p-Synephrine, ephedrine, p-octopamine and m-synephrine: Comparative mechanistic, physiological and pharmacological properties.

Confusion and misunderstanding exist regarding the lack of cardiovascular and other adverse health effects of p-synephrine and p-octopamine relative to ephedrine and m-synephrine (phenylephrine) which are known for their effects on the cardiovascular system. These four molecules have some structural similarities. However, the structural and stereochemical differences of p-synephrine and p-octopamine as related to ephedrine and m-synephrine result in markedly different adrenergic receptor binding characteristics as well as other mechanistic differences which are reviewed. p-Synephrine and p-octopamine exhibit little binding to α-1, α-2, ß-1 and ß-2 adrenergic receptors, nor are they known to exhibit indirect actions leading to an increase in available levels of endogenous norepinephrine and epinephrine at commonly used doses. The relative absence of these mechanistic actions provides an explanation for their lack of production of cardiovascular effects at commonly used oral doses as compared to ephedrine and m-synephrine. As a consequence, the effects of ephedrine and m-synephrine cannot be directly extrapolated to p-synephrine and p-octopamine which exhibit significantly different pharmacokinetic, and physiological/pharmacological properties. These conclusions are supported by human, animal and in vitro studies that are discussed.

Safety evaluation of p-synephrine following 15 days of oral administration to healthy subjects: A clinical study.

Extracts of bitter orange (BOE, Citrus aurantium L.) and its primary protoalkaloid p-synephrine are extensively consumed as dietary supplements. p-Synephrine is also present in foods and juices prepared from various Citrus species. The safety of p-synephrine has been questioned as a result of structural similarities with ephedrine. This study assessed the cardiovascular (stimulant) and hemodynamic effects of BOE (49 mg p-synephrine) daily given to 16 healthy subjects for 15 days in a placebo-controlled, cross-over, double-blinded study. A physical evaluation by a cardiologist, as well as heart rates, blood pressures, and electrocardiograms were determined, and blood samples were drawn at baseline, and Days 5, 10, and 15. Serum levels for caffeine and p-synephrine were measured at 1 and 2 weeks. Subjects completed a 10-item health and metabolic questionnaire at baseline and on Day 15. No significant changes occurred in heart rate, electrocardiograms, systolic blood or diastolic pressures, blood cell counts, or blood chemistries in either the control or p-synephrine treated groups at any time point. No adverse effects were reported in response to the bitter orange (p-synephrine). Caffeine consumed by the participants varied markedly. Under these experimental conditions, BOE and p-synephrine were without stimulant (cardiovascular) and adverse effects.

Dose-Response Effects of p-Synephrine on Fat Oxidation Rate During Exercise of Increasing Intensity.

The aim of this investigation was to determine the effects different doses of p-synephrine on maximal fat oxidation during exercise. Seventeen healthy subjects volunteered to participate in a double-blind and randomised experimental design composed of four identical experimental trials. On four trials separated by 72 h, participants ingested a placebo or 1, 2 or 3 mg/kg of p-synephrine. After resting for 60 min to allow substance absorption, participants performed an exercise test of increasing intensity on a cycle ergometer while gas exchange was measured continuously. None of the doses of p-synephrine affected energy expenditure or heart rates during the test. The highest rate of fat oxidation with the placebo (0.35 ± 0.05 g/min) was reached at 38.0 ± 1.9% of VO2max . The ingestion of 1 mg/kg increased maximal fat oxidation to 0.47 ± 0.11 g/min (p = 0.01) but did not change the intensity at which it was obtained (42.0 ± 9.4% of VO2max ). The ingestion of 2 and 3 mg/kg of p-synephrine increased maximal fat oxidation to 0.55 ± 0.14 g/min (p < 0.01), although only 3 mg/kg slightly changed the intensity at which it was obtained (43.0 ± 9.5% of VO2max , p < 0.01). In conclusion, although all p-synephrine increased the maximal rate of fat oxidation during exercise, the highest effects were found with 2 and 3 mg/kg. Copyright © 2017 John Wiley & Sons, Ltd.

