anhydride, were determined in the selected-ion-monitoring (SIM) mode. The method was validated in the range 0.1-50 microg/mg or microg/mL synephrine. Mean recovery ranged between 89.3% and 90.5% in both solid and liquid dietary supplements. The quantification limit was 0.1 microg/mg or microg/ml. The method was applied to analysis of various dietary supplements promoted for aiding weight control containing, among other constituents such as ephedrine alkaloids and methylxanthines, Citrus aurantium. Amount of synephrine present in such products ranged from 3.1 microg/mg solid product to 480.2 microg/mL liquid product.

  Simultaneous quantification of adrenergic amines and flavonoids in C. aurantium, various Citrus species, and dietary supplements by liquid chromatography.:

 An analytical method was developed for the simultaneous quantitative analysis of 6 amines and 20 flavonoids in fruits and extracts of 30 Citrus species, including C. aurantium, near-Citrus relatives, and dietary supplements by liquid chromatography with photodiode array detection. The separation was achieved with a Phenomenex Synergi Hydro reversed-phase column using gradient mobile phase of sodium acetate buffer (pH 5.5) and acetonitrile. Elution was run at a flow rate of 1.0 mL/min and UV at 254, 280, and 330 nm. Among the amines analyzed, synephrine, the main component, was present in the levels from 0.11 to 2.0 mg/g dry weight in 21 Citrus species and 0.07 to 18.62% in dietary supplements claiming to contain C. aurantium. The flavanones and flavones were analyzed in the same Citrus samples and were species-specific. The levels of flavones were very low compared with those of flavanones. The method facilitated the simultaneous quantification of 6 amines and 20 flavonoids in various Citrus species, the distinction between the different Citrus species, and the analysis of dietary supplements containing C. aurantium.


  Exactly which synephrine alkaloids does Citrus aurantium (bitter orange) contain?:

 Following the withdrawal of ephedrine from the dietary supplement marketplace sales of products containing Citrus aurantium (CA) (bitter orange) for weight loss are believed to have increased dramatically. CA contains a number of constituents speculated to lead to weight loss, of which the most frequently cited constituent is synephrine. Concerns have been raised about the safety of products containing synephrine. To develop an adequate basis for clinical and public health recommendations, it is necessary to understand the nature of the synephrine alkaloids in CA. There are six possible isomers of synephrine (para, meta, ortho; and for each a d or l form). Some authors have stated that CA contains only p-synephrine, whereas other authors have stated that CA contains m-synephrine. This is an important distinction because the two molecules have different pharmacologic properties, which may differentially affect safety and efficacy. We are unable to identify published data that explicitly show whether CA contains p-synephrine, m-synephrine, or both. In this brief report, we show that at least one product purportedly containing synephrine alkaloids from CA contains both p-synephrine and m-synephrine. We believe this justifies further investigation into which synephrine alkaloids are present in CA and products purportedly containing synephrine alkaloids from CA and the relative quantities of each of the different isomers.

  Citrus aurantium and synephrine alkaloids in the treatment of overweight and obesity: an update.:

 Obesity is a major health problem facing the developed and developing world. Efforts by individuals, health professionals, educators, and policy makers to combat the escalating trend of growing obesity prevalence have been multifaceted and mixed in outcome. Various dietary supplements have been marketed to reduce obesity. These products have been suggested to accomplish this by decreasing energy intake and energy absorption, and/or increasing metabolic rate. Ephedra, one such supplement, was banned from sale in the US market because of concerns about adverse events. Another substance, Citrus aurantium, which contains several compounds including synephrine alkaloids, has been suggested as a safe alternative. This review examines the evidence for safety and efficacy of C. aurantium and synephrine alkaloids as examined in animal studies, clinical weight loss trials, acute physiologic studies and case reports. Although at least three reviews of C. aurantium have been published, our review expands upon these by: (i) distinguishing and evaluating the efficacy of C. aurantium and related compounds; (ii) including results from previously unreviewed research; (iii) incorporating recent case reports that serve to highlight, in an anecdotal way, potential adverse events related to the use of C. aurantium and related compounds; and (iv) offering recommendations to guide the design of future trials to evaluate the safety and efficacy of C. aurantium. While some evidence is promising, we conclude that larger and more rigorous clinical trials are necessary to draw adequate conclusions regarding the safety and efficacy of C. aurantium and synephrine alkaloids for promoting weight loss.