Acute cardiovascular effects of bitter orange extract (p-synephrine) consumed alone and in combination with caffeine in human subjects: A placebo-controlled, double-blind study.

The purpose was to examine cardiovascular responses to supplementation with p-synephrine alone and in combination with caffeine during quiet sitting. Sixteen subjects were given (in double-blind manner) either 103 mg of p-synephrine (S), 233 mg of caffeine +104 mg of p-synephrine (LC + S), 240 mg of caffeine (LC), 337 mg of caffeine +46 mg of p-synephrine (HC + S), 325 mg of caffeine (HC), or a placebo. The subjects sat quietly for 3 hr while heart rate (HR) and blood pressure were measured. Only HC + S and HC significantly increased mean systolic blood pressure (SBP) during the second hour and tended to increase mean SBP during the third hour. Mean diastolic blood pressure in S was significantly lower than the other trials during the first and second hours, and mean arterial pressure was significantly lower in S compared to the LC, LC + S, HC, and HC + S trials. No differences were observed in HR. Consumption of p-synephrine may acutely reduce diastolic blood pressure and mean arterial pressure and not affect SBP or HR during quiet sitting. The addition of p-synephrine to caffeine did not augment SBP or HR indicating that consumption of up to 104 mg of p-synephrine does not induce cardiovascular stress during quiet sitting.

[Risk assessment of synephrine in dietary supplements]. / Gesundheitliche Risiken von Synephrin in Nahrungsergänzungsmitteln.

Synephrine is a sympathomimetic phenylethylamine derivative that occurs naturally in citrus fruits. It is often added to dietary supplements intended for weight loss and enhancement of sports performance, typically in the form of Citrus aurantium extracts and in many cases in combination with caffeine. The health risks of synephrine were evaluated on the basis of the available toxicological data and in accordance to the EFSA guidance on the safety assessment of botanicals and botanical preparations intended for use in food supplements. In animal studies, orally applied synephrine induced adrenergic effects on the cardiovascular system (increase of blood pressure, ventricular arrhythmias), which were enhanced by the concomitant application of caffeine as well as physical activity. Some human intervention studies investigating the acute effects of synephrine on blood pressure and heart rate of healthy, normotensive test persons indicate that synephrine can induce cardiovascular effects in humans. A series of published case reports of adverse cardiovascular effects (hypertension, cardiac arrhythmia, myocardial infarction) were associated with consumption of synephrine- and caffeine-containing dietary supplements. In conclusion, consumption of high amounts of synephrine, especially in combination with caffeine and physical exercise, is associated with an increased risk of adverse effects on the cardiovascular system. According to the assessment by the BfR (Bundesinstitut für Risikobewertung), daily intake of synephrine through dietary supplements should not exceed the median intake from conventional foods.

p-Synephrine suppresses lipopolysaccharide-induced acute lung injury by inhibition of the NF-κB signaling pathway.

OBJECTIVE: We investigated whether p-synephrine exerts potent anti-inflammatory effects against acute lung injury (ALI) induced by lipopolysaccharide (LPS) in vivo, and we further investigated the inhibitory mechanism of p-synephrine in LPS-induced ALI. METHODS: Lipopolysaccharide (0.5 mg/kg) was instilled intranasally in phosphate-buffered saline to induce acute lung injury, and 6, 24, and 48 h after LPS was given, bronchoalveolar lavage fluid was obtained to measure pro-inflammatory mediator. We also evaluated the effects of p-synephrine on LPS-induced the severity of pulmonary injury. The phosphorylation of nuclear factor-κB (NF-κB) p65 protein was analyzed by Western blotting. RESULTS: Our data showed that p-synephrine significantly reduced the amount of inflammatory cells, the lung wet-to-dry weight (W/D) ratio, reactive oxygen species, myeloperoxidase activity and enhanced superoxide dismutase (SOD) in mice with LPS-induced ALI. Tumor necrosis factor α and interleukin (IL)-6 concentrations decreased significantly while the concentration of IL-10 was significantly increased after p-synephrine pretreatment. In addition, p-synephrine suppressed not only the phosphorylation of NF-κB but also the degradation of its inhibitor (IκBα). CONCLUSIONS: These results suggested that the inhibition of NF-κB activation and the regulation of SOD are involved in the mechanism of p-synephrine's protection against ALI.

A review of the human clinical studies involving Citrus aurantium (bitter orange) extract and its primary protoalkaloid p-synephrine.

This review summarizes the published as well as unpublished human studies involving Citrus aurantium (bitter orange) extract and its primary protoalkaloid p-synephrine, providing information and an assessment of the safety and efficacy of these widely used products. The results of over 20 studies involving a total of approximately 360 subjects that consumed p-synephrine alone or in combination with other ingredients are reviewed and critiqued. Over 50 % of the subjects involved in these studies were overweight/obese, and approximately two-thirds of these overweight/obese subjects consumed caffeine (132-528 mg/day) in conjunction with p-synephrine (10-53 mg/day). Bitter orange/p-synephrine containing products were consumed for up to 12 weeks. Approximately 44 % of the subjects consumed a bitter orange/p-synephrine only product, while the remainder consumed a complex product that contained multiple ingredients in addition to p-synephrine. In general, bitter orange extract alone (p-synephrine) or in combination with other herbal ingredients did not produce significant adverse events as an increase in heart rate or blood pressure, or alter electrocardiographic data, serum chemistry, blood cell counts or urinalysis. p-Synephrine alone as well as in combination products were shown to increase resting metabolic rate and energy expenditure, and modest increases in weight loss were observed with bitter orange extract/p-synephrine-containing products when given for six to 12 weeks. Longer term studies are needed to further assess the efficacy of these products and affirm their safety under these conditions.

Identification of anti-asthmatic compounds in Pericarpium citri reticulatae and evaluation of their synergistic effects.

AIM: To investigate the anti-asthmatic mechanisms of the traditional Chinese medicine Pericarpium citri reticulatae (PCR). METHODS: The alkaloid section (AS) of PCR was extracted using an ion exchange resin, separated, and purified into different fractions by semi-preparative HPLC. These fractions were screened for beta2-adrenergic receptor (beta(2)AR) agonistic activity using rat beta(2)AR-transfected CHO-CRE-EGFP cells. AS and its isolated components were characterized by ultra-performance liquid chromatography/quadrupole time-of-flight MS (UPLC/Q-Tof MS) and were evaluated for their spasmolytic and antitussive activities both in vitro and in vivo in a guinea pig model. RESULTS: We demonstrated that the AS component responsible for activating beta(2)AR signaling was synephrine. Both AS and synephrine showed significant spasmolytic effects on acetylcholine chloride (ACh)-induced contractions in isolated guinea pig trachea, and they protected against histamine-induced experimental asthma by prolonging the latent period. We further identified stachydrine as the antitussive component that could significantly reduce citric acid-induced coughing. The combination of these two bioactive compounds had a more potent spasmolytic activity in comparison with the single use of synephrine or stachydrine. CONCLUSION: We conclude that synephrine and stachydrine are the key components of AS that mediate asthma relief due to their synergism when used in combination.

[A systemic approach to the diagnosis and treatment of allergic conjunctivitis]. / Démarche diagnostique et thérapeutique des conjonctivites allergiques.

The diagnosis of allergic conjunctivis begins by a meticulous questioning emphasizing the existence of ocular itching, the way of evolution of the signs and allergic preceeding. The examination searchs after follicles and papillae of the conjunctiva who usually go with serous discharges, blepharitis and keratitis. So four clinical forms may be described the chronic conjunctivitis, the vernal kerato-conjunctivitis, the atopic conjunctivitis and the giganto-papillar conjunctivitis. For the treatment, all non specific signs of allergy must be eliminated, the focal infections also and allergic substance isolated. If evolution is worse, an antiallergic eye drop is given until the disappearance of all the physical signs. In the same time, steroids and anti H1 drugs must be avoided. In case of failure, the specialist in allergy will be helpful to exam the patient.