  Blood pressure and heart rate effects following a single dose of bitter orange.:

 BACKGROUND: The ingredients of numerous "ephedra-free" dietary supplements used for weight loss include bitter orange, which contains sympathomimetic alkaloids such as synephrine. Due to the similarity in chemical structure to ephedrine and the potential sympathomimetic effects of synephrine, it is hypothesized that bitter orange may increase blood pressure (BP) and heart rate (HR). OBJECTIVE: To determine the effects on BP and HR after a single dose of bitter orange in healthy adults. METHODS: In a prospective, randomized, double-blind, placebo-controlled, crossover study, 15 young, healthy, adult subjects received either a single dose of Nature's Way Bitter Orange--a 900 mg dietary supplement extract standardized to 6% synephrine--or matching placebo, with a one week washout period. Systolic BP (SBP), diastolic BP (DBP), and HR were measured at baseline and every hour for 6 hours after administration. RESULTS: SBP after bitter orange was significantly increased versus placebo at hours 1-5 (p < 0.0001); the peak difference was 7.3 +/- 4.6 mm Hg. Although the baseline DBP was higher than after administration of both placebo and bitter orange, DBP after bitter orange was significantly increased versus placebo at hours 4 and 5 (p < or = 0.02); the peak difference was 2.6 +/- 3.8 mm Hg. HR was significantly increased after bitter orange versus placebo for hours 2-5 (p < 0.01); the peak difference was 4.2 +/- 4.5 beats/min. CONCLUSIONS: SBP, DBP, and HR were higher for up to 5 hours after a single dose of bitter orange versus placebo in young, healthy adults.

  Hemodynamic effects of ephedra-free weight-loss supplements in humans.:

 PURPOSE: Ephedra-free weight loss dietary supplements containing bitter orange (Citrus aurantium), a botanical source of the adrenergic amines synephrine and octopamine, have quickly emerged on consumer markets to replace banned ephedra products. These supplements may have some of the health risks associated with ephedra, but studies in humans are lacking. Our aim was to characterize the pharmacokinetics and cardiovascular effects of C. aurantium dietary supplements. SUBJECTS AND METHODS: Ten healthy adult nonsmokers participated in a randomized, double-blind, placebo-controlled, three-arm crossover study. Single doses of C. aurantium (Advantra Z) containing 46.9 mg synephrine, Xenadrine EFX, a multi-component formulation containing 5.5 mg synephrine, and placebo were administered with a one-week washout. RESULTS: Compared with placebo, Xenadrine EFX but not Advantra Z increased systolic and diastolic blood pressure with peak changes from baseline at 2 hours of 9.6 +/- 6.2 mm Hg systolic (P = 0.047), and 9.1 +/- 7.8 mm Hg diastolic (P = 0.002). Heart rate was increased from baseline at 6 hours compared with placebo (16.7 beats per minute with Xenadrine EFX, P = 0.011; 11.4 beats per minute with Advantra Z, P = 0.031). Dose-adjusted synephrine pharmacokinetics were similar between treatments with t(max) = 90 min, t(1/2) = 3.0 hours, V/F = 16347 L, and CL/F = 88.9 L/min for Xenadrine EFX. CONCLUSION: Ephedra-free weight loss supplements have significant cardiovascular stimulant actions, similar to ephedra. These effects are not likely caused by C. aurantium alone, because an eightfold higher dose of synephrine (Advantra Z) had no effect on blood pressure, but may be attributable to caffeine and other stimulants in the multi-component formulation.