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.

Fructus aurantii reduced portal pressure in portal hypertensive rats.

The purpose of this study was to investigate the effects of Fructus Aurantii (the unripe fruits of Citrus aurantium L.) on portal hypertensive rats. Portal hypertension was induced by partial portal vein ligation (PVL) in Sprague-Dawley rats. Sham-operated (Sham) rats served as controls. Hemodynamic and in vitro contractile studies were performed at 14 days after surgery. Both the aqueous extract of Fructus Aurantii and synephrine, one of its purified principles with pressor activity, were infused into the conscious PVL and Sham rats via a syringe pump. Fructus Aurantii (1.25, 2.5, & 5.0 mg/kg/min) dose-dependently reduced portal pressure in PVL and Sham rats, with the percentage change in portal pressure more pronounced in PVL rats. Mean arterial pressure was dose-dependently elevated by Fructus Aurantii. Synephrine (0.095, 0.19, & 0.38 mg/kg/min) also dose-dependently reduced portal pressure and elevated mean arterial pressure in PVL and Sham rats. Fructus Aurantii (2.8-280 micrograms/ml) induced dose-dependent contractile responses mainly in aorta and mesenteric artery, but little response in portal vein. The results showed that Fructus Aurantii infusion reduced portal pressure, possibly by way of arterial vasoconstriction.

Anti-shock effects of synthetic effective compositions of fructus aurantii immaturus. Experimental study and clinical observation.

Satisfactory results have been obtained in treating infective shock with injection of natural Fructus Aurantii immaturus (nat-FAI). The results of animal experiments and clinical observations on the anti-shock effects of the synthetic effective compositions of Fructus Aurantii immaturus (syn-FAI) are reported. The cardiac output increased from 0.53 to 0.87 L/min (P less than 0.01), and the cardiac index increased from 0.99 to 1.63 L/m2/min (P less than 0.01) in the endotoxic shock dogs after the treatment with syn-FAI. At the same time the blood stream in bulbar conjunctiva became accelerated and the dilated microvessels began to get smaller in most dogs. Of fifty children with infective shock treated with syn-FAI, forty-eight showed curative effects, with a total effective rate of 96%. The anti-shock effective compositions in FAI have been proved to be synephrine and N-methyltyrosamine. Moreover, syn-FAI has shown a more stable property, less side-effects and better clinical results than nat-FAI.

Estrogenic sensitivity of alpha-receptors in the urethra musculature.

Estrogene has a tonicising effect upon urethra musculature. There is also the same demonstrable influence of alpha-receptor stimulating drugs upon the urethra pressure profile. After preliminary treatment with estrogene, there is a considerably stronger tonicising effect of alpha-stimulating drugs than without such a treatment. So the combination of estrogene and alpha-stimulating drugs seems a useful addition to the conservative treatment of stress incontinence.

PIP: Estrogenic sensitivity of alpha-receptors in the urethra musculature was investigated. The main object of this study was to determine if est rogene could cause the alpha-receptors to be more sensitive to the alpha -receptor stimulating drugs, so that by using an equal dosage of alpha-r eceptor stimulating drugs in a preliminary estrogenic treatment, a stronger tonic effect would be achieved in the urethra musculature than by using the alpha-receptor stimulating drugs alone. 5 healthy continen t females and 3 females suffering from 1st-degree stress incontinence were studied. There was a demonstrable influence of estrogene upon the urethra musculature. And there was also the same demonstrable influence of alpha-receptor stimulating drugs upon the urethra pressure profile. Following preliminary treatment with estrogene, there was a considerally stronger tonicising effect of alpha-stimulating drugs than without such a treatment. Therefore, it appears that the combination of estrogene and alpha-stimulating drugs is a useful addition to the conservative treatment of stress incontinuence.