  Ischemic stroke associated with use of an ephedra-free dietary supplement containing synephrine.:

 In response to concerns regarding the safety of ephedra-containing dietary supplements, manufacturers have marketed "ephedra-free" products. Many of these contain synephrine, a sympathomimetic amine from the plant Citrus aurantium. Synephrine is structurally similar to ephedrine and has vasoconstrictor properties. We describe a 38-year-old patient with ischemic stroke associated with an ephedra-free dietary supplement containing synephrine and caffeine. The patient presented with memory loss and unsteady gait after taking 1 or 2 capsules per day of a dietary supplement (Stacker 2 Ephedra-Free) for 1 week. He had no notable medical history or major atherosclerotic risk factors and took no other medications. Physical examination showed a mildly ataxic gait and substantial Impairment of both concentration and memory. Computed tomography and magnetic resonance Imaging of the brain showed subacute infarctions in the left thalamus and left cerebellum in the distribution of the vertebrobasilar circulation. Other causes of ischemic stroke were evaluated, and findings were unremarkable; a vasospastic origin was considered most likely. The patient was discharged with nearly complete resolution of symptoms. Synephrine, a sympathomimetic amine related to ephedrine, may be associated with Ischemic stroke. Consumers and clinicians need to be Informed about the potential risks of ephedra-free products.


  Safety and efficacy of citrus aurantium for weight loss.:

 To examine the safety and efficacy of citrus aurantium, an herb now commonly used as a substitute for ephedra in dietary supplements marketed to promote weight loss, we conducted a systematic review. An extensive search of MEDLINE, EMBASE, BIOSIS, and the Cochrane Collaboration Database identified only 1 eligible randomized placebo controlled trial, which followed 20 patients for 6 weeks, demonstrated no statistically significant benefit for weight loss, and provided limited information about the safety of the herb.

  Citrus aurantium, an ingredient of dietary supplements marketed for weight loss: current status of clinical and basic research.:

 Seville orange (Citrus aurantium) extracts are being marketed as a safe alternative to ephedra in herbal weight-loss products, but C. aurantium may also have the potential to cause adverse health effects. C. aurantium contains synephrine (oxedrine), which is structurally similar to epinephrine. Although no adverse events have been associated with ingestion of C. aurantium products thus far, synephrine increases blood pressure in humans and other species, and has the potential to increase cardiovascular events. Additionally, C. aurantium contains 6',7'-dihydroxybergamottin and bergapten, both of which inhibit cytochrome P450-3A, and would be expected to increase serum levels of many drugs. There is little evidence that products containing C. aurantium are an effective aid to weight loss. Synephrine has lipolytic effects in human fat cells only at high doses, and octopamine does not have lipolytic effects in human adipocytes.

  High-performance liquid chromatography methods for the analysis of adrenergic amines and flavanones in Citrus aurantium L. var. amara.:

 Reverse-phase HPLC coupled with photodiode array detection was used for the simultaneous separation and determination of naturally occurring adrenergic amines (octopamine, synephrine and tyramine) in fruits and dry extracts of Citrus aurantium L. var. amara and in herbal medicines derived therefrom. Synephrine was the main component in fruits (0.10-0.35%) and in dry extracts (3.00-3.08%) and was present in the range 0.25-0.99% in herbal medicines. Flavanones were analysed in the same samples using a reverse-phase HPLC technique which allowed the identification and quantification of neoeriocitrin, narirutin, naringin, hesperidin, neohesperidin, naringenin and hesperetin. C. aurantium fruits and derivatives contained mainly glycosylated flavanones: in particular, naringin and neohesperidin were found to be the major flavonoids and their concentrations ranged from 1.80 to 26.30 and from 3.90 to 14.71 mg/g, respectively. The levels of aglycones were very low in all samples tested.


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  Scientific References:

  1.Research Update:Citrus aurantium.